Integrase inhibitors and their uses

Abstract

The present application discloses compounds of Formula I, their stereoisomers, pharmaceutically acceptable salts and deuterated compounds, and methods for treating, inhibiting and / or preventing diseases or disorders in a subject in need thereof. [Formula 1] TIFF2026501678000048.tif40170 (wherein A, R, G, Y, and n are defined as in the present application.)

Description

[Technical Field]

[0001] This application relates to the pharmaceutical field, and more particularly to prodrugs of integrase inhibitors and uses thereof. [Background technology]

[0002] Significant progress has been made in developing effective diagnostics and treatments for human immunodeficiency virus type 1 (HIV-1). Antiretroviral therapy (ART) has significantly reduced disease-related morbidity and mortality, thereby enabling infected individuals to achieve a near-normal quality of life. However, ART requires lifelong treatment to suppress viral replication and prevent the development of AIDS.

[0003] Additionally, the effectiveness of ART can be hindered by HIV-1 resistance, drug toxicity, and poor patient adherence. Treatment fatigue, lack of financial and social support, comorbid psychiatric symptoms, and / or substance abuse can all contribute to poor adherence to important ART regimens. Dolutegravir (DTG), cabotegravir (CAB), and bictegravir (BTG) are types of integrase inhibitors or integrase strand transfer inhibitors (INSTIs). Summary of the Invention

[0004] In one aspect, the present application relates to compounds of Formula I, their stereoisomers, pharmaceutically acceptable salts and deuterated compounds:

[0005] [ka] (where, A is, TIFF2026501678000003.tif26170; where * represents the R or S configuration, n is 0, 1, 2 or 3; G is independently selected from oxygen or Gr; Here, Gr is TIFF2026501678000004.tif18170, where R2 and R3 are each independently hydrogen, a hydroxy group, a cyano group, or C 1-6 Alkyl group, C 6-10 Aryl group, C 3-10 Cycloalkyl groups, aryl heterocyclic groups, C 1-6 Alkyl group-C 6-10 Aryl group, C 1-6 Alkyl group-aryl heterocyclic group and C 1-6 Alkyl group-C 3-10 cycloalkyl groups, or R2 and R3, together with the atoms to which they are attached, can form a 4-10 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with 1-4 R4; R4 independently represents hydrogen, halogen, C 1-6 selected from the group consisting of alkyl groups and alkoxy groups; Or, any two R4's bond with the atoms to which they are connected to form C 3-10 A cycloalkyl group can be formed, where the cycloalkyl group is selected from 1 to 4 hydrogen, halogen, or C 1-6 may be substituted with an alkyl group, X is selected from the group consisting of oxygen and nitrogen; Y is a halogen; m is 0 to 20; R is independently C 2-30 wherein the hydrocarbon and aliphatic groups are optionally substituted with at least one heteroatom selected from the group consisting of N, O, and S; R is a halogen, a carboxyl group, a sulfonyl group, -S=O, -S(=O)2, an aryl group, a heteroaryl group, or C 3-10 saturated or unsaturated carbocyclic rings of C 3-10and optionally substituted with a substituent selected from the group consisting of aryl, heteroaryl, carbocyclic, and heterocyclic groups, wherein the aryl, heteroaryl, carbocyclic, and heterocyclic groups are selected from the group consisting of H, C, 1-20 Alkyl group, C 2-20 Alkenyl group, C 2-20 Alkynyl group, C 1-20 Haloalkyl group, C 2-20 Halogenated alkenyl groups, C 2-20 Halogenated alkynyl groups, C 0-20 Alkyl group-C 6-10 Aryl group, heterocyclic group, C 0-20 Alkyl group-C 3-10 Cycloalkyl groups, C 0-20 Alkyl group -OC 1-6 Alkyl groups and C 0-20 Alkyl group -OC 1-6 Optionally substituted with haloalkyl groups.

[0006] In another aspect, the present application relates to a composition comprising a compound of Formula I of the present application, a stereoisomer, a pharmaceutically acceptable salt, or a deuterated compound thereof.

[0007] In another aspect, the present application relates to a method for treating, inhibiting, and / or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula I of the present application, its stereoisomer, pharmaceutically acceptable salt, or deuterated compound. [Brief explanation of the drawings]

[0008] [Figure 1] 1 shows the plasma concentration-time curves (AUC) of compounds of the present application after subcutaneous injection. [Figure 2] The concentration of the active ingredient in plasma after administration of the compound is shown. [Figure 3] 1 shows the mean plasma concentration of the corresponding active ingredient (bictegravir) versus time after a single subcutaneous injection of compound 13 and compound 21 (dose equivalent to 18 mg / kg of bictegravir) in rats. [Figure 4]1 shows the relationship between the mean plasma concentration of the corresponding active ingredient (cabotegravir) and time after a single subcutaneous injection of compound 14 (dose: equivalent to 18 mg / kg of cabotegravir) in rats. DETAILED DESCRIPTION OF THE INVENTION

[0009] The following description includes some specific details to provide a thorough understanding of the various disclosed embodiments. However, one skilled in the relevant art will recognize that the embodiments may be practiced with other methods, components, materials, etc., without one or more of these specific details.

[0010] Unless otherwise required herein, throughout the specification and claims, the terms "comprise" and "comprising" are to be interpreted in an open and inclusive sense, i.e., "including, but not limited to."

[0011] As used in this application and the claims, reference to the singular without a designation of quantity is intended to include reference to the plural unless the context clearly dictates otherwise.

[0012] Throughout this specification, the references to "one embodiment," "one embodiment," "another embodiment," or "in some embodiments" mean that at least one embodiment includes the particular referenced element, structure, or feature associated with that embodiment. Thus, the appearances of the phrases "in one embodiment," "in one embodiment," "in another embodiment," or "in some embodiments" in various places throughout the specification do not necessarily refer to the same embodiment. Furthermore, particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.

[0013] As used in the specification and claims of this application, the singular forms "a," "an," and "the" should be understood to include plural referents unless the context clearly dictates otherwise. Thus, for example, a sustained-release tablet referring to a "pharmaceutically acceptable excipient" includes a pharmaceutically acceptable excipient, or two or more pharmaceutically acceptable excipients.

[0014] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. A dashed line at the beginning or end of a chemical group is intended to facilitate indicating the point of attachment to the parent molecule, and a chemical group may be depicted with or without one or more dashed lines without losing its ordinary meaning. "C u-v " or "C u -C v " indicates that the group below has u to v carbon atoms, where u and v are integers. For example, "C 1-6 By "alkyl group" or "C1-C6 alkyl group" it is meant that the alkyl group has from 1 to 6 carbon atoms.

[0015] An "alkyl group" is a monovalent or divalent, straight- or branched-chain saturated hydrocarbon group. For example, an alkyl group can be a group having 1 to 10 carbon atoms (i.e., C 1-10 alkyl group), 1 to 8 carbon atoms (i.e., C 1-8 alkyl group), 1 to 6 carbon atoms (i.e., C 1-6 alkyl group), or 1 to 4 carbon atoms (i.e., C 1-4 alkyl group).

