Tetracyclic heterocyclic compounds useful as HIV integrase inhibitors

Abstract

The present invention relates to tetracyclic heterocyclic compounds of Formula (I): and pharmaceutically acceptable salts or prodrugs thereof, wherein R 1 as defined herein. The present invention also relates to 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.

Description

Invention Field

[0001] This invention relates to tetracyclic heterocyclic compounds, compositions comprising at least one tetracyclic heterocyclic compound, and methods of treating or preventing HIV infection in subjects using said tetracyclic heterocyclic compounds. Background of the Invention

[0003] Retroviruses, known as human immunodeficiency virus (HIV), particularly strains called HIV type 1 (HIV-1) and HIV type 2 (HIV-2), are pathogens responsible for complex diseases including progressive destruction of the immune system (acquired immunodeficiency 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 via a virus-encoded integrase, a necessary step for HIV replication in human T-lymphoblast-like cells and monocyte-like cells. Integration is thought to be mediated by integrase in three steps: the assembly of a stable nucleoprotein complex with the viral DNA sequence; the cleavage of two nucleotides from the 3' end of the linear proviral DNA; and the covalent attachment of the recessed 3' OH end of the proviral DNA at an interleaved cleavage site formed at the host target site. The fourth step in this process—the repair synthesis of the resulting gap—is achieved by cellular enzymes.

[0004] Nucleotide sequencing of HIV revealed the presence of the pol gene within an 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.

[0005] It is known that some antiviral compounds that act as HIV replication inhibitors are effective drugs for treating AIDS and similar diseases, including reverse transcriptase inhibitors such as azidothymidine (AZT) and efavirenz, and protease inhibitors such as indinavir and nelfinavir. The compounds of this invention are HIV integrase inhibitors and HIV replication inhibitors. Invention Overview

[0007] In one aspect, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0008]

[0009] in:

[0010] R1 It is CHR 2 -OC(O)-YR 3 C(O)-C1-C 10 Alkyl, CHR 2 -OP(O)(OH)2 or

[0011]

[0012] Y represents a key or -O-;

[0013] R 2 It is hydrogen or C1-C6 alkyl;

[0014] R 3 Selected from C1-C6 alkyl groups, (CH2) x -O-C1-C6 alkyl groups and (CH2) x -NR 4 R 5 The C1-C6 alkyl group may optionally be substituted with one to three groups independently selected from halogen, hydroxy, methoxy and ethoxy groups;

[0015] R 4 It is hydrogen or C1-C6 alkyl;

[0016] R 5 It is hydrogen or C1-C6 alkyl;

[0017] x is an integer from 1 to 4.

[0018] Compounds of formula (I) (also referred to herein as “tetracyclic heterocyclic compounds”) and their pharmaceutically acceptable salts or prodrugs may be used, for example, to inhibit HIV viral replication or replicon activity, or to treat or prevent HIV infection in subjects. Without being bound by any particular theory, it is believed that the tetracyclic heterocyclic compounds inhibit HIV viral replication by inhibiting HIV integrase.

[0019] Therefore, 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 pharmaceutically acceptable salt thereof.

[0020] The details of the invention are set forth in the accompanying description.

[0021] Exemplary methods and materials are now described, although any methods and materials similar to those described herein may be used in the practice or testing of the invention. Further embodiments, aspects, and features of the invention are further described or will become apparent in the following description, examples, and appended claims. Invention Details

[0023] The present invention includes tetracyclic heterocyclic compounds, compositions comprising at least one tetracyclic heterocyclic compound, and methods for treating or preventing HIV infection in subjects using said tetracyclic heterocyclic compounds.

[0024] Definitions and abbreviations

[0025] The terms used herein have their common meanings and their meanings are independent each time they appear. Nevertheless, and unless otherwise specified, the following definitions apply throughout this specification and claims. Chemical names, common names, and chemical structures are used interchangeably to describe the same structure. Unless otherwise specified, these definitions apply whether a term is used alone or in combination with other terms. Therefore, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portion of "hydroxyalkyl," "haloalkyl," "-O-alkyl," etc.

[0026] Unless otherwise specified, the following terms used throughout this document and disclosure shall be understood to have the following meanings:

[0027] The “object” is a human or a non-human mammal. In one embodiment, the object is a human. In another embodiment, the object is a primate. In yet another embodiment, the object is a monkey. In another embodiment, the object is a chimpanzee. In still another embodiment, the object is a rhesus monkey.

[0028] As used herein, the term "effective amount" refers to the amount of a tetracyclic heterocyclic compound and / or other therapeutic agent or combination thereof that, when administered to a subject with HIV infection or AIDS, effectively inhibits HIV replication and produces the desired therapeutic, ameliorative, inhibitory, or preventative effect. In the combination therapy of the present invention, the effective amount may refer to individual agents or the entire combination, wherein the amounts of all agents administered are effective together, but wherein the constituent agents of the combination may not be present individually in an effective amount.

[0029] Regarding HIV infection or AIDS, the term "treatment" as used in this article includes suppressing the severity of HIV infection or AIDS, that is, preventing or reducing the development of HIV infection or AIDS or their clinical symptoms; or alleviating HIV infection or AIDS, that is, the reduction of the severity of HIV infection or AIDS or their clinical symptoms.

[0030] Regarding HIV infection or AIDS, the terms “preventing” or “prophylaxis” used in this article refer to reducing the likelihood or severity of HIV infection or AIDS.

[0031] As used herein, the term "alkyl" refers to an aliphatic hydrocarbon group in which one of its hydrogen atoms is replaced by a bond. Alkyl groups can be straight-chain or branched and contain from about 1 to about 20 carbon atoms. In one embodiment, the alkyl group contains from about 1 to about 12 carbon atoms. In various embodiments, the alkyl group contains from 1 to 6 carbon atoms (C1-C6 alkyl) or from about 1 to about 10 carbon atoms (C1-C6 alkyl). 10 Alkyl groups. Non-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, the alkyl group is straight-chain. In another embodiment, the alkyl group is branched. Unless otherwise specified, the alkyl group is unsubstituted.

[0032] The term "halogenated" as used in this article refers to -F, -Cl, -Br, or -I.

[0033] The term "substituted" means that one or more hydrogen atoms on a specified atom are replaced by a group selected from the indicated group, provided that the substitution does not exceed the normal valence of the specified atom under its current condition and that the substitution produces a stable compound. Combinations of substituents and / or variables are only permitted if such combinations produce a stable compound. A "stable compound" or "stable structure" means that the compound is robust enough to withstand separation from the reaction mixture to a usable purity and formulation into an effective therapeutic agent.

[0034] As used herein, the term "basic purified form" refers to the physical state of a compound after it has been isolated from a synthetic process (e.g., from a reaction mixture), a natural source, or a combination thereof. The term "basic purified form" also refers to the physical state of a compound after it has been obtained with a purity sufficient to be characterized by standard analytical techniques described herein or known to those skilled in the art (e.g., chromatography, recrystallization, etc.).

[0035] It should also be noted that any carbon atoms with unsaturated valences and heteroatoms in the text, schemes, embodiments and tables herein are assumed to have a number of hydrogen atoms sufficient to saturate their valences.

