TWI700281B - Benzazepine derivatives, preparation method and medical use thereof - Google Patents

Abstract

The present invention relates to a benzazepine derivative, a preparation method and medical use thereof. Specifically, the present invention relates to a novel benzazepine derivative represented by the formula (I), a preparation method thereof, and a pharmaceutical composition containing the same and an use thereof as a therapeutic agent, especially as a TLR8 agonist. Each substituent of the formula (I) is the same as defined in the specification.

Description

Benzazepine derivatives, their preparation methods and their applications in medicine

This application claims the priority of Chinese patent application CN201711396645.1 whose filing date is December 21, 2017. This application quotes the full text of the aforementioned Chinese patent application.

The present invention belongs to the field of medicine, and relates to a new benzazepine derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as a TLR8 promoter the use of.

Toll-like receptors (TLRs) are an important class of receptors involved in innate immunity. TLRs are monomeric transmembrane non-catalytic receptors, usually expressed in sentinel cells such as macrophages and dendritic cells, and can recognize structurally conserved molecules produced by microorganisms. Once these microorganisms break through physical barriers such as the skin or intestinal mucosa, they will be recognized by TLRs and then activate immune cell responses (Mahla, RS. et al., Front Immunol. 4: 248 (2013)). The ability of the immune system to widely recognize pathogenic microorganisms is partly due to the widespread existence of Toll-like immune receptors.

There are at least 10 different TLRs in mammals. Some of these receptor ligands and corresponding signal cascades have been identified. TLR8 is a member of the subgroup of TLRs (TLRs 3, 7, 8 and 9) and is limited to the endosomal compartment of cells that specifically recognize non-hex nucleic acids. TLR8 is mainly expressed in humans by monocytes, NK cells and myeloid dendritic cells (mDC). TLR8 promoters can cause the release of various pro-inflammatory cytokines, such as IL-6, IL-12, TNF-α and IFN-γ.

TLR8 plays an important role in the body's innate immunity and acquired immunity. As an immunomodulator, TLR8 promoters can be used for the treatment of various immune-related diseases, such as ovarian cancer, melanoma, non-small cell lung cancer, hepatocellular carcinoma, basal cell carcinoma, renal cell carcinoma, Myeloma, allergic rhinitis, asthma, chronic obstructive pneumonia (COPD), ulcerative colitis, liver fibrosis, HBV, Flaviviridae virus, HCV, HPV, RSV, SARS, HIV or influenza Virus infection and so on.

Since TLR8 and TLR7 are highly homologous, TLR8 promoters are also TLR7 promoters in most cases. Therefore, dual accelerators of TLR8 and TLR7 have been reported in many patents, such as WO2009111337, WO2011022508, WO2011017611, WO2011068233, WO2011139348, WO2012066336, WO2013033345. There are relatively few reports on TLR8 selective promoters, mainly VTX-2337 from VentiRX (WO2007024612) and GS-9688 from Gilead (WO2016141092). Therefore, it is still necessary to continue to develop safe and therapeutically more effective TLR8 promoters.

或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， 其中： R¹ 選自-NR³ R⁴ 、烷基、鹵代烷基、環烷基、雜環基、芳基和雜芳基，其中所述的烷基、環烷基、雜環基、芳基和雜芳基各自獨立地任選被選自鹵素、烷基、烷氧基、鹵代烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； R² 選自氫原子、烷基、鹵代烷基、羥烷基、氰基、環烷基、雜環基、芳基和雜芳基，其中所述的烷基、環烷基、雜環基、芳基和雜芳基各自獨立地任選被選自鹵素、烷基、烷氧基、鹵代烷基、鹵代烷氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、雜環基烷基、芳基和雜芳基中的一個或多個取代基所取代； R³ 和R⁴ 相同或不同，且各自獨立地選自氫原子、烷基、鹵代烷基、環烷基、雜環基、芳基和雜芳基，其中所述的烷基、環烷基、雜環基、芳基和雜芳基各自獨立地任選被選自烷基、烷氧基、鹵素、胺基、氰基、硝基、羥基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代；且 n為0或1。The object of the present invention is to provide a compound represented by general formula (I):

Or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein: R ^{1 is} selected from- NR ³ R ⁴ , alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently Optionally selected from one of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or Multiple substituents are substituted; R ^{2 is} selected from hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group, cyano group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein the alkyl group, ring Alkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro Substituted by one or more substituents in the group, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl; R ³ and R ^{4 are the} same or different, and are each independently selected from hydrogen atoms , Alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected Substituted by one or more substituents among alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; And n is 0 or 1.

或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， 其中： R³ 和R⁴ 為烷基，其中所述的烷基任選被選自烷氧基、鹵素、胺基、氰基、硝基、羥基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； R² 和n如通式(I)所示的化合物中所定義。In a preferred embodiment of the present invention, the compound represented by general formula (I) is a compound represented by general formula (II):

Or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein: R ³ and R ⁴ It is an alkyl group, wherein the alkyl group is optionally selected from alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Is substituted by one or more substituents; R ² and n are as defined in the compound represented by the general formula (I).

或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， 其中： R³ 和R⁴ 為烷基，其中所述的烷基任選被選自烷氧基、鹵素、胺基、氰基、硝基、羥基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； R² 如通式(I)所示的化合物中所定義。In a preferred embodiment of the present invention, the compound represented by general formula (I) is a compound represented by general formula (III):

Or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein: R ³ and R ⁴ It is an alkyl group, wherein the alkyl group is optionally selected from alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Is substituted by one or more substituents; R ^{2 is} as defined in the compound represented by general formula (I).

In a preferred embodiment of the present invention, the compound represented by the general formula (I), wherein the R ^{2 is} selected from a hydrogen atom, an alkyl group and a cyano group; preferably a hydrogen atom.

In a preferred embodiment of the present invention, the compound represented by the general formula (I), wherein the R ³ and R ⁴ are each independently methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl, tertiary butyl, secondary butyl or n-pentyl.

或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽。Typical compounds of the present invention include but are not limited to:

Or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

所述的掌性HPLC分析條件包括： 色譜柱為OD Phenomenex Lux Cellulose-1 150Í4.6mm, 5μm； 流動相為正己烷/乙醇/二乙胺=70/30/0.1，比例為體積比；柱溫為35℃；流速為1.0 ml/min；檢測波長為254 nm。In one embodiment of the present invention, the compound represented by the general formula (I) is a compound with a corresponding RT value of 7.039 minutes or 10.077 minutes for compound 1 under palm HPLC analysis conditions;

The palm HPLC analysis conditions include: chromatographic column is OD Phenomenex Lux Cellulose-1 150Í4.6mm, 5μm; mobile phase is n-hexane/ethanol/diethylamine=70/30/0.1, and the ratio is volume ratio; column temperature The temperature is 35°C; the flow rate is 1.0 ml/min; the detection wavelength is 254 nm.

