Formulation for integrase inhibition and preparation method therefor

Abstract

Disclosed are a formulation for integrase inhibition and a preparation method for the formulation. The formulation comprises a compound of formula I, and a stereoisomer, a pharmaceutically acceptable salt or a deuterated compound thereof, and at least one pharmaceutically acceptable carrier. Each substituent is as defined in the present disclosure.

Description

Integrase inhibitor preparation and preparation method thereof

[0001] Citation of Related Applications

[0002] This disclosure claims all benefits of the Chinese invention patent application No. 202310851935.X, filed with the State Intellectual Property Office of the People's Republic of China on July 12, 2023, entitled “A preparation of integrase inhibitors and its preparation method”, the Chinese invention patent application No. 202310960689.1, filed with the State Intellectual Property Office of the People's Republic of China on August 1, 2023, entitled “A preparation of integrase inhibitors and its preparation method”, and U.S. provisional application No. 63 / 530,876, filed with the United States Patent and Trademark Office on August 4, 2023, entitled “Formulation Comprising Integrase Inhibitor and Process for Making The Same”, and incorporates the entire contents of each of them into this disclosure by reference.

[0003] field

[0004] The present disclosure relates generally to the field of medicine, and more particularly to formulations of integrase inhibitor drugs and methods for preparing the same.

[0005] background

[0006] 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, enabling individuals with HIV to achieve a near-normal quality of life. However, ART requires lifelong treatment to suppress viral replication and prevent the onset of AIDS. Furthermore, the effectiveness of ART can be hampered by HIV-1 drug resistance, drug toxicity, and poor patient adherence. Treatment fatigue, lack of financial and social support, comorbid psychiatric symptoms, and / or substance abuse can contribute to nonadherence to critical ART regimens.

[0007] Overview

[0008] In one aspect, the present disclosure relates to a formulation comprising a compound of Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt, or a deuterated compound thereof, and at least one pharmaceutically acceptable carrier:

[0009] in

[0010] A is selected from: Wherein * represents R or S configuration, or a mixture thereof;

[0011] n is 0, 1, 2, or 3;

[0012] G is independently selected from oxygen or a group Gr;

[0013] Wherein Gr is selected from

[0014] Wherein R2 and R3 are independently selected from hydrogen, hydroxy, cyano, C 1-6 Alkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, aromatic heterocyclic group, C 1-6 Alkyl-C 6-10 Aryl, C 1-6 Alkyl-aromatic heterocyclic group, C 1- 6-alkyl-C 3-10 Cycloalkyl;

[0015] Or R2 and R3 may be combined with the atoms to which they are attached to form a 4-10 membered heterocyclic group; the heterocyclic group may be substituted by 1 to 4 R4;

[0016] R4 is independently selected from hydrogen, halogen, C1-6 alkyl, alkoxy; any two R4 can be combined with the atoms to which they are connected to form C 3-10 Cycloalkyl; the cycloalkyl may be substituted by 1 to 4 hydrogen, halogen, or C1-6 alkyl;

[0017] X is selected from oxygen or nitrogen;

[0018] F is selected from halogen;

[0019] m is 0 to 20;

[0020] R is independently selected from C 2-30 a saturated or unsaturated alkyl or aliphatic group, wherein the alkyl or aliphatic group may be optionally substituted by at least one heteroatom selected from N, O, and S;

[0021] R may be optionally substituted by the following groups: halogen, carboxyl, sulfonic acid, -S=O, -S(=O)2, aryl, heteroaryl, C 3-10 Saturated or unsaturated carbon ring, C 3-10 wherein the aryl, heteroaryl, carbocyclic and heterocyclic groups may be optionally substituted with hydrogen, C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 1-20 Halogenated alkyl, C 2-20 Halogenated alkenyl, C 2-20 Haloalkynyl, C 0-20 Alkyl-C 6-10 Aryl, heterocycloalkyl, C 0-20 Alkyl-C 3-10 Cycloalkyl, C0-20 Alkyl-OC 1-6 Alkyl and C 0-20 Alkyl-OC 1-6 Halogenated alkyl.

[0022] In another aspect, the present disclosure relates to a method for treating and / or preventing HIV / AIDS in a subject, comprising administering to an individual in need thereof a therapeutically and / or prophylactically effective amount of a formulation of the present disclosure.

[0023] In certain embodiments, the disclosed integrase inhibitors are formulated to reduce the treatment schedule from daily to monthly, or even less frequently, providing greater patient privacy and satisfaction and improving treatment regimen compliance.

[0024] BRIEF DESCRIPTION OF THE DRAWINGS

[0025] FIG1 shows the in vivo blood drug concentration of the oil solution of the present disclosure after SC administration to SD rats.

[0026] FIG2 shows the in vivo blood drug concentration of the oil solution of the present disclosure after IM administration to SD rats.

[0027] FIG3 shows the in vivo blood drug concentration of the hydrophilic solution of the present disclosure after SC administration to SD rats.

[0028] FIG4 shows a graph of the in vivo blood drug concentration of the hydrophilic solution of the present disclosure after IM administration to SD rats.

[0029] FIG5 shows the in vivo blood drug concentration of the polymer gel of the present disclosure after SC administration to SD rats.

[0030] FIG6 shows the in vivo blood drug concentration of the suspension of the present disclosure after IM administration to SD rats.

[0031] FIG7 shows the in vivo blood drug concentration of the self-microemulsifying solution of the present disclosure after SC administration to SD rats.

[0032] FIG8 shows the in vivo blood drug concentration of the suspension of the present disclosure after IM administration in SD rats.

[0033] Details

[0034] In the following description, certain specific details are included to provide a thorough understanding of the various disclosed embodiments. However, one skilled in the relevant art will recognize that the embodiments can be implemented without one or more of these specific details and with other methods, components, materials, etc.

[0035] Unless otherwise required by this disclosure, throughout this specification and the claims that follow, the words "include" and "comprising" should be construed in an open, inclusive sense, ie, "including, but not limited to."

[0036] As used in this disclosure and the appended claims, singular references without indications of quantity include plural references unless the context clearly dictates otherwise.

[0037] Reference throughout this specification to "one embodiment" or "an embodiment" or "in another embodiment" or "in certain embodiments" means that the specific referenced elements, structures, or features described in connection with that embodiment are included in at least one embodiment. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the specific elements, structures, or features may be combined in any suitable manner in one or more embodiments.

[0038] It should be understood that the singular articles "a," "an," and "the" used in the specification and appended claims of this disclosure include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to a sustained-release tablet containing "a pharmaceutically acceptable excipient" includes one pharmaceutically acceptable excipient, or two or more pharmaceutically acceptable excipients.

[0039] definition

[0040] 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 dash at the beginning or end of a chemical group is used for convenience to indicate the point of attachment to the parent molecule; a chemical group may be described with or without one or more dashes without losing its ordinary meaning. A prefix such as "C u-v ” or “C u -C v " means the following group has u to v carbon atoms, where u and v are integers. For example, "C 1-6 "Alkyl" or "C1-C6 alkyl" means that the alkyl group has 1 to 6 carbon atoms.

[0041] "Alkyl" is a monovalent or divalent linear or branched saturated hydrocarbon radical. For example, an alkyl group can have 1 to 10 carbon atoms (i.e., C 1-10 Alkyl) or 1 to 8 carbon atoms (ie C 1-8 Alkyl) or 1 to 6 carbon atoms (ie C 1-6 Alkyl) or 1 to 4 carbon atoms (ie C 1-4Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH3), 2-propyl (i-Pr, i-Propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-Methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-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). The alkyl group may be unsubstituted or substituted.

[0042] "Alkenyl" is a monovalent or divalent linear or branched hydrocarbon radical having at least one carbon-carbon double bond. For example, an alkenyl group can have 2 to 8 carbon atoms (i.e., C 2-8 alkenyl) or 2 to 6 carbon atoms (ie C 2-6 alkenyl) or 2 to 4 carbon atoms (ie C 2-4 Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and -CH2-CH=CH-CH3. Alkenyl groups may be unsubstituted or substituted.