[0016] Examples of alkyl groups include methyl (Me, -CH), ethyl (Et, -CHCH), 1-propyl (n-Pr, n-propyl, -CHCHCH), 2-propyl (i-Pr, isopropyl, -CH(CH)), 1-butyl (n-Bu, n-butyl, -CHCHCHCH), 2-methyl-1-propyl (i-Bu, isobutyl, -CHCH(CH)), 2-butyl (s-Bu, s-butyl, -CH H(CH3)CH2CH3), 2-methyl-2-propyl group (t-Bu, t-butyl group, -C(CH3)3), 1-pentyl group (n-pentyl group, -CH2CH2CH2CH3), 2-pentyl group (-CH(CH3)CH2CH3), 3-pentyl group (-CH(CH2CH3)2), 2-methyl-2-butyl group (-C(CH3)2CH2CH3), 3-methyl-2-butyl group (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl group (- CH2CH2CH(CH3)2), 2-methyl-1-butyl group (-CH2CH(CH3)CH2CH3), 1-hexyl group (-CH2CH2CH2CH3), 2-hexyl group (-CH(CH3)CH2CH2CH3), 3-hexyl group (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl group (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl group (-CH(CH3)CH(CH3)CH2CH3), 4 Examples of alkyl groups include, but are not limited to, 3-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), and octyl (-(CH2)7CH3). Alkyl groups can be unsubstituted or substituted.

[0017] An "alkenyl group" is a monovalent or divalent, straight- or branched-chain hydrocarbon group having at least one carbon-carbon double bond. For example, an alkenyl group can be an alkyl group having 2 to 8 carbon atoms (i.e., C 2-8 alkenyl groups), 2 to 6 carbon atoms (i.e., C2-6 alkenyl groups), or 2 to 4 carbon atoms (i.e., C 2-4 Examples of alkenyl groups include, but are not limited to, -CH=CH, -CHCH=CH, and -CH-CH=CH-CH. Alkenyl groups can be unsubstituted or substituted.

[0018] An "alkynyl group" is a monovalent or divalent, straight- or branched-chain hydrocarbon group having at least one carbon-carbon triple bond. For example, an alkynyl group can be an alkynyl group having 2 to 8 carbon atoms (i.e., C 2-8 alkynyl groups), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl groups), or 2 to 4 carbon atoms (i.e., C 2-4 Examples of alkynyl groups include, but are not limited to, -C≡CH, -CHC≡CH, and -CH-C≡C-CH. Alkynyl groups can be unsubstituted or substituted.

[0019] An "alkoxyalkyl group" is a group formed by linking an alkoxy group to a divalent alkyl group (as defined above for alkyl groups). For example, C 2-6 Alkoxyalkyl groups include -CH2-OMe, -CH2-O-iPr, -CH2-CH2-OMe, -CH2-CH2-O-CH2-CH3 and -CH2-CH2-O-tBu. Alkoxyalkyl groups can be unsubstituted or substituted.

[0020] "Halogen" refers to fluorine (-F), chlorine (-Cl), bromine (-Br) and iodine (-I).

[0021] A "haloalkyl group" is an alkyl group, as defined herein, where one or more hydrogen atoms of the alkyl group are independently replaced with a halogen, which may be the same or different, making the alkyl group divalent. The alkyl group and halogen may be any one of those described above. In some embodiments, the haloalkyl group determines the number of carbon atoms in the alkyl group portion, e.g., C 1-4 Haloalkyl groups include CF3, CH2F, CHF2, CH2CF3, CH2CH2CF3, CCl2CH2CH3, and C(CH3)2(CF2H). Haloalkyl groups can be unsubstituted or substituted.

[0022] "Aryl group" refers to a monovalent or divalent, mono-fused or poly-fused, all-carbon, aromatic ring system, wherein the rings are aromatic. For example, in some embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl groups include a phenyl group. Aryl groups also include multiple fused ring systems (e.g., ring systems consisting of 2, 3, or 4 rings) having about 9 to 20 carbon atoms, wherein the multiple rings are aromatic. Where valency requirements permit, the rings of multiple fused ring systems can be linked together by fused bonds.

[0023] Furthermore, when referring to an aryl group having a certain range of atoms (e.g., a 6- to 10-membered aryl group), it should be understood that the range of atoms refers to the total number of atoms in the aryl group ring. For example, a 6-membered aryl group includes a phenyl group, and a 10-membered aryl group includes a naphthyl group. Non-limiting examples of aryl groups include, but are not limited to, a phenyl group, a naphthyl group, an anthracenyl group, and the like. An aryl group may be unsubstituted or substituted.

[0024] "Alkylaryl group" refers to an alkyl group, as defined herein, where one or more hydrogen atoms of the alkyl group are independently replaced with an aryl group, where the aryl groups can be the same or different. The alkyl and aryl groups can be any one of those described above. Such alkyl groups are divalent. In some embodiments, the alkylaryl group has 7 to 24 carbon atoms, 7 to 16 carbon atoms, 7 to 13 carbon atoms, or 7 to 11 carbon atoms. An alkylaryl group defined by the number of carbon atoms refers to the total number of carbon atoms present in the alkyl and aryl groups. For example, a C7 alkylaryl group refers to a benzyl group, while a C7 alkylaryl group refers to a C 11 Alkylaryl groups include 1-methylnaphthalene and n-pentylphenyl groups.

[0025] In some embodiments, the number of carbon atoms in the alkyl and aryl group moieties can each be independently designated, e.g., C 1-6 Alkyl group-C 6-10 Aryl groups. Non-limiting examples of alkylaryl groups include, but are not limited to, benzyl, 2,2-dimethylphenyl, n-pentylphenyl, 1-methylnaphthyl, 2-ethylnaphthyl, etc. Alkylaryl groups can be unsubstituted or substituted.

[0026] A "5- to 10-membered aromatic heterocycle" or "heteroaromatic ring" refers to a single aromatic ring having at least one atom other than carbon in the ring, where said atom is selected from the group consisting of oxygen, nitrogen, and sulfur; a "heteroaryl group" also includes fused ring systems having at least one aromatic ring of this type, which are further described below.

[0027] Thus, a "heteroaryl group" comprises a single aromatic ring having about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms can also be present in oxidized form, so long as the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furanyl groups.

[0028] The term "heteroaryl group" further includes multiple fused ring systems (e.g., ring systems consisting of 2, 3, or 4 rings), where a heteroaryl group as defined above is fused to one or more rings selected from the group consisting of heteroaryl groups (e.g., to form a 1,8-naphthyridinyl group) and aryl groups (e.g., to form a benzimidazolyl or indazolyl group) to form a multiple fused ring system. Thus, a heteroaryl group (single aromatic ring or multiple fused ring system) may have about 1 to 20 carbon atoms and about 1 to 6 heteroatoms in the heteroaryl ring.

