WO2024151855A1 - Inhibiteurs de transfert de brins intégrase à base de carbamoyl pyridone bicyclique - Google Patents

Inhibiteurs de transfert de brins intégrase à base de carbamoyl pyridone bicyclique Download PDF

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WO2024151855A1
WO2024151855A1 PCT/US2024/011244 US2024011244W WO2024151855A1 WO 2024151855 A1 WO2024151855 A1 WO 2024151855A1 US 2024011244 W US2024011244 W US 2024011244W WO 2024151855 A1 WO2024151855 A1 WO 2024151855A1
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substituted
alkyl
aryl
alkenyl
alkynyl
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PCT/US2024/011244
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English (en)
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Pankaj S. MAHAJAN
Steven J. Smith
Stephen H. Hughes
Zuezhi ZHAO
Jr. Terrence R. Burke
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The United States Of America, As Represented By The Secretary, Department Of Health And Human Services
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Publication of WO2024151855A1 publication Critical patent/WO2024151855A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

Definitions

  • HIV-1 Human Immunodeficiency Virus Type 1
  • Integrase (IN) Strand Transfer Inhibitors are a class of antiretrovirals that block integration of viral DNA (vDNA) into host chromosomes, a process that is mediated by the viral IN enzyme, which assembles into oligomeric nucleoprotein complexes on the ends of viral DNA, termed “intasomes”.
  • INSTIs selectively target intasomes and represent first-line therapies in the clinic.
  • the emergence of IN variants resistant to INSTIs is becoming a greater clinical problem.
  • FDA-approved INSTI drugs include Raltegravir (RAL, 1), Elvitegravir (EVG, 2), Dolutegravir (DTG, 3), Bictegravir (BIC, 4), and Cabotegravir (CAB, 5).
  • SUMMARY Disclosed herein is a compound, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, having a structure of: 4239-109618-02 01/11/24 E-058-2023-0-PC-01 wherein R 1 is H, alkyl, or substituted alkyl; R 2 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, or substituted amino; X is halogen; and a is 1 to 5.
  • a compound, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof having a structure of: O OH R1 O a wherein R 1 is H, alkyl, or substituted alkyl; R 2 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, or substituted amino; X is halogen; and a is 1 to 5.
  • a compound, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof having a structure of: O OH a wherein R 1 is H, alkyl, or substituted alkyl; 4239-109618-02 01/11/24 E-058-2023-0-PC-01 R 2 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, or substituted amino; X is halogen; a is 1 to 5; and represents a cyclic structure.
  • R 1 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl
  • R 2 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, substituted amino, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl
  • Z is nitrogen
  • X is halogen or CF3
  • b is 1 to 4.
  • R 1 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl
  • R 2 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, substituted amino, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl
  • Z is nitrogen
  • X is halogen or CF3
  • b is 0 to 2
  • c is 1 to 4.
  • R 1 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl
  • R 2 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, substituted amino, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl
  • Z is nitrogen
  • X is halogen or CF3
  • b is 1 to 4.
  • R 1 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl
  • R 2 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, substituted amino, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl
  • Z is nitrogen
  • X is halogen or CF3
  • b is 0 to 2
  • c is 1 to 4.
  • R 1 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl
  • R 2 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, substituted amino, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl
  • Z is nitrogen
  • X is halogen or CF3
  • b is 1 to 4; and represents a cyclic structure.
  • R 1 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl
  • R 2 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, substituted amino, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl
  • Z is nitrogen
  • X is halogen or CF3
  • b is 0 to 2
  • c is 1 to 4; and represents a cyclic structure.
  • “Acyl” refers to a group having the structure –C(O)R, where R may be, for example, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • “Lower acyl” groups are those that contain one to six carbon atoms.
  • “Acyloxy” refers to a group having the structure –OC(O)R-, where R may be, for example, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • “Lower acyloxy” groups contain one to six carbon atoms.
  • administering as used herein is inclusive of administration by another person to the subject or self-administration by the subject.
  • aliphatic is defined as including alkyl, alkenyl, alkynyl, halogenated alkyl and cycloalkyl groups.
  • a "lower aliphatic” group is a branched or unbranched aliphatic group having from 1 to 10 carbon atoms.
  • Alkanediyl refers to a divalent radical derived from aliphatic, cycloaliphatic, aryl, and alkanearyl hydrocarbons.
  • Alkenyl refers to a cyclic, branched or straight chain group containing only carbon and hydrogen, and contains one or more double bonds that may or may not be conjugated. Alkenyl groups may be unsubstituted or substituted. “Lower alkenyl” groups contain one to six carbon atoms.
  • alkoxy refers to a straight, branched or cyclic hydrocarbon configuration and combinations thereof, including from 1 to 20 carbon atoms, preferably from 1 to 8 carbon atoms (referred to as a “lower alkoxy”), more preferably from 1 to 4 carbon atoms, that include an oxygen atom at the point of attachment.
  • An example of an “alkoxy group” is represented by the formula –OR, where R can be an alkyl group, optionally substituted with an alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, alkoxy or heterocycloalkyl group.
  • alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy cyclopropoxy, cyclohexyloxy, and the like.
  • Alkoxycarbonyl refers to an alkoxy substituted carbonyl radical, –C(O)OR, wherein R represents an optionally substituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl or similar moiety.
  • alkyl refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like.
  • a “lower alkyl” group is a saturated branched or unbranched hydrocarbon having from 1 to 6 carbon atoms. Preferred alkyl groups have 1 to 4 carbon atoms.
  • Alkyl groups may be “substituted alkyls” wherein one or more hydrogen atoms are substituted with a substituent such as halogen, cycloalkyl, alkoxy, amino, hydroxyl, aryl, alkenyl, or carboxyl.
  • a lower alkyl or (C1-C6)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3- pentyl, or hexyl;
  • (C 3 -C 6 )cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • (C 3 - C 6 )cycloalkyl(C 1 -C 6 )alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, or 2-cyclohexylethyl;
  • (C 1 - C 6 )alkoxy substituent can be methoxy, ethoxy, propoxy
  • Alkynyl refers to a cyclic, branched or straight chain group containing only carbon and hydrogen, and contains one or more triple bonds. Alkynyl groups may be unsubstituted or substituted. “Lower alkynyl” groups are those that contain one to six carbon atoms.
  • amine or “amino” refers to a group of the formula –NRR', where R and R' can be, independently, hydrogen or an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group.
  • an “alkylamino” or “alkylated amino” refers to –NRR', wherein at least one of R or R' is an alkyl.
  • “Aminocarbonyl” alone or in combination means an amino substituted carbonyl (carbamoyl) radical, wherein the amino radical may optionally be mono- or di-substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkoxycarbonyl and the like.
  • An aminocarbonyl group may be –N(R)-C(O)-R (wherein R is a substituted group or H).
  • a suitable aminocarbonyl group is acetamido.
  • amide or “amido” is represented by the formula –C(O)NRR', where R and R' independently can be a hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described above.
