Tetracyclic heterocycles useful as HIV integrase inhibitors

Abstract

The present invention relates to tetracyclic heterocyclic compounds of formula (I) and pharma- ceutically acceptable salts or prodrugs thereof, wherein R 1 is as defined herein. The present invention also relates to compositions comprising at least one tetracyclic heterocyclic compound, and methods of using such tetracyclic heterocyclic compounds for the treatment or prevention of HIV infection in a subject. [Formula 1] TIFF2024507788000037.tif40149

Description

[Technical field]

[0001] The present invention relates to tetracyclic heterocyclic compounds, compositions comprising at least one tetracyclic heterocyclic compound, and methods of using the tetracyclic heterocyclic compounds to treat or prevent HIV infection in a subject. [Background technology]

[0002] The retrovirus designated human immunodeficiency virus (HIV), particularly the strains known as HIV type 1 (HIV-1) and type 2 (HIV-2), is the etiological agent of a complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous systems. A common feature of retroviral replication is the insertion of proviral DNA into the host cell genome by a virus-encoded integrase, a step required for HIV replication in human T-lymphoid and monocytoid cells. Integration is thought to be mediated by integrase in three steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from the 3′ end of the linear proviral DNA; and covalent attachment of the 3′ recessed end of the proviral DNA to the staggered break created at the host target site. The fourth step of this process, repair synthesis of the resulting gap, may be accomplished by cellular enzymes.

[0003] Nucleotide sequencing of HIV indicates the presence of the pol gene in a single open reading frame [Ratner, L. et al., Nature, 313, 277(1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase, and HIV protease [Toh, H et al., EMBO J. 4, 1267(1985);Power, MD et al., Science, 231, 1567(1986);Pearl, LH et al., Nature, 329, 351(1987)]. All three enzymes have been shown to be essential for HIV replication.

[0004] Some antiviral compounds that act as inhibitors of HIV replication are known to be effective drugs in the treatment of AIDS and similar diseases, such as reverse transcriptase inhibitors such as azidothymidine (AZT) and efavirenz, and protease inhibitors such as indinavir and nelfinavir. The compounds of the present invention are inhibitors of HIV integrase and inhibitors of HIV replication. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Ratner, L. et al., Nature, 313, 277(1985) [Non-Patent Document 2] Toh, H et al., EMBO J. 4, 1267(1985) [Non-Patent Document 3] Power, MD et al., Science, 231, 1567(1986) [Non-Patent Document 4] Pearl, LH et al., Nature, 329, 351(1987) Summary of the Invention

[0006] In one aspect, the present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof. [ka] During the ceremony, R 1 is CHR 2 -OC(O)-YR 3 , C(O)-C1-C 10 Alkyl, CHR 2 -OP(O)(OH)2 or [ka] and; Y is a bond or -O-; R 2 is hydrogen or C1-C6 alkyl; R 3 is C1-C6 alkyl, (CH2) x -O-C1-C6 alkyl, and (CH2) x -NR 4 R 5 wherein the C1-C6 alkyl group is optionally substituted with 1 to 3 groups independently selected from the group consisting of halo, hydroxy, methoxy and ethoxy; R 4 is hydrogen or C1-C6 alkyl; R 5 is hydrogen or C1-C6 alkyl; and x is an integer from 1 to 4.

[0007] The compounds of formula (I) (also referred to herein as "tetracyclic heterocyclic compounds") and pharma- ceutically acceptable salts or prodrugs thereof can be useful, for example, in inhibiting HIV viral replication or replicon activity, or in treating or preventing HIV infection in a subject. Without being bound to any particular theory, it is believed that the tetracyclic heterocyclic compounds inhibit HIV viral replication by inhibiting HIV integrase.

[0008] Accordingly, the present invention provides a method for treating or preventing HIV infection in a subject, comprising administering to the subject an effective amount of at least one tetracyclic heterocyclic compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0009] The following detailed description explains the invention in more detail.

[0010] Although any methods and materials similar to those described herein can be used in the practice or testing of the present invention, exemplary methods and materials are described herein. Other embodiments, aspects, and features of the present invention are further described or will be apparent from the following description, examples, and appended claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The present invention includes tetracyclic heterocyclic compounds, compositions comprising at least one tetracyclic heterocyclic compound, and methods of using the tetracyclic heterocyclic compounds to treat or prevent HIV infection in a subject.

[0012] Definitions and Abbreviations The terms used herein have their usual meanings, and the meaning of such terms is independent in each case.Nevertheless, the following definitions apply throughout the specification and claims, unless otherwise specified.Chemical names, common names, and chemical structures may be used interchangeably to indicate the same structure.These definitions apply regardless of whether the term is used alone or in combination with other terms, unless otherwise specified.Thus, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portion of "hydroxyalkyl", "haloalkyl", "-O-alkyl", etc.

[0013] As used herein, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0014] A "subject" is a human or non-human mammal. In one embodiment, the subject is a human. In another embodiment, the subject is a primate. In another embodiment, the subject is a monkey. In another embodiment, the subject is a chimpanzee. In another embodiment, the subject is a rhesus monkey.

[0015] As used herein, the term "effective amount" refers to an amount of a Tetracyclic Heterocyclic Compound and / or additional therapeutic agent or composition thereof that is effective to inhibit HIV replication and produce the desired therapeutic, ameliorative, inhibitory or prophylactic effect when administered to a subject suffering from HIV infection or AIDS. In the combination therapy of the invention, the effective amount can refer to each individual agent or to the entire combination, where the amounts of all agents administered are effective together and the individual component agents of the combination may not be present in effective amounts.

[0016] The term "treating" or "treatment" as used herein with respect to HIV viral infection or AIDS includes inhibiting the severity of HIV infection or AIDS, i.e., halting or reducing the progression of HIV infection or AIDS or clinical symptoms thereof; or alleviating HIV infection or AIDS, i.e., causing regression of the severity of HIV infection or AIDS or clinical symptoms thereof.

[0017] The terms "prevent" or "prevention," as used herein in reference to HIV viral infection or AIDS, refer to the reduction in the likelihood or severity of HIV infection or AIDS.

[0018] The term "alkyl" as used herein refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond. An alkyl group can be straight or branched chain and contains from about 1 to about 20 carbon atoms. In one embodiment, an alkyl group contains from about 1 to about 12 carbon atoms. In different embodiments, an alkyl group contains from 1 to 6 carbon atoms (C1-C6 alkyl) or from about 1 to about 10 carbon atoms (C1-C 10Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl, and neohexyl. In one embodiment, an alkyl group is linear. In another embodiment, an alkyl group is branched.

[0019] Unless otherwise specified, an alkyl group is unsubstituted.

[0020] The term "halo" as used herein means -F, -Cl, -Br or -I.

[0021] The term "substituted" means that one or more hydrogens on the specified atom have been replaced with a choice from the indicated list of substituents, provided that the substitutions do not exceed the normal valence of the specified atom in its current state, and that the substitutions result in stable compounds. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. A "stable compound" or "stable structure" means a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0022] As used herein, the term "in substantially purified form" refers to the physical state of a compound after it has been isolated from a synthetic process (e.g., a reaction mixture), a natural source, or a combination thereof. The term "in substantially purified form" also refers to the physical state of a compound after it has been obtained from a purification process(es) described herein or known to one of ordinary skill in the art (e.g., chromatography, recrystallization, etc.), in such a way that the compound has a purity that is capable of being characterized by standard analytical techniques described herein or known to one of ordinary skill in the art.

[0023] It should be noted that in the text, schemes, examples, and tables herein, all carbon and heteroatoms with unsatisfied valences are assumed to have sufficient hydrogen atoms to satisfy the valences.

[0024] When a functional group of a compound is referred to as being "protected," this means that the group is in a modified form so as to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups are understood by those skilled in the art and can be understood by reference to standard texts such as, for example, TW Greene et al., Protective Groups in Organic Synthesis (1991), Wiley, New York.

[0025] Substituents or variables (e.g., R 4 When <RTIgt;(s)< / RTI> occur more than once in any constituent or in formula (I), its definition at each occurrence is independent of its definition at every other occurrence, unless otherwise stated.