或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽（其可以作為合成通式(I)所示化合物的中間體）， 其中： R^a 為胺基保護基，優選為三級丁氧羰基； R¹ 選自-NR³ R⁴ 、烷基、鹵代烷基、環烷基、雜環基、芳基和雜芳基，其中所述的烷基、環烷基、雜環基、芳基和雜芳基各自獨立地任選被選自鹵素、烷基、烷氧基、鹵代烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； R² 選自氫原子、烷基、鹵代烷基、羥烷基、氰基、環烷基、雜環基、芳基和雜芳基，其中所述的烷基、環烷基、雜環基、芳基和雜芳基各自獨立地任選被選自鹵素、烷基、烷氧基、鹵代烷基、鹵代烷氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、雜環基烷基、芳基和雜芳基中的一個或多個取代基所取代； R³ 和R⁴ 相同或不同，且各自獨立地選自氫原子、烷基、鹵代烷基、環烷基、雜環基、芳基和雜芳基，其中所述的烷基、環烷基、雜環基、芳基和雜芳基各自獨立地任選被選自烷基、烷氧基、鹵素、胺基、氰基、硝基、羥基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代；且 n為0或1。Another aspect of the present invention relates to a compound represented by general formula (IA):

Or its tautomers, mesosomes, racemates, enantiomers, diastereomers or mixtures thereof, or its pharmaceutically acceptable salts (which can be used as synthetic general formula (I) intermediate compounds represented), wherein: R ^a is an amino protecting group, preferably a three-butoxycarbonyl group; R ¹ is selected from -NR ³ R ^4, alkyl, haloalkyl, cycloalkyl, heterocyclyl, Aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, Substituted by one or more substituents in hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl; R ^{2 is} selected from hydrogen atom, alkyl, haloalkyl , Hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally Selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl and One or more substituents in the heteroaryl group are substituted; R ³ and R ^{4 are the} same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a hetero Aryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, alkoxy, halogen, amine, cyano, nitro, Substituted by one or more substituents among hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and n is 0 or 1.

The definition of each group of the compound represented by the general formula (IA) can be as described in the compound represented by the general formula (I).

Typical compounds of the general formula (IA) of the present invention include but are not limited to:

將通式(IA)所示的化合物脫保護，得到通式(I)所示的化合物； 其中： R^a 為胺基保護基，優選為三級丁氧羰基； R¹ 、R² 和n如通式(I)所示的化合物中所定義。Another aspect of the present invention relates to a preparation method of the compound represented by general formula (I), which comprises the following steps:

The compounds of formula (IA) shown deprotected to give compounds of general formula (I) shown; wherein: R ^a is an amino protecting group, preferably a three-butoxycarbonyl group; R ^1, R ² and n are as As defined in the compound represented by the general formula (I).

將通式(IIA)所示的化合物脫保護，得到通式(II)所示的化合物； 其中： R^a 為胺基保護基，優選為三級丁氧羰基； R² 、R³ 、R⁴ 和n如通式(II)所示的化合物中所定義。Another aspect of the present invention relates to a preparation method of the compound represented by general formula (II), which comprises the following steps:

The compound of the compound of formula (IIA) shown deprotected formula (II) shown; wherein: R ^a is an amino protecting group, preferably a three-butoxycarbonyl ^{group; R 2, R 3, R} 4 And n are as defined in the compound represented by the general formula (II).

將通式(IIIA)所示的化合物脫保護，得到通式(III)所示的化合物； 其中： R^a 為胺基保護基，優選為三級丁氧羰基； R² 、R³ 和R⁴ 如通式(III)所示的化合物中所定義。Another aspect of the present invention relates to a preparation method of the compound represented by general formula (III), which comprises the following steps:

The compound of formula (IIIA) shown deprotected to give a compound of formula (III) shown; wherein: R ^a is an amino protecting group, preferably a three-butoxycarbonyl group; R ^2, R ³ and R ⁴ As defined in the compound represented by general formula (III).

Another aspect of the present invention relates to a pharmaceutical composition containing the compound represented by the general formula (I) as described above or its tautomer, mesosome, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present invention further relates to a compound represented by the above-mentioned general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or Use of a mixture form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above in the preparation of a medicament for promoting TLR8.

The present invention further relates to a compound represented by the above-mentioned general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or The use of a mixture form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above in the preparation of a medicament for treating or preventing tumors.

The present invention further relates to a compound represented by the above-mentioned general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or The use of a mixture form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above in the preparation of a medicament for treating infections caused by viruses.

The present invention further relates to a method for promoting TLR8, which comprises combining the compound represented by general formula (I) as described above or its tautomer, meso, racemate, enantiomer, non- Enantiomers, or their mixture forms or their pharmaceutically acceptable salts, or the step of contacting the pharmaceutical composition with TLR8 as described above.

The present invention further relates to a method for treating or preventing tumors, which comprises administering to a patient a therapeutically effective amount of the compound represented by the general formula (I) or its tautomers, mesosomes, racemics Isomers, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as described above.

The present invention further relates to a method for treating infections caused by viruses, the method comprising administering to a patient a therapeutically effective amount of the compound represented by the general formula (I) or its tautomer or meso , Racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as described above.

The present invention further relates to a compound represented by the above-mentioned general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or A mixture form or a pharmaceutically acceptable salt thereof, or a drug containing the same, which is used as a drug.

The present invention further relates to a compound represented by the above-mentioned general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, or a drug containing the same, it is used to promote TLR8.

The present invention further relates to a compound represented by the above-mentioned general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, or a drug containing the same, which is used to treat or prevent tumors.

The present invention further relates to a compound represented by the above-mentioned general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, or a drug containing the same, it is used to treat or prevent infections caused by viruses.

The tumor of the present invention is selected from cancer, preferably selected from melanoma, lung cancer, liver cancer, basal cell carcinoma, kidney cancer, myeloma, biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, Rectal cancer, head and neck cancer, peritoneal cancer, fallopian tube cancer, endometrial cancer, esophageal cancer, stomach cancer, leukemia, lymphoma, sarcoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, skin Cancer and thyroid cancer.

The virus of the present invention can be selected from dengue fever virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis virus, Saint Louis encephalitis virus, Encephalitis virus Musk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus, HIV, HBV, HCV, HPV, RSV, SARS and influenza viruses.

