Polycyclic carbamoylpyridone derivatives, their preparation method and pharmaceutical compositions

Abstract

Polycyclic carbamoylpyridone derivatives for treating AIDS infection, as well as preparation methods and pharmaceutical compositions thereof are provided. The derivatives include compounds of formula (I)-1 or (I)-2, their isomers, pharmaceutically acceptable salts, hydrates, or solvates, which selectively inhibit the activity of AIDS virus integrase and are useful for the prevention and treatment of AIDS infection. JPEG2026035585000062.jpg6391

Description

[Technical Field]

[0001] The present invention relates to the technical field of drugs for treating AIDS infection, and in particular to polycyclic carbamoylpyridone derivatives and their preparation methods and pharmaceutical compositions. [Background technology]

[0002] AIDS, collectively known as "acquired immunodeficiency syndrome" (AIDS), is a highly fatal, malignant infectious disease caused by human immunodeficiency virus (HIV). The HIV virus specifically attacks and destroys the body's immune cells, leading to impaired immune system function, a gradual loss of immune function, and the body becoming vulnerable to numerous diseases, which in turn leads to the development of various serious opportunistic infections and tumors, ultimately resulting in AIDS.

[0003] HIV is a reverse-transcription virus, whose genetic information is stored in ribonucleic acid (RNA). HIV selectively recognizes and invades immune cells (CD4+ lymphocytes) that have CD4 molecules on their surface, interacting with the CD4 molecules via proteins on their surface to enter the host cell. Once inside the host cell, the single-stranded RNA of HIV's genetic material is used as a template, and complementary double-stranded DNA is formed under the action of reverse transcriptase. This DNA then enters the host cell nucleus, where it is catalyzed by integrase and integrated into the host cell genome. It is then transcribed, translated, and degraded into new viral proteins under the action of proteases. Finally, new mature viral particles are released outside the cell, where they invade more host cells, and the cycle continues.

[0004] Because there is no functional analog of integrase in human cells and because drug toxicity during use is low, integrase has become an ideal target for anti-HIV drugs. Integrase inhibitors primarily inhibit HIV integrase, which is necessary for viral replication, thereby preventing the covalent insertion or integration of the HIV genome into the host cell genome early in infection, thereby achieving their antiviral effect. Integrase inhibitors have remarkable therapeutic efficacy, rapidly reduce viral load, and are generally well tolerated. They have been included as first-line treatments in relevant domestic and international guidelines. Currently available integrase inhibitors include the first-generation elvitegravir (EVG) and raltegravir (RAL), as well as the recently marketed second-generation dolutegravir (DTG), bictegravir-containing Biktarvy tablets, and the long-acting cabotegravir (CAB).

[0005] The integrase inhibitors that were first marketed had a low resistance barrier, meaning that one or two mutations were enough to reduce the virus's susceptibility, and they also had a high degree of cross-resistance. Drugs that were marketed later, such as dolutegravir, had a high resistance barrier and have been widely used since their release. While integrase inhibitors have a high resistance barrier, the emergence of drug resistance is inevitable, just like protease inhibitors and reverse transcriptase inhibitors.

[0006] With current medical technology, once infected with HIV, patients will need to take drugs for life. Lifelong treatment has already become the long-term goal of highly active antiretroviral therapy (HARRT), but there are still many issues to consider, and drug resistance is one that cannot be ignored and will affect the success of HARRT.

[0007] Therefore, it is necessary to develop novel integrase inhibitors to improve oral bioavailability, reduce clinical toxicity and side effects, and raise the barrier to drug resistance, which is of great significance in providing patients with better drug choices and improved compliance. In view of this, the present invention has been presented. Summary of the Invention [Problem to be solved by the invention]

[0008] The object of the present invention is to provide polycyclic carbamoylpyridone derivatives, their preparation method and pharmaceutical compositions, which can selectively inhibit the activity of integrase of the AIDS virus and are useful for the prevention and treatment of AIDS infection. The present invention is thus realized. [Means for solving the problem]

[0009] In a first aspect of the present invention, there is provided a polycyclic carbamoylpyridone derivative, including a compound represented by formula (I)-1 or formula (I)-2, an isomer, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, and at least one pair of functional groups selected from the following (1) to (3) forms a spiro ring or a spiro hetero ring together with the carbon atom linked to the ring A: (1) R1 and R2, (2) R3 and R4, (3) R5 and R6 (i.e., when the polycyclic carbamoylpyridone derivative is a compound represented by formula (I)-1, the functional group pair consisting of R1 and R2 or the functional group pair consisting of R3 and R4 form a spiro ring or a spiro heterocycle together with the carbon atom connected to the A ring. When the polycyclic carbamoylpyridone derivative is a compound represented by formula (I)-2, the functional group pair consisting of R1 and R2 or the functional group pair consisting of R5 and R6 form a spiro ring or a spiro heterocycle together with the carbon atom connected to the A ring.). [ka] (wherein R1, R2, R3, R4, R5, and R6 are each independently selected from any one of hydrogen, halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, -OR7, a substituted or unsubstituted aryl group, a substituted or unsubstituted monocyclic heteroaryl ring, a substituted or unsubstituted monocyclic heterocyclic ring, and a cyano group. R7 is selected from any one of hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, and a substituted or unsubstituted alkynyl group. m is any natural number between 0 and 5. If m is 0, ring A is a five-membered ring.

[0010] In a second aspect, the present invention provides a method for producing the polycyclic carbamoylpyridone derivative according to any one of the above embodiments, wherein the polycyclic carbamoylpyridone derivative is synthesized by referring to the following synthetic route: [ka]

[0011] In a third aspect, the present invention provides a pharmaceutical composition comprising a compound according to any of the preceding embodiments, an isomer, a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.

[0012] The present invention has the following beneficial effects. 1. The polycyclic carbamoylpyridone derivatives of the present invention can selectively inhibit the activity of integrase of the AIDS virus, and can be widely used in the prevention and treatment of AIDS infection. 2. It has excellent permeability and PK properties, which is advantageous for drug preparation and can reduce the number of administrations and increase patient compliance. 3. It has low cytotoxicity, improving the safety of administration and reducing the risk of adverse reactions. DETAILED DESCRIPTION OF THE INVENTION

[0013] In order to make the purpose, technical solution and advantages of the present invention clearer, the technical solution in the present invention will be described clearly and completely below. In the examples, unless specific conditions are specified, the experiments were carried out under normal conditions or under conditions recommended by the manufacturer. If the manufacturer of the reagents or equipment used is not specified, they are all ordinary products that can be purchased commercially.

[0014] An embodiment of the present invention is a polycyclic carbamoylpyridone derivative, including a compound of formula (I)-1 or formula (I)-2, an isomer, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, and at least one pair of functional groups selected from the following (1)-(3) forms a spiro ring or spiro heterocyclic ring together with the carbon atom linked to the A ring: (1) R1 and R2, (2) R3 and R4, (3) R5 and R6. [ka] (wherein R1, R2, R3, R4, R5, and R6 are each independently selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, -OR7, a substituted or unsubstituted aryl group, a substituted or unsubstituted monocyclic heteroaryl ring, a substituted or unsubstituted monocyclic heterocycle, and a cyano group; R7 is selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, and a substituted or unsubstituted alkynyl group; and m is a natural number between 0 and 5.)

[0015] Furthermore, R1, R2, R3, R4, R5 and R6 are each independently selected from any one of hydrogen, halogen, C1-4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR5, C3-C8 cycloalkyl, C6-C10 aryl, 5- to 6-membered monocyclic heteroaryl, 4- to 6-membered saturated monocyclic heterocycle and cyano, and at least one pair of functional groups selected from the following (1) to (3) together with the carbon atom linked to the A ring form a 3- to 8-membered spiro ring or a 3- to 8-membered spiro heterocycle: (1) R1 and R2, (2) R3 and R4, (3) R5 and R6; R7 is selected from any one of hydrogen, C1-4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C4 haloalkyl, and m is 0, 1, 2 or 3.

[0016] Furthermore, the tertiary carbon atom linked to the fused pyrazine of the A ring in the compounds of formula (I)-1 and formula (I)-2 has chirality, and the configuration of the compounds of formula (I)-1 and formula (I)-2 may be a single configuration or a mixture of multiple configurations. The isomers include at least one of tautomers, cis-trans isomers, racemates, and optical isomers having a mirror image or non-mirror image relationship. Specifically, the tertiary carbon atom linked to the fused pyrazine of the A ring has an S configuration.

[0017] Furthermore, R1 and R2 are selected from C1-4 alkyl groups, C3-C5 cycloalkyl groups, specifically methyl groups and cyclopropyl groups, of which methyl groups are more specifically in the R configuration; R3 and R4 are selected from hydrogen, C3-C6 cycloalkyl groups, C3-C6 heterocycloalkyl groups, specifically hydrogen, cyclopropyl groups, cyclopentyl groups, cyclohexyl groups and 6-membered oxygen-containing heterocyclic groups; and R5 and R6 are selected from hydrogen, C3-C6 cycloalkyl groups, C3-C6 heterocycloalkyl groups, specifically hydrogen, cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, cyclohexyl groups and 6-membered oxygen-containing heterocyclic groups.

[0018] Furthermore, the polycyclic carbamoylpyridone derivative is selected from any one of the compounds represented by the following structural formula: [ka] Preferably, [ka] is.

[0019] Terms referred to in the examples of the present invention have the following meanings. "Halogen" means fluorine, chlorine, bromine, or iodine. A "C1-C4 alkyl group" is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, or a t-butyl group.

[0020] A "cycloalkyl group" is a monovalent group derived from a monocyclic or polycyclic saturated or partially saturated aliphatic carbocyclic ring compound, and C3-C8 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl groups.

[0021] a cyclooctyl group, a cyclooctenyl group, a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, or a cycloheptenyl group.

[0022] An "alkenyl group" is a monovalent group derived from a hydrocarbon group, where a C2-C6 alkenyl group is an alkenyl group having 2-6 carbon atoms and containing at least one carbon-carbon double bond, including, but not limited to, vinyl, propenyl, butenyl, 2-methyl-2-butene, 2-methyl-2-pentene, and similar groups.

[0023] An "alkynyl group" is an alkynyl group having 2-6 carbon atoms and containing at least one carbon-carbon triple bond, including, but not limited to, ethynyl, propargyl, 1-butynyl, 2-butynyl, and the like.

[0024] An "aryl group" is an aromatic cyclic hydrocarbon group having one or more aromatic rings, and may be a fused or non-fused carbocyclic ring system, such as, for example, a phenyl group or a naphthyl group. An "aryl group" may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylamino groups, halogens, thiol groups, hydroxy groups, nitro groups, and cyano groups.

[0025] The term "heteroaryl group" refers to a 5- or 6-membered monocyclic heteroaryl group containing 1-4 heteroatoms selected from N, S, or O, or a bicyclic heteroaryl group fused with a benzene ring, pyridine ring, or pyrrole ring, which may be partially saturated, such as a pyridyl group, a pyrimiridyl group, or a furyl group.

[0026] "Spirocycle" refers to a polycyclic group that shares one carbon atom between monocyclic rings; these groups may contain one or more double bonds, but no ring has a completely conjugated π-electron system. Depending on the number of rings, spirocycles are divided into bicyclic spirocycles or polycyclic spirocycles, with bicyclic spirocycles being preferred.

[0027] "Spiroheterocycle" refers to a polycyclic hydrocarbon ring that shares one atom between monocyclic rings, in which one or more ring atoms are heteroatoms selected from NR6 (where R6 is hydrogen, oxygen, an alkyl group, or a haloalkyl group), oxygen, or S(O)n (where n is 0, 1, or 2), and the remaining ring atoms are carbon. These groups may contain one or more double bonds, but no ring has a completely conjugated π-electron system. Depending on the number of rings, heterospirocycles are divided into bicyclic heterospirocycles or polycyclic heterospirocycles, with bicyclic heterospirocycles being preferred.

