Integrase inhibitor and application thereof

Abstract

Compounds of Formula I, stereoisomers, pharmaceutically acceptable salts, and deuterated compounds thereof: wherein A, R, G, Y, and n are as defined herein, and methods of treating, inhibiting, and / or preventing a disease or disorder in a subject in need thereof are disclosed.

Description

Technical Field

[0001] This application relates to the pharmaceutical field, and more specifically, to prodrugs of integrase inhibitors and their applications. Background Technology

[0002] Significant progress has been made in the effective diagnosis and treatment of human immunodeficiency virus type 1 (HIV-1). Antiretroviral therapy (ART) has significantly reduced disease-related morbidity and mortality, bringing the quality of life of infected individuals closer to normal. However, ART requires lifelong treatment to suppress viral replication and prevent the onset of AIDS. Furthermore, the efficacy of ART can be hampered by HIV-1 resistance, drug toxicity, and poor patient adherence. Treatment fatigue, lack of economic and social support, coexisting psychiatric symptoms, and / or substance abuse can lead to failure to follow critical ART regimens. Dulutevir (DTG), cabotevir (CAB), and bictegravir (BTG) are a class of integrase inhibitors or integrase strand transfer inhibitors (INSTIs). Summary of the Invention

[0003] On the one hand, this application relates to compounds of formula I, their stereoisomers, pharmaceutically acceptable salts, and deuterated compounds:

[0004]

[0005]

[0006] in,

[0007] A. Choose the group consisting of the following items:

[0008] Where * indicates R or S configuration;

[0009] n is 0, 1, 2, or 3;

[0010] G is independently selected from oxygen or Gr;

[0011] Gr is

[0012] R2 and R3 are each independently selected from the group consisting of the following elements: hydrogen, hydroxyl, cyano, C. 1-6 Alkyl, C 6-10 Aryl, C 3-10 cycloalkyl, aryl heterocyclic, C 1-6 Alkyl-C 6-10 Aryl, C 1-6 alkyl-aryl heterocyclic groups and C 1-6 Alkyl-C 3-10 cycloalkyl;

[0013] Alternatively, R2 and R3 can combine with the atoms they are attached to to form 4 to 10-membered heterocyclic groups; wherein, the heterocyclic group can be replaced by 1 to 4 R4s;

[0014] R4 is independently selected from the following groups: hydrogen, halogens, C 1-6 Alkyl and alkoxy groups;

[0015] Or any two R4 atoms can combine with the atoms they are connected to to form C. 3-10 cycloalkyl; wherein the cycloalkyl group may be 1 to 4 hydrogens, halogens or C atoms. 1-6 Alkyl substitution;

[0016] X is selected from the group composed of free oxygen and nitrogen;

[0017] Y is a halogen;

[0018] m is between 0 and 20;

[0019] R can choose independently and freely. 2-30 A group consisting of saturated or unsaturated hydrocarbon groups and aliphatic groups, wherein the hydrocarbon groups and aliphatic groups may be selectively substituted by at least one heteroatom selected from the group consisting of N, O and S;

[0020] R can be selectively substituted by substituents selected from the group consisting of: halogen, carboxyl, sulfonyl, -S=O, -S(=O)2, aryl, heteroaryl, C 3-10 Saturated or unsaturated carbon rings and C 3-10 Heterocyclic groups, wherein the aryl, heteroaryl, carbocyclic, and heterocyclic groups are optionally separated by H, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 1-20 Haloalkyl, C 2-20 Haloalkenyl, C 2-20 Halogenated alkynyl group, C 0-20 Alkyl-C 6-10 Aryl, heterocyclic, 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 groups.

[0021] On the other hand, this application relates to compositions comprising compounds of formula I of this application, their stereoisomers, pharmaceutically acceptable salts, or deuterated compounds.

[0022] On the other hand, this application relates to methods for treating, inhibiting and / or preventing diseases or disorders in subjects in need of such treatment, including administering to the subject an effective amount of a compound of formula I of this application, its stereoisomers, pharmaceutically acceptable salts or deuterated compounds. Attached Figure Description

[0023] Figure 1 Plasma concentration-time curves (AUC) following subcutaneous injection of the compound of this application are shown.

[0024] Figure 2 The concentration of the active ingredient in plasma after compound administration is shown.

[0025] Figure 3 The mean plasma concentration of the corresponding active ingredient (bicitiravir) over time was shown after a single subcutaneous injection of compounds 13 and 21 (dose: equivalent to 18 mg / kg bicitiravir) in rats.

[0026] Figure 4 The mean plasma concentration of the corresponding active ingredient (cabotabolic acid) over time following a single subcutaneous injection of compound 14 (dose: equivalent to 18 mg / kg cabotevir) in rats is shown. Detailed Implementation

[0027] Certain specific details are included in the following description to provide a thorough understanding of the various embodiments disclosed. However, those skilled in the art will recognize that embodiments may be practiced without one or more of these specific details, but with other methods, components, materials, etc.

[0028] Unless otherwise required in this application, throughout the specification and appended claims, the terms “comprise” and “comprising” shall be interpreted in an open-ended, inclusive sense, meaning “including but not limited to”.

[0029] As used in this application and the appended claims, unless the context clearly indicates otherwise, singular references without a quantity indication include plural references.

[0030] Throughout this specification, references to "one embodiment," "an embodiment," "another embodiment," or "some embodiments" mean that in at least one embodiment, specific reference elements, structures, or features associated with those described in that embodiment are included. Therefore, the phrases "in one embodiment," "in an embodiment," "another embodiment," or "some embodiments" appearing 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.

[0031] It should be understood that, unless the context clearly specifies otherwise, the singular form used in the description and appended claims of this application includes plural indicators. Thus, for example, a sustained-release tablet referring to "pharmaceuticalally acceptable excipients" includes one or two or more pharmaceutically acceptable excipients.