The dosage of the compound or composition used in the treatment method of the present invention will generally vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compound. However, as a general guide, a suitable unit dose can be 0.1 to 1000 mg.

In addition to the active compound, the pharmaceutical composition of the present invention may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions. Such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives to provide pleasing to the eye And delicious medicinal preparations. The tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing. These excipients can be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

Oral preparations can also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or the active ingredient is mixed with a water-soluble carrier or oil vehicle.

Aqueous suspensions contain the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending agents, dispersing agents or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

Oil suspensions can be formulated by suspending the active ingredients in vegetable oil or mineral oil. The oil suspension may contain thickening agents. The above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

The pharmaceutical composition of the invention may also be in the form of an oil-in-water emulsion. The oil phase can be vegetable oil, or mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives and antioxidants. Such preparations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.

The pharmaceutical composition of the present invention may be in the form of a sterile injectable aqueous solution. Acceptable solvents or solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. The sterile injection preparation may be a sterile injection oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injection or microemulsion can be injected into the patient's bloodstream by local mass injection. Alternatively, it is best to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS. TM. 5400 intravenous pump.

The pharmaceutical composition may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injection preparation may also be a sterile injection solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, sterile fixed oil can be conveniently used as a solvent or suspension medium.

The compounds of the present invention can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thus will melt in the rectum to release the drug. Such substances include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycol.

As is well known to those skilled in the art, the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, The patient’s diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the best treatment mode, such as the mode of treatment, the daily dosage of compound (I), or the type of pharmaceutically acceptable salt It can be verified according to the traditional treatment plan.

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably containing 1 to 6 carbons Atom of the alkyl group. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, secondary butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 -Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, di Butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl Group, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methyl Benzylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available point of attachment. The substituents are independently optionally selected from halogen, alkyl, haloalkyl, alkoxy Group, haloalkoxy, alkylthio, alkylamino, alkenyl, alkynyl, mercapto, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, hetero One or more substituents among aryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo groups are substituted.

The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl and cycloalkyl are as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, and the substituent is independently optionally selected from halogen, alkyl, haloalkyl , Alkoxy, haloalkoxy, alkylthio, alkylamino, alkenyl, alkynyl, mercapto, hydroxyl, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclic, aromatic Group, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo group are substituted by one or more substituents.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 Carbon atoms (e.g. 3, 4, 5 or 6 carbon atoms), most preferably 5 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.

。The term "spirocycloalkyl" refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings. It may contain one or more double bonds, but none of the rings have complete conjugate Π electronic system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the ring and the ring, the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

.

。The term "fused cycloalkyl" refers to a 5- to 20-membered, all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system. One or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl. Non-limiting examples of fused cycloalkyl groups include:

.

。The term "bridged cycloalkyl" refers to a 5- to 20-membered all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a complete Conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). It can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

.

The cycloalkyl ring includes the above-mentioned cycloalkyl group fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl , Tetrahydronaphthyl, benzocycloheptyl, etc.; preferably phenylcyclopentyl, tetrahydronaphthyl. Cycloalkyl groups can be optionally substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment. The substituents are independently optionally selected from halogen, alkyl, haloalkyl , Alkoxy, haloalkoxy, alkylthio, alkylamino, alkenyl, alkynyl, mercapto, hydroxyl, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclic, aromatic Group, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo group are substituted by one or more substituents.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) _m (where m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably contains 3 to 8 ring atoms (for example, 3, 4, 5, 6, 7, 8, 9 or 10 members), of which 1 to Three are heteroatoms; most preferably contain 5 to 6 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyranyl Hydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidyl, and pyrrolidinyl. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

。The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5- to 20-membered monocyclic rings, in which one or more ring atoms are selected from nitrogen, oxygen or S(O ) _m (where m is an integer of 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiro atoms between the ring and the ring, the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group. Non-limiting examples of spiroheterocyclic groups include:

.

。The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated π-electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), and the rest of the ring The atom is carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

.

。The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings have a complete common A conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

.

。The heterocyclic ring includes the above heterocyclic group fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples thereof include:

.

The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is independently optionally selected from halogen, alkyl, haloalkyl , Alkoxy, haloalkoxy, alkylthio, alkylamino, alkenyl, alkynyl, mercapto, hydroxyl, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclic, aromatic Group, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo group are substituted by one or more substituents.

； 芳基可以是取代的或非取代的，當被取代時，取代基可以在任何可使用的連接點上被取代，所述取代基獨立地任選選自鹵素、烷基、鹵代烷基、烷氧基、鹵代烷氧基、烷硫基、烷基胺基、烯基、炔基、巰基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基和氧代基中的一個或多個取代基所取代。The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated π-electron system, preferably 6 to 10 members, such as benzene Base and naphthyl. The aryl ring includes the above-mentioned aryl group fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:

; Aryl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point, and the substituents are independently optionally selected from halogen, alkyl, haloalkyl, alkane Oxy, haloalkoxy, alkylthio, alkylamino, alkenyl, alkynyl, mercapto, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, Heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo are substituted by one or more substituents.

。The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 membered (for example, 5, 6, 7, 8, 9 or 10 membered), containing 1 to 3 heteroatoms; more preferably 5 membered or 6 membered, containing 1 to 2 heteroatoms; Preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, 1 H -1,2,3-triazolyl, 4 H -1,2,4-triazolyl , 4 H -1,2,3-triazolyl, 1 H -tetrazolyl, 2 H -tetrazolyl, 5 H -tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., Preferably it is imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or imidazolyl. The heteroaryl ring includes the above-mentioned heteroaryl group fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:

.

Heteroaryl groups can be optionally substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment, and the substituents are independently optionally selected from halogen, alkyl, haloalkyl , Alkoxy, haloalkoxy, alkylthio, alkylamino, alkenyl, alkynyl, mercapto, hydroxyl, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclic, aromatic Group, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo group are substituted by one or more substituents.

The term "amino group protecting group" is to keep the amine group unchanged when other parts of the molecule react, and to protect the amine group with a group that is easy to remove. Non-limiting examples include tertiary butoxycarbonyl, acetyl, benzyl, allyl, 2,4-dimethoxybenzyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro. The amine protecting group is preferably a tertiary butoxycarbonyl group.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above.

The term "hydroxyl" refers to the -OH group.

The term "hydroxyalkyl" refers to an alkyl group substituted by a hydroxy group, where the alkyl group is as defined above.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "amino" refers to -NH ₂ .

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

The term "oxo or oxo" refers to =O.