[0026] As used herein, the term "composition" is intended to encompass an article of manufacture containing the specified ingredients in the specified amounts, as well as an article of manufacture resulting from a combination of the specified ingredients in the specified amounts.

[0027] The compounds of the present invention are prodrugs of (11aS,11bR)-N-(3-chloro-2-fluorobenzyl)-5-hydroxy-4,6-dioxo-1,2,4,6,9,10,11a,11b-octahydro-8H-[1,3]oxazino[2',3':3,4]pyrazino[2,1,6-cd]indolizine-3-carboxamide (also referred to as Compound A, which has the following chemical structure): [ka] The synthesis of (11aS,11bR)-N-(3-chloro-2-fluorobenzyl)-5-hydroxy-4,6-dioxo-1,2,4,6,9,10,11a,11b-octahydro-8H-[1,3]oxazino[2',3':3,4]pyrazino[2,1,6-cd]indolizine-3-carboxamide and its ability to inhibit HIV integrase are described in PCT International Patent Application WO2018 / 102485, published on June 7, 2018 to Merck Sharp & Dohme Corp., which is incorporated by reference in its entirety.

[0028] The term "prodrug" means a compound (e.g., a drug precursor) that is transformed in vivo to produce a pharmacologically active compound or a pharma- ceutically acceptable salt of that compound. This transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, by hydrolysis in blood.

[0029] Solvates of the compounds of the invention are also contemplated herein.

[0030] One or more compounds of the present invention may exist in unsolvated and solvated forms with pharma- ceutically acceptable solvents (e.g., water, ethanol, etc.), and the present invention is intended to encompass both solvated and unsolvated forms. "Solvate" refers to a physical association of a compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding (e.g., hydrogen bonding). In certain circumstances, a solvate may be capable of isolation, for example, when one or more solvent molecules are incorporated within the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Non-limiting examples of solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate in which the solvent molecule is water.

[0031] One or more compounds of the invention may be converted into a solvate. The preparation of solvates is generally known. Thus, for example, see M. Caira et al., J. Pharmaceutical Sci., 93(3) , 601-611 (2004) describes the preparation of solvates of the antifungal drug fluconazole in ethyl acetate as well as in water. Similar preparations of solvates, hemisolvates, hydrates, etc. are described in EC van Tonder et al., AAPS PharmSciTechours., 5(1) , article 12 (2004); and AL Bingham et al., Chem. Commun., 603-604 (2001). A representative, non-limiting process involves dissolving the compound of the present invention in a desired amount of a desired solvent (organic or water or mixtures thereof) at a temperature above room temperature and cooling the solution at a rate sufficient to form crystals, which are then isolated by standard methods. For example, analytical techniques such as IR spectroscopy indicate the presence of the solvent (or water) in the crystals as a solvate (or hydrate).

[0032] The tetracyclic heterocyclic compounds may form salts, which are also included within the scope of the present invention. References to tetracyclic heterocyclic compounds herein should be understood to include references to their salts, unless otherwise specified. As used herein, the term "salt(s)" refers to acid salts formed with inorganic and / or organic acids, and basic salts formed with inorganic and / or organic bases. Also, when the tetracyclic heterocyclic compounds contain both a basic moiety (such as, but not limited to, pyridine or imidazole) and an acidic moiety (such as, but not limited to, carboxylic acid), zwitterions ("internal salts") may be formed and are included in the term "salt(s)" as used herein. In one embodiment, the salt is a pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salt. In another embodiment, the salt is a salt other than a pharmaceutically acceptable salt. Salts of compounds of formula (I) can be formed, for example, by reacting a tetracyclic heterocyclic compound with an amount (e.g., an equivalent amount) of an acid or base in a medium (e.g., one in which the salt precipitates, or an aqueous medium) followed by lyophilization.

[0033] Exemplary acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphosulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), etc. Additionally, acids that are generally considered suitable for the formation of pharma- ceutical useful salts from basic pharmaceutical compounds are described, for example, in P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1)1-19; P. Gould, International J. of Pharmaceutics (1986) 33 Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC (online)), the disclosures of which are incorporated herein by reference.

[0034] Exemplary basic salts include ammonium salts, alkali metal salts (such as sodium, lithium, and potassium salts), alkaline earth metal salts (such as calcium and magnesium salts), salts with organic bases (e.g., organic amines) (dicyclohexylamine, t-butylamine, choline, etc.), and salts with amino acids (arginine, lysine, etc.). Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfate), long chain halides (e.g., decyl chlorides, bromides, and iodides, lauryl, and stearyl), aryl alkyl halides (e.g., benzyl and phenethyl bromides), and the like.

[0035] All such acid and base salts are intended to be pharma- ceutically acceptable salts within the scope of this invention, and all acid and base salts are considered equivalent in terms of this invention to the free forms of the corresponding compounds.

[0036] Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods known to those skilled in the art, such as, for example, chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers to the corresponding pure enantiomers (e.g., hydrolysis). Stereochemically pure compounds can also be prepared by using chiral starting materials or by using salt resolution techniques. Some tetracyclic heterocyclic compounds can also be atropisomers (e.g., substituted biaryls) and are considered part of the present invention. Enantiomers can also be directly separated using chiral chromatographic techniques.

[0037] It is also possible that the tetracyclic heterocyclic compounds may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. For example, all keto-enol and imine-enamine forms of the compounds are included in the invention.

[0038] Unless otherwise specified, all stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the compounds of the invention (including the salts, solvates, hydrates, esters and prodrugs of the compounds and the salts, solvates and esters of the prodrugs), such as those that may exist by virtue of asymmetric carbons on various substituents, such as enantiomeric forms (which may exist even when there are no asymmetric carbons), rotamer forms, atropisomers, and diastereomeric forms, are contemplated within the scope of the invention. When a tetracyclic heterocyclic compound incorporates double bonds or fused rings, both the cis and trans forms as well as mixtures are encompassed within the scope of the invention.

[0039] When a substituent on a chiral carbon atom is depicted without any specific stereochemistry (by using a linear bond to the chiral center), it is to be understood that both the alpha and beta configurations of that substituent are to be considered as part of the invention. For example, a compound of the invention depicted as follows: [ka] is understood to include both stereoisomers at the specified chiral center, such as those of the structure below. [ka] and [ka] The "right" fused ring of compounds of formula (I): [ka] The N-C bond in may be in any possible orientation.

[0040] In the Examples section below, compounds of the invention that have been purified as individual stereoisomers may be depicted in non-stereospecific form but are identified using one or more of the terms "Diastereomer 1", "Diastereomer 2", "Isomer 1", "Isomer 2", "Enantiomer A" and "Enantiomer B", in which case the absolute stereochemistry of each isolated diastereomeric and enantiomeric center has not been determined and the terminology used above is used to describe each individual purified stereochemically pure compound.

[0041] The individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, e.g., as racemates or mixed with all other or selected stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of terms such as "salts", "solvates", and the like, is intended to apply equally to salts and solvates of enantiomers, stereoisomers, rotamers, tautomers, or racemates of the compounds of the invention.

[0042] In the compounds of formula (I), atoms may exhibit their natural isotopic abundance or one or more atoms may be artificially enriched with a particular isotope having the same atomic number but an atomic mass or mass number different from that predominantly found in nature. The present invention is intended to include all appropriate isotopic variations of the compounds of general formula I. For example, hydrogen ( 1 The different isotopic forms of H include protium ( 1 H) and deuterium ( 2 H). Protium is the hydrogen isotope found predominantly in nature. Enrichment with deuterium may provide certain therapeutic advantages (such as increased in vivo half-life or reduced dosage requirements) or provide compounds useful as standards for characterization of biological samples. Isotopically enriched compounds of formula (I) may be prepared without undue experimentation by routine techniques known to those skilled in the art or by processes similar to those described in the schemes and examples herein, using appropriate isotopically enriched reagents and / or intermediates. In one embodiment, compounds of formula (I) have one or more hydrogen atoms replaced with deuterium.

