Pyrrolo [3, 2-d] pyrimidine-4-ketone derivative as well as preparation method and medical application thereof

Abstract

Compounds of formula (I), processes for their preparation and their use in medicine. Specifically, provided are compounds of formula (I) or stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, and also relate to pharmaceutical compositions containing these compounds and uses of the compounds in drugs for treatment and / or prevention of cardiovascular diseases. These compounds are inhibitors of myeloperoxidase (MPO). # imgabs0 #

Description

A pyrrolo[3,2-d]pyrimidin-4-one derivative, its preparation method and medical use Technical Field

[0001] The present invention belongs to the technical field of chemical medicines and provides a series of myeloperoxidase (MPO) inhibitors. The present invention also relates to pharmaceutical compositions containing these compounds and the use of the compounds in drugs for treating cardiovascular diseases. Background Art

[0002] Myeloperoxidase (MPO) is a highly sensitive and specific marker of vascular inflammatory mediators and has become an important indicator for predicting the risk of cardiovascular and cerebrovascular events. MPO catalyzes the oxidation of chloride ions to produce hypochlorous acid, which kills microorganisms within phagocytes, destroys various target substances, and plays a multifaceted role in generating and regulating inflammatory responses. More importantly, its oxidative modification of low-density lipoprotein (LDL) can cause atherosclerosis, leading to its involvement in the development of cardiovascular disease.

[0003] Currently, MPO is considered the most promising cardiovascular biomarker. Elevated MPO levels indicate the risk of arteriosclerosis and coronary heart disease, serving as an early warning of myocardial infarction. It is more sensitive than other markers such as troponin T, CK-MB, and CRP, enabling earlier diagnosis and risk assessment. MPO levels can rise significantly within 2 hours of chest pain onset. Therefore, for patients with chest pain, MPO will have greater clinical significance in diagnosing acute coronary syndrome (ACS).

[0004] Therefore, the present invention aims to discover new MPO inhibitors, especially new compounds with good biological properties that can be safely applied to the human body. The present invention also provides the necessary tools for preventing and / or treating related diseases, especially cardiovascular diseases.

[0005] Summary of the Invention

[0006] The present invention provides a series of pyrrolo[3,2-d]pyrimidin-4-one derivatives, preparation methods thereof and medical applications thereof.

[0007] Specifically, the present invention provides compounds of formula (I) or stereoisomers, tautomers, pharmaceutically acceptable salts thereof, wherein all variables are as defined herein.

[0008] These compounds are inhibitors of myeloperoxidase (MPO). The present invention also relates to pharmaceutical compositions containing these compounds and the use of these compounds in medicines for preventing and / or treating cardiovascular-related diseases.

[0009] Specifically, the present invention is achieved through the following technical solutions:

[0010] Compounds of formula (I):

[0011] The R 1 、R 2 、R 3 、R 4 、R 5 independently selected from hydrogen, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, alkoxyalkyl, cycloalkyl, aryl or heteroaryl, wherein aryl and heteroaryl may be optionally substituted by one or more independently selected from halogen, hydroxy, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, and halogenated C 1-6 Alkyl substitution;

[0012] X, Y are independently selected from O, CH2, NR 6 , R 6 independently selected from hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, alkoxyalkyl, cycloalkyl, hydroxy, amino, cyano, cyano-substituted C 1-6 Alkyl, amino substituted C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -(CH2) n -C(=O)-R 7 、-(CH2) n -C(=O)OR 8 、-(CH2) n -NHC(=O)-R 9 ; R 7 、R 8 、R 9 are independently selected from hydrogen, C 1-6 alkyl;

[0013] n is 0, 1, 2 or 3.

[0014] As a preferred embodiment of the present invention, the compound is as shown in formula (II):

[0015] Where: X, Y, R 1 , n are as defined above.

[0016] As a preferred embodiment of the present invention, the alkyl group refers to a branched, unbranched and cyclic saturated hydrocarbon chain containing a specified number of carbon atoms, preferably selected from C1-6 The alkyl group, the C 1-6 The alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl.

[0017] As a preferred embodiment of the present invention, the C 2-6The alkenyl group is selected from the group consisting of vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl. , 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl.

[0018] As a preferred embodiment of the present invention, the alkoxy group refers to an alkyl ether radical, preferably selected from C 1-6 The alkoxy group, the C 1-6The alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentoxy, 1,2-dimethylpropoxy, isopentoxy, neopentoxy, n-hexyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy, neohexyloxy, 2-methylpentoxy, 1,2-dimethylbutoxy, and 1-ethylbutoxy.

[0019] As a preferred embodiment of the present invention, the alkoxyalkyl group refers to an alkyl group in which one or more hydrogen atoms are replaced by an alkoxy group, preferably selected from C 1-4 Alkoxy C 1-4 The alkyl group is further selected from methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl and the like.

[0020] As a preferred embodiment of the present invention, the halogen is selected from fluorine, chlorine, bromine, iodine, halogenated C 1-6 Alkyl refers to C 1-6 More than one hydrogen atom in an alkyl group is replaced by a halogen. 1-6 Alkoxy refers to C 1-6 One or more hydrogen atoms in the alkoxy group are substituted by halogen.

[0021] The cyano-substituted C 1-6 Alkyl refers to C 1-6 More than one hydrogen atom of the alkyl group is replaced by a cyano group or an amino group. 1-6 Alkyl refers to C 1-6 One or more hydrogen atoms in the alkyl group are replaced by an amino group.

[0022] As a preferred embodiment of the present invention, the aryl group is selected from phenyl; the heteroaryl group is selected from 5- to 12-membered heteroaryl groups; the 5- to 12-membered heteroaryl groups are selected from

[0023] As a preferred embodiment of the present invention, the "alkylene group" refers to an alkyl group that can be independently substituted by 0 to 2 substituents when the valence permits, the cyano group refers to the group -CN, the hydroxyl group refers to the group -OH, and the sulfone group refers to the group -SO2.

[0024] As a preferred embodiment of the present invention, the cycloalkane is selected from C 3-6 Cycloalkyl, C 3-6 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0025] As a preferred embodiment of the present invention, the compound or its stereoisomers, tautomers, and pharmaceutically acceptable salts are as shown in formula (I), wherein: R 1 selected from hydrogen or chlorine;

[0026] R 2 、R 3 、R 5 selected from hydrogen;

[0027] R 4 is selected from hydrogen, methyl, methoxy;

[0028] X is O, CH2, N-CH3, NC(=O)-O-CH2-CH3;

[0029] Y is O, CH2, N-CH3;

[0030] n is 0, 1, or 2.

[0031] As a preferred embodiment of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from the following compounds:

[0032] As a preferred embodiment of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from the following compounds:

[0033] As a preferred embodiment of the present invention, the pharmaceutically acceptable salt refers to a salt prepared by reacting a compound with a pharmaceutically acceptable acid or base.

[0034] As a preferred embodiment of the present invention, one or more hydrogen atoms in the compound are substituted by an isotope, preferably by deuterium.

[0035] Another object of the present invention is to provide a pharmaceutical composition comprising the aforementioned compound of formula (I), or its stereoisomers, tautomers, pharmaceutically acceptable salts and one or more pharmaceutically acceptable carriers.

[0036] Another object of the present invention is to provide the medical use of the compound of formula (I), or its stereoisomers, tautomers, and pharmaceutically acceptable salts, specifically, its use in the preparation of drugs for treating and / or preventing MPO enzyme-related diseases, particularly, its use in drugs for cardiovascular-related diseases.

[0037] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered as undefined or unclear in the absence of a specific definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0038] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is prepared by reacting a compound having a specific substituent discovered in the present invention with a pharmaceutically acceptable acid or base.

[0039] In addition to the form of salts, the compounds provided by the present invention also exist in prodrug form. The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to be converted into the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.

[0040] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrates. In general, the solvated forms are equivalent to the unsolvated forms and are encompassed within the scope of the present invention.

[0041] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0042] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, separation of enantiomers and diastereomers is typically accomplished by using chromatography using a chiral stationary phase, optionally combined with chemical derivatization (e.g., formation of carbamates from amines).

[0043] The atoms of the molecules of the compounds of the present invention are isotopes, and isotope derivatization can generally extend half-life, reduce clearance, stabilize metabolism, and increase in vivo activity. In addition, an embodiment is included in which at least one atom is replaced by an atom having the same atomic number (number of protons) and a different mass number (protons and neutrons). Examples of isotopes included in the compounds of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, chlorine atoms, which respectively include 2 H. 3 H. 13 C. 14 C. 15 N. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 In particular, radioactive isotopes that emit radiation as they decay, such as 3 H or 14 C can be used for local anatomy testing of pharmaceutical preparations or compounds in vivo. Stable isotopes neither decay nor change with their amount nor are they radioactive, so they can be used safely. When the atoms constituting the molecules of the compounds of the present invention are isotopes, the isotopes can be converted according to general methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

[0044] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), iodine-125( 125 I) or C-14( 14C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0045] Furthermore, the compounds of the present invention may have one or more hydrogen atoms replaced by deuterium isotopes ( 2 After deuteration, the compounds of the present invention have the effects of extending half-life, reducing clearance rate, stabilizing metabolism and improving in vivo activity.

[0046] The preparation method of the isotopic derivative generally includes a phase transfer catalytic method. For example, a preferred deuteration method uses a phase transfer catalyst (e.g., tetrabutylammonium bromide, TBAB). The use of a phase transfer catalyst to exchange the methylene protons of the diphenylmethane compound results in a higher deuterium incorporation than reduction with a deuterated silane (e.g., triethyldeuterated monosilane) in the presence of an acid (e.g., methanesulfonic acid) or with a Lewis acid such as aluminum trichloride using sodium deuterated borate.

[0047] The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, etc. Their preparations are well known to those skilled in the art of cosmetics or topical medicine. For additional information about carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0048] The term "excipient" generally refers to a carrier, diluent and / or vehicle required to formulate an effective pharmaceutical composition.

[0049] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of an active substance in the composition means the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0050] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0051] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0052] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] FIG1 is a schematic diagram of the single crystal structure of 6A hydrochloride in Example 6. DETAILED DESCRIPTION

[0054] The present invention will be further described in detail below with reference to examples, but the embodiments of the present invention are not limited thereto.

[0055] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-III NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6) and deuterated chloroform (CDCl3) as solvents and tetramethylsilane (TMS) as the internal standard.

[0056] MS was measured using an ISQ EC mass spectrometer (manufacturer: Thermo, model: ISQ EC).

[0057] High performance liquid chromatography (HPLC) analysis was performed using a Thermo U3000 HPLC DAD and an Agilent 1260 HPLC.

[0058] The CombiFlash rapid preparation instrument used CombiFlash Rf+LUMEN (TELEDYNE ISCO).

[0059] Thin layer chromatography silica gel plate using Yantai Yinlong HSGF 254 or GF 254 Silica gel plates, the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.17mm~0.23mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm~0.5mm.

[0060] Silica gel column chromatography generally uses Rushan Shangbang silica gel 100-200 mesh silica gel as the carrier.

[0061] Reagents: NaBH3-sodium borohydride, EtOH-ethanol, NaOAc-sodium acetate, toluene-toluene, rt-room temperature, NaCO3-sodium carbonate, MeOH-methanol, AcOH-acetic acid, AcONa-sodium acetate, H2SO4-sulfuric acid, NaOH-sodium hydroxide, CS2CO3-cesium carbonate, TEMPO-2,2,6,6,-tetramethylpiperidinium oxide, TMSN3-azidotrimethylsilane, ACN-acetonitrile, NaBH3CN-cyano Sodium borohydride, p-TsOH-p-toluenesulfonic acid, NaH-sodium hydride, THF-tetrahydrofuran, CH3I-iodomethane, Acetone-acetone, CCL4-carbon tetrachloride, NBS-N-bromosuccinimide, AIBN-azobisisobutyronitrile, DIEA-N,N-diisopropylethylamine, DMF-N,N-dimethylformamide, Pd(PPh3)2Cl2-bistriphenylphosphine palladium dichloride, LiCL-lithium chloride, n-BuLi-n-butyllithium, NH2OH HCl-hydroxylamine hydrochloride, AgNO3-silver nitrate.

[0062] abs refers to absolute configuration.

[0063] Example 1 1-((3-amino-7-chloro-2,3-dihydro-1H-inden-4-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, Compounds 1A and 1B

[0064] Synthesis route:

[0065] Step A: Synthesis of ethyl 3-(5-bromo-2-chlorophenyl)acrylate

[0066] Ethyl 2-(diethoxyphosphate)acetate (11.2 g, 50.2 mmol) was dissolved in THF (100 ml) and placed in an ice-water bath. NaH (2.0 g, 50.2 mmol) was added and the mixture was reacted for 30 minutes. Then, 5-bromo-2-chlorobenzaldehyde (10 g, 45.6 mmol) was added and the mixture was reacted at room temperature for 12 hours.

[0067] After the reaction was complete, the mixture was quenched by adding 30 mL of water and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. Without further purification, 13 g of ethyl 3-(5-bromo-2-chlorophenyl)acrylate was obtained as a white solid (yield: 98.5%). 1H NMR (400MHz, DMSO) δ8.20(d,J=2.4Hz,1H),7.81(d,J=16.0Hz,1H),7.64(dd,J=8.4,2.4Hz,1H ), 7.51 (d, J = 8.4Hz, 1H), 6.85 (d, J = 16.0Hz, 1H), 4.22 (q, J = 7.0Hz, 2H), 1.26 (q, J = 6.8Hz, 4H).

[0068] Step B: Synthesis of 2-bromo-4-chlorophenylethyl-2-methylpropane-2-sulfenamide

[0069] Ethyl 3-(5-bromo-2-chlorophenyl)acrylate (11.7 g, 40.6 mmol) was dissolved in methanol (100 ml), cobalt chloride (968 mg, 4.07 mmol) was added, and sodium borohydride (2.3 g, 61.0 mmol) was added under ice-water bath, and the mixture was reacted at 0°C for 30 minutes.

[0070] After the reaction was complete, the methanol in the solution was evaporated, and 30 mL of water was added to the mixture. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Without further purification, 11 g of 2-bromo-4-chlorophenylethyl-2-methylpropane-2-sulfenamide (yield: 92.9%) was obtained as a green solid. 1 H NMR (400MHz, DMSO) δ7.58 (d, J=2.4Hz, 1H), 7.45 (dd, J=8.5, 2.4Hz, 1H), 7.39 (d, J=8.5Hz ,1H),4.15–3.95(m,2H),2.94(t,J=7.6Hz,2H),2.63(t,J=7.6Hz,2H),1.21–1.10(m,4H).

[0071] Step C: Synthesis of 3-(5-bromo-2-chlorophenyl)propionic acid

[0072] 2-Bromo-4-chlorophenylethyl-2-methylpropane-2-sulfenamide (11 g, 37.8 mmol) was dissolved in a 1:1 mixture of tetrahydrofuran and water (30 ml) and added to sodium hydroxide (3.0 g, 75.6 mmol) dissolved in water and reacted at room temperature for 16 hours.

