Integrase strand transfer inhibitors

Abstract

Compounds having a substituted phenyl group at the 6-position of a 1-hydroxy-1,8-naphthyridin-2(1H)-one based metal chelating platform that function as integrase strand transfer inhibitors.

Description

[0001] 4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01 INTEGRASE STRAND TRANSFER INHIBITORS CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No.63 / 707,882 filed October 16, 2024, which is incorporated by reference herein in its entirety. ACKNOWLEDGMENT OF GOVERNMENT SUPPORT This invention was made with government support under project number ZIA BC 007363 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND The Human Immunodeficiency Virus Type 1 (HIV-1, hereafter referred to as HIV) currently infects ~40 million people worldwide, and the number of infected individuals continues to rise. In the absence of a cure, antiretroviral therapy represents the primary treatment option, because it slows disease progression and reduces new infections. Integrase (IN) Strand Transfer Inhibitors (INSTIs) 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. However, the emergence of IN variants resistant to INSTIs is becoming a greater clinical problem. SUMMARY Disclosed herein are compounds having a structure according to Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof: 4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01 wherein at least one of R1-R5is an acyl, acyloxy, alkoxy, substituted alkoxy, alkyl, substituted alkyl, amino, aminocarbonyl, aryl, substituted aryl, aryloxy, substituted aryloxy, carbonylamino, carboxyl, halogen, hydroxy, sulfonyl, or substituted sulfonyl; X is a halogen; and a is 0 to 5. Further disclosed herein is a compound having a structure according to Formula III, or a stereoisomer or pharmaceutically acceptable salt thereof: Formula III wherein X is a heteroaryl, substituted heteroaryl, carbobicyclyl, substituted carbobicyclyl, heterobicyclyl, substituted heterobicyclyl, heterocyclic, or substituted heterocyclic. Additionally disclosed herein is a compound having a structure according to Formula IV, or V, or VI, or a stereoisomer or pharmaceutically acceptable salt thereof: 4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01 X is a halogen; a is 0 to 5; Z and Y are each independently C or N; represents a cyclic structure, that may or may not be present; provided if is not present, then at least one of Z and Y is N. DETAILED DESCRIPTION The following explanations of terms and methods are provided to better describe the present compounds, compositions and methods, and to guide those of ordinary skill in the art in the practice of the present disclosure. It is also to be understood that the terminology used in the disclosure is for the purpose of describing particular embodiments and examples only and is not intended to be limiting. “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, optionally substituted heteroaryl or halogen. “Lower acyloxy” groups contain one to six carbon atoms. “Administration” as used herein is inclusive of administration by another person to the subject or self-administration by the subject. The term “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. Suitable alkoxy groups include4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy cyclopropoxy, cyclohexyloxy, and the like. The term “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. For example, a lower alkyl or (C1-C6)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl; (C3-C6)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (C3-C6)cycloalkyl(C1-C6)alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2- cyclobutylethyl, 2-cyclopentylethyl, or 2-cyclohexylethyl; (C1-C6)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (C2- C6)alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,-pentenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl; (C2- C6)alkynyl can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2- pentynyl, 3-pentynyl, 4-pentynyl, 1- hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl; (C1- C6)alkanoyl can be acetyl, propanoyl or butanoyl; halo(C1-C6)alkyl can be iodomethyl, bromomethyl, chloromethyl, fluoromethyl, trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, or pentafluoroethyl; hydroxy(C1-C6)alkyl can be hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1- hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 4-hydroxybutyl, 1- hydroxypentyl, 5-hydroxypentyl, 1-hydroxyhexyl, or 6-hydroxyhexyl; (C1-C6)alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or hexyloxycarbonyl; (C1-C6)alkylthio can be methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, or hexylthio; (C2-C6)alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy. The term “amine” or “amino” refers to a group of the formula –NRR', where R and R' can be, independently, hydrogen or an alkyl, alkenyl, alkynyl, acyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, heterocycloalkyl, or carboxyl group. For example, an “alkylamino” or “alkylated amino” refers to –NRR', wherein at least one of R or R' is an alkyl. A suitable amine or amino group is acetamido. The term "aminoalkyl" refers to alkyl groups as defined above where at least one hydrogen atom is replaced with an amino group (e.g, -CH2-NH2). “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, for example, with alkyl, aryl, acyl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkoxycarbonyl and the like. For example, an aminocarbonyl may be represented by the formula –C(O)NRR', where4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01R and R' independently can be, for example, a hydrogen, alkyl, alkenyl, alkynyl, acyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group. 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. Similarly, the term “subject” includes both human and non-human subjects, including birds and non- human mammals. Illustrative non-human mammals include animal models (such as mice), 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. The term 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). “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. “Aryloxy” or “heteroaryloxy” refers to a group of the formula –OAr, wherein Ar is an aryl group or a heteroaryl group, respectively. A “carbonylamino” group may be –N(R)-C(O)-R (wherein each R is independently H, or a substitution group such as, for example, alkyl, alkenyl, alkynyl, acyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group). A suitable carbonylamino group is acetamido. The term “carboxylate” or “carboxyl” refers to the group -COO- or -COOH. The carboxyl group can form a carboxylic acid. “Substituted carboxyl” refers to -COOR where R is alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group. For example, a substituted carboxyl group could be a carboxylic acid ester or a salt thereof (e.g., a carboxylate).4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01The term “co-administration” or “co-administering” refers to administration of a compound disclosed herein with at least one other therapeutic agent or therapy 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). Thus, co- administration may be on the same day or on different days, or in the same week or in different weeks. In some embodiments, the co-administration of two or more agents or therapies is concurrent. In other embodiments, a first agent / therapy is administered prior to a second agent / therapy. Those of skill in the art understand that the formulations and / or routes of administration of the various agents or therapies used may vary. The appropriate dosage for co-administration can be readily determined by one skilled in the art. In some embodiments, when agents or therapies are co-administered, the respective agents or therapies are administered at lower dosages than appropriate for their administration alone. Thus, co-administration is especially desirable in embodiments where the co- administration of the agents or therapies lowers the requisite dosage of a potentially harmful (e.g., toxic) agent and / or lowers the frequency of administering the potentially harmful (e.g., toxic) agent. “Co-administration” or “co-administering” encompass administration of two or more active agents to a subject so that both the active agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more active agents are present. The term "hydroxyalkyl" refers to an alkyl group that has at least one hydrogen atom substituted with a hydroxyl group. The term "alkoxyalkyl group" is defined as an alkyl group that has at least one hydrogen atom substituted with an alkoxy group described above. “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-heteroaryl” refers to mono or bicyclic aryl systems that include at least one nitrogen heteroatom 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. The term 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” refers to replacement of a hydrogen atom of a molecule or an R-group with one or more additional R-groups. Unless otherwise defined, 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. The4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01substituents may be selected, for example, from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, hydroxyl, oxo, C1-6alkoxy, aryloxy, C1-6alkoxyaryl, halo, C1-6alkylhalo (such as CF3and CHF2), C1-6alkoxyhalo (such as OCF3 and OCHF2), 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, sulfonyl, substituted sulfonyl, sulfonylamides, substituted sulfonamides, disubstituted sulfonamides, aryl, arC1-6alkyl, heterocyclyl and heteroaryl wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl and groups containing them may be further optionally substituted. Optional substituents in the case N- heterocycles may also include but are not limited to C1-6alkyl i.e. N-C1-3alkyl, more preferably methyl, particularly N-methyl. 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. Ideally, a therapeutically effective amount of an agent is an amount sufficient to inhibit or treat the disease or condition without causing a substantial cytotoxic 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. “Treatment” refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after it has begun to develop. As used herein, 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. A “prophylactic” treatment is a treatment administered 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 a pathology or condition, or diminishing the severity of a pathology or condition. “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. Such pharmaceutical 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). The terms “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,4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01malic 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. These salts may be prepared by standard procedures, for example by reacting the free acid with a suitable organic or inorganic base. 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. Pharm. Sci. 66:1 (1977). “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. Representative 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). A “pharmaceutically acceptable ester” also includes inorganic esters such as mono-, di-, or tri-phosphate esters. In such esters, unless otherwise specified, 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. Pharmaceutically acceptable 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.4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01Additional pharmaceutically acceptable esters include aliphatic L-amino acid esters such as leucyl, isoleucyl and especially valyl. For therapeutic use, salts of the compounds are those wherein the counter-ion is pharmaceutically acceptable. However, 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. hydroxybutanedioic acid), tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. Conversely said 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. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. The term “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. The term “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. Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p- toluenesulfonates. A quaternary amine has 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. 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 prodrug4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01to a subject. The term “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. F or a general discussion of prodrugs involving esters see Svensson and Tunek, Drug Metabolism Reviews 165 (1988) and Bundgaard, Design of Prodrugs, Elsevier (1985). The term “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 may include compounds having a phosphonate, hydroxy, thio and / or amino group functionalized with any group that is cleaved in vivo to yield the corresponding amino, hydroxy, thio and / or phosphonate group, respectively. Examples of prodrugs can include, without limitation, compounds having an acylated amino group and / or a phosphonate ester or phosphonate amide group. 