[0043] "Alkynyl" is a monovalent or divalent linear or branched hydrocarbon radical having at least one carbon-carbon triple bond. For example, an alkynyl group can have 2 to 8 carbon atoms (i.e., C 2-8 Alkynyl) or 2 to 6 carbon atoms (ie C 2-6 Alkynyl) or 2 to 4 carbon atoms (ie C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), and -CH2-C≡C-CH3. Alkynyl groups may be unsubstituted or substituted.

[0044] "Alkoxyalkyl" is an alkoxy group attached to an alkyl group as defined above, thereby making the alkyl group divalent. 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 may be unsubstituted or substituted.

[0045] "Halogen" refers to fluorine (-F), chlorine (-Cl), bromine (-Br) and iodine (-I).

[0046] "Haloalkyl" is an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently replaced by a halogen, which halogens may be the same or different, such that the alkyl group is divalent. Alkyl and halogen may be any of those described above. In some embodiments, haloalkyl defines the number of carbon atoms in the alkyl group, for example, C1-4 haloalkyl includes CF3, CH2F, CHF2, CH2CF3, CH2CH2CF3, CCl2CH2CH3, and C(CH3)2(CF2H). Halogenated hydrocarbon groups may be unsubstituted or substituted.

[0047] "Aryl" refers to a monovalent or divalent all-carbon aromatic ring or a polycondensed all-carbon 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 includes a phenyl group. Aryl also includes multiple condensed ring systems (e.g., ring systems composed of 2, 3, or 4 rings) having about 9 to 20 carbon atoms, wherein multiple rings are aromatic. Where valence requirements permit, the rings of multiple condensed ring systems may be interconnected by fusion bonds. It is also understood that when referring to a certain atomic range of member aryl groups (e.g., a 6-10 member aryl group), the atomic range refers to the total ring atoms of the aryl group. For example, a 6-member aryl group includes phenyl, and a 10-member aryl group includes naphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like. Aryl groups can be unsubstituted or substituted.

[0048] "5-10 membered aromatic heterocycle" or "heteroaryl ring" refers to a single aromatic ring having at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; "heteroaryl" also includes multiple condensed ring systems having at least one such aromatic ring, which multiple condensed ring systems are further described below. Thus, "heteroaryl" includes a single aromatic ring of about 1-6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also be present in oxidized form, as long as the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl or furanyl. "Heteroaryl" also includes multiple condensed ring systems (e.g., ring systems consisting of 2, 3 or 4 rings) in which a heteroaryl as defined above is condensed with one or more rings selected from heteroaryl (forming, for example, 1,8-naphthyridinyl) and aryl (forming, for example, benzimidazolyl or indazolyl) to form multiple condensed ring systems. Thus, a heteroaryl group (single aromatic ring or multiple condensed ring systems) can have about 1 to 20 carbon atoms and about 1 to 6 heteroatoms within the heteroaryl ring. For example, tetrazolyl has 1 carbon atom and 4 nitrogen heteroatoms within the ring. Where valence requirements permit, the rings of multiple condensed ring systems can be interconnected by fusion bonds. It should be understood that the individual rings of multiple condensed ring systems can be interconnected in any order. It should be understood that the point of attachment of a heteroaryl or heteroaryl multiple condensed ring system can be any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). It should also be understood that when a heteroaryl group is referred to as having a range of atoms (e.g., a 5 to 10 member heteroaryl group), that range is for the total ring atoms of the heteroaryl group, including carbon atoms and heteroatoms. It is also understood that the rings of the multiple condensed ring systems may include an aryl ring fused to a heterocyclic ring having saturated or partially unsaturated bonds (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) having from about 1 to 6 ring carbon atoms and from about 1 to 3 ring heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. For example, a 5-membered heteroaryl includes thiazolyl, and a 10-membered heteroaryl includes quinolinyl. Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxazolyl, quinazolyl, benzofuranyl, benzimidazolyl, thiophenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, and tetrazolyl. The heteroaryl group can be unsubstituted or substituted.

[0049] "Cycloalkyl" is a monovalent or divalent single all-carbon ring or multiple condensed all-carbon ring systems, wherein the ring in each example is a non-aromatic saturated or unsaturated ring. For example, in some embodiments, cycloalkyl 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 cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl, cycloheptyl, cycloheptenyl and cyclooctyl. Cycloalkyl also includes multiple condensed ring systems (for example, ring systems including 2 rings) with about 7 to 12 carbon atoms. Where valence requirements permit, the rings of multiple condensed ring systems can be interconnected by fusion bonds, spiral bonds or bridge bonds. Exemplary polycyclic cycloalkyls include octahydropentane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[2.2]oct-2ene, and spiro[2.5]octane.Cycloalkyl groups can be unsubstituted or substituted.

[0050] As used herein, "heterocycle" or "heterocyclic ring" or "heterocyclyl" refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic ring system having at least one heteroatom (i.e., at least one cyclic (i.e., annular) heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, a heterocyclic group has 3 to about 20 ring atoms, such as 3 to 12 ring atoms, such as 4 to 12 ring atoms, 4 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 4 to 6 ring atoms, or 4 to 5 ring atoms. Thus, the term includes single saturated or partially unsaturated rings (e.g., 3-, 4-, 5-, 6-, or 7-membered rings) having about 1 to 6 ring carbon atoms and about 1 to 3 ring heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Where valence requirements permit, the rings of multiple condensed ring systems (e.g., bicyclic heterocycles) may be interconnected by fusion bonds, spiral bonds, and bridge bonds. Heterocycles include, but are not limited to, nitrogen heterocycles, aziridines, imidazolidines, morpholine, oxirane, oxygen heterocycles, sulfur heterocycles, piperazine, and piperidine. Pyrazolidine, piperidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, 2-oxo-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 2-thia-6-azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2-azabicyclo[3.1.0]hexan-2-yl, 3-azabicyclo[3.0]hexan-2-yl, 2-azabicyclo[2.1.1]hexan-2-yl, 2-azabicyclo[2.2.1]heptan-2-yl, 4-azaspiro[2.4]heptyl, 5-azaspiro[2.4]heptyl, and the like. The heterocyclyl group can be unsubstituted or substituted.

[0051] As used herein, "substituted" refers to a group wherein one or more hydrogen atoms of the group are independently replaced with one or more substituents (eg, 1, 2, 3, or 4 or more), as indicated.

[0052] "Compounds of the present disclosure" include compounds disclosed herein, for example, compounds of the present disclosure include compounds of formula (I), including the compounds of the Examples. In some embodiments, "compounds of the present disclosure" include compounds of formula (I).

[0053] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, vehicle, lubricant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or veterinary animals.

[0054] As used herein, "therapeutically effective amount" or "effective amount" refers to an amount that is effective to elicit a desired biological or medical response, including an amount of a compound that, when administered to a subject being treated for a disease, is sufficient to affect the treatment of the disease. The effective amount will vary depending on factors such as the compound, the disease and its severity, and the age, weight, and other factors of the subject being treated. An effective amount may include a range of amounts. 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 endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if, when used in conjunction with one or more other agents, a desired or beneficial result may or has been achieved. Due to the combined action of the compounds (e.g., additive or synergistic), the appropriate dose of any co-administered compound may be selectively reduced.

[0055] As used herein, "co-administration" 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, for example, administering a compound of the present disclosure within a few 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 a unit dose of one or more additional therapeutic agents within a few seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of a compound of the present disclosure within a few seconds or minutes. In some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by a unit dose of one or more additional therapeutic agents a few hours later (e.g., 1-12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of a compound of the present disclosure a few hours later (e.g., 1-12 hours). Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to administering a compound disclosed herein and one or more additional therapeutic agents simultaneously or sequentially, such that a therapeutically effective amount of each agent is present in the subject's body.