[0028] A "pharmaceutically acceptable salt" is a relatively non-toxic acid or base addition salt of a compound provided by an embodiment of the present invention. The acid addition salt is a salt formed by a compound of Formula (I)-1 or (I)-2 provided by an embodiment of the present invention with a suitable inorganic or organic acid, such as a hydrochloride salt or a fumarate salt.

[0029] The base addition salt is a salt formed by the compound of formula (I)-1 or (I)-2 provided by the present invention with a suitable inorganic or organic base, such as a sodium salt or a methylamine salt.

[0030] In a second aspect, an embodiment of the present invention provides a method for preparing the polycyclic carbamoylpyridone derivative, which is a method for synthesizing the polycyclic carbamoylpyridone derivative by referring to the following synthesis route: [ka]

[0031] That is, the process for preparing the compound represented by formula (I)-1 or (I)-2 provided by the embodiments of the present invention is as follows: Compound II is used as a starting material, and is reacted with compound III-1 or III-2 under the action of an acid catalyst, followed by intramolecular ring closure to obtain intermediate IV-1 or IV-2, which is then demethylated.

[0032] Among them, the compound represented by general formula (II) can be prepared by the method provided in Organic Letters, 2015, 17, 564-567, or by other conventional methods in the art.

[0033] When preparing intermediate IV-1 or IV2, the acid catalyst used may be an organic acid catalyst or an inorganic acid catalyst, such as formic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, magnesium sulfate, sodium sulfate, 4A molecular sieve, or magnesium trifluoromethanesulfonate, preferably acetic acid.

[0034] Specifically, the conditions for preparing intermediate IV-1 include the following: the molar ratio of compound II to compound III-1 is 1:1-1:5, preferably 1:1.5-1:3; the molar ratio of compound II to acid catalyst is 1:1-1:10, preferably 1:4-1:8; the temperature is 30-100°C, preferably 60-80°C; the reaction solvent is acetonitrile, toluene, etc., preferably acetonitrile; and the reaction time is 5 minutes to 16 hours.

[0035] The conditions for preparing intermediate IV-2 include: the molar ratio of compound II to compound III-2 is 1:1-1:5, preferably 1:1.5-1:3; the molar ratio of compound II to acid catalyst is 1:1-1:10, preferably 1:4-1:8; the temperature is 30-100°C, preferably 60-80°C; the reaction solvent is acetonitrile, toluene, etc., preferably acetonitrile; and the reaction time is 5 minutes to 16 hours.

[0036] When preparing the compound represented by general formula (I)-1 or (I)-2, the demethylation reagent is boron tribromide, sodium bromide, sodium iodide, magnesium bromide, lithium bromide, magnesium chloride, preferably lithium bromide.

[0037] Specifically, the conditions for preparing the compound represented by general formula (I)-1 include the following: the molar ratio of intermediate IV-1 to demethylation reagent is 1:1-1:10, preferably 1:4-1:6; the reaction temperature is 30-100°C, preferably 50-70°C; the reaction solvent is dichloromethane, tetrahydrofuran, etc., preferably tetrahydrofuran; and the reaction time is several minutes to several hours, preferably 5 minutes to 16 hours.

[0038] The conditions for preparing the compound represented by general formula (I)-2 include the following: the molar ratio of intermediate IV-2 to demethylation reagent is 1:1-1:10, preferably 1:4-1:6; the reaction temperature is 30-1:100°C, preferably 50-70°C; the reaction solvent is dichloromethane, tetrahydrofuran, etc., preferably tetrahydrofuran; and the reaction time is several minutes to several hours, preferably 5 minutes to 16 hours.

[0039] In a third aspect, the present invention provides a pharmaceutical composition comprising a compound according to any of the preceding embodiments, an isomer, a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is selected from water for injection, a lyophilized powder supplement, or an oral formulation supplement. The features and performance of the present invention will be described in more detail below with reference to examples.

[0040] Example 1 An embodiment of the present invention provides a polycyclic carbamoylpyridone derivative, the structural formula of which is: [ka] and named it (4R, 12aS)-N-(2, 4-difluorophenyl)-7-hydroxy-4-methyl-6, 8-dioxo-6,8,12,12a-tetrahydro-2H, 4H-spiro[cyclopropane-1,3-pyrido[1,2:4,5]pyrazino[2, 1-b][1, 3]oxazine]-9'-carboxamide.

[0041] An embodiment of the present invention provides a method for preparing the polycyclic carbamoylpyridone derivatives, comprising the steps of: Preparation of intermediate 1a: [ka]

[0042] Step 1: Thionyl chloride (20.4 g, 172 mmol) was added to 160 mL of methanol and cooled to 0°C. Compound 1a.1 (12 g, 116 mmol) was added dropwise to the reaction mixture. After the addition was complete, the mixture was stirred at room temperature for 5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to remove the solvent and obtain a concentrate. Methanol / dichloromethane (1:1) was added to the concentrate and concentrated several times to remove the remaining thionyl chloride, yielding an off-white solid, 1a.2 (14.8 g).

[0043] 1 H NMR (400 MHz, CDCl3) δ 8.34 (br s, 3H), 3.79 (br s, 1H), 3.69 (s, 3H), 2.95 (d, J = 15.9 Hz, 1H), 2.72 (d, J = 15.8 Hz, 1H), 1.46 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 171.0, 52.4, 45.1, 38.2, 18.7.

[0044] Step 2: Compound 1a.2 (10 g, 65 mmol) and sodium bicarbonate (35.8 g, 426.8 mmol) were added to a mixture of 120 mL of tetrahydrofuran and 80 mL of DMSO. Finally, benzyl bromide (29.2 g, 170.7 mmol) was added and the mixture was stirred at 90-100 °C for 12 h. After cooling to room temperature, the mixture was quenched with water and ethyl acetate. The organic layer was separated and washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The mixture was purified by silica gel column chromatography eluting with ethyl acetate and petroleum ether (1:19) to give 1a.3 (19 g, 98%) as a white solid.

[0045] 1 H NMR (400 MHz, CDCl3) δ 7.40-7.28 (m, 8H), 7.27-7.21 (m, 2H), 3.69 (d, J = 13.7 Hz, 2H), 3.63 (s, 3H), 3.47 (d, J = 13.7 Hz, 2H), 3.40-3.28 (m, 1H), 2.68 (dd, J = 14.0, 8.1 Hz, 1H), 2.32 (dd, J = 14.0, 6.9 Hz, 1H), 1.13 (d, J = 6.7 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 172.8, 140.1, 128.9, 128.2, 126.9, 53.4, 51.5, 50.9, 39.2, 14.0.

[0046] Step 3: Compound 1a.3 (0.5 g, 1.7 mmol) was added to 4 mL of anhydrous THF and cooled to -78 °C under nitrogen gas protection. 2.6 mL of LDA (2 M THF solution, 3.0 equivalents) was added dropwise and the mixture was stirred for 1-2 hours. Subsequently, a terminally substituted bromoalkane chloride was added dropwise at -78 °C. For the compound in Example 1, 1-bromo-2-chloroethane (1.45 g, 10.1 mmol, 6 equivalents) (n = 1) was used. After the addition was complete, the mixture was cooled to room temperature and stirred for 24 hours. The mixture was quenched with ammonium chloride solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the mixture. The mixture was purified by silica gel column chromatography eluting with ethyl acetate and petroleum ether (1:19) to obtain oily product 1a.4 (0.9 g), which was used directly in the next step.

[0047] Step 4: Compound 1a.4 (0.8 g) was placed in 5 mL of anhydrous THF and DMPU (1:1), cooled to -78 °C under a nitrogen atmosphere, and 5.6 mL of LiHMDS (1 M THF solution, 2.5 equivalents) was added dropwise. After the addition was complete, the reaction was stirred at room temperature for 4-5 h. The mixture was quenched with ammonium chloride solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a mixture. The mixture was purified by aluminum trioxide column chromatography eluting with ethyl acetate:petroleum ether (1:19) to give 1a.5 (0.43 g, 30% yield for two steps) as a colorless oil.

[0048] 1 H NMR (400 MHz, CDCl3) δ 7.32-7.16 (m, 10H), 3.85 (d, J = 13.6 Hz, 2H), 3.55 (s, 3H), 3.40 (d, J = 13.6 Hz, 2H), 3.37 (q, J = 6.9 Hz, 1H), 1.30-1.21 (m, 1H), 0.96 (d, J = 6.9 Hz, 3H), 0.89-0.76 (m, 2H), 0.63-0.54 (m, 1H).

[0049] Step 5: Compound 1a.5 (0.42 g) was placed in 10 mL of anhydrous ethyl ether and cooled to 0°C under a nitrogen atmosphere. Lithium aluminum hydride (75 mg, 1.96 mmol, 1.5 equivalents) was added and the mixture was stirred for 2-3 h. After completion of the reaction, the mixture was quenched by slowly adding water at 0°C, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by aluminum trioxide column chromatography eluting with ethyl acetate:petroleum ether (1:9) to give colorless oil 1a.6 (0.25 g, 65%).

[0050] 1 H NMR (400 MHz, CDCl3) δ 7.44-7.20 (m, 10H), 4.01 (d, J = 13.0 Hz, 2H), 3.52 (dd, J = 11.2, 1.7 Hz, 1H), 3.37 (q, J = 6.8 Hz, 1H), 3.30 (d, J = 13.0 Hz, 2H), 3.19 (d, J = 11.2 Hz, 1H), 0.80 (d, J = 6.8 Hz, 3H), 0.82-0.72 (m, 1H), 0.69-0.61 (m, 1H), 0.33-0.23 (m, 1H), 0.13-0.05 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 139.0, 129.4, 128.7, 127.4, 72.3, 55.5, 54.1, 22.9, 7.0, 6.5, 5.9.

[0051] Step 6: Compound 1a.6 (0.25 g, 0.84 mmol) was dissolved in 5 mL of methanol and 80 mg of Pd(OH) / C (20% carbon-supported, 50% water content) was added. The mixture was stirred at room temperature under a hydrogen gas atmosphere (balloon) for 12 h. After completion of the reaction, the mixture was filtered through diatomaceous earth to remove the carbon. The filtrate was concentrated under reduced pressure to give compound 1a (90 mg, 93%) as a colorless oil.

[0052] 1 H NMR (400 MHz, CDCl3) δ 4.18 (dd, J = 11.2, 1.8 Hz, 1H), 3.48 (s, 1H), 2.94 (dd, J = 11.3, 1.3 Hz, 1H), 2.61 (qd, J = 6.6, 1.2 Hz, 1H), 1.23 (d, J = 6.6 Hz, 3H), 0.69-0.60 (m, 1H), 0.51-0.42 (m, 1H), 0.33-0.20 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 68.4, 54.8, 25.7, 19.9, 11.4, 7.6.

[0053] Preparation of intermediate 1b: [ka]

[0054] Step 1: Compound 1b.1 (50 g, 158.6 mmol) and N,N'-carbonyldiimidazole (30.8 g, 190.3 mmol) were added to 500 mL of acetonitrile and allowed to react under reflux for 2-3 h while stirring under nitrogen gas protection. The temperature was lowered to 0-10 °C, and a mixture of 2,4-difluorobenzylamine (27.2 g, 190.3 mmol) and 30 mL of acetonitrile was slowly added dropwise. After the addition was complete, the reaction was allowed to react at room temperature for 1 h. After the reaction was complete, the mixture was quenched with 200 mL of water, rotary evaporated under reduced pressure to remove the acetonitrile, diluted with 300 mL of ethyl acetate, washed with 300 mL of 2 M hydrochloric acid, washed twice with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a pale yellow solid. This was then washed with ethyl ether and dried to give an off-white solid, 1b.2 (53.4 g, 77%).