[0036] When a functional group in a compound is referred to as “protected,” it means that the group is in a modified form to exclude unwanted side reactions at the protected site when the compound reacts. Those skilled in the art, as well as by referring to standard textbooks such as T.W. Greene et al., Protective Groups in Organic Synthesis (1991), Wiley, New York, can identify suitable protecting groups.

[0037] Unless otherwise specified, when any substituents or variables (e.g., R) 4When a ) appears more than once in any component or in formula (I), its definition at each place is independent of its definition at every other place.

[0038] As used herein, the term "composition" is intended to cover products containing specified amounts of specified ingredients, and any product obtained from a combination of specified amounts of specified ingredients.

[0039] The compound of the present invention is a prodrug 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]indazine-3-carboxamide, also known as compound A, and has the following chemical structure:

[0040]

[0041] 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]indazine-3-carboxamide and its ability to inhibit HIV integrase are described in PCT International Application WO2018 / 102485, published June 7, 2018, by Merck Sharp & Dohme Corp., the entire contents of which are incorporated herein by reference.

[0042] The term "prodrug" refers to a compound that is converted in vivo to provide a pharmacologically active compound or a pharmaceutically acceptable salt of that compound (e.g., a drug prodrug). This conversion can occur through various mechanisms (e.g., through metabolic or chemical processes), such as hydrolysis in the blood.

[0043] This document also considers solvates of the compounds of the present invention.

[0044] One or more compounds of the present invention may exist in unsolvated and solvated forms in pharmaceutically acceptable solvents such as water, ethanol, etc., and the present invention is intended to cover both solvated and unsolvated forms. "Solvate" refers to the 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, including hydrogen bonding. In some cases, solvates can segregate, for example, when one or more solvent molecules are incorporated into the lattice of a crystalline solid. "Solvate" includes solution phases and segregable solvates. Non-limiting examples of solvates include ethanolides, methanolides, etc. "Hydrate" is a solvate in which the solvent molecule is water.

[0045] One or more compounds of the present invention may optionally be converted into solvates. The preparation of solvates is well known. Thus, for example, M. Caira et al., J. Pharmaceutical Sci., 93(3) ,601-611 (2004) describes the solvation of the antifungal agent fluconazole in ethyl acetate and from water. EC van Tonder et al., AAPSPharmSciTechours., 5(1) Article 12 (2004) and ALBingham et al., Chem. Commun., 603-604 (2001) describe similar preparations of solvates, semi-solvates, hydrates, etc. Typical non-limiting methods involve dissolving the compounds of the invention in a desired amount of a desired solvent (organic solvent or water or a mixture thereof) at above room temperature, cooling the solution at a rate sufficient to form crystals, and then separating the crystals by standard methods. Analytical techniques, such as infrared spectroscopy, indicate that the solvent (or water) is present in the crystals as a solvate (or hydrate).

[0046] Tetracyclic heterocyclic compounds can form salts, which are also within the scope of this invention. Unless otherwise specified, reference to a tetracyclic heterocyclic compound herein is understood to include reference to its salts. The term "salt" as used herein refers to an acidic salt formed with inorganic and / or organic acids, and a basic salt formed with inorganic and / or organic bases. Furthermore, when a tetracyclic heterocyclic compound contains both a basic moiety (e.g., but not limited to pyridine or imidazole) and an acidic moiety (e.g., but not limited to carboxylic acids), a zwitterion ("internal salt") can be formed and included in the term "salt" as used herein. In one embodiment, the salt is a pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salt. In another embodiment, the salt is not a pharmaceutically acceptable salt. Salts of compounds of formula (I) can be formed, for example, by reacting a tetracyclic heterocyclic compound with a certain amount (e.g., equivalent) of an acid or base in a medium (e.g., a medium in which the salt precipitates) or an aqueous medium and subsequently lyophilizing.

[0047] Exemplary acid addition salts include acetates, ascorbic acid salts, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodates, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates (also known as tosylates), etc. Additionally, for example, P. Stahl et al., Camille G. (ed.) 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, InternationalJ.ofPharmaceutics(1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC on its website) discuss acids generally considered suitable for forming pharmaceutically usable salts from basic pharmaceutical compounds. These publications are hereby cited and incorporated herein by reference.

[0048] 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) such as dicyclohexylamine, tert-butylamine, and choline, and salts with amino acids such as arginine and lysine. The basic nitrogen-containing group can be quaternized with reagents such as lower alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, and butyl), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, and dibutyl sulfate), long-chain halides (e.g., chlorides, bromides, and iodides of decyl, dodecyl, and octadecyl), and aralkyl halides (e.g., benzyl bromide and phenethyl bromide).

[0049] All such acid salts and basic salts are meant to be pharmaceutically acceptable salts within the scope of this invention, and for the purposes of this invention, all acid salts and basic salts are considered equivalent to the free form of the corresponding compound.

[0050] A mixture of diastereomers can be separated into their individual diastereomers based on their physicochemical differences using methods known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated as follows: by reacting the enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acyl chloride), separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers into their respective pure enantiomers. Stereochemically pure compounds can also be prepared using chiral raw materials or salt resolution techniques. Some tetracyclic heterocyclic compounds can also be transisomers (e.g., substituted biaromatics) and are considered part of this invention. Enantiomers can also be directly separated using chiral chromatography.

[0051] This tetracyclic heterocyclic compound may also exist in different tautomeric forms, and all such forms are covered within the scope of this invention. For example, all keto-enol and imine-enamine forms of this compound are included in this invention.

[0052] Unless otherwise specified, all stereoisomers of the compounds of this invention (e.g., geometric isomers, optical isomers, etc.) (including all stereoisomers of the salts, solvates, hydrates, esters, and prodrugs of the compounds, as well as all stereoisomers of the salts, solvates, and esters of the prodrugs), such as those stereoisomers that may exist due to asymmetric carbons on various substituents, including enantiomers (which may exist even if the asymmetric carbon is not present), rotational isomers, trans-blocking isomers, and diastereoisomeric forms, are considered to be within the scope of this invention. If the tetracyclic heterocyclic compound contains a double bond or a fused ring, the cis- and trans-forms, as well as mixtures thereof, are covered within the scope of this invention.

[0053] When a substituent on a chiral carbon atom is described as having no specific stereochemistry (by using a straight bond to the chiral center), it should be understood that both the α and β configurations of the substituent are considered part of this invention. For example, the compounds of this invention are described as follows:

[0054]

[0055] The two stereoisomers, understood to be encompassed at the chiral center shown, have the following structures:

[0056]

[0057] The "right-side" fused ring of the compound of formula (I) The NC bond in the matrix can exist in any feasible orientation.

[0058] In the Examples section below, compounds of the invention that have been purified into individual stereoisomers are sometimes described in a non-stereospecific form, but are identified using one or more terms: “diastereomer 1,” “diastereomer 2,” “isomer 1,” “isomer 2,” “enantiomer A,” and “enantiomer B.” In this case, the absolute stereochemistry of each isolated diastereomer and enantiomer center has not been determined, and the terms used above are used to denote each individually purified stereochemically pure compound.