[0073] After the reaction, HCl was added to adjust the pH to 3. The tetrahydrofuran was dried by rotary evaporation and extracted with ethyl acetate (20 ml x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporation to obtain 9 g of 3-(5-bromo-2-chlorophenyl)propanoic acid as a white solid (yield: 90.5%). 1H NMR (400MHz, DMSO) δ12.25 (s, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.43 (dt, J = 22.4, 5.4 Hz, 2H), 2.91 (t, J = 7.6 Hz, 2H), 2.54 (dd, J = 14.0, 6.4 Hz, 2H).

[0074] Step D: Synthesis of 7-bromo-4-chloro-2,3-dihydro-1H-inden-1-one

[0075] 3-(5-Bromo-2-chlorophenyl)propionic acid (3.5 g, 13.3 mmol) was dissolved in dichloromethane (10 ml), and chlorosulfonic acid (6 ml) was added to the reaction solution and reacted at room temperature for 2 hours.

[0076] After the reaction was complete, the reaction was quenched with ice water, the pH was adjusted to 10 with 1 M sodium hydroxide solution, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 1.2 g of 7-bromo-4-chloro-2,3-dihydro-1H-inden-1-one (yield: 36.8%). 1 H NMR (400MHz, DMSO) δ7.76–7.53(m,2H), 3.12–2.93(m,2H), 2.76–2.65(m,2H).

[0077] Step E: Synthesis of 7-bromo-4-chloro-2,3-dihydro-1H-inden-1-amine

[0078] 7-Bromo-4-chloro-2,3-dihydro-1H-inden-1-one (500 mg, 2.03 mmol) was dissolved in anhydrous ethanol (6 ml), and ammonium acetate (2.35 g, 30.5 mmol) and sodium cyanoborohydride (153 mg, 2.44 mmol) were added and reacted at 130°C in a microwave for 2 hours.

[0079] After the reaction, the ethanol in the solution was dried by rotary evaporation, the pH was adjusted to 10 with 1 M sodium hydroxide solution, and the mixture was extracted with ethyl acetate (10 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by reverse phase column chromatography (0.1% TFA system) to obtain 1.1 g of 7-bromo-4-chloro-2,3-dihydro-1H-inden-1-amine (yield 79.0%). 1H NMR (400 MHz, DMSO) δ 8.28 (s, 3H), 7.57 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 4.81 (d, J = 6.4 Hz, 1H), 3.25 (dt, J = 17.0, 8.4 Hz, 1H), 3.00 (dd, J = 16.8, 9.2, 1.6 Hz, 1H), 2.50–2.42 (m, 1H), 2.16 (dd, J = 14.4, 7.8 Hz, 1H). Step F: Synthesis of tert-butyl (7-bromo-4-chloro-2,3-dihydro-1H-inden-1-yl)carbamate

[0080] 7-Bromo-4-chloro-2,3-dihydro-1H-inden-1-amine (1.1 g, 4.5 mmol), di-tert-butyl dicarbonate (1.07 g, 4.9 mmol) and triethylamine (1.35 g, 13.4 mmol) were dissolved in dichloromethane (10 ml) and reacted at room temperature for 2 hours.

[0081] The reaction mixture was added to 25 mL of water and extracted with dichloromethane (20 mL x 2). The combined organic phases were washed with aqueous NaHCO₃, dried over anhydrous sodium sulfate, filtered, and spin-dried. Without further purification, 1.5 g of tert-butyl (7-bromo-4-chloro-2,3-dihydro-1H-inden-1-yl)carbamate was obtained (yield: 97%). 1 H NMR (400MHz, CDCl3) δ7.31(d,J=8.4Hz,1H),7.12(d,J=8.4Hz,1H),5.27(d,J=22.0Hz,1H),4.68(s,1 H), 2.94 (dd, J=17.0, 9.0, 4.0Hz, 1H), 2.48 (td, J=16.8, 8.0Hz, 1H), 2.12–2.04 (m, 1H), 1.46 (s, 9H).

[0082] Step G: Synthesis of tert-butyl (7-bromo-4-chloro-2,3-dihydro-1H-inden-1-yl) (tert-butyloxycarbonyl) carbamate

[0083] tert-Butyl (7-bromo-4-chloro-2,3-dihydro-1H-inden-1-yl) carbamate (1.5 g, 4.32 mmol), di-tert-butyl dicarbonate (1.89 g, 8.65 mmol) and 4-dimethylaminopyridine (1.05 g, 8.65 mmol) were dissolved in dimethyltetrahydrofuran (15 ml) and reacted at 55° C. for 4 hours.

[0084] After the reaction, the mixture was cooled to room temperature and then dried by rotary evaporation. 20 mL of water was added and the mixture was extracted with ethyl acetate (25 mL x 2). The combined organic phases were washed with aqueous NaHCO₃, dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The resulting residue was purified using a reverse-phase column (0.1% aqueous ammonia system) to obtain 1.4 g of tert-butyl (7-bromo-4-chloro-2,3-dihydro-1H-inden-1-yl) (tert-butoxycarbonyl) carbamate (yield: 72.5%). 1 H NMR (400MHz, CDCl3) δ7.25 (s, 1H), 7.08 (t, J = 8.8Hz, 1H), 5.96 (dd, J = 9.8, 6.4Hz, 1H), 3.18 (ddd, J = 3 2.4,18.4,13.2Hz,1H),2.95–2.82(m,1H),2.63–2.50(m,1H),2.25–2.16(m,1H),1.46–1.27(m,18H).

[0085] Step H: Synthesis of tert-butyl(tert-butyloxycarbonyl)(4-chloro-7-vinyl-2,3-dihydro-1H-inden-1-yl)carbamate

[0086] Tert-butyl (7-bromo-4-chloro-2,3-dihydro-1H-inden-1-yl) (tert-butoxycarbonyl) carbamate (1.4 g, 3.13 mmol), potassium ethylene trifluoroborate (0.54 g, 4.07 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (0.42 g, 0.62 mmol) and potassium carbonate (1.29 g, 9.39 mmol) were dissolved in dimethyl sulfoxide (14 ml), protected by nitrogen, and reacted at 100°C for 12 hours.

[0087] After the reaction was complete, the mixture was cooled to room temperature and filtered through Celite. The filtrate was collected and then added with 50 mL of water. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and spin-dried. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain 1.2 g of tert-butyl (tert-butoxycarbonyl)(4-chloro-7-vinyl-2,3-dihydro-1H-inden-1-yl)carbamate (yield: 97%). 1H NMR (400MHz, DMSO) δ7.53–7.32(m,1H),7.36–7.20(m,1H),6.68(dd,J=17.6,11.2Hz,1H),5.93(dt,J=31.2,15.6Hz,1H),5.77(dt,J= 17.6,5.2Hz,1H),5.38–5.09(m,1H),3.11–2.96(m,1H),2.91–2.75(m,1H),2.59–2.51(m,1H),2.14–2.01(m,1H),1.34–1.20(m,18H).

[0088] Step I: Synthesis of tert-butyl(tert-butyloxycarbonyl)(4-chloro-7-formyl-2,3-dihydro-1H-inden-1-yl)carbamate

[0089] Tert-butyl (tert-butoxycarbonyl) (4-chloro-7-vinyl-2,3-dihydro-1H-inden-1-yl) carbamate (1.2 g, 3.04 mmol) was dissolved in a mixture of tetrahydrofuran (24 ml) and water (6 ml), and potassium osmate (112 mg, 0.30 mmol) was added to the reaction solution. After stirring at room temperature for 30 minutes, sodium periodate (2.61 g, 12.2 mmol) was added to the reaction solution and reacted at room temperature for 2 hours.

[0090] After the reaction, 20 ml of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 ml x 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and spun down to dryness. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain 1.0 g of tert-butyl (tert-butoxycarbonyl)(4-chloro-7-formyl-2,3-dihydro-1H-inden-1-yl)carbamate (yield: 83.3%). 1 H NMR (400MHz, DMSO) δ10.03(s,1H),7.74(d,J=8.0Hz,1H),7.58(d,J=8.0Hz,1H),6.22(dd,J=9.6,4. 8Hz,1H),3.16–2.99(m,1H),2.95–2.82(m,1H),2.69–2.50(m,3H),2.13–2.02(m,1H),1.30(s,18H).

[0091] Step J: Synthesis of methyl 3-(((3-(bis(tert-butoxycarbonyl)amino)-7-chloro-2,3-dihydro-1H-inden-4-yl)methyl)amino)-1H-pyrrole-2-carboxylate

[0092] 3-Amino-2-ethoxycarbonylpyrrole hydrochloride (529 mg, 2.78 mmol) was dissolved in 10 ml of anhydrous ethanol, and then N,N-diisopropylethylamine (359 mg, 2.78 mmol) and glacial acetic acid (456 mg, 7.59 mmol) were added to the mixture. After stirring at room temperature for 10 minutes, tert-butyl(tert-butoxycarbonyl)(4-chloro-7-formyl-2,3-dihydro-1H-inden-1-yl)carbamate (1.0 g, 2.53 mmol) was added to the mixture. After stirring at room temperature for 2 hours, sodium cyanoborohydride (191 mg, 3.04 mmol) was added to the mixture, and the mixture was reacted at room temperature for 12 hours.

[0093] After the reaction was complete, the anhydrous ethanol in the reaction solution was removed by rotary evaporation. The mixture was extracted with 10 mL of water and ethyl acetate (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary evaporation. The resulting residue was purified using a reverse-phase column (eluent: 0.1% aqueous ammonia solution) to obtain 1.0 g of methyl 3-(((3-(bis(tert-butoxycarbonyl)amino)-7-chloro-2,3-dihydro-1H-inden-4-yl)methyl)amino)-1H-pyrrole-2-carboxylate (yield: 74.6%). 1 H NMR (400MHz, DMSO) δ10.77 (s, 1H), 7.33–7.20 (m, 1H), 7.14 (d, J = 8.0Hz, 1H), 6. 70(t,J=3.2Hz,1H),5.97(dd,J=9.6,4.4Hz,1H),5.77(s,1H),5.44(t,J=2.4Hz, 1H),4.26–4.09(m,4H),3.12–2.98(m,1H),2.91–2.75(m,1H),2.56(dd,J=14.0, 9.9,5.0Hz,1H),2.09(tt,J=16.0,5.2Hz,1H),1.30(s,18H),1.30-1.24(m,3H).

[0094] Step K: Synthesis of tert-butyl(tert-butyloxycarbonyl)(4-chloro-7-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)-2,3-dihydro-1H-inden-1-yl

[0095] 3-(((3-(Bis(tert-butoxycarbonyl)amino)-7-chloro-2,3-dihydro-1H-inden-4-yl)methyl)amino)-1H-pyrrole-2-carboxylic acid methyl ester (0.9 g, 1.68 mmol) and benzoyl isothiocyanate (0.32 g, 2.02 mmol) were dissolved in methanol (5 ml). After stirring at room temperature for 3 hours, cesium carbonate (1.09 g, 3.36 mmol) was added, and the reaction solution was reacted at 65°C for 2 hours.

[0096] After the reaction was complete, the anhydrous methanol in the reaction solution was removed by rotary evaporation. The mixture was extracted with 20 mL of water and ethyl acetate (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary evaporation. The resulting residue was purified by reverse-phase column chromatography (eluent: 0.1% aqueous ammonia solution) to obtain 700 mg of tert-butyl(tert-butyloxycarbonyl)(4-chloro-7-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)-2,3-dihydro-1H-inden-1-yl (yield: 76%). 1 H NMR (400MHz, DMSO) δ12.51(s,1H),12.38(d,J=8.0Hz,1H),7.32(t,J=2.8Hz,1H),7.19(dd,J= 13.6,8.0Hz,1H),6.57(t,J=7.2Hz,1H),6.11(dd,J=9.6,4.4Hz,1H),5.89(dd,J=9.6,7.2Hz,1 H),5.78(d,J=16.4Hz,1H),5.29(d,J=16.4Hz,1H),3.11(ddd,J=16.0,10.0,5.6Hz,1H),2.97 –2.76(m,1H),2.63(ddd,J=20.0,12.4,7.4Hz,1H),2.17(td,J=9.9,5.1Hz,1H),1.33(s,18H).

[0097] Step L: Synthesis of 1-((3-amino-7-chloro-2,3-dihydro-1H-inden-4-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0098] Tert-butyl(tert-butoxycarbonyl)(4-chloro-7-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)-2,3-dihydro-1H-inden-1-yl) (80 mg, 0.14 mmol) was dissolved in ethyl acetate (2 ml), and a hydrochloric acid ethyl acetate solution (2 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour.

[0099] The solvent in the reaction solution was evaporated to dryness. The pH of the solution was then adjusted to 8 with aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate (15 ml x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The resulting residue was purified on a reverse phase column (eluent: 0.1% aqueous ammonia solution) to obtain 30 mg of 1-((3-amino-7-chloro-2,3-dihydro-1H-inden-4-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (yield: 60%). LC-MS: [M+H] + =347.2. 1 H NMR (400MHz, DMSO) δ7.19 (dd, J=14.1, 2.6Hz, 1H), 7.10 (dd, J=8.2, 3.9Hz, 1H ),6.56(dd,J=23.0,16.3Hz,1H),6.07(d,J=2.7Hz,1H),5.99–5.89(m,1H),5. 79(d,J=16.4Hz,1H),4.60(dd,J=7.1,3.0Hz,1H),3.13–2.96(m,1H),2.84–2 .66(m,1H),2.37(dt,J=16.1,7.5Hz,1H),1.84(ddd,J=12.4,8.3,4.0Hz,1H).

[0100] Step M: Synthesis of compounds M-1 and M-2

[0101] 1-((3-Amino-7-chloro-2,3-dihydro-1H-inden-4-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (120 mg, 0.34 mmol), di-tert-butyl dicarbonate (83 mg, 0.38 mmol) and triethylamine (103 mg, 1.02 mmol) were dissolved in dichloromethane (2 ml) and reacted at room temperature for 2 hours.

[0102] The reaction solution was added to 10 ml of water and extracted with dichloromethane (10 ml x 2). The combined organic phases were washed with aqueous NaHCO3, dried over anhydrous sodium sulfate, filtered, and spun dry. The resulting residue was purified by reverse phase column (eluent: 0.1% aqueous ammonia solution) to obtain 96 mg of tert-butyl 1-((3-((tert-butoxycarbonyl)amino)-7-chloro-2,3-dihydro-1H-inden-4-yl)methyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidine-5-carboxylate. The white solid was sent for SFC separation ( Chiral separation was performed on an IC column (250*25mm 10um) using Supercritical CO2 and MEOH (+0.1% 7.0mol / l Ammonia in MEOH) as the mobile phase to obtain isomers M-1 (RT=2.4min, 20mg, yield=21%, ee>99%) and M-2 (RT=3.4min, 15mg, yield=16%, ee>99%).

[0103] Step N:

[0104] M-1 (20 mg, 0.036 mmol) was dissolved in ethyl acetate (2 ml), and a hydrochloric acid ethyl acetate solution (2 ml) was added to the reaction solution and stirred at room temperature for 1 hour. The solvent in the reaction solution was dried by vortexing. The reaction solution was dried by vortexing. The pH of the solution was then adjusted to 8 with aqueous sodium bicarbonate solution, and then extracted with ethyl acetate (15 ml x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried by vortexing. The resulting residue was purified by reverse phase column purification (eluent: 0.1% aqueous ammonia solution) and lyophilized to obtain 10.6 mg of compound 1A (yield 84%). LC-MS: [M+H] + =347.2

[0105] M-2 (15 mg, 0.027 mmol) was dissolved in ethyl acetate (2 ml), and a hydrochloric acid ethyl acetate solution (2 ml) was added to the reaction solution and stirred at room temperature for 1 hour. The solvent in the reaction solution was dried by rotary evaporation. The pH of the solution was then adjusted to 8 with an aqueous sodium bicarbonate solution, and then extracted with ethyl acetate (15 ml x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The resulting residue was purified by reverse phase column purification (eluent: 0.1% ammonia solution) and lyophilized to obtain 8.5 mg of compound 1B (yield 89%). LC-MS: [M+H] + =347.2.