[0055] 1H NMR (400 MHz, CDCl3) δ 10.39 (t, J = 5.4 Hz, 1H), 8.42 (s, 1H), 7.41-7.35 (m, 1H), 6.85-6.77 (m, 2H), 4.62 (d, J = 5.6 Hz, 2H), 4.50 (t, J = 4.8 Hz, 1H), 4.04 (d, J = 4.8 Hz, 2H), 3.99 (s, 3H), 3.96 (s, 3H), 3.39 (s, 6H).

[0056] Step 2: Compound 1b.2 (20 g, 45.4 mmol) was added to 100 mL of formic acid and stirred at 60 °C for 3 h. After the reaction was completed, the solvent was removed by rotary evaporation, the residue was diluted with acetonitrile and concentrated several times, and then 80 mL of methyl t-butyl ether was added and stirred for 10-12 h to precipitate crystals. The crystals were then filtered and dried to give a white solid, 1b (17.2 g).

[0057] 1 H NMR (400 MHz, DMSO-d6)(hydrate) δ 10.31 (t, J = 5.8 Hz, 1H), 8.46 (s, 1H), 7.45-7.39(m, 1H), 6.28-6.72 (m, 1H), 7.10-7.05 (m, 1H), 6.39 (d, J = 5.8 Hz, 2H), 4.96 (t, J = 5.6 Hz, 1H), 4.53 (d, J = 5.7 Hz, 2H), 3.95 (d, J=5.1 Hz, 2H), 3.93(s, 3H), 3.81(s, 3H).

[0058] Compound 1b is the acetal deprotection product ( 1 H NMR showed that it was mainly a hydrate), but any structural form does not affect the ring-closure reaction, so in the following examples, compound 1b (MW: 412.1) is calculated as a hydrate. Preparation of Compound 1 [ka]

[0059] Step 1: Compound 1b (160 mg, 0.39 mmol), compound 1a (90 mg, 0.78 mmol), and acetic acid (140 mg, 2.34 mmol) were added to 2 mL of acetonitrile and reacted at 70-80°C with stirring for 5-6 hours. After the reaction was complete, the mixture was washed with aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give intermediate 1c, which was used directly in the next step. MS m / z (ESI): 460.2 [M+1] + .

[0060] Step 2: Intermediate 1c was dissolved in anhydrous THF, and LiBr (4.0 equiv.) was added. The mixture was stirred at 70-80°C for 5-6 hours. After completion of the reaction, the mixture was quenched with 0.5M sulfuric acid solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to give a mixture. The mixture was separated and purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol to give compound 1 (off-white solid, 128 mg, 74.0% yield for two steps). MS m / z (ESI): 446.2 [M+1] + .

[0061] 1 H NMR (400 MHz, DMSO-d6) δ 12.51 (br s, 1H), 10.36 (t, J = 5.9 Hz,1H), 8.53 (s, 1H), 7.42-7.36 (m, 1H), 7.27-7.21 (m, 1H), 7.09-7.04 (m, 1H ), 5.53(t, J = 4.6 Hz, 1H), 4.59 (dd, J = 14.1, 3.9 Hz, 1H), 4.55 (d, J = 5.9 Hz, 2H), 4.49 (dd, J = 14.0, 5.0 Hz, 1H), 4.33 (d, J = 11.8 Hz, 1H), 4.09 (q, J = 6.9 Hz, 1H), 3.10 (d, J =11.8 Hz, 1H), 1.37 (d, J = 7.0 Hz, 3H), 0.56-0.52 (m, 3H), 0.44-0.42 (m, 1H).

[0062] Example 2 An embodiment of the present invention provides a polycyclic carbamoylpyridone derivative, the structural formula of which is: [ka] and named it (4'R, 12a'S)-N-(2, 4-difluorophenyl)-7'-hydroxy-4'-methyl-6', 8'-dioxo-6',8',12',12a'-tetrahydro-2'H, 4'H-spiro[cyclobutane-1,3'-pyrido[1',2':4,5]pyrazino[2, 1-b][1, 3]pyrazine]-9'-carboxamide.

[0063] An embodiment of the present invention provides a method for preparing the polycyclic carbamoylpyridone derivatives, comprising the steps of: Intermediate 2a [ka] Preparation of intermediate 2a: Referring to the synthesis of intermediate 1a in Example 1, in step 3, the bromochloroalkane was converted to 1-bromo-3-chloropropane (n=2), which was then subjected to LDA-catalyzed substitution and ring closure with LiHMDS to give a spiro-cyclobutane intermediate, which was then reduced and deprotected to give intermediate 2a (colorless oil, 490 mg).

[0064] 1 H NMR (400 MHz, CDCl3) δ 3.89 (dd, J = 11.1, 1.2 Hz, 1H), 3.67 (dd, J = 11.0, 1.2 Hz, 1H), 3.43 (s, 1H), 3.29 (qd, J = 6.6, 1.2 Hz, 1H), 2.15-2.00 (m, 1H), 1.97-1.75 (m, 3H), 1.71-1.60 (m, 1H), 1.52-1.41 (m, 1H), 1.01 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 67.9, 55.5, 44.4, 27.9, 26.3, 16.8, 14.9.

[0065] Synthesis of compound 2: [ka]

[0066] Step 1: Compound 1b (412 mg, 1 mmol), compound 2a (260 mg, 2 mmol), and acetic acid (360 mg, 6 mmol) were added to 4 mL of acetonitrile and reacted at 70-80°C with stirring for 6-7 hours. After the reaction was completed, the mixture was washed with aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give intermediate 2c, which was used directly in the next step. MS m / z (ESI): 474.2 [M+1] + .

[0067] Step 2: Intermediate 2c was dissolved in anhydrous THF, LiBr (4.0 equiv.) was added, and the mixture was stirred at 70-80°C for 7-8 hours. After completion of the reaction, the mixture was quenched with 0.5M sulfuric acid solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to give a mixture. The mixture was separated and purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol to give compound 2 (off-white solid, 260 mg, 56.6% yield for two steps). MS m / z (ESI): 460.2 [M+1] + .

[0068] 1H NMR (400 MHz, CDCl3) δ 12.48(br s, 1H), 10.38 (t, J = 5.84 Hz, 1H), 8.32(s, 1H), 7.39-7.33 (m, 1H), 6.84-6.77 (m, 2H), 5.18 (dd, J = 6.0, 4.1 Hz,1H), 4.88 (q, J = 7.0 Hz, 1H), 4.65 (dd, J = 15.9, 6.1 Hz, 1H), 4.61 (dd, J = 15.9, 6.0 Hz, 1H), 4.28 (dd, J = 13.6, 4.1 Hz, 1H), 4.12 (dd, J = 13.5, 5.9 Hz, 1H), 3.92 (d, J = 12.2 Hz, 1H), 3.87 (d, J = 11.8 Hz, 1H), 2.07-1.55 (m, 6H), 1.23 (d, J = 7.0 Hz, 3H).

[0069] Example 3 An embodiment of the present invention provides a polycyclic carbamoylpyridone derivative, the structural formula of which is: [ka] and named it (4'R, 12a'S)-N-(2, 4-difluorophenyl)-7'-hydroxy-4'-methyl-6', 8'-dioxo-6',8',12',12a'-tetrahydro-2'H, 4'H-spiro[cyclopentane-1,3'-pyrido[1',2':4,5]pyrazino[2, 1-b][1,3]oxazine]-9'-carboxamide.

[0070] An embodiment of the present invention provides a method for preparing the polycyclic carbamoylpyridone derivatives, comprising the steps of: Intermediate 3a [ka] Preparation of: Refer to the synthesis of intermediate 1a in Example 1, in which the bromochloroalkane in step 3 was converted to 1-bromo-4-chlorobutane (n=4), which was then converted to a cyclopentane spiro intermediate through LDA-catalyzed substitution and LiHMDS ring closure, followed by reduction and deprotection to prepare intermediate 3a (colorless oil, 320 mg).

[0071] 1 H NMR (400 MHz, CDCl3) δ 3.73 (dd, J = 10.9, 1.3 Hz, 1H), 3.45 (s, 1H), 3.34 (dd, J = 10.9, 1.3 Hz, 1H), 3.06 (qd, J = 6.6, 1.3 Hz, 1H), 2.01-1.89 (m, 1H), 1.72-1.50 (m, 4H), 1.40-1.20 (m, 3H), 1.18 (d, J = 6.6 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 68.1, 56.6, 49.5, 33.7, 32.1, 25.3, 25.2, 19.0.

[0072] Synthesis of compound 3: [ka]

[0073] Step 1: Compound 1b (412 mg, 1 mmol), compound 3a (311 mg, 2.17 mmol), and acetic acid (360 mg, 6 mmol) were added to 4 mL of acetonitrile and reacted at 70-80°C with stirring for 6-7 hours. After the reaction was completed, the mixture was washed with aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give intermediate 3c, which was used directly in the next step. MS m / z (ESI): 488.2 [M+1] + .

[0074] Step 2: Intermediate 3c was dissolved in anhydrous THF, LiBr (5.0 equiv.) was added, and the mixture was stirred at 70-80 °C for 8 h. Subsequently, LiBr (5.0 equiv.) was added and the mixture was reacted for 12 h. After the reaction was complete, the mixture was quenched with 0.5 M sulfuric acid solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to give a mixture. The mixture was purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol to give compound 2 (pale yellow solid, 170 mg, 36.0% yield for two steps). MS m / z (ESI): 474.2 [M+1] + .

[0075] 1 H NMR (400 MHz, CDCl3) δ 12.48 (br s, 1H), 10.40 (t, J = 5.8 Hz, 1H), 8.33 (s, 1H), 7.39-7.33 (m, 1H), 6.84-6.77 (m, 2H), 5.24 (dd, J = 6.1, 4.2Hz, 1H), 4.69-4.59 (m, 3H), 4.28 (dd, J = 13.6, 4.2 Hz, 1H), 4.13 (dd, J = 13.5, 6.2 Hz, 1H), 3.82 (d, J = 11.2 Hz, 1H), 3.56 (d, J = 11.6 Hz, 1H), 1.87-1.16 (m, 8H), 1.33 (d, J = 7.04 Hz, 3H).

[0076] Example 4 An embodiment of the present invention provides a polycyclic carbamoylpyridone derivative, the structural formula of which is: [ka] and named it (4'R, 12a'S)-N-(2, 4-difluorophenyl)-7'-hydroxy-4'-methyl-6', 8'-dioxo-6',8',12',12a'-tetrahydro-2'H, 4'H-spiro[cyclohexane-1,3'-pyrido[1',2':4,5]pyrazino[2, 1-b][1,3]oxazine]-9'-carboxamide.

[0077] An embodiment of the present invention provides a method for preparing the polycyclic carbamoylpyridone derivatives, comprising the steps of: Intermediate 4a [ka] Preparation of: Refer to the synthesis of intermediate 1a in Example 1, where in step 3, the bromochloroalkane was replaced with 1-bromo-5-chloropentane (n=5), which was then subjected to LDA-catalyzed substitution and LiHMDS ring closure to give a cyclohexane spiro intermediate, which was then reduced and deprotected to prepare intermediate 4a (colorless oil, 130 mg).

[0078] 1 H NMR (400 MHz, CDCl3) δ 3.77 (d, J = 11.1 Hz, 1H), 3.59 (dd, J = 11.2, 1.4 Hz, 1H), 3.03 (qd, J = 6.6, 1.4 Hz, 1H), 1.93-1.80 (m, 1H), 1.63-1.39 (m, 4H), 1.35-1.25 (m, 4H), 1.14 (d, J = 6.6 Hz, 3H), 1.08-0.97 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 66.5, 55.6, 38.5, 30.9, 30.4, 26.4, 21.7, 21.5, 17.4.