"Optional" or "optionally" means that the event or environment described later can but need not occur, and the description includes the occasion where the event or environment occurs or does not occur. For example, "a heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may but does not have to be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group .

"Substituted" refers to one or more hydrogen atoms in the group, preferably at most 5, and more preferably 1 to 3 hydrogen atoms are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amine group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond.

When any variable (such as R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, and R has independent options in each case. In addition, combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredients and thus the biological activity.

"Pharmaceutically acceptable salt" refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has due biological activity.

The present invention introduces a cyclized sulfinimide group, which is different from the heterocyclic group substituted by an oxo group in the prior art, and it can act as a hydrogen bond acceptor to form a good hydrogen bond with TLR8 to improve activity. Therefore, the present invention provides a new pharmaceutical compound with good selectivity and more obvious activation effect, which is a safer and more effective TLR8 promoter.

Synthesis method of the compound of the present invention

In order to accomplish the purpose of the present invention, the present invention adopts the following technical solutions:

Option One

將通式(IA)所示的化合物在酸性條件下脫保護，得到通式(I)所示的化合物； 其中： R^a 為胺基保護基，優選為三級丁氧羰基； R¹ 、R² 和n如通式(I)所示的化合物中所定義。The compound represented by the general formula (III) of the present invention or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its medicine The preparation method of the salt used includes the following steps:

The compounds of formula (IA) as shown in the de-protection under acidic conditions, to give compounds of general formula (I),; wherein: R ^a is an amino protecting group, preferably a three-butoxycarbonyl group; R ^1, R ² and n are as defined in the compound represented by the general formula (I).

Reagents that provide acidic conditions include, but are not limited to, hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me ₃ SiCl and TMSOTf are preferably trifluoroacetic acid.

The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfide, 1 ,4-Dioxane, water, N , N -dimethylformamide and mixtures thereof.

Option II

將通式(IIA)所示的化合物在酸性條件下脫保護，得到通式(II)所示的化合物； 其中： R^a 為胺基保護基，優選為三級丁氧羰基； R² 、R³ 、R⁴ 和n如通式(II)所示的化合物中所定義。The compound represented by the general formula (IIII) of the present invention or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or medicines thereof The preparation method of the salt used includes the following steps:

The compound of the compound of formula (IIA) shown deprotected under acidic conditions to give the general formula (II); wherein: R ^a is an amino protecting group, preferably a three-butoxycarbonyl group; R ^2, R ^3. R ⁴ and n are as defined in the compound represented by the general formula (II).

Reagents that provide acidic conditions include, but are not limited to, hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me ₃ SiCl and TMSOTf are preferably trifluoroacetic acid.

The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfide, 1 ,4-Dioxane, water, N , N -dimethylformamide and mixtures thereof.

third solution

將通式(IIIA)所示的化合物在酸性條件下脫保護，得到通式(III)所示的化合物； 其中： R^a 為胺基保護基，優選為三級丁氧羰基； R² 、R³ 和R⁴ 如通式(III)所示的化合物中所定義。The compound represented by the general formula (IIIII) of the present invention or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its medicine The preparation method of the salt used includes the following steps:

The compound of formula (IIIA) as shown in the de-protection under acidic conditions, to give compounds of general formula (III) shown; wherein: R ^a is an amino protecting group, preferably a three-butoxycarbonyl group; R ^2, R ³ and R ⁴ are as defined in the compound represented by the general formula (III).

Reagents that provide acidic conditions include, but are not limited to, hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me ₃ SiCl and TMSOTf are preferably trifluoroacetic acid.

The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfide, 1 ,4-Dioxane, water, N , N -dimethylformamide and mixtures thereof.

detailed description

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (d) is given in units of 10 ^-6 (ppm). NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four Methyl Silane (TMS).

The MS was measured with a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

High performance liquid chromatography (HPLC) analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.

The hand-held HPLC analysis and determination used Agilent 1260 DAD high performance liquid chromatograph.

Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson-281 preparative chromatographs were used for HPLC preparation.

For palm preparation, Shimadzu LC-20AP preparative chromatograph was used.

CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15 mm～0.2 mm, and the size of thin layer chromatography separation and purification products is 0.4 mm ~0.5 mm.

The silica gel column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

The average value of ₅₀ measured kinase inhibition rate and IC NovoStar using a microplate reader (BMG, Germany).

The known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Companies such as Darui Chemicals.

There is no special description in the examples, and the reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.

The argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.

The hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.

The microwave reaction uses a CEM Discover-S 908860 microwave reactor.

No special instructions in the examples, the solution refers to an aqueous solution.

There are no special instructions in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.

The monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC). The developing reagent used in the reaction, the eluent system of column chromatography used in the purification of the compound and the developing reagent system of thin-layer chromatography include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound. A small amount of triethylamine and acetic acid can also be added Adjust with alkaline or acidic reagents.

Example 1

2-amino-8-(1-imino-1-oxo-1λ ⁴ -dihydrobenzothiopyran-7-yl) -N , N -dipropyl-3 H -benzo[ b ] Aza-4-methylamide 1

first step

7-bromo-1-imino-1λ ⁴ -dihydrobenzothiopyran 1-oxide 1b

7-Bromodihydrobenzothiopyran 1a (1.6 g, 7.0 mmol, prepared by the well-known method " J. Med. Chem. , 2014, 57(1), 159-170") was added to 30 mL In methanol, ammonium carbonate (2.0 g, 21.0 mmol) and diacetoxy iodobenzene (11.9 g, 35.0 mmol) were added at room temperature. After the addition, the reaction was carried out at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, 20 mL ethyl acetate was added to the residue, the organic phase was washed with saturated sodium thiosulfate solution (20 mL×3), water (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate It was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to obtain the title product 1b (1.1 g, yield: 60.6%).

MS m/z (ESI): 260.3 [M+1].

Second step

1-imino-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1λ ⁴ -dihydrobenzothiopyran 1- Oxide 1c

Compound 1b (500 mg, 1.92 mmol), double pinacol borate (586 mg, 2.31 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ( 140 mg, 0.19 mmol) and potassium carbonate (795 mg, 5.76 mmol) were added to 10 mL of 1,4-dioxane and replaced with nitrogen three times. The reaction solution was heated to 80°C and stirred for 4 hours. The reaction solution was naturally cooled to room temperature, 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), and the organic phases were combined. The organic phases were respectively water (20 mL) and saturated sodium chloride solution (20 mL). ) Wash, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue obtained by silica gel column chromatography with eluent system B to obtain the title product 1c (410 mg, yield: 69.4%).