[0106] Example 2 1-((3-amino-7-chloro-2,3-dihydrobenzofuran-4-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0107] Synthesis route:

[0108] Step A: 5-Bromo-2-chlorophenyl 2-chloroacetate

[0109] 5-Bromo-2-chlorophenol (12 g, 0.058 mol) and chloroacetyl chloride (19.6 g, 0.774 mol) were added to a three-necked flask and heated under reflux for 16 hours.

[0110] After the reaction, the reaction solution was dried and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain 16 g (0.056 mol) of a white solid product, 5-bromo-2-chlorophenyl 2-chloroacetate (yield: 97.1%). 1 H NMR (400MHz, DMSO) δ7.73 (d, J = 1.6Hz, 1H), 7.61–7.57 (m, 2H), 4.78 (s, 2H).

[0111] Step B: Synthesis of 4-bromo-7-chlorobenzofuran-3(2H)-one

[0112] 5-Bromo-2-chlorophenyl 2-chloroacetate (16 g, 0.056 mol) was added to a three-necked flask, replaced with nitrogen, heated to 150 degrees, and AlCl3 (22.54 g, 0.168 mol) was added, and the reaction was carried out at 150 degrees for 0.5 hours.

[0113] After the reaction, ice water (50 mL) was added to quench the reaction, followed by extraction with ethyl acetate (50 mL x 3), washing with saturated sodium chloride solution (30 mL x 3), drying over anhydrous sodium sulfate, filtering, and spin-drying to obtain a crude product. The crude product was purified on a silica gel column (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain 3.2 g (0.013 mol) of 4-bromo-7-chlorobenzofuran-3(2H)-one (yield: 23.1%). 1 H NMR (400MHz, DMSO) δ7.74 (d, J = 8.3 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 4.95 (s, 2H).

[0114] Step C: Synthesis of 4-bromo-7-chloro-2,3-dihydrobenzofuran-3-amine

[0115] 4-Bromo-7-chlorobenzofuran-3(2H)-one (3.2 g, 12.95 mmol) was dissolved in EtOH solution (20 ml) at room temperature, and ammonium acetate (9.98 g, 129.5 mmol) was added. The mixture was heated to 100°C and reacted for 12 hours.

[0116] After the reaction, ice water (20 ml) was added to quench the reaction mixture. The ethanol in the reaction mixture was then removed by rotary evaporation. Saturated sodium bicarbonate solution was added to adjust the pH to 4-5. The mixture was then extracted with ethyl acetate (20 ml x 3), washed with saturated sodium chloride solution (30 ml x 3), dried over anhydrous sodium sulfate, filtered, and rotary evaporation to obtain the crude product. The crude product was purified by C18 reverse phase column chromatography (NH4CO3 / CAN system) to obtain 1.5 g (6.04 mmol) of 4-bromo-7-chloro-2,3-dihydrobenzofuran-3-amine (yield: 46.9%). LC-MS: [M+H] + =248.50. 1H NMR (400MHz, DMSO) δ7.30(d,J=8.5Hz,1H),7.10(d,J=8.5Hz,1H),5.91(d,J=7.2Hz,1H), 5.25(td,J=6.9,2.0Hz,1H), 4.63(dd,J=10.4,6.5Hz,1H), 4.42(dd,J=10.4,2.1Hz,1H).

[0117] Step D: Synthesis of tert-butyl (4-bromo-7-chloro-2,3-dihydrobenzofuran-3-yl)carbamate

[0118] 4-Bromo-7-chloro-2,3-dihydrobenzofuran-3-amine (1.5 g, 6.03 mmol) was dissolved in dichloromethane (20 ml) at room temperature, and (Boc)2O (2.63 g, 12.07 mmol) and TEA (2.5 ml, 18.09 mmol) were added and stirred at room temperature for 12 hours.

[0119] After the reaction was complete, saturated sodium bicarbonate (20 mL) was added to quench the reaction, followed by extraction with DCM (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (NH4CO3 / CAN system) to obtain 1.2 g (3.44 mmol) of tert-butyl (4-bromo-7-chloro-2,3-dihydrobenzofuran-3-yl)carbamate (yield 57.1%). LC-MS: [M+H] + =348.12. 1 H NMR (400MHz, DMSO) δ7.60(d,J=8.6Hz,1H),7.27(d,J=8.5Hz,1H),7.08(d,J=8.5Hz, 1H),5.38–5.30(m,1H),4.78(t,J=9.2Hz,1H),4.32(dd,J=9.5,4.1Hz,1H),1.39(s, 9H).

[0120] Step E: Synthesis of tert-butyl (4-bromo-7-chloro-2,3-dihydrobenzofuran-3-yl)(tert-butoxycarbonyl)carbamate

[0121] To tert-Butyl (4-bromo-7-chloro-2,3-dihydrobenzofuran-3-yl)carbamate (1.2 g, 3.45 mmol) was dissolved in dichloromethane (20 ml) at room temperature, (Boc)2O (1.5 g, 6.9 mmol) and DMAP (0.84 g, 6.9 mmol) were added and the mixture was stirred at room temperature for 12 hours.

[0122] After the reaction was complete, saturated sodium bicarbonate (20 mL) was added to quench the reaction, followed by extraction with DCM (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by C18 reverse-phase column chromatography (NH4CO3 / CAN system) to obtain 1.2 g (2.67 mmol) of tert-butyl (4-bromo-7-chloro-2,3-dihydrobenzofuran-3-yl)(tert-butoxycarbonyl)carbamate (yield 80%). LC-MS: [M+H] + =448.74. 1 H NMR (400MHz, DMSO) δ7.31–7.25(m,1H),7.07(d,J=8.5Hz,1H),6.19(dd,J=10.2, 4.8Hz, 1H), 4.91–4.84 (m, 1H), 4.58 (dd, J = 9.8, 4.9Hz, 1H), 1.43–1.20 (m, 18H).

[0123] Step F: Synthesis of (tert-butyl(tert-butyloxycarbonyl)(7-chloro-4-vinyl-2,3-dihydrobenzofuran-3-yl)carbamate

[0124] (tert-Butyl(tert-butoxycarbonyl)(7-chloro-4-vinyl-2,3-dihydrobenzofuran-3-yl)carbamate (1.2 g, 2.68 mmol), potassium ethylene trifluoroborate (0.54 g, 4.01 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (0.22 g, 0.3 mmol) and potassium carbonate (1.11 g, 8.04 mmol) were dissolved in dimethyl sulfoxide (15 ml) and reacted at 100°C for 12 hours under nitrogen protection.

[0125] After the reaction was complete, the mixture was cooled to room temperature and filtered through Celite. The filtrate was collected and then 50 mL of water was added. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and spun down to dryness. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain 0.552 g (1.32 mmol) of tert-butyl(tert-butoxycarbonyl)(7-chloro-4-vinyl-2,3-dihydrobenzofuran-3-yl)carbamate (yield: 55%). LC-MS: [M+H] + =395.88. 1H NMR (400MHz, DMSO) δ7.30(d,J=8.4Hz,1H),7.13(d,J=8.4Hz,1H),6.62(dd,J=17.6,11.1Hz,1H),6.24(dd,J=9.9,4.3Hz ,1H),5.83(d,J=17.5Hz,1H),5.35(d,J=11.2Hz,1H),4.80(t,J=9.9Hz,1H),4.57(dd,J=9.9,4.4Hz,1H),1.29(s,18H).

[0126] Step G: Synthesis of tert-butyl(tert-butoxycarbonyl)(7-chloro-4-formyl-2,3-dihydrobenzofuran-3-yl)carbamate

[0127] (tert-Butyl(tert-butoxycarbonyl)(7-chloro-4-vinyl-2,3-dihydrobenzofuran-3-yl)carbamate (552 mg, 1.39 mmol) was dissolved in a mixture of tetrahydrofuran (4 ml) and water (1 ml), potassium osmate (51.49 mg, 0.14 mmol) was added to the reaction solution, and after stirring at room temperature for 30 minutes, sodium periodate (1.2 g, 5.56 mmol) was added to the reaction solution, and the reaction was allowed to react at room temperature for 2 hours.

[0128] After the reaction was complete, 20 ml of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 ml x 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and spun down to dryness. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain 315 mg (0.79 mmol) of tert-butyl (tert-butoxycarbonyl)(7-chloro-4-formyl-2,3-dihydrobenzofuran-3-yl)carbamate (yield: 56.9%). LC-MS: [M+H] + =397.85. 1 H NMR (400MHz, DMSO) δ9.97(s,1H),7.62(d,J=8.2Hz,1H),7.46(d,J=8.2Hz,1H),6.45(dd ,J=10.1,4.7Hz,1H),4.92(t,J=10.1Hz,1H),4.61(dd,J=9.9,4.7Hz,1H),1.31(s,18H).

[0129] Step H: Synthesis of ethyl 3-(((3-(bis(tert-butoxycarbonyl)amino)-7-chloro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-1H-pyrrole-2-carboxylate

[0130] 3-Amino-2-ethoxycarbonylpyrrole hydrochloride (181.2 mg, 0.951 mmol) was dissolved in 10 ml of anhydrous ethanol, and then N,N-diisopropylethylamine (122.83 mg, 0.951 mmol) and glacial acetic acid (57.1 mg, 0.951 mmol) were added to the mixture, and after stirring at room temperature for 10 minutes, tert-butyl (tert-butoxycarbonyl) (7-chloro-4-formyl-2,3-dihydrobenzofuran-3-yl) carbamate (315 mg, 0.792 mmol) was added to the mixture, and after stirring at room temperature for 2 hours, sodium cyanoborohydride (59.8 mg, 0.95 mmol) was added to the mixture, and the mixture was reacted at room temperature for 4 hours.

[0131] After the reaction was complete, the anhydrous ethanol in the reaction solution was removed by spin drying. The mixture was extracted with 10 mL of water and ethyl acetate (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and spin dried. The resulting residue was purified using a reverse phase column (eluent: 0.1% aqueous ammonia solution) to obtain 221 mg (0.41 mmol) of ethyl 3-(((3-(bis(tert-butoxycarbonyl)amino)-7-chloro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-1H-pyrrole-2-carboxylate (yield: 52.0%). LC-MS: [M+H] + =536.02. 1 H NMR (400MHz, DMSO) δ10.77(s,1H),7.31–7.18(m,1H),6.81(d,J=7.8Hz,1H),6.69(s,1H),6.24(d,J=9.8Hz,1H),5 .79(s,1H),5.46(s,1H),4.82(t,J=8.7Hz,1H),4.61(d,J=2.9Hz,1H),4.28–4.08(m,4H),1.27(d,J=12.0Hz,21H).

[0132] Step I: Synthesis of tert-butyl (7-chloro-4-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)-2,3-dihydrobenzofuran-3-yl)carbamate

[0133] Ethyl 3-(((3-(bis(tert-butoxycarbonyl)amino)-7-chloro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-1H-pyrrole-2-carboxylate (221 mg, 0.41 mmol) and benzoyl isothiocyanate (80.75 mg, 0.49 mmol) were dissolved in methanol (5 ml) and stirred at room temperature for 3 hours. Then, cesium carbonate (537.4 mg, 1.64 mmol) was added, and the reaction solution was reacted at 65°C for 2 hours.

[0134] After the reaction, the anhydrous methanol in the reaction solution was removed by spin drying. The mixture was extracted with 20 mL of water and ethyl acetate (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and then spin dried. The resulting residue was purified by reverse phase column chromatography (eluent: 0.1% aqueous ammonia solution) to obtain 65 mg (0.14 mmol) of tert-butyl (7-chloro-4-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)-2,3-dihydrobenzofuran-3-yl)carbamate (yield: 35.1%). LC-MS: [M+H]+ = 448.92. 1 H NMR (400MHz, DMSO) δ12.50(s,1H),12.39(s,1H),7.84(d,J=8.7Hz,1H),7.32(s,1H),7.16(d,J=8.3Hz,1H),6.28(d,J=8.3Hz,1H),6.0 0(s,1H),5.72(d,J=16.7Hz,1H),5.67–5.60(m,1H),5.48(d,J=16.4Hz,1H),4.81(t,J=9.3Hz,1H),4.40(d,J=5.5Hz,1H),1.39(s,9H).

[0135] Step J: Synthesis of 1-((3-amino-7-chloro-2,3-dihydrobenzofuran-4-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0136] Dissolve tert-butyl (7-chloro-4-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)-2,3-dihydrobenzofuran-3-yl)carbamate (65 mg, 0.15 mmol) in DMF (2 mL). Add 1,4-dioxane hydrochloride solution (5 mL) to the reaction mixture, and stir at room temperature for 1 hour. Add 10 mL of water to the reaction mixture, extract with dichloromethane (10 mL x 2), and combine the organic phases, wash with aqueous NaHCO₃, dry over anhydrous sodium sulfate, filter, and spin dry. The resulting residue was purified by reverse phase column chromatography (eluent: 0.1% aqueous ammonia solution) to afford 24.01 mg of (1-((3-amino-7-chloro-2,3-dihydrobenzofuran-4-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (yield 47.5%). LC-MS: [M+H] + =348.81. 1HNMR (400MHz, DMSO) δ7.30(d,J=2.8Hz,1H),7.12(d,J=8.3Hz,1H),6.31(d,J=8.3Hz,1H),6.16(d,J=2.8Hz,1H),5. 88(d,J=16.6Hz,1H), 5.76(d,J=16.6Hz,1H), 4.92–4.83(m,1H), 4.71(t,J=8.7Hz,1H), 4.30(dd,J=9.4,4.1Hz,1H).

[0137] Example 3 1-(3-amino-2,3-dihydrobenzofuran-4-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0138] Step A: Synthesis of 4-bromo-2,3-dihydrobenzofuran-3-amine

[0139] 4-Bromobenzofuran-3(2H) (2.4 g, 11.26 mmol), ammonium acetate (8.7 g, 112.6 mmol) and sodium cyanoborohydride (3.54 g, 56.3 mmol) were dissolved in ethanol (30 ml) at room temperature and the reaction was carried out at 100°C in a stew pot for 72 hours.

[0140] After the reaction, the reaction mixture was spin-dried on a water pump and extracted with ethyl acetate and water (30 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain 2.2 g of crude oily product, 4-bromo-2,3-dihydrobenzofuran-3-amine (yield 91.28%). LC-MS: [M+H]+ = 214.06.

[0141] Step B: Synthesis of tert-butyl (4-bromo-2,3-dihydrobenzofuran-3-yl)carbamate

[0142] 4-Bromo-2,3-dihydrobenzofuran-3-amine (2.2 g, 10.33 mmol), (Boc)2O (4.74 mL, 20.66 mmol) and triethylamine (2.9 mL, 20.66 mmol) were dissolved in DCM (30 mL) at room temperature and stirred for 2 h.