[0043] The tetracyclic heterocyclic compounds may be useful in human and veterinary medicine for treating or preventing HIV infection in a subject. In one embodiment, the tetracyclic heterocyclic compounds may be inhibitors of HIV viral replication. In a specific embodiment, the tetracyclic heterocyclic compounds are inhibitors of HIV-1. Thus, the tetracyclic heterocyclic compounds may be useful in treating HIV infection and AIDS. In accordance with the present invention, the tetracyclic heterocyclic compounds may be administered to a subject in need of treatment or prevention of HIV infection.

[0044] Thus, in one embodiment, the present invention provides a method for treating HIV infection in a subject, comprising administering to the subject an effective amount of at least one tetracyclic heterocyclic compound, or a pharma- ceutically acceptable salt thereof, hi a specific embodiment, the present invention provides a method for treating AIDS in a subject, comprising administering to the subject an effective amount of at least one tetracyclic heterocyclic compound, or a pharma- ceutically acceptable salt thereof.

[0045] Compounds of formula (I) The present invention provides tetracyclic heterocyclic compounds of formula (I) and pharma- ceutically acceptable salts thereof: [ka] During the ceremony, R 1 is CHR 2 -OC(O)-YR 3 , C(O)-C1-C 10 Alkyl, CHR 2 -OP(O)(OH)2 or [ka] and; Y is a bond or -O-; R 2 is hydrogen or C1-C6 alkyl; R 3 is C1-C6 alkyl, (CH2) x -O-C1-C6 alkyl, and (CH2) x -NR4 R 5 wherein the C1-C6 alkyl group is optionally substituted with 1 to 3 groups independently selected from the group consisting of halo, hydroxy, methoxy and ethoxy; R 4 is hydrogen or C1-C6 alkyl; R 5 is hydrogen or C1-C6 alkyl; and x is an integer from 1 to 4.

[0046] In one embodiment of the present invention, R 1 is CHR 2 -OC(O)-YR 3 In another embodiment of the present invention, R 1 is C(O)-C1-C 10 In another embodiment of the present invention, R 1 is CHR 2 In another embodiment of the present invention, R 1 teeth [ka] In one class of the embodiment, R 1 teeth [ka] In a subclass of this embodiment, R 1 teeth [ka] It is.

[0047] In one embodiment of the present invention, R 2 is hydrogen or methyl. In one class of this embodiment, R 2 is hydrogen. In another class of this embodiment, R 2 is methyl.

[0048] In one embodiment of the present invention, R 3is C1-C6 alkyl optionally substituted with 1 to 3 groups independently selected from the group consisting of halo, hydroxy, methoxy and ethoxy. 3 is (CH2) x In another embodiment of the present invention, R 3 (CH2) x -NR 4 R 5 It is.

[0049] In one embodiment of the present invention, R 4 is methyl.

[0050] In one embodiment of the present invention, R 5 is methyl.

[0051] In one embodiment of the invention Y is -O-. In another embodiment of the invention Y is a bond.

[0052] In one embodiment of the invention, x is 1. In another embodiment of the invention, x is 2. In another embodiment of the invention, x is 3. In another embodiment of the invention, x is 4.

[0053] In another embodiment, the compound of formula (I) is in a substantially purified form.

[0054] It should be understood that any of the above embodiments may be combined with one or more of the other embodiments.

[0055] Other embodiments of the present invention include: (a) a pharmaceutical composition comprising an effective amount of a compound of formula (I) and a pharma- ceutically acceptable carrier; (b) the pharmaceutical composition of (a), further comprising a second therapeutic agent selected from the group consisting of an HIV antiviral agent, an immunomodulatory agent, and an anti-infective agent; (c) the pharmaceutical composition of (b), wherein the HIV antiviral agent is an antiviral agent selected from the group consisting of HIV NRTIs (nucleoside reverse transcriptase inhibitors) and HIV NNRTIs (non-nucleoside reverse transcriptase inhibitors); (d) a pharmaceutical combination which is (i) a compound of formula (I) and (ii) a second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulatory agents and anti-infective agents, wherein the compound of formula (I) and the second therapeutic agent are each used in an amount such that the combination is effective for inhibiting HIV replication or treating HIV infection and / or reducing the likelihood of or severity of symptoms of HIV infection; (e) the combination of (d), wherein the HIV antiviral agent is an antiviral agent selected from the group consisting of HIV NRTIs (nucleoside reverse transcriptase inhibitors) and HIV NNRTIs (non-nucleoside reverse transcriptase inhibitors); (f) a method of inhibiting HIV replication in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I); (g) a method for treating and / or reducing HIV infection and / or reducing the likelihood or severity of a symptom of HIV infection in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I); (h) the method of (g), wherein the compound of formula (I) is administered in combination with an effective amount of at least one second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulatory agents, and anti-infective agents; (i) the method of (h), wherein the HIV antiviral agent is an antiviral agent selected from the group consisting of HIV NRTIs (nucleoside reverse transcriptase inhibitors) and HIV NNRTIs (non-nucleoside reverse transcriptase inhibitors); (j) a method of inhibiting HIV replication in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of (a), (b) or (c), or a combination of (d) or (e); (k) A method for treating and / or reducing HIV infection and / or reducing the likelihood or severity of a symptom of HIV infection in a subject in need thereof comprising administering to the subject a pharmaceutical composition of (a), (b) or (c), or a combination of (d) or (e). etc.

[0056] Further embodiments of the present invention include: (l) a pharmaceutical composition comprising an effective amount of a pharma- ceutically acceptable salt of a compound of formula (I) and a pharma- ceutically acceptable carrier; (m) the pharmaceutical composition of (l), further comprising a second therapeutic agent selected from the group consisting of an HIV antiviral agent, an immunomodulatory agent, and an anti-infective agent; (n) the pharmaceutical composition of (m), wherein the HIV antiviral agent is an antiviral agent selected from the group consisting of HIV NRTIs (nucleoside reverse transcriptase inhibitors) and HIV NNRTIs (non-nucleoside reverse transcriptase inhibitors); (o) a pharmaceutical combination which is (i) a pharma- ceutical salt of a compound of formula (I) and (ii) a second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulatory agents and anti-infective agents, wherein the pharma- ceutical combination of the pharma-ceutical salt of the compound of formula (I) and the second therapeutic agent are each used in an amount such that the combination is effective for inhibiting HIV replication or treating HIV infection and / or reducing the likelihood or severity of symptoms of HIV infection; (p) the combination of (o), wherein the HIV antiviral agent is an antiviral agent selected from the group consisting of HIV NRTIs (nucleoside reverse transcriptase inhibitors) and HIV NNRTIs (non-nucleoside reverse transcriptase inhibitors); (q) a method of inhibiting HIV replication in a subject in need thereof, comprising administering to the subject an effective amount of a pharma- ceutically acceptable salt of a compound of formula (I); (r) a method for treating and / or reducing HIV infection and / or reducing the likelihood or severity of symptoms of HIV infection in a subject in need thereof, comprising administering to the subject an effective amount of a pharma- ceutically acceptable salt of a compound of formula (I); (s) the method of (r), wherein a pharma- ceutically acceptable salt of a compound of formula (I) is administered in combination with an effective amount of at least one second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulatory agents, and anti-infective agents; (t) the method of (s), wherein the HIV antiviral agent is an antiviral agent selected from the group consisting of HIV NRTIs (nucleoside reverse transcriptase inhibitors) and HIV NNRTIs (non-nucleoside reverse transcriptase inhibitors); (u) a method of inhibiting HIV replication in a subject in need thereof comprising administering to the subject a pharmaceutical composition of (l), (m) or (n), or a combination of (o) or (p); (v) A method for treating and / or reducing HIV infection and / or reducing the likelihood or severity of symptoms of HIV infection in a subject in need thereof comprising administering to the subject a pharmaceutical composition of (l), (m) or (n) or a combination of (o) or (p). etc.