[0059] The stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers or may, for example, be mixed as racemates or mixed with all other stereoisomers or other selected stereoisomers. The chiral center of the present invention may have an S or R configuration as defined in IUPAC 1974 Recommendations. The terms “salt,” “solvent,” etc., are intended to equally apply to salts and solvates of enantiomers, stereoisomers, rotational isomers, tautomers, or racemates of the compounds of the present invention.

[0060] In compounds of formula (I), atoms may exhibit their natural isotopic abundances, or one or more atoms may be artificially enriched with specific isotopes having the same atomic number but different atomic masses or mass numbers from those predominantly found in nature. This invention is intended to include all suitable isotopic variants of compounds of general formula I. For example, different isotopic forms of hydrogen (H) include protium (… 1 H) and deuterium ( 2 H). Protium is the main hydrogen isotope found in nature. Enrichment of deuterium can provide certain therapeutic advantages, such as increased in vivo half-life or reduced dose requirements, or can provide compounds that can be used as characterization standards for biological samples. Isotope-enriched compounds of formula (I) can be prepared using conventional techniques known to those skilled in the art or methods similar to those described in the schemes and examples herein, using appropriate isotope-enriching reagents and / or intermediates, without the need for excessive experimentation. In one embodiment, one or more hydrogen atoms of the compound of formula (I) are replaced by deuterium.

[0061] This tetracyclic heterocyclic compound can be used in human and veterinary medicines for the treatment or prevention of HIV infection. In one embodiment, the tetracyclic heterocyclic compound can be an inhibitor of HIV viral replication. In a specific embodiment, the tetracyclic heterocyclic compound is an inhibitor of HIV-1. Therefore, this tetracyclic heterocyclic compound can be used to treat HIV infection and AIDS. According to the present invention, the tetracyclic heterocyclic compound can be administered to individuals who require treatment or prevention of HIV infection.

[0062] Therefore, 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 pharmaceutically acceptable salt thereof. In 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 pharmaceutically acceptable salt thereof.

[0063] Compound of formula (I)

[0064] This invention provides tetracyclic heterocyclic compounds of formula (I):

[0065]

[0066] Or its pharmaceutically acceptable salt.

[0067] in:

[0068] R 1 It is CHR 2 -OC(O)-YR 3 C(O)-C1-C 10 Alkyl, CHR 2 -OP(O)(OH)2 or

[0069]

[0070] Y represents a key or -O-;

[0071] R 2 It is hydrogen or C1-C6 alkyl;

[0072] R 3 Selected from C1-C6 alkyl groups, (CH2) x -O-C1-C6 alkyl groups and (CH2) x -NR 4 R 5 The C1-C6 alkyl group may optionally be substituted with one to three groups independently selected from halogen, hydroxy, methoxy and ethoxy groups;

[0073] R 4 It is hydrogen or C1-C6 alkyl;

[0074] R 5 It is hydrogen or C1-C6 alkyl;

[0075] x is an integer from 1 to 4.

[0076] In one embodiment of the invention, R 1 It is CHR 2 -OC(O)-YR 3 In another embodiment of the invention, R1 It is C(O)-C1-C 10 Alkyl group. In another embodiment of the invention, R 1 It is CHR 2 -OP(O)(OH)2. In another embodiment of the invention, R 1 yes In one type of implementation, R 1 Selected from:

[0077]

[0078] In one subclass implementation, R 1 yes

[0079] In one embodiment of the invention, R 2 It is hydrogen or methyl. In one type of implementation, R 2 It is hydrogen. In another type of implementation, R 2 It is a methyl group.

[0080] In one embodiment of the invention, R 3 It is a C1-C6 alkyl group, optionally substituted with one to three groups independently selected from halogen, hydroxyl, methoxy, and ethoxy groups. In another embodiment of the invention, R 3 It is (CH2) x -O-C1-C6 alkyl. In another embodiment of the invention, R 3 It is (CH2) x -NR 4 R 5 .

[0081] In one embodiment of the invention, R 4 It is a methyl group.

[0082] In one embodiment of the invention, R 5 It is a methyl group.

[0083] In one embodiment of the invention, Y is -O-. In another embodiment of the invention, Y is a bond.

[0084] 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 yet another embodiment of the invention, x is 4.

[0085] In another embodiment, the compound of formula (I) is in its basic purified form.

[0086] It should be understood that any of the aforementioned implementation schemes can be combined with one or more individual implementation schemes.

[0087] Other embodiments of the present invention include the following:

[0088] (a) A pharmaceutical composition comprising an effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier.

[0089] (b)(a) a pharmaceutical composition further comprising a second therapeutic agent selected from HIV antiviral agents, immunomodulators and anti-infective agents.

[0090] (c)(b) pharmaceutical compositions, wherein the HIV antiviral agent is an antiviral agent selected from HIV NRTI (nucleoside reverse transcriptase inhibitor) and HIV NNRTI (non-nucleoside reverse transcriptase inhibitor).

[0091] (d) A pharmaceutical combination comprising (i) a compound of formula (I) and (ii) a second therapeutic agent selected from HIV antiviral agents, immunomodulators and anti-infective agents; wherein the compound of formula (I) and the second therapeutic agent are each used in an amount that enables the combination to effectively inhibit HIV replication or effectively treat HIV infection and / or reduce the likelihood of HIV infection or the severity of symptoms.

[0092] The combination of (e) and (d), wherein the HIV antiviral agent is an antiviral agent selected from HIV NRTI (nucleoside reverse transcriptase inhibitor) and HIV NNRTI (non-nucleoside reverse transcriptase inhibitor).

[0093] (f) A method for inhibiting HIV replication in a subject in which it is needed, comprising administering an effective amount of a compound of formula (I) to the subject.

[0094] (g) A method for treating HIV infection and / or reducing the likelihood of HIV infection or the severity of symptoms in a subject in need, comprising administering an effective amount of a compound of formula (I) to the subject.

[0095] The method of (h)(g) wherein the compound of formula (I) is administered in combination with an effective amount of at least one second therapeutic agent selected from HIV antiviral agents, immunomodulators and anti-infective agents.

[0096] The method of (i)(h), wherein the HIV antiviral agent is an antiviral agent selected from HIV NRTI (nucleoside reverse transcriptase inhibitor) and HIV NNRTI (non-nucleoside reverse transcriptase inhibitor).

[0097] (j) A method for inhibiting HIV replication in a subject in which it is desired, comprising administering to the subject a pharmaceutical composition of (a), (b) or (c) or a combination of (d) or (e).

[0098] (k) A method of treating HIV infection and / or reducing the likelihood of HIV infection or the severity of symptoms in a subject in need of it, comprising administering to said subject a pharmaceutical composition of (a), (b) or (c) or a combination of (d) or (e).

[0099] Other embodiments of the present invention include the following:

[0100] (l) A pharmaceutical composition comprising an effective amount of a pharmaceutically acceptable salt of a compound of formula (I) and a pharmaceutically acceptable carrier.

[0101] The pharmaceutical composition (m)(l) further comprises a second therapeutic agent selected from HIV antiviral agents, immunomodulators and anti-infective agents.

[0102] The pharmaceutical composition of (n)(m), wherein the HIV antiviral agent is an antiviral agent selected from HIV NRTI (nucleoside reverse transcriptase inhibitor) and HIV NNRTI (non-nucleoside reverse transcriptase inhibitor).