[0079] Synthesis of compound 4: [ka]

[0080] Step 1: Compound 1b (173 mg, 0.42 mmol), compound 4a (130 mg, 0.84 mmol), and acetic acid (185 mg, 2.5 mmol) were added to 2 mL of acetonitrile and reacted at 70-80°C with stirring for 7-8 hours. After the reaction was complete, the mixture was washed with aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give intermediate 4c, which was used directly in the next step. MS m / z (ESI): 502.2 [M+1] + .

[0081] Step 2: Intermediate 4c was dissolved in anhydrous THF, LiBr (4.0 equiv.) was added, and the mixture was stirred at 70-80°C for 22 hours. After completion of the reaction, the mixture was quenched with 0.5M sulfuric acid solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to give a mixture. The mixture was separated and purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol to give compound 4 (pale yellow solid, 90 mg, 43.9% yield over two steps). MS m / z (ESI): 488.2 [M+1] + .

[0082] 1 H NMR (400 MHz, CDCl3) δ 12.52 (br s, 1H), 10.41 (t, J = 8.96 Hz, 1H), 8.36 (s, 1H), 7.38-7.35 (m, 1H), 6.84-6.77 (m, 2H), 5.17 (t, J = 4.8 Hz, 1H), 4.87 (q, J = 7.0 Hz, 1H), 4.68-4.58 (m, 2H), 4.32 (dd, J = 13.6, 3.8 Hz, 1H), 4.15 (dd, J = 13.6, 5.4 Hz, 1H), 3.73 (d, J = 12.0 Hz, 1H), 3.67 (d, J = 12.0 Hz, 1H), 1.57-1.08 (m, 10H), 1.31 (d, J = 7.08 Hz, 3H).

[0083] Example 5 An embodiment of the present invention provides a polycyclic carbamoylpyridone derivative, the structural formula of which is: [ka] and named it (4'R, 12a'S)-N-(2, 4-difluorophenyl)-7'-hydroxy-4'-methyl-6', 8'-dioxo-2,3,5.6,6',8',12',12a'-octahydro-2'H, 4'H-spiro[pyran-4,3'-pyrido[1',2':4,5]pyrazino[2, 1-b][1,3]oxazine]-9'-carboxamide.

[0084] An embodiment of the present invention provides a method for preparing the polycyclic carbamoylpyridone derivatives, comprising the steps of: Intermediate 5a [ka] Preparation of: Refer to the synthesis of intermediate 1a in Example 1, where in step 3, the bromochloroalkane was converted to 1-bromo-2-(2-chloroethoxy)ethane, which was then subjected to LDA-catalyzed substitution and ring closure with LiHMDS to obtain a pyran spiro intermediate, which was then reduced and deprotected to prepare intermediate 4a (colorless oil, 0.29 g).

[0085] 1 H NMR (400 MHz, CDCl3) δ 3.80-3.75 (m, 3H), 3.74-3.68 (m, 1H), 3.64 (td, J = 11.8, 2.6 Hz, 1H), 3.43 (td, J = 11.8, 3.0 Hz, 2H), 2.95 13C NMR (100 MHz, CDCl3) δ 64.1, 63.68, 63.65, 57.1, 36.6, 30.5, 17.0.

[0086] Synthesis of compound 5: [ka]

[0087] Step 1: Compound 1b (412 mg, 1 mmol), compound 5a (270 mg, 1.7 mmol), and acetic acid (360 mg, 6 mmol) were added to 4 mL of acetonitrile and reacted at 70-80°C with stirring for 7-8 hours. After the reaction was completed, the mixture was washed with aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give intermediate 5c, which was used directly in the next reaction step. MS m / z (ESI): 504.2 [M+1] + .

[0088] Step 2: Intermediate 5c was dissolved in anhydrous THF, and LiBr (4.0 equiv.) was added. The mixture was stirred at 70-80°C for 21 h. After completion of the reaction, the mixture was quenched with 0.5 M sulfuric acid solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to give a mixture. The mixture was separated and purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol to give compound 4 (pale yellow solid, 72 mg, 14.7% yield for two steps). MS m / z (ESI): 490.2 [M+1] + .

[0089] 1H NMR (400 MHz, CDCl3) δ 12.38 (br s, 1H), 10.37 (t, J = 5.9 Hz, 1H), 8.38 (s, 1H), 7.38-7.32 (m, 1H), 6.84-6.77 (m, 2H), 5.21 (t, J = 5.2 Hz, 1H), 4.91 (q, J = 7.0 Hz, 1H), 4.65 (dd, J = 16.3, 5.1 Hz, 1H), 4.61 (dd, J = 16.6, 5.1 Hz, 1H), 4.17 (dd, J = 13.7, 4.1 Hz, 1H), 3.98 (d, J = 12.1 Hz, 1H), 3.88 (d, J = 12.1 Hz, 1H), 3.80-3.55 (m, 4H), 1.78-1.72 (m, 1H), 1.64-1.59 (m, 1H), 1.54-1.48 (m, 1H), 1.34 (d, J = 7.1 Hz, 3H), 1.32-1.29 (m, 1H).

[0090] Example 6 An embodiment of the present invention provides a polycyclic carbamoylpyridone derivative, the structural formula of which is: [ka] and named it (4'R, 12a'S)-N-(2, 4-difluorophenyl)-7'-hydroxy-4'-methyl-6', 8'-dioxo-3',4',6',8',12',12a'-hexahydrospiro[cyclopropane-1,2'-pyrido[1',2':4,5]pyrazino[2, 1-b][1,3]oxazine]-9'-carboxamide.

[0091] An embodiment of the present invention provides a method for preparing the polycyclic carbamoylpyridone derivatives, comprising the steps of: Preparation of intermediate 6a: [ka]

[0092] Step 1: Compound 1a.3 (500 mg, 1.7 mmol) was placed in anhydrous THF (10 mL) and cooled to -30 °C under nitrogen gas protection. i Pr)4 (0.25 equiv.) and EtMgBrs (3M / Et2O, 3.0 equiv.) were added dropwise, and the mixture was allowed to cool to room temperature and react for 10-12 h with stirring. After completion of the reaction, the mixture was quenched with ammonium chloride solution, extracted with ethyl acetate, washed with sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Separation by aluminum trioxide column chromatography, eluting with ethyl acetate:petroleum ether (1:9), afforded intermediate 6a.1 (colorless oil, 254 mg, 51%).

[0093] 1 H NMR (400 MHz, CDCl3) δ 7.40-7.19 (m, 10H), 6.78 (s, 1H), 3.99 (d, J = 12.9 Hz, 2H), 3.38-3.24 (m, 1H), 3.28 (d, J = 12.9 Hz, 2H), 2.52 (ddd, J = 14.3, 12.4, 1.9 Hz, 1H), 1.07 (d, J = 6.7 Hz, 3H), 0.77 (dd, J = 14.6, 2.9 Hz, 1H), 0.74-0.65 (m, 1H), 0.39-0.22 (m, 2H), 0.01-(-0.10) (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 138.5, 129.5, 128.5, 127.4, 56.6, 53.6, 53.3, 40.1, 12.7, 12.6, 12.0.

[0094] Step 2: The reaction for removing the Bn protecting group was carried out in accordance with Step 6 for Compound 1a to give Compound 6a (colorless oil, 390 mg, ∼100%). 1H NMR (400 MHz, CDCl3) δ: 3.46 (s, 1H), 3.35-3.19 (m, 1H), 1.80 (ddd, J = 14.4, 9.9, 1.7 Hz, 1H), 1.28-1.22 (m, 1H), 1.17 (d, J = 6.4 Hz, 3H), 0.82-0.73 (m, 1H), 0.73-0.65 (m, 1H), 0.50-0.38 (m, 1H), 0.38-0.29 (m, 1H).

[0095] Preparation of Compound 6: [ka]

[0096] Step 1: Compound 1b (268 mg, 0.65 mmol), compound 6a (150 mg, 1.3 mmol), and acetic acid (234 mg, 3.9 mmol) were added to 3 mL of acetonitrile and reacted at 70-80°C with stirring for 6-8 hours. After the reaction was complete, the mixture was washed with aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give intermediate 6c, which was used directly in the next step. MS m / z (ESI): 460.2 [M+1] + .

[0097] Step 2: Intermediate 6c was dissolved in anhydrous THF, LiBr (4.0 equiv.) was added, and the mixture was stirred at 70-80°C for 14 h. After completion of the reaction, the mixture was quenched with 0.5 M sulfuric acid solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to give a mixture. The mixture was separated and purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol to give compound 4 (pale yellow solid, 110 mg, 38% yield for two steps). MS m / z (ESI): 446.2 [M+1] + .

[0098] 1H NMR (400 MHz, CDCl3) δ 12.50 (br s, 1H), 10.39 (t, J = 5.8 Hz, 1H), 8.36 (s, 1H), 7.38-7.32 (m, 1H), 6.84-6.76 (m, 2H), 5.21 (t, J = 5.2 Hz, 1H), 5.08-5.01 (m, 1H), 4.63 (dd, J = 16.3, 6.2 Hz, 1H), 4.59 (dd, J = 16.0, 6.1 Hz, 1H), 4.35 (dd, J = 13.4, 3.0 Hz, 1H), 4.15 (dd, J = 12.5, 5.0 Hz, 1H), 2.62 (dd, J = 13.1, 5.2 Hz, 1H), 1.49 (d, J = 7.1 Hz, 3H), 1.13 (dd, J = 13.9, 1.1 Hz, 1H), 1.05-0.98 (m, 1H), 0.88-0.82 (m, 1H), 0.70-0.64 (m, 1H), 0.56-0.50 (m, 1H).

[0099] Example 7 An embodiment of the present invention provides a polycyclic carbamoylpyridone derivative, the structural formula of which is: [ka] and named it (4'R, 12a'S)-N-(2, 4-difluorophenyl)-7'-hydroxy-4'-methyl-6', 8'-dioxo-3',4',6',8',12',12a'-hexahydrospiro[cyclopentane-1,2'-pyrido[1',2':4,5]pyrazino[2, 1-b][1,3]oxazine]-9'-carboxamide.

[0100] An embodiment of the present invention provides a method for preparing the polycyclic carbamoylpyridone derivatives, comprising the steps of: Preparation of intermediate 7a: [ka]

[0101] Step 1: Under a nitrogen atmosphere, magnesium turnings (14.59 g, 600 mmol), iodine particles (0.91 g, 3.6 mmol), and 50 mL of anhydrous THF were added. The mixture was heated to 60 °C and 1,2-dibromoethane (0.1 mL) was rapidly added dropwise, followed by 1,4-dibromobutane (14.3 mL, 120 mmol). After the addition was complete, the mixture was stirred for 1 h. After the reaction was complete, the mixture was heated to 80 °C and Intermediate 1a.3 (8.92 g, dissolved in 20 mL of anhydrous THF, 30 mmol) was added. The mixture was stirred at the same temperature for 2 h. After the reaction was complete, the mixture was quenched with ammonium chloride solution, filtered, and the filtrate was extracted with ethyl acetate, washed with sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure to obtain a mixture. Separation by silica gel column chromatography eluting with ethyl acetate:petroleum ether gave intermediate 7a.3 (pale yellow oil 4.36 g, 45%).