[0057] Further embodiments of the present invention include: (w) a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier; (x) the pharmaceutical composition of (w), further comprising a second therapeutic agent selected from the group consisting of an HIV antiviral agent, an immunomodulatory agent, and an anti-infective agent; (y) the pharmaceutical composition of (x), wherein the HIV antiviral agent is an antiviral agent selected from the group consisting of HIV NRTIs (nucleoside reverse transcriptase inhibitors) and HIV NNRTIs (non-nucleoside reverse transcriptase inhibitors); (z) a pharmaceutical combination which is (i) a compound of formula (I) and (ii) or a pharma- ceutical acceptable salt thereof, and a second therapeutic agent selected from the group consisting of an HIV antiviral agent, an immunomodulatory agent, and an anti-infective agent, wherein the compound of formula (I) and the second therapeutic agent are each used in an amount such that the combination is effective for inhibiting HIV replication or treating HIV infection and / or reducing the likelihood or severity of symptoms of HIV infection; (z), wherein (aa) the HIV antiviral agent is an antiviral agent selected from the group consisting of an HIV protease inhibitor and an HIV NNRTI inhibitor; (bb) a method of inhibiting HIV replication in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof; (cc) a method for treating and / or reducing HIV infection and / or reducing the likelihood or severity of symptoms of HIV infection in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof; (dd) the method of (cc), wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with an effective amount of at least one second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulatory agents, and anti-infective agents; (ee) the method of (dd), wherein the HIV antiviral agent is an antiviral agent selected from the group consisting of HIV NRTIs (nucleoside reverse transcriptase inhibitors) and HIV NNRTIs (non-nucleoside reverse transcriptase inhibitors); (ff) a method of inhibiting HIV replication in a subject in need thereof comprising administering to the subject a pharmaceutical composition of (w), (x) or (y), or a combination of (z) or (aa); (gg) A method for treating and / or reducing HIV infection and / or reducing the likelihood or severity of symptoms of HIV infection in a subject in need thereof comprising administering to the subject a pharmaceutical composition of (w), (x) or (y) or a combination of (z) or (aa). etc.

[0058] The invention also includes a compound of the invention for use (i) in (a) medicine, (b) in inhibiting HIV replication, or (c) in treating HIV infection and / or reducing the likelihood or severity of symptoms of HIV infection, (ii) as a medicament for such inhibition or treatment and / or reduction, or (iii) in the preparation of a medicament for such inhibition or treatment and / or reduction. In such uses, the compound of the invention may be used in combination with one or more second therapeutic agents selected from HIV antiviral agents, anti-infective agents and immunomodulatory agents.

[0059] Further embodiments of the invention include the pharmaceutical compositions, combinations and methods set out in (a) to (gg) above, and the uses set out in the preceding paragraphs, in which the compound of the invention used is a compound which is one of the compound embodiments, aspects, types, subtypes or features described above. In all of these embodiments, the compound may be used in the form of a pharma- ceutically acceptable salt or hydrate (as appropriate).

[0060] It should be further understood that the composition and method embodiments set forth above as (a) through (gg) are understood to include all embodiments of that compound (e.g., embodiments resulting from combinations of embodiments, etc.).

[0061] Non-limiting examples of compounds of formula (I) include compounds 1-8 set forth in the Examples below, as well as pharma- ceutically acceptable salts thereof.

[0062] Methods for preparing compounds of formula (I) Compounds of formula (I) can be prepared from known or readily prepared starting materials according to methods known to those skilled in the art of organic synthesis. Methods useful for preparing compounds of formula (I) are described in the Examples below and outlined in the Schemes below. Alternative synthetic routes and related structures will be apparent to those skilled in the art of organic synthesis.

[0063] Abbreviations and acronyms used herein include the following:

[0064] [Table 1] TIFF2024507788000015.tif114156

[0065] General Procedure Starting materials and intermediates are either commercially available, prepared using known procedures, or as otherwise described. The general routes applicable to the synthesis of compounds of formula I are depicted in the following schemes. In some cases, the order of carrying out the reaction steps in the schemes can be varied to facilitate the reaction or to avoid undesired reaction products.

[0066] Moisture- or air-sensitive reactions were carried out under nitrogen or argon with anhydrous solvents and reagents. Reaction progress was monitored by analytical thin-layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS), usually performed using E. Merck precoated TLC plates, silica gel 60F-254, layer thickness 0.25 mm.

[0067] Typically, the analytical LC-MS system used consisted of a Waters ZQ™ platform with electrospray ionization in positive ion detection mode using a Waters Acquity™ Ultra Performance LC equipped with an autosampler. The column was commonly a Waters Acquity UPLC™ BEH C18 1.0×50 mm, 1.7 μm. The flow rate was 1 mL / min and the injection volume was 10 μL. UV detection was in the range of 210 to 400 nm. The mobile phase consisted of solvent A (water + 0.05% TFA) and solvent B (MeCN + 0.05% TFA) with a gradient of 100% solvent A for 0.7 min, changing to 100% solvent B over 3.75 min, holding for 1.1 min, then returning to 100% solvent A over 0.2 min.

[0068] Preparative HPLC purification was typically performed using a non-mass guided system. Typically it was performed on a Teledyne ISCO ACCQPrep HP150 UV system configured with ELSD, UV (254 and 215 nm) and ELSD triggered collection, and an XBridge™ C-18 5 micron OBD™, 30 mm (id) x 250 mm column. The mobile phase consisted of a mixture of acetonitrile (10% to 100%) in water containing 0.1% TFA. The flow rate was maintained at 50 mL / min, injection volumes ranged from 1500 to 8000 μL, and UV detection range was 210 to 400 nm. Mobile phase gradients were optimized for individual compounds. Flash chromatography was typically performed on silica gel (32-63 μM, 60 Å pore size) in prepacked RediSep® High Performance Gold cartridges of the sizes indicated, using an ISCO CombiFlash® Rf instrument or an ISCO CombiFlash® Companion XL. 1 H NMR spectra were obtained on a 500 MHz spectrometer in CDCl3 solutions unless otherwise noted. Chemical shifts are reported in parts per million (ppm). Tetramethylsilane (TMS) was used as the internal reference in CDCl3 solutions, and the residual CH3OH peak or TMS was used as the internal reference in CD3OD solutions. Coupling constants (J) are reported in Hertz (Hz).

[0069] Several methods for preparing the compounds of the invention are also described in the Examples. Starting materials and intermediates were either commercially purchased from commercial catalog sources, or prepared using known procedures or as otherwise described.

[0070] Preparation of intermediates Intermediate A [ka] Step 1: Iodomethyl(4-nitrophenyl)carbonate (Intermediate A) [ka] To a solution of chloromethyl(4-nitrophenyl)carbonate (10.0 g, 43.2 mmol) in acetone (43.2 mL) at 25° C. was added sodium iodide (9.7 g, 64.8 mmol). The solution was stirred at 40° C. overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated. The residue was dissolved in EtOAc (150 mL) and washed with saturated sodium thiosulfate solution (50 mL). The organic layer was washed with brine (30 mL), dried (MgSO4), filtered and concentrated to give iodomethyl(4-nitrophenyl)carbonate (Intermediate A). This material was carried forward without purification.