  • an “analog” is a molecule that differs in chemical structure from a parent compound, for example a homolog (differing by an increment in the chemical structure or mass, such as a difference in the length of an alkyl chain or the inclusion of one of more isotopes), a molecular fragment, a structure that differs by one or more functional groups, or a change in ionization.
  • An analog is not necessarily synthesized from the parent compound.
  • a derivative is a molecule derived from the base structure.
  • An “animal” refers to living multi-cellular vertebrate organisms, a category that includes, for example, mammals and birds. The term mammal includes both human and non-human mammals.
  • the term “subject” includes both human and non-human subjects, including birds and non-human mammals, such as non-human primates, companion animals (such as dogs and cats), livestock (such as pigs, sheep, cows), as well as non-domesticated animals, such as the big cats.
  • non-human mammals such as non-human primates, companion animals (such as dogs and cats), livestock (such as pigs, sheep, cows), as well as non-domesticated animals, such as the big cats.
  • livestock such as pigs, sheep, cows
  • non-domesticated animals such as the big cats.
  • subject applies regardless of the stage in the organism’s life-cycle.
  • the term subject applies to an organism in utero or in ovo, depending on the organism (that is, whether the organism is a mammal or a bird, such as a domesticated or wild fowl).
  • Aryl refers to a monovalent unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), which can optionally be unsubstituted or substituted.
  • a “heteroaryl group,” is defined as an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorous.
  • Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and the like.
  • the aryl or heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy, or the aryl or heteroaryl group can be unsubstituted.
  • aralkyl refers to an alkyl group wherein an aryl group is substituted for a hydrogen of the alkyl group.
  • An example of an aralkyl group is a benzyl group.
  • Aryloxy or “heteroaryloxy” refers to a group of the formula –OAr, wherein Ar is an aryl group or a heteroaryl group, respectively.
  • the term “carbocycle” refers to a cyclic structure that only includes carbon atoms as part of the core ring structure. Carbocycle is inclusive, for example, of cycloalkyl, cycloalkenyl, and aryl. In certain embodiments, the carbocycle has 3, 4, 5, 6, 7 or 8 ring carbon atoms.
  • the term “carboxylate” or “carboxyl” refers to the group -COO- or -COOH.
  • co-administration refers to administration of a HIV-1 integrase inhibitor disclosed herein with at least one other therapeutic agent, preferably another anti-HIV agent, within the same general time period, and does not require administration at the same exact moment in time (although co-administration is inclusive of administering at the same exact moment in time).
  • co- administration may be on the same day or on different days, or in the same week or in different weeks.
  • the additional therapeutic agent may be included in the same composition, or different composition, as the HIV- 1 integrase inhibitor.
  • “co-administration” or “co-administering” is inclusive of administering a compound disclosed herein with at least one anti-HIV agent as component of a combination antiretroviral therapy or highly active antiretroviral therapy (HAART).
  • cycloalkyl refers to a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • heterocycloalkyl group is a cycloalkyl group as defined above where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorous.
  • ester refers to a carboxyl group having the hydrogen replaced with, for example, a C1- 6alkyl group (“carboxylC1-6alkyl” or “alkylester”), an aryl or aralkyl group (“arylester” or “aralkylester”) and so on.
  • CO2C1-3alkyl groups are preferred, such as for example, methylester (CO 2Me), ethylester (CO2Et) and propylester (CO2Pr) and includes reverse esters thereof (e.g. –OCOMe, -OCOEt and –OCOPr).
  • halogen refers to fluoro, bromo, chloro and iodo substituents.
  • halogenated alkyl or “haloalkyl group” refer to an alkyl group as defined above with one or more hydrogen atoms present on these groups substituted with a halogen (F, Cl, Br, I).
  • hydroxyl is represented by the formula –OH.
  • “Inhibiting” refers to inhibiting the full development of a disease or condition. “Inhibiting” also refers to any quantitative or qualitative reduction in biological activity or binding, relative to a control.
  • “N-heterocyclic” or “N-heterocycle” refers to mono or bicyclic rings or ring systems that include at least one nitrogen heteroatom. The rings or ring systems generally include 1 to 9 carbon atoms in addition to 4239-109618-02 01/11/24 E-058-2023-0-PC-01 the heteroatom(s) and may be saturated, unsaturated or aromatic (including pseudoaromatic).
  • Aromatic refers to a ring system which is not strictly aromatic, but which is stabilized by means of delocalization of electrons and behaves in a similar manner to aromatic rings.
  • Aromatic includes pseudoaromatic ring systems, such as pyrrolyl rings.
  • Examples of 5-membered monocyclic N-heterocycles include pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, (including 1,2,3 and 1,2,4 oxadiazolyls) isoxazolyl, furazanyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1,2,3 and 1,3,4 triazolyls), tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls), and dithiazolyl.
  • 6-membered monocyclic N-heterocycles include pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and triazinyl.
  • the heterocycles may be optionally substituted with a broad range of substituents, and preferably with C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, cyano or mono or di(C1-6alkyl)amino.
  • the N-heterocyclic group may be fused to a carbocyclic ring such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl.
  • Examples of 8, 9 and 10-membered bicyclic heterocycles include 1H thieno[2,3-c]pyrazolyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, purinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzotriazinyl, and the like.
  • heterocycles may be optionally substituted, for example with C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, cyano or mono or di(C1-6alkyl)amino.
  • optionally substituted N-heterocyclics includes pyridinium salts and the N-oxide form of suitable ring nitrogens. “Nitro” refers to an R-group having the structure –NO 2 .
  • R-group refers to a single atom (for example, a halogen atom) or a group of two or more atoms that are covalently bonded to each other, which are covalently bonded to an atom or atoms in a molecule to satisfy the valency requirements of the atom or atoms of the molecule, typically in place of a hydrogen atom.
  • R-groups/substituents include alkyl groups, hydroxyl groups, alkoxy groups, acyloxy groups, mercapto groups, and aryl groups.
  • subject includes both human and non-human subjects, including birds and non-human mammals, such as non-human primates, companion animals (such as dogs and cats), livestock (such as pigs, sheep, cows), as well as non-domesticated animals, such as the big cats.
  • non-human mammals such as non-human primates, companion animals (such as dogs and cats), livestock (such as pigs, sheep, cows), as well as non-domesticated animals, such as the big cats.
  • livestock such as pigs, sheep, cows
  • non-domesticated animals such as the big cats.
  • subject applies regardless of the stage in the organism’s life-cycle. Thus, the term subject applies to an organism in utero or in ovo, depending on the organism (that is, whether the organism is a mammal or a bird, such as a domesticated or wild fowl).
  • “Substituted” or “substitution” refer to replacement of a hydrogen atom of a molecule or an R-group with one or more additional
  • the term “optionally-substituted” or “optional substituent” as used herein refers to a group which may or may not be further substituted with 1, 2, 3, 4 or more groups, preferably 1, 2 or 3, more preferably 1 or 2 groups.