[0032] definition

[0033] 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. Dashed lines at the front or back of chemical groups are for convenience in indicating the connection point with the parent molecule; chemical groups may be described with or without one or more dashed lines without losing their ordinary meaning. Prefixes such as "C" u-v "or "C u -C v "" indicates that the following groups have u to v carbon atoms, where u and v are integers. For example, "C 1-6 "Alkyl" or "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms.

[0034] "Alkyl" is a monovalent or divalent straight-chain or branched saturated hydrocarbon group. For example, an alkyl group can have 1 to 10 carbon atoms (i.e., C64-C ... 1-10 Alkyl groups or 1 to 8 carbon atoms (i.e., C14) 1-8 Alkyl groups or 1 to 6 carbon atoms (i.e., C64) 1-6 Alkyl groups or 1 to 4 carbon atoms (i.e., C46) 1-4Alkyl groups. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH( CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, tert-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 (-CH 2CH2CH(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)CH 2CH3), 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 can be unsubstituted or substituted.

[0035] "Alkenyl" is a monovalent or divalent straight-chain or branched hydrocarbon group having at least one carbon-carbon double bond. For example, an alkenyl group can contain 2 to 8 carbon atoms (i.e., C24-C ... 2-8 Alkenyl) or 2 to 6 carbon atoms (i.e., C) 2-6 alkenyl) or 2 to 4 carbon atoms (i.e., C) 2-4 Alkenyl groups. Examples of alkenyl groups include, but are not limited to, -CH=CH2, -CH2CH=CH2, and -CH2-CH=CH-CH3. Alkenyl groups can be unsubstituted or substituted.

[0036] "Alynyl" is a monovalent or divalent straight-chain or branched hydrocarbon group having at least one carbon-carbon triple bond. For example, an alkynyl group can contain 2 to 8 carbon atoms (i.e., C64-C ... 2-8(alkynyl group) or 2 to 6 carbon atoms (i.e., C64) 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C) 2-4 (Alynyl group). Examples of alkynyl groups include, but are not limited to, -C≡CH, -CH2C≡CH, and -CH2-C≡C-CH3. The alkynyl group can be unsubstituted or substituted.

[0037] "Alkoxyalkyl" refers to a group formed by attaching an alkoxy group to a divalent alkyl group (as defined in the alkyl definition above). 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. The alkoxyalkyl group can be unsubstituted or substituted.

[0038] "Halogens" refer to fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

[0039] "Haloalkyl" is an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently substituted with a halogen, which may be the same or different, such that the alkyl group is divalent. The alkyl group and the halogen can be any of those described above. In some embodiments, the haloalkyl group determines the number of carbon atoms in the alkyl moiety, for example, C... 1-4 Alkyl halogens include CF3, CH2F, CHF2, CH2CF3, CH2CH2CF3, CCl2CH2CH3, and C(CH3)2(CF2H). Alkyl halogens can be unsubstituted or substituted.

[0040] "Aryl" refers to a monovalent or divalent mono- or condensation-polymerized all-carbon aromatic ring system, wherein the ring is 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. An aryl group includes a phenyl group. Aryl groups also include multiple condensation 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. When valence requirements permit, the rings of multiple condensation ring systems may be interconnected by fused bonds. It should also be understood that when referring to an aryl group having a certain atomic number range (e.g., a 6- to 10-membered aryl group), the atomic number range refers to the total number of atoms in the aryl 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, phenyl, naphthyl, anthracene, etc. Aryl groups can be unsubstituted or substituted.

[0041] "alkylaryl" means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently replaced by an aryl group, wherein the aryl group may be the same or different. The alkyl and aryl groups can be any 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. The 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, C7 alkylaryl refers to benzyl, while C7 alkylaryl refers to alkyl. 11 Alkyl aryl groups include 1-methylnaphthalene and n-pentylphenyl. In some embodiments, the number of carbon atoms in the alkyl and aryl moieties can be specified separately, for example, C... 1-6 Alkyl-C 6-10 Aryl. Non-limiting examples of alkyl aryl groups include, but are not limited to, benzyl, 2,2-dimethylphenyl, n-pentylphenyl, 1-methylnaphthyl, 2-ethylnaphthyl, etc. The alkyl aryl group may be unsubstituted or substituted.

[0042] "5- to 10-membered aromatic heterocycles" or "heteroaromatic rings" refer to a single aromatic ring having atoms other than at least one carbon atom, wherein said atoms are 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 are further described below. Thus, "heteroaryl" 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. Sulfur and nitrogen atoms may also be present in oxidized forms, provided the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridinyl, pyrimidinyl, oxazolyl, or furanyl. "Heteroaryl" also includes multiple condensed ring systems (e.g., ring systems consisting of 2, 3, or 4 rings), wherein the heteroaryl group as defined above is fused with one or more rings selected from the group consisting of: a heteroaryl group (to form, for example, 1,8-naphthidyl) and an aryl group (to form, for example, benzimidazolyl or indazole) to form multiple condensed ring systems. Thus, the heteroaryl group (a 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, a tetrazolyl group has 1 carbon atom and 4 nitrogen heteroatoms in the ring. When valence requirements permit, the rings of multiple condensed ring systems can be interconnected by fused bonds. It will be understood that each ring of a multiple condensed ring system can be interconnected in any order. It should be understood that the connection points of a heteroaryl group or a heteroaryl multiple condensed ring system can be any suitable atom of the heteroaryl group or a heteroaryl multiple condensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). It should also be understood that when referring to a heteroaryl group having a certain atomic number range (e.g., 5- to 10-membered heteroaryl groups), the atomic number range refers to the total number of atoms in the heteroaryl ring, including carbon atoms and heteroatoms. It should also be understood that the rings of multiple condensed ring systems may include aryl rings fused to a heterocycle having saturated or partially unsaturated bonds (e.g., 3-, 4-, 5-, 6-, or 7-membered rings) having about 1 to 6 cyclic carbon atoms and about 1 to 3 cyclic heteroatoms selected from oxygen, nitrogen, and sulfur. For example, 5-membered heteroaryls include thiazolyl groups and 10-membered heteroaryls include quinolinyl groups. Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrroloyl, pyrazinyl, pyrimidinyl, pyrazolyl, thiophenyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzooxazolyl, inzolyl, quinoxazolyl, quinazolinyl, benzofuranyl, benzimidazolyl, phenylthio, pyrrolo[2,3-b]pyridyl, quinazolinyl-4(3H)-one, triazolyl, and tetrazolyl. The heteroaryl group may be unsubstituted or substituted.