[0071] Preparation of the Examples Example 1 [ka] (((11aS,11bR)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-4,6-dioxo-1,2,4,6,9,10,11a,11b-octahydro-8H-[1,3]oxazino[2′,3′:3,4]pyrazino[2,1,6-cd]indolizin-5-yl)oxy)methyl(2-methoxyethyl)carbonate [ka] (11aS,11bR)-N-(3-chloro-2-fluorobenzyl)-5-hydroxy-4,6-dioxo-1,2,4,6,9,10,11a,11b-octahydro-8H-[1,3]oxazino[2′,3′:3,4]pyrazino[2,1,6-cd]indolizine-3-carboxamide (compound A) (10.0 g, 22.33 mmol) and chloromethyl To a mixture of ethyl 2-methoxyethyl carbonate (5.65 g, 33.5 mmol) in acetonitrile (112 mL) was added potassium carbonate (9.26 g, 67 mmol), potassium iodide (11.12 g, 67 mmol), and 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane) (0.59 g, 2.23 mmol). The resulting mixture was stirred at 80° C. until the reaction was judged complete by LCMS (5 h). The reaction mixture was cooled to ambient temperature, diluted with DCM (200 mL) and MeCN (100 mL), and stirred at the same temperature for 20 min. The mixture was filtered, washed with DCM (200 mL), and the filtrate was concentrated. The residue was taken up in DCM (500 mL) and filtered. The filtrate was directly purified by flash chromatography (330 g RediSep Rf Gold; 0% to 10% MeOH / DCM in 60 min; filtrate (DCM) was pumped onto a CombiFlash Companion XL system and then gradient run on the CombiFlash Rf system) and the pure fractions were concentrated to give (((11aS,11bR)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-4,6-dioxo-1,2,4,6,9,10,11a,11b-octahydro-8H-[1,3]oxazino[2',3':3,4]pyrazino[2,1,6-cd]indolizin-5-yl)oxy)methyl(2-methoxyethyl)carbonate (Example 1). The material was then crystallized from 100% IPA. 1H NMR (500MHz, chloroform-d) δ10.82(t, J=5.8Hz, 1H), 7.28(t, J=9.0Hz, 4H), 7.02(td, J=7.9, 0.8Hz, 1H), 5.91-5.84(m, 2H), 4 .95(d, J=3.3Hz, 1H), 4.79(dd, J=13.2, 4.7Hz, 1H), 4.65(qd, J=15.5, 5.9Hz, 2H), 4.48(ddd,, J=10.8, 6.9, 3.3Hz, 1H), 4.3 9-4.27(m, 2H), 4.22(dd, J=11.6, 4.8Hz, 1H), 4.13(dd, J=19.2, 8.9Hz, 1H), 3.93(td, J=12.4, 2.5Hz, 1H), 3.69-3.58(m, 2 H), 3.36(s, 3H), 3.31-3.41(m, 1H), 3.10(td, J=12.9, 2.9Hz, 1H), 2.46-2.25(m, 2H), 2.04(m, 1H), 1.54(d, J=13.9Hz, 1H). LRMS(M+H) + :580.3.

[0072] Example 2 [ka] Phase 1: (((11aS,11bR)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-4,6-dioxo-1,2,4,6,9,10,11a,11b-octahydro-8H-[1,3]oxazino[2′,3′:3,4]pyrazino[2,1,6-cd]indolizin-5-yl)oxy)methyl(4-nitrophenyl)carbonate [ka] To a mixture of (11aS,11bR)-N-(3-chloro-2-fluorobenzyl)-5-hydroxy-4,6-dioxo-1,2,4,6,9,10,11a,11b-octahydro-8H-[1,3]oxazino[2',3':3,4]pyrazino[2,1,6-cd]indolizine-3-carboxamide (compound A) (7.5 g, 16.8 mmol) and iodomethyl(4-nitrophenyl)carbonate (intermediate A) (10.8 g, 33.5 mmol) in acetonitrile (120 mL) was added potassium carbonate (8.0 g, 57.8 mmol). The resulting mixture was stirred at 80° C. for 4 hours. The reaction mixture was cooled to ambient temperature, diluted with DCM (120 mL) and stirred at the same temperature for 20 minutes. The mixture was filtered, washed with DCM (100 mL) and the filtrate was concentrated. The residue was taken up in DCM (20 mL) and directly purified by flash chromatography (330 g RediSep Rg Gold; 0% to 10% MeOH / DCM in 35 min; CombiFlash Rf system; DP eluted with approximately 4% MeOH). Pure fractions were combined and concentrated to give (((11aS,11bR)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-4,6-dioxo-1,2,4,6,9,10,11a,11b-octahydro-8H-[1,3]oxazino[2′,3′:3,4]pyrazino[2,1,6-cd]indolizin-5-yl)oxy)methyl(4-nitrophenyl)carbonate. LRMS (M+H) + :643.3.

[0073] Phase 2: (((11aS,11bR)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-4,6-dioxo-1,2,4,6,9,10,11a,11b-octahydro-8H-[1,3]oxazino[2′,3′:3,4]pyrazino[2,1,6-cd]indolizin-5-yl)oxy)methyl(2-(2-methoxyethoxy)ethyl)carbonate [ka] To a solution of (((11aS,11bR)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-4,6-dioxo-1,2,4,6,9,10,11a,11b-octahydro-8H-[1,3]oxazino[2',3':3,4]pyrazino[2,1,6-cd]indolizin-5-yl)oxy)methyl(4-nitrophenyl)carbonate (6.5 g, 10.1 mmol) in DCM (25.3 mL) was added 2-(2-methoxyethoxy)ethan-1-ol (11.9 mL, 101 mmol) followed by DMAP (0.25 g, 2.0 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was directly purified by flash chromatography (330 g RediSep Rf Gold; 30% to 100% 3:1 EtOAc / EtOH mixture / hexanes over 50 min; CombiFlash Rf system). A small amount of parent compound A co-elutes with the desired product 2. Fractions containing compound 2 were combined and concentrated. The residue was dissolved in DMSO and repurified by preparative reversed-phase chromatography (Waters XBridge™ 5 micron OBD™ 30×250 mm C18 column; 200-275 mg / injection; 20% to 80% MeCN / water + 0.1% TFA modifier over 27 min). The pure fractions were neutralized with saturated aqueous sodium bicarbonate, extracted with DCM, and concentrated to give (((11aS,11bR)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-4,6-dioxo-1,2,4,6,9,10,11a,11b-octahydro-8H-[1,3]oxazino[2',3':3,4]pyrazino[2,1,6-cd]indolizin-5-yl)oxy)methyl(2-(2-methoxyethoxy)ethyl)carbonate (Example 2). The material was then crystallized from 1:1 heptane / isopropyl acetate (300 mg / mL). 1H NMR (500MHz, chloroform-d) δ10.87(t, J=5.8Hz, 1H), 7.26(d, J=7.7Hz, 2H), 7.03(t, J=7.9Hz, 1H), 5.85(q, J=6.5Hz, 2H), 4.96(d, J= 3.3Hz, 1H), 4.76(dd, J=13.1, 4.3Hz, 1H), 4.59-4.70(m, 2H), 4.52(ddd,, J=10.7, 7.0, 3.2Hz, 1H), 4.39-4.28(m, 2H), 4.21(dd, J =11.6, 4.6Hz, 1H), 4.10(dd, J=19.1, 9.1Hz, 1H), 3.93(td, J=12.4, 2.2Hz, 1H), 3.74(t, J=4.9Hz, 2H), 3.66-3.61(m, 2H), 3.53(d d, J=5.5, 3.6Hz, 2H), 3.37(s, 3H), 3.33-3.41(m, 1H), 3.16-3.06(m, 1H), 2.27-2.43(m, 2H), 2.02(m, 1H), 1.55(d, J=13.7Hz, 1H). LRMS(M+H) + :624.3.

[0074] Example 3 [ka] Phase 1: (((11aS,11bR)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-4,6-dioxo-1,2,4,6,9,10,11a,11b-octahydro-8H-[1,3]oxazino[2′,3′:3,4]pyrazino[2,1,6-cd]indolizin-5-yl)oxy)methyl(3-(dimethylamino)propyl)carbonate·2,2,2-trifluoroacetate [ka] To a solution of (((11aS,11bR)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-4,6-dioxo-1,2,4,6,9,10,11a,11b-octahydro-8F[-[1,3]oxazino[2′,3′:3,4]pyrazino[2,1,6-cd]indolizin-5-yl)oxy)methyl(4-nitrophenyl)carbonate (1.09 g, 1.70 mmol) in DCM (8.5 mL) was added 3-(dimethylamino)propan-1-ol (2.97 mL, 25.4 mmol) followed by DMAP (21 mg, 0.17 mmol).