[0103] (o) A pharmaceutical combination comprising (i) a pharmaceutically acceptable salt of a compound of formula (I) and (ii) a second therapeutic agent selected from HIV antiviral agents, immunomodulators and anti-infective agents; wherein the pharmaceutically acceptable salt of the compound of formula (I) and the second therapeutic agent are each used in an amount that enables the combination to effectively inhibit HIV replication or effectively treat HIV infection and / or reduce the likelihood of HIV infection or the severity of symptoms.

[0104] The combination of (p)(o), wherein the HIV antiviral agent is an antiviral agent selected from HIV NRTI (nucleoside reverse transcriptase inhibitor) and HIV NNRTI (non-nucleoside reverse transcriptase inhibitor).

[0105] (q) A method for inhibiting HIV replication in a subject in which it is desired, comprising administering to the subject an effective amount of a pharmaceutically acceptable salt of a compound of formula (I).

[0106] (r) A method for treating HIV infection and / or reducing the likelihood of HIV infection or the severity of symptoms in a subject who requires it, comprising administering to the subject an effective amount of a pharmaceutically acceptable salt of a compound of formula (I).

[0107] The method of (s)(r) wherein a pharmaceutically 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 HIV antiviral agents, immunomodulators and anti-infective agents.

[0108] The method of (t)(s), wherein the HIV antiviral agent is an antiviral agent selected from HIV NRTI (nucleoside reverse transcriptase inhibitor) and HIV NNRTI (non-nucleoside reverse transcriptase inhibitor).

[0109] (u) A method for inhibiting HIV replication in a subject in which it is desired, comprising administering to the subject a pharmaceutical composition of (l), (m), or (n) or a combination of (o) or (p).

[0110] (v) A method of treating HIV infection and / or reducing the likelihood of HIV infection or the severity of symptoms in a subject in need, comprising administering to the subject a pharmaceutical composition of (l), (m), or (n) or a combination of (o) or (p).

[0111] Further embodiments of the present invention include the following:

[0112] (w) A pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0113] (x)(w) pharmaceutical compositions, further comprising a second therapeutic agent selected from HIV antiviral agents, immunomodulators and anti-infective agents.

[0114] The pharmaceutical composition of (y)(x), wherein the HIV antiviral agent is an antiviral agent selected from HIV NRTI (nucleoside reverse transcriptase inhibitor) and HIV NNRTI (non-nucleoside reverse transcriptase inhibitor).

[0115] (z) A pharmaceutical combination comprising (i) a compound of formula (I) or a pharmaceutically acceptable salt thereof and (ii) a second therapeutic agent selected from HIV antiviral agents, immunomodulators and anti-infective agents; wherein the compound of formula (I) and the second therapeutic agent are each used in an amount that enables the combination to effectively inhibit HIV replication or effectively treat HIV infection and / or reduce the likelihood of HIV infection or the severity of symptoms.

[0116] The combination of (aa)(z), wherein the HIV antiviral agent is an antiviral agent selected from HIV protease inhibitors and HIV NNRTI inhibitors.

[0117] (bb) A method for inhibiting HIV replication in a subject in which it is desired, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0118] (cc) A method for treating HIV infection and / or reducing the likelihood of HIV infection or the severity of symptoms in a subject who requires it, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0119] The method of (dd)(cc) wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an effective amount of at least one second therapeutic agent selected from HIV antiviral agents, immunomodulators and anti-infective agents.

[0120] The method of (ee)(dd) wherein the HIV antiviral agent is an antiviral agent selected from HIV NRTI (nucleoside reverse transcriptase inhibitor) and HIV NNRTI (non-nucleoside reverse transcriptase inhibitor).

[0121] (ff) A method for inhibiting HIV replication in a subject in which it is desired, comprising administering to said subject a pharmaceutical composition of (w), (x), or (y) or a combination of (z) or (aa).

[0122] (gg) A method for treating HIV infection and / or reducing the likelihood of HIV infection or the severity of symptoms in a subject who needs it, comprising administering to said subject a pharmaceutical composition of (w), (x), or (y) or a combination of (z) or (aa).

[0123] The present invention also includes compounds of the present invention for (i) medical use; (b) inhibiting HIV replication or (c) treating HIV infection and / or reducing the likelihood of HIV infection or the severity of symptoms; (ii) as a medicament for (a) medical use, (b) inhibiting HIV replication or (c) treating HIV infection and / or reducing the likelihood of HIV infection or the severity of symptoms; or (iii) for the preparation of a medicament for (a) medical use, (b) inhibiting HIV replication or (c) treating HIV infection and / or reducing the likelihood of HIV infection or the severity of symptoms. In these uses, the compounds of the present invention may optionally be used in combination with one or more second therapeutic agents selected from HIV antiviral agents, anti-infective agents, and immunomodulators.

[0124] Other embodiments of the invention include pharmaceutical compositions, combinations, and methods as set forth in (a)-(g) above, and uses as described in the preceding paragraph, wherein the compounds used are compounds of one of the embodiments, aspects, classes, subclasses, or characteristics of the compounds described above. In all these embodiments, the compound may optionally be used, as appropriate, in the form of a pharmaceutically acceptable salt or hydrate.

[0125] It should be further understood that the embodiments of the compositions and methods provided above as (a) to (gg) are to be understood as including all embodiments of the compound, including such embodiments obtained by combinations of the embodiments.

[0126] Non-limiting examples of compounds of formula (I) include compounds 1-8 and their pharmaceutically acceptable salts as illustrated in the examples below.

[0127] Method for preparing compounds of formula (I)

[0128] Compounds of formula (I) can be prepared from known or readily prepared raw materials using methods known to those skilled in the art of organic synthesis. Methods for preparing compounds of formula (I) are illustrated in the following examples and are summarized in the schemes below. Alternative synthetic routes and similar structures are readily apparent to those skilled in the art of organic synthesis.

[0129] The abbreviations and acronyms used in this article include the following:

[0130] Ac Acetyl Me methyl aq Water-based MeCN Acetonitrile AUC Area under the curve MeoH methanol Bu Butyl mg mg Bz benzoyl MHz megahertz DCM dichloromethane min minute DHP 3,4-Dihydro-2H-pyran μL microliter DIEA or Hiinig's base N,N-Diisopropylethylamine mL milliliters DMAP 4-Dimethylaminopyridine mmol millimole DMF dimethylformamide MS Mass spectrometry DMS0 Dimethyl sulfoxide NaI Sodium iodide Et Ethyl NMR Nuclear magnetic resonance spectroscopy EtOH ethanol Ph Phenyl EtOAc Ethyl acetate PO oral g gram PTSA p-Toluenesulfonic acid GI Gastrointestinal Pr propyl h Hour RP Inverted HCl hydrochloric acid RT or rt Room temperature (ambient, approximately 25°C) HIV Human Immunodeficiency Virus sat or sat'd saturated HPLC High performance liquid chromatography SFC Supercritical fluid chromatography Hz hertz tBu tert-butyl IPA Isopropanol TEA <![CDATA[Triethylamine (Et3N)]]> IV Intravenous TEMED Tetramethylethylenediamine iPr Isopropyl TFA Trifluoroacetic acid <![CDATA[K2CO3]]> Potassium carbonate THF Tetrahydrofuran KI Potassium iodide TMS Tetramethylsilane L Lift UPLC Ultra-high pressure liquid chromatography LC Liquid chromatography UV Ultraviolet rays LC / MS Liquid chromatography-mass spectrometry UV / VIS Ultraviolet / Visible Light

[0131] General Procedure

[0132] Raw materials and intermediates are commercially available or prepared using known procedures, or as otherwise stated. The general route for synthesizing compounds of formula I is described in the following scheme. In some cases, the order of reaction steps in the scheme may be altered to promote the reaction or avoid unwanted reaction products.