[0043] "Cycloalkyl" is a monovalent or divalent single all-carbon ring or a system of multiple fused all-carbon rings, 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. Cycloalkyl also includes multiple condensed ring systems having about 7 to 12 carbon atoms (e.g., ring systems comprising 2 rings). When valence requirements permit, the rings of multiple condensed ring systems can be interconnected by fusion bonds, solenoids, or bridging bonds. Exemplary polycyclic 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. The cycloalkyl groups may be unsubstituted or substituted.

[0044] As used herein, “heterocyclic” or “heterocyclic group” refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic system containing at least one heteroatom (i.e., at least one cyclic (i.e., ring-shaped) heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, heterocyclic groups have 3 to about 20 ring atoms, for example 3-12 ring atoms, such as 4-12 ring atoms, 4-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 4-5 ring atoms. Thus, the term includes a single saturated or partially unsaturated ring (e.g., 3, 4, 5, 6, or 7-membered ring) having about 1 to 6 ring carbon atoms and about 1 to 3 ring heteroatoms, wherein the heteroatoms in these rings are selected from the group consisting of oxygen, nitrogen, and sulfur. When valence requirements permit, multiple condensed rings (such as bicyclic heterocycles) can be interconnected by fusion bonds, solenoids, and bridging bonds. Heterocycles include, but are not limited to, azahexacycles, aziridine, imidazoline, morpholine, ethylene oxide, thiohexacycles, piperazine, piperidine, pyrazolidineamine, piperidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinine ring, 2-oxo-6-azaspirocyclic [3.3]hept-6-yl, 6-oxa-1-azaspirocyclic [3.3]hept-1-yl, 2-thio- 6-Azaspirocyclic [3.3]hept-6-yl, 2,6-diazaspirocyclic [3.3]hept-2-yl, 2-azabicyclic [3.1.0]hex-2-yl, 3-azabicyclic [3.0]hexyl, 2-azabicyclic [2.1.1]hexyl, 2-azabicyclic [2.2.1]hept-2-yl, 4-azaspirocyclic [2.4]heptyl, 5-azaspirocyclic [2.4]heptyl, etc. The heterocyclic group can be unsubstituted or substituted.

[0045] "alkylheteroaryl" refers to an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently substituted by a heteroaryl group, wherein the heteroaryl groups may be the same or different, such that the alkyl group is divalent. The alkyl and heteroaryl groups can be either of the above. In some embodiments, the atomic number of the alkyl and heteroaryl moieties may be specified separately, for example, a C1 having 1 to 4 heteroatoms. 1-6 Alkyl-5 to 10-membered heteroaryl groups, wherein each heteroatom is independently N, O, or S. Alkyl heteroaryl groups can be unsubstituted or substituted.

[0046] "Oxytochemical" means =O.

[0047] As used herein, “substituted” means that one or more hydrogen atoms of a group are independently substituted by one or more substituents (e.g., 1, 2, 3, or 4 or more).

[0048] "Compounds of this application" includes compounds disclosed herein, such as compounds of formula I, including the compounds of the embodiments. In some embodiments, "compounds of this application" includes compounds of formula I.

[0049] "Pharmaceutical acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, lubricants, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0050] As used herein, "therapeutic effective amount" or "effective amount" means an amount that effectively elicits a desired biological or medical response, including, when administered to a subject treating a disease, an amount sufficient to affect the treatment of that disease. Effective amounts will vary depending on the compound, the disease and its severity, and factors such as the age and weight of the subject being treated. Effective amounts can include a range of amounts. As understood in the art, an effective amount can be one or more doses, meaning that one or more doses may be required to achieve the desired therapeutic endpoint. An effective amount can be considered in the context of administration of one or more therapeutic agents, where a single agent may be considered to be administered in an effective amount if, when used with one or more other agents, a desirable or beneficial result may have been achieved. Due to the combined effects of compounds (e.g., additive or synergistic effects), the appropriate dose of any co-administered compound may be selectively reduced. As used herein, "co-administration" means administering a unit dose of the disclosed compound before or after administration of a unit dose of one or more additional therapeutic agents, for example, administering the disclosed compound within seconds, minutes, or hours after administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of the disclosed compound is administered first, followed by a unit dose of one or more additional therapeutic agents within 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 the disclosed compound within seconds or minutes. In some embodiments, a unit dose of the disclosed compound is administered first, followed by a unit dose of one or more additional therapeutic agents several 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 the disclosed compound several hours later (e.g., 1-12 hours). Co-administration of the disclosed compound with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of the disclosed compound and one or more additional therapeutic agents, such that a therapeutically effective amount of each agent is present in the subject.

[0051] Pharmaceutically acceptable salts, hydrates, solvates, isomers, polymorphs, and prodrugs of the compounds described herein are also provided.

[0052] "Pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms and other materials that are useful in the preparation of pharmaceutical compositions suitable for veterinary or human use.