[0056] Also provided are pharmaceutically acceptable salts, hydrates, solubilized forms, isomeric forms, polymorphs, and prodrugs of the compounds described herein.

[0057] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other materials that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0058] The compounds described herein can 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 compound that possess the pharmacological activity required of the free base. These salts can be extracted from inorganic or organic acids or bases. For example, compounds containing 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 sulfates, pyrosulfates, disulfates, sulfites, disulfates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, and pyrophosphates. Chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propanolates, oxalates, malonates, ferrites, sebacates, and fumarates.

[0065] Pharmaceutically acceptable salts include maleates, butyne-1,4-dioate, hexyne-1,6-dioate, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propanesulfonates. Benzenesulfonates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, and mandelates. A list of other suitable pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0059] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include salts derived from appropriate bases, such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and N(C1-C4 alkyl)4 + Also included are base addition salts such as sodium, potassium or calcium salts.

[0060] Also provided are compounds described herein or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom, or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds may increase resistance to metabolism and, therefore, may be used to increase the half-life of a compound described herein or a pharmaceutically acceptable salt, isomer, or mixture thereof when administered to a mammal. See "Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., 5(12): 524-527 (1984)". Such compounds are synthesized by methods well known in the art, for example, using starting materials in which one or more hydrogen atoms are replaced by deuterium.

[0061] Examples of isotopes that may be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 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 I. Using positron-emitting isotopes, such as 11 C. 18 F. 15 O and 13 N substitution can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the examples below, using an appropriate isotopically labeled reagent in place of the previously used non-labeled reagent.

[0062] 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 enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)-, or, for amino acids, as (D)- or (L)-. This statement is meant to include all such possible isomers, as well as their racemates and optically pure forms. Optically active (+) and (-), (R) and (S), or (D) and (L)-isomers can be prepared using chiral syntheses or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolving racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, these compounds are intended to include both E and Z geometric isomers. Likewise, all isomeric forms are also included. When a compound is indicated in its chiral form, it is understood that the embodiment includes, but is not limited to, the specific diastereomer or enantiomerically enriched form. If chirality is not specified but is present, it is understood that the embodiment is directed to the specific diastereomer or enantiomerically enriched form; or a racemic or scalar mixture of such a compound. As used herein, "scalar mixture" refers to a mixture of stereoisomers in a ratio other than 1:1.

[0063] As used herein, "stereoisomers" refer to compounds bound by the same atoms but having different three-dimensional structures that are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

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

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

[0066] As used herein, "hydrate" refers to a compound of the present invention chemically bound to one or more water molecules.

[0067] "Prevention" or "prevention" refers to any treatment of a disease or condition that results in the non-development of clinical symptoms of the disease or condition. In some embodiments, the compound can be administered to a subject (including a human) at risk for or with a family history of the disease or condition.

[0068] As used herein, "prodrug" refers to a derivative of a drug that is converted to the parent drug according to 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 to the biologically active parent drug according to some chemical or enzymatic pathway after administration to the human body.

[0069] As used herein, "treat" or "treatment" or "treatment" refers to an approach to obtaining beneficial or desired results. For the purposes of this disclosure, beneficial or desired results include, but are not limited to, alleviating symptoms and / or reducing the extent of symptoms and / or preventing worsening of symptoms associated with a disease or condition. In one embodiment, "treat" or "treatment" includes one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or reducing the extent of the disease or condition); b) slowing or arresting the development of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying worsening or progression of the disease or condition); and c) alleviating the disease or condition, e.g., causing regression of clinical symptoms, improving the disease state, delaying disease progression, improving quality of life, and / or prolonging survival. As used herein, an "at-risk individual" refers to an individual who is at risk of developing a disease for which treatment is desired. An individual who is "at risk" may or may not have a detectable disease or condition and may or may not have exhibited detectable disease prior to the treatment methods described herein. "At risk" means that the individual has one or more so-called risk factors, which are measurable parameters that are associated with the development of a disease or condition and are known in the art to increase the probability of individuals with one or more of these risk factors developing the disease or condition compared to individuals without these risk factors.

[0070] preparation

[0071] In one aspect, the present disclosure relates to a formulation comprising a compound of Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt, or a deuterated compound thereof, and at least one pharmaceutically acceptable carrier:

[0072] in

[0073] A is selected from: Wherein * represents R or S configuration, or a mixture thereof;

[0074] n is 0, 1, 2, or 3;

[0075] G is independently selected from oxygen or a group Gr;

[0076] Wherein Gr is selected from

[0077] Wherein R2 and R3 are independently selected from hydrogen, hydroxy, cyano, C 1-6 Alkyl, C6-10 Aryl, C 3-10 Cycloalkyl, aromatic heterocyclic group, C 1-6 Alkyl-C 6-10 Aryl, C 1-6 Alkyl-aromatic heterocyclic group, C 1- 6-alkyl-C 3-10 Cycloalkyl;

[0078] Or R2 and R3 may be combined with the atoms to which they are attached to form a 4-10 membered heterocyclic group; the heterocyclic group may be substituted by 1 to 4 R4;

[0079] R4 is independently selected from hydrogen, halogen, C1-6 alkyl, alkoxy; any two R4 can be combined with the atoms to which they are connected to form C 3-10 Cycloalkyl; the cycloalkyl may be substituted by 1 to 4 hydrogen, halogen, or C1-6 alkyl;

[0080] X is selected from oxygen or nitrogen;

[0081] F is selected from halogen;

[0082] m is 0 to 20;

[0083] R is independently selected from C 2-30 a saturated or unsaturated alkyl or aliphatic group, wherein the alkyl or aliphatic group may be optionally substituted by at least one heteroatom selected from N, O, and S;

[0084] R may be optionally substituted by the following groups: halogen, carboxyl, sulfonic acid, -S=O, -S(=O)2, aryl, heteroaryl, C 3-10 Saturated or unsaturated carbon ring, C 3-10 wherein the aryl, heteroaryl, carbocyclic and heterocyclic groups may be optionally substituted with hydrogen, C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 1-20 Halogenated alkyl, C 2-20 Halogenated alkenyl, C 2-20 Haloalkynyl, C 0-20 Alkyl-C 6-10 Aryl, heterocycloalkyl, C 0-20 Alkyl-C 3-10 Cycloalkyl, C 0-20 Alkyl-OC 1-6 Alkyl and C 0-20 Alkyl-OC 1-6 Halogenated alkyl.

[0085] In certain embodiments, G is independently selected from oxygen or Gr;

[0086] where Gr is

[0087] R2 and R3 are each independently selected from hydrogen, C 1-6 Alkyl, aromatic heterocyclic group, C 1-6 Alkyl-aromatic heterocyclic group;

[0088] Alternatively, R2 and R3 may be combined with the atoms to which they are attached to form a 4-10 membered heterocyclic group; wherein the heterocyclic group is substituted with 1 to 4 R4;

[0089] R4 is independently selected from hydrogen, halogen, C 1-6 Alkyl, alkoxy; any two R4 can be combined with the atoms to which they are attached to form a C 3-10 Cycloalkyl; the C 3-10 The cycloalkyl group may be substituted with 1 to 4 hydrogen atoms, halogen atoms, C 1-6 Alkyl substitution;

[0090] R is independently selected from C 2-30 Saturated or unsaturated hydrocarbon or aliphatic group, wherein the C 2-30 The saturated or unsaturated hydrocarbon group or aliphatic group may be optionally substituted by at least one heteroatom selected from N, O, S;

[0091] R can be optionally substituted by the following groups: halogen, aryl, heteroaryl, C 3-10 Saturated or unsaturated carbon ring and C 3-10 Heterocyclic group, wherein the aryl, heteroaryl, C 3-10 Saturated or unsaturated carbon ring and C 3-10 The heterocyclic group may be optionally substituted with hydrogen, C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 1-20 Halogenated alkyl, C 2-20 Halogenated alkenyl and C 2-20 Haloalkynyl.