[0143] After the reaction was complete, water (30 mL) was added and the mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 20:1) to obtain 1.6 g of tert-butyl (4-bromo-2,3-dihydrobenzofuran-3-yl)carbamate as an oily liquid (yield 53.12%). LC-MS: [M+H]+ = 314.18.1 H NMR (400MHz, DMSO) δ7.54(d,J=8.5Hz,1H),7.15(t,J=7.9Hz,1H),7.06(d,J=7.9Hz,1H),6.84(t,J=9.5Hz,1 H), 5.29 (dt, J = 12.3, 6.3Hz, 1H), 4.67 (t, J = 8.2Hz, 1H), 4.23 (dd, J = 9.5, 4.0Hz, 1H), 1.44 (d, J = 28.9Hz, 9H).

[0144] Step C: Synthesis of tert-butyl (4-bromo-2,3-dihydrobenzofuran-3-yl)(tert-butoxycarbonyl)carbamate

[0145] At 50°C, tert-butyl (4-bromo-2,3-dihydrobenzofuran-3-yl)carbamate (1.6 g, 5.11 mmol), (Boc)2O (11.68 ml, 51.2 mmol) and DMAP (1.25 g, 10.24 mmol) were dissolved in 2-methyltetrahydrofuran (15 ml) and stirred at 50°C for 12 hours.

[0146] After the reaction was complete, water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 20:1) to obtain 2 g of the oily liquid product, tert-butyl (4-bromo-2,3-dihydrobenzofuran-3-yl)(tert-butoxycarbonyl)carbamate (yield 94.78%). LC-MS: [M+H]+ = 414.30. 1 H NMR (400MHz, DMSO) δ7.27–7.11(m,1H),7.06(t,J=12.2Hz,1H),6.83(t,J=10.9Hz,1H),6. 10(dd,J=10.1,4.8Hz,1H),4.77(t,J=10.0Hz,1H),4.57–4.44(m,1H),1.61–1.19(m,18H).

[0147] Step D: Synthesis of tert-butyl (4-vinyl-2,3-dihydrobenzofuran-3-yl)carbamate

[0148] Tert-butyl (4-bromo-2,3-dihydrobenzofuran-3-yl)(tert-butoxycarbonyl)carbamate (2 g, 4.84 mmol), potassium trifluoroborate (973 mg, 7.26 mmol), potassium carbonate (3.23 g, 23.43 mmol) and DPPF palladium dichloride (351 mg, 0.484 mmol) were dissolved in 30 ml of 1,4-dioxane and 3 ml of water, and the reaction was carried out at 100° C. for 12 hours.

[0149] After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 20:1) to obtain 1.16 g of the oily liquid product, tert-butyl (4-vinyl-2,3-dihydrobenzofuran-3-yl)carbamate (yield 66.36%). LC-MS: [M+H] + =361.44. 1 H NMR (400MHz, DMSO) δ7.28–7.17(m,1H),7.10(d,J=7.7Hz,1H),6.79–6.62(m,2H),6.14(dd,J=9.9,4.2Hz,1H),5. 88–5.68(m,1H),5.31(dd,J=11.1,0.8Hz,1H),4.69(t,J=9.9Hz,1H),4.48(dd,J=9.8,4.3Hz,1H),1.28(s,18H).

[0150] Step E: Synthesis of tert-butyl (4-formyl-2,3-dihydrobenzofuran-3-yl)carbamate

[0151] At room temperature, tert-butyl (4-vinyl-2,3-dihydrobenzofuran-3-yl) carbamate (1.16 g, 3.21 mmol) was dissolved in a mixture of tetrahydrofuran (12 ml) and water (3 ml), potassium osmate (59 mg, 0.16 mmol) was added to the reaction solution, and after stirring at room temperature for 30 minutes, sodium periodate (2.08 g, 9.63 mmol) was added to the reaction solution, and the reaction was carried out at room temperature for 1.5 hours.

[0152] After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 20:1) to obtain 430 mg of tert-butyl(4-formyl-2,3-dihydrobenzofuran-3-yl)carbamate as an oily liquid (yield: 36.87%). LC-MS: [M+H]+ = 363.41. 1H NMR (400MHz, DMSO) δ10.01(s,1H),7.57–7.38(m,2H),7.16(d,J=7.8Hz,1H),6.34(dt,J=6 1.4,30.8Hz,1H),4.91–4.71(m,1H),4.52(dd,J=9.8,4.6Hz,1H),1.33(d,J=23.6Hz,18H).

[0153] Step F: Synthesis of ethyl 3-((3-(bis(tert-butoxycarbonyl)amino)-2,3-dihydrobenzofuran-4-ylmethyl)amino)-1H-pyrrole-2-carboxylate

[0154] 3-Amino-2-ethoxycarbonylpyrrole hydrochloride (271 mg, 1.42 mmol) and DIEA (0.22 ml, 1.42 mmol) were added to ethanol (20 ml) at room temperature, and the reaction was carried out for 5 minutes. Glacial acetic acid (0.11 ml, 1.42 mmol) was added, and the reaction was carried out at room temperature for 30 minutes. Tert-butyl (4-formyl-2, 3-dihydrobenzofuran-3-yl) carbamate (430 mg, 1.18 mmol) was added, and the reaction was carried out at room temperature for 1 hour. Then, sodium cyanoborohydride (219 mg, 2.48 mmol) was added, and the reaction was carried out at room temperature for 12 hours.

[0155] After the reaction, the ethanol in the reaction mixture was evaporated, and water (20 ml) was added. The mixture was extracted with ethyl acetate (20 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by reverse-phase column chromatography (eluent: 0.1% aqueous ammonium bicarbonate: acetonitrile = 0-50%) to obtain 450 mg of ethyl 3-((3-(bis(tert-butoxycarbonyl)amino)-2,3-dihydrobenzofuran-4-ylmethyl)amino)-1H-pyrrole-2-carboxylate (yield 75.88%). LC-MS: [M+H] + =501.58. 1 H NMR (400MHz, DMSO) δ10.76(s,1H),7.17(t,J=7.8Hz,1H),6.89–6.59(m,3H),6.14(dd,J=9.8,4.1Hz,1H),5.75(s,1H),5.51(t,J= 2.5Hz, 1H), 4.69 (t, J = 9.9Hz, 1H), 4.51 (dd, J = 9.9, 4.2Hz, 1H), 4.33–4.06 (m, 4H), 1.27 (d, J = 3.7Hz, 18H), 1.24 (d, J = 6.3Hz, 3H).

[0156] Step G: Synthesis of tert-butyl (4-(4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)-2,3-dihydrobenzofuran-3-yl)carbamate

[0157] At room temperature, ethyl 3-((3-(bis(tert-butoxycarbonyl)amino)-2,3-dihydrobenzofuran-4-ylmethyl)amino)-1H-pyrrole-2-carboxylate (450 mg, 0.9 mmol) and benzoyl isothiocyanate (0.18 ml, 1.08 mmol) were added to 30 ml of anhydrous methanol, and the mixture was reacted at room temperature for 2 hours. Cesium carbonate (1.18 g, 3.6 mmol) was then added, and the mixture was reacted at 65°C for 2 hours.

[0158] After the reaction, the methanol in the reaction mixture was evaporated, and water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by reverse-phase column chromatography (eluent: 0.1% aqueous ammonium bicarbonate: acetonitrile = 0-50%) to obtain 300 mg of tert-butyl (4-(4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)-2,3-dihydrobenzofuran-3-yl)carbamate (yield 65.07%). LC-MS: [M+H] + =414.48. 1 H NMR (400 MHz, DMSO) δ 7.75 (d, J = 8.3 Hz, 1H), 7.16–6.92 (m, 2H), 6.66 (d, J = 7.9 Hz, 1H), 6.29 (d, J = 7.7 Hz, 1H), 5.92–5.64 (m, 2H), 5.56 (d, J = 15.4 Hz, 2H), 4.69 (t, J = 9.2 Hz, 1H), 4.35–4.20 (m, 1H), 1.39 (s, 9H). Step H: Synthesis of 1-(3-amino-2,3-dihydrobenzofuran-4-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0159] At room temperature, tert-butyl (4-(4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)-2,3-dihydrobenzofuran-3-yl)carbamate (300 mg, 0.58 mmol) was dissolved in DCM (20 ml), and 1,4-dioxane hydrochloride (4.38 ml, 17.5 mmol) was added, and the reaction was carried out at room temperature for 12 hours.

[0160] After the reaction, the mixture was slurried with dichloromethane for 1 hour and filtered to obtain 209 mg of solid 1-(3-amino-2,3-dihydrobenzofuran-4-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one hydrochloride. LC-MS: [M+H]+ = 314.36. 1 H NMR (400MHz, DMSO) δ12.45(d,J=46.4Hz,2H),8.69(s,3H),7.27(dt,J=15.9,5.4Hz,2H),6.86(d,J=8.0Hz,1H) ,6.38(d,J=7.7Hz,1H),6.12(dd,J=12.9,10.3Hz,2H),5.65(d,J=16.7Hz,1H),5.35(s,1H),4.78–4.60(m,2H).

[0161] Example 4

[0162] Referring to the preparation method of Example 1, the following compound 4 was prepared.

[0163] LC-MS: [M+H]+=361.1.

[0164] Example 5 1-((4-amino-8-chlorochroman-5-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0165] Synthesis route:

[0166] Step A: 3-(5-bromo-2-chlorophenoxy)propionic acid

[0167] At room temperature, 5-bromo-2-chlorophenol (3 g, 0.014 mol) was dissolved in THF (40 ml), cooled to 0°C, t-BuOK (1.79 g, 0.16 mol) was added, and the mixture was reacted at 0°C for 0.5 h. Oxan-2-one (1.15 g, 0.016 mol) was added, and the temperature was raised to room temperature for 16 h.

[0168] After the reaction was completed, ice water (10 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain 4.7 g (147 mmol) of crude 3-(5-bromo-2-chlorophenoxy)propionic acid as a white solid product.

[0169] Step B: 5-Bromo-8-chlorochroman-4-one

[0170] 3-(5-Bromo-2-chlorophenoxy)propionic acid (1.5 g, 5.4 mmol) was dissolved in Eation's reagent (7 ml) at room temperature and heated at 60°C with stirring for 2 h.

[0171] After the reaction was completed, ice water (10 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column (PE:EA = 100:1 to 10:1) to obtain 1 g (1.47 mmol) of 5-bromo-8-chlorochroman-4-one (yield 70.8%). 1 H NMR (400MHz, DMSO) δ7.59 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 4.68 (t, J = 6.5 Hz, 2H), 2.93–2.83 (m, 2H).

[0172] Step C: Synthesis of 5-bromo-8-chlorochroman-4-amine

[0173] At room temperature, 5-bromo-8-chlorochroman-4-one (1 g, 3.82 mmol) was dissolved in EtOH (10 ml), and AcONH4 (2.95 g, 38.2 mmol) and NaBH3CN (1.2 g, 19.1 mmol) were added, and the mixture was stirred at 100°C for 16 h.

[0174] After the reaction, the ethanol was removed by spin drying, and water (20 mL) and saturated NaHCO₃ (10 mL) were added. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain 1.3 g of 5-bromo-8-chlorochroman-4-amine as a colorless oil. LC-MS: [M+H] + =271.1.

[0175] Step D: Synthesis of tert-butyl (5-bromo-8-chlorochroman-4-yl) carbamate

[0176] 5-Bromo-8-chlorochroman-4-amine (2 g, 7.61 mmol) was dissolved in DCM (30 ml) at room temperature, and TEA (2.31 g, 22.86 mmol) and (Boc)2O (3.32 g, 15.2 mmol) were added. The mixture was stirred at room temperature for 48 hours.

[0177] After the reaction was completed, water (10 mL) was added to quench the reaction, and the product was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain 1.2 g (3.31 mmol) of tert-butyl (5-bromo-8-chlorochroman-4-yl) carbamate (yield 43.5%). 1 H NMR (400MHz, DMSO) δ7.43(d,J=7.6Hz,1H),7.32(d,J=8.5Hz,1H),7.18(d,J=8.5Hz,1H),4.67(d,J= 7.4Hz, 1H), 4.43 (d, J=10.9Hz, 1H), 4.11 (dd, J=22.6, 11.8Hz, 1H), 2.04–1.82 (m, 2H), 1.41 (s, 9H).

[0178] Step E: Synthesis of tert-butyl (5-bromo-8-chlorochroman-4-yl) (tert-butoxycarbonyl) carbamate

[0179] 5-Bromo-8-chlorochroman-4-amine (1.2 g, 3.31 mmol) was dissolved in 2-MeTHF (15 ml) at room temperature, and DMAP (0.808 g, 6.62 mmol) and (Boc)2O (1.44 g, 6.62 mmol) were added. The mixture was heated to 50°C and stirred for 16 hours.

[0180] After the reaction was completed, water (20 ml) was added to quench the reaction, and the product was extracted with ethyl acetate (20 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by reverse phase column to obtain 1.1 g (2.38 mmol) of tert-butyl (5-bromo-8-chlorochroman-4-yl) (tert-butoxycarbonyl) carbamate (yield 69.8%). 1 H NMR (400MHz, DMSO) δ7.34(d,J=8.5Hz,1H),7.17(d,J=8.5Hz,1H),5.30(t,J=4.2H z,1H),4.41(qd,J=11.1,5.1Hz,2H),2.19–2.08(m,2H),1.35(d,J=27.6Hz,18H).

[0181] Step F: Synthesis of tert-butyl(tert-butoxycarbonyl)(8-chloro-5-vinylchroman-4-yl)carbamate

[0182] Tert-butyl (5-bromo-8-chlorochroman-4-yl) (tert-butoxycarbonyl) carbamate (1 g, 2.16 mmol), potassium vinyl trifluoroborate (0.43 g, 3.24 mmol), Pd (ppf) Cl2 (0.158 g, 0.216 mmol), K2CO3 (0.9 g, 6.483 mmol) were dissolved in anhydrous dioxane (20 ml) and stirred at 100 ° C for 16 hours.

[0183] After the reaction was completed, water (30 mL) was added to quench the reaction, and the product was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain 1 g (2.44 mmol) of tert-butyl (tert-butoxycarbonyl) (8-chloro-5-vinylchroman-4-yl) carbamate (crude) as a colorless oily product.

[0184] Step G: Synthesis of tert-butyl(tert-butoxycarbonyl)(8-chloro-5-formylchroman-4-yl)carbamate

[0185] At room temperature, tert-butyl (tert-butoxycarbonyl) (8-chloro-5-vinylchroman-4-yl) carbamate (1 g, 2.44 mmol) was dissolved in THF / H2O (30 ml / 6 ml), and K2OsO4 (90 mg, 0.244 mmol) and NaIO4 (2.087 g, 9.785 mmol) were added, and the mixture was stirred at room temperature for 1 hour.

[0186] TLC showed that the reaction was complete, and water (30 ml) was added to quench the reaction. The product was extracted with ethyl acetate (30 ml x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 10:1) to give 0.5 g (1.21 mmol) of brown oily product tert-butyl (tert-butoxycarbonyl) (8-formyl-1,2,4-tetrahydronaphthalen-1-yl) carbamate (yield 49.6%).