  • the substituents may be selected, 4239-109618-02 01/11/24 E-058-2023-0-PC-01 for example, from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, hydroxyl, oxo, C 1-6 alkoxy, aryloxy, C 1- 6 alkoxyaryl, halo, C 1-6 alkylhalo (such as CF 3 and CHF 2 ), C 1-6 alkoxyhalo (such as OCF 3 and OCHF 2 ), carboxyl, esters, cyano, nitro, amino, substituted amino, disubstituted amino, acyl, ketones, amides, aminoacyl, substituted amides, disubstituted amides, thiol, alkylthio, thioxo, sulfates, sulfonates, sulfinyl, substituted sulfinyl, sulfon
  • N-heterocycles may also include but are not limited to C 1-6 alkyl i.e. N-C 1-3 alkyl, more preferably methyl particularly N-methyl.
  • sulfonyl refers to the group -SO 2 H.
  • substituted sulfonyl refers to a sulfonyl group having the hydrogen replaced with, for example a C1-6alkyl group (“sulfonylC1-6alkyl”), an aryl (“arylsulfonyl”), an aralkyl (“aralkylsulfonyl”) and so on.
  • SulfonylC1-3alkyl groups are preferred, such as for example, -SO2Me, -SO2Et and -SO2Pr.
  • the term “sulfonate” refers to the group SO3H and includes groups having the hydrogen replaced with, for example a C1-6alkyl group (“alkylsulfonate”), an aryl (“arylsulfonate”), an aralkyl (“aralkylsulfonate”) and so on.
  • C 1-3 sulfonates are preferred, such as for example, SO 3 Me, SO 3 Et and SO 3 Pr.
  • a "therapeutically effective amount” refers to a quantity of a specified agent sufficient to achieve a desired effect in a subject being treated with that agent.
  • a therapeutically amount may be an amount of an HIV-1 integrase inhibitor that is sufficient to inhibit HIV or the development of AIDS in a subject.
  • a therapeutically effective amount of an agent is an amount sufficient to inhibit or treat the disease or condition without causing a substantial toxic effect in the subject.
  • the therapeutically effective amount of an agent will be dependent on the subject being treated, the severity of the affliction, and the manner of administration of the therapeutic composition.
  • Thiol refers to the group -SH.
  • C 1-6 alkylthio refers to a thiol group having the hydrogen replaced with a C 1-6 alkyl group.
  • Treatment refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after it has begun to develop.
  • the term “ameliorating,” with reference to a disease or pathological condition refers to any observable beneficial effect of the treatment.
  • the beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease.
  • the phrase “treating a disease” refers to inhibiting the full development of a disease, for example, in a subject who is at risk for a disease.
  • “Preventing” a disease or condition refers to prophylactic administering a composition to a subject who does not exhibit signs of a disease or exhibits only early signs for the purpose of decreasing the risk of developing 4239-109618-02 01/11/24 E-058-2023-0-PC-01 a pathology or condition, or diminishing the severity of a pathology or condition.
  • the treatment inhibits the development of AIDS in a subject.
  • “Pharmaceutical compositions” are compositions that include an amount (for example, a unit dosage) of one or more of the disclosed compounds together with one or more non-toxic pharmaceutically acceptable additives, including carriers, diluents, and/or adjuvants, and optionally other biologically active ingredients.
  • compositions can be prepared by standard pharmaceutical formulation techniques such as those disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA (19th Edition).
  • pharmaceutically acceptable salt or ester refers to salts or esters prepared by conventional means that include salts, e.g., of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like.
  • “Pharmaceutically acceptable salts” of the presently disclosed compounds also include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.
  • bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tri
  • any chemical compound recited in this specification may alternatively be administered as a pharmaceutically acceptable salt thereof.
  • “Pharmaceutically acceptable salts” are also inclusive of the free acid, base, and zwitterionic forms. Descriptions of suitable pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts, Properties, Selection and Use, Wiley VCH (2002). When compounds disclosed herein include an acidic function such as a carboxy group, then suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkaline, alkaline earth, ammonium, quaternary ammonium cations and the like. Such salts are known to those of skill in the art. For additional examples of “pharmacologically acceptable salts,” see Berge et al., J.
  • “Pharmaceutically acceptable esters” includes those derived from compounds described herein that are modified to include a carboxyl group.
  • An in vivo hydrolysable ester is an ester, which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • esters thus include carboxylic acid esters in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, methyl, n-propyl, t-butyl, or n-butyl), cycloalkyl, alkoxyalkyl (for example, methoxymethyl), aralkyl (for example benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl, optionally substituted by, for example, halogen, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy) or amino); sulphonate esters, such as alkyl- or aralkylsulphonyl (for example, methanesulphonyl); or amino acid esters (for example, L-valyl or L-isoleucyl).
  • alkyl for example, methyl, n-propyl, t
  • esters such as mono-, di-, or tri-phosphate esters.
  • any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms.
  • Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms.
  • Any aryl moiety present in such esters advantageously comprises a phenyl group, optionally substituted as shown in the definition of carbocycylyl above.
  • esters thus include C1-C22 fatty acid esters, such as acetyl, t-butyl or long chain straight or branched unsaturated or omega-6 monounsaturated fatty acids such as palmoyl, stearoyl and the like.
  • Alternative aryl or heteroaryl esters include benzoyl, pyridylmethyloyl and the like any of which may be substituted, as defined in carbocyclyl above.
  • Additional pharmaceutically acceptable esters include aliphatic L-amino acid esters such as leucyl, isoleucyl and especially valyl.
  • salts of the compounds are those wherein the counter-ion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
  • the pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds are able to form.
  • the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g.
  • hydrochloric or hydrobromic acid sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic (i.e.
  • salt forms can be converted by treatment with an appropriate base into the free base form.
  • the compounds containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g.
  • addition salt as used hereinabove also comprises the solvates which the compounds described herein are able to form. Such solvates are for example hydrates, alcoholates and the like.
  • quaternary amine as used hereinbefore defines the quaternary ammonium salts which the compounds are able to form by reaction between a basic nitrogen of a compound and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide.
  • an appropriate quaternizing agent such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide.
  • Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates.
  • a quaternary amine has 4239-109618-02 01/11/24 E-058-2023-0-PC-01 a positively charged nitrogen.
  • Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins. Some of the compounds described herein may also exist in their tautomeric form. Prodrugs of the disclosed compounds also are contemplated herein.
  • a prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into an active compound following administration of the prodrug to a subject.
  • prodrug as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds described herein.
  • Prodrugs preferably have excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo.
  • Prodrugs of a compounds described herein may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art.
  • prodrug also is intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when the prodrug is administered to a subject. Since prodrugs often have enhanced properties relative to the active agent pharmaceutical, such as, solubility and bioavailability, the compounds disclosed herein can be delivered in prodrug form. Thus, also contemplated are prodrugs of the presently disclosed compounds, methods of delivering prodrugs and compositions containing such prodrugs.
  • Prodrugs of the disclosed compounds typically are prepared by modifying one or more functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to yield the parent compound.
  • Prodrugs include compounds having a phosphonate and/or amino group functionalized with any group that is cleaved in vivo to yield the corresponding amino and/or phosphonate group, respectively.