[0092] In certain embodiments, R is independently selected from C 2-30 Saturated or unsaturated hydrocarbon; R can be optionally selected from halogen, aryl, heteroaryl, C 3-10 Saturated or unsaturated carbon ring and C 3-10 Heterocyclic group, wherein the aryl, heteroaryl, C 3-10 Saturated or unsaturated carbon ring and C 3-10 The heterocyclic group may be optionally substituted with hydrogen, C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 1-20 Halogenated alkyl, C 2-20 Halogenated alkenyl and C 2-20 Haloalkynyl.

[0093] In certain embodiments, G is oxygen;

[0094] R is selected from heteroatoms C 10-20 Alkyl-C(O)-substituted heterocycloalkyl; wherein the heteroatom in the heterocycloalkyl is a nitrogen atom.

[0095] In certain embodiments, R is selected from the group consisting of 15-18 Alkyl-C(O)-substituted heterocycloalkyl; wherein the heteroatom in the heterocycloalkyl is a nitrogen atom.

[0096] In certain embodiments, R is selected from the group consisting of 15 A straight-chain -C(O)-substituted heterocycloalkyl group, wherein the heteroatom in the heterocycloalkyl group is a nitrogen atom.

[0097] In certain embodiments, the heterocycloalkyl group is a four-membered heterocycloalkyl group or a five-membered heterocycloalkyl group, and the carbon atoms in the heterocycloalkyl group are preferably substituted with H or halogen atoms.

[0098] In certain embodiments, R is selected from any one or more of the following

[0099] In certain embodiments, R is a saturated C 10-20 alkyl.

[0100] In certain embodiments, R is a saturated C 15-18 Alkyl groups in which one or more methylene groups are replaced by -O-.

[0101] In certain embodiments, R is

[0102] In certain embodiments, R is C 10-20 A straight-chain alkyl group whose terminal group is substituted by an alkynyl group or a carboxyl group.

[0103] In certain embodiments, R is C 11-16 A straight-chain alkyl group whose terminal group is substituted by an alkynyl group or a carboxyl group.

[0104] In certain embodiments, R is selected from

[0105] In certain embodiments,

[0106] G is

[0107] In certain embodiments, R is independently selected from unsaturated hydrocarbons and C 0-18 Alkyl-heteroaryl-C 0-18 alkyl;

[0108] R may optionally be selected from halogen, aryl, heteroaryl C 3-10 Saturated or unsaturated carbon ring and C 3-10 Heterocyclic group.

[0109] In certain embodiments, G is oxygen.

[0110] In certain embodiments, R is independently selected from -C 1-20 Alkyl-C≡CC 0-20 wherein the alkyl group is optionally substituted by halogen.

[0111] In certain embodiments, R is independently selected from -C 5-10 Alkyl-C≡CC 5-10 wherein the alkyl group is optionally substituted by halogen.

[0112] In certain embodiments, R is independently selected from -C 6-7 Alkyl-C≡CC 5-9 Alkyl; wherein the alkyl is optionally substituted with halogen.

[0113] In certain embodiments, R is independently selected from -C 0-18 Alkyl-heteroaryl-C 0-18 Alkyl; wherein the alkyl group is optionally substituted with halogen.

[0114] In certain embodiments, R is independently selected from -C 5-12 Alkyl-heteroaryl-C 3-10 Alkyl; wherein the alkyl group is optionally substituted with halogen.

[0115] In certain embodiments, R is independently selected from -C 7-11 Alkyl-heteroaryl-C 3-8 Alkyl; wherein the alkyl group is optionally substituted with halogen.

[0116] In certain embodiments,

[0117] The heteroaryl group is

[0118] In certain embodiments, the compound of formula I is of formula II:

[0119] In certain embodiments, the compound of Formula I is Formula III:

[0120] In certain embodiments, the compound of formula I is of formula IV:

[0121] In certain embodiments, the compound is selected from:

[0122] In certain embodiments, the formulations of the present disclosure comprise an oily vehicle and an organic solvent to form an oil solution.

[0123] In certain embodiments, illustrative examples of oily vehicles that can be used in the present disclosure include, but are not limited to, castor oil, rapeseed oil, sesame oil, fractionated coconut oil, fatty acid glycerides, benzyl benzoate, and any mixtures thereof.

[0124] In certain embodiments, the oily vehicle is selected from one or any mixture of fatty acid glycerides, castor oil, and benzyl benzoate.

[0125] In certain embodiments, the oily vehicle is a fatty acid glyceride.

[0126] In certain embodiments, illustrative examples of organic solvents that can be used in the present disclosure include, but are not limited to, benzyl alcohol, ethanol, N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), and any mixtures thereof.

[0127] In certain embodiments, the organic solvent is selected from one of benzyl alcohol, ethanol, N-methylpyrrolidone (NMP), or any mixture thereof.

[0128] In certain embodiments, the weight ratio of the oily vehicle to the organic solvent ranges from 6:4 to 10:0.

[0129] In certain embodiments, the weight ratio of the oily vehicle to the organic solvent ranges from 7:3 to 10:0.

[0130] In certain embodiments, the weight ratio of the oily vehicle to the organic solvent ranges from 8:2 to 10:0.

[0131] In certain embodiments, the formulations of the present disclosure comprise a hydrophilic vehicle and an organic solvent, forming a hydrophilic solution.

[0132] In certain embodiments, illustrative examples of hydrophilic vehicles that can be used in the present disclosure include, but are not limited to, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, propylene glycol, glycerol, water, and any mixtures thereof.

[0133] In certain embodiments, the hydrophilic vehicle is polyethylene glycol 300.

[0134] In certain embodiments, illustrative examples of organic solvents that can be used in the present disclosure include, but are not limited to, ethanol, benzyl benzoate, benzyl alcohol, NMP, and any mixture thereof.

[0135] In certain embodiments, the organic solvent is selected from one of ethanol and benzyl alcohol or any mixture thereof.

[0136] In certain embodiments, the weight ratio of the hydrophilic vehicle to the organic solvent ranges from 5:5 to 10:0.

[0137] In certain embodiments, the weight ratio of the hydrophilic vehicle to the organic solvent ranges from 6:4 to 10:0.

[0138] In certain embodiments, the weight ratio of the hydrophilic vehicle in the formulation is 7:3 to 10:0.

[0139] In certain embodiments, the formulations of the present disclosure further include a pH adjuster.

[0140] In certain embodiments, illustrative examples of pH adjusters that can be used in the present disclosure include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, sodium citrate, phosphoric acid, sodium hydrogen phosphate, and any mixtures thereof.

[0141] In certain embodiments, the formulations of the present disclosure further comprise a release retardant.

[0142] In certain embodiments, illustrative examples of release retardants that can be used in the present disclosure include, but are not limited to, poly(lactic-co-glycolic acid) (PLGA) and polylactic acid (PLA).

[0143] In certain embodiments, the weight ratio of the release retardant in the hydrophilic solution is 1% to 10%.

[0144] In certain embodiments, the formulations of the present disclosure comprise an oily solvent, an oleogel, and an organic solvent to form an oleogel.

[0145] In certain embodiments, illustrative examples of oily solvents that can be used in the present disclosure include, but are not limited to, castor oil, rapeseed oil, sesame oil, fractionated coconut oil, fatty acid glycerides, benzyl benzoate, and any mixtures thereof.

[0146] In certain embodiments, the oily solvent is selected from castor oil, fatty acid glycerides, and sesame oil.

[0147] In certain embodiments, the oily solvent is medium-chain fatty acid glyceride, which accounts for 60% to 90% by weight in the oil gel.

[0148] In certain embodiments, illustrative examples of oleogels that can be used in the present disclosure include, but are not limited to, stearic acid, 12-hydroxystearic acid, palmitic acid, and any combination thereof.