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. In general, 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 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. Other conventional protecting groups are known and suitable protecting groups can be selected by those of skill in the art in consultation with Greene and Wuts, Protective4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01Groups in Organic Synthesis; 3rd Ed.; John Wiley & Sons, New York, 1999. When an amine is deprotected, the resulting salt can readily be neutralized to yield the free amine. Similarly, when an acid moiety, such as a phosphonic acid moiety is unveiled, the compound may be isolated as the acid compound or as a salt thereof. Particular examples of the presently disclosed compounds may include one or more asymmetric centers; thus the compounds described can exist in different stereoisomeric forms. Accordingly, compounds and compositions may be provided as individual pure enantiomers or as stereoisomeric mixtures, including racemic mixtures. In certain embodiments the compounds disclosed herein may be synthesized in or may be 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 presently disclosed compounds can have at least one asymmetric center or geometric center, cis-trans center(C=C, C=N). All chiral, diasteromeric, racemic, meso, rotational, conformational and geometric isomers of the structures are intended unless otherwise specified. The compounds can be isolated as a single isomer or as mixture of isomers by methods utilizing specific chiral resolving agents like quinine, Chiral HPLC, SFC (super critical fluid chromatography) etc. All 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,13C,18F, stable and radioisotope, etc. Overview The compounds and pharmaceutical compositions disclosed herein may be useful in treating AIDS or an HIV infection. They may be used prophylactically to prevent new HIV infections. In certain embodiments, the compounds disclosed herein exhibit high inhibitory potency against wild- type HIV-1 integrase and raltegravir (RAL)-, elvitegravir (EVG)-, dolutegravir (DTG)-, bictegravir (BIC)-, and cabotegravir (CAB)-resistant HIV-1 integrase. Certain compounds disclosed herein exhibit therapeutic selectivity indices of greater than 10,000, and more particularly greater than 25,000, based on low cytotoxicity and nanomolar efficacies. Compounds Disclosed herein are compounds having a substituted phenyl group at the 6-position of a 1- hydroxy-1,8-naphthyridin-2(1H)-one based metal chelating platform. The 6-phenyl provides access to the nucleobase that overlays planar naphthyridine platform while at the same time allowing mimicry of the uncleared vDNA binding regions. These compounds allow improved pi-pi stack with the 4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01 terminal adenine nucleobase and in so doing, enhance retention of antiviral efficacy against drug- resistant mutant form of IN. They combine different combinations of specific substituents on the 6- aryl ring, which could potentially interact with both IN catalytic pocket side and vDNA side and help them to retain antiviral potencies against a broader range of resistant IN mutants. Disclosed herein are compounds having a structure according to Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof: wherein at least one of R1-R5is an acyl, acyloxy, alkoxy, substituted alkoxy, alkyl, substituted alkyl, amino, aminocarbonyl, aryl, substituted aryl, aryloxy, substituted aryloxy, carbonylamino, carboxyl, halogen, hydroxy, sulfonyl, or substituted sulfonyl; X is a halogen; and a is 0 to 5. In certain embodiments, X is F. In certain embodiments, a is at least one. In certain embodiments, a is 2. In certain embodiments, the compound has a structure of: In certain embodiments of Formulae I and II, at least one of R1-R5is a hydroxyalkyl, a substituted acyloxyalkyl, or amino. In certain embodiments of Formulae I and II, at least one of R1-R5is a hydroxy(C1-C6)alkyl. In certain embodiments of Formulae I and II, at least one of R1-R5is a haloalkyl-substituted acyloxy(C1-C6)alkyl. In certain embodiments of Formulae I and II, at least one of R1-R5is -NH2. In certain embodiments of Formulae I and II, at least one of R1-R5is acyloxy(C1-C6)alkyl. 4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01 In certain embodiments of Formulae I and II, at least one of R1-R5is cyano(C1-C6)alkyl. In certain embodiments of Formulae I and II, at least one of R1-R5is amino(C1-C6)alkyl. In certain embodiments of Formulae I and II, at least one of R1or R3is a hydroxyalkyl or a substituted acyloxyalkyl. In certain embodiments of Formulae I and II, at least one of R1or R3is a hydroxymethyl. In certain embodiments of Formulae I and II, at least one of R1or R3is a hydroxyethyl. In certain embodiments of Formulae I and II, at least one of R1or R3is a hydroxypropyl. In certain embodiments of Formulae I and II, at least one of R1or R3is -NH2. In certain embodiments of Formulae I and II, at least one of R1or R3is a haloalkyl-substituted acyloxy(C1-C6)alkyl. In certain embodiments of Formulae I and II, at least one of R1or R3is –(CH2)x-OCO-R6, wherein x is 1 to 6, and R6is a haloalkyl. In certain embodiments, R6is a fluoroalkyl (for example, - CF3). Also disclosed herein is a compound having a structure according to Formula III, or a stereoisomer or pharmaceutically acceptable salt thereof: Formula III wherein X is a heteroaryl, substituted heteroaryl, carbobicyclyl, substituted carbobicyclyl, heterobicyclyl, substituted heterobicyclyl, heterocyclic, or substituted heterocyclic. In certain embodiments, X is a N-heteroaryl or substituted N-heteroaryl. In certain embodiments, X is naphthyl or substituted naphthyl. Also disclosed herein is a compound having a structure according to Formula IV, or V, or VI, or a stereoisomer or pharmaceutically acceptable salt thereof: 4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01 wherein R is H; X is a halogen; a is 0 to 5; Z and Y are each independently C or N; represents a cyclic structure, that may or may not be present; provided that if is not present, then at least one of Z and Y is N. In certain embodiments, is not present, Z is N, and Y is C. In certain is not present, Z is N, and Y is N. In certain embodiments, is not present, Z is C, and Y is N. Compositions and Methods of Use4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01The compounds and compositions disclosed herein may be used to inhibit both wild-type and drug-resistant HIV-1 integrase. The compounds and compositions disclosed herein may be used for treating a subject infected with AIDS or an HIV infection. In certain embodiments, the compounds and compositions disclosed herein may be used to inhibit raltegravir-resistant HIV-1 integrase in the subject. In certain embodiments, the compounds and compositions disclosed herein may overcome resistance to raltegravir and / or evitegravir. In certain embodiments, the compounds disclosed herein may be co-administered with at least one other anti-HIV or anti-AIDS therapeutic agent. Illustrative 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. Illustrative HIV protease inhibitors include amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and fosamprenavir, or a pharmaceutically acceptable salt thereof. Illustrative 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 block the virus’s ability to interact 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. Also disclosed herein is the use of a compound disclosed herein 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. Specific factors that can be taken into account include disease severity and stage, weight, diet and concurrent medications. The relationship of these factors to determining a therapeutically effective amount of the disclosed compounds is understood by those of skill in the art. Pharmaceutical 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 compositions4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01can 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. Martin, Mack Publishing Co., Easton, PA, 19th Edition (1995), describes compositions and formulations suitable for pharmaceutical delivery of the compounds herein disclosed. In general, the nature of the carrier will depend on the particular mode of administration being employed. For instance, 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. For 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. In addition to biologically-neutral carriers, pharmaceutical 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. Examples of 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 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 isonicotinic acid, and, in addition, with amino acids, for example with α-amino acids, and also with methanesulfonic acid, ethanesulfonic acid, 2-hydroxymethanesulfonic acid, ethane-1,2-disulfonic acid, benzenedisulfonic acid, 4-methylbenzenesulfonic acid, naphthalene-2- sulfonic acid, 2- or 3- phosphoglycerate, glucose-6-phosphate or N-cyclohexylsulfamic acid (with formation of the cyclamates) or with other acidic organic compounds, such as ascorbic acid. In particular, 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. Examples of salts formed from inorganic bases include salts of the presently disclosed compounds with alkali metals such as potassium and sodium, alkaline earth4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01metals, including calcium and magnesium and the like. Similarly, salts of acidic compounds with an organic base, such as an amine (as used herein terms that refer to amines should be understood to include their conjugate acids unless the context clearly indicates that the free amine is intended) are contemplated, including salts formed with basic amino acids, aliphatic amines, heterocyclic amines, aromatic amines, pyridines, guanidines and amidines. Of the aliphatic amines, the acyclic aliphatic amines, and cyclic and acyclic di- and tri- alkyl amines are particularly suitable for use in the disclosed compounds. In addition, quaternary ammonium counterions also can be used. Particular examples of suitable amine bases (and their corresponding ammonium ions) 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. For additional examples of "pharmacologically acceptable salts," see Berge et al., J. Pharm. Sci.66:1 (1977). Compounds disclosed herein can be crystallized and can be provided in a single crystalline form or as a combination of different crystal polymorphs. As such, the compounds can be provided in one or more physical form, such as different crystal forms, crystalline, liquid crystalline or non- crystalline (amorphous) forms. Such different physical forms of the compounds can be prepared using, for example different solvents or different mixtures of solvents for recrystallization. Alternatively or additionally, different polymorphs can be prepared, for example, by performing recrystallizations at different temperatures and / or by altering cooling rates during recrystallization. The presence of polymorphs can be determined by X-ray crystallography, or in some cases by another spectroscopic technique, such as solid phase NMR spectroscopy, IR spectroscopy, or by differential scanning calorimetry. The pharmaceutical compositions can be administered to subjects by a variety of mucosal administration modes, including by oral, rectal, intranasal, intrapulmonary, or transdermal delivery, or by topical delivery to other surfaces. Optionally, the compositions can be administered by non- mucosal routes, including by intramuscular, subcutaneous, intravenous, intra-arterial, intra-articular, intraperitoneal, intrathecal, intracerebroventricular, or parenteral routes. In other alternative embodiments, the compound can be administered ex vivo by direct exposure to cells, tissues or organs originating from a subject. To formulate the pharmaceutical compositions, 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. In addition, local anesthetics (for example, benzyl alcohol), isotonizing agents (for example, sodium chloride, mannitol, sorbitol), adsorption inhibitors (for4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01example, Tween 80 or Miglyol 812), solubility enhancing agents (for example, cyclodextrins and derivatives thereof), stabilizers (for example, serum albumin), and reducing agents (for example, glutathione) can be included. 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. When the composition is a liquid, the tonicity of the formulation, as measured with reference to the tonicity of 0.9% (w / v) physiological saline solution taken as unity, is typically adjusted to a value at which no substantial, irreversible tissue damage will be induced at the site of administration. Generally, 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. Often, 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. Alternatively or additionally, 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. In some circumstances, the compound is dispersed in microcapsules (microspheres) or nanocapsules (nanospheres) prepared from a suitable polymer, for example, isobutyl 2-cyanoacrylate (see, for example, Michael et al., J. Pharmacy Pharmacol.43:1-5, 1991), and dispersed in a biocompatible dispersing medium, which yields sustained delivery and biological activity over a protracted time. The 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, and4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01triethanolamine oleate. For solid compositions, conventional 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. In many cases, it will be desirable to include isotonic agents, 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. In certain embodiments, the compound can be administered in a time release formulation, for example in a composition which includes a slow release polymer. These 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. When controlled release formulations are desired, 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. A number of these are known in the art to be biodegradable and to lead to degradation products having no or low toxicity. 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). Other useful biodegradable or bioerodable polymers include, but are not limited to, such polymers as poly(epsilon-caprolactone), poly(epsilon-aprolactone-CO-lactic acid),4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01poly(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. Many methods for preparing such formulations are well known to those skilled in the art (see, for example, Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978). Other useful formulations include controlled-release microcapsules (U.S. Patent Nos.4,652,441 and 4,917,893), lactic acid-glycolic acid copolymers useful in making microcapsules and other formulations (U.S. Patent Nos.4,677,191 and 4,728,721) and sustained-release compositions for water-soluble peptides (U.S. Patent No.4,675,189). The pharmaceutical 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. Generally, 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. In the case of sterile powders, 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. In accordance with the various treatment methods of the disclosure, 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. In accordance with the disclosure herein, 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. 