[0029] For example, a tetrazolyl group has one carbon atom and four nitrogen heteroatoms in the ring. Where valency requirements permit, the rings of multiple fused ring systems can be connected to each other through fused bonds. It is understood that the rings of multiple fused ring systems can be connected to each other in any order. It should be understood that the connection point of a heteroaryl group or heteroaryl group poly-fused ring system can be any suitable atom of the heteroaryl group or heteroaryl group poly-fused ring system, including carbon atoms and heteroatoms (e.g., nitrogen).

[0030] It should also be understood that when referring to a heteroaryl group having a range of atoms (e.g., a 5- to 10-membered heteroaryl group), the range of atoms refers to the total number of atoms in the heteroaryl ring, including carbon atoms and heteroatoms.

[0031] It should also be understood that the rings of the multiple fused ring system may include an aryl group ring fused to a heterocycle having saturated or partially unsaturated bonds (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) and having about 1 to 6 ring carbon atoms and about 1 to 3 cycloheteroatoms selected from oxygen, nitrogen, and sulfur in the ring.

[0032] For example, a 5-membered heteroaryl group includes a thiazolyl group, and a 10-membered heteroaryl group includes a quinolyl group. Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinozolinyl, benzofuranyl, benzimidazolyl, phenylthio, pyrrolo[2,3-b]pyridyl, quinazolinyl-4(3H)-one, triazolyl, and tetrazolyl. Heteroaryl groups can be unsubstituted or substituted.

[0033] A "cycloalkyl group" is a monovalent or divalent all-carbon ring or multiple fused all-carbon ring system, wherein the ring in each embodiment is a non-aromatic saturated or unsaturated ring. For example, in some embodiments, the cycloalkyl group has 3 to 12 carbon atoms, 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, 3 to 5 carbon atoms, or 3 to 4 carbon atoms. Exemplary monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl, cycloheptyl, cycloheptenyl, and cyclooctyl groups.

[0034] Cycloalkyl groups also include multiple fused ring systems (e.g., ring systems containing two rings) having about 7 to 12 carbon atoms. Where valence requirements permit, the rings of multiple fused ring systems may be connected to each other by fused, spiro, or bridged bonds. Exemplary multicyclic cycloalkyl groups include octahydropentene, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[2.2]oct-2-ene, and spiro[2.5]octane. Cycloalkyl groups can be unsubstituted or substituted.

[0035] As used herein, a "heterocycle," "heterocyclic ring," or "heterocyclic group" refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic ring system having at least one heteroatom in the ring (i.e., at least one cyclic (i.e., ring-shaped) heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, a heterocyclic group has 3 to about 20 ring atoms, e.g., 3 to 12 ring atoms, e.g., 4 to 12 ring atoms, 4 to 10 ring atoms, 3 to 8 ring atoms, 3 to 6 ring atoms, 4 to 6 ring atoms, or 4 to 5 ring atoms.

[0036] Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) having about 1 to 6 ring carbon atoms and about 1 to 3 cycloheteroatoms, the heteroatoms in which are selected from the group consisting of oxygen, nitrogen, and sulfur. Where valency requirements permit, rings of multiple fused rings (e.g., bicycloheterocycles) may be linked together by fused, spiro, and bridged bonds.

[0037] Heterocycles include azacyclo, aziridine, imidazolidine, morpholine, ethylene oxide, thiacyclo, piperazine, piperidine, pyrazolidineamine, piperidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, 2-oxo-6-azaspiro[3.3]hept-6-yl, 6-oxa-1-azaspiro[3.3]hept-6-yl, and 1-azaspiro[3.3]hept-6-yl. 2-azabicyclo[3.1.0]hex-2-yl, 3-azabicyclo[3.0]hexyl, 2-azabicyclo[2.1.1]hexyl, 2-azabicyclo[2.2.1]hept-2-yl, 4-azaspiro[2.4]heptyl, 5-azaspiro[2.4]heptyl, and the like.

[0038] The heterocyclic group can be unsubstituted or substituted.

[0039] "Alkylheteroaryl group" refers to an alkyl group, as defined herein, where one or more hydrogen atoms of the alkyl group are independently replaced with heteroaryl groups, where the heteroaryl groups can be the same or different, thereby making the alkyl group divalent. The alkyl group and heteroaryl group can be any one of the above.

[0040] In some embodiments, the number of atoms in the alkyl and heteroaryl groups can be adjusted to, for example, C 1-6 The alkyl group may be separately designated as a 5- to 10-membered heteroaryl group, where each heteroatom is independently N, O, or S. The alkylheteroaryl group may be unsubstituted or substituted.

[0041] "Oxo" refers to =O.

[0042] As used herein, "substituted" refers to one or more hydrogen atoms of the group therein being independently replaced with one or more substituents (eg, 1, 2, 3, 4 or more).

[0043] "Compounds of the present application" include compounds disclosed herein, for example, compounds of the present application include compounds of Formula I, including compounds of the Examples. In some embodiments, "compounds of the present application" include compounds of Formula I.

[0044] A "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, filler, lubricant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonicity agent, solvent, or emulsifier, which has been approved by the U.S. Food and Drug Administration (FDA) for use in humans or veterinary animals.

[0045] As used herein, a "therapeutically effective amount" or "effective amount" refers to an amount that effectively induces a desired biological or medical response, and includes an amount of a compound that, when administered to a subject to treat a disease, is sufficient to affect treatment for that disease. The effective amount varies depending on factors such as the compound, the disease and its severity, and the age and weight of the subject being treated. The effective amount can include a range of amounts.

[0046] As is understood in the art, an effective amount may be one or more doses, i.e., one dose or multiple doses may be required to achieve the desired therapeutic goal. An effective amount is considered when administering one or more therapeutic agents, and a single agent can be considered to be administered in an effective amount if it is likely to achieve, or has already achieved, an ideal or beneficial result in combination with one or more other agents. The combined effect of the compounds (e.g., additive or synergistic effect) can selectively reduce the appropriate dose of any co-administered compound.

[0047] As used herein, "co-administered" refers to administering a unit dose of a compound of the present disclosure before or after administering a unit dose of one or more additional therapeutic agents, e.g., administering a compound of the present disclosure within seconds, minutes, or hours of administering one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by administration of a unit dose of one or more additional therapeutic agents within seconds or minutes.

[0048] Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed within seconds or minutes by a unit dose of a compound of the present disclosure. In some embodiments, a unit dose of a compound of the present disclosure is administered first, followed several hours (e.g., 1-12 hours) later by a unit dose of one or more additional therapeutic agents.

[0049] In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed several hours (e.g., 1-12 hours) later by a unit dose of a compound of the present disclosure. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents such that a therapeutically effective amount of each agent is present in the subject's body.

[0050] Further provided are pharmaceutically acceptable salts, hydrates, solvates, isomeric forms, polymorphs and prodrugs of the compounds described herein.