[0102] 1 H NMR (400 MHz, CDCl3) δ 7.34-7.29 (m, 8H), 7.28-7.22 (m, 2H), 6.70 (s, 1H), 3.93 (d, J = 12.8 Hz, 2H), 3.29-3.21 (m, 1H), 3.21 (d, J = 12.8 Hz, 2H), 2.18 (dd, J = 14.6, 11.8 Hz, 1H), 1.78-1.62 (m, 2H), 1.60-1.51 (m, 1H), 1.47-1.33 (m, 3H), 1.13 (dd, J = 14.6, 2.4 Hz, 1H), 1.08 (d, J = 6.7 Hz, 3H), 0.95-0.84 (m, 1H), 0.80-0.71 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ 138.39, 129.76, 128.45, 127.33, 82.41, 52.88, 51.46, 42.37, 41.53, 38.08, 23.96, 23.47, 12.39.

[0103] Step 2: Referring to the procedure for removing Boron in 1a, intermediate 7a was obtained as a white solid, which was used as it was in the reaction of the next step. 1 H NMR (400 MHz, CDCl3) δ 3.21-3.08 (m, 1H), 1.88-1.40 (m, 10H), 1.13 (d, J = 6.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 82.2, 47.4, 46.5, 41.7, 39.2, 28.2, 24.1, 23.7.

[0104] Preparation of Compound 7: [ka]

[0105] Step 1: Compound 1b (346 mg, 0.84 mmol), compound 7a (300 mg, 2.1 mmol), and acetic acid (403 mg, 7.72 mmol) were added to 4 mL of acetonitrile and reacted at 70-80°C with stirring for 6 hours. After the reaction was completed, the mixture was washed with aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give intermediate 7c, which was used directly in the next reaction step. MS m / z (ESI): 488.2 [M+1] + .

[0106] Step 2: Intermediate 7c was dissolved in anhydrous THF, LiBr (4.0 equiv.) was added, and the mixture was stirred at 70-80°C for 6 hours. After completion of the reaction, the mixture was quenched with 0.5M sulfuric acid solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to give a mixture. The mixture was separated and purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol to give compound 4 (pale yellow solid, 70 mg, 17.6% yield for two steps). MS m / z (ESI): 474.2 [M+1] + .

[0107] 1H NMR (400 MHz, CDCl3) δ 12.47 (br s, 1H), 10.42 (t, J = 5.8 Hz, 1H), 8.34(s, 1H), 7.40-7.34 (m, 1H), 6.84-6.77 (m, 2H), 5.35 (t, J = 3.4 Hz, 1H), 4.83-4.75 (m, 1H), 4.66 (dd, J = 15.3, 6.0 Hz, 1H), 4.60 (dd, J = 15.3, 5.8 Hz, 1H), 4.30 (dd, J = 13.7, 3.4 Hz, 1H), 4.17(dd,J = 13.7, 3.5 Hz, 1H), 2.11 (dd, J = 14.5, 6.8 Hz, 1H), 2.07-1.89 (m, 2H), 1.83 (dd, J = 14.5, 8.1 Hz, 1H), 1.80-1.49 (m, 6H), 1.39 (d, J = 6.8 Hz, 3H).

[0108] Example 8 An embodiment of the present invention provides a polycyclic carbamoylpyridone derivative, the structural formula of which is: [ka] and named it (4'R, 12a'S)-N-(2, 4-difluorophenyl)-7'-hydroxy-4'-methyl-6', 8'-dioxo-3',4',6',8',12',12a'-hexahydrospiro[cyclohexane-1,2'-pyrido[1',2':4,5]pyrazino[2, 1-b][1,3]oxazine]-9'-carboxamide.

[0109] An embodiment of the present invention provides a method for preparing the polycyclic carbamoylpyridone derivatives, comprising the steps of: Preparation of intermediate 8a: [ka]

[0110] Step 1: Referring to the operating conditions for intermediate 7a.3, 1,5-dibromopentane was used to give intermediate 8a.3 (white solid, 2.68 g, 16%). 1 H NMR (400 MHz, CDCl3) δ 7.35-7.30 (m, 8H), 7.27-7.21 (m, 2H), 6.62 (s, 1H), 3.92 (d, J = 12.8 Hz, 2H), 3.24-3.13 (m, 1H), 3.19 (d, J = 12.8 Hz, 2H), 1.81 (dd, J = 14.8, 12.0 Hz, 1H), 1.70-1.58 (m, 1H), 1.52 (dd, J = 12.9, 5.6 Hz, 1H), 1.46-1.32 (m, 3H), 1.25-1.08 (m, 4H), 1.05 (d, J = 6.7 Hz, 3H), 0.71 (dd, J = 7.3, 4.8 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ 138.50, 129.90, 128.52, 127.40, 71.51, 52.95, 49.18, 42.67, 40.60, 35.77, 26.14, 22.24, 22.13, 12.52.

[0111] Step 2: Using the same conditions as for the Boron removal procedure for Intermediate 1a, Intermediate 8a was produced as a white solid, which was used as is in the reaction of the next step. Synthesis of compound 8: [ka]

[0112] Step 1: Compound 1b (412 mg, 1 mmol), compound 8a (300 mg, 2.2 mmol), and acetic acid (360 mg, 6 mmol) were added to 4 mL of acetonitrile and reacted at 70-80°C with stirring for 16 hours. After the reaction was completed, the mixture was washed with aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give intermediate 7c, which was used directly in the next reaction step. MS m / z (ESI): 502.2 [M+1] + .

[0113] Step 2: Intermediate 8c was dissolved in anhydrous THF, LiBr (4.0 equiv.) was added, and the mixture was stirred at 70-80°C for 6 hours. After completion of the reaction, the mixture was quenched with 0.5M sulfuric acid solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to give a mixture. The mixture was separated and purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol to give compound 8 (pale yellow solid, 194 mg, 40.0% yield for two steps). MS m / z (ESI): 488.2 [M+1] + .

[0114] 1 H NMR (400 MHz, CDCl3) δ 12.40 (br s, 1H), 10.48 (t, J = 5.9 Hz, 1H), 8.42 (s, 1H), 7.40-7.34 (m, 1H), 6.85-6.77 (m, 2H), 5.35 (t, J = 2.5 Hz, 1H), 4.70-4.59 (m, 3H), 4.28 (dd, J = 13.9, 3.1 Hz, 2H), 2.04 (dd, J = 15.0, 6.9 Hz, 1H), 1.80 (dd, J = 15.0, 10.4 Hz, 1H), 1.68-1.54 (m, 2H), 1.44-1.21 (m, 8H), 1.35 (d, J = 6.5 Hz, 3H).

[0115] Example 9 An embodiment of the present invention provides a polycyclic carbamoylpyridone derivative, the structural formula of which is: [ka] and named it (4R, 12aS)-N-(2, 4-difluorophenyl)-7'-hydroxy-4'-methyl-6', 8'-dioxo-2,3,3',4',5,6,6',8',12',12a'-decahydrospiro[pyran-4,2'-pyrido[1',2':4,5]pyrazino[2, 1-b][1,3]oxazine]-9'-carboxamide.

[0116] An embodiment of the present invention provides a method for preparing the polycyclic carbamoylpyridone derivatives, comprising the steps of: Preparation of intermediate 9a: [ka]

[0117] Process: The preparation method was based on the reference Tetrahedron Asymmetry 1996, 2911-2922. (R)-2-aminopropanol was used as the starting material, and after Bz amino protection and hydroxychlorination, it was added to tetrahydropyrone in the n-BuLi / lithium naphthalenide system. Finally, Bz was deprotected to obtain intermediate 9a. MS m / z (ESI): 160.23 [M+1] + .

[0118] 1 H NMR(DMSO-d6)δ 3.64-3.48 (m, 4H), 3.53-3.36 (m, 3H), 3.12-2.85 (m, 1H), 1.51-1.26 (m, 6H), 1.02 (d, J = 6.4 Hz, 3H);

[0119] Synthesis of compound 9: [ka]

[0120] Step 1: Compound 1b (412 mg, 1 mmol), compound 9a (318 mg, 2 mmol), and acetic acid (360 mg, 6 mmol) were added to 4 mL of acetonitrile and reacted at 70-80°C with stirring for 10-12 hours. After the reaction was complete, the mixture was washed with aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give intermediate 9c, which was used directly in the next step. MS m / z (ESI): 504.2 [M+1] + .

[0121] Step 2: Intermediate 9c was dissolved in anhydrous THF, LiBr (4.0 equiv.) was added, and the mixture was stirred at 70-80°C for 6-8 hours. After completion of the reaction, the mixture was quenched with 0.5M sulfuric acid solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to give a mixture. The mixture was separated and purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol to give compound 9 (pale yellow solid, 68 mg, 13.9% yield for two steps). MS m / z (ESI): 490.2 [M+1] + .

[0122] 1H NMR (400 MHz, CDCl3) δ 12.31 (br s, 1H), 10.40 (t, J = 5.8 Hz, 1H), 8.36 (s, 1H), 7.40-7.34 (m, 1H), 6.85-6.77 (m, 2H), 5.39 (t, J = 2.1 Hz, 1H), 4.74-4.60 (m, 3H), 4.31 (dd, J = 13.9, 3.0 Hz, 1H), 4.24 (dd, J = 14.0, 1.9 Hz, 1H), 3.72-3.65 (m, 2H), 3.60 (dt, J = 11.6, 4.2 Hz, 1H), 3.48 (td, J = 11.1, 2.6 Hz, 1H), 2.04 (dd, J = 15.0, 6.9 Hz, 1H), 1.90 (dd, J = 15.0, 10.3 Hz, 1H), 1.74-1.62 (m, 2H), 1.59 (dd, J = 10.8, 4.7 Hz, 1H), 1.55(dd, J = 10.8, 4.6 Hz, 1H), 1.39 (d, J = 6.5 Hz, 3H).

[0123] Example 10 An embodiment of the present invention provides a polycyclic carbamoylpyridone derivative, the structural formula of which is: [ka] and named it (3R, 11aS)-N-(2, 4-difluorophenyl)-6-hydroxy-3-methyl-5,7-dioxo-5,7,11,11a-tetrahydro-3H-spiro[cyclopropane-1,2-oxazolo[3,2-a]pyrido[1,2-d]pyrazine]-8-carboxamide.

[0124] An embodiment of the present invention provides a method for preparing the polycyclic carbamoylpyridone derivatives, comprising the steps of: Preparation of Intermediate 10a: [ka]

[0125] Step 1: In a nitrogen gas atmosphere, compound 1a.1 (4.06 g, 20 mmol) was placed in 40 mL of anhydrous THF, and the temperature was lowered to -30 to -35 °C. Ti(O i Pr)4 (0.3 equiv.) and EtMgBrs (2M / Et2O, 3.0 equiv.) were added dropwise and reacted with stirring for 1 h, then the mixture was transferred to -5 to 0 °C and reacted with stirring for 10-12 h. After the reaction was complete, the mixture was quenched with ammonium chloride solution, extracted with ethyl acetate, washed with sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was separated by silica gel column chromatography using a gradient elution with ethyl acetate and petroleum ether to give intermediate 10a.2 (0.6 g, 15%) as a white solid.

[0126] 1 H NMR (400 MHz, CDCl3) δ 3.31 (q, J = 6.8 Hz, 1H), 1.45 (s, 9H), 1.23 (d, J = 6.9 Hz, 3H), 0.82-0.72 (m, 3H), 0.54-0.51 (s, 1H).

[0127] Step 2: Intermediate 10a.2 (390 mg, 1.94 mmol) was placed in 4 mL of dioxane, and a 3M solution of hydrochloric acid in dioxane (7.76 mmol) (preparation of 3M hydrochloric acid: 1 mL of concentrated hydrochloric acid in 3 mL of dioxane) was added dropwise. The mixture was stirred at room temperature for 20-22 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and dehydrated several times with acetonitrile to give a pink oil. 4 mL of acetonitrile was added and the mixture was refrigerated for 10-12 h. The oil was filtered, washed with cold acetonitrile, and dried to give Intermediate 10a (white solid, 180 mg, 91.8%).