[0053] 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 a compound that possess the desired pharmacological activity of a free base. These salts can be extracted from inorganic or organic acids or bases. For example, a compound containing a basic nitrogen can be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, disulfates, sulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanates, propoxides, oxalates, malonates, ferrates, sebates, and fumarates. Maleate, butyn-1,4-diacidate, hexyn-1,6-diacidate, benzoate, chlorobenzoate, tolueneate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methanesulfonate, propanesulfonate, benzenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0054] Examples of pharmaceutically acceptable salts of the compounds disclosed herein also include salts derived from suitable bases, such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and N (C1-C4 alkyl). 4+ It also includes base addition salts, such as sodium or potassium salts.

[0055] Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein one to n hydrogen atoms bonded to a carbon atom may be substituted with 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 can increase resistance to metabolism and thus can be used to increase the half-life of compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, when administered to mammals. 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 substituted with deuterium.

[0056] Examples of isotopes that can be incorporated into the disclosed compounds 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. use 11 C 18 F, 15 O and 1 3 Positron emission isotope substitution, such as N, can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotopically labeled compounds of formula (IA-1) can typically be prepared using conventional techniques known to those skilled in the art, or by methods similar to those described in the examples below, using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent.

[0057] The compounds of embodiments disclosed herein, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers, thus producing enantiomers, diastereomers, and other stereoisomers, which may be defined by absolute stereochemistry as (R)- or (S)-, or in the case of amino acids as (D)- or (L)-. This application is intended to include all such possible isomers as well as their racemic and optically pure forms. Optically active (+) and (-), (R) and (S) or (D) and (L)- isomers may be prepared by chiral synthesis or chiral reagents, or resolved by conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, such compounds are intended to include E and Z geometric isomers unless otherwise specified. 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, a specific diastereomer or enantiomer-enriched form. If not specified, but chirality is present, it should be understood that the embodiment is for a specific diastereomer or enantiomer-enriched form; or a racemic or scalar mixture of such compounds. As used herein, a “scalar mixture” means a mixture of stereoisomers in a ratio other than 1:1.

[0058] As used herein, a “stereoisomer” refers to a compound composed of identical atoms bonded together but having different three-dimensional structures, and which are not interchangeable. This application considers different stereoisomers and mixtures thereof, and includes “enantiomers,” which are two stereoisomers whose molecules are non-overlapping mirror images of each other.

[0059] As used herein, "tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. In some embodiments, this application includes tautomers of compounds.

[0060] As used herein, "solvent" refers to the result of the interaction between the solvent and the compound. Solvents of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0061] As used herein, “hydrate” refers to the compound of the present invention that is chemically bonded to one or more water molecules. “Preventive treatment” or “prevention” refers to any treatment that prevents the development of clinical symptoms of a disease or condition. In some embodiments, the compound may be given to subjects (including humans) at risk of a disease or condition or a family history of it.

[0062] As used herein, a "prodrug" refers to a derivative that, after administration to the human body, is converted into the parent drug via some chemical or enzymatic pathway. In some embodiments, a prodrug is a bioactive derivative of a drug that, after administration to a human body, is converted into the bioactive parent drug via certain chemical or enzymatic pathways.

[0063] As used herein, “treatment” or “treating” refers to a method of achieving a beneficial or desired outcome. For the purposes of this application, beneficial or desired outcomes include, but are not limited to, alleviating symptoms and / or reducing the severity of symptoms and / or preventing the worsening of symptoms associated with a disease or condition. In one embodiment, “treatment” or “treating” includes one or more of the following: a) suppressing a disease or condition (e.g., reducing one or more symptoms caused by a disease or condition, and / or reducing the severity of a disease or condition); b) slowing or preventing the development of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, delaying the progression of a disease or condition); and c) alleviating a disease or condition, for example, causing the disappearance of clinical symptoms, improving disease status, slowing disease progression, improving quality of life, and / or prolonging survival. As used herein, “at-risk individual” means an individual who is at risk of developing a disease requiring treatment. An individual “at risk” may or may not have a detectable disease or condition and may or may not have a detectable disease prior to the treatments described herein. "At risk" means that an individual has one or more so-called risk factors, which are measurable parameters related to the development of a disease or condition and are known in the art to have a higher probability of developing the disease or condition than an individual without such risk factors.

[0064] compound

[0065] In one aspect, this application relates to compounds of formula I, their stereoisomers, pharmaceutically acceptable salts, and deuterated compounds:

[0066]

[0067] in,

[0068] A. Choose the group consisting of the following items:

[0069] Where * indicates R or S configuration;

[0070] n is 0, 1, 2, or 3;

[0071] G is independently selected from oxygen or Gr;

[0072] Gr is

[0073] R2 and R3 are each independently selected from the group consisting of the following elements: hydrogen, hydroxyl, cyano, C. 1-6 Alkyl, C 6-10 Aryl, C 3-10 cycloalkyl, aryl heterocyclic, C 1-6 Alkyl-C 6-10 Aryl, C 1-6 alkyl-aryl heterocyclic groups and C 1-6 Alkyl-C 3-10 cycloalkyl;

[0074] Alternatively, R2 and R3 can combine with the atoms they are attached to to form 4 to 10-membered heterocyclic groups; wherein, the heterocyclic group can be replaced by 1 to 4 R4s;

[0075] R4 is independently selected from the following groups: hydrogen, halogens, C 1-6 Alkyl and alkoxy groups;

[0076] Or any two R4 atoms can combine with the atoms they are connected to to form C. 3-10 cycloalkyl; wherein the cycloalkyl group may be 1 to 4 hydrogens, halogens or C atoms. 1-6 Alkyl substitution;

[0077] X is selected from the group composed of free oxygen and nitrogen;

[0078] Y is a halogen;

[0079] m is between 0 and 20;