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. When provided therapeutically, the compound is provided at (or shortly after) the onset of a symptom of disease or infection. For prophylactic and therapeutic purposes, 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, by an hourly, daily or weekly, repeated administration protocol).4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01The 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. Using such models, only ordinary calculations and adjustments are required to determine an appropriate concentration and dose to administer a therapeutically effective amount of the compound (for example, amounts that are effective to alleviate one or more symptoms of a targeted disease). In alternative embodiments, 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)).4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01Examples General Synthetic Procedures. Proton (1H) and carbon (13C) NMR spectra were recorded on a Varian 400 MHz spectrometer or a Varian 500 MHz spectrometer and are reported in ppm relative to TMS and referenced to the solvent in which the spectra were collected. Solvent was removed by rotary evaporation under reduced pressure, and anhydrous solvents were obtained commercially and used without further drying. Purification by silica gel chromatography was performed using Combiflash with EtOAc−hexanes or DCM / MeOH solvent systems. Preparative high pressure liquid chromatography (HPLC) was conducted either using a Waters 2545 Binary Grandient Module system having Waters 2998 photodiode array detector, Waters 2707 autosampler, Waters fraction collector III and Phenomenex C18 columns (catalogue no.00G-4436-P0-AX, 250 mm × 21.2 mm 10 μm particle size, 110 Å pore) at a flow rate of 20 mL / min. Binary solvent systems consisting of A = 0.1% aqueous TFA and B = 0.1% TFA in acetonitrile were employed with gradients as indicated. Products were obtained as amorphous solids following lyophilization. Electrospray ionization-mass spectrometric (ESI-MS) were acquired with an Agilent LC / MSD system equipped with a multimode ion source or Shimadzu LC-MS 2020 ESI and APCI dual ionization-mass spectrometric (DUIS-MS) system. High resolution mass spectra (HRMS) were acquired using an Agilent 6520 Accurate-Mass Q-TOF LC / MS system. 3,4DMB3,4 3,4DMB DMB O O O N F diMeO-BnONH2(3,4DMB-ONH2), DMSO; ii) ClCOCH2CO2CH3, TEA, DCM; iii) NaOMe, MeOH; iv) 2,4-diF-BnNH2, DMF; v) TsCl, TEA, CH3CN, DCM; vi) 2,4-diMeOBnNH2(2,4DMB-NH2), TEA DIEA, DMF; vii) ArB(OH)2or ArBpin, Pd(PPh3)4, K2CO3, 1,4-Dioxane, 80 °C; viii) TFA, DCM.4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01Methyl 5-bromo-2-(N-((3,4-dimethoxybenzyl)oxy)-3-methoxy-3oxopropanamido)nicotinate (3). Ethyl 5-bromo-2-chloronicotinate (1, 3.6 g, 14.4 mmol) was mixed with O-(3,4- dimethoxybenzyl)hydroxylamine (7.90 g, 43 mmol). The mixture was flushed with Argon and protected with argon balloon. The solution was heated (105 °C, 16 h). The resultant mixture was purified by CombiFlash with a solid loading. The afforded yellow oil methyl 5-bromo-2-(((3,4- dimethoxybenzyl)oxy)amino)nicotinate (2) [ESI-MS m / z: 397.1, 399.0 (MH+), 419.0, 421.0 (MNa+)] was used in next step directly. To a solution of the yellow oil methyl 5-bromo-2-(((3,4- dimethoxybenzyl)oxy)amino)nicotinate (2) and triethylamine (8.28 mL, 59.1 mmol) in CH2Cl2(100 mL), methyl 3-chloro-3-oxopropanoate (6.54 mL, 59 mmol) was added dropwise. The mixture was stirred (rt, 1 h). The formed mixture was extracted by DCM and washed by brine. The organic phase was dried by Na2SO4. The solution was filtered and concentrated. The residue was purified by CombiFlash. Methyl 5-bromo-2-(N-((3,4-dimethoxybenzyl)oxy)-3-methoxy- 3oxopropanamido)nicotinate (3, 4 g, 56 % yield two steps from 1) was afforded as yellow oil.1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.25 (s, 1H), 6.94 (s, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 4.93 (s, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.86 (s, 3H), 3.72 (s, 3H), 3.56 (s, 2H). ESI-MS m / z: 519.0, 521.0 (MNa+) Methyl 6-bromo-1-((3,4-dimethoxybenzyl)oxy)-4-hydroxy-2-oxo-1,2-dihydro-1,8naphthyridine-3- carboxylate (4). To a solution of methyl 5-bromo-2-(N-((3,4-dimethoxybenzyl)oxy)-3-methoxy- 3oxopropanamido)nicotinate (3, 2.09 g, 4.2 mmol) in MeOH (20 mL), was added sodium methoxide (2.40 mL, 10.5 mmol) (25% in methanol) at rt. The resultant orange suspension was stirred at rt. After 1 hour, the suspension turn to white. The suspension was stirred (rt, 16 h). The reaction was brought to pH 4 by the addition of HCl (aq.2 N) at 0 °C. After 15 minutes, the formed solids were filtered and washed by water and collected. Methyl 6-bromo-1-((3,4-dimethoxybenzyl)oxy)-4-hydroxy-2- oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate (4, 1.94 g, 98 % yield) was afforded as white solid.1H NMR (400 MHz, CDCl3) δ 14.17 (s, 1H), 8.80 (d, J = 2.4 Hz, 1H), 8.56 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.18 (dd, J = 8.2, 2.0 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 5.20 (s, 2H), 4.10 (s, 3H), 3.96 (s, 3H), 3.90 (s, 3H).13C NMR (101 MHz, CDCl3) δ 172.11, 169.05, 156.14, 155.39, 149.81, 148.88, 148.12, 136.49, 126.39, 122.98, 113.97, 113.20, 110.78, 110.76, 99.57, 78.31, 55.95, 55.92, 53.53. ESI-MS m / z: 487.0, 489.0 (MNa+). 6-Bromo-N-(2,4-difluorobenzyl)-1-((3,4-dimethoxybenzyl)oxy)-4-hydroxy-2-oxo-1,2-dihydro-1,8- naphthyridine-3-carboxamide (5). Methyl 6-bromo-1-((3,4-dimethoxybenzyl)oxy)-4-hydroxy-2-oxo- 1,2-dihydro-1,8-naphthyridine-3-carboxylate (4, 1.04 g, 2.23 mmol) was mixed with (2,4- difluorophenyl)methanamine (1.33 mL, 11.2 mmol). The suspension was heated (140 °C, 2 hr). The brown solution was stirred (100 °C, 16 h). The formed brownish oil was stirred with MeOH (5 mL).4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01Suspension was formed. The mixture was filtered, and the white solid was washed by MeOH.6- Bromo-N-(2,4-difluorobenzyl)-1-((3,4-dimethoxybenzyl)oxy)-4-hydroxy-2-oxo-1,2-dihydro-1,8- naphthyridine-3-carboxamide (5, 974 mg, 76 % yield) was collected as white solid.1H NMR (400 MHz, CDCl3) δ 10.22 (t, J = 5.8 Hz, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.50 (d, J = 2.4 Hz, 1H), 7.32 (td, J = 8.4, 6.3 Hz, 1H), 7.18 (d, J = 1.9 Hz, 1H), 7.05 (dd, J = 8.2, 2.0 Hz, 1H), 6.83 – 6.75 (m, 3H), 5.12 (s, 2H), 4.59 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 3.81 (s, 3H). ESI-MS m / z: 576.0, 578.0 (MH+). 6-Bromo-3-((2,4-difluorobenzyl)carbamoyl)-1-((3,4-dimethoxybenzyl)oxy)-2-oxo-1,2dihydro-1,8- naphthyridin-4-yl 4-methylbenzenesulfonate (6).6-Bromo-N-(2,4-difluorobenzyl)-1-((3,4- dimethoxybenzyl)oxy)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (5, 0.97 g, 1.7 mmol) was dissolved in CH3CN (4.0 mL) and DCM (4 ml). Triethylamine (1.4 mL, 10 mmol) and 4- methylbenzenesulfonyl chloride (0.96 g, 5.1 mmol) were added. The brown solution was stirred (rt, 16 h). The mixture was purified by CombiFlash using solid loading.6-Bromo-3-((2,4- difluorobenzyl)carbamoyl)-1-((3,4-dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl 4-methylbenzenesulfonate (6, 0.4 g, 33 % yield) was afforded as white solid.1H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 2.3 Hz, 1H), 8.25 (t, J = 6.1 Hz, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.83 (d, J = 8.3 Hz, 2H), 7.47 (td, J = 8.5, 6.4 Hz, 1H), 7.37 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 2.0 Hz, 1H), 7.07 (dd, J = 8.2, 2.0 Hz, 1H), 6.86 – 6.78 (m, 3H), 5.18 (s, 2H), 4.52 (d, J = 5.9 Hz, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 2.48 (s, 3H). 6-Bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4-dimethoxybenzyl)oxy)-2- oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7).6-Bromo-3-((2,4-difluorobenzyl)carbamoyl)- 1-((3,4-dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro- 1,8-naphthyridin-4-yl 4-methylbenzenesulfonate (6, 400 mg, 0.55 mmol) and (2,4- dimethoxyphenyl)methanamine (0.25 ml, 1.6 mmol) were dissolved in DMF (4.0 mL). The solution was heated (50 °C, 3 h). The mixture was purified by CombiFlash.6-Bromo-N-(2,4-difluorobenzyl)- 4-((2,4-dimethoxybenzyl)amino)-1-((3,4-dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8- naphthyridine-3-carboxamide (7, 352 mg, 89 % yield) was afforded as white solid.1H NMR (400 MHz, CDCl3) δ 12.13 (t, J = 6.1 Hz, 1H), 10.70 (t, J = 5.8 Hz, 1H), 8.66 (d, J = 2.1 Hz, 1H), 8.43 (d, J = 2.2 Hz, 1H), 7.37 (td, J = 8.6, 8.0, 5.9 Hz, 1H), 7.29 (d, J = 1.9 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.15 (dd, J = 8.1, 2.0 Hz, 1H), 6.87 – 6.79 (m, 3H), 6.51 – 6.46 (m, 2H), 5.19 (s, 2H), 4.73 (d, J = 6.0 Hz, 2H), 4.61 (d, J = 5.8 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H). ESI-MS m / z: 747.1, 749.1 (MNa+). General Procedure A Preparation of compounds 9 (XZ900-XZ943) using key Suzuki coupling reactions. Compound 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4-4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7, 0.1 mmol), aryl boronic acids or aryl pinacolboranes (0.15 mmol), Pd(PPh3)4(0.01 mmol) and K2CO3(0.25 mmol) were mixed in 1,4-dioxane and water (2.5 mL, 4 / 1). The mixture was heated (80 °C, 2 hr). The reaction was cooled to rt and purified by silica gel column on CombiFlash. The fractions were collected and concentrated. The coupling products 8 were afforded and used next step directly. The compounds 8 (0.1 mmol) were dissolved in DCM (1.0 mL) and TFA (0.5 mL). The reaction mixture was stirred (rt, 1 hr). The solvent was evaporated, and the residue was purified by preparative HPLC. The products 9 (XZ900-XZ939) were afforded after HPLC purification. Synthesis of methyl 4-(5-amino-6-((2,4-difluorobenzyl)carbamoyl)-8-hydroxy-7-oxo-7,8-dihydro-1,8- naphthyridin-3-yl)benzoate (XZ900) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (4-(methoxycarbonyl)phenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 40% B to 60% B over 20 min with a flow rate 20 mL / min, retention time = 14.0 min) provided the title compound XZ900 as a white fluffy solid.1H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 10.67 (t, J = 5.9 Hz, 1H), 9.19 (d, J = 2.1 Hz, 1H), 9.13 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 8.3 Hz, 2H), 8.07 (d, J = 8.3 Hz, 2H), 7.47 (td, J = 8.7, 6.6 Hz, 1H), 7.28 (ddd, J = 10.5, 9.3, 2.6 Hz, 1H), 7.13 – 7.08 (m, 1H), 4.57 (d, J = 5.8 Hz, 2H), 3.93 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -112.01 (d, J = 6.9 Hz), -114.56 (d, J = 6.9 Hz). DUIS-MS m / z: 480.2 (MH+) / 479.0 (M-H)-. ESI-MS m / z: 481.1 (MH+). HRMS calcd. for C24H19F2N4O5(MH+), 481.1318; found, 481.1334. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-2-oxo-6-(4-(trifluoromethyl)phenyl)-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ901) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (4-(trifluoromethyl)phenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 40% B to 65% B over 20 min with a flow rate 20 mL / min, retention time = 17.6 min) provided the title compound XZ901 as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.72 (s, 1H), 10.64 (t, J = 5.9 Hz, 1H), 9.15 (d, J = 2.1 Hz, 1H), 9.10 (d, J = 2.2 Hz, 1H), 8.11 (d, J = 8.1 Hz, 2H), 7.91 (d, J = 8.2 Hz, 2H), 7.44 (td, J = 8.7, 6.6 Hz, 1H), 7.25 (ddd, J = 10.5, 9.3, 2.6 Hz, 1H), 7.08 (td, J = 8.6, 2.6 Hz, 1H), 4.53 (d, J = 5.8 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ -60.88(CF3), -112.01 (d, J = 7.0 Hz, CF), -114.56 (d, J = 7.0 Hz, CF). DUIS-MS m / z: 491.0 (MH+) / 488.9 (M-H)-. ESI-MS m / z: 491.1 (MH+). HRMS calcd. for C23H16F5N4O3 (MH+), 491.1137; found, 491.1134.4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-2-oxo-6-(3-(trifluoromethyl)phenyl)-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ902) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (3-(trifluoromethyl)phenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 40% B to 65% B over 20 min with a flow rate 20 mL / min, retention time = 17.7 min) provided the title compound XZ902 as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 10.68 (t, J = 5.8 Hz, 1H), 9.20 (d, J = 2.1 Hz, 1H), 9.10 (d, J = 2.3 Hz, 1H), 8.25 (s, 1H), 8.22 (d, J = 7.2 Hz, 1H), 7.87 – 7.78 (m, 2H), 7.47 (td, J = 8.7, 6.6 Hz, 1H), 7.28 (ddd, J = 10.6, 9.3, 2.6 Hz, 1H), 7.14 – 7.07 (m, 1H), 6.55 (s, 1H), 4.57 (d, J = 5.8 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ -60.88 (CF3), -112.01 (d, J = 6.9 Hz), -114.56 (d, J = 6.9 Hz). DUIS-MS m / z: 491.0 (MH+) / 488.9 (M-H)-. ESI-MS m / z: 491.2 (MH+). HRMS calcd. for C23H16F5N4O3 (MH+), 491.1137; found, 491.1142. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-6-(3-(hydroxymethyl)phenyl)-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ903) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (3-(hydroxymethyl)phenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 30% B to 50% B over 20 min with a flow rate 20 mL / min, retention time = 14.0 min) provided the title compound XZ903 as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.68 (t, J = 6.5 Hz, 1H), 9.05 (s, 1H), 9.00 (s, 1H), 7.79 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.50 (td, J = 7.7, 2.1 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.25 (t, J = 9.9 Hz, 1H), 7.08 (t, J = 8.7 Hz, 1H), 4.61 (d, J = 2.1 Hz, 2H), 4.54 (d, J = 5.7 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ -112.02 (d, J = 7.1 Hz), -114.56 (d, J = 7.1 Hz). DUIS- MS m / z: 453.0 (MH+) / 451.0 (M-H)-. ESI-MS m / z: 453.3 (MH+). HRMS calcd. for C23H19F2N4O4 (MH+), 453.1369; found, 453.1367. Synthesis of 6-(2-acetamidophenyl)-4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-2-oxo-1,2-dihydro- 1,8-naphthyridine-3-carboxamide (XZ904) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (2-acetamidophenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 30% B to 55% B over 20 min with a flow rate 20 mL / min, retention time = 12.1 min) provided the title compound as a white solid XZ904.1H NMR (400 MHz, DMSO-d6) δ 10.75 – 10.69 (m, 2H), 9.43 (s, 1H), 8.80 (d, J = 2.1 Hz, 1H), 8.71 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.53 – 7.43 (m, 3H), 7.36 (t, J = 7.4 Hz, 1H), 7.29 (ddd,4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01J = 10.6, 9.3, 2.6 Hz, 1H), 7.16 – 7.08 (m, 1H), 4.57 (d, J = 5.7 Hz, 2H), 1.92 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -111.97 (d, J = 6.9 Hz), -114.52 (d, J = 6.9 Hz). DUIS-MS m / z: 480 (MH+) / 478 (M-H)-. ESI-MS m / z: 480.0 (MH+). HRMS calcd. for C24H20F2N5O4 (MH+), 480.1478; found, 480.1480. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-6-(2-(hydroxymethyl)phenyl)-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ906) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (2-(hydroxymethyl)phenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 30% B to 55% B over 20 min with a flow rate 20 mL / min, retention time = 13.9 min) provided the title compound XZ906 as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.71 (t, J = 5.9 Hz, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.73 (d, J = 2.1 Hz, 1H), 7.65 (dd, J = 7.7, 1.4 Hz, 1H), 7.51 – 7.42 (m, 3H), 7.39 (dd, J = 7.5, 1.5 Hz, 1H), 7.28 (ddd, J = 11.6, 9.4, 2.6 Hz, 1H), 7.11 (td, J = 8.6, 2.6 Hz, 1H), 4.56 (d, J = 5.8 Hz, 2H), 4.50 (s, 2H).19F NMR (376 MHz, DMSO-d6) δ -112.00 (d, J = 7.1 Hz), -114.54 (d, J = 6.9 Hz). DUIS-MS m / z: 453 (MH+) / 451 (M-H)-. ESI-MS m / z: 453.1 (MH+). HRMS calcd. for C23H19F2N4O4(MH+), 453.1369; found, 453.1371. Synthesis of 2-(5-amino-6-((2,4-difluorobenzyl)carbamoyl)-8-hydroxy-7-oxo-7,8-dihydro-1,8- naphthyridin-3-yl)benzyl 2,2,2-trifluoroacetate (XZ907) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (2-(hydroxymethyl)phenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 30% B to 55% B over 20 min with a flow rate 20 mL / min, retention time = 24.1 min) provided the title compound XZ907 as a pink solid. This compound is not stable and easily decomposed to XZ906.1H NMR (500 MHz, DMSO-d6) δ 10.68 (t, J = 5.9 Hz, 1H), 8.81 – 8.72 (m, 2H), 7.68 (dd, J = 7.3, 1.8 Hz, 1H), 7.63 – 7.56 (m, 2H), 7.53 – 7.48 (m, 1H), 7.48 – 7.43 (m, 1H), 7.28 (ddd, J = 10.5, 9.3, 2.6 Hz, 1H), 7.11 (tdd, J = 8.6, 2.6, 1.0 Hz, 1H), 5.51 (s, 2H), 4.56 (d, J = 5.8 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ -74.29 (CF3), - 111.99 (d, J = 6.7 Hz), -114.54 (d, J = 6.9 Hz). DUIS-MS m / z: 549 (MH+) / 547 (M-H)-. ESI-MS m / z: 549.2 (MH+). HRMS calcd. for C25H18F5N4O5(MH+), 549.1192; found, 549.1196. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-6-(2-hydroxyphenyl)-2-oxo-1,2-dihydro-1,8- naphthyridine-3-carboxamide (XZ908) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01available (2-hydroxyphenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 30% B to 55% B over 20 min with a flow rate 20 mL / min, retention time = 15.5 min) provided the title compound XZ908 as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 10.73 (t, J = 5.8 Hz, 1H), 9.89 (s, 1H), 8.96 (d, J = 1.9 Hz, 1H), 8.83 (d, J = 2.0 Hz, 1H), 7.49 – 7.43 (m, 2H), 7.30 – 7.24 (m, 2H), 7.10 (td, J = 8.5, 2.6 Hz, 1H), 7.03 (dd, J = 8.2, 1.2 Hz, 1H), 6.98 (td, J = 7.5, 1.2 Hz, 1H), 4.56 (d, J = 5.7 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ -112.01 (d, J = 6.9 Hz), -114.55 (d, J = 6.9 Hz). DUIS-MS m / z: 439.0 (MH+) / 437.0 (M-H)-. ESI-MS m / z: 439.2 (MH+). HRMS calcd. for C22H17F2N4O4(MH+), 439.1212; found, 439.1219. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-6-(2-fluorophenyl)-1-hydroxy-2-oxo-1,2-dihydro-1,8- naphthyridine-3-carboxamide (XZ911) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (2-fluorophenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 40% B to 55% B over 20 min with a flow rate 20 mL / min, retention time = 15.1 min) provided the title compound XZ911 as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 10.69 (t, J = 5.8 Hz, 1H), 8.95 (d, J = 1.5 Hz, 2H), 7.74 (td, J = 7.8, 1.7 Hz, 1H), 7.55 (ddd, J = 7.1, 5.6, 1.8 Hz, 1H), 7.51 – 7.41 (m, 3H), 7.29 (td, J = 9.9, 2.6 Hz, 1H), 7.12 (td, J = 8.6, 2.6 Hz, 1H), 6.58 (s, 1H), 4.57 (d, J = 5.8 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ -112.00 (d, J = 6.8 Hz), -114.55 (d, J = 6.9 Hz), -118.08. DUIS-MS m / z: 441.0 (MH+) / 438.9 (M-H)-. ESI-MS m / z: 441.2 (MH+). HRMS calcd. for C22H16F3N4O3(MH+), 441.1169; found, 441.1167. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-2-oxo-6-(2-(trifluoromethyl)phenyl)-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ912) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (2-(trifluoromethyl)phenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 40% B to 55% B over 20 min with a flow rate 20 mL / min, retention time = 17.7 min) provided the title compound XZ912 as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 10.67 (t, J = 5.9 Hz, 1H), 8.76 (d, J = 2.1 Hz, 1H), 8.71 (d, J = 1.9 Hz, 1H), 7.96 (dd, J = 8.1, 1.2 Hz, 1H), 7.86 (t, J = 7.5 Hz, 1H), 7.75 (t, J = 7.7 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.47 (td, J = 8.7, 6.6 Hz, 1H), 7.28 (ddd, J = 11.9, 9.5, 2.6 Hz, 1H), 7.11 (td, J = 8.6, 2.6 Hz, 1H), 4.57 (d, J = 5.7 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ -55.40 (CF3), -112.00 (d, J = 6.8 Hz), -114.54 (d, J = 7.2 Hz). DUIS-MS m / z: 491.1 (MH+) / 489.0 (M-H)-. ESI-MS m / z: 491.2 (MH+). HRMS calcd. for C23H16F5N4O3 (MH+), 491.1137; found, 491.1141.4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-6-(4-(2-hydroxyethyl)phenyl)-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ913) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (4-(2-hydroxyethyl)phenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 30% B to 45% B over 20 min with a flow rate 20 mL / min, retention time = 16.3 min) provided the title compound XZ913 as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.71 (t, J = 5.8 Hz, 1H), 9.09 (d, J = 2.1 Hz, 1H), 9.01 (d, J = 2.3 Hz, 1H), 7.83 – 7.79 (m, 2H), 7.47 (td, J = 8.7, 6.7 Hz, 1H), 7.41 (d, J = 8.3 Hz, 2H), 7.28 (ddd, J = 10.5, 9.3, 2.6 Hz, 1H), 7.13 – 7.08 (m, 1H), 4.56 (d, J = 5.7 Hz, 2H), 3.68 (t, J = 7.0 Hz, 2H), 2.82 (t, J = 7.0 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ -112.02 (d, J = 6.9 Hz), -114.56 (d, J = 6.9 Hz). DUIS-MS m / z: 467.0 (MH+) / 465.0 (M-H)-. ESI-MS m / z: 467.1 (MH+). HRMS calcd. for C24H21F2N4O4 (MH+), 467.1525; found, 465.1527. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-6-(3-(2-hydroxyethyl)phenyl)-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ914) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (3-(2-hydroxyethyl)phenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 30% B to 45% B over 20 min with a flow rate 20 mL / min, retention time = 17.5 min) provided the title compound XZ914 as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.69 (t, J = 5.8 Hz, 1H), 9.07 (d, J = 2.0 Hz, 1H), 8.98 (d, J = 2.2 Hz, 1H), 7.72 – 7.67 (m, 2H), 7.45 (tt, J = 8.6, 4.5 Hz, 2H), 7.32 – 7.27 (m, 1H), 7.26 – 7.22 (m, 1H), 7.09 (td, J = 8.6, 2.6 Hz, 1H), 4.55 (d, J = 5.7 Hz, 2H), 3.70 (t, J = 7.1 Hz, 2H), 2.84 (t, J = 7.1 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ -112.02 (d, J = 7.2 Hz), -114.56 (d, J = 7.2 Hz). DUIS- MS m / z: 467.1 (MH+) / 465.0 (M-H)-. ESI-MS m / z: 467.2 (MH+). HRMS calcd. for C24H21F2N4O4 (MH+), 467.1525; found, 467.1527. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-6-(2-(2-hydroxyethyl)phenyl)-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ915) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (2-(2-hydroxyethyl)phenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 30% B to 45% B over 20 min with a flow rate 20 mL / min, retention time = 17.7 min) provided the title compound XZ915 as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.68 (t, J = 5.9 Hz, 1H), 8.73 (d, J = 1.9 Hz, 1H), 8.71 (d, J4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01= 2.2 Hz, 1H), 7.55 (td, J = 7.5, 2.9 Hz, 2H), 7.43 (td, J = 13.3, 11.8, 7.9 Hz, 3H), 7.34 (t, J = 7.3 Hz, 1H), 7.30 (d, J = 7.4 Hz, 1H), 7.25 (td, J = 9.9, 2.6 Hz, 1H), 7.08 (td, J = 8.6, 2.6 Hz, 1H), 4.53 (d, J = 5.7 Hz, 2H), 3.46 (t, J = 7.3 Hz, 2H), 2.73 (t, J = 7.3 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ - 112.01 (d, J = 6.9 Hz), -114.54 (d, J = 7.1 Hz). DUIS-MS m / z: 467.0 (MH+) / 464.9 (M-H)-. ESI-MS m / z: 467.0 (MH+). HRMS calcd. for C24H19F2N4O5 (MH+), 467.1525; found, 467.1531. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-6-(4-(3-hydroxypropyl)phenyl)-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ916) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (4-(3-hydroxypropyl)phenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 30% B to 50% B over 20 min with a flow rate 20 mL / min, retention time = 16.9 min) provided the title compound XZ916 as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.71 (t, J = 5.8 Hz, 1H), 10.69 (brs, 1H), 9.09 (d, J = 2.1 Hz, 1H), 9.01 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 8.1 Hz, 2H), 7.67 – 7.55 (m, 2H), 7.57-7.44 (m, 1H), 7.40 (d, J = 7.9 Hz, 2H), 7.32 – 7.24 (m, 1H), 7.11 (td, J = 8.6, 2.6 Hz, 1H), 4.56 (d, J = 5.9 Hz, 2H), 3.47 (t, J = 6.4 Hz, 2H), 2.74 – 2.69 (m, 2H), 1.82 – 1.75 (m, 2H).19F NMR (376 MHz, DMSO- d6) δ -112.02 (d, J = 6.9 Hz), -114.56 (d, J = 6.9 Hz). DUIS-MS m / z: 481.1 (MH+) / 479.0 (M-H)-. ESI-MS m / z: 481.1 (MH+). HRMS calcd. for C25H23F2N4O4 (MH+), 481.1682; found, 481.1684. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-6-(3-(3-hydroxypropyl)phenyl)-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ917) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (3-(3-hydroxypropyl)phenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 35% B to 45% B over 20 min with a flow rate 20 mL / min, retention time = 16.6 min) provided the title compound XZ917 as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.71 (t, J = 5.9 Hz, 1H), 9.10 (d, J = 2.0 Hz, 1H), 9.00 (d, J = 2.2 Hz, 1H), 7.73 – 7.67 (m, 2H), 7.50 – 7.44 (m, 2H), 7.33 – 7.25 (m, 2H), 7.11 (td, J = 8.5, 2.6 Hz, 1H), 4.57 (d, J = 5.7 Hz, 2H), 3.49 (t, J = 6.4 Hz, 2H), 2.75 (dd, J = 9.0, 6.6 Hz, 2H), 1.89 – 1.78 (m, 2H).19F NMR (376 MHz, DMSO-d6) δ -112.02 (d, J = 6.9 Hz), -114.56 (d, J = 7.0 Hz). DUIS-MS m / z: 481.0 (MH+) / 479.1 (M-H)-. ESI-MS m / z: 481.2 (MH+). HRMS calcd. for C25H23F2N4O4 (MH+), 481.1682; found, 481.1685. Synthesis of 4-amino-6-(2-aminophenyl)-N-(2,4-difluorobenzyl)-1-hydroxy-2-oxo-1,2-dihydro-1,8- naphthyridine-3-carboxamide (XZ918)4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (2-aminophenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 20% B to 55% B over 20 min with a flow rate 20 mL / min, retention time = 14.8 min) provided the title compound XZ918 as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 10.72 (t, J = 5.8 Hz, 1H), 8.78 – 8.72 (m, 2H), 7.47 (td, J = 8.7, 6.6 Hz, 1H), 7.28 (td, J = 9.9, 2.6 Hz, 1H), 7.17 (td, J = 7.7, 1.6 Hz, 1H), 7.14 – 7.08 (m, 2H), 6.86 (d, J = 8.0 Hz, 1H), 6.75 (t, J = 7.4 Hz, 1H), 4.56 (d, J = 5.7 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ -111.99 (d, J = 7.3 Hz), -114.53 (d, J = 7.3 Hz). DUIS-MS m / z: 438.4 (MH+) / 436.0 (M-H)-. ESI-MS m / z: 438.1 (MH+). HRMS calcd. for C22H18F2N5O3(MH+), 438.1372; found, 438.1371. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-6-(2-(methylcarbamoyl)phenyl)-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ919) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (2-(methylcarbamoyl)phenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 30% B to 45% B over 20 min with a flow rate 20 mL / min, retention time = 12.9 min) provided the title compound XZ919 as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.71 (d, J = 6.0 Hz, 1H), 8.77 (d, J = 2.1 Hz, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.29 (q, J = 4.6 Hz, 1H), 7.65 – 7.60 (m, 1H), 7.60 – 7.56 (m, 2H), 7.54 (q, J = 6.9 Hz, 1H), 7.47 (td, J = 8.6, 6.6 Hz, 1H), 7.28 (ddd, J = 11.6, 9.6, 2.5 Hz, 1H), 7.11 (td, J = 8.5, 2.5 Hz, 1H), 6.57 (s, 1H), 4.56 (d, J = 5.8 Hz, 2H), 2.65 (d, J = 4.5 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -112.00 (d, J = 7.2 Hz), -114.54 (d, J = 6.9 Hz). DUIS-MS m / z: 480.1 (MH+) / 478.0 (M-H)-. ESI-MS m / z: 480.2 (MH+). HRMS calcd. for C24H20F2N5O4(MH+), 480.1478; found, 480.1484. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-6-(3-hydroxyphenyl)-2-oxo-1,2-dihydro-1,8- naphthyridine-3-carboxamide (XZ920) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (3-hydroxyphenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 30% B to 55% B over 20 min with a flow rate 20 mL / min, retention time = 15.1 min) provided the title compound XZ920 as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 10.70 (t, J = 5.8 Hz, 1H), 9.69 (s, 1H), 9.03 (d, J = 2.0 Hz, 1H), 8.98 (d, J = 2.2 Hz, 1H), 7.47 (td, J = 8.6, 6.6 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 2.1 Hz, 1H), 7.28 (d, J = 3.4 Hz, 1H), 7.25 (dt, J = 4.1, 2.3 Hz, 1H), 7.11 (td, J = 8.6, 2.6 Hz, 1H), 6.884239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01(dd, J = 8.0, 2.3 Hz, 1H), 4.56 (d, J = 5.7 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ -112.02 (d, J = 6.9 Hz), -114.56 (d, J = 6.9 Hz). DUIS-MS m / z: 439.0 (MH+) / 437.0 (M-H)-. ESI-MS m / z: 439.2 (MH+). HRMS calcd. for C22H17F2N4O4 (MH+), 439.1212; found, 439.1212. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-6-(4-hydroxyphenyl)-2-oxo-1,2-dihydro-1,8- naphthyridine-3-carboxamide (XZ921) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (4-hydroxyphenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 30% B to 50% B over 20 min with a flow rate 20 mL / min, retention time = 15.5 min) provided the title compound as XZ921 a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 10.73 (t, J = 5.8 Hz, 1H), 10.66 (brs, 1H), 9.75 (brs, 1H), 9.02 (d, J = 2.0 Hz, 1H), 8.93 (d, J = 2.2 Hz, 1H), 7.72 (d, J = 8.7 Hz, 2H), 7.46 (td, J = 8.6, 6.6 Hz, 1H), 7.28 (ddd, J = 10.5, 9.4, 2.6 Hz, 1H), 7.11 (td, J = 8.6, 2.6 Hz, 1H), 6.94 (d, J = 8.6 Hz, 2H), 4.56 (d, J = 5.7 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ -112.03 (d, J = 6.9 Hz), -114.57 (d, J = 7.3 Hz). DUIS-MS m / z: 439.0 (MH+) / 437.0 (M-H)-. ESI-MS m / z: 439.2 (MH+). HRMS calcd. for C22H17F2N4O4(MH+), 439.1212; found, 439.1213. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-6-(4-(hydroxymethyl)phenyl)-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ922) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7), and commercially available (4-(hydroxymethyl)phenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 30% B to 55% B over 20 min with a flow rate 20 mL / min, retention time = 12.9 min) provided the title compound XZ922 as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.71 (t, J = 5.9 Hz, 2H), 9.11 (d, J = 2.0 Hz, 1H), 9.03 (d, J = 2.2 Hz, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.47 (td, J = 8.7, 6.6 Hz, 1H), 7.28 (td, J = 9.9, 2.6 Hz, 1H), 7.11 (td, J = 8.5, 2.6 Hz, 1H), 4.60 (s, 2H), 4.57 (d, J = 5.8 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ -112.02 (d, J = 6.8 Hz), -114.56 (d, J = 7.3 Hz). DUIS-MS m / z: 453.0 (MH+) / 451.0 (M-H)-. ESI-MS m / z: 453.1 (MH+). HRMS calcd. for C23H19F2N4O4(MH+), 453.1369; found, 453.1376. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-2-oxo-6-phenyl-1,2-dihydro-1,8- naphthyridine-3-carboxamide (XZ923) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available phenylboronic acid as outlined in general procedure A and purification by preparative HPLC4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01(CAT# 00G-4436-P0-AX) (linear gradient of 40% B to 60% B over 20 min with a flow rate 20 mL / min, retention time = 13.7 min) provided the title compound XZ923 as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.70 (t, J = 5.8 Hz, 2H), 9.11 (d, J = 2.0 Hz, 1H), 9.04 (d, J = 2.2 Hz, 1H), 7.93 – 7.87 (m, 2H), 7.58 (t, J = 7.7 Hz, 2H), 7.51 – 7.43 (m, 2H), 7.28 (ddd, J = 10.5, 9.3, 2.6 Hz, 1H), 7.11 (td, J = 8.6, 2.6 Hz, 1H), 4.57 (d, J = 5.7 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ - 112.02 (d, J = 7.4 Hz), -114.56 (d, J = 6.9 Hz). ESI-MS m / z: 423.3 (MH+). HRMS calcd. for C22H17F2N4O3 (MH+), 423.1263; found, 423.1260. Synthesis of 2-(5-amino-6-((2,4-difluorobenzyl)carbamoyl)-8-hydroxy-7-oxo-7,8-dihydro-1,8- naphthyridin-3-yl)phenyl sulfurofluoridate (XZ924) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (2-hydroxylphenyl)boronic acid as outlined in general procedure A afforded the intermediate N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4-dimethoxybenzyl)oxy)- 6-(2-hydroxyphenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide. The intermediate was mixed with 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate (FDIT) and triethylamine in acetonitrile (1 hr, rt) and afforded colorless oil 2-(6-((2,4- difluorobenzyl)carbamoyl)-5-((2,4-dimethoxybenzyl)amino)-8-((3,4-dimethoxybenzyl)oxy)-7-oxo- 7,8-dihydro-1,8-naphthyridin-3-yl)phenyl sulfurofluoridate [49 % yield, DUIS-MS: 821.20 (MH+)]. This oil was deprotected by TFA in DCM and purification by preparative HPLC (CAT# 00G-4436- P0-AX) (linear gradient of 45% B to 80% B over 20 min with a flow rate 20 mL / min, retention time = 11.5 min) provided the title compound XZ924 as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 10.65 (t, J = 5.9 Hz, 1H), 8.96 (d, J = 2.1 Hz, 1H), 8.92 (d, J = 2.0 Hz, 1H), 7.88 – 7.80 (m, 2H), 7.78 – 7.69 (m, 2H), 7.47 (td, J = 8.7, 6.6 Hz, 1H), 7.28 (ddd, J = 10.5, 9.3, 2.6 Hz, 1H), 7.14 – 7.07 (m, 1H), 4.57 (d, J = 5.7 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ -112.02 (d, J = 7.3 Hz), - 114.56 (d, J = 7.1 Hz). DUIS-MS m / z: 521.10 (MH+) / 519.00 (M-H)-. ESI-MS m / z: 521.2 (MH+). HRMS calcd. for C22H16F3N4O6S (MH+), 521.0737; found, 521.0741. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-6-(2-hydroxynaphthalen-1-yl)-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ925) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (2-hydroxynaphthalen-1-yl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 30% B to 80% B over 20 min with a flow rate 20 mL / min, retention time = 14.4 min) provided the title compound XZ925 as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 10.75 (t, J = 5.9 Hz, 1H), 10.71 (brs, 1H), 9.86 (s, 1H), 8.77 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 1.9 Hz, 1H), 7.92 (dd, J = 8.6, 6.1 Hz, 2H), 7.48 (td, J =4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-018.6, 6.5 Hz, 1H), 7.43 – 7.34 (m, 4H), 7.29 (td, J = 9.9, 2.6 Hz, 1H), 7.12 (td, J = 8.5, 2.6 Hz, 1H), 4.57 (d, J = 5.7 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ -112.00 (d, J = 6.9 Hz), -114.52 (d, J = 7.0 Hz). ESI-MS m / z: 489.2 (MH+), 977.3 (M2H+). ESI-MS m / z: 489.2 (MH+). HRMS calcd. for C26H19F2N4O4 (MH+), 489.1369; found, 489.1368. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-6-(2-methoxyphenyl)-2-oxo-1,2-dihydro-1,8- naphthyridine-3-carboxamide (XZ926) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (2-methoxyphenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 40% B to 55% B over 20 min with a flow rate 20 mL / min, retention time = 15.6 min) provided the title compound XZ926 as a cotton like white solid.1H NMR (500 MHz, DMSO-d6) δ 10.72 (t, J = 5.8 Hz, 1H), 10.67 (brs, 1H), 8.89 (d, J = 1.9 Hz, 1H), 8.81 (d, J = 2.1 Hz, 1H), 7.51 – 7.44 (m, 3H), 7.28 (td, J = 9.9, 2.6 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 7.17 – 7.12 (m, 1H), 7.10 (dd, J = 8.7, 2.6 Hz, 1H), 4.56 (d, J = 5.7 Hz, 2H), 3.84 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -112.02 (d, J = 7.3 Hz), -114.55 (d, J = 7.3 Hz). DUIS-MS m / z: 453.1 (MH+) / 451.0 (M-H)-. ESI-MS m / z: 453.2 (MH+). HRMS calcd. for C23H19F2N4O4(MH+), 453.1369; found, 453.1371. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-6-(2-(methoxymethyl)phenyl)-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ927) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (2-(methoxymethyl)phenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 40% B to 55% B over 20 min with a flow rate 20 mL / min, retention time = 14.0 min) provided the title compound XZ927 as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.70 (t, J = 5.9 Hz, 1H), 8.76 (dd, J = 13.1, 2.0 Hz, 2H), 7.59 (dd, J = 5.6, 3.5 Hz, 1H), 7.52 – 7.48 (m, 2H), 7.48 – 7.43 (m, 2H), 7.28 (ddd, J = 10.5, 9.3, 2.6 Hz, 1H), 7.11 (td, J = 8.6, 2.6 Hz, 1H), 4.56 (d, J = 5.7 Hz, 2H), 4.39 (s, 2H), 3.24 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -112.00 (d, J = 6.9 Hz), -114.54 (d, J = 6.9 Hz). DUIS-MS m / z: 467.1 (MH+) / 465.0 (M-H)-. ESI-MS m / z: 467.1 (MH+). HRMS calcd. for C24H21F2N4O4(MH+), 467.1525; found, 467.1524. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-2-oxo-6-(2-phenoxyphenyl)-1,2-dihydro-1,8- naphthyridine-3-carboxamide (XZ928) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01available (2-phenoxyphenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 40% B to 80% B over 20 min with a flow rate 20 mL / min, retention time = 16.3 min) provided the title compound XZ928 as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.67 (t, J = 5.9 Hz, 1H), 8.91 (q, J = 2.1 Hz, 2H), 7.70 (dd, J = 7.6, 1.7 Hz, 1H), 7.51 (td, J = 7.8, 1.7 Hz, 1H), 7.45 (td, J = 8.7, 6.6 Hz, 1H), 7.40 (td, J = 7.6, 1.2 Hz, 1H), 7.34 (dd, J = 8.6, 7.3 Hz, 2H), 7.27 (ddd, J = 10.5, 9.3, 2.6 Hz, 1H), 7.13 – 7.06 (m, 3H), 6.96 (dd, J = 8.7, 1.1 Hz, 2H), 4.55 (d, J = 5.7 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ -112.02 (d, J = 6.9 Hz), -114.56 (d, J = 7.3 Hz). ESI-MS m / z: 515.2 (MH+). HRMS calcd. for C28H21F2N4O4(MH+), 515.1525; found, 515.1519. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-6-(3-hydroxynaphthalen-2-yl)-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ929) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (3-hydroxynaphthalen-2-yl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 30% B to 80% B over 20 min with a flow rate 20 mL / min, retention time = 15.7 min) provided the title compound XZ929 as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 10.73 (t, J = 5.9 Hz, 1H), 10.28 (s, 1H), 9.04 (d, J = 1.9 Hz, 1H), 8.97 (d, J = 2.1 Hz, 1H), 8.02 (s, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.51 – 7.45 (m, 2H), 7.38 – 7.34 (m, 2H), 7.29 (ddd, J = 10.5, 9.3, 2.6 Hz, 1H), 7.14 – 7.09 (m, 1H), 4.57 (d, J = 5.7 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ -112.01 (d, J = 7.3 Hz), -114.54 (d, J = 7.0 Hz). DUIS-MS m / z: 489.0 (MH+), 977.13 (M2H+) / 487.0 (M-H)-, 975.1 (M2-H)-. ESI-MS m / z: 489.1 (MH+). HRMS calcd. for C26H19F2N4O4(MH+), 489.1369; found, 489.1365. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-6-(6-hydroxynaphthalen-2-yl)-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ930) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (6-hydroxynaphthalen-2-yl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 30% B to 80% B over 20 min with a flow rate 20 mL / min, retention time = 14.5 min) provided the title compound XZ930 as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.73 (t, J = 5.9 Hz, 1H), 10.71 (brs, 1H), 9.93 (s, 1H), 9.21 (d, J = 2.1 Hz, 1H), 9.11 (d, J = 2.1 Hz, 1H), 8.37 – 8.23 (m, 1H), 7.99 – 7.90 (m, 2H), 7.90 – 7.84 (m, 1H), 7.48 (td, J = 8.7, 6.6 Hz, 1H), 7.28 (ddd, J = 10.5, 9.3, 2.6 Hz, 1H), 7.22 – 7.16 (m, 2H), 7.11 (ddd, J = 10.9, 8.1, 2.5 Hz, 1H), 6.56 (s, 2H), 4.57 (d, J = 5.8 Hz, 2H).19F NMR (376 MHz, DMSO- d6) δ -112.02 (d, J = 6.9 Hz), -114.56 (d, J = 6.9 Hz). ESI-MS m / z: 489.0 (MH+) / 487.0 (M-H)-. ESI- MS m / z: 489.2 (MH+). HRMS calcd. for C26H19F2N4O4 (MH+), 489.1369; found, 489.1370.4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01Synthesis of 4-amino-6-(4-aminophenyl)-N-(2,4-difluorobenzyl)-1-hydroxy-2-oxo-1,2-dihydro-1,8- naphthyridine-3-carboxamide (XZ931) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (4-aminophenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 20% B to 40% B over 20 min with a flow rate 20 mL / min, retention time = 14.2 min) provided the title compound XZ931 as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.74 (t, J = 5.8 Hz, 1H), 9.00 (d, J = 2.1 Hz, 1H), 8.87 (d, J = 2.2 Hz, 1H), 7.65 – 7.60 (m, 2H), 7.46 (td, J = 8.7, 6.6 Hz, 1H), 7.27 (ddd, J = 10.6, 9.3, 2.6 Hz, 1H), 7.14 – 7.07 (m, 1H), 6.80 (d, J = 8.2 Hz, 2H), 4.56 (d, J = 5.8 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ -112.04 (d, J = 6.9 Hz), -114.57 (d, J = 6.8 Hz). ESI-MS m / z: 438.1 (MH+). HRMS calcd. for C22H18F2N5O3 (MH+), 438.1372; found, 438.1372. Synthesis of 6-(4-acetamidophenyl)-4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-2-oxo-1,2-dihydro- 1,8-naphthyridine-3-carboxamide (XZ932) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (4-aminophenyl)boronic acid as outlined in general procedure A and the afforded amine was dissolved DCM with pyridine and acetic anhydride, the formed acetamide was deprotected by TFA and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 30% B to 45% B over 20 min with a flow rate 20 mL / min, retention time = 16.5 min) provided the title compound XZ932 as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 10.71 (t, J = 5.8 Hz, 1H), 10.68 (s, 1H), 10.13 (s, 1H), 9.08 (d, J = 2.1 Hz, 1H), 8.99 (d, J = 2.2 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.47 (td, J = 8.7, 6.6 Hz, 1H), 7.32 – 7.20 (m, 1H), 7.11 (td, J = 8.6, 2.6 Hz, 1H), 4.56 (d, J = 5.7 Hz, 2H), 2.11 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -112.03 (d, J = 7.0 Hz), -114.57 (d, J = 6.9 Hz). ESI-MS m / z: 480.3 (MH+). HRMS calcd. for C24H20F2N5O4 (MH+), 480.1478; found, 480.1486. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-6-(4-(methylcarbamoyl)phenyl)-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ933) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (4-(methylcarbamoyl)phenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 20% B to 60% B over 20 min with a flow rate 20 mL / min, retention time = 15.5 min) provided the title compound XZ933 as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.74 (brs, 1H), 10.68 (t, J = 5.8 Hz, 1H), 9.18 (d, J =4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-012.0 Hz, 1H), 9.10 (d, J = 2.2 Hz, 1H), 8.58 (q, J = 4.5 Hz, 1H), 8.10 – 7.98 (m, 5H), 7.47 (td, J = 8.6, 6.6 Hz, 1H), 7.28 (ddd, J = 11.5, 9.4, 2.6 Hz, 1H), 7.11 (td, J = 8.6, 2.5 Hz, 1H), 4.57 (d, J = 5.7 Hz, 2H), 2.85 (d, J = 4.4 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -112.01 (d, J = 6.9 Hz), -114.56 (d, J = 6.9 Hz). ESI-MS m / z: 480.2 (MH+). HRMS calcd. for C24H20F2N5O4 (MH+), 480.1478; found, 480.1481. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-6-(4-(4-hydroxybutyl)phenyl)-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ935) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butan-1-ol as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 30% B to 50% B over 20 min with a flow rate 20 mL / min, retention time = 19.9 min) provided the title compound XZ935 as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.69 (t, J = 5.8 Hz, 1H), 10.66 (brs, 1H), 9.07 (d, J = 2.1 Hz, 1H), 8.98 (d, J = 2.2 Hz, 1H), 7.79 (d, J = 7.9 Hz, 2H), 7.45 (td, J = 8.7, 6.6 Hz, 1H), 7.37 (d, J = 7.9 Hz, 2H), 7.26 (ddd, J = 10.5, 9.3, 2.6 Hz, 1H), 7.09 (td, J = 8.7, 2.7 Hz, 1H), 6.53 (s, 1H), 4.54 (d, J = 5.8 Hz, 2H), 4.39 (t, J = 5.2 Hz, 1H), 3.43 (q, J = 6.2 Hz, 2H), 2.66 (t, J = 7.6 Hz, 3H), 1.65 (p, J = 7.6 Hz, 2H), 1.47 (p, J = 6.6 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ - 112.03 (d, J = 6.9 Hz), -114.56 (d, J = 7.3 Hz). DUIS-MS m / z: 495.1 (MH+). ESI-MS m / z: 495.3 (MH+). HRMS calcd. for C26H25F2N4O4 (MH+), 495.1838; found, 495.1840. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-6-(4-morpholinophenyl)-2-oxo-1,2-dihydro- 1,8-naphthyridine-3-carboxamide (XZ936) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (4-morpholinophenyl) boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 35% B to 50% B over 20 min with a flow rate 20 mL / min, retention time = 15.2 min) provided the title compound +++ as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 10.73 (t, J = 5.8 Hz, 1H), 9.06 (d, J = 2.1 Hz, 1H), 8.95 (d, J = 2.2 Hz, 1H), 7.79 (d, J = 8.9 Hz, 2H), 7.46 (td, J = 8.7, 6.6 Hz, 1H), 7.28 (ddd, J = 10.5, 9.3, 2.6 Hz, 1H), 7.15 – 7.07 (m, 3H), 4.56 (d, J = 5.8 Hz, 2H), 3.80 (dd, J = 6.1, 3.6 Hz, 4H), 3.28 – 3.17 (m, 4H).19F NMR (376 MHz, DMSO-d6) δ -112.03 (d, J = 7.3 Hz), -114.56 (d, J = 7.2 Hz). DUIS-MS m / z: 508.2 (MH+). ESI-MS m / z: 508.3 (MH+). HRMS calcd. for C26H23F2N5O4 (MH+), 508.1791; found, 508.1788. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-6-(2-(methylcarbamoyl)phenyl)-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ937)4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (2-(methylcarbamoyl)phenyl) boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 20% B to 60% B over 20 min with a flow rate 20 mL / min, retention time = 15.5 min) provided the title compound XZ937 as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.70 (t, J = 5.8 Hz, 2H), 8.77 (d, J = 2.2 Hz, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.28 (q, J = 4.5 Hz, 1H), 7.66 – 7.60 (m, 1H), 7.57 (dd, J = 7.7, 2.2 Hz, 2H), 7.56 – 7.51 (m, 1H), 7.47 (td, J = 8.7, 6.6 Hz, 1H), 7.28 (ddd, J = 10.4, 9.3, 2.6 Hz, 1H), 7.11 (td, J = 8.6, 2.6 Hz, 1H), 4.57 (d, J = 5.7 Hz, 2H), 2.65 (d, J = 4.6 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -112.00 (d, J = 6.9 Hz), -114.54 (d, J = 7.3 Hz). ESI-MS m / z: 480.1 (MH+), 959.3 (M2H+) / 478.0 (M- H)-. ESI-MS m / z: 480.2 (MH+). HRMS calcd. for C24H20F2N5O4 (MH+), 480.1478; found, 480.1477. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-6-(2-fluoro-6-hydroxyphenyl)-1-hydroxy-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ938) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 30% B to 55% B over 20 min with a flow rate 20 mL / min, retention time = 17.7 min) provided the title compound XZ938 as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.70 (t, J = 5.9 Hz, 2H), 10.26 (d, J = 1.7 Hz, 1H), 8.77 (dd, J = 25.1, 1.9 Hz, 2H), 7.47 (td, J = 8.7, 6.6 Hz, 1H), 7.34 – 7.25 (m, 2H), 7.11 (td, J = 8.5, 2.6 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.84 (t, J = 8.9 Hz, 1H), 4.56 (d, J = 5.7 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ -112.00 (d, J = 7.2 Hz), -114.54 (d, J = 6.9 Hz), -116.19. DUIS-MS m / z: 457.0 (MH+), 913.1 (M2H+) / 454.9 (M-H)-, 911.0 (M2-H)-. ESI-MS m / z: 457.2 (MH+). HRMS calcd. for C22H16F3N4O4(MH+), 457.1118; found, 457.1124. Synthesis of 4-acetamido-2-(5-amino-6-((2,4-difluorobenzyl)carbamoyl)-8-hydroxy-7-oxo-7,8- dihydro-1,8-naphthyridin-3-yl)benzyl acetate (XZ939) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (5-amino-2-(hydroxymethyl)phenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 30% B to 55% B over 20 min with a flow rate 20 mL / min, retention time = 14.3 min) provided the title compound XZ939 as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 10.69 (t, J = 5.9 Hz, 1H), 10.18 (s, 1H), 8.73 (q, J = 2.1 Hz, 2H), 7.70 (dd, J = 8.4, 2.2 Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.47 (td, J = 8.7, 6.6 Hz, 1H), 7.28 (ddd, J = 10.6, 9.3, 2.6 Hz, 1H), 7.15 – 7.07 (m, 1H), 4.97 (s, 2H), 4.56 (d, J = 5.8 Hz, 2H), 2.09 (s, 3H), 1.96 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -112.004239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01(d, J = 7.3 Hz), -114.54 (d, J = 6.9 Hz). ESI-MS m / z: 552.1 (MH+), 1103.3 (M2H+) / 550.0 (M-H)-. ESI-MS m / z: 552.3 (MH+). HRMS calcd. for C27H24F2N5O6(MH+), 552.1689; found, 552.1687. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-6-(4-(dimethylamino)phenyl)-1-hydroxy-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ940) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (4-(dimethylamino)phenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 20% B to 50% B over 20 min with a flow rate 20 mL / min, retention time = 14.7 min) provided the title compound XZ940 as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.74 (t, J = 5.8 Hz, 1H), 10.63 (brs, 1H), 9.03 (d, J = 2.1 Hz, 1H), 8.91 (d, J = 2.2 Hz, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.47 (td, J = 8.7, 6.6 Hz, 1H), 7.28 (ddd, J = 10.6, 9.3, 2.6 Hz, 1H), 7.14 – 7.07 (m, 1H), 6.89 (d, J = 8.9 Hz, 2H), 4.56 (d, J = 5.7 Hz, 2H), 3.00 (s, 6H).19F NMR (376 MHz, DMSO-d6) δ -112.04 (d, J = 7.3 Hz), -114.57 (d, J = 6.8 Hz). DUIS-MS m / z: 466.1 (MH+) / 464.0 (M-H)-. ESI-MS m / z: 466.1 (MH+). HRMS calcd. for C24H22F2N5O3(MH+), 466.1685; found, 466.1690. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-6-(4-(methylamino)phenyl)-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ941) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 20% B to 40% B over 20 min with a flow rate 20 mL / min, retention time = 15.6 min) provided the title compound XZ941 as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 10.75 (t, J = 5.9 Hz, 1H), 9.00 (d, J = 2.1 Hz, 1H), 8.88 (d, J = 2.2 Hz, 1H), 7.69 – 7.64 (m, 2H), 7.50 – 7.39 (m, 1H), 7.28 (td, J = 9.9, 2.6 Hz, 1H), 7.11 (td, J = 8.5, 2.6 Hz, 1H), 6.72 (d, J = 8.3 Hz, 2H), 4.56 (d, J = 5.7 Hz, 2H), 2.77 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -112.04 (d, J = 6.9 Hz), -114.57 (d, J = 7.2 Hz). DUIS-MS m / z: 452.1 (MH+). ESI-MS m / z: 452.2 (MH+). HRMS calcd. for C23H20F2N5O3 (MH+), 452.1529; found, 452.1532. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-6-(2-(dimethylamino)phenyl)-1-hydroxy-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ942) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available (2-(dimethylamino)phenyl)boronic acid as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 20% B to 50% B over 20 min4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01with a flow rate 20 mL / min, retention time = 14.4 min) provided the title compound XZ942 as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.71 (t, J = 5.8 Hz, 1H), 8.95 (d, J = 1.9 Hz, 1H), 8.83 (d, J = 2.1 Hz, 1H), 7.47 (dd, J = 8.7, 6.6 Hz, 1H), 7.45 – 7.39 (m, 1H), 7.37 (dd, J = 7.6, 1.7 Hz, 1H), 7.27 (ddt, J = 10.6, 5.9, 2.6 Hz, 2H), 7.18 (t, J = 7.5 Hz, 1H), 7.10 (tdd, J = 8.6, 2.6, 1.1 Hz, 1H), 4.56 (d, J = 5.7 Hz, 2H), 2.55 (s, 6H).19F NMR (376 MHz, DMSO-d6) δ -112.03 (d, J = 7.1 Hz), - 114.55 (d, J = 7.3 Hz). DUIS-MS m / z: 466.2 (MH+) / 464.0 (M-H)-. ESI-MS m / z: 466.2 (MH+). HRMS calcd. for C24H21F2N5O3 (MH+), 466.1685; found, 466.1681. Synthesis of 4-amino-N-(2,4-difluorobenzyl)-1-hydroxy-6-(2-(methylamino)phenyl)-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ943) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) and commercially available N-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 25% B to 50% B over 20 min with a flow rate 20 mL / min, retention time = 20.1 min) provided the title compound XZ943 as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 10.72 (t, J = 5.8 Hz, 2H), 8.70 (dd, J = 14.7, 2.0 Hz, 2H), 7.47 (td, J = 8.7, 6.6 Hz, 1H), 7.28 (ddt, J = 9.8, 7.0, 3.7 Hz, 2H), 7.10 (ddd, J = 12.9, 7.9, 2.1 Hz, 2H), 6.74 (t, J = 7.3 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 4.56 (d, J = 5.7 Hz, 2H), 2.68 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -111.98 (d, J = 6.9 Hz), -114.52 (d, J = 6.9 Hz). DUIS-MS m / z: 452.1 (MH+) / 450.0 (M-H)-. ESI-MS m / z: 452.2 (MH+). HRMS calcd. for C23H20F2N5O3 (MH+), 152.1529; found, 452.1531. Synthesis of 2-(5-amino-6-((2,4-difluorobenzyl)carbamoyl)-8-hydroxy-7-oxo-7,8-dihydro-1,8- naphthyridin-3-yl)phenethyl acetate (XZ944) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 40% B to 55% B over 20 min with a flow rate 20 mL / min, retention time = 17.2 min.) provided the title compound XZ944 as a white solid. ESI-MS m / z: 509.1 (MH+). HRMS calcd. for C26H23F2N4O5 (MH+), 509.1631; found, 509.1636. Synthesis of 4-amino-6-(2-(cyanomethyl)phenyl)-N-(2,4-difluorobenzyl)-1-hydroxy-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ945) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 45% B to 50% B over 20 min with a flow rate 20 mL / min, retention time = 12.2 min.) provided the title4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01compound XZ945 as a white solid. DUIS-MS m / z: 462.1 (MH+) / 460.0 (M-H)-. HRMS calcd. for C24H18F2N5O3(MH+), 462.1372; found, 462.1377. Synthesis of 4-amino-6-(2-(2-aminoethyl)phenyl)-N-(2,4-difluorobenzyl)-1-hydroxy-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxamide (XZ946) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 20% B to 40% B over 20 min. with a flow rate 20 mL / min, retention time = 14.2 min.) provided the title compound XZ946 as a white solid. DUIS-MS m / z: 466.5 (MH+) / 464.0 (M-H)-. HRMS calcd. for C24H22F2N5O3 (MH+), 466.1685; found, 466.1686. Synthesis of (4-(5-amino-6-((2,4-difluorobenzyl)carbamoyl)-8-hydroxy-7-oxo-7,8-dihydro-1,8- naphthyridin-3-yl)-1,3-phenylene)bis(ethane-2,1-diyl) diacetate (XZ948) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 45% B to 55% B over 20 min. with a flow rate 20 mL / min, retention time = 14.3 min.) provided the title compound XZ948 as a white solid. DUIS-MS m / z: 595.1 (MH+) / 593.2 (M-H)-. HRMS calcd. for C30H29F2N4O7 (MH+), 595.1999; found, 595.2015. Synthesis of 4-amino-6-(2,4-bis(2-hydroxyethyl)phenyl)-N-(2,4-difluorobenzyl)-1-hydroxy-2-oxo- 1,2-dihydro-1,8-naphthyridine-3-carboxamide (XZ949) Treatment of 6-bromo-N-(2,4-difluorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-1-((3,4- dimethoxybenzyl)oxy)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7) as outlined in general procedure A and purification by preparative HPLC (CAT# 00G-4436-P0-AX) (linear gradient of 20% B to 40% B over 20 min. with a flow rate 20 mL / min, retention time = 17.6 min.) provided the title compound XZ949 as a white solid. DUIS-MS m / z: 511.1 (MH+) / 509.0 (M-H)-. HRMS calcd. for C26H25F2N4O5 (MH+), 511.1788; found, 511.1794. Biological Evaluation Cellular Cytotoxicity of XZ900 – XZ939. Compounds XZ900 – XZ939 showed minimal cellular cytotoxicity, which is similar to the second-generation INSTIs DTG, BIC, and CAB and our previous lead compound XZ426. The following compounds had a cellular cytotoxicy > 250 µM: XZ900, XZ913, XZ914, XZ916, XZ917, XZ918, XZ919, XZ922, XZ924, XZ927, XZ931, XZ932, XZ933, XZ934, XZ935, XZ937, and XZ939. Compounds XZ909, XZ911, XZ920, XZ923 XZ928, XZ936, and XZ938 showed cellular4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01cytotoxicity ranging from 100 µM to 200 µM. Compounds XZ901, XZ902, XZ904, XZ906, XZ907, XZ908, XZ912, XZ915, XZ921, XZ925, XZ929, and XZ930 showed cellular cytotoxicity < 100 µM. Antiviral EC50 values of XZ900 – XZ939 against HIV-1 with WT IN. Antiviral EC50 values of XZ900 – XZ939 were determined in single round infection assays against HIV-1 with wild-type (WT) IN. Compounds XZ903, XZ904, XZ906, XZ907, XZ908, XZ909, XZ911, XZ913, XZ914, XZ915, XZ916, XZ917, XZ918, XZ919, XZ920, XZ921, XZ922, XZ923, XZ926, XZ927, XZ931, XZ935, XZ936, XZ937, and XZ938 were found to have good antiviral potencies comparable to the second-generation INSTIs with EC50values < 5 nM. The EC50values of XZ900, XZ912, XZ932 were < 10 nM and the EC50values of XZ901, XZ902, XZ924, XZ925, XZ928, XZ929, XZ930, XZ933, and XZ939 were < 50 nM, while the EC50 values of XZ929, and XZ934 were > 500 nM. Antiviral EC50 values of XZ900 – XZ939 against a panel of HIV-1 viral constructs having mutant forms of IN. To determine the ability of XZ900 – XZ939 to retain potency against IN resistant mutants, we measured antiviral EC50values in single round infection assays against the following panel of leading IN mutants: G118R, N155H, R263K, and G140S / Q148H. Compounds showing EC50values < 6 nM, were improved when compared to the second-generation INSTIs DTG, BIC, and CAB. Nearly all members of this series retained good antiviral potencies against the IN mutant N155H. Compounds XZ903, XZ904, XZ906, XZ907, XZ908, XZ911, XZ913, XZ914, XZ915, XZ916, XZ917, XZ918, XZ920, and XZ922 showed EC50values < 6 nM. Most members of this series displayed antiviral EC50values that were improved when compared to the second-generation INSTIs. Most members of this series retained good antiviral EC50values against the IN mutant R263K. Compounds XZ900, XZ903, XZ904, XZ906, XZ907, XZ908, XZ911, XZ913, XZ914, XZ915, XZ916, XZ917, XZ918, XZ920, and XZ922 displayed antiviral EC50 values < 6 nM. The IN double mutant G140S / Q148H is regarded as a key determinant in establishing whether a compound is clinically relevant Compounds showing antiviral EC50 values around 6 nM include XZ906, XZ907, XZ913, XZ915, XZ916, and XZ918. Compound XZ915 was distinguished as being improved when compared to the leading second- generation INSTIs DTG and BIC. In summary, we identified six (XZ906, XZ907, XZ913, XZ915, XZ916, and XZ918) as exhibiting antiviral profiles against this initial panel of leading IN mutants that are improved compared to the second-generation INSTIs DTG, BIC, and CAB. Antiviral EC50 values of XZ compounds against a panel of viral constructs having IN bearing well- characterized IN double, triple, and quadruple mutants. To further evaluate antiviral EC50 values of the most promising new compounds (XZ906, XZ907, XZ913, XZ915, and XZ916, as of this writing), we measured EC50 values in single round4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01infection assays using BIC and XZ426 against the following panel of well-defined IN double and triple mutants: E138K / Q148K, G140A / Q148K, T97A / G140S / Q148H, E138K / G140A / Q148K, and E138K / G140S / Q148H. Compounds XZ906, XZ907, XZ913 and XZ916 were found to be largely ineffective at potently inhibiting this panel of IN double and triple mutants with antiviral EC50 values > 20 nM. However, XZ915 retained antiviral potencies against the IN mutants in this panel. All potencies were < 5 nM and were an improvement when compared to BIC and XZ426 against E138K / Q148K, G140A / Q148K, T97A / G140S / Q148H, while the potencies the other two IN mutants were similar. To further distinguish XZ915 from BIC and XZ426, we measured the EC50values in a single round infection assay against the following panel of IN triple and quadruple mutants: V72I / E138K / Q148K, E138K / G140A / Q148R, G140S / Q148H / N155H, G140S / Q148H / G163K, L74M / E138K / Q148R / R263K, E138K / G140A / Q148R / G163R, E138K / G140A / S147G / Q148K, C56S / G140S / Q148H / G149A, L74M / V75A / G140S / Q148H, and L74M / G140S / S147G / Q148K. Noticeable improvements in potencies were observed for XZ915 versus BIC and XZ426 against G140S / Q148H / N155H and E138K / G140A / Q148R / G163R. Preliminary antiviral results have shown additional improvements in potencies for XZ915 when compared against BIC and XZ426 versus the remaining IN mutants in this panel. These data highlight the overall superior antiviral performance of XZ915. Materials and Methods Vector constructs The transfection vector, pNLNgoMIVR-ΔLUC was made from pNLNgoMIVR-ΔEnv.HSA by removing the HSA reporter gene and replacing it with a luciferase reporter gene between the NotI and XhoI restriction sites and previously described. (Oh, J. et al J Virol.2008, 82, 719–727. Zhao, X. et al J. Med. Chem.2008, 51, 251–259) Construction of the IN mutants used in the study have been previously described in detail. (Zhao, X. Z., et. al. J. Med. Chem.2014, 57, 1573-1582; J. Med. Chem. 2014, 57, 5190-5202; ACS Chem. Bio.2016, 11, 1074-1081; J. Med. Chem.2017, 60, 7315-7332; WO2014186398 A1, 2014; US9676771 B2, 2017. Smith, S. J., et al ACS Infect. Dis.2021, 7, 1469- 1482. D. O. Passos et al. Science 2020, 367, 810-814. Li, M. et al et al. Sci. Adv.2023, 9, eadg5953) Cell-based assays. Human embryonic kidney cell culture cell line 293 was acquired from the American Type Culture Collection (ATCC). The human osteosarcoma cell line, HOS, was obtained from Dr. Richard Schwartz (Michigan State University, East Lansing, MI) and grown in Dulbecco’s modified Eagle’s medium (Quality Biological, Gaithersburg, MD) supplemented with 5% (v / v) fetal bovine serum, 5% newborn calf serum, and penicillin (50 units / mL) plus streptomycin (50 µg / mL; Quality Biological, Gaithersburg, MD).4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01VSV-g-pseudotyped HIV was produced by transfections of 293 cells. On the day prior to transfection, 293 cells were plated on 100-mm-diameter dishes at a density of 1.5 X 106 cells per plate.293 cells were transfected with 10 µg of pNLNgoMIVR-ΔLUC and 2 µg of pHCMV-g (obtained from Dr. Jane Burns, University of California, San Diego) using the calcium phosphate method. At approximately 6 h after the calcium phosphate precipitate was added, 293 cells were washed twice with phosphate-buffered saline (PBS) and incubated with fresh media for 48 h. The virus-containing supernatants were then harvested, clarified by low-speed centrifugation, filtrated, and diluted for preparation in antiviral infection assays. On the day prior to the screen, HOS cells were seeded in a 96-well luminescence cell culture plate at a density of 4000 cells in 100 µL per well. On the day of the screen for cellular cytotoxicity determination, cells were treated with compounds from a concentration range of 250 µM to 0.05 µM and then incubated at 37oC for 48 h. On the day of the screen for antiviral activity infection assays, cells were treated with drugs or compounds from a concentration range of 5 µM to 0.0001 µM using 11 serial dilutions and then incubated at 37oC for 3 h. After compound incorporation and activation in the cell, 100 µL of virus-stock diluted to achieve a luciferase signal between 0.2 and 1.5 Relative Luciferase Units (RLUs) was added to each well and further incubated at 37oC for 48 h. Cellular cytotoxicity was measured by using the ATP Lite Luminescence detection system and monitored by adding 100 µL of ATPlite buffer from the Luminescence ATP detection assay (Revvity) to each well followed by mixing at 700 rpm at room temperature for 2 mins using a compact thermomixer, incubated at room temperature for 20 mins to allow time for signal development, and finally cytotoxicity was determined using the microplate reader. Infectivity was measured by using the Steady-lite plus luminescence reporter gene assay system (Revvity, Waltham, MA). Luciferase activity was measured by adding 100 µL of Steady-lite plus buffer (Revvity) to the cells, incubating at room temperature for 20 mins, and measuring luminescence using a microplate reader. Both cytotoxicity and antiviral activity were normalized to the cellular cytotoxicity and infectivity in cells that featured the absence of target compounds, respectively. KaleidaGraph (Synergy Software, Reading, PA) was used to perform non-linear regression analysis on the data. EC50and CC50values were determined from the fit model.