  • Examples of prodrugs include, without limitation, compounds having an acylated amino group and/or a phosphonate ester or phosphonate amide group.
  • a prodrug is a lower alkyl phosphonate ester, such as an isopropyl phosphonate ester.
  • Protected derivatives of the disclosed compounds also are contemplated.
  • a variety of suitable protecting groups for use with the disclosed compounds are disclosed in Greene and Wuts, Protective Groups in Organic Synthesis; 3rd Ed.; John Wiley & Sons, New York, 1999.
  • protecting groups are removed under conditions that will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like.
  • One preferred method involves the removal of an ester, such as cleavage of a phosphonate ester using Lewis acidic conditions, such as in TMS-Br mediated ester cleavage to yield the free phosphonate.
  • a second preferred method involves removal of a protecting group, such as removal of a benzyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and 4239-109618-02 01/11/24 E-058-2023-0-PC-01 the like or mixtures thereof.
  • a t-butoxy-based group including t-butoxy carbonyl protecting groups can be removed utilizing an inorganic or organic acid, such as HCl or trifluoroacetic acid, in a suitable solvent system, such as water, dioxane and/or methylene chloride.
  • Another exemplary protecting group, suitable for protecting amino and hydroxy functions amino is trityl.
  • the compounds disclosed herein are synthesized in or are purified to be in substantially enantiopure form, such as in a 90% enantiomeric excess, a 95% enantiomeric excess, a 97% enantiomeric excess or even in greater than a 99% enantiomeric excess, such as in enantiopure form.
  • the compounds can be isolated as a single isomer or as mixture of isomers.
  • tautomers of the compounds are also considered part of the disclosure.
  • the presently disclosed compounds also include all isotopes of atoms present in the compounds, which can include, but are not limited to, deuterium, tritium, 18 F, etc.
  • Compounds Disclosed herein is a compound, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, having a structure of: wherein R 1 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl; R 2 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, substituted amino, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl; 4239-109618-
  • R 1 is (C1-C10)alkyl. In certain embodiments, R 1 is (C1-C6)alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl. In certain embodiments, R 1 is substituted alkyl.
  • Illustrative substituted alkyls include hydroxylalkyl, alkoxyalkyl, carboxylate-substituted alkyl, acetoxy-substituted alkyl, benzoxy-substituted alkyl, aminoalkyl, (cycloalkyl)alkyl, aralkyl, hydroxyalkoxyalkyl, amidoalkyl, thioalkyl, sulfonyl alkyl, substituted-sulfonyl alkyl, or alkenyl-substituted alkyl.
  • R 1 is hydroxyalkyl.
  • R 1 is hydroxy(C 1 -C 6 )alkyl.
  • R 1 is (C1-C6)alkoxyalkyl. In certain embodiments, R 1 is methoxyalkyl. In certain embodiments, R 1 or R 2 is is , Z is hydroxy, -NHR 8 , or -NR 8 R 9 ; Ar is aryl or heteroaryl; R 8 is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, or acyl; R 9 is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, or acyl; and m is 1 to 8.
  • R 2 is H.
  • X is F.
  • a is 2.
  • a is 2 to 5.
  • a is 2 and each X is fluoro (particularly 2 ⁇ ,4 ⁇ - difluoro).
  • a compound, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof having a structure of: O OH R1 O N a wherein R 1 is H, alkyl, substituted alkenyl, alkynyl, or substituted alkynyl; R 2 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, substituted amino, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl; X is halogen or CF3; and a is 1 to 5.
  • R 1 is (C1-C10)alkyl, In certain embodiments, R 1 is (C1-C6)alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl. In certain embodiments, R 1 is substituted alkyl.
  • Illustrative substituted alkyls include hydroxylalkyl, alkoxyalkyl, carboxylate-substituted alkyl, acetoxy-substituted alkyl, benzoxy-substituted alkyl, aminoalkyl, (cycloalkyl)alkyl, aralkyl, hydroxyalkoxyalkyl, amidoalkyl, thioalkyl, sulfonyl alkyl, substituted-sulfonyl alkyl, or alkenyl-substituted alkyl.
  • R 1 is hydroxyalkyl.
  • R 1 is hydroxy(C1-C6)alkyl.
  • R 1 is (C 1 -C 6 )alkoxyalkyl. In certain embodiments, R 1 is methoxyalkyl. In certain embodiments, R 1 or R 2 is is , 4239-109618-02 01/11/24 E-058-2023-0-PC-01 wherein R is alkyl, substituted alkyl, aryl, substituted aryl, -NHR 8 , or -NR 8 R 9 ; Z is hydroxy, -NHR 8 , or -NR 8 R 9 ; Ar is aryl or heteroaryl; R 8 is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, or acyl; R 9 is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, or acyl; R 9
  • R 2 is H.
  • X is F.
  • a is 2.
  • a is 2 to 5.
  • a is 2 and each X is fluoro (particularly 2 ⁇ ,4 ⁇ - difluoro).
  • a compound, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof having a structure of: O OH R1 O a wherein R 1 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl; R 2 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, substituted amino, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl; X is halogen or CF 3 ; a is 1 to 5; and represents a cyclic structure.
  • R 1 is (C1-C10)alkyl, In certain embodiments, R 1 is (C1-C6)alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl. In certain embodiments, R 1 is substituted alkyl.
  • Illustrative substituted alkyls include hydroxylalkyl, alkoxyalkyl, carboxylate-substituted alkyl, acetoxy-substituted alkyl, benzoxy-substituted alkyl, aminoalkyl, 4239-109618-02 01/11/24 E-058-2023-0-PC-01 (cycloalkyl)alkyl, aralkyl, hydroxyalkoxyalkyl, amidoalkyl, thioalkyl, sulfonyl alkyl, substituted-sulfonyl alkyl, or alkenyl-substituted alkyl.
  • R 1 is hydroxyalkyl.
  • R 1 is hydroxy(C1-C6)alkyl. In certain embodiments, R 1 is (C1-C6)alkoxyalkyl. In certain embodiments, R 1 is methoxyalkyl. In certain embodiments, R 1 or R 2 is is , Z is hydroxy, -NHR 8 , or -NR 8 R 9 ; Ar is aryl or heteroaryl; R 8 is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, or acyl; R 9 is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, or acyl; and m is 1 to 8.
  • R 2 is H.
  • X is F.
  • a is 2.
  • a is 2 to 5.
  • a is 2 and each X is fluoro (particularly 2 ⁇ ,4 ⁇ - difluoro).
  • In certain is a carbocyclic structure. In certain is a heterocyclic structure.
  • R 1 is (C 1 -C 10 )alkyl. In certain embodiments, R 1 is (C 1 -C 6 )alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl. In certain embodiments, R 1 is substituted alkyl.