[0128] 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (br s, 3H), 5.81 (br s, 1H), 2.79-2.74 (m ,1H), 1.23 (d, J = 6.7 Hz, 3H), 0.72-0.54 (m, 4H).

[0129] Synthesis of compound 10: [ka]

[0130] Step 1: Compound 1b (206 mg, 0.5 mmol) was added to a 3 mL acetonitrile solution. Separately, DIEA (130 mg, 1 mmol) was added to a 2 mL acetonitrile solution of compound 10a hydrochloride (138 mg, 1 mmol) and mixed homogeneously. The mixture was then added to a acetonitrile solution of compound 1b. Finally, acetic acid (150 mg, 2.5 mmol) was added, and the mixture was stirred at 70-80 °C for 4-5 h. After the reaction was complete, the mixture was washed with aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 10c, which was used directly in the next step. MS m / z (ESI): 446.2 [M+1] + .

[0131] Step 2: Intermediate 10c was dissolved in anhydrous THF, LiBr (4.0 equiv.) was added, and the mixture was stirred at 70-80°C for 6-8 hours. After completion of the reaction, the mixture was quenched with 0.5M sulfuric acid solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to give a mixture. The mixture was separated and purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol to give compound 10 (off-white solid, 142 mg, 66% yield for two steps). MS m / z (ESI): 432.2 [M+1] + .

[0132] 1H NMR (400 MHz, CDCl3) δ 11.47 (br s, 1H), 10.31 (s, 1H), 8.36 (s, 1H), 7.38-7.32 (m, 1H), 6.83-6.78 (m, 2H), 5.41-5.39 (m, 1H), 4.68-4.56 (m, 1H), 4.45 (dd, J = 12.3, 3.0 Hz, 1H), 4.35 (q, J = 6.1 Hz, 1H), 3.98 (t, J = 11.2 Hz, 1H), 1.34 (d, J = 6.2 Hz, 3H), 1.25-1.10 (m, 1H), 0.94-0.76 (m, 3H).

[0133] Example 11 An embodiment of the present invention provides a polycyclic carbamoylpyridone derivative, the structural formula of which is: [ka] and named it (3'R, 11a'S)-N-(2, 4-difluorophenyl)-6'-hydroxy-3'-methyl-5', 7'-dioxo-5',7',11',11a'-tetrahydro-3'H-spiro[cyclopentane-1,2'-oxazolo[3,2-a]pyrido[1,2-d]pyrazine]-8'-carboxamide.

[0134] An embodiment of the present invention provides a method for preparing the polycyclic carbamoylpyridone derivatives, comprising the steps of: Preparation of intermediate 11a: [ka]

[0135] Step 1: Referring to the operating conditions of 7a.3, intermediate 11a.1 was placed into the freshly prepared Grignard reaction mixture 7a.2 to produce intermediate 11a.2 (light yellow oil, 3.91 g, 50%).

[0136] 1H NMR (400 MHz, CDCl3) δ 7.35-7.27 (m, 8H), 7.26-7.21 (m, 2H), 4.35 (s, 1H), 3.89 (d, J = 13.5 Hz, 2H), 3.34 (d, J = 13.5 Hz, 2H), 2.92 (q, J = 7.0 Hz, 1H), 1.90-1.78 (m, 1H), 1.78-1.68 (m, 1H), 1.69-1.54 (m, 3H), 1.52-1.38 (m, 3H), 1.09 (d, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 139.53, 129.09, 128.55, 127.30, 82.63, 59.33, 55.09, 38.98, 35.53, 24.89, 23.12, 7.13.

[0137] Step 2: Following the conditions for deboronation in 1a, oily substance 11a was produced, which was used as it was in the reaction of the next step. Synthesis of compound 11: [ka]

[0138] Step 1: Compound 1b (251 mg, 0.84 mmol), compound 7a (160 mg, 1.22 mmol), and acetic acid (220 mg, 3.66 mmol) were added to 3 mL of acetonitrile and reacted at 70-80°C with stirring for 16 hours. After the reaction was completed, the mixture was washed with aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give intermediate 11c, which was used directly in the next step. MS m / z (ESI): 474.2 [M+1] + .

[0139] Step 2: Intermediate 11c was placed in anhydrous THF, LiBr (4.0 equiv.) was added, and the mixture was stirred at 70-80°C for 6-8 h. After the reaction was complete, 0.5 M sulfuric acid solution was added to quench the reaction. 3-5 mL of water was added and stirred to precipitate a solid. The solid was filtered, washed with THF / water (1:1), and dried to give compound 11 (white solid, 230 mg, 63.5% yield for 2 steps). MS m / z (ESI): 432.2 [M+1] + .

[0140] 1 H NMR (400 MHz, DMSO-d6) δ 11.44 (br s, 1H), 10.33 (t, J = 3.6Hz, 1H), 8.46 (s, 1H), 7.43-7.37 (m, 1H), 7.28-7.22 (m, 1H), 7.09-7.04 (m, 1H), 5.42 (d, J = 10.2, 4.0 Hz, 1H), 4.83 (d, J = 12.2, 4.0 Hz, 1H), 4.59-4.50 (m, 2H), 4.17 (q, J = 6.5 Hz, 1H), 3.99 (dd, J = 11.6, 10.44 Hz, 1H), 1.79-1.59 (m, 8H), 1.30 (d, J = 6.7 Hz, 3H).

[0141] Example 12 An embodiment of the present invention provides a polycyclic carbamoylpyridone derivative, the structural formula of which is: [ka] and named it (3'R, 11a'S)-N-(2, 4-difluorophenyl)-6'-hydroxy-3'-methyl-5', 7'-dioxo-5',7',11',11a'-tetrahydro-3'H-spiro[cyclohexane-1,2'-oxazolo[3,2-a]pyrido[1,2-d]pyrazine]-8'-carboxamide.

[0142] An embodiment of the present invention provides a method for preparing the polycyclic carbamoylpyridone derivatives, comprising the steps of: Preparation of intermediate 12a: [ka]

[0143] Step 1: Referring to the operating conditions of 7a.3, intermediate 11a.1 was used in a Grignard reaction to prepare intermediate 12a.1 (white solid, 2.03 g, 12%). 1 H NMR (400 MHz, CDCl3) δ 7.34-7.29 (m, 7H), 7.28-7.21 (m, 1H), 3.89 (d, J = 13.7 Hz, 2H), 3.71 (s, 1H), 3.36 (d, J = 13.7 Hz, 2H), 2.61 (q, J = 7.1 Hz, 1H), 1.73-1.18 (m, 10H), 1.09 (d, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 139.62, 129.10, 128.53, 127.28, 72.56, 62.38, 56.18, 36.32, 33.35, 26.05, 22.42, 21.96, 7.50.

[0144] Step 2: Following the conditions for deboronation in 1a, oily product 12a was prepared, which was used as it was in the next step. Synthesis of compound 12: [ka]

[0145] Step 1: Compound 1b (231 mg, 0.56 mmol), compound 12a (200 mg, 1.4 mmol), and acetic acid (202 mg, 3.36 mmol) were added to 3 mL of acetonitrile and reacted for 4-5 hours with stirring at 70-80°C. After the reaction was completed, the mixture was washed with aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 11a, which was used directly in the next reaction step. MS m / z (ESI): 488.2 [M+1]+ .

[0146] Step 2: Intermediate 11c was dissolved in anhydrous THF, LiBr (4.0 equiv.) was added, and the mixture was stirred at 70-80°C for 10-12 h. After completion of the reaction, the mixture was quenched with 0.5 M sulfuric acid solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give a mixture. The mixture was crystallized with methyl t-butyl ether for 2-4 h, filtered, washed with methyl t-butyl ether, and dried to give compound 12 (off-white solid, 180 mg, 67.9% yield for two steps). MS m / z (ESI): 474.2 [M+1] + .

[0147] 1 H NMR (400 MHz, CDCl3) δ 11.55 (br s, 1H), 10.33 (t, J = 5.7 Hz, 1H), 8.35 (s, 1H), 7.39-7.32 (m, 1H), 6.84-6.77 (m, 2H), 5.40 (dd, J = 10.1, 4.0 Hz, 1H), 4.65 (dd, J = 16.0, 6.2 Hz, 1H), 4.61 (dd, J = 16.2, 6.2 Hz, 1H), 4.42 (dd, J = 12.4, 4.2 Hz, 1H), 4.13 (q, J = 6.7 Hz, 1H), 3.87 (dd, J = 12.3, 10.3 Hz, 1H), 1.80-1.50 (m, 10H), 1.36 (d, J = 6.8 Hz, 3H).

[0148] Example 13 An embodiment of the present invention provides a polycyclic carbamoylpyridone derivative, the structural formula of which is: [ka] in, (2,4-Difluorophenyl)-7'-hydroxy-6',8'-dioxo-2',3',6',8',12',12a'-hexahydrospiro[cyclopropane-1,4'-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine]-9'-carboxamide (compound 13), (S)-N-(2,4-difluorophenyl)-7'-hydroxy-6',8'-dioxo-2',3',6',8',12',12a'-hexahydrospiro[cyclopropane-1,4'-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine]-9'-carboxamide (compound 14), This compound was named (R)-N-(2,4-difluorophenyl)-7'-hydroxy-6',8'-dioxo-2',3',6',8',12',12a'-hexaspiro[cyclopropane-1,4'-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine]-9'-carboxamide (compound 15).

[0149] An embodiment of the present invention provides a method for preparing the polycyclic carbamoylpyridone derivatives, comprising the steps of: Preparation of intermediate 13a: [ka]

[0150] Steps 1 and 2: Referring to the synthetic route in the literature, Journal of Medicinal Chemistry, 2016, 59, 8, 3732-3749, 2-cyanoethanol was used as a starting material, and the hydroxyl group was protected with TBSCl, followed by the Klinkovich reaction of cyclopropane to produce a TBS-protected amino alcohol.

[0151] 1H NMR (DMSO-d6) δ 3.78 (t, J = 6.8 Hz, 1H), 1.65 (br s, 2H), 1.53 (t, J = 6.9 Hz, 2H), 0.83 (s, 9H), 0.37-0.30 (m, 3H), 0.04(s, 6H).

[0152] Step 3: Deprotection of TBS with acetic acid gave reddish-brown oil 13a, which was used directly in the next step reaction. Synthesis of compounds 13, 14 and 15: [ka]

[0153] Step 1: Compound 1b (412 mg, 1 mmol), compound 13a (202 mg, 2 mmol), and acetic acid (360 mg, 6 mmol) were added to 4 mL of acetonitrile and reacted at 70-80°C with stirring for 14-16 hours. After the reaction was completed, the mixture was washed with aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give intermediate 13c, which was used directly in the next step. MS m / z (ESI): 446.1 [M+1] + .

[0154] Step 2: Intermediate 13c was placed in anhydrous THF, LiBr (4.0 equiv.) was added, and the mixture was stirred at 70-80°C for 4-6 h. After the reaction was complete, the mixture was quenched with 0.5 M sulfuric acid solution, and water was added and stirred for 1-3 h to precipitate crystals. The solid was filtered and washed with THF:water = 1:1 to give compound 13 (off-white solid, 177 mg, 41% yield for 2 steps). MS m / z (ESI): 432.2 [M+1] + .