[0187] Step H: Synthesis of ethyl 3-(((4-(bis(tert-butoxycarbonylamino)-8-chlorochroman-5-yl)methyl)amino)-1H-pyrrole-2-carboxylate

[0188] Ethyl 3-amino-1H-pyrrole-2-carboxylate hydrochloride (277 mg, 1.457 mmol) was dissolved in anhydrous MeOH (10 ml) at room temperature, and DIEA (188 mg, 1.457 mmol) and AcOH (87 mg, 1.457 mmol) were added. Tert-butyl (tert-butoxycarbonyl)(8-formyl-1,2,4-tetrahydronaphthalen-1-yl)carbamate (500 mg, 1.214 mmol) was added, and the mixture was stirred at room temperature for 1 hour. NaBH3CN (91 mg, 1.457 mmol) was added, and the mixture was stirred at room temperature for 1 hour.

[0189] After the reaction, methanol was removed by rotary evaporation, and water (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified using a reverse phase column to obtain 300 mg (0.545 mmol) of ethyl 3-(((4-(bis(tert-butoxycarbonyl)amino)-8-chlorochroman-5-yl)methyl)amino)-1H-pyrrole-2-carboxylate (yield 44.9%). LC-MS: [M+H] + =550.3. 1 H NMR (400MHz, DMSO) δ10.80(s,1H),7.32(d,J=8.3Hz,1H),6.86(d,J=8.3Hz,1H),6.72(t,J=3.0Hz,1H),5.72(s,1H),5.5 4–5.40(m,2H),4.47(dt,J=13.5,6.8Hz,1H),4.32–4.24(m,2H),4.23–4.09(m,3H),2.15(d,J=5.6Hz,2H),1.28(s,7H).

[0190] Step I: tert-Butyl(tert-butoxycarbonyl)(8-chloro-5-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)pyran-4-yl)carbamate

[0191] Ethyl 3-(((4-(bis(tert-butoxycarbonyl)amino)-8-chlorochroman-5-yl)methyl)amino)-1H-pyrrole-2-carboxylate (300 mg, 0.545 mmol) was dissolved in anhydrous MeOH (10 ml) at room temperature, and benzoyl isothiocyanate (107 mg, 0.654 mmol) was added. The mixture was stirred at room temperature for 1 hour, and Cs2CO3 (355 mg, 1.091 mmol) was added, and the mixture was stirred at 65°C for 3 hours.

[0192] After the reaction, the solvent was concentrated to dryness, and the resulting residue was purified using a reaction column to obtain 189 mg (0.336 mmol) of tert-butyl(tert-butoxycarbonyl)(8-chloro-5-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)pyran-4-yl)carbamate (yield 61.7%). LC-MS: [M+H] + =563.2. 1 H NMR (400MHz, DMSO) δ12.51(s,1H),12.38(s,1H),7.33(t,J=2.9Hz,1H),7.23(d,J=8.4Hz,1H),6.24(d,J=8.4Hz,1H),5.94(s,1H),5 .65(t,J=5.2Hz,2H),5.28(d,J=16.5Hz,1H),4.51(dt,J=12.1,6.0Hz,1H),4.38–4.27(m,1H),2.29(t,J=12.3Hz,2H),1.33(s,18H).

[0193] Step J: Synthesis of 1-((4-amino-8-chlorochroman-5-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0194] To the solution of tert-butyl(tert-butoxycarbonyl)(8-chloro-5-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)pyran-4-yl)carbamate (240 mg, 0.426 mmol) in DCM (10 mL) at room temperature, hydrochloric acid (1.1 mg, 4.26 mmol, 4 M in dioxane) was added, and the mixture was stirred at room temperature for 3 hours.

[0195] After the reaction was complete, the reaction mixture was filtered, and the filter cake was washed with DCM (5 mL) and dried to obtain 150 mg (0.376 mmol) of 1-((8-amino-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one hydrochloride (yield 88.2%). LC-MS: [M+H] + =362.1. 1H NMR (400MHz, DMSO) δ12.53(s,1H),12.40(s,1H),8.76(s,3H),7.36(dd,J=9.8,5.5Hz,2H),6.27(d,J=8.4Hz,1H),6.19(s,1H),5.95(d,J=16.7 Hz,1H),5.71(d,J=16.7Hz,1H),4.95(s,1H),4.57(dd,J=11.4,4.0Hz,1H),4.39(t,J=11.8Hz,1H),2.42(d,J=13.6Hz,1H),2.29–2.15(m,1H).

[0196] Example 6 1-((4-aminochroman-5-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, Compound 6A and Compound 6B

[0197] Synthesis route:

[0198] Step A: Synthesis of 5-bromochroman-4-amine

[0199] 5-Bromo-4-chromanone (4.4 g, 19.37 mmol) was dissolved in anhydrous methanol (44 ml) and isopropanol (55 ml), and ammonium acetate (29.87 g, 387 mmol) and sodium cyanoborohydride (6.08 g, 96.85 mmol) were added, and the mixture was refluxed at 80°C for 12 hours.

[0200] After the reaction, the solvent in the solution was dried by rotary evaporation, and the pH was adjusted to 10 with 1 M sodium hydroxide solution. The mixture was extracted with ethyl acetate (30 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 0 / 1) to obtain 3.0 g of 5-bromo-4-chromanamine as a white solid (yield 68.0%). 1 H NMR (400MHz, DMSO) δ7.16–7.01(m,2H),6.86–6.76(m,1H),4.32–4.17(m,2H),4.09–3.98(m,1H),1.96–1.77(m,2H).

[0201] Step B: Synthesis of tert-butyl (5-bromo-4-chroman-amine) carbamate

[0202] 5-Bromo-4-chromanamine (3.0 g, 13.2 mmol), di-tert-butyl dicarbonate (3.15 g, 14.5 mmol) and triethylamine (4.0 g, 39.6 mmol) were dissolved in dichloromethane (30 ml) and reacted at room temperature for 6 hours.

[0203] The reaction mixture was added to 20 mL of water and extracted with dichloromethane (20 mL x 2). The combined organic phases were washed with aqueous NaHCO₃, dried over anhydrous sodium sulfate, filtered, and spin-dried. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain 3.8 g of tert-butyl (5-bromo-4-chroman) carbamate (yield: 88.3%). LCMS: m / z (ESI), [M+Na] + =350.0; 1 H NMR(400MHz,DMSO)δ7.41(d,J=7.6Hz,1H),7.16-7.09(m,2H),6.81(dd,J=8.0,1.2Hz,1H),4.6 3(s,1H),4.25(d,J=10.8Hz,1H),4.04(dd,J=17.2,6.4Hz,1H),1.98–1.78(m,2H),1.42(s,9H).

[0204] Step C: Synthesis of tert-butyl (5-bromo-4-chroman)(tert-butoxycarbonyl) carbamate

[0205] Tert-butyl (5-bromo-4-chroman) carbamate (3.8 g, 11.58 mmol), di-tert-butyl dicarbonate (5.05 g, 23.16 mmol) and 4-dimethylaminopyridine (2.83 g, 23.16 mmol) were dissolved in dimethyltetrahydrofuran (20 ml) and reacted at 60° C. for 12 hours.

[0206] After the reaction was complete, the mixture was cooled to room temperature and then dried by rotary evaporation. 20 ml of water was added and the mixture was extracted with ethyl acetate (30 ml x 2). The combined organic phases were washed with aqueous NaHCO₃, dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain 3.5 g of tert-butyl (5-bromo-4-chroman)(tert-butoxycarbonyl)carbamate (yield: 71.4%).

[0207] 1H NMR (400MHz, DMSO) δ7.19–7.08(m,2H),6.87–6.78(m,1H),5.26(t,J=4.2Hz, 1H),4.37-4.32(m,1H),4.27–4.15(m,1H),2.16–2.00(m,2H),1.34(s,18H).

[0208] Step D: Synthesis of tert-butyl (5-vinyl-4-chroman)(tert-butoxycarbonyl) carbamate

[0209] Tert-butyl (5-bromo-4-chroman)(tert-butoxycarbonyl) carbamate (3.5 g, 8.17 mmol), potassium ethylene trifluoroborate (1.42 g, 10.6 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (1.18 g, 1.63 mmol) and potassium carbonate (3.38 g, 24.5 mmol) were dissolved in dimethyl sulfoxide (30 ml), protected by nitrogen, and reacted at 100°C for 12 hours.

[0210] After the reaction was complete, the mixture was cooled to room temperature and filtered through celite. The filtrate was collected, 50 ml of water was added, and the mixture was extracted with ethyl acetate (40 ml x 3). The combined organic phases were washed with aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and spin-dried. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain 1.8 g of tert-butyl (5-vinyl-4-chroman)(tert-butoxycarbonyl)carbamate as a yellow oil (yield: 58.8%). 1 H NMR (400MHz, DMSO) δ7.15–7.06(m,1H),7.06(d,J=7.2Hz,1H),6.76-6.69(m,2H),5.65(dd,J=17.2,1.2Hz,1H),5.41( t,J=5.2Hz,1H),5.30–5.21(m,1H),4.36(dd,J=7.2,3.6Hz,1H),4.17–4.08(m,1H),2.17–2.02(m,3H),1.26(s,18H).

[0211] Step E: Synthesis of tert-butyl (5-formyl-4-chroman)(tert-butoxycarbonyl)carbamate

[0212] Tert-butyl (5-vinyl-4-chroman)(tert-butoxycarbonyl) carbamate (1.0 g, 2.67 mmol) was dissolved in a mixture of tetrahydrofuran (16 ml) and water (4 ml), and potassium osmate (98.2 mg, 0.267 mmol) was added to the reaction solution. After stirring at room temperature for 30 minutes, sodium periodate (2.28 g, 10.68 mmol) was added to the reaction solution, and the reaction was allowed to react at room temperature for 2 hours.

[0213] After the reaction was complete, 20 ml of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 ml x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and spun down to dryness. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain 600 mg of tert-butyl (5-formyl-4-chroman)(tert-butoxycarbonyl)carbamate as a yellow oil (yield: 60.0%). LCMS: m / z (ESI), [M+Na] + =400.1; 1 H NMR(400MHz,DMSO)δ10.02(s,1H),7.42–7.39(m,2H),7.14-7.01(m,1H),5.89(t,J =5.6Hz,1H),4.43–4.37(m,1H),4.23–4.18(m,1H),2.2-2.12(m,2H),1.26(s,18H).

[0214] Step F: Synthesis of ethyl 3-(((4-(bis(tert-butoxycarbonyl)amino)pyran-5-yl)methyl)amino)-1H-pyrrole-2-carboxylate

[0215] 3-Amino-2-ethoxycarbonylpyrrole hydrochloride (333 mg, 1.75 mmol) was dissolved in 6 ml of anhydrous ethanol, and then N,N-diisopropylethylamine (190 mg, 1.75 mmol) and glacial acetic acid (270 mg, 4.74 mmol) were added to the mixture. After stirring at room temperature for 10 minutes, tert-butyl (5-formyl-4-benzodihydropyran) (tert-butoxycarbonyl) carbamate (600 mg, 1.58 mmol) was added to the mixture. After stirring at room temperature for 2 hours, sodium cyanoborohydride (180 mg, 3.16 mmol) was added to the mixture, and the mixture was reacted at room temperature for 12 hours.

[0216] After the reaction was complete, the anhydrous ethanol in the reaction solution was removed by rotary evaporation. The mixture was extracted with 10 mL of water and ethyl acetate (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary evaporation. The resulting residue was purified using a reverse-phase column (eluent: 0.1% aqueous ammonia solution) to obtain 450 mg of ethyl 3-(((4-(bis(tert-butoxycarbonyl)amino)pyran-5-yl)methyl)amino)-1H-pyrrole-2-carboxylate (yield: 81.9%). 1 H NMR (400MHz, DMSO) δ10.78(s,1H),7.13(t,J=8.0Hz,1H),6.86(d,J=7.6Hz,1H),6.73–6.67(m,2H),5.63(s,1H),5.52(t,J=2.4Hz,1H),5.4 3(t,J=4.4Hz,1H),4.47–4.34(m,1H),4.35–4.21(m,1H),4.24–4.08(m,4H),2.13-2.09(m,2H),1.26(m,18H),1.18(dd,J=9.2,5.2Hz,3H).

[0217] Step G: Synthesis of tert-butyl(tert-butoxycarbonyl)(5-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)chroman-4-yl)carbamate

[0218] Ethyl 3-(((4-(bis(tert-butoxycarbonyl)amino)pyran-5-yl)methyl)amino)-1H-pyrrole-2-carboxylate (450 mg, 0.87 mmol) and benzoyl isothiocyanate (171 mg, 1.05 mmol) were dissolved in methanol (10 ml) and stirred at room temperature for 3 hours. Cesium carbonate (567 mg, 1.74 mmol) was added and the reaction solution was reacted at 65°C for 2 hours.

[0219] After the reaction was completed, the anhydrous methanol in the reaction solution was dried by rotary evaporation. The mixture was extracted with 20 ml of water and ethyl acetate (20 ml x 2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The resulting residue was purified by reverse phase column purification (eluent: 0.1% ammonium bicarbonate solution) to obtain 400 mg of tert-butyl (tert-butoxycarbonyl) (5-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)chroman-4-yl)carbamate (yield: 86.9%). LCMS: m / z (ESI), [M+H] + =529.0; 1H NMR (400MHz, DMSO) δ7.33(t,J=2.8Hz,1H),7.04(t,J=8.0Hz,1H),6.71(d,J=8.0Hz,1H),6.24(d,J=7.6Hz,1H),5.91(t,J=2.4Hz,1H),5 .71-5.67(m,1H),5.60(t,J=5.2Hz,1H),5.35(d,J=16.4Hz,1H),4.44-4.41(m,1H),4.21–4.17(m,1H),2.26-2.22(m,1H),1.32(s,18H).

[0220] Step H: Synthesis of 1-((4-aminochroman-5-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0221] Tert-butyl(tert-butoxycarbonyl)(5-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)chroman-4-yl)carbamate (200 mg, 0.37 mmol) was dissolved in ethyl acetate (10 mL). A hydrochloric acid / ethyl acetate solution (10 mL) was added to the reaction mixture and stirred at room temperature for 12 hours. The reaction mixture was then dried by rotary evaporation. The pH of the solution was then adjusted to 8 with aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate (15 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The resulting residue was purified by reverse phase column purification (eluent: 0.1% aqueous ammonia solution) to obtain 93.83 mg of 1-((4-aminochroman-5-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (yield: 68.4%). LCMS: m / z (ESI), [M+H] + =329.1; 1 H NMR (400MHz, DMSO-d6) δ7.29(d,J=2.9Hz,1H),6.96(t,J=7.9Hz,1H),6.64(d,J=8.1Hz,1H),6.21-6.15(m,2H),5.97( d,J=16.4Hz,1H),5.83(d,J=16.4Hz,1H),4.34-4.18(m,2H),4.15-4.05(m,1H),2.07-1.95(m,1H),1.87-1.79(m,1H).