  • Illustrative substituted alkyls include hydroxylalkyl, alkoxyalkyl, carboxylate-substituted alkyl, acetoxy-substituted alkyl, benzoxy-substituted alkyl, aminoalkyl, (cycloalkyl)alkyl, aralkyl, hydroxyalkoxyalkyl, amidoalkyl, thioalkyl, sulfonyl alkyl, substituted-sulfonyl alkyl, or alkenyl-substituted alkyl.
  • R 1 is hydroxyalkyl.
  • R 1 is hydroxy(C 1 -C 6 )alkyl.
  • R 1 is (C 1 -C 6 )alkoxyalkyl. In certain embodiments, R 1 is methoxyalkyl. In certain embodiments, R 1 or R 2 is is , 4239-109618-02 01/11/24 E-058-2023-0-PC-01 or - or - Ar is aryl or heteroaryl; R 8 is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, or acyl; R 9 is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, or acyl; and m is 1 to 8.
  • R 2 is H.
  • X is F.
  • b is 2.
  • b is 2 to 4.
  • b is 2 and each X is fluoro.
  • R 1 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl;
  • R 2 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, substituted amino, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl;
  • Z is nitrogen;
  • X is halogen or CF 3 ;
  • R 1 is (C 1 -C 10 )alkyl. In certain embodiments, R 1 is (C 1 -C 6 )alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl. In certain embodiments, R 1 is substituted alkyl.
  • Illustrative substituted alkyls include hydroxylalkyl, alkoxyalkyl, carboxylate-substituted alkyl, acetoxy-substituted alkyl, benzoxy-substituted alkyl, aminoalkyl, (cycloalkyl)alkyl, aralkyl, hydroxyalkoxyalkyl, amidoalkyl, thioalkyl, sulfonyl alkyl, substituted-sulfonyl alkyl, or alkenyl-substituted alkyl.
  • R 1 is hydroxyalkyl.
  • R 1 is hydroxy(C 1 -C 6 )alkyl.
  • R 1 is (C 1 -C 6 )alkoxyalkyl. In certain embodiments, R 1 is methoxyalkyl. In certain embodiments, R 1 or R 2 is is or Z is hydroxy, -NHR 8 , or -NR 8 R 9 ; Ar is aryl or heteroaryl; R 8 is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, or acyl; R 9 is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, or acyl; and m is 1 to 8.
  • R 2 is H.
  • X is F.
  • c is 2.
  • c is 2 to 4.
  • c is 2 and each X is fluoro. 4239-109618-02 01/11/24 E-058-2023-0-PC-01
  • R 1 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl
  • R 2 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, substituted amino, alkenyl, substituted alkenyl, alkynyl, or substituted alky
  • R 1 is (C1-C10)alkyl. In certain embodiments, R 1 is (C1-C6)alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl. In certain embodiments, R 1 is substituted alkyl.
  • Illustrative substituted alkyls include hydroxylalkyl, alkoxyalkyl, carboxylate-substituted alkyl, acetoxy-substituted alkyl, benzoxy-substituted alkyl, aminoalkyl, (cycloalkyl)alkyl, aralkyl, hydroxyalkoxyalkyl, amidoalkyl, thioalkyl, sulfonyl alkyl, substituted-sulfonyl alkyl, or alkenyl-substituted alkyl.
  • R 1 is hydroxyalkyl.
  • R 1 is hydroxy(C1-C6)alkyl.
  • R 2 is H.
  • X is F.
  • b is 2.
  • b is 2 to 4.
  • b is 2 and each X is fluoro.
  • R 1 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl;
  • R 2 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, substituted amino, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl;
  • Z is nitrogen;
  • X is halogen or CF3; b
  • R 1 is (C 1 -C 10 )alkyl. In certain embodiments, R 1 is (C 1 -C 6 )alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl. In certain embodiments, R 1 is substituted alkyl.
  • Illustrative substituted alkyls include hydroxylalkyl, alkoxyalkyl, carboxylate-substituted alkyl, acetoxy-substituted alkyl, benzoxy-substituted alkyl, aminoalkyl, 4239-109618-02 01/11/24 E-058-2023-0-PC-01 (cycloalkyl)alkyl, aralkyl, hydroxyalkoxyalkyl, amidoalkyl, thioalkyl, sulfonyl alkyl, substituted-sulfonyl alkyl, or alkenyl-substituted alkyl.
  • R 1 is hydroxyalkyl.
  • R 1 is hydroxy(C1-C6)alkyl. In certain embodiments, R 1 is (C1-C6)alkoxyalkyl. In certain embodiments, R 1 is methoxyalkyl. In certain embodiments, R 1 or R 2 is is or Z is hydroxy, -NHR 8 , or -NR 8 R 9 ; Ar is aryl or heteroaryl; R 8 is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, or acyl; R 9 is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, or acyl; and m is 1 to 8.
  • R 2 is H.
  • X is F.
  • c is 2.
  • c is 2 to 4.
  • c is 2 and each X is fluoro.
  • R 1 is H, alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl;
  • R 2 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, substituted amino, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl;
  • Z is nitrogen;
  • X is halogen or
  • R 1 is (C1-C10)alkyl, In certain embodiments, R 1 is (C1-C6)alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl. In certain embodiments, R 1 is substituted alkyl.
  • Illustrative substituted alkyls include hydroxylalkyl, alkoxyalkyl, carboxylate-substituted alkyl, acetoxy-substituted alkyl, benzoxy-substituted alkyl, aminoalkyl, (cycloalkyl)alkyl, aralkyl, hydroxyalkoxyalkyl, amidoalkyl, thioalkyl, sulfonyl alkyl, substituted-sulfonyl alkyl, or alkenyl-substituted alkyl.
  • R 1 is hydroxyalkyl.
  • R 1 is hydroxy(C1-C6)alkyl.
  • R 1 is (C1-C6)alkoxyalkyl. In certain embodiments, R 1 is methoxyalkyl. In certain embodiments, R 1 or R 2 is is or 4239-109618-02 01/11/24 E-058-2023-0-PC-01 Ar Z , R is alkyl, substituted alkyl, aryl, substituted aryl, -NHR 8 , or -NR 8 R 9 ; -NHR 8 , or -NR 8 R 9 ; Ar is aryl or heteroaryl; R 8 is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, or acyl; R 9 is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, or acyl; and m is 1
  • R 2 is H.
  • X is F.
  • b is 2.
  • b is 2 to 4.
  • b is 2 and each X is fluoro.
  • In certain is a carbocyclic structure. In certain is a heterocyclic structure.
  • R 1 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl
  • R 2 is H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, substituted amino, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl
  • Z is nitrogen
  • X is halogen or CF 3
  • b is 0 to 2
  • c is 1 to 4
  • R 1 is (C 1 -C 10 )alkyl
  • R 1 is (C 1 -C 6 )alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl.
  • R 1 is substituted alkyl.
  • Illustrative substituted alkyls include hydroxylalkyl, alkoxyalkyl, carboxylate-substituted alkyl, acetoxy-substituted alkyl, benzoxy-substituted alkyl, aminoalkyl, (cycloalkyl)alkyl, aralkyl, hydroxyalkoxyalkyl, amidoalkyl, thioalkyl, sulfonyl alkyl, substituted-sulfonyl alkyl, or alkenyl-substituted alkyl.