MS m/z (ESI): 308.1 [M+1].

third step

(4-(Dipropylaminomethanyl)-8-(1-imino-1-oxo-1λ ⁴ -dihydrobenzothiopyran-7-yl-3 H -benzo[ b ] Aza-2-yl)carbamic acid tertiary butyl ester 1e

Compound 1c (410 mg, 1.32 mmol), (8-bromo-4-(dipropylaminomethanyl)-3 H -benzo[ b ]azapyr-2-yl)aminocarboxylic acid tertiary Butyl ester 1d (410 mg, 0.89 mmol, prepared by the synthetic method of compound G disclosed on page 33 of the patent application "WO2016096778A1"), [1,1'-bis(diphenylphosphino)ferrocene] bis Palladium chloride (33 mg, 0.04 mmol) and potassium carbonate (370 mg, 2.65 mmol) were added to 10 mL of a mixed solvent of 1,4-dioxane and 2 mL of water, after the addition, nitrogen replacement was performed three times. The reaction solution was heated to 80°C and stirred for 1 hour. The reaction solution was naturally cooled to room temperature, 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), and the organic phases were combined. The organic phases were respectively water (20 mL) and saturated sodium chloride solution (20 mL). ) Wash, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue obtained by silica gel column chromatography with eluent system B to obtain the title product 1e (330 mg, yield: 66.2%).

MS m/z (ESI): 565.1 [M+1].

the fourth step

2-amino-8-(1-imino-1-oxo-1λ ⁴ -dihydrobenzothiopyran-7-yl) -N,N -dipropyl-3 H -benzo[ b ] Aza-4-methylamide 1

Compound 1e (330 mg, 0.58 mmol) was added to 10 ml of trifluoroacetic acid, the reaction solution was stirred at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure, 10 mL of ethyl acetate was added to the residue, and the organic phase was sequentially saturated with Sodium bicarbonate solution (10 mL×3), washed with water (10 mL), dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by high performance liquid preparation (Gilson-281, elution system: acetonitrile or water) From the residue, the title product 1 (150 mg, yield: 55.7%) was obtained.

MS m/z (ESI): 465.2 [M+1].

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.17 (d, 1H), 7.70 (dd, 1H), 7.62-7.51 (m, 1H), 7.46-7.35 (m, 2H), 7.31 (d, 1H), 6.85 (s, 1H), 3.63-3.26 (m, 8H), 3.08 (t, 2H), 2.99 (s, 2H), 2.63-2.36 (m, 2H), 2.03 (s, 1H), 1.74-1.51 ( m, 4H), 0.93 (t, 6H).

Examples 1-1, 1-2

( S )-2-Amino-8-(1-imino-1-oxo-1λ ⁴ -dihydrobenzothiopyran-7-yl) -N,N -dipropyl-3 H -benzene And [ b ]aza-4-methylamide 1-1

( R )-2-Amino-8-(1-imino-1-oxo-1λ ⁴ -dihydrobenzothiopyran-7-yl) -N,N -dipropyl-3 H -benzene And [ b ]aza-4-methylamide 1-2

Compound 1 (150 mg, 0.32 mmol) was prepared by palm (separation conditions: palm preparation column phenomonex cellulose-2, 21.2Í250mm, 5μm; mobile phase: ethanol (containing 0.1% diethylamine): n-hexane=30: 70, flow rate: 20 mL/min), collect the corresponding components, and concentrate under reduced pressure to obtain the title product (10 mg, 15 mg).

Single configuration compound (shorter retention time):

MS m/z (ESI): 464.8 [M+1].

Palm HPLC analysis: retention time 7.039 minutes, palm purity: 100% (Column: OD Phenomenex Lux Cellulose-1 150Í4.6mm, 5μm; column temperature: 35℃; flow rate: 1.0 ml/min; detection wavelength: 254 nm ; Mobile phase: n-hexane/ethanol/diethylamine=70/30/0.1(v/v/v)).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.17 (d, 1H), 7.71 (dd, 1H), 7.61 (s, 1H), 7.48-7.36 (m, 2H), 7.32 (d, 1H), 6.86 ( s, 1H), 3.67-3.31 (m, 6H), 3.08 (d, 2H), 3.03 (s, 2H), 2.54 (d,4H), 2.03 (s, 1H), 1.72-1.50 (m, 4H) , 0.95 (t, 6H).

Single configuration compound (longer retention time):

MS m/z (ESI): 464.8 [M+1].

Palm HPLC analysis: retention time 10.077 minutes, palm purity: 100% (Column: OD Phenomenex Lux Cellulose-1 150Í4.6mm, 5μm; column temperature: 35℃; flow rate: 1.0 ml/min; detection wavelength: 254 nm ; Mobile phase: n-hexane/ethanol/diethylamine=70/30/0.1(v/v/v)).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.17 (d, 1H), 7.71 (dd, 1H), 7.61 (s, 1H), 7.48-7.36 (m, 2H), 7.32 (d, 1H), 6.86 ( s, 1H), 3.67-3.31 (m, 6H), 3.08 (d, 2H), 3.03 (s, 2H), 2.54 (d, 4H), 2.03 (s, 1H), 1.72-1.50 (m, 4H) , 0.95 (t, 6H).

Example 2

2-amino-8-(1-imino-1-oxo-2,3-dihydro-1 H -1λ ⁴ -benzo[ b ]thiophen-6-yl)- N , N -dipropyl Group-3 H -benzo[ b ]azapyridine-4-methamide 2

first step

6-Bromo-1-imino-2,3-dihydro-1 H -1λ ⁴ -benzo[ b ]thiophene 1-oxide 2b

6-Bromo-2,3-dihydrobenzo[ b ]thiophene 2a (500 mg, 2.32 mmol, prepared by the synthesis method of compound 6-c disclosed on page 38 of the patent application "KR20140068637A") was added to In 20 mL of methanol, ammonium carbonate (1.2 g, 12.49 mmol) and diacetoxy iodobenzene (4.0 g, 11.76 mmol) were added at room temperature. After the addition, the reaction was carried out at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, 20 mL ethyl acetate was added to the residue, the organic phase was washed with saturated sodium thiosulfate solution (20 mL×3), water (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate Concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to obtain the title product 2b (75 mg, yield: 13.1%).

MS m/z (ESI): 247.1 [M+1].