[0133] Reactions sensitive to moisture or air are carried out under nitrogen or argon atmosphere using anhydrous solvents and reagents. Reaction progress is determined by analysis using thin-layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS), typically with E. Merck pre-coated TLC plates, silica gel 60F-254, and a layer thickness of 0.25 mm.

[0134] Typically, the analytical LC-MS system used consists of a Waters ZQ electrospray ionizer with a positive ion detection mode. TM Platform with Waters Acquity with autosampler TM Ultra Performance LC components. The columns are typically WatersAcquity. BEH C18 1.0 x 50 mm, 1.7 μm. Flow rate was 1 mL / min, and injection volume was 10 μL. UV detection was performed in the range of 210–400 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, followed by 3.75 min to 100% solvent B, held for 1.1 min, and then restored to 100% solvent A for 0.2 min.

[0135] Preparative HPLC purification is typically performed using a non-quality-guided system. It is usually carried out on a Teledyne ISCOACCQPrep HP150 UV system, which is equipped with ELSD, UV (254 and 215 nm) and ELSD-triggered collections, and XBridge. TM C-185 micrometer OBD TM A 30 mm (id) x 250 mm column was used. The mobile phase consisted of a mixture of acetonitrile (10-100%) and water containing 0.1% TFA. The flow rate was maintained at 50 mL / min, the injection volume was 1500-8000 μL, and the UV detection range was 210-400 nm. The mobile phase gradient was optimized for each compound. ISCO was used. Rf device or ISCO Companion XL pre-filled in the dimensions shown Silica gel in HighPerformance Gold columns (32-63μM, Rapid chromatography was performed at the pore size. Unless otherwise specified, samples were collected in CDCl3 solution using a 500 MHz energy dispersive spectrometer. 1 1H NMR spectra. Chemical shifts are reported in parts per million (ppm). Tetramethylsilane (TMS) was used as an internal standard in CD3Cl solution, and the residual CH3OH peak or TMS was used as an internal standard in CD3OD solution. Coupling constants (J) are reported in Hertz (Hz).

[0136] Several methods for preparing the compounds of the present invention are also described in the examples. Raw materials and intermediates are commercially available from common catalog sources or prepared using known procedures, or as otherwise stated.

[0137] Preparation of intermediates

[0138] Intermediate A

[0139]

[0140] Step 1:

[0141] Iodomethyl (4-nitrophenyl) carbonate (intermediate A)

[0142]

[0143] Sodium iodide (9.7 g, 64.8 mmol) was added to a solution of chloromethyl (4-nitrophenyl) carbonate (10.0 g, 43.2 mmol) in acetone (43.2 mL) at 25 °C. The solution was stirred overnight at 40 °C. The reaction mixture was cooled to room temperature and then filtered. The filtrate was concentrated. The residue was dissolved in EtOAc (150 mL) and washed with a saturated sodium thiosulfate solution (50 mL). The organic layer was then washed with brine (30 mL), dried (MgSO4), filtered, and concentrated to provide iodomethyl (4-nitrophenyl) carbonate (intermediate A). This substance was used without further purification.

[0144] Preparation of Examples

[0145] Example 1

[0146]

[0147] (((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]indazin-5-yl)oxy)methyl(2-methoxyethyl)carbonate

[0148]

[0149] Add potassium carbonate (9.26 g, 67 mmol), potassium iodide (11.12 g, 67 mmol), and 18-crown ether-6 (1,4,7,10,13,11b-octahydro-8H-[1,3]oxazino[2',3':3,4]pyrazino[2,1,6-cd]indazine-3-carboxamide (compound A) (10.0 g, 22.33 mmol) and chloromethyl 2-methoxyethyl carbonate (5.65 g, 33.5 mmol) to a mixture of acetonitrile (112 mL) in potassium carbonate (9.26 g, 67 mmol), potassium iodide (11.12 g, 67 mmol), and 18-crown ether-6 (1,4,7,10,13,16-hexaoxane) (0.59 g, 2.23 mmol) to the 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]indazine-3-carboxamide (compound A) (10.0 g, 22.33 mmol) and chloromethyl 2-methoxyethyl carbonate (5.65 g, 33.5 mmol) in potassium carbonate (112 mL), potassium iodide (11.12 g, 67 mmol), and 18-crown ether-6 (1,4,7,10,13,16-hexaoxane) (0.59 g, 2.23 mmol). The resulting mixture was stirred at 80°C until the reaction was complete as determined by LCMS (5 hours). 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 minutes. The mixture was filtered, washed with DCM (200 mL), and the filtrate was concentrated. The residue was reconstituted in DCM (500 mL) and filtered. The filtrate was directly purified by rapid chromatography (330 g RediSep RfGold; 0-10% MeOH / DCM, within 60 minutes; the filtrate (DCM) was pumped through a CombiFlash Companion XL system and then gradient-run on a CombiFlash Rf system) and the pure fraction was concentrated to provide (((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]inazin-5-yl)oxy)methyl(2-methoxyethyl)carbonate (Example 1). This substance was then crystallized from 100% IPA.1HNMR (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),4.39 –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),2.04m,1H),1.54(d,J=13.9Hz,1H). LRMS(M+H). + :580.3.

[0150] Example 2

[0151]

[0152] Step 1:

[0153] (((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]indazin-5-yl)oxy)methyl(4-nitrophenyl)carbonate

[0154]

[0155] Potassium carbonate (8.0 g, 57.8 mmol) was added 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]indazine-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). 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 reconstituted in DCM (20 mL) and purified directly by rapid chromatography (330 g RediSep RfGold; 0-10% MeOH / DCM, over 35 min; CombiFlash Rf system; DP eluent ~4% MeOH). The purified fractions were combined and concentrated to provide (((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]inazin-5-yl)oxy)methyl(4-nitrophenyl)carbonate. LRMS(M+H) + :643.3.