[0051] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other materials useful in preparing pharmaceutical compositions suitable for use in veterinary or human medicine.

[0052] The compounds described herein may be prepared and / or formulated as pharmaceutically acceptable salts, or, where appropriate, as free bases. Pharmaceutically acceptable salts are non-toxic salts of the free base form of the compounds, which salts possess the pharmacological activity of the desired free base. These salts can be extracted from inorganic or organic acids or bases.

[0053] For example, compounds containing a basic nitrogen can be prepared into pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, disulfite, disulfate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, caproate, enanthate, propanolate, oxalate, malonate, ferrite, sebacate, fumarate, maleate, butyne-1,4 diacid, hexyne-1,6-diacid, and the like. Includes diacid salts, benzoates, chlorobenzoates, toluates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methanesulfonates, propanesulfonates, benzenesulfonates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates and mandelates.

[0054] A list of other suitable pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0055] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein further include alkali metal (e.g., sodium, potassium), alkaline earth metal (e.g., magnesium), ammonium, and N(C1-C4 alkyl) salts. 4+Also included are salts from appropriate bases such as sodium or potassium salts.

[0056] Further provided are compounds described herein or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein 1 to n hydrogen atoms linked to a carbon atom may be replaced with deuterium atoms or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds can have increased resistance to metabolism and can therefore be used to extend the half-life of the compounds described herein or pharmaceutically acceptable salts, isomers, or mixtures thereof when administered to mammals.

[0057] See Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci., 5(12):524-527 (1984), such compounds have been synthesized by methods well known in the art, for example, using starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0058] Examples of isotopes that can be incorporated into the disclosed compounds further include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 There is I. 11 C. 18 F, 15 O and 1 3Substitution with a positron-emitting isotope, such as N, can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (IA-1) can be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described in the Examples below, substituting appropriate isotopically labeled reagents for the previously used unlabeled reagents.

[0059] The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and may therefore give rise to enantiomeric, non-enantiomeric and other stereoisomeric forms, which may be defined according to their absolute stereochemistry as (R)- or (S)-, or, in the case of amino acids, as (D)- or (L)-.

[0060] This application is intended to include all these possible isomers and their racemic and optically pure forms. Optically active (+) and (-), (R) and (S), or (D) and (L)-isomers can be prepared by chiral syntheses or chiral reagents, or separated by conventional techniques such as chromatography and fractional crystallization.

[0061] Conventional techniques for preparing / separating single enantiomers include chiral synthesis from appropriate optically pure precursors or resolution of the racemate (or a racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). Where the compounds described herein contain an ethylenic double bond or other center of geometric asymmetry, unless specified otherwise, such compounds are intended to include E and Z geometric isomers.

[0062] Similarly, all isomeric forms are included. When a compound is represented in its chiral form, it should be understood that the embodiment includes, but is not limited to, the specific non-enantiomer or enantiomer-enriched form. Unless otherwise specified, when chirality is present, it should be understood that the embodiment applies to the specific non-enantiomer or enantiomer-enriched form, or to racemized or scalar mixtures of such compounds. As used herein, a "scalar mixture" refers to a mixture in which the stereoisomers are in a ratio other than 1:1.

[0063] As used herein, "stereoisomers" refer to compounds with the same atoms bonded together but different three-dimensional structures, which are not interchangeable. This application contemplates different stereoisomers and mixtures thereof, and includes "enantiomers," which are two stereoisomers whose molecules are not superimposable with one another.

[0064] As used herein, "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. In some embodiments, the present application includes tautomers of compounds.

[0065] As used herein, "solvate" refers to the result of the interaction of a solvent with a compound. Further provided are solvates of salts of the compounds described herein. Further provided are hydrates of the compounds described herein.

[0066] As used herein, "hydrate" refers to a compound of the invention chemically bound to one or more water molecules. "Prophylactic treatment" or "prevention" refers to any treatment of a disease or condition in which the clinical symptoms of the disease or condition do not progress. In some embodiments, a compound is administered to a subject (including a human) with a disease, condition, or family history.

[0067] As used herein, a "prodrug" refers to a derivative that is converted into the parent drug by some chemical or enzymatic pathway after administration to the human body. In some embodiments, a prodrug is a biologically active derivative of a drug that is converted into the biologically active parent drug by some chemical or enzymatic pathway after administration to a human.

[0068] As used herein, "treatment," "treating," or "treat" refers to a method of obtaining beneficial or desired results. For purposes of this application, beneficial or desired results include, but are not limited to, alleviation of symptoms and / or the extent to which symptoms are alleviated and / or prevention of worsening of symptoms associated with a disease or condition.

[0069] In one embodiment, "treatment" or "treating" includes one or more of: a) inhibiting a disease or condition (e.g., reducing one or more symptoms caused by a disease or condition and / or reducing the extent of the disease or condition); b) alleviating or preventing the progression of one or more symptoms associated with a disease or condition (e.g., stabilizing the disease or condition, slowing the progression of the disease or condition); and c) relieving a disease or condition (e.g., reducing clinical symptoms, improving the disease state, slowing disease progression, improving quality of life, and / or prolonging survival).

[0070] As used herein, an "at-risk individual" refers to an individual who is at risk of developing a disease requiring treatment. An "at-risk" individual may or may not have a detectable disease or condition, and may or may not have developed detectable disease prior to the treatment methods described herein. "At-risk" refers to an individual having one or more so-called risk factors, which are measurable parameters associated with the progression of a disease or condition, and as is known in the art, individuals who have one or more of these risk factors have a higher probability of developing a disease or condition compared to individuals who do not have these risk factors.

[0071] compound In one aspect, the present application relates to compounds of Formula I, their stereoisomers, pharmaceutically acceptable salts and deuterated compounds:

[0072] [ka] (where, A is, TIFF2026501678000006.tif21170; where * represents the R or S configuration, n is 0, 1, 2 or 3; G is independently selected from oxygen or Gr; Here, Gr is TIFF2026501678000007.tif18170, where R2 and R3 are each independently hydrogen, a hydroxy group, a cyano group, or C 1-6 Alkyl group, C 6-10 Aryl group, C 3-10 Cycloalkyl groups, aryl heterocyclic groups, C 1-6 Alkyl group-C 6-10 Aryl group, C 1-6 Alkyl group-aryl heterocyclic group and C 1-6 Alkyl group-C 3-10 cycloalkyl groups, or R2 and R3, together with the atoms to which they are attached, can form a 4-10 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with 1-4 R4; R4 independently represents hydrogen, halogen, C 1-6 selected from the group consisting of alkyl groups and alkoxy groups; Or, any two R4's bond with the atoms to which they are connected to form C 3-10 A cycloalkyl group can be formed, where the cycloalkyl group is selected from 1 to 4 hydrogen, halogen, or C 1-6 may be substituted with an alkyl group, X is selected from the group consisting of oxygen and nitrogen; Y is a halogen; m is 0 to 20; R is independently C 2-30 wherein the hydrocarbon and aliphatic groups are optionally substituted with at least one heteroatom selected from the group consisting of N, O, and S; R is a halogen, a carboxyl group, a sulfonyl group, -S=O, -S(=O)2, an aryl group, a heteroaryl group, or C 3-10 saturated or unsaturated carbocyclic rings and C 3-10 and optionally substituted with a substituent selected from the group consisting of aryl, heteroaryl, carbocyclic, and heterocyclic groups, wherein the aryl, heteroaryl, carbocyclic, and heterocyclic groups are selected from the group consisting of H, C, 1-20 Alkyl group, C 2-20 Alkenyl group, C 2-20 Alkynyl group, C 1-20 Haloalkyl group, C 2-20 Halogenated alkenyl groups, C 2-20 Halogenated alkynyl groups, C 0-20 Alkyl group-C 6-10 Aryl group, heterocyclic group, C 0-20 Alkyl group-C 3-10 Cycloalkyl groups, C 0-20 Alkyl group -OC 1-6 Alkyl groups and C 0-20 Alkyl group -OC 1-6 Optionally substituted with haloalkyl groups.

[0073] In some embodiments, G is independently selected from oxygen or Gr; Here, Gr is The file is TIFF2026501678000008.tif18170.

[0074] R2 and R3 are each independently hydrogen, C 1-6 Alkyl group, aryl heterocyclic group, C 1-6 alkyl-aryl heterocyclic group; or R2 and R3, together with the atoms to which they are attached, can form a 4-10 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with 1-4 R4; R4 independently represents hydrogen, halogen, C 1-6 selected from the group consisting of alkyl groups and alkoxy groups; Or, any two R4's bond with the atoms to which they are connected to form C 3-10 A cycloalkyl group can be formed, where the cycloalkyl group is selected from 1 to 4 hydrogen, halogen, or C 1-6 may be substituted with an alkyl group, R is independently C 2-30 wherein the hydrocarbon and aliphatic groups are optionally substituted with at least one heteroatom selected from N, O, and S; R is a halogen, an aryl group, a heteroaryl group, or C 3-10 saturated or unsaturated carbocyclic rings and C 3-10 and optionally substituted with a substituent selected from the group consisting of an aryl group, a heteroaryl group, a C 3-10 saturated or unsaturated carbocyclic rings of C 3-10 Heterocyclic groups include H, C 1-20 Alkyl group, C 2-20 Alkenyl group, C 2-20 Alkynyl group, C 1-20 Haloalkyl group, C 2-20 Halogenated alkenyl groups and C 2-20 It is optionally substituted with a halogenated alkynyl group.

[0075] In some embodiments, G is The file is TIFF2026501678000009.tif18170.

[0076] R is independently C 2-30 The saturated or unsaturated hydrocarbon groups are selected from the group consisting of:

[0077] Preferably, R is a halogen, an aryl group, a heteroaryl group, C 3-10saturated or unsaturated carbocyclic rings and C 3-10 and optionally substituted with a substituent selected from the group consisting of an aryl group, a heteroaryl group, a C 3-10 saturated or unsaturated carbocyclic rings of C 3-10 Heterocyclic groups include H, C 1-20 Alkyl group, C 2-20 Alkenyl group, C 2-20 Alkynyl group, C 1-20 Haloalkyl group, C 2-20 Halogenated alkenyl groups, and C 2-20 It is optionally substituted with a halogenated alkynyl group.

[0078] In some embodiments, G is oxygen.

[0079] Preferably, R is C 10-20 A heterocycloalkyl group having a heteroatom substituted with an alkyl group -C(O)-, preferably R is C 15-18 A heterocycloalkyl group having a heteroatom substituted with an alkyl group -C(O)-, preferably R is C 15 A heterocycloalkyl group having a heteroatom substituted with a straight chain alkyl group -C(O)-, wherein the heteroatom in the heterocycloalkyl group is a N atom, preferably the heterocycloalkyl group is a 4-membered heterocycloalkyl group or a 5-membered heterocycloalkyl group, and the carbon atom in the heterocycloalkyl group is preferably substituted with an H or halogen atom, more preferably R is TIFF2026501678000010.tif31170, Or, R is saturated C 10-20 alkyl group, preferably a saturated C 15-18 alkyl group, where one or more methylene groups are replaced with -O-, more preferably R is TIFF2026501678000011.tif11170, Or, R is a C group substituted with an alkynyl group or a carboxyl group at the end. 10-20R is a straight chain alkyl group, preferably a C 11-16 A straight chain alkyl group, more preferably R is Selected from TIFF2026501678000012.tif17170.

[0080] In some embodiments, G is oxygen.

[0081] R is independently an unsaturated hydrocarbon group and C 0-18 Alkyl group-heteroaryl-C 0-18 The alkyl group is selected from the group consisting of:

[0082] R is a halogen, an aryl group, a heteroaryl group, or C 3-10 saturated or unsaturated carbocyclic rings of C 3-10 It is optionally substituted with a substituent selected from the group consisting of heterocyclic groups.

[0083] In some embodiments, R is independently -C 1-20 Alkyl group -C≡CC 0-20 alkyl groups, preferably R is independently selected from the group consisting of -C 5-10 Alkyl group -C≡CC 5-10 alkyl groups, preferably R is independently selected from the group consisting of C 6-7 Alkyl group -C≡CC 5-9 alkyl groups, wherein the alkyl groups are optionally substituted with halogen.

[0084] In some embodiments, R is independently -C 0-18 Alkyl group-heteroaryl-C 0-18 alkyl groups, preferably R is independently selected from the group consisting of -C 5-12 Alkyl group-heteroaryl-C 3-10 alkyl groups, preferably R is independently selected from the group consisting of -C 7-11 Alkyl group-heteroaryl-C 3-8alkyl groups, wherein the alkyl groups are optionally substituted with halogen.

[0085] In some embodiments, the heteroaryl group is The file is TIFF2026501678000013.tif18170.

[0086] In some embodiments, the compound of formula I is any selected from the following structures: TIFF2026501678000014.tif228170TIFF2026501678000015.tif185170

[0087] Treatment method In one aspect, the present application relates to a method for treating, inhibiting, and / or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula I of the present application, a stereoisomer thereof, a pharmaceutically acceptable salt, or a deuterated compound thereof.

[0088] In another aspect, the present application relates to a composition comprising a compound of Formula I of the present application, a stereoisomer, a pharmaceutically acceptable salt, or a deuterated compound thereof.

[0089] In some embodiments, the disease or disorder of the present application includes, but is not limited to, a viral infection.

[0090] In some embodiments, viral infections of the present application include, but are not limited to, HIV infection.

[0091] In some embodiments, the subject is administered a compound of Formula I, a stereoisomer, a pharmaceutically acceptable salt, or a deuterated compound thereof, of the present application, monthly.