[0080] R can choose independently and freely. 2-30 The group consisting of saturated or unsaturated hydrocarbon groups and aliphatic groups, wherein the hydrocarbon groups and aliphatic groups may be selectively substituted by at least one heteroatom selected from N, O and S;

[0081] R can be selectively substituted by substituents selected from the group consisting of: halogen, carboxyl, sulfonyl, -S=O, -S(=O)2, aryl, heteroaryl, C 3-10 Saturated or unsaturated carbon rings and C 3-10 Heterocyclic groups, wherein aryl, heteroaryl, carbocyclic, and heterocyclic groups can be selectively converted by H, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 1-20 Haloalkyl, C 2-20 Haloalkenyl, C 2-20 Halogenated alkynyl group, C 0-20 Alkyl-C 6-10 Aryl, heterocyclic, C 0-20 Alkyl-C 3-10cycloalkyl, C 0-20 Alkyl-OC 1-6 Alkyl and C 0-20 Alkyl-OC 1-6 Halogenated alkyl groups.

[0082] In some implementations, G is independently selected from oxygen or Gr;

[0083] Among them, Gr is

[0084] R2 and R3 are each independently selected from the following groups: hydrogen, C 1-6 Alkyl, aryl heterocyclic, C 1-6 alkyl-aryl heterocyclic groups;

[0085] Alternatively, R2 and R3 can combine with the atoms they are attached to form 4- to 10-membered heterocyclic groups; wherein, the heterocyclic group can be replaced by 1 to 4 R4s;

[0086] R4 is independently selected from hydrogen, halogen, and C. 1-6 The group consisting of alkyl and alkoxy groups;

[0087] Or any two R4 atoms can combine with the atoms they are connected to to form C. 3-10 cycloalkyl; wherein the cycloalkyl group may be 1 to 4 hydrogens, halogens or C atoms. 1-6 Alkyl substitution;

[0088] R can choose independently and freely. 2-30 The group consisting of saturated or unsaturated hydrocarbon groups and aliphatic groups, wherein the hydrocarbon groups and aliphatic groups may be selectively substituted by at least one heteroatom selected from N, O and S;

[0089] R can be selectively substituted by substituents selected from the group consisting of: halogens, aryl groups, heteroaryl groups, and C. 3-10 Saturated or unsaturated carbon rings and C 3-10 Heterocyclic groups, including aryl, heteroaryl, and C 3-10 Saturated or unsaturated carbon rings and C 3-10 Heterocyclic groups can be optionally H, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 1-20 Haloalkyl, C 2-20 Haloalkenyl and C 2-20 Halogenated alkynyl substitution.

[0090] In some implementations, G is

[0091] R can choose independently and freely. 2-30 A group composed of saturated or unsaturated hydrocarbon groups.

[0092] Preferably, R can be selectively substituted with substituents selected from the group consisting of: halogens, aryl groups, heteroaryl groups, C... 3-10 Saturated or unsaturated carbon rings and C 3-10 Heterocyclic groups, including aryl, heteroaryl, and C 3-10 Saturated or unsaturated carbon rings and C 3-10 Heterocyclic groups can be optionally H, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 1-20 Haloalkyl, C 2-20 Haloalkenyl and C 2-20 Halogenated alkynyl substitution.

[0093] In some implementations, G is oxygen;

[0094] Preferably, R is a form of C 10-20 Heterocyclic alkyl groups with alkyl-C(O)-substituted heteroatoms; preferably, R is a heterocyclic alkyl group having C-substituted heteroatoms. 15-18 Heterocyclic alkyl groups with alkyl-C(O)-substituted heteroatoms; preferably, R is a heterocyclic alkyl group having C-substituted heteroatoms. 15 A straight-chain alkyl-C(O)-substituted heteroatom heterocyclic alkyl group, wherein the heteroatom in the heterocyclic alkyl group is an N atom; preferably, the heterocyclic alkyl group is a four-membered or five-membered heterocyclic alkyl group, and the carbon atom in the heterocyclic alkyl group is preferably substituted by H or a halogen atom; more preferably, R is selected from any one or more of the following:

[0095] Or R is saturated C 10-20 Alkyl groups, preferably saturated C 15-18 alkyl, wherein one or more methylene groups are replaced by -O-; more preferably, R is

[0096] Or R is a C whose terminal group is replaced by an alkynyl or carboxyl group. 10-20 Straight-chain alkyl; preferably, R is a C-chain whose terminal group is substituted with an alkynyl or carboxyl group. 11-16 Straight-chain alkyl; more preferably, R is selected from...

[0097] In some implementations, G is oxygen.

[0098] R is independently selected from the group consisting of: unsaturated hydrocarbon groups and C. 0-18 alkyl-heteroaryl-C 0-18 alkyl.

[0099] R can be selectively substituted by substituents selected from the group consisting of: halogens, aryl groups, heteroaryl groups, and C.3-10 Saturated or unsaturated carbon rings and C 3-10 Heterocyclic group.

[0100] In some implementations, R is independently selected from the group consisting of: -C 1-20 Alkyl-C≡CC 0-20 Alkyl; preferably, R is independently selected from the group consisting of: -C 5-10 Alkyl-C≡CC 5-10 Alkyl; preferably, R is independently selected from the group consisting of: -C 6-7 Alkyl-C≡CC 5-9 Alkyl group; wherein the alkyl group may optionally be substituted with a halogen.

[0101] In some implementations, R is independently selected from -C 0-18 alkyl-heteroaryl-C 0-18 The group consisting of alkyl groups; preferably, R is independently selected from -C. 5-12 alkyl-heteroaryl-C 3-10 The group consisting of alkyl groups; preferably, R is independently selected from -C. 7-11 alkyl-heteroaryl-C 3-8 The group consisting of alkyl groups; wherein the alkyl groups may optionally be substituted with halogens.