[0149] In certain embodiments, the oleogel agent is stearic acid, which is present in the oleogel in an amount of 5% to 10% by weight.

[0150] In certain embodiments, illustrative examples of organic solvents that can be used in the present disclosure include, but are not limited to, N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), and any combination thereof.

[0151] In certain embodiments, the organic solvent is selected from N-methylpyrrolidone (NMP), and its weight ratio in the oil gel is 10% to 40%.

[0152] In certain embodiments, the formulations of the present disclosure comprise a biodegradable polymer solution forming a polymer gel solution comprising a polymer gel material and an organic solvent.

[0153] In certain embodiments, illustrative examples of polymer gel materials that can be used in the present disclosure include, but are not limited to, poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), polyoxyethylene-polycaprolactone block copolymers, and polyoxyethylene-polyoxypropylene block copolymers.

[0154] In certain embodiments, the polymer gel material is poly(lactic-co-glycolic acid) (PLGA).

[0155] In certain embodiments, the ratio of lactic acid to glycolic acid in the poly(lactic-co-glycolic acid) molecule is 75:25 or 50:50.

[0156] In certain embodiments, the intrinsic viscosity of the poly(lactic acid-co-glycolic acid) is in the range of 0.1 to 0.3 dL / g.

[0157] In certain embodiments, the weight ratio of the lactic acid-glycolic acid copolymer in the polymer gel solution is 10% to 60%.

[0158] In certain embodiments, illustrative examples of organic solvents that can be used in the present disclosure include, but are not limited to, N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), benzyl alcohol, benzyl benzoate, and any combination thereof.

[0159] In certain embodiments, the organic solvent is N-methylpyrrolidone (NMP), and its weight ratio in the polymer gel solution is 40% to 90%.

[0160] In certain embodiments, the formulations of the present disclosure comprise a stabilizer solution to form a suspension of drug-loaded microparticles or nanoparticles.

[0161] In certain embodiments, illustrative examples of stabilizers that can be used in the present disclosure include, but are not limited to, polyethylene glycol, poloxamer, Tween, vitamin E polyethylene glycol succinate (TPGS), and any combination thereof.

[0162] In certain embodiments, the stabilizer is selected from poloxamer and polyethylene glycol 3350, the weight ratio of poloxamer in the drug-loaded microparticle or nanoparticle suspension is 1% to 10%, and the weight ratio of polyethylene glycol 3350 in the drug-loaded microparticle or nanoparticle suspension is 0.5% to 5%.

[0163] In certain embodiments, the active ingredient in the micro- or nanoparticulate suspension is present in the form of particles having a median particle size of about 0.1 to 10 μm.

[0164] In certain embodiments, the median particle size of the drug-loaded microparticle suspension is in the range of 1 to 10 microns.

[0165] In certain embodiments, the median particle size of the drug-loaded nanosuspension ranges from 100 to 1000 nanometers.

[0166] In certain embodiments, the formulations of the present disclosure comprise an oily vehicle, a surfactant, and an organic solvent to form a self-microemulsion solution.

[0167] In certain embodiments, illustrative examples of oily vehicles that can be used in the present disclosure include, but are not limited to, castor oil, rapeseed oil, sesame oil, fractionated coconut oil, fatty acid glycerides, benzyl benzoate, and any mixtures thereof.

[0168] In certain embodiments, the oily vehicle is selected from one or any mixture of fatty acid glycerides, castor oil, and benzyl benzoate.

[0169] In certain embodiments, illustrative examples of surfactants that can be used in the present disclosure include, but are not limited to, Kolliphor ELP, Solutol HS15, Vitamin E polyethylene glycol succinate (TPGS), polyoxyethylene hydrogenated castor oil, poloxamer, Tween 80, and any mixture thereof.

[0170] In certain embodiments, the surfactant is selected from one of polyoxyethylene 35 castor oil (Kolliphor ELP) and polyethylene glycol 15 hydroxystearate (Solutol HS15) or any mixture thereof.

[0171] In certain embodiments, illustrative examples of organic solvents that can be used in the present disclosure include, but are not limited to, ethanol, benzyl alcohol, NMP, DMSO, and any mixtures thereof.

[0172] In certain embodiments, the organic solvent is selected from one of ethanol, benzyl alcohol, NMP, or any mixture thereof.

[0173] In certain embodiments, the weight ratio of the oily solvent in the self-microemulsification solution ranges from 30% to 95%, the weight ratio of the surfactant in the self-microemulsification solution ranges from 5% to 50%, and the weight ratio of the organic solvent in the self-microemulsification solution ranges from 0% to 40%.

[0174] In certain embodiments, the weight ratio of the oily solvent in the self-microemulsification solution ranges from 50% to 90%, the weight ratio of the surfactant in the self-microemulsification solution ranges from 5% to 30%, and the weight ratio of the organic solvent in the self-microemulsification solution ranges from 0% to 35%.

[0175] In certain embodiments, the weight ratio of the oily solvent in the self-microemulsification solution ranges from 60% to 90%, the weight ratio of the surfactant in the self-microemulsification solution ranges from 5% to 20%, and the weight ratio of the organic solvent in the self-microemulsification solution ranges from 0% to 30%.

[0176] In certain embodiments, the concentration of the compound of Formula I and its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds in the formulation is 0.1 to 400 mg / mL.

[0177] In certain embodiments, the concentration of the compound of Formula I and its stereoisomers, pharmaceutically acceptable salts or deuterated compounds in the formulation is preferably 1 to 200 mg / mL.

[0178] In certain embodiments, the formulations of the present disclosure are suitable for intramuscular or subcutaneous administration.

[0179] Treatment

[0180] In another aspect, the present disclosure relates to a method for treating and / or preventing HIV / AIDS in a subject, comprising administering to an individual in need thereof a therapeutically and / or prophylactically effective amount of a formulation of the present disclosure.

[0181] The present disclosure is further described below with reference to specific examples. It should be understood that these examples are intended only to illustrate the present disclosure and are not intended to limit the scope of the present disclosure. Experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions or conditions recommended by the manufacturer.

[0182] Unless otherwise defined, all technical and scientific terms used herein have the same meanings 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 methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0183] The features described above, or the features described in the examples, may be combined in any combination. All features disclosed in this patent specification may be used in any combination, and each feature disclosed in the specification may be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the features disclosed are merely general examples of equivalent or similar features.

[0184] Synthesis of compounds

[0185] Example 1: Synthesis of compounds of formula I

[0186] Route 1:

[0187] Route 2:

[0188] n=0, 1, 2, 3.

[0189] Route 3:

[0190] n=1, 2, 3.

[0191] Route 4:

[0192] n=0,1,2,3; m=0,1,2,3.

[0193] Example 2: Preparation of compounds

[0194] Compound 1: Preparation of (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)

[0195] DTG (10 g, 23.8 mmol), (S)-1-(tert-Butyloxycarbonyl)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 solution to precipitate a solid, which was filtered to obtain Intermediate 1-A (12.3 g, yield: 83.7%).

[0196] Compound 1-A (12.3 g, 19.95 mmol) was added to a 2M solution of hydrogen chloride in ethyl acetate (100 ml) and stirred at room temperature overnight. The precipitated solid was filtered to obtain the target compound 1-B (9.7 g, yield: 94.2%).

[0197] 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 purified by column chromatography (dichloromethane / methanol 20:1) to obtain the target compound 1, 6.4 g, in a yield of 54.7%.

[0198] Compound 3: Preparation of (4R,12aS)-9-((2,4-difluorobenzyl)carbamoyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyridinium[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazin-7-yl-(S)-1-palmitoylazetidine-2-carboxylate (3)

[0199] Compound 3-1 (5.00 g, 49.45 mmol) and triethylamine (7.51 g, 74.18 mmol) were dissolved in dichloromethane (50 ml). Palmitoyl chloride (16.31 g, 59.34 mmol) was added dropwise under ice bath and reacted for 1 hour. After the reaction was completed, water (50 ml) was added and the liquid was extracted to obtain an organic phase. The organic phase was washed twice with brine and concentrated to dryness under reduced pressure to obtain 9.3 g of a white solid with a yield of 55.4%.