[0222] Step I: Synthesis of compounds I-1 and I-2

[0223] Tert-butyl (tert-butoxycarbonyl) (5-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)chroman-4-yl)carbamate (200 mg, 0.38 mmol) was subjected to SFC separation ( Chiral separation was performed on an OZ column (250*25mm 10μm) using Supercritical CO2 and MEOH (+0.1% 7.0mol / l Ammonia in MEOH) as the mobile phase to obtain isomers I-1 (RT=4.18min, 70mg, yield=34%, ee>99%) and I-2 (RT=5.16min, 65mg, yield=32%, ee>99%).

[0224] Preparation of compound 6A:

[0225] Compound I-1 (200 mg, 0.37 mmol) was dissolved in ethyl acetate (10 mL). A hydrochloric acid / ethyl acetate solution (10 mL) was added to the reaction mixture and stirred at room temperature for 12 hours. The reaction mixture was spun down to dryness. The pH of the solution was then adjusted to 8 with aqueous sodium bicarbonate solution and extracted with ethyl acetate (15 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and spun down to dryness. The resulting residue was purified on a reverse phase column (eluent: 0.1% aqueous ammonia solution) to obtain 96.5 mg of compound 6A (R)-1-((4-aminochroman-5-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (yield: 77.8%). ee >99%. LCMS: m / z (ESI), [M+H] + =329.1; 1 H NMR (400MHz, DMSO-d6) δ7.28(d,J=2.8Hz,1H),6.95(t,J=7.9Hz,1H),6.64(d,J=8.1Hz,1H),6.21–6.13(m,2H),5.9 7(d,J=16.4Hz,1H),5.83(d,J=16.4Hz,1H),4.34–4.17(m,2H),4.11(s,1H),2.07–1.94(m,1H),1.88–1.76(m,1H).

[0226] Preparation of compound 6A hydrochloride:

[0227] (R)-tert-Butyl(tert-butoxycarbonyl)(5-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)chroman-4-yl)carbamate (200 mg, 0.37 mmol) was dissolved in ethyl acetate (10 mL). 4 M hydrochloric acid in ethyl acetate (10 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours. The mixture was filtered and washed with ethyl acetate to obtain 94 mg of (R)-1-((4-aminochroman-5-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one hydrochloride as a white solid (yield: 68%). LCMS: m / z (ESI), [M+H]+ = 329.1. 1 H NMR (400MHz, DMSO-d6) δ12.52(s,1H),12.38(s,1H),8.63(s,3H),7.36(t,J=3. 0Hz,1H),7.15(t,J=8.0Hz,1H),6.77(d,J=8.2Hz,1H),6.26(d,J=7.7Hz,1H),6 .16(t,J=2.5Hz,1H),5.93(d,J=16.6Hz,1H),5.71(d,J=16.6Hz,1H),4.89(s,1 H),4.45-4.36(m,1H),4.34-4.25(m,1H),2.39-2.31(m,1H),2.26-2.14(m,1H).

[0228] The single crystal structure of compound 6A hydrochloride is shown in Figure 1, and the specific crystal parameters are as follows:

[0229] Preparation of compound 6B:

[0230] Compound I-2 (200 mg, 0.37 mmol) was dissolved in ethyl acetate (10 mL). A hydrochloric acid / ethyl acetate solution (10 mL) was added to the reaction mixture and stirred at room temperature for 12 hours. The reaction mixture was spun down to dryness. The pH of the solution was then adjusted to 8 with aqueous sodium bicarbonate solution and extracted with ethyl acetate (15 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and spun down to dryness. The resulting residue was purified on a reverse phase column (eluent: 0.1% aqueous ammonia solution) to obtain 93.6 mg of compound 6B (S)-1-((4-aminochroman-5-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (yield: 75.3%). ee >99%. LCMS: m / z (ESI), [M+H] + =329.1.

[0231] The synthesis steps of compound 6B hydrochloride are the same as above. LCMS: m / z (ESI), [M+H] + =329.1. 1 H NMR (400MHz, DMSO-d6) δ12.52(s,1H),12.38(s,1H),8.63(s,3H),7.36(t,J=3. 0Hz,1H),7.15(t,J=8.0Hz,1H),6.77(d,J=8.2Hz,1H),6.26(d,J=7.7Hz,1H),6 .16(t,J=2.5Hz,1H),5.93(d,J=16.6Hz,1H),5.71(d,J=16.6Hz,1H),4.89(s,1 H),4.45–4.36(m,1H),4.34–4.25(m,1H),2.39–2.31(m,1H),2.26–2.14(m,1H).

[0232] Example 7 1-((8-amino-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, Compound 7A and Compound 7B

[0233] Synthesis route:

[0234] Step A: Synthesis of 8-bromo-1,2,3,4-tetrahydronaphthalene-1-amine

[0235] At room temperature, 8-bromo-3,4-dihydronaphthalen-1(2H)-one (500 mg, 2.22 mmol) was dissolved in ETOH (10 ml), and NH4OAC (1.7 g, 22.22 mmol) and NaBH3(CN) (700 mg, 11.11 mmol) were added, and the mixture was stirred at 100°C for 4 h.

[0236] After the reaction was completed, ethanol was removed by spin drying, and water (50 ml) was added to quench the reaction. The mixture was extracted with dichloromethane (50 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain 330 mg (1.47 mmol) of white solid product 8-bromo-1,2,3,4-tetrahydronaphthalene-1-amine (yield 66.0%). 1 H NMR (400MHz, DMSO-d6) δ7.40(d,J=7.3Hz,1H),7.16-6.94(m,2H),4.08–3.96(m,1H),2.88–2.56(m,2H),2.05–1.79(m,4H),1.74–1.56(m,2H).

[0237] Step B: Synthesis of tert-butyl (8-bromo-1,2,3,4-tetrahydronaphthalen-1-yl) carbamate

[0238] 8-Bromo-1,2,3,4-tetrahydronaphthalen-1-amine (330 mg, 1.46 mmol) was dissolved in DCM (30 mL) at room temperature, and TEA (440 mg, 4.38 mmol) and (BOC)2O (640 mg, 2.92 mmol) were added, and the mixture was stirred at room temperature for 12 hours.

[0239] After the reaction was completed, water (40 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to obtain 370 mg (1.14 mmol) of yellow liquid product tert-butyl (8-bromo-1,2,3,4-tetrahydronaphthalen-1-yl) carbamate (yield 78.0%). 1 H NMR (400MHz, DMSO-d6) δ7.42(t,J=4.5Hz,1H),7.22–7.04(m,3H),4.70(d,J=7.9Hz,1H),2.80–2.58(m,2H),1.93–1.54(m,4H),1.39(s,9H).

[0240] Step C: Synthesis of methyl tert-butyl (8-bromo-1,2,3,4-tetrahydronaphthalen-1-yl) (tert-butoxycarbonyl) carbamate

[0241] (8-Bromo-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate (370 mg, 1.14 mmol) was dissolved in 2-methyltetrahydrofuran, and DMAP (280 mg, 2.28 mmol) and (BOC)2O (500 mg, 2.21 mmol) were added, and the mixture was stirred at 50°C for 12 hours.

[0242] After the reaction was completed, water (40 ml) was added to quench the reaction, and the product was extracted with ethyl acetate (30 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to give 220 mg (0.52 mmol) of a colorless liquid product, methyl tert-butyl (8-bromo-1,2,3,4-tetrahydronaphthalen-1-yl) (tert-butoxycarbonyl) carbamic acid (yield 45.8%). 1 H NMR (400MHz, DMSO-d6) δ7.42(t,J=4.5Hz,1H),7.22–6.95(m,3H),4.70(d,J=7.9Hz,1H),2.82–2.56(m,2H),1.96–1.53(m,4H),1.39(s,18H).

[0243] Step D: Synthesis of tert-butyl(tert-butoxycarbonyl)(8-vinyl-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate

[0244] Methyl tert-butyl(8-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)(tert-butoxycarbonyl)carbamic acid (220 mg, 0.52 mmol), potassium vinyl trifluoroborate (100 mg, 0.78 mmol), Pd(ppf)Cl2 (36 mg, 0.05 mmol), K2CO3 (200 mg, 1.56 mmol) were dissolved in anhydrous dioxane (10 ml) and stirred at 100°C for 12 hours.

[0245] After the reaction was completed, water (40 mL) was added to quench the reaction, and the product was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to obtain 30 mg (0.08 mmol) of colorless liquid product tert-butyl (tert-butoxycarbonyl) (8-vinyl-1,2,3,4-tetrahydronaphthalen-1-yl) carbamate (yield 15.7%). 1 H NMR (400MHz, DMSO-d6) δ11.01–10.45(m,1H),7.24–6.91(m,3H),6.72(s,1H),5.75(s,1H),5.48(s,1H), 4.41–4.05(m,4H),2.89–2.63(m,1H),2.01(s,3H),1.62–1.55(m,1H),1.25(s,19H),0.89–0.67(m,2H).

[0246] Step E: Synthesis of tert-butyl(tert-butoxycarbonyl)(8-formyl-1,2,4-tetrahydronaphthalen-1-yl)carbamate

[0247] At room temperature, tert-butyl (tert-butoxycarbonyl) (8-vinyl-1,2,3,4-tetrahydronaphthalen-1-yl) carbamate (30 mg, 0.08 mmol) was dissolved in anhydrous THF (5 ml), K2OsO4 (5 mg, 0.01 mmol) was added, and after stirring at room temperature for 1 hour, NaIO4 (136 mg, 0.64 mmol) was added and stirred at room temperature for 1 hour.

[0248] After the reaction was completed, water (40 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to give 30 mg (0.08 mmol) of tert-butyl (tert-butoxycarbonyl) (8-formyl-1,2,4-tetrahydronaphthalen-1-yl) carbamate as a white solid product (yield 98.0%). 1 H NMR(400MHz,DMSO-d6)δ10.06(s,1H),7.61(dd,J=7.2,1.8Hz,1H),7.48–6.94(m,2H),5.9 1(t,d=6.6Hz,1H),2.88–2.64(m,2H),2.23–1.90(m,3H),1.75–1.56(m,2H),1.25(s,18H).

[0249] Step F: Synthesis of ethyl 3-((8-(bis(tert-butoxycarbonyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)amino)-1H-pyrrole-2-carboxylate

[0250] At room temperature, tert-butyl (tert-butoxycarbonyl) (8-formyl-1,2,4-tetrahydronaphthalen-1-yl) carbamate (30 mg, 0.08 mmol) was dissolved in anhydrous MeOH (5 ml), and DIEA (20 mg, 0.1 mmol) and ACOH (6 mg, 0.1 mmol) were added. After stirring at room temperature for 5 minutes, ethyl 3-amino-1H-pyrrole-2-carboxylate (14 mg, 0.1 mmol) was added. After stirring at room temperature for 1 hour, NaBH3(CN) (6 mg, 0.1 mmol) was added, and the mixture was stirred at room temperature for 1 hour.

[0251] After the reaction, methanol was removed by rotary evaporation, and water (40 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: acetonitrile:water = 5:1) to obtain 40 mg (0.08 mmol) of ethyl 3-((8-(bis(tert-butoxycarbonyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)amino)-1H-pyrrole-2-carboxylate as a white solid (yield 97.5%). LC-MS: [M+H] + =514.3. 1H NMR (400MHz, DMSO-d6) δ10.88–10.08(m,1H),7.20–6.93(m,3H),6.72(s,1H),5.75(s,1H),5.48(s,2H),4.35 –4.11(m,4H),2.87–2.63(m,2H),2.01(s,3H),1.62–1.48(m,1H),1.21(d,J=31.1Hz,19H),0.88–0.71(m,2H).

[0252] Step G: tert-Butyl(tert-butoxycarbonyl)(8-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate

[0253] At room temperature, ethyl 3-((8-(bis(tert-butoxycarbonyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)amino)-1H-pyrrole-2-carboxylate (40 mg, 0.08 mmol) was dissolved in anhydrous MeOH (5 ml), and benzoyl isothiocyanate (17 mg, 0.1 mmol) was added. The mixture was stirred at room temperature for 2 hours, and Cs2CO3 (104 mg, 0.32 mmol) was added, and the mixture was stirred at 65°C for 5 hours.

[0254] After the reaction was complete, water (40 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: acetonitrile:water = 5:1) to obtain 40 mg (0.08 mmol) of tert-butyl(tert-butoxycarbonyl)(8-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate as a white solid (yield 95.2%). LC-MS: [M+H] + =527.2. 1 H NMR (400MHz, DMSO-d6) δ12.41(d,J=65.8Hz,2H),7.33(s,1H),7.03(d,J=7.5Hz,2H),6.62-6.36(m,1H),5.91– 5.57(m,3H),5.47–5.26(m,1H),2.83–2.68(m,2H),2.01(s,3H),2.07(s,3H),1.69–1.59(m,2H),1.29(s,18H).

[0255] Step H: Synthesis of 1-((8-amino-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0256] Tert-butyl(tert-butoxycarbonyl)(8-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate (40 mg, 0.08 mmol) was dissolved in ethyl acetate (10 ml) at room temperature, and hydrochloric acid in ethyl acetate (10 ml) was added and stirred at room temperature for 2 hours.

[0257] Filter and wash with ethyl acetate to obtain 7 mg (0.02 mmol) of 1-((8-amino-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one hydrochloride (yield 26.9%). LC-MS: [M+H] + =327.2. 1 H NMR (400MHz, DMSO-d6) δ12.52(s,2H),8.21(s,3H),7.36(d,J=2.7Hz,1H),7.24-7.05(m,2H),6.57(d,J=7.5Hz,1H),6.14(d,J=15.5 Hz,1H),5.90(s,1H),5.86(s,1H),5.77(dd,J=6.8Hz,16.0Hz,2H),4.89(s,1H),2.84(m,2H),2.24–2.11(m,1H),1.98–1.82(m,3H).

[0258] Step I: Synthesis of compounds L-1 and L-2

[0259] Tert-butyl-(tert-butoxycarbonyl)(8-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate (1 g, 1.90 mmol) was sent to SFC for separation ( Chiral separation was performed on an OZ column (250*25mm 10μm) using Supercritical CO2 and MEOH (+0.1% 7.0mol / l Ammonia in MEOH) as the mobile phase to obtain isomers L-1 (RT=2.82min, 400mg, yield=40%, ee>99%) and L-2 (RT=3.87min, 450mg, yield=45%, ee>99%).

[0260] Preparation of compound 7A:

[0261] Compound L-1 (400 mg, 0.76 mmol) was dissolved in dichloromethane (10 mL). A solution of dioxane hydrochloride (5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated to dryness. The pH of the solution was then adjusted to 8 with aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate (15 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and spin-dried. The resulting residue was purified on a reverse-phase column (eluent: 0.1% aqueous ammonia solution) to obtain 208.42 mg of compound 7A (yield 84%). LCMS: [M+H]+ = 327.2; (ee > 99%, RT = 3.932 min, colum DEA C4OJ).

[0262] Preparation of compound 7B:

[0263] Compound L-2 (450 mg, 0.85 mmol) was dissolved in dichloromethane (10 mL). A solution of dioxane hydrochloride (5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated to dryness. The pH of the solution was then adjusted to 8 with aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate (15 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and spin-dried. The resulting residue was purified on a reverse-phase column (eluent: 0.1% aqueous ammonia solution) to yield 216.08 mg of compound 7B (yield 77%). LCMS: [M+H]+ = 327.2; (ee > 99%, RT = 3.770 min, colum DEA C4 OJ).