[0156] Step 2:

[0157] (((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]inazin-5-yl)oxy)methyl(2-(2-methoxyethoxy)ethyl)carbonate

[0158]

[0159] 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]inazin-5-yl)oxy)methyl(4-nitrophenyl)carbonate (6.5 g, 10.1 mmol) in DCM (25.3 mL), 2-(2-methoxyethoxy)ethanol-1-ol (11.9 mL, 101 mmol) was added, followed by DMAP (0.25 g, 2.0 mmol). The resulting mixture was stirred overnight at room temperature. The reaction mixture was purified directly by rapid chromatography (330 g RediSep RfGold; 30-100% 3:1 EtOAc / EtOH blend / hexane, 50 min; CombiFlash Rf system). Some parent compound A was co-eluted with the desired product 2. Fractions containing compound 2 were combined and concentrated. The residue was dissolved in DMSO and further purified by preparative reversed-phase chromatography (Waters XBridge). TM 5-micron OBD TM30x250mm C18 column; 200-275mg injection per dose; 20-80% MeCN / water containing 0.1% TFA modifier, over 27 minutes). The pure fraction was neutralized with saturated sodium bicarbonate aqueous solution, extracted with DCM and concentrated to provide (((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]inazin-5-yl)oxy)methyl(2-(2-methoxyethoxy)ethyl)carbonate (Example 2). This substance was then crystallized from 1:1 heptane / isopropyl acetate (300mg / 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=3.3 Hz,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(dd, 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.

[0160] Example 3

[0161]

[0162] Step 1:

[0163] (((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]indazin-5-yl)oxy)methyl(3-(dimethylamino)propyl)carbonate 2,2,2-trifluoroacetate

[0164]

[0165] 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]indazine-5-yl)oxy)methyl(4-nitrophenyl)carbonate (1.09 g, 1.70 mmol) in DCM (8.5 mL), 3-(dimethylamino)prop-1-ol (2.97 mL, 25.4 mmol) was added, followed by DMAP (21 mg, 0.17 mmol). 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, the residue was dissolved in DMF, and purified directly by preparative reversed-phase chromatography (Phenomenex Luna 5 μm 50 x 250 mm C18 column; 2 injections; 5-70% MeCN / water containing 0.1% TFA modifier, over 30 min). The purified fractions were combined and concentrated under reduced pressure (azeotropically with MeCN) to provide (((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]inazin-5-yl)oxy)methyl(3-(dimethylamino)propyl)carbonate 2,2,2-trifluoroacetate. LRMS(M+H) + :607.4.

[0166] Step 2:

[0167]

[0168]

[0169] (((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]indazin-5-yl)oxy)methyl(3-(dimethylamino)propyl)carbonate hydrochloride

[0170]

[0171] A solution of 4N HCl in dioxane (4.24 mL, 16.95 mmol) was added 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]indazine-5-yl)oxy)methyl(3-(dimethylamino)propyl)carbonate 2,2,2-trifluoroacetate (960 mg, 1.33 mmol) in MeOH (5 mL). The resulting mixture was stirred at room temperature for 5 minutes. The mixture was concentrated, then dissolved in MeOH (5 mL), concentrated again, and dried under vacuum to provide (((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]inazin-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),2.90 (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.

[0172] The compounds in the table below were prepared using appropriate raw materials in a manner similar to that described above for Example 1.

[0173] Canine pharmacokinetics study

[0174] Male beagle dogs (Marshall Farms) were used for pharmacokinetic studies. The studies were conducted according to the WP-IACUC approved protocol (Animal Procedure Statement #2018-600787-MAR). After an overnight fast, dogs were orally administered 10 mg / kg and 25 mg / kg of compound A, or one of the corresponding prodrugs at equivalent doses of compound A, prepared as a suspension in 0.5% methylcellulose or 10% Tween 80–5 mM HCl containing 0.25% sodium dodecyl sulfate. Feeding was resumed 4 hours after administration. Blood (0.5 mL) was drawn before administration and at 0.25, 0.5, 1, 2, 4, 6, 24, 48, 72, 96, and 168 hours after administration into EDTA-coated collection tubes containing 25 μL of 2 mM dichlorvos aqueous solution. The tubes were kept refrigerated before blood collection and throughout plasma separation. Plasma was separated by centrifugation (2 minutes at 10000g). Plasma samples were immediately frozen and kept at –70°C until analysis by LC-MS / MS.

[0175] The mean [±SD] pharmacokinetic parameters of the compound after oral administration at a dose equivalent to 10 mg / kg of compound A to fasted beagle dogs.

[0176]

[0177]

[0178] *Comparison data of amorphous prodrugs

[0179] The mean [±SD] pharmacokinetic parameters of the compound after oral administration to fasted beagle dogs at a dose equivalent to 25 mg / kg of compound A.

[0180]

[0181] As shown above, compounds 1 and 6, which are representative compounds of the present invention, exhibit increased absorption relative to their metabolite compound A.

[0182] Treatment or prevention of HIV infection

[0183] The tetracyclic heterocyclic compounds can be used to inhibit HIV, inhibit HIV integrase, treat HIV infection and / or reduce the likelihood of HIV infection or the severity of symptoms, and inhibit HIV replication and / or HIV production in cell-based systems. For example, the tetracyclic heterocyclic compounds can be used to treat HIV infection following suspected exposure to HIV through routes such as blood transfusion, body fluid exchange, bites, accidental needle pricks, or exposure to the subject's blood during surgery or other medical procedures.

[0184] Accordingly, in one embodiment, the present invention provides a method for treating HIV infection in a subject, the method comprising administering to the subject an effective amount of at least one tetracyclic heterocyclic compound or a pharmaceutically acceptable salt or prodrug thereof. In one specific embodiment, the administered amount is effective in treating or preventing HIV infection in the subject. In another specific embodiment, the administered amount is effective in inhibiting HIV viral replication and / or viral production in the subject. In one embodiment, the HIV infection has progressed to AIDS.

[0185] The tetracyclic heterocyclic compounds can also be used for the preparation and implementation of screening tests for antiviral compounds. For example, they can be used to identify drug-resistant HIV cell lines carrying mutations, serving as excellent screening tools for more potent antiviral compounds. Furthermore, they can be used to establish or determine the binding sites of other antiviral agents to HIV integrase.

[0186] The compositions and combinations of the present invention can be used to treat individuals suffering from infections associated with any HIV genotype.

[0187] Combination therapy

[0188] In another embodiment, the method of the present invention for treating or preventing HIV infection may further include administering one or more additional therapeutic agents that are not tetracyclic heterocyclic compounds.

[0189] In one implementation, the additional treatment agent is an antiviral agent.

[0190] In another embodiment, the additional therapeutic agent is an immunomodulator, such as an immunosuppressant.

[0191] Accordingly, in one embodiment, the present invention provides a method for treating a viral infection in a subject, the method comprising administering to the subject: (i) at least one tetracyclic heterocyclic compound (which may include two or more different tetracyclic heterocyclic compounds) or a pharmaceutically acceptable salt or prodrug thereof, and (ii) at least one additional therapeutic agent that is not a tetracyclic heterocyclic compound, wherein the amounts administered together effectively treat or prevent the viral infection.

[0192] When administering the combination therapy of the present invention to a subject, the therapeutic agents in the combination, or one or more pharmaceutical compositions containing therapeutic agents, may be administered in any order, such as successively, in parallel, together, simultaneously, etc. The amounts of the various active agents in such a combination therapy may be different amounts (different doses) or the same amount (same dose). Therefore, for non-limiting illustrative purposes, tetracyclic heterocyclic compounds and additional therapeutic agents may be present in fixed amounts (dosages) in single-dose units (e.g., capsules, tablets, etc.).