  • R 1 is hydroxyalkyl.
  • R 1 is hydroxy(C1-C6)alkyl.
  • R 1 is (C 1 -C 6 )alkoxyalkyl. In certain embodiments, R 1 is methoxyalkyl. In certain embodiments, R 1 or R 2 is is or Z is hydroxy, -NHR 8 , or -NR 8 R 9 ; Ar is aryl or heteroaryl; R 8 is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, or acyl; R 9 is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, or acyl; and m is 1 to 8.
  • R 2 is H.
  • X is F.
  • c is 2.
  • c is 2 to 4.
  • c is 2 and each X is fluoro.
  • the aldehyde 9 was achieved by heating the acetal 8 in formic acid at 80 o C, the solvent was evaporated, dried under vacuum, and the crude aldehyde was used for the next reaction without purification.
  • the next cyclized pyridone 10 and a precursor for both 6a and 7a was achieved by reacting crude aldehyde 9 with 2,4-dimethoxy benzylamine under reflux condition mediated by acetic acid.
  • the benzyl deprotection of 10 was done with TFA as a sole solvent and the crude 11 was used for the next demethylation reaction after evaporating TFA and drying to yield desired bicycle 6a.
  • the reduced bicycle 7a was achieved in three steps from pyridone 10 by reduction of double bond followed by debenzylation and demethylation.
  • Scheme 1 Synthesis of N-H bicyclic carbamoyl pyridones 6a and 7a a . reflux 19 h; iii) TFA, 60 o C, 6 h; iv) LiBr, MeCN, 85 o C, 16 h; v) H2, Pd/C, DMF/MeOH (2:1), rt, 20 h; vi) TFA, reflux, 24 h.
  • Antiviral activities of bicyclic carbamoyl pyridones Compounds INSTI activity EC 50 (nM) Wild t S230N 4239-109618-02 01/11/24 E-058-2023-0-PC-01 Table 3.
  • Antiviral potencies against IN mutants G118R and R263K Compounds INSTI activity EC50 (nM) G118R R263K Table 4.
  • Preparative high-pressure liquid chromatography was conducted using a Waters Prep LC4000 system having photodiode array detection and Phenomenex C18 columns (catalog no.00G-4436-P0-AX, 250 mm ⁇ 21.2 mm 10 ⁇ m particle size, 110 ⁇ pore) at a flow rate of 20 mL/min.
  • Electrospray ionization-mass spectrometric (ESI-MS) were acquired with an Agilent LC/MSD system equipped with a multimode ion source. Purities of samples subjected to biological testing were assessed using this system and shown to be ⁇ 95%.
  • High resolution mass spectrometric HRMS were acquired by LC/MS-ESI using LTQ-Orbitrap-XL at 30K resolution. All the reactions carried out under inert atmosphere using an argon balloon; otherwise noted.
  • reaction product aldehyde 9 was confirmed by LC-MS. The solvent was removed under vacuum, residue was dissolved in DCM (20 mL) and the washing of 10% NaH2PO4 (2 ⁇ 10 mL) was given. The organic layer was then separated, dried over sodium sulfate and concentrated. The crude aldehyde 9 was used for further transformation without purification.
  • the crude aldehyde 9 was dissolved in acetonitrile (15 mL) followed by addition of (2,4-dimethoxypheyl)methylamine or 2,4-dimethoxy benzyl amine (1.0 mL, 6.81 mmol, 3 equiv) and acetic acid (0.45 mL, 7.95 mmol, 3.5 equiv) and reaction mixture was refluxed (85 o C, 19 h).
  • the expected product 10 is very difficult to purify using column chromatography from the unreacted starting material.
  • the efforts to isolate the product (DCM:Methanol) were met with failures. Therefore, the product was recrystallized with hot ethyl acetate (Water bath temperature 50 o C) and was collected with filtration.
  • the titled compound (6a, 15 mg) was afforded as a brownish amorphous solid (11% over 2 steps) after lyophilization.
  • the titled compound (7a, 25 mg) was afforded as a brownish amorphous solid (37% over 2 steps) after lyophilization.
  • the solvent formic acid was evaporated over rotavapor, and a high vacuum was applied to remove traces of formic acid.
  • the solvent was evaporated on rotavapor, and a high vacuum was applied to remove solvent traces.
  • Acetonitrile was removed over rotavapor and the resulting suspension of the final enone product 6b -m in H 2 O was filtered through Whatman’s filter paper and the filtrate was again diluted with H2O (5 mL ⁇ 3) and the resulting solid product was collected by filtration. The product was then dissolved in DMSO and purified by Prep-HPLC using a binary mixture of 0.1% aqueous TFA and 0.1% TFA in in acetonitrile as eluents were employed with gradients 0-100%.
  • compositions and Methods of Use The compounds and compositions disclosed herein may be used to inhibit both wild-type and drug- resistant HIV-1 integrase and, by extension, the replication of HIV-1.
  • the compounds and compositions disclosed herein may be used for treating a subject infected with AIDS or an HIV infection.
  • the compounds and compositions disclosed herein may be used to inhibit raltegravir-resistant HIV-1 integrase in the subject.
  • the compounds and compositions disclosed herein may overcome resistance to raltegravir and/or evitegravir.
  • the compounds disclosed herein may be co-administered with at least one other anti-HIV or anti-AIDS therapeutic agent.
  • anti-HIV or anti-AIDS therapeutic agents include nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, inhibitors that block the virus’s ability to interact with the co-receptors CXR4 or CCR5, HIV budding or maturation inhibitors, and HIV integrase inhibitors.
  • Illustrative nucleoside HIV reverse transcriptase inhibitors include abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine, or a pharmaceutically acceptable salt thereof.
  • Illustrative non-nucleoside HIV reverse transcriptase inhibitors include delavirdine, efavirenz, etravirine, rilpivirine and nevirapine, or a pharmaceutically acceptable thereof.
  • HIV protease inhibitors include amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and fosamprenavir, or a pharmaceutically acceptable salt thereof.
  • HIV fusion inhibitors include enfuvirtide or T-1249, or a pharmaceutically acceptable salt thereof.
  • Illustrative inhibitors that block the virus’s ability to interact with CCR5 include Sch-C, Sch-D, TAK-220, PRO-140, and UK-427,857, or a pharmaceutically acceptable salt thereof.
  • An illustrative inhibitor that blocks the virus’s ability to interact 4239-109618-02 01/11/24 E-058-2023-0-PC-01 with CXCR4 is AMD-3100, or a pharmaceutically acceptable salt thereof.
  • An illustrative budding or maturation inhibitor is PA-457, or a pharmaceutically acceptable salt thereof.
  • a compound of formula I in the manufacture of a medicament for the treatment of AIDS or HIV infection.
  • Another aspect of the disclosure includes pharmaceutical compositions prepared for administration to a subject and which include a therapeutically effective amount of one or more of the compounds disclosed herein. The therapeutically effective amount of a disclosed compound will depend on the route of administration, the species of subject and the physical characteristics of the subject being treated.