[0200] Dissolve 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). Add phosphorus oxychloride (0.49 g, 3.58 mmol) dropwise under ice and allow to react for 1 hour. Quench the reaction by adding water (0.5 ml). Concentrate to dryness under reduced pressure and purify by column chromatography to obtain 550 mg of the product (31.1% yield).

[0201] 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-4-yl)octanoic acid (19)

[0202] 1-Octane azide (0.4 g, 2.58 mmol) and compound 19-1 (1.62 g, 2.84 mmol) were dissolved in PEG (10 ml), and copper iodide (0.098 g, 0.52 mmol) was added. The mixture was heated to 50°C for 3 hours. The reaction solution was added with saline (20 ml) and stirred for 10 minutes. Ethyl acetate was added, and the organic phase was extracted and separated. The organic phase was washed with brine, dried over sodium sulfate, and then concentrated under reduced pressure and purified by column chromatography to obtain 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-4-yl)octanoic acid.

[0203] According to the preparation method of compound 19, compounds 20, 21, 2, 23, and 24 were prepared by click chemistry.

[0204] The following compounds were prepared according to the preparative methods described herein using appropriate starting materials and appropriate protecting group chemistries as needed.

[0205] Formulation Examples

[0206] Example 1: Preparation of oil solution

[0207] The compound of the present disclosure is prepared into an oil solution injection, and the excipients are selected from castor oil, sesame oil, medium-chain fatty acid glyceride (MCT), benzyl benzoate, NMP, benzyl alcohol, and ethanol, and the solution is prepared by ultrasonic dissolution method.

[0208] Example 2: Administration of the oil solution injection in SD rats

[0209] Some of the preparation samples in Example 1 were administered subcutaneously (SC) or intramuscularly (IM) to SD rats. The administration information is shown in the following table.

[0210] SD rat subcutaneous injection (SC) administration information:

[0211] SD rat intramuscular injection (IM) administration information:

[0212] Example 3: In vivo data of the oil solution injection in SD rats after injection

[0213] Blood drug concentrations of some of the preparation samples in Example 1 after administration to SD rats:

[0214] Figure 1 (In vivo data after SC administration of oil solution in SD rats)

[0215] Figure 2 (In vivo data after IM administration of the oil solution in SD rats)

[0216] The AUC of some of the advantageous preparation samples in Example 1 after administration to SD rats are shown in the table below.

[0217] AUC of the oil solution after SC administration in SD rats

[0218] AUC of the oil solution after IM administration in SD rats

[0219] Example 4: Preparation of hydrophilic solution

[0220] The compound of the present disclosure is prepared into a hydrophilic solution injection, and the excipients are selected from PEG200, PEG300, PEG400, benzyl benzoate, ethanol, benzyl alcohol, and water, and the solution is prepared by ultrasonic dissolution method.

[0221] Example 5: Injection of hydrophilic solution in SD rats

[0222] Some of the preparation samples in Example 4 were administered subcutaneously (SC) or intramuscularly (IM) to SD rats. The administration information is shown in the following table.

[0223] SD rat subcutaneous injection (SC) administration information:

[0224] SD rat subcutaneous injection (IM) dosing information:

[0225] Example 6: In vivo data of hydrophilic solution after injection in SD rats

[0226] Blood drug concentrations of some advantageous preparation samples in Example 4 after administration to SD rats:

[0227] Figure 3 (In vivo data after SC administration of hydrophilic solution in SD rats)

[0228] Figure 4 (In vivo data after IM administration of hydrophilic solution in SD rats)

[0229] The AUC of some of the advantageous preparation samples in Example 4 after administration to SD rats are shown in the table below.

[0230] AUC of hydrophilic solution after SC administration in SD rats

[0231] AUC of hydrophilic solution after IM administration in SD rats

[0232] Example 7: Preparation of polymer gel

[0233] The compound disclosed herein is prepared into a polymer gel, and the auxiliary materials are selected from PLGA and NMP. The polymer PLGA gel is prepared by an ultrasonic dissolution method.

[0234] Example 8: Information on the injection of polymer gel in SD rats

[0235] Some of the preparation samples in Example 7 were injected subcutaneously (SC) in SD rats, and the dosing information is shown in the following table.

[0236] Example 9: In vivo data of polymer gel after injection in SD rats

[0237] Blood drug concentrations of some of the preparation samples in Example 7 after administration to SD rats:

[0238] Figure 5 (In vivo data after SC administration of polymer gel in SD rats)

[0239] The AUC of some of the advantageous preparation samples in Example 7 after administration to SD rats are shown in the table below.

[0240] Example 10: Preparation of micron or nanoscale suspensions by media milling

[0241] The compound of the present disclosure was dispersed in a stabilizer solution and prepared into a micron- or nanometer-scale suspension injection via a media milling process. The stabilizer was selected from polyethylene glycol 3350, poloxamer 188, poloxamer 338, poloxamer 407, and ethylene glycol 35 castor oil (Kolliphor ELP). The following suspension was obtained by adjusting the media milling speed and time according to the formula ratios shown in the table below.

[0242] Example 11: Information on the administration of the suspension by injection in SD rats

[0243] Some of the preparation samples in Example 10 were injected intramuscularly (IM) into SD rats, and the dosing information is shown in the following table.

[0244] Example 12: In vivo data after injection of the suspension in SD rats

[0245] Blood drug concentrations of some advantageous preparation samples in Example 10 after administration to SD rats:

[0246] Figure 6 (In vivo data after IM administration of the suspension in SD rats)

[0247] The AUC of some of the advantageous preparation samples in Example 10 after administration to SD rats are shown in the table below.

[0248] Example 13: Preparation of self-microemulsifying solution using the compound disclosed herein

[0249] The compound of the present disclosure is prepared into a self-microemulsifying solution, and the excipients are selected from polycastor oil, MCT, ethylene oxide 35 castor oil (Kolliphor ELP), NMP, ethanol, and benzyl benzoate. The self-microemulsifying solution is prepared by ultrasonic dissolution method.

[0250] Example 14: Injection administration of self-microemulsified solution in SD rats

[0251] Some of the preparation samples in Example 13 were injected subcutaneously (SC) in SD rats, and the dosing information is shown in the following table.

[0252] Example 15: In vivo data of self-microemulsified solution after injection in SD rats

[0253] Blood drug concentrations of some advantageous preparation samples in Example 13 after administration to SD rats:

[0254] Figure 7 (In vivo data after SC administration of self-microemulsified solution in SD rats)

[0255] The AUC of some of the advantageous preparation samples in Example 13 after administration to SD rats are shown in the table below.

[0256] Example 16: Preparation of oil gel solution

[0257] The compound of the present disclosure is prepared into an oil gel, and the excipients are selected from castor oil, sesame oil, medium-chain fatty acid glycerides (MCT), benzyl benzoate, stearic acid, 12-hydroxystearic acid, and N-methylpyrrolidone (NMP), and the solution is prepared by ultrasonic dissolution method.

[0258] Example 17: Preparation of oil solution

[0259] The compound of the present disclosure is selected to prepare an oil solution injection, and the excipients include medium-chain fatty acid glyceride (MCT), benzyl benzoate, benzyl alcohol, NMP, and ethanol, and the solution is prepared by ultrasonic dissolution method.

[0260] Example 18: Administration of Oil Solution Injection in SD Rats

[0261] Some of the advantageous preparation samples in Example 17 were administered subcutaneously (SC) to SD rats. The administration information is shown in the following table.