[0264] Examples 8-14

[0265] Referring to the preparation method of Example 6, the following compounds 8-14 were prepared respectively.

[0266] Example 15 1-((5-amino-2,3,4,5-tetrahydrobenzo[b]oxypyrimidin-6-yl)methyl)-2-thioxo-1,2,3,5-tetrahydroxy-4H-pyrrolo[3,2-d]pyrimidin-4-one, Compounds 15A and 15B

[0267] Step A: Synthesis of compounds tert-butyl (R)(tert-butoxycarbonyl)(6-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)-2,3,4.5-tetrahydrobenzo[b]oxypyrimidin-5-yl)carbamate and tert-butyl (S)(tert-butoxycarbonyl)(6-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)-2,3,4.5-tetrahydrobenzo[b]oxypyrimidin-5-yl)carbamate

[0268] Tert-butyl (R) (tert-butoxycarbonyl) (6-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)-2,3,4,5-tetrahydrobenzo[b]oxypyrimidin-5-yl)carbamate (380 mg, 0.70 mmol) was subjected to SFC separation ( Chiral separation was performed using an OJ column (250*25mm 10μm) with Supercritical CO2 and MEOH (+0.1% 7.0mol / l Ammonia in MEOH) as the mobile phase, and the solvent after separation was spin-dried at low temperature. 120 mg of white solid 15-1, tert-butyl (R or S) (tert-butoxycarbonyl) (6-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)-2,3,4.5-tetrahydrobenzo[b]oxypyrimidin-5-yl)carbamate (RT=1.46 min, ee>99%) and 115 mg of 15-2, tert-butyl (S or R) (tert-butoxycarbonyl) (6-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)-2,3,4.5-tetrahydrobenzo[b]oxypyrimidin-5-yl)carbamate (RT=2.47 min, ee>99%) were obtained respectively.

[0269] Step B: Synthesis of Compound 15A Hydrochloride

[0270] Tert-butyl (R)(tert-butoxycarbonyl)(6-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)-2,3,4,5-tetrahydrobenzo[b]oxypyrimidin-5-yl)carbamate (120 mg, 0.22 mmol) was dissolved in ethyl acetate (2 mL). Hydrochloric acid in ethyl acetate (4 mL) was added to the reaction mixture and stirred at room temperature for 2 hours. The reaction mixture was directly spin-dried. Without further purification, it was lyophilized to obtain 70.95 mg of 15A hydrochloride as a white solid.

[0271] LCMS: RT=1.233min, [Ms+H]+=343.2; 1H NMR(400MHz,DMSO)δ12.50(s,1H),12.39(s,1H),8.40(s,3H),7.33(s,1H),7. 19(t,J=8.0Hz,1H),6.98(d,J=8.0Hz,1H),6.42(d,J=8.0Hz,1H),6.22(d,J=2. 0Hz,1H),6.01(d,J=16.4Hz,1H),5.74(d,J=16.4Hz,1H),4.89(s,1H),4.46(d ,J=11.2Hz,1H),3.62(t,J=11.6Hz,1H),2.35–2.20(m,2H),1.87-1.80(m,2H).

[0272] Step C: Synthesis of Compound 15B Hydrochloride

[0273] Tert-butyl (S)(tert-butoxycarbonyl)(6-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)-2,3,4,5-tetrahydrobenzo[b]oxypyrimidin-5-yl)carbamate (115 mg, 0.21 mmol) was dissolved in ethyl acetate (2 mL). Hydrochloric acid in ethyl acetate (4 mL) was added to the reaction mixture and stirred at room temperature for 2 hours. The reaction mixture was directly spin-dried. Without further purification, it was lyophilized to obtain 70.28 mg of 15B hydrochloride as a pink solid.

[0274] LCMS: RT=1.223min, [Ms+H]+=343.2; 1H NMR (400MHz, DMSO) δ12.50(s,1H),12.38(s,1H),8.42(s,3H),7.33(t,J=2.8H z,1H),7.19(t,J=8.0Hz,1H),6.98(d,J=8.0Hz,1H),6.41(d,J=7.6Hz,1H),6.2 4(s,1H),6.01(d,J=16.4Hz,1H),5.74(d,J=16.4Hz,1H),4.88(s,1H),4.46(d ,J=11.2Hz,1H),3.62(t,J=11.6Hz,1H),2.34-2.25(m,2H),1.81-1.80(m,2H).

[0275] Example 16 1-(4-aminobenzopyran-5-yl)methyl)-7-methyl-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0276] Synthesis route:

[0277] Step A: Synthesis of compound 3-((4-(bis(tert-butoxycarbonyl)amino)chroman-5-ylmethyl)amino)-4-methylpyrrole-2-carboxylic acid ethyl ester

[0278] Ethyl 3-amino-4-methylpyrrole-2-carboxylate (80 mg, 0.39 mmol) and DIEA (0.07 ml, 0.39 mmol) were added to ethanol (10 ml) at room temperature and allowed to react for 5 minutes. Glacial acetic acid (0.02 ml, 0.39 mmol) was then added and the mixture was allowed to react for 30 minutes at room temperature. Tert-butyl (tert-butyloxycarbonyl) (5-formylchroman-4-yl) carbamate (124 mg, 0.33 mmol) was then added and allowed to react for 1 hour at room temperature. Sodium cyanoborohydride (62 mg, 0.99 mmol) was then added and the mixture was allowed to react for 12 hours at room temperature. Upon completion of the reaction, the ethanol in the reaction mixture was evaporated, water (20 ml) was added, and the mixture was extracted with ethyl acetate (20 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by reverse phase column chromatography (eluent: 0.1% aqueous ammonium bicarbonate:acetonitrile = 65%) to give 90 mg of ethyl 3-((4-(bis(tert-butoxycarbonyl)amino)chroman-5-ylmethyl)amino)-4-methylpyrrole-2-carboxylate as a white solid product (yield: 51.72%).

[0279] LC-MS: [M+H]+=529.63; 1H NMR (400MHz, DMSO) δ10.60(s,1H),7.17(t,J=7.9Hz,1H),6.95(d,J=7.5Hz,1H),6.71(d,J=8.2Hz,1H),6.58(d,J=3.1Hz,1H),5.46–5. 28(m,2H),4.47–4.32(m,2H),4.17(dt,J=10.6,9.8Hz,4H),2.12–2.02(m,2H),2.01(d,J=11.0Hz,3H),1.23(dd,J=13.8,6.5Hz,21H).

[0280] Step B: Synthesis of compound tert-butyl (5-((7-methyl-4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)chroman-4-yl)carbamate

[0281] Ethyl 3-((4-(bis(tert-butoxycarbonyl)amino)chroman-5-ylmethyl)amino)-4-methylpyrrole-2-carboxylate (90 mg, 0.17 mmol) and benzoyl isothiocyanate (0.04 ml, 0.2 mmol) were added to 10 ml of anhydrous methanol at room temperature and reacted for 2 hours. Cesium carbonate (222 mg, 0.68 mmol) was then added and the mixture was reacted at 65°C for 2 hours. After the reaction, the methanol in the reaction solution was evaporated, water (20 ml) was added, and the mixture was extracted with ethyl acetate (30 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by reverse phase column chromatography (eluent: 0.1% aqueous ammonium bicarbonate solution: acetonitrile = 65%) to give 90 mg of a white solid product, tert-butyl (5-((7-methyl-4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)chroman-4-yl)carbamate (yield: 97.61%).

[0282] LC-MS: [M+H]+=542.65; 1H NMR (400MHz, DMSO) δ12.31(s,2H),7.10(dd,J=33.8,25.9Hz,2H),6.73(d,J=8.1Hz,1H),6.26(s,1H),6.03–4.80(m, 3H), 4.41 (s, 1H), 4.19–4.03 (m, 1H), 2.24 (d, J = 22.5Hz, 2H), 1.99 (dd, J = 45.5, 37.5Hz, 3H), 1.28 (d, J = 32.4Hz, 18H).

[0283] Step C: Synthesis of compound 1-(4-aminobenzopyran-5-yl)methyl)-7-methyl-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one hydrochloride

[0284] Tert-butyl (5-((7-methyl-4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)chroman-4-yl)carbamate (90 mg, 0.17 mmol) was dissolved in DCM (10 mL) at room temperature, and hydrochloric acid-ethyl acetate (1.3 mL, 5 mmol) was added. The mixture was allowed to react at room temperature for 12 hours. After the reaction, the dichloromethane was evaporated. The resulting residue was slurried in dichloromethane (30 mL) for 1 hour and filtered to obtain 40 mg of the solid product, 1-(4-aminobenzopyran-5-yl)methyl)-7-methyl-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one hydrochloride (yield: 70.5%).

[0285] LC-MS: [M+H]+=342.42; 1H NMR (400MHz, DMSO) δ12.33(d,J=28.3Hz,2H),8.62(s,3H),7.20(t,J=8.0Hz,2H),6.80(d,J=8.2Hz,1H),6.33(d,J=7.5H z,1H),4.87(s,1H),4.40(d,J=7.9Hz,1H),4.28(t,J=12.1Hz,1H),2.36(t,J=14.3Hz,1H),2.14(dd,J=17.1,7.0Hz,1H).

[0286] Example 17 1-((4-aminochroman-5-yl)methyl)-7-methoxy-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0287] Synthesis route:

[0288] Step A: 5-Bromo-4-chroman-amine

[0289] 5-Bromo-4-chromanone (45 g, 198 mmol) was dissolved in anhydrous ethanol (500 mL) at room temperature. Ammonium acetate (124 g, 1.98 mol) and sodium cyanoborohydride (76 g, 0.99 mol) were added and the mixture was refluxed at 100°C for 12 hours. LC-MS indicated the reaction was complete. The solvent was removed from the solution by rotary evaporation, and water (300 mL) was added. The pH was adjusted to 10 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (500 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to yield 29 g of 5-bromo-4-chromanone as a white solid (yield: 64%).

[0290] 1 H NMR (400MHz, DMSO) δ7.16–7.01(m,2H),6.86–6.76(m,1H),4.32–4.17(m,2H),4.09–3.98(m,1H),1.96–1.77(m,2H).

[0291] Step B: Synthesis of compound tert-butyl (5-bromo-4-chroman-amine) carbamate

[0292] 5-Bromo-4-chroman-amine (29 g, 127 mmol), di-tert-butyl dicarbonate (56 g, 254 mmol), and triethylamine (39 g, 381 mmol) were dissolved in dichloromethane (300 ml) and reacted at room temperature for 12 hours. After the reaction, the reaction solution was added to 200 ml of water and extracted with dichloromethane (300 ml x 3). The combined organic phases were washed with aqueous NaHCO₃, dried over anhydrous sodium sulfate, filtered, and spin-dried. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain 30 g of tert-butyl (5-bromo-4-chroman)carbamate (yield: 71%).

[0293] 1 H NMR(400MHz,DMSO)δ7.41(d,J=7.6Hz,1H),7.16-7.09(m,2H),6.81(dd,J=8.0,1.2Hz,1H),4.6 3(s,1H),4.25(d,J=10.8Hz,1H),4.04(dd,J=17.2,6.4Hz,1H),1.98–1.78(m,2H),1.42(s,9H).

[0294] Step C: Synthesis of compound tert-butyl (5-bromo-4-chroman)(tert-butoxycarbonyl) carbamate

[0295] Tert-butyl (5-bromo-4-chroman) carbamate (30 g, 91.4 mmol), di-tert-butyl dicarbonate (199 g, 914 mmol), and 4-dimethylaminopyridine (22 g, 183 mmol) were dissolved in dimethyltetrahydrofuran (300 ml) and reacted at 60°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and dried by rotary evaporation. 100 ml of water was added and the mixture was extracted with ethyl acetate (300 ml x 3). The combined organic phases were washed with aqueous NaHCO₃, dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain 32 g of tert-butyl (5-bromo-4-chroman)(tert-butoxycarbonyl) carbamate as a yellow solid (yield: 82%). 1 H NMR (400MHz, DMSO) δ7.19–7.08(m,2H),6.87–6.78(m,1H),5.26(t,J=4.2Hz, 1H),4.37-4.32(m,1H),4.27–4.15(m,1H),2.16–2.00(m,2H),1.34(s,18H).

[0296] Step D: Synthesis of the compound tert-butyl (5-vinyl-4-chroman)(tert-butoxycarbonyl) carbamate

[0297] Tert-butyl (5-bromo-4-chroman)(tert-butoxycarbonyl) carbamate (31 g, 72 mmol), potassium ethylene trifluoroborate (12.5 g, 93.6 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (5.2 g, 7.2 mmol), and potassium carbonate (2.9 g, 216 mmol) were dissolved in anhydrous 1,4-dioxane (300 ml) and water (75 ml) under nitrogen atmosphere at 100°C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered through Celite. The filtrate was collected, 100 ml of water was added, and the mixture was extracted with ethyl acetate (300 ml x 3). The combined organic phases were washed with aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and dried. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain 16 g of a yellow solid, tert-butyl (5-vinyl-4-chroman)(tert-butoxycarbonyl) carbamate (yield: 59%). 1 H NMR (400MHz, DMSO) δ7.15–7.06(m,1H),7.06(d,J=7.2Hz,1H),6.76-6.69(m,2H),5.65(dd,J=17.2,1.2Hz,1H),5.41( t,J=5.2Hz,1H),5.30–5.21(m,1H),4.36(dd,J=7.2,3.6Hz,1H),4.17–4.08(m,1H),2.17–2.02(m,3H),1.26(s,18H).

[0298] Step E: Synthesis of tert-butyl (5-formyl-4-chroman)(tert-butoxycarbonyl)carbamate

[0299] tert-Butyl (5-vinyl-4-chroman)(tert-butoxycarbonyl) carbamate (5 g, 13.3 mmol) was dissolved in a mixture of tetrahydrofuran (120 ml) and water (30 ml). Potassium osmate (490 mg, 1.33 mmol) was added to the reaction mixture, and after stirring at room temperature for 30 minutes, sodium periodate (11.4 g, 53.2 mmol) was added to the reaction mixture, and the mixture was allowed to react at room temperature for 2 hours. After the reaction, 50 ml of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 ml x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and spin-dried to dryness. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain 2.6 g of tert-butyl (5-formyl-4-chroman)(tert-butoxycarbonyl) carbamate as a yellow solid (yield: 52%). LCMS: m / z(ESI),[M+Na] + =400.1. 1H NMR(400MHz,DMSO)δ10.02(s,1H),7.42–7.39(m,2H),7.14-7.01(m,1H),5.89(t,J =5.6Hz,1H),4.43–4.37(m,1H),4.23–4.18(m,1H),2.2-2.12(m,2H),1.26(s,18H).