[0075] The resulting mixture was stirred at room temperature until the reaction was complete (LCMS showed the reaction was nearly complete after 3 hours.) The mixture was concentrated and the residue was dissolved in DMF and directly purified by preparative reverse phase chromatography (Phenomenex Luna 5 micron 50×250 mm C18 column; 2 injections; 5% to 70% MeCN / water + 0.1% TFA modifier over 30 minutes). Pure fractions were combined and concentrated under reduced pressure (azeotroped with MeCN) to give (((11aS,11bR)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-4,6-dioxo-1,2,4,6,9,10,11a,11b-octahydro-8H-[1,3]oxazino[2',3':3,4]pyrazino[2,1,6-cd]indolizin-5-yl)oxy)methyl(3-(dimethylamino)propyl)carbonate 2,2,2-trifluoroacetate. LRMS (M+H). + :607.4.

[0076] Phase 2:

[0077] [Table 2] TIFF2024507788000026.tif157160

[0078] (((11aS,11bR)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-4,6-dioxo-1,2,4,6,9,10,11a,11b-octahydro-8H-[1,3]oxazino[2',3':3,4]pyrazino[2,1,6-cd]indolizin-5-yl)oxy)methyl(3-(dimethylamino)propyl)carbonate hydrochloride [ka] To a solution of (((11aS,11bR)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-4,6-dioxo-1,2,4,6,9,10,11a,11b-octahydro-8H-[1,3]oxazino[2',3':3,4]pyrazino[2,1,6-cd]indolizin-5-yl)oxy)methyl(3-(dimethylamino)propyl)carbonate 2,2,2-trifluoroacetate (960 mg, 1.33 mmol) in MeOH (5 mL) was added 4N HCl / dioxane solution (4.24 mL, 16.95 mmol). The resulting mixture was stirred at room temperature for 5 min. The mixture was concentrated, redissolved in MeOH (5 mL), concentrated again, and dried under vacuum to give (((11aS,11bR)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-4,6-dioxo-1,2,4,6,9,10,11a,11b-octahydro-8H-[1,3]oxazino[2′,3′:3,4]pyrazino[2,1,6-cd]indolizin-5-yl)oxy)methyl(3-(dimethylamino)propyl)carbonate hydrochloride (Example 3). 1H NMR (500MHz, methanol-d4) δ7.40(t, J=7.6Hz, 1H), 7.34(t, J=6.8Hz, 1H), 7.14(t, J=7.9Hz, 1H), 5.83(d , J=6.8Hz, 1H), 5.65(d, J=6.8Hz, 1H), 5.21(d, J=3.3Hz, 1H), 4.74-4.59(m, 4H), 4.36-4.25(m, 2H), 4. 19(dd, J=11.4, 4.6Hz, 1H), 4.07-3.99(m, 1H), 3.99-3.89(m, 1H), 3.66(s, 3H), 3.41-3.33(m, 2H), 2.9 0(d, J=15.6Hz, 6H), 2.39-2.30(m, 2H), 2.22-2.11(m, 2H), 1.98-1.91(m, 1H), 1.60(d, J=13.4Hz, 1H). LRMS(M+H) + :607.4.

[0079] The compounds in the following table were prepared in a manner similar to that described for Example 1 above, using the appropriate starting materials.

[0080] Pharmacokinetic study in dogs Male beagle dogs (Marshall Farms) were used in the pharmacokinetic study. The study was conducted under a protocol approved by the WP-IACUC (Animal Procedure Statement#2018-600787-MAR). After an overnight fast, the dogs were orally administered 10 mg / kg and 25 mg / kg of compound A or one of the individual prodrugs at doses equivalent to 10 mg / kg and 25 mg / kg of the compound formulated as a suspension in either 0.5% methylcellulose + 0.25% sodium lauryl sulfate or 10% Tween 80-5 mM HCl. Food was returned 4 hours after dosing. Blood (0.5 mL) was collected into EDTA-coated blood collection tubes containing 25 μL of 2 mM dichlorvos aqueous solution at pre-dose, 0.25, 0.5, 1, 2, 4, 6, 24, 48, 72, 96, and 168 hours after dosing. Tubes were kept chilled prior to blood collection and throughout plasma separation. Plasma was separated by centrifugation (10,000 g for 2 min). Plasma samples were immediately frozen and kept at -70°C until analysis by LC-MS / MS.

[0081] [Table 3]

[0082] [Table 4]

[0083] As shown above, representative compounds of the present invention, Compounds 1 and 6, exhibit increased absorption relative to their metabolite, Compound A.

[0084] Treatment or prevention of HIV infection The tetracyclic heterocyclic compounds can be useful in inhibiting HIV, inhibiting HIV integrase, treating HIV infection and / or reducing the likelihood or severity of HIV infection, and inhibiting HIV viral replication and / or production in cell-based systems. For example, the tetracyclic heterocyclic compounds can be useful in treating infection by HIV where previous exposure to HIV is suspected, such as by blood transfusion, fluid exchange, biting, accidental needlestick, or exposure to a subject's blood during surgery or other medical procedure.

[0085] Thus, in one embodiment, the present invention provides a method for treating HIV infection in a subject, comprising administering to the subject an effective amount of at least one tetracyclic heterocyclic compound or a pharma- ceutically acceptable salt or prodrug thereof. In a specific embodiment, the amount administered is effective to treat or prevent infection by HIV in the subject. In another specific embodiment, the amount administered is effective to inhibit HIV viral replication and / or viral production in the subject. In one embodiment, the HIV infection has progressed to AIDS.

[0086] The tetracyclic heterocyclic compounds are also useful in the preparation and execution of screening assays for antiviral compounds. For example, the tetracyclic heterocyclic compounds may be useful in identifying resistant HIV cell lines that have mutations that are good screening tools for more potent antiviral compounds. Additionally, the tetracyclic heterocyclic compounds are useful in establishing or determining the binding site of other antiviral agents to HIV integrase.

[0087] The compositions and combinations of the present invention may be useful in treating subjects suffering from infection associated with any HIV genotype.

[0088] Combination therapy In another embodiment, the present invention for treating or preventing HIV infection can further comprise the administration of one or more additional therapeutic agents that are not Tetracyclic Heterocyclic Compounds.

[0089] In one embodiment, the additional therapeutic agent is an antiviral agent.

[0090] In another embodiment, the additional therapeutic agent is an immunomodulatory agent, such as an immunosuppressant.

[0091] Accordingly, in one embodiment, the invention provides a method of treating a viral infection in a subject, comprising administering to the subject (i) at least one tetracyclic heterocyclic compound (which can include two or more different tetracyclic heterocyclic compounds) or a pharma- ceutically acceptable salt or prodrug thereof, and (ii) an additional therapeutic agent other than the at least one tetracyclic heterocyclic compound, wherein the amounts administered are, in total, effective to treat or prevent the viral infection.

[0092] When administering the combination therapy of the present invention to a subject, the combined therapeutic agents or pharmaceutical composition (or pharmaceutical compositions) containing the therapeutic agents can be administered in any order, for example, sequentially, simultaneously, together, simultaneously, etc. The amounts of the various active agents in such combination therapy can be different amounts (different doses) or the same amounts (same doses). Thus, by way of example (and not limitation), the Tetracyclic Heterocyclic Compound and the additional therapeutic agent can be present in fixed amounts (doses) in a single dosage unit (e.g., capsule, tablet, etc.).

[0093] In one embodiment, at least one Tetracyclic Heterocyclic Compound is administered during the period during which the additional therapeutic agent exerts its prophylactic or therapeutic effect, or vice versa.

[0094] In another embodiment, at least one Tetracyclic Heterocyclic Compound and said additional therapeutic agent are administered in dosages typically used when such agents are used as monotherapy to treat viral infections.

[0095] In another embodiment, the at least one Tetracyclic Heterocyclic Compound and the additional therapeutic agent are administered in dosages that are lower than the dosages typically used when such agents are used as monotherapy to treat viral infections.

[0096] In yet another embodiment, the at least one Tetracyclic Heterocyclic Compound and the additional therapeutic agent act synergistically and are administered at dosages lower than those typically used when such agents are used as monotherapy to treat viral infections.

[0097] In one embodiment, the at least one Tetracyclic Heterocyclic Compound and the additional therapeutic agent are present in the same composition. In one embodiment, the composition is suitable for oral administration. In another embodiment, the composition is suitable for intravenous administration. In another embodiment, the composition is suitable for subcutaneous administration. In yet another embodiment, the composition is suitable for parenteral administration.