[0002] 4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01Table 1. Structures of examples. XZ900 4'-CO2Me 4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01 XZ931 4’-NH2 XZ932 4’-NHAc Additional compound examples include: , 4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01 Table 2. Cytotoxicity and antiviral potency in cells infected with HIV-1 vectors that carry drug- resistant mutants of IN. Dolutegravir (DTG) bictegravir (BIC), cabotegravir (CAB), and XZ426 are comparative examples. XZ426 has a structure of: Compound EC50 (nM) CC50 (µM) WT G118R N155H R263K G140S / Q148H 8 .1 4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01XZ926 3.6 ± 0.5 26.9 ± 2.6 6.9 ± 1.8 4.3 ± 0.6 45.9 ± 6.5 168.3 ± 5.4 XZ927 1.4 ± 0.2 13.0 ± 3.6 1.5 ± 0.1 3.7 ± 0.2 16.4 ± 3.6 >250 9 .4 .0 Table 3. Antiviral potencies in cells infected with HIV-1 vectors that carry drug-resistant double and triple mutants of IN. IN and mutants INSTIs EC50 (nM) .8 Table 4. Antiviral potencies in cells infected with HIV-1 vectors that carry drug-resistant double, triple, quadruple mutants of IN.4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01INSTIs EC50 (nM) IN mutantsBIC XZ426 XZ9150 1 3 4 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 and should not be taken as limiting the scope of the invention.