Second step

(4-(Dipropylaminomethanyl)-8-(1-imino-1-oxo-2,3-dihydro-1 H -1λ ⁴ -benzo[ b ]thiophene-6- 3- H -benzo[ b ]aza-2-yl)carbamic acid tertiary butyl ester 2d

The compound 2b (50 mg, 0.20 mmol), (4-(dipropylaminomethyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxolane) Boran-2-yl)-3 H -benzo[ b ]azapyr-2-yl)aminocarboxylic acid tertiary butyl ester 2c (65 mg, 0.13 mmol, as disclosed on page 37 of the patent application "WO2016096778A1" Compound H was prepared by the synthetic method), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (10 mg, 0.014 mmol) and potassium carbonate (55 mg, 0.40 mmol) were added Into a mixed solvent of 5 mL of 1,4-dioxane and 1 mL of water, after the addition is completed, nitrogen replacement is performed three times, the reaction solution is heated to 80°C, and the reaction is stirred for 1 hour. The reaction solution was naturally cooled to room temperature, and 5 mL of water was added to the reaction solution, extracted with ethyl acetate (5 mL×3), and the organic phases were combined. The organic phases were respectively water (10 mL) and saturated sodium chloride solution (10 mL). ) Wash, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue obtained by silica gel column chromatography with eluent system B to obtain the title product 2d (45 mg, yield: 64.3%).

MS m/z (ESI): 551.5 [M+1].

third step

2-amino-8-(1-imino-1-oxo-2,3-dihydro-1 H -1λ ⁴ -benzo[ b ]thiophen-6-yl)- N , N -dipropyl Group-3 H -benzo[ b ]azapyridine-4-methamide 2

Compound 2d (45 mg, 0.082 mmol) was added to 5 ml of trifluoroacetic acid, the reaction solution was stirred at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure, 5 mL of ethyl acetate was added to the residue, and the organic phase was saturated with Sodium bicarbonate solution (5 mL×3), washed with water (5 mL), dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by high performance liquid preparation (Gilson-281, elution system: acetonitrile or water) From the residue, the title product 2 (1.7 mg, yield: 4.6%) was obtained.

MS m/z (ESI): 451.2 [M+1].

¹ H NMR (400 MHz, CD3OD) δ 8.00 (s, 1H), 7.92 (d, 1H), 7.57 (d, 1H), 7.38-7.53 (m, 3H), 6.92 (s, 1H), 3.63 (t , 2H), 3.35-3.50 (m, 6H), 1.57-1.79 (m, 4H), 1.25-1.41 (m, 2H), 0.91 (t, 6H).

Test case:

Biological evaluation

Test Example 1. Determination of the compound of the present invention for promoting activity of human TLR8

The activating effect of the compounds of the present invention on hTLR8 expressed by HEK-Blue ^TM hTLR8 stable transgenic cells was determined by the following experimental method:

1. Experimental materials and equipment 1. DMEM (Gibco, 10564-029), 2. Fetal Bovine Serum (GIBCO, 10099), 3. Trypan Blue Solution (Sigma, T8154-100ML), 4. Flexstation 3 multifunctional enzyme label Instrument (Molecµlar Devices), 5. HEK-Blue ^TM hTLR8 cell line (InvivoGen, hkb-hTLR8), 6. HEK-Blue detection reagent (InvivoGen, hb-det3), 7. Phosphate buffered saline (PBS) pH7.4 (Shanghai Yuanpei Biotechnology Co., Ltd., B320).

2. Experimental steps

Configure the HEK-Blue detection medium, take a bag of HEK-Blue detection dry powder, add 50ml of endotoxin-free water to dissolve it, and then put it into the 37°C incubator, and filter aseptically after 10 minutes. The compound was first prepared as a 20 mM stock solution; then diluted with pure DMSO to a maximum concentration of 6Í10 ⁶ nM, and then diluted by a 3-fold gradient, a total of 10 points; the compound was first diluted 20-fold with the medium, and then 20 µl was added to each well. compound of.

Take HEK-Blue ^TM hTLR8 cells, first remove the supernatant, add 2-5ml of pre-warmed PBS, put in the incubator for 1-2 minutes, gently pipette the cells, trypan blue staining and counting. Resuspend the cells with HEK-Blue detection medium to adjust the concentration to 2.2Í 10 ⁵ cells/ml, add 180µl of cells to the above 96-well cell culture plate with 20µl of drug added, and incubate at 37°C for 6-16h.

Reading with microplate reader, the wavelength is 620nm. The corresponding OD value can be obtained, and the EC ₅₀ value of the drug can be calculated by Graphpad Prism.

The activating effect of the compound of the present invention on human TLR8 can be determined by the above test, and the measured EC ₅₀ value is shown in Table 1. Table 1 EC _{50 of the} compounds of the present invention against human TLR8

Conclusion: The compound of the present invention has a good activating effect on human TLR8.

Test Example 2. Determination of the promoting activity of the compound of the present invention on human TLR7

The activating effect of the compounds of the present invention on hTLR7 expressed by HEK-Blue ^TM hTLR7 stable transgenic cells was determined by the following experimental method:

1. Experimental materials and equipment 1. DMEM (Gibco, 10564-029), 2. Fetal Bovine Serum (GIBCO, 10099), 3. Trypan Blue Solution (Sigma, T8154-100ML), 4. Flexstation 3 multifunctional enzyme label Instrument (Molecµlar Devices), 5. HEK-Blue ^TM hTLR7 cell line (InvivoGen, hkb-hTLR7), 6. HEK-Blue detection reagent (InvivoGen, hb-det3), 7. Phosphate buffered saline (PBS) pH7.4 (Shanghai Yuanpei Biotechnology Co., Ltd., B320).

2. Experimental steps

Configure the HEK-Blue detection medium, take a bag of HEK-Blue detection dry powder, add 50ml of endotoxin-free water to dissolve it, and then put it into the 37°C incubator, and filter aseptically after 10 minutes. The compound was first prepared into a 20mM stock solution; then diluted with pure DMSO to a maximum concentration of 6Í 10 ⁶ nM, and then diluted by a 3-fold gradient, a total of 10 points.

Dilute the above prepared compound 20 times with culture medium, and then add 20 µl of the diluted compound to each well.

Take HEK-Blue ^TM hTLR7 cells, first remove the supernatant, then add 2-5ml of pre-warmed PBS, put them in the incubator for 1-2 minutes, gently pipette the cells, trypan blue staining and counting. Resuspend the cells with HEK-Blue detection medium to adjust the concentration to 2.2Í 10 ⁵ cells/ml, add 180μl of cells to the above 96-well cell culture plate to which 20μl of drug has been added, and incubate at 37°C for 6-16h.