[0300] Step F: Synthesis of compound 3-(((4-(bis(tert-butoxycarbonyl)amino)pyran-5-yl)methyl)amino)-4-methoxy-1H-pyrrole-2-carboxylic acid ethyl ester

[0301] 3-Amino-4-methoxy-1H-pyrrole-2-carboxylic acid ethyl ester (118 mg, 0.64 mmol) was dissolved in 15 ml of anhydrous ethanol, and then N, N-diisopropylethylamine (83 mg, 0.64 mmol) and glacial acetic acid (38 mg, 0.64 mmol) were added to the mixture. After stirring at room temperature for 10 minutes, tert-butyl (5-formyl-4-chroman) (tert-butoxycarbonyl) carbamate (200 mg, 0.53 mmol) was added to the mixture. After stirring at room temperature for 2 hours, sodium cyanoborohydride (100 mg, 1.6 mmol) was added to the mixture, and the mixture was reacted at room temperature for 3 hours. After the reaction was completed, the anhydrous ethanol in the reaction solution was spin-dried. 20 ml of water and ethyl acetate (30 ml x 3) were extracted, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and spin-dried. The resulting residue was purified using a reverse phase column (eluent: 0.1% ammonium bicarbonate solution) to obtain 150 mg of ethyl 3-(((4-(bis(tert-butoxycarbonyl)amino)pyran-5-yl)methyl)amino)-4-methoxy-1H-pyrrole-2-carboxylate as a yellow solid (yield: 52%). LCMS: RT = 1.99 min, [Ms+H] + = 546; 1 H NMR (400MHz, DMSO) δ10.34(s,1H),7.11(t,J=7.9Hz,1H),6.88(d,J=7.5Hz,1H),6.65(d,J=8.2Hz,1H),6.54(d,J=3.5Hz,1H),5.41(s,1H) ,5.31(d,J=6.4Hz,1H),4.45(ddd,J=18.0,13.0,7.4Hz,3H),4.29–4.09(m,5H),3.55(s,3H),2.17–2.01(m,3H),1.25(d,J=10.1Hz,18H).

[0302] Step G: Synthesis of the compound tert-butyl(tert-butoxycarbonyl)(5-((7-methoxy-4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)pyran-4-yl)carbamate

[0303] Ethyl 3-(((4-(bis(tert-butoxycarbonyl)amino)pyran-5-yl)methyl)amino)-4-methoxy-1H-pyrrole-2-carboxylate (150 mg, 0.27 mmol) and benzoyl isothiocyanate (68 mg, 0.42 mmol) were dissolved in methanol (15 ml) and stirred at room temperature for 3 hours. Cesium carbonate (274 mg, 0.84 mmol) was then added, and the reaction mixture was reacted at 65° C. for 3 hours. Upon completion of the reaction, the anhydrous methanol in the reaction mixture was evaporated. The resulting residue was purified on a reverse-phase column (eluent: 0.1% ammonium bicarbonate solution) to provide 150 mg of tert-butyl(tert-butoxycarbonyl)(5-((7-methoxy-4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)pyran-4-yl)carbamate as a white solid (yield: 76%). LCMS: RT = 1.82 min, [Ms+H]+ = 559.

[0304] Step H: Synthesis of compound 1-((4-aminochroman-5-yl)methyl)-7-methoxy-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one hydrochloride

[0305] Tert-butyl(tert-butoxycarbonyl)(5-((7-methoxy-4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)pyran-4-yl)carbamate (150 mg, 0.27 mmol) was dissolved in EA (2 mL). A hydrochloric acid / ethyl acetate solution (2 mL, 8.1 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered to obtain a crude white solid. The resulting filter cake was lyophilized to yield 35 mg of 1-((4-aminochroman-5-yl)methyl)-7-methoxy-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one hydrochloride as a white solid. LCMS: RT=1.29min, [Ms+H]+=359; 1H NMR (400MHz, DMSO) δ12.35(s,1H),12.14(s,1H),8.59(s,3H),7.25–7.10(m,2H),6.76(d,J=8.2Hz,1H),6.43(d,J=7.7Hz,1H),6.31–5.95 (m,1H),5.55(s,1H),4.87(s,1H),4.37(dt,J=20.6,10.4Hz,2H),3.60(d,J=29.0Hz,3H),2.43(d,J=14.8Hz,1H),2.13(t,J=13.8Hz,1H).

[0306] Example 18: In vitro evaluation of the inhibitory effect of the compounds of the present invention on human myeloperoxidase (hMPO) activity

[0307] 50 μL of 2× substrate (composed of 3'-(p-aminophenyl)fluorescein and H2O2, 3'-(p-aminophenyl)fluorescein and H2O2 are both Km concentrations, purchased from Invitrogen, A36003) was added to a black opaque low protein adsorption 96-well plate (purchased from PerkinElmer, 6005270), and 45 μL of different concentrations of 2× compound (DMSO final concentration is 1%) was added. After thorough pipetting and mixing, 5 μL of 2μg / mL human myeloperoxidase (purchased from PLANTA NATURAL, 700-03-001) was added and mixed. The fluorescence value of 0-30 min (read every 20 s) was immediately read using a microplate reader at Ex / Em: 488 / 520 nm wavelength using kinetic mode. Calculate the inhibitory effect of different concentrations of compound: Inhibition rate (%) = [1-(Slope Control -Slope cpd ) / Slope Control –Slope Blank)]*100, where Slope Blank SlopeControl is the slope of the control without compound and the MPO well from 0 to 5 min (Ex / Em: 544 / 620 nm reading / reaction time t); SlopeControl is the slope of the well without compound (containing 1% DMSO) from 0 to 5 min (linear reaction stage); Slope cpd The slope of the compound from 0 to 5 min was calculated by fitting a 4-parameter nonlinear regression curve with the logarithm of the compound concentration as the horizontal axis and the inhibition rate as the vertical axis. 50 Value(Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)), where Hillslope represents the slope of the fitting curve, IC 50 The results are shown in Table 1.

[0308] Table 1 Inhibitory activity of compounds on the peroxidative cycle of human myeloperoxidase (hMPO) in vitro Conclusion: The compounds of the present invention have the effect of inhibiting hMPO activity.

[0309] Example 19: Pharmacokinetic study of the compounds of the present invention in rats

[0310] 19.1 Experimental Materials

[0311] SD rats: male, 180-350 g, purchased from Zhejiang Weitonglihua Experimental Animal Technology Co., Ltd.

[0312] Reagents: DMSO (dimethyl sulfoxide), PEG-400 (polyethylene glycol 400), normal saline, acetonitrile, formic acid, and propranolol (internal standard) are all commercially available.

[0313] Instrument: Thermo Fisher LC-MS (Ultimate 3000 UPLC, TSQ QUANTUMN ULTRA triple quadrupole mass spectrometer).

[0314] 19.2 Experimental Methods

[0315] Compounds were weighed and dissolved in DMSO-PEG-400-saline (5:60:35, v / v / v). After intravenous or oral administration, 200 μL of venous blood was collected from rats at 15, 30, 1, 2, 5, 7, and 24 hours (5 minutes additionally for the IV group) in EDTA-K2 anticoagulant tubes. The blood was centrifuged at 10,000 rpm for 2 minutes, and plasma was frozen at -80°C for analysis. A precisely weighed amount of test compound was dissolved in DMSO to 2 mg / mL to prepare a stock solution. An appropriate amount of the stock solution was accurately aspirated and diluted with acetonitrile to prepare a series of standard solutions. 4 μL of each standard solution was accurately aspirated and added to 36 μL of blank plasma. Vortex-mixed, the resulting plasma samples were prepared at concentrations equivalent to 1, 3, 5, 10, 30, 100, 300, 1000, and 3000 ng / mL. Duplicate samples were analyzed at each concentration to construct a standard curve. 30 μL of plasma (5, 15, and 30 minutes after intravenous administration, diluted 5-fold) was collected and added with propranolol acetonitrile solution (internal standard, 50 ng / mL) to precipitate protein. 100 μL of water was then added and vortexed to mix thoroughly. The mixture was centrifuged at 4000 rpm for 5 minutes, and the supernatant was analyzed by LC-MS. LC-MS detection conditions were as follows:

[0316] Chromatographic column: YMC-Triart C 18 50×3.0mmI.DS-3μm,12nm

[0317] Mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile, flow rate: 0.5 mL / min, gradient elution:

[0318] 19.3 Data Processing

[0319] After LC-MS detection of blood drug concentration, WinNonlin 6.1 software was used to calculate the pharmacokinetic parameters using the non-compartmental model method. The test results are shown in Table 2.

[0320] Table 2 Pharmacokinetic results of the compounds of the present invention in rats

[0321] From the experimental results in Table 2, it can be seen that the compound of the present invention is metabolized more slowly in rats and has a higher oral exposure and bioavailability.

[0322] Example 20: Enzyme induction test study of the compounds of the present invention

[0323] 20.1 Experimental Materials and Instruments

[0324] Materials: Williams' Medium E (without phenol red) was purchased from Sigma-Aldrich Trading Co., Ltd.; Williams' Medium E, human recombinant insulin, GlutaMAX, and HEPES were purchased from Life Technologies; Isotonic Percoll was purchased from General Electric; Fetal bovine serum was purchased from Corning; Dexamethasone was commercially available; CellTiter-Fluor TM The Cell Viability Assay kit was purchased from Promega; Taqman Gene Expression Assay probe (20×, CYP1A2, FAM labeled), Taqman Gene Expression Assay probe (20×, CYP2B6, FAM labeled), Taqman Gene Expression Assay probe (20×, CYP3A4, FAM labeled), and Taqman Gene Expression Assay probe (20×, ACTB, VIC labeled) were purchased from AB (Applied biosystems); human primary hepatocytes were purchased from BioIVT.

[0325] Instrument: QuantStudio 6.

[0326] 20.2 Experimental Design

[0327] Accurately weigh the test compound, positive inducer, negative inducer, and internal standard to prepare stock solutions of appropriate concentrations. Prepare cell recovery and incubation solutions, as well as reagents and consumables for mRNA extraction, reverse transcription, and quantitative PCR.

[0328] The frozen primary human hepatocytes were revived and seeded on appropriate cell culture plates at a certain density for monolayer cell culture to meet cell growth requirements.

[0329] Freshly prepared and preheated solutions containing positive / negative inducers or test substances (10 μM) were added to the corresponding wells. Duplicate wells were incubated for 3 consecutive days with daily changes of medium. CYP enzyme mRNA levels were then measured. mRNA extraction, reverse transcription, and quantitative fluorescence PCR were performed according to the relevant kit instructions.

[0330] 20.3 Experimental Results

[0331] The results of the induction effect of the test compounds on the CYP enzyme mRNA levels are shown in Table 3 below.

[0332] Table 3 Experimental results

[0333] It can be seen from the experimental results in Table 3 that the compound of the present invention has a lower induction risk than the compound of Example 3 (CN201580065064.2).

[0334] Example 21: Enzyme inhibition test study of the compounds of the present invention

[0335] 21.1 Experimental Materials and Instruments

[0336] Materials: Midazolam and testosterone were purchased from Cerilliant and PANPHY; ketoconazole was purchased from MCE; and human liver microsomes were purchased from Corning.

[0337] Instrument: AB Sciex5500+.

[0338] 21.2 Experimental Design

[0339] A phosphate buffered saline (100 mM, pH 7.4) system containing 0.2 mg / mL human liver microsomes was used to evaluate the inhibitory potential of the compounds against the cytochrome P450 enzyme CYP3A. The test concentrations of the compounds were 0.068, 0.206, 0.62, 1.85, 5.56, 16.67 and 50 μM. The positive substrates in the incubation system were 1 μM midazolam and 40 μM testosterone (CYP3A), respectively, and the concentration of the positive inhibitor ketoconazole (CYP3A) in the incubation system was 0.05 μM. The incubation was carried out at 37°C, and the reaction was initiated by adding NADPH solution with a final concentration of 1 mM. The incubation time was 10 minutes. After the incubation, all samples were added with 300 μL of acetonitrile solution containing 3% formic acid and internal standard (0.5 μM tolbutamide) to precipitate the protein and UPLC-MS / MS was used to detect the amount of metabolites produced by the labeled substrate to calculate the IC of the compound inhibition. 50 value.

[0340] 21.3 Experimental Results

[0341] IC of the test compound's inhibitory effect on CYP3A 50 See the table below for values.

[0342] Table 4 Experimental results

[0343] It can be seen from the experimental results in Table 4 that the compound of the present invention has a lower risk of inhibiting CYP3A than the compound of Example 3 (CN201580065064.2).

[0344] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. Compounds of formula (I): or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 、R 2 、R 3 、R 4 、R 5 independently selected from hydrogen, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, alkoxyalkyl, cycloalkyl, aryl or heteroaryl, wherein aryl and heteroaryl may be optionally substituted by one or more independently selected from halogen, hydroxy, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, and halogenated C 1-6 Alkyl substitution; X, Y are independently selected from O, CH2, NR 6 , R 6 independently selected from hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, alkoxyalkyl, cycloalkyl, hydroxy, amino, cyano, cyano-substituted C 1-6 Alkyl, amino substituted C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -(CH2) n -C(=O)-R 7 、-(CH2) n -C(=O)OR 8 、-(CH2) n -NHC(=O)-R 9 ; R 7 、R 8 、R 9 are independently selected from hydrogen, C 1-6 alkyl; n is 0, 1, 2 or 3.

2. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, characterized in that: The compound is shown in formula (II): Where: X, Y, R 1 , n are as defined above.

3. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, characterized in that: The C 1-6 The alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl; The C 2-6 The alkenyl group is selected from the group consisting of vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl. , 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl.

4. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, characterized in that: The C 1-6 Alkoxy is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentoxy, 1,2-dimethylpropoxy, isopentoxy, neopentoxy, n-hexoxy, isohexoxy, sec-hexoxy, tert-hexoxy, neohexoxy, 2-methylpentoxy, 1,2-dimethylbutoxy, 1-ethylbutoxy; the alkoxyalkyl group is selected from C 1-4 Alkoxy C 1-4 The alkyl group is further selected from methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl and the like.

5. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, characterized in that: The halogen is selected from fluorine, chlorine, bromine, iodine, halogenated C 1-6 Alkyl refers to C 1-6 More than one hydrogen atom in an alkyl group is replaced by a halogen. 1-6 Alkoxy refers to C 1-6 More than one hydrogen atom of the alkoxy group is replaced by a halogen, and the C 1-6 Alkyl refers to C 1-6 More than one hydrogen atom of the alkyl group is replaced by a cyano group, or an amino group is replaced by a C 1-6 Alkyl refers to C 1-6 One or more hydrogen atoms in the alkyl group are replaced by an amino group.

6. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, characterized in that: The aryl group is selected from phenyl; the heteroaryl group is selected from 5 to 12 membered heteroaryl groups, the 5 to 12 membered heteroaryl groups are selected from 7. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, characterized in that: The cycloalkyl group is selected from C 3-6 Cycloalkyl, C 3-6 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

8. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, characterized in that: The R 1 selected from hydrogen or chlorine; R 2 、R 3 、R 5 selected from hydrogen; R 4 is selected from hydrogen, methyl, methoxy; X is O, CH2, N-CH3, NC(=O)-O-CH2-CH3; Y is O, CH2, N-CH3; n is 0, 1, or 2.

9. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, characterized in that: Selected from the following compounds:

10. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, characterized in that: Selected from the following compounds:

11. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, characterized in that: The pharmaceutically acceptable salt refers to a salt prepared by a compound and a pharmaceutically acceptable acid or base.

12. A pharmaceutical composition, characterized in that The invention comprises the compound according to any one of claims 1 to 11, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

13. Use of the compound according to any one of claims 1 to 11, or its stereoisomers, tautomers, or pharmaceutically acceptable salts in the preparation of a medicament for treating myeloperoxidase-related diseases, preferably cardiovascular-related diseases.

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