[0092] In some embodiments, a subject is administered a compound of Formula I, a stereoisomer, a pharmaceutically acceptable salt, or a deuterated compound thereof, of the present application once every two months.

[0093] In some embodiments, the subject is administered a compound of Formula I, a stereoisomer, a pharmaceutically acceptable salt, or a deuterated compound thereof, of the present application once every six months.

[0094] In some embodiments, the subject is administered a compound of Formula I, a stereoisomer, a pharmaceutically acceptable salt, or a deuterated compound thereof, of the present application once every 12 months.

[0095] In some embodiments, the method comprises administering at least one additional anti-HIV agent.

[0096] (Example) The present application will be further described below with reference to specific examples. It should be understood that these examples are merely illustrative of the present application and do not limit the scope of the present application. Experimental methods not described in detail in the following examples generally follow conventional conditions or manufacturer's recommended conditions.

[0097] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the disclosed methods. The preferred embodiments and materials described herein are merely exemplary.

[0098] The above features mentioned in the present application or the features mentioned in the embodiments can be combined in any combination. All features disclosed in the specification of this patent can be used in any composition form, and each feature disclosed in the specification can be replaced with any alternative feature serving the same, equivalent, or similar purpose. Therefore, unless otherwise stated, the disclosed features are merely generic examples of equivalent or similar features.

[0099] preparation The compounds of the present application can be prepared using the methods disclosed herein and conventional modifications thereof, which modifications are obvious in light of the methods disclosed herein and methods familiar in the art. In addition to the teachings provided herein, conventional and well-known preparation methods can also be used. The preparation of exemplary compounds of Formula I, their stereoisomers, pharmaceutically acceptable salts, and deuterated compounds (e.g., compounds having one or more structures described in Formula I) can be accomplished as described in the Examples below.

[0100] Preparation method Exemplary embodiments of the compounds of the present application can be synthesized using the general reaction schemes and / or examples set forth below. In light of the description herein, it will be apparent that the general schemes can be modified by substituting other materials of similar structure for the starting materials, thereby yielding correspondingly different products.

[0101] In the synthetic descriptions that follow, numerous examples are provided to illustrate how starting materials can be varied to provide the corresponding products. Starting materials are generally obtained from commercial sources or synthesized using published methods for synthesizing compounds, which are embodiments of the present application. Inspection of the structure of the compound to be synthesized can provide the identity of each substituent, and in light of the examples herein, the identity of the final product will usually reveal the identity of the required starting materials through a simple inspection process.

[0102] Group labels (e.g., R1, R2) used in the reaction schemes herein are used for illustrative purposes only and do not necessarily correspond in name or function to labels used elsewhere to describe compounds of Formula I or embodiments or fragments thereof, unless otherwise specified.

[0103] Preparation reaction parameters The compounds of the present disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, it is understood that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the use of particular reactants or solvents, although such conditions can be determined by one skilled in the art by routine optimization procedures.

[0104] Those skilled in the art will also recognize that common protecting groups may be necessary to prevent undesired reactions of some functional groups. Suitable protecting groups for various functional groups, as well as appropriate conditions for protecting and deprotecting particular functional groups, are well known in the art. Many protecting groups are described, for example, in T.W. Greene and G.M. Wuts (1999) "Protective Groups in Organic Synthesis," 3rd ed., Wiley, New York, and the references cited therein.

[0105] Additionally, the compounds of the present application may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., individual enantiomers or non-enantiomers, or as stereoisomer-enriched mixtures.

[0106] Unless otherwise specified, all of these stereoisomers (and enriched mixtures) are intended to be encompassed within the scope of this application. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Additionally, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.

[0107] The starting materials for the following reactions are generally known compounds or are prepared by known procedures or obvious modifications. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA).

[0108] Others can be prepared by procedures described in standard reference works such as Fieser, Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd, Carbon Chemistry, Volumes 1-5 and supplementary versions (Elsevier Scientific Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March, Advanced Organic Chemistry (John Wiley and Sons, 5th Edition, 2001), and Larock, Comprehensive Organic Transformations (VCH Publishing Company, 1989), or obvious modifications thereof.

[0109] The terms "solvent," "inert organic solvent," or "inert solvent" refer to a solvent inert to the relevant reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), N,N-dimethylformamide ("DMF"), chloroform, dichloromethane (or dichloromethane), diethyl ether, methanol, pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions herein are inert organic solvents, and the reactions are conducted under an inert gas, preferably nitrogen gas.

[0110] The term "qs" refers to adding enough to achieve the function, eg, to bring a solution to the required volume (ie, 100%).

[0111] The compounds provided herein can be prepared according to the general schemes provided below. In the schemes below, it should be understood that each compound shown can have protecting groups present at any step where desired. Standard protecting groups are within the skill of one of ordinary skill in the art.

[0112] Example 1 Preparation scheme for compounds of formula I Scheme 1: TIFF2026501678000016.tif68170

[0113] Scheme 2: TIFF2026501678000017.tif28170n=0, 1, 2, 3,

[0114] Scheme 3: TIFF2026501678000018.tif26170n=0, 1, 2, 3,

[0115] Scheme 4 TIFF2026501678000019.tif28170 n=0, 1, 2, 3 and m=0, 1, 2, 3.

[0116] Example 2 Preparation of Compound 1: (4R,12aS)-9-((2,4-difluorobenzyl)carbamoyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazin-7-yl(S)-1-palmitoylpyrrolidine-3-carboxylate (1) TIFF2026501678000020.tif154170.

[0117] DTG (10 g, 23.8 mmol), (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (6.16 g, 28.6 mmol), HATU (13.6 g, 35.7 mmol), and DIPEA (6.15 g, 47.6 mmol) were added to DMF (100 mL) and stirred at room temperature for 2 hours. Water (500 mL) was added to the reaction mixture, and the solid precipitated and filtered to obtain Intermediate 1-A (12.3 g, 83.7% yield).

[0118] Compound 1-A (12.3 g, 19.95 mmol) was added to a solution of hydrochloric acid in ethyl acetate (2 M, 100 mL) and stirred overnight at room temperature. The solid precipitated and was filtered to obtain target compound 1-B (9.7 g, yield: 94.2%).

[0119] Compound 1-B (8.0 g, 15.5 mmol) and DIPEA (5.0 g, 38.7 mmol) were added to dichloromethane (50 mL). Palmitoyl chloride (5.11 g, 18.6 mmol) was dissolved in dichloromethane (25 mL) and added dropwise to the reaction mixture at 0 °C. The mixture was stirred for 3 hours. Water (100 mL) was added, and the organic phase was extracted. The organic phase was concentrated under reduced pressure and then purified by column chromatography (dichloromethane / methanol 20:1) to obtain target compound 1 (6.4 g, yield: 54.7%).

