Polycyclic nonene compounds and preparation method and use thereof

Abstract

The present invention relates to a class of polycyclic nonene compounds and their preparation methods and uses. Specifically, the compounds of the present invention have a structure shown in Formula I, wherein the definitions of each group and substituent are as described in the specification. The present invention also discloses a preparation method of the compound and its use in promoting the secretion of IL-2 by the body.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a class of polycyclic nonene compounds and a preparation method and application thereof. Background Art

[0002] Interleukin-2 (IL-2) is a cell growth factor with immunomodulatory effects. IL-2 can not only promote the proliferation and differentiation of T lymphocytes and B lymphocytes, but also has important biological effects such as enhancing the activity of natural killer cells and inducing lymphokine activation. Therefore, it plays an important role in the treatment of tumors, viral infections, bacterial infections and autoimmune diseases. IL-2 is mainly produced by T cell lines. Under the stimulation of mitogens, CD4-positive or CD8-positive T cells can produce IL-2. Allogeneic antibodies mainly stimulate CD4-positive T cells to secrete IL-2. In addition, some T cell leukemia cell lines (such as Jurkat cell lines) can also produce high levels of IL-2 under the stimulation of mitogens, calcium ion carriers or PMA.

[0003] Studies have shown that IL-2 has a certain effect on some patients who are infected by viruses due to low cellular immune function and need to enhance cellular immune function. IL-2 itself has no direct antiviral activity, but it can mediate antiviral infection by enhancing the activity of CTL cells and NK cells and inducing IFN-γ production. The use of IL-2 to treat active hepatitis has shown promising results, and it also has a certain effect on herpes simplex virus infection, AIDS, tuberculous leprosy, and tuberculosis infection. For example, IL-2 can significantly prolong the half-life of mice and guinea pigs infected with the H37RV strain of Mycobacterium tuberculosis, reduce the mortality rate, and reduce the number of Mycobacterium tuberculosis in the spleen and lung tissues of infected animals.

[0004] Although IL-2 has a positive therapeutic effect in viral or bacterial infectious diseases, the high production and storage costs of macromolecular drugs and the fact that they cannot be taken orally greatly limit the potential application of IL-2 as a therapeutic drug in the field of anti-infection. Therefore, the development of small molecule drugs that can promote the body to produce endogenous IL-2 to achieve anti-infection effects has important scientific significance and application prospects.

[0005] Tecovirimat is an inhibitor of the VP37 envelope protein of orthopoxvirus. It was obtained by SIGA Technologies in the United States through high-throughput screening and was approved by the FDA for the treatment of smallpox in 2018. It was then urgently approved by the European Medicines Agency (EMA) for the treatment of monkeypox in 2022. Tecovirimat research has found that Tecovirimat inhibits the encapsulation of intracellular mature particles IMV by the Golgi to form intracellular envelope particles IEV, thereby preventing the release of the virus and interfering with the spread of orthopoxvirus in the host. Summary of the invention

[0006] The object of the present invention is to provide a compound represented by formula I, a preparation method thereof and use thereof in stimulating the production of endogenous IL-2.

[0007] The first aspect of the present invention provides a compound represented by formula I, or a pharmaceutically acceptable salt thereof:

[0008]

[0009] in:

[0010] L is absent, or L is selected from the group consisting of NH, -C(=O)-, -C(=NH)-, -C(=S)-, -C(=NH)NH-, -C(=O)NH-, -C(=S)NH-, -NHC(=S)-, -NHS(=O)2-, -NHS(=O)-;

[0011] R is selected from the following substituted or unsubstituted groups: C1-C8 alkyl, C3-C8 cycloalkyl, 5-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, C3-C8 cycloalkyl-(C1-C6 alkylene)-, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkenyl, C6-C10 aryl, monocyclic or cyclic 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S, C6-C10 aryl-(C1-C6 alkylene)-, monocyclic or cyclic 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S 5-10 membered heteroaryl-(C1-C6 alkylene)-; wherein the substitution refers to substitution by 1, 2, 3 or 4 groups selected from the group consisting of amino, hydroxy, thiol, halogen, cyano, nitro, acyloxy, acylamino, C1-C6 alkoxy, C1-C6 alkyl-NH-, C1-C6 alkyl-S-, C1-C8 alkyl, halogenated C1-C8 alkyl, hydroxy-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbamate, allyloxy, propargyloxy, sulfonyloxy, sulfonylamino;

[0012] Alternatively, L is -NHC(=O)-, and R is selected from the following groups which are substituted or unsubstituted: a 5-10 membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from N, O or S, a 5-10 membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from N, O or S -(C1-C6 alkylene)-; wherein the substitution refers to substitution by 1, 2, 3 or 4 groups selected from the following groups: amino, hydroxyl, thiol, halogen, cyano, nitro, acyloxy, acylamino, C1-C6 alkoxy, C1-C6 alkyl-NH-, C1-C6 alkyl-S-, C1-C8 alkyl, halo-substituted C1-C8 alkyl, hydroxy-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbamate, allyloxy, propargyloxy, sulfonyloxy, and sulfonylamino.