[0102] In some implementations, heteroaryl is In some embodiments, the compound of formula I is selected from one of the following structures:

[0103]

[0104]

[0105] Treatment

[0106] In one aspect, this application relates to a method for treating, inhibiting, and / or preventing a disease or disorder in a subject in need of it, the method comprising administering to the subject an effective amount of a compound of formula I of this application, its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds.

[0107] On the other hand, this application relates to compositions comprising compounds of formula I of this application, their stereoisomers, pharmaceutically acceptable salts, or deuterated compounds.

[0108] In some embodiments, the diseases or disorders of this application include, but are not limited to, viral infections.

[0109] In some embodiments, the viral infection of this application includes, but is not limited to, HIV infection.

[0110] In some embodiments, the subject is given monthly a compound of Formula I of this application, its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds.

[0111] In some embodiments, the subject is given a compound of formula I of this application, its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds every two months.

[0112] In some embodiments, the subject is given a compound of formula I of this application, its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds every 6 months.

[0113] In some embodiments, the subject is given a compound of Formula I of this application, its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds once every 12 months.

[0114] In some embodiments, the method includes administering at least one additional anti-HIV agent.

[0115] Example

[0116] The present application will be further described below with reference to specific embodiments. It should be understood that these embodiments are merely illustrative of the present application and are not intended to limit the scope of the present application. Experimental methods not described in detail in the following embodiments generally follow conventional conditions or conditions recommended by the manufacturer.

[0117] 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 to or equivalent to those described herein may be applied to the disclosed methods. The preferred embodiments and materials described herein are merely exemplary.

[0118] The features mentioned above or in the embodiments mentioned in this application can be combined arbitrarily. All features disclosed in this patent specification can be used in any combination, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, the same, or similar purpose. Therefore, unless otherwise stated, the disclosed features are merely general examples of equivalent or similar features.

[0119] preparation

[0120] The compounds of this application can be prepared using the methods disclosed herein and their conventional modifications, which will be readily apparent given the methods disclosed herein and those well known in the art. In addition to the teachings herein, conventional and well-known preparation methods can also be used. The preparation of typical 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 following examples.

[0121] Preparation method

[0122] Typical embodiments of the compounds according to this application can be synthesized using the general reaction scheme and / or examples described below. Given the description herein, it is apparent that the general scheme can be modified by substituting the starting materials with other materials having similar structures, resulting in correspondingly different products. The subsequent synthetic descriptions provide numerous examples illustrating how the starting materials can be varied to yield the corresponding products. Starting materials are typically obtained from commercial sources or synthesized using methods for synthesizing compounds described in this application. Examining the structure of the compound to be synthesized will provide the identity of each substituent, and given the examples herein, the identity of the final product will generally become apparent through a simple examination process that reveals the identity of the necessary starting materials. Group labels (such as R1, R2) used in the reaction schemes herein are for illustrative purposes only and, unless otherwise stated, do not necessarily correspond in name or function to labels used elsewhere to describe compounds of Formula I or aspects or fragments thereof.

[0123] Parameters of the preparation reaction

[0124] The compounds disclosed herein can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be understood that where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other process conditions may also be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization procedures.

[0125] Furthermore, conventional protecting groups may be necessary for those skilled in the art to prevent undesirable reactions of certain functional groups. Suitable protecting groups for a wide range of functional groups, as well as appropriate conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, many protecting groups are described in, for instance, TW Greene and GMWuts (1999), *Protecting Groups in Organic Synthesis*, Third Edition, Wiley, New York, and the references cited therein.

[0126] Furthermore, the compounds of this application may contain one or more chiral centers. Therefore, such compounds can be prepared or separated, if desired, as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as a mixture of enriched stereoisomers. Unless otherwise stated, all such stereoisomers (and enriched mixtures) are included 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 dissociation agents, etc.

[0127] The starting materials for the following reactions are generally known compounds, or can be prepared by known procedures or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). Others can be prepared by procedures described in standard references or obvious modifications thereof, such as Fieser's *Organic Synthetic Reagents*, Volumes 1-15 (John Wiley, and Sons, 1991); Rodd's *Chemistry of Carbon Compounds*, Volumes 1-5, and Supplements (Elsevier Science Press, 1989); *Organic Reactions*, Volumes 1-40 (John Wiley, and Sons, 1991); March's *Advanced Organic Chemistry* (John Wiley, and Sons, 5th Edition, 2001); and Larock's *Comprehensive Organic Transformations* (VCH Publishing, 1989).

[0128] The terms "solvent," "inert organic solvent," or "inert solvent" refer to an inert solvent under the associated reaction conditions (e.g., including benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), N,N-dimethylformamide ("DMF"), chloroform, dichloromethane (or dichloromethane), diethyl ether, methanol, pyridine, etc.). Unless otherwise specified, the solvent used in the reactions of this application is an inert organic solvent, and the reactions are carried out under an inert gas, preferably nitrogen.

[0129] The term "qs" refers to the amount added sufficient to achieve the stated function, for example, to bring the solution to the desired volume (i.e., 100%).

[0130] The compounds provided herein can be prepared according to the general schemes provided below. In these schemes, it should be understood that each compound shown may have a protecting group as desired in any step. Standard protecting groups are within the scope of those skilled in the art.

[0131] Example 1

[0132] Preparation scheme of compound I

[0133] Route 1:

[0134]

[0135] Route 2:

[0136]

[0137] n = 0, 1, 2, 3; Line 3:

[0138]

[0139] n = 0, 1, 2, 3; Line 4

[0140]

[0141] n=0, 1, 2, 3; m=0, 1, 2, 3.

[0142] Example 2

[0143] 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-carboxylic acid ester (1)

[0144]

[0145]

[0146] 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 solution, and a solid precipitated. The solid was filtered to obtain intermediate 1-A (12.3 g, yield: 83.7%).