[0120] Preparation of Compound 3: (4R,12aS)-9-((2,4-difluorobenzyl)carbamoyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-p-pyridine[1',2':4,5]pyrazino[2,1-b][1,3]oxazin-7-yl (S)-1-palmitoylazetidine-2-carboxylate (3) TIFF2026501678000021.tif150170.

[0121] Compound 3-1 (5.00 g, 49.45 mmol) and triethylamine (7.51 g, 74.18 mmol) were dissolved in dichloromethane (50 mL) to prepare a mixture. Palmitoyl chloride (16.31 g, 59.34 mmol) was added dropwise to the mixture in an ice bath and allowed to react for 1 hour. After the reaction was completed, water (50 mL) was added. The organic phase was extracted and separated. The organic phase was washed twice with brine and concentrated to dryness under reduced pressure to obtain a white solid (9.3 g, yield: 55.4%).

[0122] A mixture was prepared by dissolving DTG (1.0 g, 2.38 mmol), compound 3-3 (1.62 g, 4.77 mmol), and triethylamine (0.97 g, 9.54 mmol) in dichloromethane (10 mL). Phosphorus oxychloride (0.49 g, 3.58 mmol) was added dropwise to the mixture in an ice bath, and the reaction was allowed to proceed for 1 hour. Water (0.5 mL) was added to quench the reaction. After concentration under reduced pressure to dryness, the solid was subjected to column chromatography to obtain the title compound (550 mg, yield: 31.1%).

[0123] Preparation of Compound 19: (4R,12aS)-9-((2,4-difluorobenzyl)carbamoyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazin-7-yl 8-(1-octyl-1H-1,2,3-triazol-4yl)octanoate (19) TIFF2026501678000022.tif119170.

[0124] To a solution of 1-azidooctane (0.4 g, 2.58 mmol) and 19-1 (1.62 g, 2.84 mmol) in PEG (polyethylene glycol), copper iodide (0.098 g, 0.52 mmol) was added, and the reaction mixture was stirred at 50 °C for 3 h. Brine (20 mL) was then added to the mixture and stirred for 10 min. The aqueous layer was extracted twice with EtOAc (30 mL). The combined organic layers were washed three times with brine (30 mL) and dried over NaSO. The organic layer was filtered and concentrated under reduced pressure to give a residue.

[0125] The crude product was purified by silica gel column chromatography, eluting with PE: EtOAc = 2:1 to give product 19: (4R,12aS)-9-((2,4-difluorobenzyl)carbamoyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazin-7-yl-8-(1-octyl-1H-1,2,3-triazol-4yl)octanoate.

[0126] After preparing compound 19, compounds 20, 21, 22, 23 and 24 can be obtained by Click-Reaction.

[0127] Following the preparative methods described herein, using the appropriate starting materials and appropriate protecting group chemistry (as desired), the following compounds are prepared.

[0128] TIFF2026501678000023.tif222170TIFF2026501678000024.tif205170TIFF2026501678000025.tif221170TIFF20265016780 00026.tif194170TIFF2026501678000027.tif244170TIFF2026501678000028.tif233170TIFF2026501678000029.tif210170 TIFF2026501678000030.tif216170TIFF2026501678000031.tif200170TIFF2026501678000032.tif222170TIFF20265016780 00033.tif233170TIFF2026501678000034.tif211170TIFF2026501678000035.tif211170TIFF2026501678000036.tif112170

[0129] Example 3 Pharmacokinetics research The compounds of formula I of the present application are metabolized in the body to the corresponding active ingredients dolutegravir (DTG), cabotegravir (CAB) and bictegravir (BTG).

[0130] As shown in Figure 1, rats were given a single subcutaneous injection of Compounds 1, 3, 5, 7, 8, 13, 14, 15, and 16 (equivalent to a dose of 18 mg / kg of the active ingredient), and the time course of the mean plasma concentration of the corresponding active ingredient (DTG, CAB, or BTG) was measured.

[0131] As shown in Figure 2, rats were given a single subcutaneous injection of compound 15 (dose: equivalent to 18 mg / kg of dolutegravir) and compound 19 (dose: equivalent to 45 mg / kg of dolutegravir), and the time course of the mean plasma concentration of the corresponding active ingredient (dolutegravir) was measured.

[0132] As shown in Figure 3, after a single subcutaneous injection of Compound 13 and Compound 21 (equivalent to 18 mg / kg of bictegravir) into rats, the time course of the mean plasma concentration of the corresponding active ingredient (bictegravir) was measured.

[0133] As shown in Figure 4, after a single subcutaneous injection of compound 14 (equivalent to 18 mg / kg of cabotegravir) into rats, the time course of the mean plasma concentration of the corresponding active ingredient (cabotegravir) was measured.

[0134] The compounds of the present application have long-term efficacy properties, demonstrating the potential for administration every 1, 2, 6, or even 12 months.

Claims

1. Compounds having the structure of Formula I, their stereoisomers, pharmaceutically acceptable salts and deuterated compounds. 【Chemistry 1】 (where, A is, 【Chemistry 2】 wherein * represents the R or S configuration; n is 0, 1, 2 or 3; G is independently selected from oxygen or Gr; Here, Gr is 【Transformation 3】 and Here, R 2 and R 3 are each independently hydrogen, a hydroxy group, a cyano group, or C 1-6 Alkyl group, C 6-10 Aryl group, C 3-10 Cycloalkyl group, aryl heterocyclic group, C 1-6 Alkyl group -C 6-10 Aryl group, C 1-6 Alkyl group-aryl heterocyclic group and C 1-6 Alkyl group -C 3-10 cycloalkyl groups, Or, R 2 and R 3 can combine with the atoms to which they are attached to form a 4- to 10-membered heterocyclic group, where the heterocyclic group is composed of 1 to 4 R 4 may be substituted with R 4 are independently hydrogen, halogen, C 1-6 selected from the group consisting of alkyl groups and alkoxy groups; Or, any two R 4 are bonded to the atoms to which they are attached to form C 3-10 A cycloalkyl group can be formed, wherein the C 3-10 The cycloalkyl group is a group having 1 to 4 hydrogen, halogen or C 1-6 may be substituted with an alkyl group, X is selected from the group consisting of oxygen and nitrogen; Y is a halogen; m is 0 to 20; R is independently C 2-30 wherein the C is selected from the group consisting of saturated or unsaturated hydrocarbon groups and aliphatic groups. 2-30 wherein the saturated or unsaturated hydrocarbon and aliphatic groups are optionally substituted with at least one heteroatom, said heteroatom being selected from the group consisting of N, O, and S; R is a halogen, a carboxy group, a sulfonyl group, -S=O, -S(=O) 2 , an aryl group, a heteroaryl group, C 3-10 saturated or unsaturated carbocyclic rings of C 3-10 and optionally substituted with a substituent selected from the group consisting of aryl, heteroaryl, carbocyclic, and heterocyclic groups, wherein the aryl, heteroaryl, carbocyclic, and heterocyclic groups are selected from the group consisting of H, C, 1-20 Alkyl group, C 2-20 Alkenyl group, C 2-20 Alkynyl group, C 1-20 Haloalkyl group, C 2-20 Halogenated alkenyl group, C 2-20 Halogenated alkynyl groups, C 0-20 Alkyl group -C 6-10 Aryl group, heterocyclic group, C 0-20 Alkyl group -C 3-10 Cycloalkyl group, C 0-20 Alkyl group -O-C 1-6 Alkyl group and C 0-20 Alkyl group -O-C 1-6 Optionally substituted with haloalkyl groups.