[0155] 1H NMR (400 MHz, DMSO-d6) δ 12.53 (br s, 1H), 10.41 (t, J = 5.8 Hz, 1H), 8.57 (s, 1H), 7.48-7.42 (m, 1H), 7.33-7.27 (m, 1H), 7.15-7.10 (m, 1H), 5.38-5.34 (d, 1H), 4.74 (dd, J = 14.7, 1.2 Hz, 1H), 4.63 (dd, J = 15.2, 6.2 Hz, 1H), 4.57 (dd, J = 15.0, 5.7 Hz, 1H), 4.43 (dd, J = 14.4, 2.9 Hz, 1H), 4.15 (dd, J = 11.1, 4.8 Hz, 1H), 4.07 (td, J = 11.8, 2.3 Hz, 1H), 2.33 (td, J = 12.4, 5.2, 1H), 1.52-1.47 (m, 1H), 1.18-1.08 (m, 2H), 0.88-0.82 (m, 1H), 0.77-0.72 (m, 1H).

[0156] Preparation of chiral compounds 14 and 15: Compound 14 (retention time: 1.21 min, MS m / z (ESI): 432.1 [M+1]) was isolated from the suspension 13 (50 mg) by SFC separation (preparative column: ChiralPak AD, 250 × 30 mm ID, 10 μm; mobile phase: CO2 in A phase / isopropanol in B phase, gradient: B 25%, flow rate: 70 ml / min, column pressure: 100 bar, column temperature: 38 °C, wavelength: 220 nm). + ), compound 15 (retention time: 1.46 min, m / z (ESI): 432.1 [M+1] + ) was manufactured.

[0157] Chiral HPLC purification method (preparative column: ChiralPak AD, 150 × 4.6 mm ID, 3 μm; mobile phase: CO2 in A phase / isopropanol in B phase (0.05% DEA), gradient: B 40%, flow rate: 2.5 ml / min, column pressure: 100 bar, column temperature: 35 °C, wavelength: 220 nm).

[0158] Example 14 An embodiment of the present invention provides a polycyclic carbamoylpyridone derivative, the structural formula of which is: [ka] in, N-(2,4-difluorophenyl)-6'-hydroxy-5',7'-dioxo-5',7',11',11a'-tetrahydro-2'H-spiro[cyclopropane-1,3'-oxazolo[3,2-a]pyrido[1,2-d]pyrazine]-8'-carboxamide (compound 16), (S)-N-(2,4-difluorophenyl)-6'-hydroxy-5',7'-dioxo'-5',7',11',11a'-tetrahydro-2'H-spiro[cyclopropane-1,3'-oxazolo[3,2-a]pyrido[1,2-d]pyrazine]-8'-carboxamide (compound 17), This compound was named (R)-N-(2,4-difluorophenyl)-6'-hydroxy-5',7'-dioxo'-5',7',11',11a'-tetrahydro-2'H-spiro[cyclopropane-1,3'-oxazolo[3,2-a]pyrido[1,2-d]pyrazine]-8'-carboxamide (compound 18).

[0159] An embodiment of the present invention provides a method for preparing the polycyclic carbamoylpyridone derivatives, comprising the steps of: Synthesis of compounds 16, 17 and 18: [ka]

[0160] Step 1: Compound 1b (618 mg, 1.5 mmol) was added to 5 mL of acetonitrile solution. Separately, DIEA (387 mg, 3 mmol) was added to a solution of compound 16a hydrochloride (371 mg, 3 mmol) in acetonitrile (1 mL) and mixed homogeneously. This mixture was then added to the acetonitrile solution of compound 1b. Finally, acetic acid (540 mg, 9 mmol) was added, and the mixture was stirred at 70-80 °C for 20-24 h. After completion of the reaction, the mixture was washed with aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 16c, which was used directly in the next reaction step. MS m / z (ESI): 432.2 [M+1] + .

[0161] Step 2: Intermediate 16c was placed in anhydrous THF, LiBr (4.0 equiv.) was added, and the mixture was stirred at 70-80°C for 6-8 h. After the reaction was complete, 0.5 M sulfuric acid solution was added to quench the reaction, and the mixture was stirred for 2-4 h to precipitate a solid. The solid was filtered, washed with THF / water (1:1), and dried to give compound 10 (off-white solid, 230 mg, 36.7% yield for 2 steps). MS m / z (ESI): 418.2 [M+1] + .

[0162] 1 H NMR (400 MHz, CDCl3) δ 11.70 (br s, 1H), 10.25 (s, 1H), 8.27 (s, 1H), 7.31-7.25 (m, 1H), 6.77-6.71 (m, 2H), 5.32 (dd, J = 10.1, 3.6 Hz, 1H), 4.56 (d, J = 5.8 Hz, 2H), 4.41 (dd, J = 12.2, 3.5 Hz, 1H), 4.13 (d, J = 8.6 Hz, 1H), 4.06-3.95 (m, 2H), 2.19-2.11 (m,1H), 2.02-1.94 (m, 1H), 0.83-0.73 (m, 2H).

[0163] Preparation of chiral compounds 17 and 18: Suspension 16 (100 mg) was separated by SFC (preparative column: ChiralPak AD, 250 × 30 mm ID, 10 μm; mobile phase: CO2 in A phase / isopropanol in B phase (0.1% aqueous ammonia), gradient: B 40%, flow rate: 80 ml / min, column pressure: 100 bar, column temperature: 38 °C, wavelength: 220 nm).

[0164] Compound 17 (51 mg, retention time 2.79 min, MS m / z (ESI): 418.1 [M+1] + ), compound 18 (39 mg, retention time 5.84 min, MS m / z (ESI): 418.1 [M+1] + ) was manufactured. Chiral HPLC purification method (preparative column: ChiralPak AD, 150 × 4.6 mm ID, 3 μm; mobile phase: CO₂ in phase A / isopropanol (0.05% DEA) in phase B, gradient: B 40%, flow rate: 2.5 ml / min, column pressure: 100 bar, column temperature: 35 °C, wavelength: 220 nm).

[0165] Example 15: Evaluation of Compounds The properties of the compound of the present invention were verified by a compound activity test, an integrase inhibitory activity test, an oil-water partition coefficient of the compound, a compound PK test (mice), and a compound PK test (cynomolgus monkeys).

[0166] The structures of the control drugs used in the above tests are as follows: [ka]

[0167] 1. Activity test 1. Experimental Materials -Virus: The HIV-1 pseudotyped virus used in this experiment was a replication-defective virus constructed by Yasunori Yakami. - The cell line HEK 293T cells were purchased from ATCC, catalog number CRL-11268. The cells were cultured in DMEM medium supplemented with 10% fetal bovine serum and 1% double antibiotics.

[0168] -reagent [Table 1]

[0169] -Main equipment [Table 2]

[0170] 2. Experimental Method [Table 3]

[0171] (1) Inoculating cells into plates: On the first day, HEK 293T cells were seeded into a 96-well test plate at a density of 55,000 cells / well, 100 μL per well, and cultured overnight in a 5% CO 2 , 37°C incubator.

[0172] (2) Compound treatment and virus infection: On the second day, the test compounds (compounds provided by the examples of the present invention) and control compounds were diluted 4-fold with cell culture medium to a total of eight concentrations, with 50 μL of diluted compound added to each well in duplicate. Then, HIV-1 pseudotyped virus was diluted to 100 TCID50 / 50 μL with cell culture medium, and 50 μL of diluted virus was added to each well.

[0173] A cell control (cells without compound treatment or virus infection) and a virus control (cells infected with virus but without compound treatment) were set up. The final initial test concentration of the test compound and control compound was 1000 nM (Table 1), and the virus infection dose was 100 TCID50 / well. The total volume of cell culture medium was 200 μL / well, and the final concentration of DMSO in the culture medium was 0.5%. The cells were then cultured in a 5% CO 2 , 37°C incubator for three days.

[0174] (3) Detection of luciferase activity: On the fifth day, 100 μL of cell supernatant was aspirated from each well of the antiviral activity detection plate and, protected from light, 100 μL of 2x luciferase reporter gene detection reagent Britelite plus was added. The luciferase activity of each well in the test plate was detected using Envision. The data were used to analyze the antiviral activity of the samples.

[0175] (4) Cytotoxicity detection: On the fifth day, 100 μL of cell supernatant was aspirated from each well of the cytotoxicity detection plate, and 100 μL of the cell vitality detection reagent CellTiter Glo was added in the dark. The cell vitality of each well was detected using a BioTek microplate reader, and the data were used to analyze the cytotoxicity of the samples.

[0176] (5) Data processing: The dose-effect curves were plotted using GraphPad Prism software. The formulas for calculating antiviral activity (% Inhibition) and cell viability were as follows: Antiviral activity (%) = (test well reading - mean value of virus control) / (mean value of cell control - mean value of virus control) x 100 Cell vitality (%) = (test well reading - mean value of medium control) / (mean value of cell control - mean value of medium control) x 100

[0177] EC 50 and CC 50 The values ​​were calculated using GraphPad Prism (version 5) software, and nonlinear fitting analysis was performed on the inhibitory activity of the compound and the cell viability, with the fitting method being "log(inhibitor) vs. response -- Variable slope".

[0178] 3. Using HIV-1 pseudotype virus experiments, the effects of the test compounds on in vitro antiviral activity and cytotoxicity in HEK 293T cells were measured, and the experimental results are shown in the table below. [Table 4]

[0179] The results showed that the control compounds RAL, DTG, and the test compounds all had antiviral activity against HIV-1 pseudotyped viruses, and the compounds did not show any obvious cytotoxicity in HEK 293T cells. 50 values ​​were shown to be greater than the highest tested concentration.

[0180] 2. Integrase activity test In this experiment, we quantitatively measured integrase activity using a non-radioactive integrase assay kit. HIV-1 integrase cleaves two bases from the 3' end of donor double-stranded DNA (DS DNA), incorporates the cleaved DS DNA into double-stranded target substrate DNA (TS DNA) containing a 3'-end modification, and specifically modifies the 3' end with an HRP-labeled antibody. The absorbance was measured at 450 nm, and integrase activity was quantified.

[0181] 1. Reagents and Materials: HIV-1 Integrase Assay Kit # EZ-1700 14.5 M β-mercaptoethanol (BME), metal bath, constant temperature oven, 96-well culture plate (NEST) benchtop microplate reader (SpectraMaxR iD5), DMSO; Test compounds: Compound 1, dolutegravir (DTG), bictegravir (BIC)

[0182] 2. Test Procedure (1) Preparation of reagents: Each component was prepared according to the kit instructions. For test sample preparation, a 5 mM DMSO solution of the test sample was prepared for use. The initial final concentration determined during method establishment was used to prepare a working solution, which was then diluted 4-fold to a concentration of 10. (2) Establishment of methodology: The methodology was established using the EZ-1700 kit. <1> Azide performed data reproducibility experiments to determine antibody incubation times. <2> The detection concentrations of Compound 1, DTG, and BIC were explored.

[0183] (3) Test product test <1> Working solutions of the test articles were prepared at initial concentrations determined during the methodology development process. <2> Reagent preparation was carried out according to the method provided in the kit. <3> Coating of DS DNA – blocking – addition of integrase solution – addition of test article – addition of TS DNA – addition of HRP antibody – addition of TMB peroxidase substrate – reaction stopped with TMB – detection of light absorbance at 450 nm. Calculate the IC using the formula Log(inhibitor) vs. response - variable slope using Graphpad Prism 8.0 software. 50 Curve fitting was performed.

[0184] The IC of the compounds of the present invention measured in the above test 50 The values ​​are shown in the table below. [Table 5] Conclusion: The compounds of the present invention can inhibit HIV integrase activity, and have better inhibitory effects on integrase activity than dolutegravir (DTG) and bictegravir (BIC).

[0185] 3. Oil-water partition coefficient of the compound Oil-water partition coefficient of the compound a) 1 mL of n-octanol and 1 mL of pH 7.4 phosphate buffer were placed in each 5 mL glass bottle. b) Compounds were dissolved in DMSO to prepare stock solutions of compounds at a concentration of 10 mM, and 20 μL of the stock solutions of compounds were then added to a mixture of n-octanol and phosphate buffer.