[0262] Example 19: In vivo data after injection of the suspension in SD rats

[0263] The blood drug concentration of the preparation sample in Example 17 after administration to SD rats:

[0264] Figure 8 (In vivo data after IM administration of the suspension in SD rats)

[0265] The AUC of the preparation samples in Example 17 after administration to SD rats is shown in the table below.

[0266] In this disclosure, relational terms such as first and second, etc. are used merely to distinguish one entity or operation from another entity or operation, but do not necessarily require or imply any actual relationship or order between these entities or operations.

[0267] It will be appreciated from the foregoing that, although specific embodiments of the present disclosure have been described for illustrative purposes, various modifications or variations may be made by those skilled in the art without departing from the spirit and scope of the present disclosure. Such modifications or variations are intended to fall within the scope of the appended claims of the present disclosure.

Claims

1. A preparation comprising a compound of formula I and its stereoisomers, a pharmaceutically acceptable salt or a deuterated compound and at least one pharmaceutically acceptable carrier: in A is selected from: Wherein * represents R or S configuration, or a mixture thereof; n is 0, 1, 2 or 3; G is independently selected from oxygen or a group Gr; Where Gr is selected from Wherein R2 and R3 are independently selected from hydrogen, hydroxy, cyano, C 1-6 Alkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, aromatic heterocyclic group, C 1-6 Alkyl-C 6-10 Aryl, C 1-6 Alkyl-aromatic heterocyclic group, C 1- 6-Alkyl-C 3-10 Cycloalkyl; or R2 and R3 may be combined with the atoms to which they are attached to form a 4-10 membered heterocyclic group; the heterocyclic group may be substituted by 1 to 4 R4; R4 is independently selected from hydrogen, halogen, C1-6 alkyl, alkoxy; any two R4 can be combined with the atoms to which they are connected to form C 3-10 Cycloalkyl; the cycloalkyl may be substituted by 1 to 4 hydrogen, halogen, C1-6 alkyl; X is selected from oxygen or nitrogen; F is selected from halogen; m is 0 to 20; R is independently selected from C 2-30 Saturated or unsaturated alkyl or aliphatic group, where alkyl or the aliphatic group may be optionally substituted by at least one heteroatom selected from N, O, S; R may be optionally substituted by halogen, carboxyl, sulfonic acid, -S=O, -S(=O)2, aryl, heteroaryl, C 3-10 Saturated or unsaturated carbon ring, C 3-10 wherein the aryl, heteroaryl, carbocyclic and heterocyclic groups may be optionally substituted by the following substituents: hydrogen, C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 1-20 Haloalkyl, C 2-20 Halogenated alkenyl, C 2-20 Haloalkynyl, C 0-20 Alkyl-C 6-10 Aryl, Heterocycloalkyl, C 0-20 Alkyl-C 3-10 Cycloalkyl, C 0-20 Alkyl-OC 1-6 Alkyl and C 0-20 Alkyl-OC 1-6 Halogenated alkyl.

2. The preparation of claim 1, wherein G is independently selected from oxygen or Gr; Where Gr is R2 and R3 are each independently selected from hydrogen, C 1-6 Alkyl, aromatic heterocyclic group, C 1-6 Alkyl-aromatic heterocyclic group; Or R2 and R3 can be combined with the atoms to which they are attached to form a 4-10 membered heterocyclic group; wherein the heterocyclic group is substituted with 1 to 4 R4; R4 is independently selected from hydrogen, halogen, C 1-6 Alkyl, alkoxy; any two R4 can combine with the atoms to which they are attached to form a C 3-10 Cycloalkyl; said C 3-10 The cycloalkyl group may be substituted with 1 to 4 hydrogen atoms, halogen atoms, C 1-6 Alkyl substitution; R is independently selected from C 2-30 A saturated or unsaturated hydrocarbon or aliphatic group, wherein the C 2-30 The saturated or unsaturated hydrocarbon or aliphatic group may be optionally substituted by at least one heteroatom selected from N, O, S; R can be optionally substituted by the following groups: halogen, aryl, heteroaryl, C 3-10 Saturated or unsaturated carbon ring and C 3-10 Heterocyclic group, wherein the aryl, heteroaryl, C 3-10 Saturated or unsaturated carbon ring and C 3-10 The heterocyclic group may be optionally substituted with hydrogen, C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 1-20 Haloalkyl, C 2-20 Halogenated alkenyl and C 2-20 Haloalkynyl.

3. The preparation of claim 2, wherein R is independently selected from C 2-30 Saturated or unsaturated hydrocarbon; R may be optionally selected from halogen, aryl, heteroaryl, C 3-10 Saturated or unsaturated carbon ring and C 3-10 heterocyclic group, wherein the aryl group, Heteroaryl, C 3-10 Saturated or unsaturated carbon ring and C 3-10 The heterocyclic group may be optionally substituted with hydrogen, C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 1-20 Haloalkyl, C 2-20 Halogenated alkenyl and C 2-20 Haloalkynyl.

4. The preparation according to any one of claims 1 to 3, wherein G is oxygen; R is selected from heteroatoms C 10-20 Alkyl-C(O)-substituted heterocycloalkyl; preferably, R is selected from the group consisting of 15-18 Alkyl-C(O)-substituted heterocycloalkyl; preferably, R is selected from the group consisting of 15 Straight-chain-C(O)-substituted heterocycloalkyl; wherein, The heteroatom in the heterocycloalkyl group is an N atom; preferably, the heterocycloalkyl group is a four-membered heterocycloalkyl group or a five-membered heterocycloalkyl group, and the carbon atoms in the heterocycloalkyl group are preferably substituted by H or halogen atoms; preferably, R is selected from any one or more of the following Or R is saturated C 10-20 Alkyl, preferably saturated C 15-18 Alkyl, wherein one or more methylene groups are substituted by -O-; preferably, R is or R is C 10-20 A straight chain alkyl group, the terminal of which is substituted by an alkynyl or carboxyl group; preferably, R is C 11-16 A straight chain alkyl group, the terminal of which is substituted by an alkynyl group or a carboxyl group; further, preferably, R is selected from 5. The preparation of claim 2, wherein G is 6. The preparation of claim 2, wherein R is independently selected from unsaturated hydrocarbons and C 0-18 Alkyl-heteroaryl-C 0-18 alkyl; R may be optionally selected from halogen, aryl, heteroaryl C 3-10 Saturated or unsaturated carbon ring and C 3-10 Heterocyclic group; Preferably, G is oxygen.

7. The preparation of claim 6, wherein The R is independently selected from -C 1-20 Alkyl-C≡CC 0-20 alkyl; Preferably, R is independently selected from -C 5-10 Alkyl-C≡CC 5-10 Preferably, R is independently selected from -C 6-7 Alkyl-C≡CC 5-9 Alkyl; wherein the alkyl is optionally substituted with halogen.

8. The preparation of claim 6, wherein The R is independently selected from -C 0-18 Alkyl-heteroaryl-C 0-18 Preferably, R is independently selected from -C 5-12 Alkyl-heteroaryl-C 3-10 Preferably, R is independently selected from -C 7-11 Alkyl-heteroaryl-C 3-8 Alkyl; wherein the alkyl is optionally substituted by halogen.

9. The preparation of claim 8, wherein The heteroaryl group is 10. The formulation of claim 1, wherein the compound of formula I is formula II:

11. The formulation of claim 1, wherein the compound of formula I is formula III:

12. The formulation of claim 1, wherein the compound of formula I is formula IV:

13. The formulation of claim 1, wherein the compound is selected from:

14. The preparation according to any one of claims 1 to 13, comprising an oily vehicle and an organic solvent to form an oil solution; Preferably, the oily solvent is selected from castor oil, rapeseed oil, sesame oil, fractionated coconut oil, fatty acid glyceride, benzyl benzoate or any mixture thereof; More preferably, the oily solvent is selected from fatty acid glycerides, castor oil and benzyl benzoate. Esters or any mixture thereof; More preferably, the oily solvent is fatty acid glyceride; Preferably, the organic solvent is selected from benzyl alcohol, ethanol, N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO) or any mixture thereof; More preferably, the organic solvent is selected from benzyl alcohol, ethanol, N-methylpyrrolidone (NMP) or any mixture thereof.