2. wherein G is independently selected from oxygen or Gr; Here, Gr is 【Chemistry 4】 and The R 2 and the R 3 are each independently hydrogen, C 1-6 Alkyl group, aryl heterocyclic group, C 1-6 selected from the group consisting of alkyl-aryl heterocyclic groups; Or, the R 2 and the R 3 can combine with the atoms to which they are attached to form a 4- to 10-membered heterocyclic group, where the heterocyclic group is composed of 1 to 4 of the R 4 may be substituted with The R 4 are independently hydrogen, halogen, C 1-6 selected from the group consisting of alkyl groups and alkoxy groups; Or, any two R 4 are bonded to the atoms to which they are attached to form C 3-10 A cycloalkyl group can be formed, where the cycloalkyl group contains 1 to 4 hydrogen, halogen or C 1-6 may be substituted with an alkyl group, The R is independently C 2-30 wherein the C is selected from the group consisting of saturated or unsaturated hydrocarbon groups and aliphatic groups. 2-30 wherein the saturated or unsaturated hydrocarbon and aliphatic groups are optionally substituted with at least one heteroatom, said heteroatom being selected from the group consisting of N, O, and S; The R is a halogen, an aryl group, a heteroaryl group, or C 3-10 saturated or unsaturated carbocyclic rings of C 3-10 and optionally substituted with a substituent selected from the group consisting of aryl groups, heteroaryl groups, C 3-10 saturated or unsaturated carbocyclic rings of C 3-10 The heterocyclic group is H, C 1-20 Alkyl group, C 2-20 Alkenyl group, C 2-20 Alkynyl group, C 1-20 Haloalkyl group, C 2-20 Halogenated alkenyl groups, and C 2-20 10. The compound of claim 1, its stereoisomer, pharmaceutically acceptable salt or deuterated compound, optionally substituted with a halogenated alkynyl group.

3. The G is 【Transformation 5】 and The R is independently C 2-30 and is selected from the group consisting of saturated or unsaturated hydrocarbon groups of Preferably, R is a halogen, an aryl group, a heteroaryl group, C 3-10 saturated or unsaturated carbocyclic rings of C 3-10 and optionally substituted with a substituent selected from the group consisting of aryl groups, heteroaryl groups, C 3-10 saturated or unsaturated carbocyclic rings of C 3-10 The heterocyclic group is H, C 1-20 Alkyl group, C 2-20 Alkenyl group, C 2-20 Alkynyl group, C 1-20 Haloalkyl group, C 2-20 Halogenated alkenyl groups, and C 2-20 3. The compound of claim 2, its stereoisomer, pharmaceutically acceptable salt or deuterated compound, optionally substituted with a halogenated alkynyl group.

4. G is oxygen; Preferably, R is C 10-20 A heterocycloalkyl group having a heteroatom substituted with an alkyl group -C(O)-, preferably, R is C 15-18 A heterocycloalkyl group having a heteroatom substituted with an alkyl group -C(O)-, preferably, R is C 15 A heterocycloalkyl group having a heteroatom substituted with a linear alkyl group -C(O)-, wherein the heteroatom in the heterocycloalkyl group is a N atom, preferably the heterocycloalkyl group is a 4-membered heterocycloalkyl group or a 5-membered heterocycloalkyl group, and the carbon atom in the heterocycloalkyl group is preferably substituted with a H or halogen atom, more preferably the R is 【Transformation 6】 is selected from the group consisting of Or, the R is saturated C 10-20 alkyl group, preferably saturated C 15-18 alkyl groups, where one or more methylene groups are replaced with -O-, more preferably R is 【Transformation 7】 and Alternatively, the R may be a C alkyl group whose terminal group is substituted with an alkynyl group or a carboxyl group. 10-20 The R is a straight-chain alkyl group, and preferably the R is a C 11-16 is a linear alkyl group, and more preferably, said R is 【Transformation 8】 2. The compound of claim 1, its stereoisomer, pharmaceutically acceptable salt or deuterated compound selected from:

5. G is oxygen; The R independently represents an unsaturated hydrocarbon group and C 0-18 Alkyl group-heteroaryl-C 0-18 alkyl groups, Preferably, R is a halogen, an aryl group, a heteroaryl group, C 3-10 saturated or unsaturated carbocyclic rings of C 3-10 3. The compound of claim 2, its stereoisomer, pharmaceutically acceptable salt or deuterated compound, optionally substituted with a substituent selected from the group consisting of heterocyclic groups.

6. The R is independently —C 1-20 Alkyl group -C≡C-C 0-20 alkyl groups, and preferably, each R is independently selected from the group consisting of -C 5-10 Alkyl group -C≡C-C 5-10 alkyl groups, and preferably, each R is independently selected from the group consisting of -C 6-7 Alkyl group -C≡C-C 5-9 6. The compound of claim 5, its stereoisomer, pharmaceutically acceptable salt or deuterated compound, wherein the alkyl group is selected from the group consisting of alkyl groups, wherein the alkyl group is optionally substituted with halogen.

7. The R is independently —C 0-18 Alkyl group-heteroaryl-C 0-18 alkyl groups, and preferably, each R is independently selected from the group consisting of -C 5-12 Alkyl group-heteroaryl-C 3-10 alkyl groups, and preferably, each R is independently selected from the group consisting of -C 7-11 Alkyl group-heteroaryl-C 3-8 6. The compound of claim 5, its stereoisomer, pharmaceutically acceptable salt or deuterated compound, wherein the alkyl group is selected from the group consisting of alkyl groups, wherein the alkyl group is optionally substituted with halogen.

8. The heteroaryl group is 【Chemistry 9】 8. The compound of claim 7, a stereoisomer thereof, a pharmaceutically acceptable salt or a deuterated compound thereof, wherein:

9. The compound of formula I, its stereoisomer, pharmaceutically acceptable salt, and deuterated compound according to any one of claims 1 to 8, wherein the compound is any one selected from the following structures:

10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9, its stereoisomer, pharmaceutically acceptable salt or deuterated compound, and a pharmaceutically acceptable excipient.

11. 10. A method for treating, inhibiting and / or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject an effective amount of a compound, stereoisomer, pharmaceutically acceptable salt or deuterated compound thereof according to any one of claims 1 to 9.

12. 12. The method of claim 11, wherein the disease or disorder is a viral infection.

13. The method of claim 12, wherein the viral infection is an HIV infection.

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