[0098] Viral infections and virus-related disorders that can be treated or prevented using the combination therapies of the present invention include, but are not limited to, those listed above.

[0099] In one embodiment, the viral infection is an HIV infection.

[0100] In another embodiment, the viral infection is AIDS.

[0101] The at least one tetracyclic heterocyclic compound and the additional therapeutic agent may act additively or synergistically. A synergistic combination may allow for lower dosages of one or more agents and / or less frequent administration of one or more agents of the combination therapy. Lowering the dosage or less frequent administration of one or more agents may reduce the toxicity of the therapy without reducing the efficacy of the therapy.

[0102] In one embodiment, administration of at least one Tetracyclic Heterocyclic Compound and the additional therapeutic agent can inhibit the resistance of a viral infection to these agents.

[0103] As mentioned above, the present invention also relates to the use of the compounds of formula I with one or more anti-HIV agents. An "anti-HIV agent" is an agent that is directly or indirectly effective in inhibiting HIV reverse transcriptase or another enzyme required for HIV replication or infection, treating or preventing HIV infection, and / or treating, preventing, or delaying the onset or progression of AIDS. It is clear that an anti-HIV agent is effective in treating, preventing, or delaying the onset or progression of HIV infection or AIDS and / or diseases or conditions resulting therefrom or related thereto. For example, the compounds of the present invention can be effectively administered in combination with an effective amount of one or more anti-HIV agents selected from HIV antiviral agents, immunomodulators, anti-infectives, or vaccines useful in treating HIV infection or AIDS, whether at pre-exposure and / or post-exposure time points. Suitable HIV antiviral agents for use in combination with the compounds of the present invention include, for example, those listed in Table A, as follows:

[0104] [Table 5] TIFF2024507788000031.tif145160

[0105] Some of the drugs listed in the table are used in the form of a salt, for example, abacavir sulfate, indinavir sulfate, atazanavir sulfate, nelfinavir mesylate.

[0106] In one embodiment, the one or more anti-HIV drugs are selected from lamivudine, abacavir, ritonavir, darunavir, atazanavir, emtricitabine, tenofovir, rilpivirine, doravirine, EFdA, and lopinavir.

[0107] In another embodiment, a compound of formula (I) is used in combination with lamivudine.

[0108] In yet another embodiment, a compound of formula (I) is used in combination with atazanavir.

[0109] In another embodiment, a compound of formula (I) is used in combination with darunavir.

[0110] In another embodiment, a compound of formula (I) is used in combination with rilpivirine.

[0111] In one embodiment, a compound of formula (I) is used in combination with lamivudine and abacavir.

[0112] In another embodiment, a compound of formula (I) is used in combination with islatravir.

[0113] In another embodiment, the compound of formula (I) is used in combination with emtricitabine and tenofovir.

[0114] In yet another embodiment, a compound of formula (I) is used in combination with doravirine.

[0115] In yet another embodiment, a compound of formula (I) is used in combination with doravirine, lamivudine and tenofovir DF.

[0116] In another embodiment, the compound of formula (I) is used in combination with ritonavir and lopinavir.

[0117] In one embodiment, a compound of formula (I) is used in combination with abacavir and lamivudine.

[0118] In another embodiment, the compound of formula (I) is used in combination with lopinavir and ritonavir.

[0119] In one embodiment, the invention provides a pharmaceutical composition comprising: (i) a compound of formula (I) or a pharma- ceutically acceptable salt or prodrug thereof; (ii) a pharma- ceutically acceptable carrier; and (iii) one or more additional anti-HIV agents selected from lamivudine, abacavir, ritonavir, islatravir, doravirine and lopinavir or pharma- ceutically acceptable salts or prodrugs thereof, wherein the amounts of components (i) and (iii) present together are effective in the treatment or prevention of infection by HIV or the treatment, prevention, or delay of the onset or progression of AIDS in a subject in need of such treatment.

[0120] In another embodiment, the present invention provides a method for the treatment or prevention of infection by HIV or the treatment, prevention, or delay of the onset or progression of AIDS in a subject in need of such treatment, comprising administering to the subject (i) a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof and (ii) one or more additional anti-HIV agents selected from lamivudine, abacavir, ritonavir, islatravir, doravirine and lopinavir or pharmaceutically acceptable salts or prodrugs thereof, wherein the administered amounts of components (i) and (ii) together are effective in the treatment or prevention of infection by HIV or the treatment, prevention, or delay of the onset or progression of AIDS in a subject in need of such treatment.

[0121] It will be understood that the scope of combinations of the compounds of the invention with anti-HIV agents is not limited to the HIV antivirals listed in Table A, but includes essentially any combination with any pharmaceutical composition useful in the treatment or prevention of AIDS. The HIV antivirals and other agents are typically used in these combinations according to conventional dosage ranges and regimens reported in the art, e.g., Physicians' Desk Reference , Thomson PDR, Thomson PDR, 57th Edition (2003), 58th Edition (2004), 59th Edition (2005), etc. In these combinations, the dosage ranges for the compounds of the invention are the same as those described above.

[0122] The dose and administration method of the other drug used in the combination therapy of the present invention for the treatment or prevention of HIV infection can be determined by the attending physician, taking into consideration the dose and administration method approved in the package insert; the age, sex, and general health of the subject; and the type and severity of the viral infection or related disease or disorder. When administered in combination, the tetracyclic heterocyclic compound(s) and the other drug(s) can be administered simultaneously (i.e., one immediately after the other in the same composition or in separate compositions) or sequentially. This is particularly useful when the components of the combination are administered on different administration schedules (e.g., one component is administered once a day and another component is administered every 6 hours) or when the pharmaceutical compositions are different (e.g., one component is a tablet and one component is a capsule). Therefore, a kit containing separate formulations is advantageous.

[0123] Compositions and Administration When administered to a subject, the tetracyclic heterocyclic compound may be administered as a component of a composition that includes a pharma- ceutically acceptable carrier or vehicle. The present invention provides a pharmaceutical composition that includes an effective amount of at least one tetracyclic heterocyclic compound and a pharma- ceutically acceptable carrier. In the pharmaceutical compositions and methods of the present invention, the active ingredient is typically administered in admixture with a suitable carrier material selected appropriately for the intended administration form, i.e., oral tablets, capsules (either solid-filled, semi-solid-filled or liquid-filled), powders for construction, oral gels, elixirs, dispersible granules, syrups, suspensions, etc., and consistent with conventional pharmaceutical practice. For example, for oral administration in the form of tablets or capsules, the active drug ingredient may be combined with any oral non-toxic pharma- ceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid form), etc. The solid formulations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may comprise about 0.5 to about 95 percent of the composition of the present invention. Tablets, powders, cachets and capsules may be used as solid formulations suitable for oral administration.

[0124] Furthermore, if desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and wax.Among the lubricants for use in such preparations, boric acid, sodium benzoate, sodium acetate, sodium chloride and the like can be included.Disintegrating agents include starch, methylcellulose, guar gum and the like.Sweeteners and flavoring agents and preservatives can also be included if appropriate.

[0125] Liquid preparations include solutions, suspensions and emulsions, and may include water or water-propylene glycol solutions for parenteral injection.

[0126] Liquid formulations may also include solutions for intranasal administration.

[0127] It also includes solid preparations which are intended to be converted, shortly before use, to liquid preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions.

[0128] For preparing suppositories, a low melting wax (such as a mixture of fatty acid glycerides or cocoa butter) is first melted and the active ingredient is dispersed homogeneously therein by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

[0129] Additionally, the compositions of the present invention may be formulated in sustained release form to provide rate controlled release of any one or more components or active ingredients to optimize therapeutic effects (i.e., antiviral activity, etc.) Formulations suitable for sustained release include layered tablets containing layers of different disintegration rates or controlled release polymer matrices impregnated with the active ingredient and formed into tablet form or capsules containing such impregnated or encapsulated porous polymer matrices.

[0130] In one embodiment, the one or more tetracyclic heterocyclic compounds are administered orally.