[0147] Compound 1-A (12.3 g, 19.95 mmol) was added to an ethyl hydrochloride solution (2 M, 100 mL) and stirred overnight at room temperature. The precipitated solid was filtered to obtain the target compound 1-B (9.7 g, yield: 94.2%).

[0148] 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, with stirring 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 6.4 g of the target compound 1, yield: 54.7%.

[0149] 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-palmitoylazacyclobutane-2-carboxylate (3)

[0150]

[0151] Compound 3-1 (5.00 g, 49.45 mmol) and triethylamine (7.51 g, 74.18 mmol) were dissolved in dichloromethane (50 mL) to give a mixture. Palmitoyl chloride (16.31 g, 59.34 mmol) was added dropwise to the mixture in an ice bath and reacted for 1 hour. After the reaction was complete, water (50 mL) was added. The organic phase was extracted and separated. The organic phase was washed twice with brine and concentrated under reduced pressure to dryness to give a white solid (9.3 g, yield: 55.4%).

[0152] DTG (1.0 g, 2.38 mmol), compound 3-3 (1.62 g, 4.77 mmol), and triethylamine (0.97 g, 9.54 mmol) were dissolved in dichloromethane (10 mL) to give a mixture. 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. The reaction was quenched by adding water (0.5 mL). After concentration to dryness under reduced pressure, the solid was subjected to column chromatography to give the title compound (550 mg, yield: 31.1%).

[0153] 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-4-yl)octanoate (19)

[0154]

[0155] Copper iodide (0.098 g, 0.52 mmol) was added to a solution of 1-azidooctane (0.4 g, 2.58 mmol) and 19-1 (1.62 g, 2.84 mmol) in PEG (ethylene glycol), and the reaction mixture was stirred at 50 °C for 3 hours. 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 Na₂SO₄. The organic layers were filtered and concentrated under reduced pressure to obtain the residue. The crude product was purified by silica gel chromatography and eluted with PE:EtOAc = 2:1, yielding 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-4-yl)octanoate.

[0156] Following the preparation of compound 19, compounds 20, 21, 22, 23, and 24 can be obtained via click reaction.

[0157] The following compounds were prepared using appropriate starting materials and appropriate protecting group chemicals (as desired) according to the preparation method described herein.

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179] Example 3: In vivo pharmacokinetic study

[0180] The compounds of Formula I of this application are metabolized in vivo into the corresponding active ingredients: dulutegravir (DTG), cabotevir (CAB), and bicitiravir (BTG).

[0181] like Figure 1 As shown, the mean plasma concentrations of the corresponding active ingredients (DTG, CAB, or BTG) were measured over time after a single subcutaneous injection of compounds 1, 3, 5, 7, 8, 13, 14, 15, and 16 (dose equivalent to 18 mg / kg of active ingredient) in rats.

[0182] like Figure 2 As shown, the mean plasma concentrations of the corresponding active ingredient (durate) relative to time were measured in rats after a single subcutaneous injection of compound 15 (dose: equivalent to 18 mg / kg durate) and compound 19 (dose: equivalent to 45 mg / kg durate).

[0183] like Figure 3 As shown, the mean plasma concentration of the corresponding active ingredient (bicitiravir) was measured over time after a single subcutaneous injection of compounds 13 and 21 (dose: equivalent to 18 mg / kg of bicitiravir) in rats.

[0184] like Figure 4 As shown, the mean plasma concentration of the corresponding active ingredient (cabotabolic acid) was measured over time after a single subcutaneous injection of compound 14 (dose: equivalent to 18 mg / kg of cabotevir) in rats.

[0185] The compounds of this application have long-acting properties and show the potential for monthly, bi-monthly, bi-monthly, or even twelfth-monthly administration.

Claims

1. A compound having the structure of Formula I, its stereoisomers, pharmaceutically acceptable salts, and deuterated compounds: in, A. Choose the group consisting of the following items: Where * indicates R or S configuration; n is 0, 1, 2, or 3; G is independently selected from oxygen or Gr; Gr is R2 and R3 are each independently selected from the group consisting of the following elements: hydrogen, hydroxyl, cyano, C. 1-6 Alkyl, C 6-10 Aryl, C 3-10 cycloalkyl, aryl heterocyclic, C 1-6 Alkyl-C 6-10 Aryl, C 1-6 alkyl-aryl heterocyclic groups and C 1-6 Alkyl-C 3-10 cycloalkyl; Alternatively, R2 and R3 can combine with the atoms they are attached to to form 4- to 10-membered heterocyclic groups; In this case, the heterocyclic group can be replaced by 1 to 4 R4 groups; R4 is independently selected from the following groups: hydrogen, halogens, C 1-6 Alkyl and alkoxy groups; Or any two R4 atoms can combine with the atoms they are connected to to form C. 3-10 cycloalkyl; Wherein, the C 3-10 Cycloalkyl groups can be substituted with 1 to 4 hydrogens, halogens, or C atoms. 1-6 Alkyl substitution; X is selected from the group composed of free oxygen and nitrogen; Y is a halogen; m is between 0 and 20; R independently chooses C 2-30 The group consisting of saturated or unsaturated hydrocarbon groups and aliphatic groups, wherein the C 2-30 Saturated or unsaturated hydrocarbon groups and aliphatic groups may optionally be replaced by at least one heteroatom, said heteroatom being selected from the group consisting of N, O and S; R can be selectively substituted by substituents selected from the group consisting of: halogen, carboxyl, sulfonyl, -S=O, -S(=O)2, aryl, heteroaryl, C 3-10 Saturated or unsaturated carbon rings and C 3-10 Heterocyclic groups, wherein the aryl, heteroaryl, carbocyclic, and heterocyclic groups are optionally separated by H, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 1-20 Haloalkyl, C 2-20 Haloalkenyl, C 2-20 Halogenated alkynyl group, C 0-20 Alkyl-C 6-10 Aryl, heterocyclic, 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 groups.