[0186] c) The mixture was uniformly shaken at room temperature at a shaking speed of 300 / min for 1 hour. d) After leaving the solution to stand for 30 minutes, the solution was completely separated into layers. The upper and lower layers were then absorbed into a 96-well deep well plate and loaded into an LC-MS / MS for detection. e) Aliquots of the 1-octanol and aqueous phase solutions were serially diluted with DMSO to obtain the final samples used for LC-MS / MS analysis. Three serial dilutions were performed for each 1-octanol phase, covering a 2500-fold concentration range. Two serial dilutions were performed for each final aqueous phase, covering a 100-fold concentration range. The MS peak areas of these solutions were used to generate a log(peak area) by log(relative concentration) calibration curve.

[0187] LogD(pH7.4)=LOG(Coct / Caq) Coct = sample concentration in n-octanol Caq = sample concentration in pH 7.4 phosphate buffer [Table 6]

[0188] Conclusion: At pH 7.4, the log D values ​​of DTG, compound 6, compound 1, and compound 2 were 1.6, 2.0, 2.2, and 2.5, respectively, suggesting that all of these compounds have good small intestinal absorption. Furthermore, during the small intestinal absorption process, the higher the log D value, the better the lipid solubility and cell permeability. Therefore, the order of cell permeability of the above compounds is compound 2 > compound 1 > compound 6 > DTG.

[0189] 4. Compound PK testing (mice) 1. Summary ICR mice were used as test animals, and the plasma drug concentrations were measured at different time points after the mice were administered compounds (Compound 1, Compound 2, Compound 6, Compound 10) and a positive control (DTG) by intragastric administration (PO) and intravenous injection (IV) using LC-MSMS. The pharmacokinetic behavior of these compounds in mice was studied, and their pharmacokinetic characteristics were evaluated.

[0190] 2. Test drug Compound 1, Compound 2, Compound 6, Compound 10 and the positive control dolutegravir (DTG). 3. Test Animals The mice were SPF ICR males, 10 weeks old, weighing approximately 32 g, with 6 mice in each group, for a total of 48 mice.

[0191] 4. Test Formulation Intragastric administration group (PO): 5% DMSO / 10% Solutol / 85% (20% Captisol aqueous solution); Intravenous group (IV): 5% DMSO / 10% Solutol / 85% (20% Captisol aqueous solution).

[0192] 5. Administration Mice were deprived of food at 5:00 PM on the day before administration, fasted overnight, and given water. Mice were administered IV at 2 mg / kg and PO at 10 mg / kg. Food intake was resumed 2 hours after administration.

[0193] 6. Sampling For intragastric administration in mice, 20 μL of blood was collected from the saphenous vein of the femur before administration and 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The blood samples were placed in EDTA-K2 anticoagulated blood collection tubes and kept on ice until centrifuged to obtain plasma samples. The plasma samples were centrifuged at 4°C (3500 rpm, 10 min). After separation, the samples were transferred to EP tubes and stored at -80°C until detection.

[0194] For intravenous administration in mice, 20 μL of blood was collected from the saphenous vein of the tibia at 0.0833, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The blood samples were placed in EDTA-K2 anticoagulated blood collection tubes and kept on ice until centrifuged to obtain plasma samples. The plasma samples were centrifuged at 4°C (3500 rpm, 10 min). After separation, the samples were transferred to EP tubes and stored at -80°C until detection.

[0195] 7. Detection After intragastric administration of various concentrations of drug, the content of the test compound in mouse plasma was measured. At each post-administration time point, 10 μL of mouse plasma was taken, and 100 μL of methanol containing the internal standard (100 ng / mL) was added. The mixture was vortexed for 1 minute and centrifuged at 4°C (12,000 rpm, 5 minutes). 1 μL of the supernatant was then analyzed by LC-MS / MS.

[0196] 8. Pharmacokinetic parameters [Table 7]

[0197] 9. Summary The mouse PK test results showed that compounds 1, 2, 6, and 10 had good bioavailability, and the bioavailability and half-life data of compound 1 were both better than those of the positive control, DTG.

[0198] 5. Compound PK study (cynomolgus monkeys) 1. Summary Cynomolgus monkeys were used as test animals, and the plasma drug concentrations at different time points after cynomolgus monkeys were administered Compound 1 by intragastric administration (PO) were measured by LC-MS / MS. The pharmacokinetic behavior of the disclosed compound in cynomolgus monkeys was studied, and its pharmacokinetic characteristics were evaluated.

[0199] 2. Test drug Compound 1. 3. Test Animals Cynomolgus monkeys (Macaca fascicularis), normal size, male, approximately 2.5-4 years old, weighing in the range of 2-5 kg, 3 per group.

[0200] 4. Test Formulation Compound 1 and a solid substrate (hydroxypropyl methylcellulose acetate succinate) were dissolved in an organic solvent, and the solvent was removed by evaporation using heat, or the solution was removed using a spray dryer, to obtain Compound 1 attached to the solid substrate.

[0201] The solid substrate-attached Compound 1 obtained in the above process was slowly added to a suitable container containing approximately 80% of the final volume of solvent while stirring. Stirring was continued until visually uniform, and the formulation was sonicated as needed. Solvent was added to the required concentration. The resulting formulation continued to be stirred and sonicated as needed until a visually uniform formulation was obtained. The dosage concentration of the API concentration was adjusted to 20 mg / mL. The solvent was prepared by adding approximately 30% of the total volume of purified water to a suitable container and heating to approximately 80°C-90°C. The required volume of Tween 80 was then slowly added to the container while simultaneously stirring until a uniform solution was obtained. Purified water was added to the final volume and the mixture was stirred until a visually uniform solution was obtained.

[0202] 5. Administration Cynomolgus monkeys were fasted overnight and allowed free access to water. The PO group received 100 mg / kg of benzodiazepine. Food intake was resumed 2 hours after administration.

[0203] 6. Sampling For intragastric administration in cynomolgus monkeys, 20 μL of blood was collected from a hind leg vein at pre-dose and 0.25, 0.5, 1, 0.25, 0.5, 1, 2, 4, 8, 24, 48, 72, and 96 hours post-dose. The blood samples were placed in EDTA-K2 anticoagulated blood collection tubes and kept on ice until centrifuged to obtain plasma samples. The plasma samples were centrifuged at 4°C (3500 rpm, 10 min). After separation, the samples were transferred to EP tubes and stored at -80°C until detection.

[0204] 7. Detection The content of the test compound in cynomolgus monkey plasma after intragastric administration of various concentrations of the drug was measured. At each post-administration time point, 10 μL of cynomolgus monkey plasma was taken, and 100 μL of methanol (100 ng / mL) containing the internal standard was added. The mixture was vortexed for 1 minute and centrifuged at 4°C (12,000 rpm, 5 minutes). 1 μL of the supernatant was then analyzed by LC-MS / MS.

[0205] 8. Pharmacokinetic parameters [Table 8]

[0206] 9. Summary The results of this test showed that oral administration of Compound 1 (30, 100 mg / kg) to cynomolgus monkeys 1 / 2 The half-lives of the preferred compound 1 of the present invention were 15.7±5.49 h and 19.8±4.78 h, respectively. The long half-life of the compound 1 reduces the frequency of administration to AIDS patients, overcomes the inconvenience of multiple administrations, and better meets the medical administration requirements.

[0207] The above description is only a preferred embodiment of the present invention, and does not limit the present invention. Those skilled in the art can make various modifications and changes to the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention are included in the protection scope of the present invention.

Claims

1. A polycyclic carbamoylpyridone derivative including a compound represented by formula (I)-1 or (I)-2, an isomer thereof, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, 【Chemistry 1】 Here, R １ , R ２ , R ３ , R ４ , R ５ and R ６ each independently represents hydrogen, halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, -OR ７ a substituted or unsubstituted aryl group, a substituted or unsubstituted monocyclic heteroaryl ring, a substituted or unsubstituted monocyclic heterocycle, and a cyano group; And the following (1)-(3): (1) R １ and R ２ , (2) R ３ and R ４ , (3) R ５ and R ６ At least one pair of functional groups among the above forms a spiro ring or spiro hetero ring together with the carbon atom connected to the A ring, R ７ is selected from any one of hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, and a substituted or unsubstituted alkynyl group; m is any natural number between 0 and 5 The polycyclic carbamoylpyridone derivative,

2. R １ , R ２ , R ３ , R ４ , R ５ and R ６ are each independently hydrogen, halogen, a C1-4 alkyl group, a C1-C4 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, -OR ７ , a C3-C8 cycloalkyl group, a C6-C10 aryl group, a 5-6 membered monocyclic heteroaryl ring, a 4-6 membered saturated monocyclic heterocycle, and a cyano group; And the following (1)-(3): (1) R １ and R ２ , (2) R ３ and R ４ , (3) R ５ and R ６ At least one pair of functional groups among the above forms a 3- to 8-membered spiro ring or a 3- to 8-membered spiro hetero ring together with the carbon atom linked to the A ring, R ７ is selected from any one of hydrogen, a C1-4 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, and a C1-C4 haloalkyl group; m is 0, 1, 2 or 3 The polycyclic carbamoylpyridone derivative according to claim 1,

3. In the compounds represented by formula (I)-1 and formula (I)-2, the tertiary carbon atom linked to ring A and the fused pyrazine has chirality, The compounds represented by formula (I)-1 and formula (I)-2 include compounds of a single configuration or a mixture of isomers, The isomers include at least one of tautomers, cis-trans isomers, racemates, and optical isomers having a mirror image or non-mirror image relationship. The polycyclic carbamoylpyridone derivative according to claim 1 or 2, characterized in that:

4. The polycyclic carbamoylpyridone derivative has the following structural formula: 【Chemistry 2】 2. The polycyclic carbamoylpyridone derivative according to claim 1, wherein the polycyclic carbamoylpyridone derivative is selected from any one of the compounds represented by the following formula:

5. The polycyclic carbamoylpyridone derivative has the following structural formula: 【Transformation 3】 The polycyclic carbamoylpyridone derivative according to claim 1, which is a compound represented by the formula:

6. A method for producing the polycyclic carbamoylpyridone derivative according to any one of claims 1 to 5, comprising the steps of: 【Chemistry 4】 The method is characterized in that the polycyclic carbamoylpyridone derivative is synthesized by referring to the formula:

7. The conditions for preparing intermediate IV-1 include: the molar ratio of compound II to compound III-1 is 1:1-1:5; the temperature is 30-100°C; and the time is 5 minutes-16 hours; The conditions for preparing intermediate IV-2 include: the molar ratio of compound II to compound III-2 is 1:1-1:5; the temperature is 30-100°C; and the time is 5 minutes-16 hours; The conditions for preparing the compound represented by general formula (I)-1 include a temperature of 30-100°C and a time of 5 minutes to 16 hours; The conditions for preparing the compound represented by general formula (I)-2 include a temperature of 30-100°C and a time of 5 minutes to 16 hours. The manufacturing method according to claim 6 .

8. A pharmaceutical composition comprising the polycyclic carbamoylpyridone derivative according to any one of claims 1 to 5, its isomer, pharmaceutically acceptable salt, hydrate or solvate, and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition according to claim 8, wherein the pharmaceutically acceptable carrier is selected from the group consisting of water for injection, lyophilized powder adjuvant, and oral administration formulation adjuvant.

10. Use of the polycyclic carbamoylpyridone derivative according to any one of claims 1 to 5 or the pharmaceutical composition according to claim 8 or 9 in the manufacture of a drug for preventing and / or treating a disease mediated by AIDS virus infection.

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