[0131] In another embodiment, the one or more tetracyclic heterocyclic compounds are administered intravenously.

[0132] In one embodiment, the pharmaceutical preparation containing at least one Tetracyclic Heterocyclic Compound is a unit dosage form. In such form, the preparation is subdivided into unit doses containing effective amounts of the active components.

[0133] The composition can be prepared according to any of the conventional mixing, granulation, or coating methods, and the composition of the present invention may contain, in one embodiment, about 0.1% to about 99% of the tetracyclic heterocyclic compound(s) by weight or volume. In various embodiments, the composition of the present invention may contain, in one embodiment, about 1% to about 70% or about 5% to about 60% of the tetracyclic heterocyclic compound(s) by weight or volume.

[0134] The compounds of formula I can be administered orally in a dosage range of 0.001 to 1000 mg / kg of mammalian (e.g., human) body weight per day, in single or divided doses. One dosage range is 0.01 to 500 mg / kg of body weight per day, orally, in single or divided doses. Another dosage range is 0.1 to 100 mg / kg of body weight per day, orally, in single or divided doses. For oral administration, the composition can be provided in the form of tablets or capsules containing 1.0 to 500 milligrams of active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 milligrams of active ingredient, in order to adjust the dosage to suit the symptoms of the subject being treated. The specific dose level and frequency of administration for a particular subject may vary and will depend on a variety of factors, including the activity of the particular compound employed, the metabolic stability and duration of action of that compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, concomitant medications, the severity of the particular condition, and the host being treated.

[0135] For convenience, if desired, the total daily dose may be divided and administered in portions throughout the day. In one embodiment, the daily dose is administered in one dose. In another embodiment, the total daily dose is administered in two separate doses over a 24 hour period. In another embodiment, the total daily dose is administered in three separate doses over a 24 hour period. In yet another embodiment, the total daily dose is administered in four separate doses over a 24 hour period.

[0136] The unit dose of the tetracyclic heterocyclic compound can be administered at various times. In one embodiment, the unit dose of the tetracyclic heterocyclic compound can be administered once a day. In another embodiment, the unit dose of the tetracyclic heterocyclic compound can be administered twice a week. In another embodiment, the unit dose of the tetracyclic heterocyclic compound can be administered once a week. In yet another embodiment, the unit dose of the tetracyclic heterocyclic compound can be administered once every two weeks. In another embodiment, the unit dose of the tetracyclic heterocyclic compound can be administered once a month. In yet another embodiment, the unit dose of the tetracyclic heterocyclic compound can be administered once every two months. In another embodiment, the unit dose of the tetracyclic heterocyclic compound can be administered once every three months. In yet another embodiment, the unit dose of the tetracyclic heterocyclic compound can be administered once every six months. In another embodiment, the unit dose of the tetracyclic heterocyclic compound can be administered once a year.

[0137] The amount and frequency of administration of the tetracyclic heterocyclic compound will be adjusted according to the judgment of the attending physician, taking into consideration factors such as the age, physical condition and size of the subject, and the severity of the condition being treated. The compositions of the present invention may further comprise one or more additional therapeutic agents selected from those described herein above.

[0138] kit In one aspect, the invention provides a kit comprising a therapeutically effective amount of at least one tetracyclic heterocyclic compound, or a pharma- ceutically acceptable salt or prodrug of said compound, and a pharma- ceutically acceptable carrier, vehicle, or diluent.

[0139] In another aspect, the present invention provides a kit comprising an amount of at least one tetracyclic heterocyclic compound or a pharma- ceutically acceptable salt or prodrug of said compound and an amount of at least one additional therapeutic agent as described above, wherein the amounts of the two or more active ingredients provide a desired therapeutic effect. In one embodiment, the one or more tetracyclic heterocyclic compounds and the one or more additional therapeutic agents are provided in the same container. In one embodiment, the one or more tetracyclic heterocyclic compounds and the one or more additional therapeutic agents are provided in separate containers.

[0140] The present invention is not limited by the specific embodiments disclosed in the illustrative examples of certain aspects of the invention, and all functionally equivalent embodiments are intended to be within the scope of the present invention. Indeed, various modifications of the invention in addition to those shown and described herein will be apparent to those skilled in the art and are intended to be encompassed by the appended claims.

[0141] A number of references are cited herein, the entire disclosures of which are incorporated herein by reference.

Claims

1. A compound having the formula (I): or a pharma- ceutically acceptable salt of said compound: 【Chemistry 1】 [In the formula, R １ is CHR ２ -O-C(O)-Y-R ３ , C(O)-C １ -C １０ Alkyl, CHR ２ -OP(O)(OH) ２ or 【Chemistry 2】 and Y is a bond or -O-; R ２ is hydrogen or C １ -C ６ is alkyl; R ３ is C １ -C ６ Alkyl, (CH ２ ) ｘ -O-C １ -C ６ Alkyl, and (CH ２ ) ｘ -NR ４ R ５ wherein said C １ -C ６ The alkyl group is optionally substituted with 1 to 3 groups independently selected from the group consisting of halo, hydroxy, methoxy and ethoxy; R ４ is hydrogen or C １ -C ６ is alkyl; R ５ is hydrogen or C １ -C ６ is alkyl; x is an integer from 1 to 4.

2. 2. The compound of claim 1, wherein Y is O; or a pharma- ceutically acceptable salt thereof.

3. R ２ 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen or methyl.

4. R ３ is optionally substituted with 1 to 3 groups independently selected from the group consisting of halo, hydroxy, methoxy and ethoxy; １ -C ６ 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

5. R ３ (CH ２ ) ｘ -O-C １ -C ６ 3. The compound of claim 1 or 2, wherein x is alkyl and x is 2; or a pharma- ceutically acceptable salt thereof.

6. R ３ (CH ２ ) ｘ -NR ４ R ５ 3. The compound of claim 1 or 2, wherein:

7. R ４ is methyl, R ５ 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein is methyl.

8. R １ but, 【Chemistry 3】 3. The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, selected from:

9. R １ but, 【Chemistry 4】 3. The compound of claim 1 or 2, wherein:

10. The following structure: 【Chemistry 5】 2. The compound of claim 1, having the formula:

11. 19. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1, 2 and 10, or a pharma- ceutically acceptable salt of said compound, and a pharma- ceutically acceptable carrier.

12. 19. Use of a compound according to any one of claims 1, 2 and 10, or a pharma- ceutically acceptable salt of said compound, in the manufacture of a medicament for the inhibition of HIV integrase in a subject in need of such treatment.

13. 19. Use of a compound according to any one of claims 1, 2 and 10, or a pharma- ceutically acceptable salt of said compound, in the manufacture of a medicament for the treatment of infection by HIV, or the treatment, prevention or delay of the onset or progression of AIDS in a subject in need of such treatment.

14. 17. A compound according to any one of claims 1, 2 and 10, or a pharma- ceutically acceptable salt of said compound, for use in the manufacture of a medicament for inhibiting HIV integrase, treating or preventing infection by HIV, or treating, preventing, or delaying the onset or progression of AIDS in a patient in need of such treatment.

15. 19. A compound according to any one of claims 1, 2 and 10, or a pharma- ceutically acceptable salt thereof, for use in therapy.

16. 12. The composition of claim 11, further comprising one or more additional therapeutic agents selected from the group consisting of raltegravir, lamivudine, abacavir, ritonavir, dolutegravir, arunavir, atazanavir, emtricitabine, tenofovir, elvitegravir, rilpivirine, lopinavir, doravirine, and islatravir.

17. 14. The use of claim 13, wherein the compound or a pharma- ceutically acceptable salt of the compound is further administered in combination with one or more additional therapeutic agents selected from the group consisting of raltegravir, lamivudine, abacavir, ritonavir, dolutegravir, arunavir, atazanavir, emtricitabine, tenofovir, elvitegravir, rilpivirine, lopinavir, doravirine, and islatravir, and the administered amounts of the compound or a pharma- ceutically acceptable salt of the compound and the one or more additional therapeutic agents are, in total, effective to treat infection by HIV or to treat, prevent, or delay the onset or progression of AIDS.

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