15. The preparation according to claim 14, wherein the weight ratio of the oily solvent to the organic solvent is in the range of 6:4 to 10:0; Preferably, the weight ratio of the oily solvent to the organic solvent is in the range of 7:3 to 10:0; More preferably, the weight ratio of the oily solvent to the organic solvent is in the range of 8:2 to 10:

0.

16. The formulation according to any one of claims 1 to 13, comprising a hydrophilic vehicle and an organic solvent to form a hydrophilic solution; Preferably, the hydrophilic solvent is selected from polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, propylene glycol, glycerol, water or any mixture thereof; More preferably, the hydrophilic solvent is polyethylene glycol 300; Preferably, the organic solvent is selected from ethanol, benzyl benzoate, benzyl alcohol, NMP or any mixture thereof; More preferably, the organic solvent is selected from one of ethanol and benzyl alcohol or any mixture thereof.

17. The preparation according to claim 16, wherein the weight ratio of the hydrophilic solvent to the organic solvent is in the range of 5:5 to 10:0; Preferably, the weight ratio of the hydrophilic solvent to the organic solvent is in the range of 6:4 to 10:0; More preferably, the weight ratio of the hydrophilic solvent in the preparation is 7:3 to 10:

0.

18. The preparation according to claim 16 or 17, further comprising a pH adjuster, preferably the pH adjuster is selected from one of sodium hydroxide, hydrochloric acid, citric acid, sodium citrate, phosphoric acid, sodium hydrogen phosphate, or any mixture thereof.

19. The formulation of any one of claims 16 to 18, further comprising a release retardant, preferably the release retardant is selected from poly(lactic-co-glycolic acid) (PLGA) or polylactic acid (PLA), more preferably the weight ratio of the release retardant in the hydrophilic solution is 1% to 10%.

20. The formulation of any one of claims 1 to 13, comprising an oily solvent, an oil gelling agent and an organic solvent to form an oil gel; Preferably, the oily solvent is selected from castor oil, rapeseed oil, sesame oil, fractionated coconut oil, fatty acid glyceride, benzyl benzoate or any mixture thereof; Preferably, the oily solvent is selected from castor oil, fatty acid glyceride and sesame oil; More preferably, the oily solvent is medium-chain fatty acid glyceride, and its weight ratio in the oil gel is 60% to 90%; Preferably, the oil gel is selected from stearic acid, 12-hydroxystearic acid, palmitic acid or any combination thereof; More preferably, the oleogel is stearic acid, which accounts for 5% to 10% by weight in the oleogel; Preferably, the organic solvent is selected from N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO) or any combination thereof; More preferably, the organic solvent is selected from N-methylpyrrolidone (NMP), and its weight ratio in the oil gel is 10% to 40%.

21. The formulation according to any one of claims 1 to 13, comprising a biodegradable polymer solution to form a polymer gel solution, wherein the polymer gel solution comprises a polymer gel material and an organic solvent; Preferably, the polymer gel material is selected from poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), polyoxyethylene-polycaprolactone block copolymer and polyoxyethylene-polyoxypropylene block copolymer; Preferably, the polymer gel material is a lactic acid-glycolic acid copolymer (poly(lactic- co-glycolic acid), PLGA); Preferably, the ratio of lactic acid to glycolic acid in the lactic acid-glycolic acid copolymer molecule is 75:25 or 50:50; Preferably, the intrinsic viscosity of the lactic acid-glycolic acid copolymer is in the range of 0.1 to 0.3 dL / g; Preferably, the weight ratio of the lactic acid-glycolic acid copolymer in the polymer gel solution is 10% to 60%; Preferably, the organic solvent is selected from one of N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), benzyl alcohol, benzyl benzoate or any combination thereof; Preferably, the organic solvent is N-methylpyrrolidone (NMP), and its weight ratio in the polymer gel solution is 40% to 90%.

22. The formulation of any one of claims 1 to 13, comprising a stabilizer solution to form a suspension of drug-loaded microparticles or nanoparticles; Preferably, the stabilizer is selected from one of polyethylene glycol, poloxamer, Tween, vitamin E polyethylene glycol succinate (TPGS) or any combination thereof; More preferably, the stabilizer is selected from poloxamer and polyethylene glycol 3350, the weight ratio of poloxamer in the drug-loaded microparticle or nanoparticle suspension is 1% to 10%, and the weight ratio of polyethylene glycol 3350 in the drug-loaded microparticle or nanoparticle suspension is 0.5% to 5%; Preferably, the active ingredient in the microparticle or nanoparticle suspension is in the form of particles having a median particle size of about 0.1 to 10 μm; Preferably, the median particle size of the drug-loaded microparticle suspension ranges from 1 to 10 microns; Preferably, the median particle size of the drug-loaded nanosuspension ranges from 100 to 1000 nanometers.

23. The formulation according to any one of claims 1 to 13, comprising an oily vehicle, a surfactant and an organic solvent to form a self-microemulsified solution; Preferably, the oily solvent is selected from castor oil, rapeseed oil, sesame oil, fractionated coconut oil, fatty acid glyceride, benzyl benzoate or any mixture thereof; More preferably, the oily solvent is selected from one of fatty acid glycerides, castor oil and benzyl benzoate or any mixture thereof; Preferably, the surfactant is selected from polyoxyethylene 35 castor oil (Kolliphor ELP), One of polyethylene glycol 15 hydroxystearate (Solutol HS15), vitamin E polyethylene glycol succinate (TPGS), polyoxyethylene hydrogenated castor oil, poloxamer, Tween 80 or any mixture thereof; More preferably, the surfactant is selected from one of polyoxyethylene 35 castor oil (Kolliphor ELP) and polyethylene glycol 15 hydroxystearate (Solutol HS15) or any mixture thereof; Preferably, the organic solvent is selected from ethanol, benzyl alcohol, NMP, DMSO or any mixture thereof; More preferably, the organic solvent is selected from ethanol, benzyl alcohol, NMP or any mixture thereof.

24. The preparation according to claim 23, wherein the weight ratio of the oily solvent in the self-microemulsification solution is in the range of 30% to 95%, the weight ratio of the surfactant in the self-microemulsification solution is in the range of 5% to 50%, and the weight ratio of the organic solvent in the self-microemulsification solution is in the range of 0% to 40%; Preferably, the weight ratio of the oily solvent in the self-microemulsification solution is in the range of 50% to 90%, the weight ratio of the surfactant in the self-microemulsification solution is in the range of 5% to 30%, and the weight ratio of the organic solvent in the self-microemulsification solution is in the range of 0% to 35%; More preferably, the weight ratio of the oily solvent in the self-microemulsification solution is in the range of 60% to 90%, the weight ratio of the surfactant in the self-microemulsification solution is in the range of 5% to 20%, and the weight ratio of the organic solvent in the self-microemulsification solution is in the range of 0% to 30%.

25. The formulation of any one of claims 1 to 24, wherein the concentration of the compound of formula I and its stereoisomers, pharmaceutically acceptable salts or deuterated compounds in the formulation is 0.1 to 400 mg / mL.

26. The formulation of claim 25, wherein the concentration of the compound of formula I and its stereoisomers, pharmaceutically acceptable salts or deuterated compounds in the formulation is preferably 1 to 200 mg / mL.

27. A formulation as claimed in any one of claims 1 to 26, wherein the formulation is suitable for intramuscular or subcutaneous administration.

28. A method for treating and / or preventing HIV / AIDS in a subject, comprising administering a therapeutically and / or prophylactically effective amount of the formulation of any one of claims 1 to 27 to an individual in need of said method.

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