Reading with microplate reader, the wavelength is 620nm. The corresponding OD value can be obtained, and the EC ₅₀ value of the drug can be calculated by Graphpad Prism.

The activating effect of the compound of the present invention on human TLR7 can be determined by the above test, and the measured EC ₅₀ value is shown in Table 2. Table 2 EC _{50 of the} compounds of the present invention against human TLR7

Conclusion: The compound of the present invention has weak activating effect on human TLR7, indicating that the compound of the present invention is selective for TLR8.

Test Example 3. The inhibitory effect of the compound of the present invention on the enzyme activity of the metabolite site of human liver microsome CYP3A4 midazolam

The enzymatic activity of the compound of the present invention on the metabolic site of human liver microsome CYP3A4 midazolam was determined by the following experimental method:

1. Experimental materials and instruments 1. Phosphate buffered saline (PBS), 2. NADPH (Sigma N-1630), 3. Human liver microsomes (Corning Gentest), 4. ABI QTrap 4000 liquid and mass meter (AB Sciex) , 5.Inertsil C8-3 column, 4.6×50mm, 5μm (American Dima company), 6.CYP probe substrate (15μM midazolam, SIGMA UC429) and positive control inhibitor (ketoconazole, SIGMA K1003).

2. Experimental steps

Prepare 100mM PBS buffer, use this buffer to prepare 2.5mg/ml microsome solution and 5mM NADPH solution, and use PBS to dilute the 5X concentration compound working solution (150, 50, 15, 5, 1.5, 0.15, 0.015 , 0μM). The 5X concentration of ketoconazole working solution (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 μM) was gradually diluted with PBS. Midazolam working solution diluted to 15μM with PBS.

Take 2.5mg/ml microsome solution, 15μM midazolam working solution, MgCl ₂ solution and compound working solution (150, 50, 15, 5, 1.5, 0.15, 0.015, 0μM, each concentration is set different Reaction system) each 20μl, mix well. The positive control group replaced the compound with the same concentration of ketoconazole. At the same time, pre-incubate the 5mM NADPH solution at 37°C for 5 minutes. After 5 minutes, add 20µl of NADPH to each well, start the reaction, and incubate for 30 minutes. All incubation samples have dual samples. After 30 minutes, add 250 µl of acetonitrile containing internal standard to all samples, mix well, shake at 800 rpm for 10 minutes, and then centrifuge at 3700 rpm for 10 minutes. Take 80μl of the supernatant and transfer it to LC-MS/MS for analysis.

The values are calculated by Graphpad Prism to obtain the IC ₅₀ value of the drug to the metabolite site of CYP3A4 midazolam, shown in Table 3. Table 3 The IC ₅₀ value of the compound of the present invention on the metabolism site of CYP3A4 midazolam

Conclusion: The compound of the present invention has no inhibitory effect on the midazolam metabolism site of human liver microsomes CYP3A4, and shows better safety, suggesting that there will be no metabolic drug interaction based on the midazolam metabolism site of CYP3A4 metabolism. effect.

Test Example 4. Inhibition of the compound of the present invention on the enzyme activity of human liver microsomes CYP2D6

The enzyme activity of the compound of the present invention on human liver microsomes CYP2D6 was determined by the following experimental method:

1. Experimental materials and equipment 1. Phosphate buffer solution (PBS), 2. NADPH (Sigma N-1630), 3. Human liver microsomes (Corning Gentest), 4. ABI QTrap 4000 liquid-mass dual-purpose instrument (AB Sciex) , 5.Inertsil C8-3 column, 4.6×50mm, 5μm (American Dima), 6.CYP probe substrate (20μM dextromethorphan, SIGMA Q0750) and positive control inhibitor (quinidine, SIGMA D9684 ).

2. Experimental steps

Prepare 100mM PBS buffer, use this buffer to prepare 2.5mg/ml microsome solution and 5mM NADPH solution, and use PBS to dilute the 5X concentration compound working solution (150, 50, 15, 5, 1.5, 0.15, 0.015 , 0μM). Dilute 5X concentration quinidine working solution (150, 50, 15, 5, 1.5, 0.15, 0.015, 0μM) with PBS. Dextromethorphan working solution diluted to 20μM with PBS.

Take 2.5mg/ml microsome solution, 20μM dextromethorphan working solution, MgCl ₂ solution and compound working solution (150, 50, 15, 5, 1.5, 0.15, 0.015, 0μM, each concentration set a different reaction System) each 20µl, mix well. The positive control group replaced the compound with the same concentration of quinidine. At the same time, pre-incubate the 5mM NADPH solution at 37°C for 5 minutes. After 5 minutes, add 20μl NADPH to each well to start the reaction and incubate for 30 minutes. All incubation samples have dual samples. After 30 minutes, add 250µl of acetonitrile containing internal standard to all samples, mix well, and shake at 800rpm for 10 minutes. Centrifuge at 3700 rpm for 10 minutes. Take 80μl of the supernatant and transfer it to LC-MS/MS for analysis.

The values are calculated by Graphpad Prism to obtain the IC ₅₀ value of the drug on the metabolic site of CYP2D6 in Table 4. Table 4 The IC ₅₀ value of the compound of the present invention on the metabolic site of CYP2D6

Conclusion: The compound of the present invention has weak inhibitory effect on the enzyme activity of human liver microsomes CYP2D6, and shows better safety, suggesting that there will be no metabolic drug interaction based on CYP2D6.

Test Example 5. The inhibitory effect of the compound of the present invention on the enzyme activity of the CYP3A4 testosterone metabolism site in human liver microsomes

The enzymatic activity of the compound of the present invention on the CYP3A4 testosterone metabolism site of human liver microsomes is determined by the following experimental method:

1. Experimental materials and instruments 1. Phosphate buffered saline (PBS), 2. NADPH (Sigma N-1630), 3. Human liver microsomes (Corning Gentest), 4. ABI QTrap 4000 liquid and mass meter (AB Sciex) , 5.Inertsil C8-3 column, 4.6×50mm, 5µm (Dima, USA), 6.CYP probe substrate (testosterone/100 µM, SIGMA K1003) and positive control inhibitor (ketoconazole, Dr.Ehrenstorfer GmbH, C17322500).

2. Experimental steps

Prepare 100mM PBS buffer, use this buffer to prepare 2.5mg/ml microsome solution and 5mM NADPH solution, and use PBS to dilute the 5X concentration compound working solution (150, 50, 15, 5, 1.5, 0.15, 0.015 , 0μM). The 5X concentration of ketoconazole working solution (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 μM) was gradually diluted with PBS. Dextromethorphan working solution diluted to 50μM with PBS.