2. The compound according to claim 1, its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds, wherein, The G is independently selected from oxygen or Gr; Wherein, Gr is R2 and R3 are each independently selected from the following components: hydrogen, C 1-6 Alkyl, aryl heterocyclic, C 1-6 alkyl-aryl heterocyclic groups; Alternatively, R2 and R3 may combine with the atoms to which they are attached to form a 4- to 10-membered heterocyclic group; wherein the heterocyclic group may be replaced by 1 to 4 of the R4; The R4 is independently selected from the group consisting of: hydrogen, halogen, C. 1-6 Alkyl and alkoxy groups; Or any two R4 atoms can combine with the atoms they are connected to to form C. 3-10 cycloalkyl; In this context, cycloalkyl groups can be substituted with 1 to 4 hydrogens, halogens, or C atoms. 1-6 Alkyl substitution; The R is independently selected from C. 2-30 The group consisting of saturated or unsaturated hydrocarbon groups and aliphatic groups, wherein the C 2-30 Saturated or unsaturated hydrocarbon groups and aliphatic groups may be selectively substituted by at least one heteroatom, said heteroatom being selected from the group consisting of N, O and S; The R can be selectively substituted by substituents selected from the group consisting of: halogens, aryl groups, heteroaryl groups, C... 3-10 Saturated or unsaturated carbon rings and C 3-10 Heterocyclic groups, wherein the aryl, heteroaryl, and C 3-10 Saturated or unsaturated carbon rings and C 3-10 Heterocyclic groups can be optionally H, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 1-20 Haloalkyl, C 2-20 Haloalkenyl and C 2-20 Halogenated alkynyl substitution.

3. The compound according to claim 2, its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds, wherein, The G is The R is independently selected from C. 2-30 A group composed of saturated or unsaturated hydrocarbon groups; Preferably, the R can be selectively substituted with substituents selected from the group consisting of: halogens, aryl groups, heteroaryl groups, C... 3-10 Saturated or unsaturated carbon rings and C 3-10 Heterocyclic groups, wherein the aryl, heteroaryl, and C 3-10 Saturated or unsaturated carbon rings and C 3-10 Heterocyclic groups can be optionally H, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 1-20 Haloalkyl, C 2-20 Haloalkenyl and C 2-20 Halogenated alkynyl substitution.

4. The compound according to claim 1, its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds, wherein, G is oxygen; Preferably, R is a form of C 10-20 Heterocyclic alkyl groups with alkyl-C(O)-substituted heteroatoms; preferably, R is a heterocyclic alkyl group having C-substituted heteroatoms. 15-18 Heterocyclic alkyl groups with alkyl-C(O)-substituted heteroatoms; preferably, R is a heterocyclic alkyl group having C-substituted heteroatoms. 15 A straight-chain alkyl-C(O)-substituted heteroatom heterocyclic alkyl group; wherein the heteroatom in the heterocyclic alkyl group is an N atom; preferably, the heterocyclic alkyl group is a four-membered or five-membered heterocyclic alkyl group, and the carbon atom in the heterocyclic alkyl group is preferably substituted by H or a halogen atom; more preferably, R is selected from the group consisting of the following: Or the R is a saturated C 10-20 Alkyl groups, preferably saturated C4 groups 15-18 alkyl, wherein one or more methylene groups are replaced by -O-; more preferably, R is Or, R is a C whose terminal group is replaced by an alkynyl or carboxyl group. 10-20 Straight-chain alkyl; preferably, R is a C-chain alkyl group whose terminal group is substituted with an alkynyl or carboxyl group. 11-16 Straight-chain alkyl; furthermore, preferably, the R is selected from...

5. The compound according to claim 2, its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds, wherein, G is oxygen; The R is independently selected from unsaturated hydrocarbon groups and C. 0-18 alkyl-heteroaryl-C 0-18 Groups composed of alkyl groups; Preferably, the R can be selectively substituted with substituents selected from the group consisting of: halogens, aryl groups, heteroaryl groups, C... 3-10 Saturated or unsaturated carbon rings and C 3-10 Heterocyclic group.

6. The compound according to claim 5, its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds, wherein, The R is independently selected from the group consisting of the following items: -C 1-20 Alkyl-C≡CC 0-20 Alkyl; preferably, the R is independently selected from the group consisting of: -C 5-10 Alkyl-C≡CC 5-10 Alkyl; preferably, the R is independently selected from the group consisting of: -C 6-7 Alkyl-C≡CC 5-9 Alkyl group; wherein the alkyl group may optionally be substituted with a halogen.

7. The compound according to claim 5, its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds, wherein, The R is independently selected from the group consisting of the following items: -C 0-18 alkyl-heteroaryl-C 0-18 Alkyl; preferably, the R is independently selected from the group consisting of: -C 5-12 alkyl-heteroaryl-C 3-10 Alkyl; preferably, the R is independently selected from the group consisting of: -C 7-11 alkyl-heteroaryl-C 3-8 Alkyl group; wherein the alkyl group may optionally be substituted with a halogen.

8. The compound according to claim 7, its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds, wherein, The heteroaryl group is 9. The compound of formula I according to any one of claims 1-8, its stereoisomers, pharmaceutically acceptable salts, and deuterated compounds, wherein, The compound of Formula I is selected from one of the following structures:

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

11. A method for treating, inhibiting, and / or preventing a disease or disorder in a subject of need, comprising administering to the subject an effective amount of a compound of formula I as described in any one of claims 1-9, its stereoisomer, a pharmaceutically acceptable salt, or a deuterated compound.

12. The method according to claim 11, wherein, The disease or disorder mentioned is a viral infection.

13. The method according to claim 12, wherein, The viral infection mentioned is HIV infection.

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