[0013] In another preferred embodiment, L is absent, or L is selected from the following group: NH, -C(=O)-, -C(=S)-, -C(=O)NH-, -NHC(=S)-;

[0014] R is selected from the following substituted or unsubstituted groups: C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, a monocyclic or cyclic 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S, C6-C10 aryl-(C1-C6 alkylene)-, a monocyclic or cyclic 5-10 membered heteroaryl-(C1-C6 alkylene)- containing 1, 2 or 3 heteroatoms selected from N, O or S; wherein the substitution refers to substitution by 1, 2, 3 or 4 groups selected from the following group: amino, hydroxy, halogen, cyano, nitro, C1-C8 alkyl, C1-C6 alkoxy, halogenated C1-C8 alkyl, hydroxy-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl;

[0015] Alternatively, L is -NHC(=O)-, and R is selected from the following groups which are substituted or unsubstituted: 5-10 membered heteroaryl rings containing 1, 2 or 3 heteroatoms selected from N, O or S, and 5-10 membered heteroaryl rings containing 1, 2 or 3 heteroatoms selected from N, O or S -(C1-C6 alkylene)-; wherein the substitution refers to substitution by 1, 2, 3 or 4 groups selected from the following groups: amino, hydroxyl, halogen, cyano, nitro, C1-C8 alkyl, C1-C6 alkoxy, halo-substituted C1-C8 alkyl, hydroxy-substituted C1-C8 alkyl, and amino-substituted C1-C8 alkyl.

[0016] In another preferred embodiment, L is absent;

[0017] R is selected from the group consisting of substituted C6-C10 aryl, 8-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; wherein the substitution refers to substitution by 1, 2, 3 or 4 groups selected from the group consisting of halogen, C1-C8 alkyl, halogenated C1-C8 alkyl;

[0018] The additional conditions are:

[0019] 1) When R is a substituted C6-C10 aryl group, at least one substituent of R is a halogen;

[0020] 2) When R is a substituted 8-10 membered heteroaryl group containing only 2 nitrogen atoms, at least one substituent of R is a halogen.

[0021] In another preferred embodiment, the 8-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S is in, is a 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S, is phenyl or a 6-membered heteroaryl group containing 1 or 2 heteroatoms selected from N, O or S;

[0022] X1, X2, X3, and X4 are each independently selected from the group consisting of CH, S, C, N, and NH.

[0023] In another preferred embodiment, the 8-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S has a structure selected from the following group:

[0024]

[0025] In another preferred embodiment, L is -NHC(=O)-, and R is selected from the following substituted or unsubstituted groups: 8-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S, 8-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S -(C1-C6 alkylene)-; wherein the substitution refers to substitution by 1, 2, 3 or 4 groups selected from the following group: halogen, C1-C8 alkyl, halogenated C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl;

[0026] The additional conditions are:

[0027] 1) The 8-10 membered cyclic heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S contains at least 1 N heteroatom.

[0028] In another preferred embodiment, the 8-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S is in, is a 6-membered aromatic group, is a 5-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, or a 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0029] X5, X8, and X9 are CH;

[0030] X6, X7, X 10 is C;

[0031] X 11 , X 12 , X 13 Each is independently selected from the group consisting of O, CH2, N, CH, NH.

[0032] In another preferred embodiment, the 8-10 membered cyclic heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S has a structure selected from the following group:

[0033]

[0034] In another preferred embodiment, the compound is selected from the following group:

[0035]

[0036]

[0037]

[0038] The second aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of one or more compounds described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof.

[0039] In another preferred embodiment, the pharmaceutical composition is used to treat IL-2 related diseases.

[0040] The third aspect of the present invention provides a method for preparing the compound of the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0041]

[0042] 1) and Reaction to obtain the compound of the first aspect of the present invention, or a pharmaceutically acceptable salt thereof;

[0043] L and R are as defined in the first aspect of the present invention.

[0044] The fourth aspect of the present invention provides a use of the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, for preparing a medicament for promoting the body to produce endogenous IL-2.

[0045] In another preferred embodiment, the drug is used to stimulate Jurkat cells, a human T-cell leukemia cell line, to secrete IL-2.

[0046] In another preferred embodiment, the drug is an immunopotentiator.

[0047] In another preferred embodiment, the drug is used for preventing and / or treating IL-2 related diseases.