[0193] In one embodiment, at least one tetracyclic heterocyclic compound is administered during the period when one or more other therapeutic agents exert their preventive or therapeutic effects, or vice versa.

[0194] In another embodiment, at least one tetracyclic heterocyclic compound and one or more other therapeutic agents are administered at the doses commonly used when these agents are used as a monotherapy for treating viral infections.

[0195] In another embodiment, at least one tetracyclic heterocyclic compound and one or more additional therapeutic agents are administered at a lower dose than those commonly used when these agents are used as a monotherapy for treating viral infections.

[0196] In yet another embodiment, at least one tetracyclic heterocyclic compound and one or more additional therapeutic agents work synergistically and are administered at a lower dose than those commonly used when these agents are used as a monotherapy for treating viral infections.

[0197] In one embodiment, at least one tetracyclic heterocyclic compound and one or more other therapeutic agents are present in the same composition. In one embodiment, this composition is suitable for oral administration. In another embodiment, this composition is suitable for intravenous administration. In yet another embodiment, this composition is suitable for subcutaneous administration. In still another embodiment, this composition is suitable for parenteral administration.

[0198] 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.

[0199] In one implementation, the viral infection is HIV infection.

[0200] In another embodiment, the viral infection is AIDS.

[0201] The at least one tetracyclic heterocyclic compound and the one or more additional therapeutic agents may act additively or synergistically. Synergistic combinations may allow for the use of lower doses of one or more agents and / or the administration of one or more agents of a combination therapy at a lower frequency. Lower doses or lower frequencies of administration of one or more agents may reduce the toxicity of the treatment without reducing its efficacy.

[0202] In one embodiment, the administration of at least one tetracyclic heterocyclic compound and one or more additional therapeutic agents can inhibit viral resistance to these agents.

[0203] As described above, the present invention also relates to compounds of Formula I used in conjunction with one or more anti-HIV agents. An "anti-HIV agent" is any agent that directly or indirectly and effectively inhibits HIV reverse transcriptase or another enzyme required for HIV replication or infection, or that treats or prevents HIV infection and / or treats AIDS, prevents AIDS, or delays the onset or progression of AIDS. It is to be understood that anti-HIV agents are effective in treating, preventing, or delaying HIV infection or AIDS and / or the disease or condition caused by or associated with it. For example, whether in the pre-exposure and / or post-exposure period, the compounds of the present invention can be effectively combined with an effective amount of one or more anti-HIV agents selected from HIV antiviral agents, immunomodulators, anti-infective agents, or vaccines that can be used to treat HIV infection or AIDS. HIV antiviral agents suitable for use in combination with the compounds of the present invention include, for example, those listed in Table A below:

[0204] Table A

[0205]

[0206]

[0207] Some of the drugs listed in this table are used in salt form; for example, abacavir sulfate, indinavir sulfate, atazanavir sulfate, and nelfinavir mesylate.

[0208] In one implementation, one or more anti-HIV drugs are selected from lamivudine, abacavir, ritonavir, darunavir, atazanavir, emtricitabine, tenofovir, rilpivirine, doravirine, EFdA, and lopinavir.

[0209] In another embodiment, the compound of formula (I) is used in combination with lamivudine.

[0210] In yet another embodiment, the compound of formula (I) is used in combination with atazanavir.

[0211] In another embodiment, the compound of formula (I) is used in combination with darunavir.

[0212] In another embodiment, the compound of formula (I) is used in combination with rilpivirine.

[0213] In one implementation, the compound of formula (I) is used in combination with lamivudine and abacavir.

[0214] In another embodiment, the compound of formula (I) is used in combination with islatravir.

[0215] In another embodiment, the compound of formula (I) is used in combination with emtricitabine and tenofovir.

[0216] In yet another embodiment, the compound of formula (I) is used in combination with doravirine.

[0217] In yet another embodiment, the compound of formula (I) is used in combination with doravirine, lamivudine and tenofovir DF.

[0218] In another embodiment, the compound of formula (I) is used in combination with ritonavir and lopinavir.

[0219] In one implementation, the compound of formula (I) is used in combination with abacavir and lamivudine.

[0220] In another embodiment, the compound of formula (I) is used in combination with lopinavir and ritonavir.

[0221] In one embodiment, the present invention provides a pharmaceutical composition comprising (i) a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof; (ii) a pharmaceutically acceptable carrier; and (iii) one or more additional anti-HIV agents selected from lamivudine, abacavir, ritonavir, islatravir, doravirin, and lopinavir or a pharmaceutically acceptable salt or prodrug thereof, wherein the amounts of components (i) and (iii) together are effective in treating or preventing HIV infection or treating AIDS, preventing AIDS, or delaying the onset or progression of AIDS in subjects in need of it.

[0222] In another embodiment, the present invention provides a method for treating or preventing HIV infection or treating AIDS, preventing AIDS, or delaying the onset or progression of AIDS in a subject in need of it, 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, doravirin, and lopinavir or pharmaceutically acceptable salts or prodrugs thereof, wherein the amounts of components (i) and (ii) administered together are effective in treating or preventing HIV infection or treating AIDS, preventing AIDS, or delaying the onset or progression of AIDS in a subject in need of it.

[0223] It should be understood that the scope of combinations of the compounds of the present invention with anti-HIV agents is not limited to the HIV antiviral agents listed in Table A, but in principle also includes any combination with any pharmaceutical composition that can be used to treat or prevent AIDS. HIV antiviral agents and other agents are typically used in these combinations at their usual dosage ranges and regimens as reported in the art, including, for example, Physicians' Desk ReferenceThe dosages described in Thomson PDR, 57th edition (2003), 58th edition (2004), 59th edition (2005), etc. The dosage ranges of the compounds of the present invention in these combinations are the same as those described above.

[0224] The dosage and administration regimen of other agents 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 account the approved dosage and administration regimen in the package insert; the subject's age, sex, and general health condition; and the type and severity of the viral infection or related disease or disorder. When administered in combination, one or more tetracyclic heterocyclic compounds and one or more other agents can be administered simultaneously (i.e., in the same composition or in a separate composition immediately following another) or sequentially. This is particularly useful when the components of the combination are administered with different administration regimens (e.g., one component is administered once daily, and another component every 6 hours), or when the pharmaceutical compositions are different (e.g., one is a tablet and the other is a capsule). A cassette containing individual dosage forms is therefore advantageous.

[0225] Composition and application

[0226] When applied to a target, the tetracyclic heterocyclic compound may be administered as a component of a composition comprising a pharmaceutically acceptable carrier or mediator. The present invention provides pharmaceutical compositions comprising an effective amount of at least one tetracyclic heterocyclic compound and a pharmaceutically acceptable carrier. In the pharmaceutical compositions and methods of the present invention, the active ingredient is typically mixed with a suitable carrier material appropriately selected and consistent with conventional pharmaceutical practice, depending on the intended form of administration, i.e., oral tablets, capsules (solid-filled, semi-solid-filled, or liquid-filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, etc. For example, for oral administration in tablet or capsule form, the active pharmaceutical component may be combined with any orally non-toxic, pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethanol (liquid form), etc. Solid form formulations include powders, tablets, dispersible granules, capsules, suppositories, and sachets. Powders and tablets may contain from about 0.5% to about 95% of the compositions of the present invention. Tablets, powders, capsules, and granules are available as solid dosage forms suitable for oral administration.