  • compositions for administration to a subject can include at least one further pharmaceutically acceptable additive such as carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice.
  • Pharmaceutical compositions can also include one or more additional active ingredients such as antimicrobial agents, anti-inflammatory agents, anesthetics, and the like.
  • the pharmaceutically acceptable carriers useful for these formulations are conventional. Remington’s Pharmaceutical Sciences, by E. W.
  • compositions and formulations suitable for pharmaceutical delivery of the compounds herein disclosed are compositions and formulations suitable for pharmaceutical delivery of the compounds herein disclosed.
  • the nature of the carrier will depend on the particular mode of administration being employed.
  • parenteral formulations usually contain injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
  • injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
  • solid compositions for example, powder, pill, tablet, or capsule forms
  • conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate.
  • compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.
  • Pharmaceutical compositions disclosed herein include those formed from pharmaceutically acceptable salts and/or solvates of the disclosed compounds.
  • Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Particular disclosed compounds possess at least one basic group that can form acid–base salts with acids. Examples of basic groups include, but are not limited to, amino and imino groups.
  • inorganic acids that can form salts with such basic groups include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.
  • Basic groups also can form salts with organic carboxylic acids, sulfonic acids, sulfo acids or phospho acids or N-substituted sulfamic acid, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric 4239-109618-02 01/11/24 E-058-2023-0-PC-01 acid, malic acid, tartaric acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2- acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotin
  • suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art.
  • Certain compounds include at least one acidic group that can form an acid–base salt with an inorganic or organic base.
  • salts formed from inorganic bases include salts of the presently disclosed compounds with alkali metals such as potassium and sodium, alkaline earth metals, including calcium and magnesium and the like.
  • salts of acidic compounds with an organic base such as an amine
  • an organic base such as an amine
  • an organic base such as an amine
  • salts formed with basic amino acids aliphatic amines, heterocyclic amines, aromatic amines, pyridines, guanidines and amidines.
  • aliphatic amines the acyclic aliphatic amines, and cyclic and acyclic di- and tri- alkyl amines are particularly suitable for use in the disclosed compounds.
  • quaternary ammonium counterions also can be used.
  • Suitable amine bases for use in the present compounds include, without limitation, pyridine, N,N-dimethylaminopyridine, diazabicyclononane, diazabicycloundecene, N-methyl-N-ethylamine, diethylamine, triethylamine, diisopropylethylamine, mono-, bis- or tris- (2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, tris(hydroxymethyl)methylamine, N,N- dimethyl-N-(2- hydroxyethyl)amine, tri-(2-hydroxyethyl)amine and N-methyl-D-glucamine.
  • compositions can be administered to subjects by a variety of mucosal administration modes, including by oral, rectal, intranasal, intrapulmonary, or transdermal delivery, or by 4239-109618-02 01/11/24 E-058-2023-0-PC-01 topical delivery to other surfaces.
  • compositions can be administered by non-mucosal routes, including by intramuscular, subcutaneous, intravenous, intra-arterial, intra-articular, intraperitoneal, intrathecal, intracerebroventricular, or parenteral routes.
  • the compound can be administered ex vivo by direct exposure to cells, tissues or organs originating from a subject.
  • the compound can be combined with various pharmaceutically acceptable additives, as well as a base or vehicle for dispersion of the compound.
  • Desired additives include, but are not limited to, pH control agents, such as arginine, sodium hydroxide, glycine, hydrochloric acid, citric acid, and the like.
  • local anesthetics for example, benzyl alcohol
  • isotonizing agents for example, sodium chloride, mannitol, sorbitol
  • adsorption inhibitors for example, Tween 80 or Miglyol 812
  • solubility enhancing agents for example, cyclodextrins and derivatives thereof
  • stabilizers for example, serum albumin
  • reducing agents for example, glutathione
  • Adjuvants such as aluminum hydroxide (for example, Amphogel, Wyeth Laboratories, Madison, NJ), Freund’s adjuvant, MPL ⁇ (3-O-deacylated monophosphoryl lipid A; Corixa, Hamilton, IN) and IL-12 (Genetics Institute, Cambridge, MA), among many other suitable adjuvants well known in the art, can be included in the compositions.
  • MPL ⁇ 3-O-deacylated monophosphoryl lipid A; Corixa, Hamilton, IN
  • IL-12 Geneetics Institute, Cambridge, MA
  • the tonicity of the solution is adjusted to a value of about 0.3 to about 3.0, such as about 0.5 to about 2.0, or about 0.8 to about 1.7.
  • the compound can be dispersed in a base or vehicle, which can include a hydrophilic compound having a capacity to disperse the compound, and any desired additives.
  • the base can be selected from a wide range of suitable compounds, including but not limited to, copolymers of polycarboxylic acids or salts thereof, carboxylic anhydrides (for example, maleic anhydride) with other monomers (for example, methyl (meth)acrylate, acrylic acid and the like), hydrophilic vinyl polymers, such as polyvinyl acetate, polyvinyl alcohol, polyvinylpyrrolidone, cellulose derivatives, such as hydroxymethylcellulose, hydroxypropylcellulose and the like, and natural polymers, such as chitosan, collagen, sodium alginate, gelatin, hyaluronic acid, and nontoxic metal salts thereof.
  • copolymers of polycarboxylic acids or salts thereof include but not limited to, copolymers of polycarboxylic acids or salts thereof, carboxylic anhydrides (for example, maleic anhydride) with other monomers (for example, methyl (meth)acrylate, acrylic acid and the like), hydrophilic vinyl polymers,
  • a biodegradable polymer is selected as a base or vehicle, for example, polylactic acid, poly(lactic acid-glycolic acid) copolymer, polyhydroxybutyric acid, poly(hydroxybutyric acid- glycolic acid) copolymer and mixtures thereof.
  • synthetic fatty acid esters such as polyglycerin fatty acid esters, sucrose fatty acid esters and the like can be employed as vehicles.
  • Hydrophilic polymers and other vehicles can be used alone or in combination, and enhanced structural integrity can be imparted to the vehicle by partial crystallization, ionic bonding, cross-linking and the like.
  • the vehicle can be provided in a variety of forms, including fluid or viscous solutions, gels, pastes, powders, microspheres and films for direct application to a mucosal surface.
  • the compound can be combined with the base or vehicle according to a variety of methods, and release of the compound can be by diffusion, disintegration of the vehicle, or associated formation of water channels.
  • the compound is dispersed in microcapsules (microspheres) or nanocapsules 4239-109618-02 01/11/24 E-058-2023-0-PC-01 (nanospheres) prepared from a suitable polymer, for example, isobutyl 2-cyanoacrylate (see, for example, Michael et al., J.
  • compositions of the disclosure can alternatively contain as pharmaceutically acceptable vehicles substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, and triethanolamine oleate.
  • pharmaceutically acceptable vehicles substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, and triethanolamine oleate.