Take 2.5mg/ml microsome solution, 50μM testosterone working solution, MgCl ₂ solution and compound working solution (150, 50, 15, 5, 1.5, 0.15, 0.015, 0μM, each concentration set a different reaction system) Each 20µl, mix well. The positive control group replaced the compound with the same concentration of ketoconazole. At the same time, pre-incubate the 5mM NADPH solution at 37°C for 5 minutes. After 5 minutes, add 20 µl of NADPH to each well, start the reaction, and incubate for 30 minutes. All incubation samples have dual samples. After 30 minutes, add 250µl of acetonitrile containing internal standard to all samples, mix well, and shake at 800rpm for 10 minutes. Centrifuge at 3700 rpm for 10 minutes. Take 80μl of the supernatant and transfer it to LC-MS/MS for analysis.

The values are calculated by Graphpad Prism to obtain the IC ₅₀ value of the drug to the CYP3A4 testosterone metabolism site, shown in Table 5. Table 5 The IC ₅₀ value of the compound of the present invention to the CYP3A4 testosterone metabolism site

Conclusion: The compound of the present invention has no inhibitory effect on the testosterone metabolism site of human liver microsome CYP3A4, and shows better safety, suggesting that there will be no metabolic drug interaction based on the testosterone metabolism site of CYP3A4.

no

no

Claims (17)

A compound represented by general formula (I):

Or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R ¹ is -NR ³ R ⁴ ; R ^{2 is} selected from a hydrogen atom, a C _1-6 alkyl group and a halogenated C _1-6 alkyl group; R ³ and R ^{4 are the} same or different, and are each independently selected from a hydrogen atom, a C _1-6 alkyl group Group, halogenated C _1-6 alkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclic group, C _6-10 aryl and 5-6 membered heteroaryl, wherein the C _1-6 Alkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-6 membered heteroaryl are each independently optionally selected from C _1-6 alkyl, C _{1 -6} alkoxy, halogen, amino, cyano, nitro, hydroxyl, C _1-6 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclic group, C _6-10 aryl and The 5-6 membered heteroaryl group is substituted by one or more substituents; and n is 0 or 1. The compound represented by the general formula (I) as described in claim 1 or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof Form, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (II):

Or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein: R ³ and R ⁴ Is a C _1-6 alkyl group, wherein the C _1-6 alkyl group is optionally selected from C _1-6 alkoxy, halogen, amino, cyano, nitro, hydroxy, C _1-6 hydroxyalkane Substituted by one or more substituents in the group, C _3-6 cycloalkyl group, 3-8 membered heterocyclic group, C _6-10 aryl group and 5-6 membered heteroaryl group; R ² and n are as claimed Defined in 1. The compound represented by the general formula (I) as described in claim 1 or 2 or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, it is a compound represented by the general formula (III):

Or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein: R ³ and R ⁴ Is a C _1-6 alkyl group, wherein the C _1-6 alkyl group is optionally selected from C _1-6 alkoxy, halogen, amino, cyano, nitro, hydroxy, C _1-6 hydroxyalkane Substituted by one or more substituents in the group, C _3-6 cycloalkyl, 3-8 membered heterocyclic group, C _6-10 aryl group and 5-6 membered heteroaryl group; R ^{2 is} as in claim 1 Defined. The compound represented by the general formula (I) as described in claim 1 or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, wherein said R ² is a hydrogen atom. The compound represented by the general formula (I) as described in claim 1 or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, which is selected from:

A compound represented by general formula (IA):

Or a tautomer thereof, the racemates, racemates, enantiomers, diastereomeric isomers or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R ^a is selected from three-butoxy Oxycarbonyl, acetyl, benzyl, allyl, 2,4-dimethoxybenzyl and p-methoxybenzyl; R ¹ is -NR ³ R ⁴ ; R ^{2 is} selected from a hydrogen atom, C _{1- 6} alkyl group and halogenated C _1-6 alkyl group; R ³ and R ^{4 are the} same or different, and are each independently selected from hydrogen atom, C _1-6 alkyl group, halogenated C _1-6 alkyl group, C _{3- 6} cycloalkyl, 3-8 membered heterocyclic group, C _6-10 aryl and 5-6 membered heteroaryl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, 3-8 The membered heterocyclic group, the C _6-10 aryl group and the 5-6 membered heteroaryl group are each independently optionally selected from C _1-6 alkyl, C _1-6 alkoxy, halogen, amino, cyano, One or more substitutions of nitro, hydroxy, C _1-6 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclic group, C _6-10 aryl and 5-6 membered heteroaryl And n is 0 or 1. The compound represented by the general formula (IA) as described in claim 6, or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein R ^a is ^a three-butoxycarbonyl. The compound represented by the general formula (IA) as described in claim 6 or 7, or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, it is selected from:

A method for preparing the compound represented by general formula (I) as described in claim 1, which comprises the following steps:

The compounds of formula (IA) shown deprotected to give a compound of formula (I) shown; wherein: R ^a is selected from three-butoxycarbonyl, acetyl, benzyl, allyl, 2,4 -Dimethoxybenzyl and p-methoxybenzyl; R ¹ , R ² and n are as defined in claim 1. The production method according to claim 9, wherein Ra is ^a tertiary butoxycarbonyl group. A pharmaceutical composition containing the compound represented by the general formula (I) as described in any one of claims 1-5 or its tautomer, meso, racemate, or enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. A compound represented by general formula (I) as described in any one of claims 1-5 or its tautomer, meso, racemate, enantiomer, diastereomer Use of the construct, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11 in the preparation of a medicament for promoting TLR8. A compound represented by general formula (I) as described in any one of claims 1-5 or its tautomer, meso, racemate, enantiomer, diastereomer Use of the construct, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11 in the preparation of a medicament for treating tumors. The use according to claim 13, wherein the tumor is cancer. The use according to claim 13, wherein the tumor is selected from melanoma, lung cancer, liver cancer, basal cell carcinoma, kidney cancer, myeloma, biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, Colon cancer, rectal cancer, head and neck cancer, peritoneal cancer, fallopian tube cancer, endometrial cancer, esophageal cancer, gastric cancer, leukemia, lymphoma, sarcoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicles Cancer, skin cancer and thyroid cancer. A compound represented by general formula (I) as described in any one of claims 1-5 or its tautomer, meso, racemate, enantiomer, diastereomer Use of the construct, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11 in the preparation of a medicament for treating infection caused by a virus. The use according to claim 16, wherein the virus is selected from dengue fever virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus, HIV, HBV, HCV, HPV, RSV, SARS and influenza viruses.