[0227] In addition, suitable binders, lubricants, disintegrants, and colorants may be incorporated into the mixture when desired or required. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as gum arabic, sodium alginate, carboxymethyl cellulose, polyethylene glycol, and waxes. Among lubricants, boric acid, sodium benzoate, sodium acetate, and sodium chloride may be mentioned for use in these dosage forms. Disintegrants include starch, methyl cellulose, guar gum, etc. Sweeteners, flavoring agents, and preservatives may also be included, if appropriate.

[0228] Liquid formulations include solutions, suspensions, and emulsions, and may include water or water-propylene glycol solutions for parenteral injection.

[0229] Liquid formulations may also include solutions for intranasal administration.

[0230] This also includes solid formulations that are to be converted into a liquid form for oral or parenteral administration before use. Such liquid forms include solutions, suspensions, and emulsions.

[0231] To prepare the suppositories, a mixture of low-melting-point waxes, such as fatty acid glycerides or cocoa butter, is first melted, and the active ingredients are uniformly dispersed within it by stirring. The molten, homogeneous mixture is then poured into a mold of suitable size, allowed to cool, and thus solidify.

[0232] Furthermore, the compositions of the present invention can be formulated in a sustained-release form to provide a controlled rate of release of any one or more components or active ingredients to optimize therapeutic effects, such as antiviral activity. Suitable sustained-release dosage forms include layered tablets containing layers or controlled-release polymeric matrices impregnated with active ingredients and formed into tablet form, or capsules containing such impregnated or encapsulated porous polymeric matrices.

[0233] In one embodiment, the one or more tetracyclic heterocyclic compounds are administered orally.

[0234] In another embodiment, the one or more tetracyclic heterocyclic compounds are administered intravenously.

[0235] In one embodiment, the pharmaceutical formulation comprising at least one tetracyclic heterocyclic compound is a unit dosage form. In such a form, the formulation is subdivided into unit doses containing an effective amount of the active ingredient.

[0236] The compositions can be prepared according to conventional mixing, granulation, or coating methods, and in one embodiment, the compositions of the present invention may contain from about 0.1% to about 99% by weight or volume of one or more tetracyclic heterocyclic compounds. In various embodiments, the compositions of the present invention may contain from about 1% to about 70% or from about 5% to about 60% by weight or volume of one or more tetracyclic heterocyclic compounds.

[0237] The compounds of Formula I can be administered orally in a single dose or fractions within a dose range of 0.001 to 1000 mg / kg of mammalian (e.g., human) body weight per day. One dose range is 0.01 to 500 mg / kg body weight per day in a single dose or fractions. Another dose range is 0.1 to 100 mg / kg body weight per day in a single dose or fractions. For oral administration, the compositions can be provided in tablet or capsule form containing 1.0 to 500 mg of active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 mg of active ingredient, to symptomatically adjust the dose given to the subject to be treated. The specific dose level and frequency of administration for any particular subject can vary and depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, weight, general health condition, sex, diet, administration pattern and time, excretion rate, drug combination, severity of the specific condition, and the host being treated.

[0238] For convenience, the total daily dose may be divided and administered in portions throughout the day if necessary. In one embodiment, the daily dose is administered as one dose. In another embodiment, the total daily dose is administered as two portions over a 24-hour period. In yet another embodiment, the total daily dose is administered as three portions over a 24-hour period. In still another embodiment, the total daily dose is administered as four portions over a 24-hour period.

[0239] The unit dose of the tetracyclic heterocyclic compound can be administered at different frequencies. In one embodiment, the unit dose of the tetracyclic heterocyclic compound can be administered once daily. In another embodiment, the unit dose of the tetracyclic heterocyclic compound can be administered twice weekly. In yet another embodiment, the unit dose of the tetracyclic heterocyclic compound can be administered once weekly. In still another embodiment, the unit dose of the tetracyclic heterocyclic compound can be administered every two weeks. In another embodiment, the unit dose of the tetracyclic heterocyclic compound can be administered once monthly. In yet another embodiment, the unit dose of the tetracyclic heterocyclic compound can be administered every two months. In another embodiment, the unit dose of the tetracyclic heterocyclic compound can be administered every three months. In a further embodiment, the unit dose of the tetracyclic heterocyclic compound can be administered every six months. In yet another embodiment, the unit dose of the tetracyclic heterocyclic compound can be administered once a year.

[0240] The dosage and frequency of administration of the tetracyclic heterocyclic compound are adjusted based on the judgment of the attending physician, taking into account factors such as the patient's age, health condition, body type, and the severity of the symptoms being treated. The compositions of the present invention may further comprise one or more additional therapeutic agents selected from those listed above herein.

[0241] medicine box

[0242] In one aspect, the present invention provides a medicament containing a therapeutically effective amount of at least one tetracyclic heterocyclic compound or a pharmaceutically acceptable salt or prodrug of said compound, and a pharmaceutically acceptable carrier, medium or diluent.

[0243] In another aspect, the present invention provides a medicament containing an amount of at least one tetracyclic heterocyclic compound or a pharmaceutically acceptable salt or prodrug of said compound, and an amount of at least one of the additional therapeutic agents listed above, wherein the amounts of the two or more active ingredients produce the desired therapeutic effect. In one embodiment, said one or more tetracyclic heterocyclic compounds and said one or more additional therapeutic agents are provided in the same container. In one embodiment, said one or more tetracyclic heterocyclic compounds and said one or more additional therapeutic agents are provided in separate containers.

[0244] This invention is not limited to the specific embodiments disclosed in the examples, which are intended to illustrate several aspects of the invention, and any functionally equivalent embodiments are within the scope of this invention. In fact, various modifications to the invention, other than those shown and described herein, will be apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

[0245] Many references have been cited in this article, and their entire public content is incorporated herein by reference.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, said compound having the following structure 。 2. A pharmaceutical composition comprising an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

3. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting HIV integrase in subjects in need of it.

4. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating HIV infection or treating AIDS, preventing AIDS, or delaying the onset or progression of AIDS in subjects in need of it.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for inhibiting HIV integrase, treating or preventing HIV infection, or treating AIDS, preventing AIDS, or delaying the onset or progression of AIDS in subjects in need of it.

6. The composition of claim 2, further comprising one or more additional therapeutic agents selected from retegvir, lamivudine, abacavir, ritonavir, dulutegravir, arunavir, atazanavir, emtricitabine, tenofovir, erteiravir, rilpivirine, lopinavir, doravirine, and islatravir.

7. The use of claim 4, wherein the compound or a pharmaceutically acceptable salt thereof is further administered in combination with one or more additional therapeutic agents selected from retegvir, lamivudine, abacavir, ritonavir, dulutegravir, arunavir, atazanavir, emtricitabine, tenofovir, erteiravir, rilpivirine, lopinavir, doravirine, and islatravir, wherein the dosage of the compound or a pharmaceutically acceptable salt thereof together with the one or more additional therapeutic agents is effective in treating HIV infection or treating AIDS, preventing AIDS, or delaying the onset or progression of AIDS.

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