  • nontoxic pharmaceutically acceptable vehicles can be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • Pharmaceutical compositions for administering the compound can also be formulated as a solution, microemulsion, or other ordered structure suitable for high concentration of active ingredients.
  • the vehicle can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • Proper fluidity for solutions can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of a desired particle size in the case of dispersible formulations, and by the use of surfactants.
  • a coating such as lecithin
  • surfactants for example, sugars, polyalcohols, such as mannitol and sorbitol, or sodium chloride in the composition.
  • Prolonged absorption of the compound can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin.
  • the compound can be administered in a time release formulation, for example in a composition which includes a slow release polymer.
  • compositions can be prepared with vehicles that will protect against rapid release, for example a controlled release vehicle such as a polymer, microencapsulated delivery system or bioadhesive gel. Prolonged delivery in various compositions of the disclosure can be brought about by including in the composition agents that delay absorption, for example, aluminum monostearate hydrogels and gelatin.
  • controlled release binders suitable for use in accordance with the disclosure include any biocompatible controlled release material which is inert to the active agent and which is capable of incorporating the compound and/or other biologically active agent. Numerous such materials are known in the art.
  • Useful controlled-release binders are materials that are metabolized slowly under physiological conditions following their delivery (for example, at a mucosal surface, or in the presence of bodily fluids).
  • Appropriate binders include, but are not limited to, biocompatible polymers and copolymers well known in the art for use in sustained release formulations. Such biocompatible compounds are non-toxic and inert to surrounding tissues, and do not trigger significant adverse side effects, such as nasal irritation, immune response, inflammation, or the like. They are metabolized into metabolic products that are also biocompatible and easily eliminated from the body.
  • Exemplary polymeric materials for use in the present disclosure include, but are not limited to, polymeric matrices derived from copolymeric and homopolymeric polyesters having hydrolyzable ester linkages.
  • Exemplary polymers include polyglycolic acids and polylactic acids, poly(DL- lactic acid-co-glycolic acid), poly(D-lactic acid-co-glycolic acid), and poly(L-lactic acid-co-glycolic acid).
  • biodegradable or bioerodable polymers include, but are not limited to, such polymers as poly(epsilon-caprolactone), poly(epsilon-aprolactone-CO-lactic acid), poly(epsilon.-aprolactone-CO-glycolic acid), poly(beta-hydroxy butyric acid), poly(alkyl-2-cyanoacrilate), hydrogels, such as poly(hydroxyethyl methacrylate), polyamides, poly(amino acids) (for example, L-leucine, glutamic acid, L-aspartic acid and the like), poly(ester urea), poly(2-hydroxyethyl DL-aspartamide), polyacetal polymers, polyorthoesters, polycarbonate, polymaleamides, polysaccharides, and copolymers thereof.
  • polymers such as polymers as poly(epsilon-caprolactone), poly(epsilon-aprolactone-CO-lactic acid
  • compositions of the disclosure typically are sterile and stable under conditions of manufacture, storage and use.
  • Sterile solutions can be prepared by incorporating the compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated herein, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the compound and/or other biologically active agent into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated herein.
  • methods of preparation include vacuum drying and freeze-drying which yields a powder of the compound plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the prevention of the action of microorganisms can be accomplished by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • the compound can be delivered to a subject in a manner consistent with conventional methodologies associated with management of the disorder for which treatment or prevention is sought.
  • a prophylactically or therapeutically effective amount of the compound and/or other biologically active agent is administered to a subject in need of such treatment for a time and under conditions sufficient to prevent, inhibit, and/or ameliorate a selected disease or condition or one or more symptom(s) thereof.
  • the administration of the compound of the disclosure can be for either prophylactic or therapeutic purpose.
  • the compound When provided prophylactically, the compound is provided in advance of any symptom.
  • the prophylactic administration of the compound serves to prevent or ameliorate any subsequent disease process.
  • the compound When provided therapeutically, the compound is provided at (or shortly after) the onset of a symptom of disease or infection.
  • the compound can be administered to the subject by the oral route or in a single bolus delivery, via continuous delivery (for example, continuous transdermal, mucosal or intravenous delivery) over an extended time period, or in a repeated administration protocol (for example, 4239-109618-02 01/11/24 E-058-2023-0-PC-01 by an hourly, daily or weekly, repeated administration protocol).
  • the therapeutically effective dosage of the compound can be provided as repeated doses within a prolonged prophylaxis or treatment regimen that will yield clinically significant results to alleviate one or more symptoms or detectable conditions associated with a targeted disease or condition as set forth herein. Determination of effective dosages in this context is typically based on animal model studies followed up by human clinical trials and is guided by administration protocols that significantly reduce the occurrence or severity of targeted disease symptoms or conditions in the subject. Suitable models in this regard include, for example, murine, rat, avian, dog, sheep, porcine, feline, non-human primate, and other accepted animal model subjects known in the art. Alternatively, effective dosages can be determined using in vitro models.
  • an effective amount or effective dose of the compound may simply inhibit or enhance one or more selected biological activities correlated with a disease or condition, as set forth herein, for either therapeutic or diagnostic purposes.
  • the actual dosage of the compound will vary according to factors such as the disease indication and particular status of the subject (for example, the subject’s age, size, fitness, extent of symptoms, susceptibility factors, and the like), time and route of administration, other drugs or treatments being administered concurrently, as well as the specific pharmacology of the compound for eliciting the desired activity or biological response in the subject.
  • Dosage regimens can be adjusted to provide an optimum prophylactic or therapeutic response.
  • a therapeutically effective amount is also one in which any toxic or detrimental side effects of the compound and/or other biologically active agent is outweighed in clinical terms by therapeutically beneficial effects.
  • a non-limiting range for a therapeutically effective amount of a compound and/or other biologically active agent within the methods and formulations of the disclosure is about 0.01 mg/kg body weight to about 20 mg/kg body weight, such as about 0.05 mg/kg to about 5 mg/kg body weight, or about 0.2 mg/kg to about 2 mg/kg body weight.
  • Dosage can be varied by the attending clinician to maintain a desired concentration at a target site (for example, the lungs or systemic circulation).
  • Higher or lower concentrations can be selected based on the mode of delivery, for example, trans-epidermal, rectal, oral, pulmonary, intraosseous, or intranasal delivery versus intravenous or subcutaneous or intramuscular delivery. Dosage can also be adjusted based on the release rate of the administered formulation, for example, of an intrapulmonary spray versus powder, sustained release oral versus injected particulate or transdermal delivery formulations, and so forth. HIV-based viral vectors with either WT or mutant IN may be used in single-round infectivity assays to determine the antiviral activity (EC50 values) of the compounds as previously described (Smith SJ, Hughes SH. J Vis Exp.2014 Apr 9;(86). doi: 10.3791/51400). In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are only preferred examples of the invention and should not be taken as limiting the scope of the invention.

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Abstract

L'invention concerne un composé, ou un stéréoisomère, un tautomère ou un sel pharmaceutiquement acceptable de celui-ci, ayant une structure de Formule I, R1, R2, X et a étant tels que définis dans les revendications.
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