Claims

4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01 What is claimed is:

1. A compound having a structure according to Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof:wherein at least one of R1-R5is an acyl, acyloxy, alkoxy, substituted alkoxy, alkyl, substituted alkyl, amino, aminocarbonyl, aryl, substituted aryl, aryloxy, substituted aryloxy, carbonylamino, carboxyl, halogen, hydroxy, sulfonyl, or substituted sulfonyl; X is a halogen; and a is 0 to 5.

2. The compound of claim 2, wherein X is F, and a is 2.

3. The compound of claim 1, wherein the compound has a structure of:

4. The compound of any one of claims 1 to 3, wherein at least one of R1-R5is a hydroxyalkyl, a substituted acyloxyalkyl, or amino.

5. The compound of any one of claims 1 to 3, wherein at least one of R1-R5is a hydroxy(C1-C6)alkyl.4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-016. The compound of any one of claims 1 to 3, wherein at least one of R1-R5is a haloalkyl-substituted acyloxy(C1-C6)alkyl.

7. The compound of any one of claims 1 to 3, wherein at least one of R1-R5is -NH2.

8. The compound of any one of claims 1 to 3, wherein at least one of R1-R5is acyloxy(C1-C6)alkyl.

9. The compound of any one of claims 1 to 3, wherein at least one of R1-R5is cyano(C1- C6)alkyl.

10. The compound of any one of claims 1 to 3, wherein at least one of R1-R5is amino(C1- C6)alkyl.

11. The compound of any one of claims 1 to 3, wherein at least one of R1or R3is a hydroxyalkyl or a substituted acyloxyalkyl.

12. The compound of any one of claims 1 to 3, wherein at least one of R1or R3is a hydroxymethyl.

13. The compound of any one of claims 1 to 3, wherein at least one of R1or R3is a hydroxyethyl.

14. The compound of any one of claims 1 to 3, wherein at least one of R1or R3is a hydroxypropyl.

15. The compound of any one of claims 1 to 3, wherein at least one of R1or R3is -NH2.

16. The compound of any one of claims 1 to 3, wherein at least one of R1or R3is a haloalkyl-substituted acyloxy(C1-C6)alkyl.

17. The compound of an one of claims 1 to 3, wherein at least one of R1or R3is –(CH2)x- OCO-R6, wherein x is 1 to 6, and R6is a haloalkyl.

18. The compound of claim 17, wherein R6is a fluoroalkyl.

19. The compound of claim 17, wherein R6is -CF3.4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01 20. A compound having a structure according to Formula III, or a stereoisomer or pharmaceutically acceptable salt thereof:Formula III wherein X is a heteroaryl, substituted heteroaryl, carbobicyclyl, substituted carbobicyclyl, heterobicyclyl, substituted heterobicyclyl, heterocyclic, or substituted heterocyclic.

21. A compound having a structure according to Formula IV, or V, or VI, or a stereoisomer or pharmaceutically acceptable salt thereof: or or4239-112081-02 10 / 15 / 25 E-125-2024-0-PC-01 Formula VI; wherein R is H; X is a halogen; a is 0 to 5; Z and Y are each independently C or N; represents a cyclic structure, that may or may not be present; provided that if is not present, then at least one of Z and Y is N.

22. A method of inhibiting drug-resistant HIV-1 integrase in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 21.

23. The method of claim 22, wherein the subject has been administered at least one HIV- 1 integrase inhibitor other than the compound of claims 1 to 21.

24. The method of claim 22, wherein the method comprises inhibiting raltegravir- resistant HIV-1 integrase in the subject.

25. The method of any one of claims 22 to 24, further comprising co-administering with the compound at least one other anti-HIV therapeutic agent.

26. A method of treating HIV in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 21 27. A pharmaceutical composition comprising any one of the compounds of claims 1 to 21, and at least one pharmaceutically acceptable excipient.

28. The pharmaceutical composition of claim 27, further comprising at least one other anti-HIV therapeutic agent.

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