[0048] In another preferred embodiment, the IL-2 related disease is selected from the following group: tumor, viral infection, bacterial infection, autoimmune disease.

[0049] In another preferred embodiment, the tumor is selected from the following group: thyroid cancer, lymphoma, leukemia, prostate cancer, kidney cancer, bladder cancer, glioma, nasopharyngeal carcinoma, neuroblastoma, head and neck squamous cell carcinoma, cervical cancer, ovarian cancer, breast cancer, colorectal cancer, pancreatic cancer, esophageal cancer, bile duct cancer, osteosarcoma, stromal sarcoma, choriocarcinoma, malignant hydatidiform mole, malignant teratoma, gastric cancer, lung cancer, liver cancer, melanoma, undifferentiated cancer, benign tumor.

[0050] In another preferred embodiment, the viral infection refers to infection with a virus selected from the group consisting of influenza virus, mumps virus, rhinovirus, adenovirus, respiratory syncytial virus, parainfluenza virus, coronavirus, measles virus, rubella virus, exanthema infantum virus, varicella virus, herpes zoster virus, herpes simplex virus, Japanese encephalitis virus, dengue virus, hepatitis virus, AIDS virus, monkeypox virus, cowpox virus, smallpox virus, vaccinia virus, camelpox virus, mousepox virus, elephantpox virus, rabbitpox virus, raccoon pox virus, skunk pox virus, and gerbil pox virus.

[0051] In another preferred embodiment, the bacterial infection refers to an infection selected from the following group of bacteria: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Escherichia coli, Haemophilus influenzae, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus, Klebsiella, Clostridium difficile, Pseudomonas aeruginosa, Mycobacterium tuberculosis, and Mycobacterium leprae.

[0052] In another preferred embodiment, the autoimmune disease is selected from the following group: rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, scleroderma, multiple sclerosis, myasthenia gravis, demyelinating lesions, primary adrenal cortical atrophy, chronic thyroiditis, ulcerative colitis, active hepatitis, pernicious anemia, atrophic gastritis, glomerulonephritis, pulmonary-renal hemorrhagic syndrome, autoimmune hemolysis, idiopathic thrombocytopenic purpura, idiopathic leukopenia.

[0053] In another preferred embodiment, the IL-2 related disease is selected from the following group: active hepatitis, herpes simplex virus infection, monkeypox virus infection, cowpox virus infection, smallpox virus infection, AIDS, tubercular leprosy, and Mycobacterium tuberculosis infection.

[0054] The fifth aspect of the present invention provides the use of Tecovirimat for preparing a drug for promoting the body to produce endogenous IL-2.

[0055] In another preferred embodiment, the drug is used to stimulate Jurkat cells, a human T-cell leukemia cell line, to secrete IL-2.

[0056] In another preferred embodiment, the drug is an immunopotentiator.

[0057] In another preferred embodiment, the drug is used for preventing and / or treating IL-2 related diseases.

[0058] In another preferred embodiment, the IL-2 related disease is selected from the following group: tumor, viral infection, bacterial infection, autoimmune disease.

[0059] In another preferred embodiment, the tumor is selected from the following group: thyroid cancer, lymphoma, leukemia, prostate cancer, kidney cancer, bladder cancer, glioma, nasopharyngeal carcinoma, neuroblastoma, head and neck squamous cell carcinoma, cervical cancer, ovarian cancer, breast cancer, colorectal cancer, pancreatic cancer, esophageal cancer, bile duct cancer, osteosarcoma, stromal sarcoma, choriocarcinoma, malignant hydatidiform mole, malignant teratoma, gastric cancer, lung cancer, liver cancer, melanoma, undifferentiated cancer, benign tumor.

[0060] In another preferred embodiment, the viral infection refers to infection with a virus selected from the group consisting of influenza virus, mumps virus, rhinovirus, adenovirus, respiratory syncytial virus, parainfluenza virus, coronavirus, measles virus, rubella virus, exanthema infantum virus, varicella virus, herpes zoster virus, herpes simplex virus, Japanese encephalitis virus, dengue virus, hepatitis virus, AIDS virus, monkeypox virus, cowpox virus, smallpox virus, vaccinia virus, camelpox virus, mousepox virus, elephantpox virus, rabbitpox virus, raccoon pox virus, skunk pox virus, and gerbil pox virus.

[0061] In another preferred embodiment, the bacterial infection refers to an infection selected from the following group of bacteria: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Escherichia coli, Haemophilus influenzae, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus, Klebsiella, Clostridium difficile, Pseudomonas aeruginosa, Mycobacterium tuberculosis, and Mycobacterium leprae.

[0062] In another preferred embodiment, the autoimmune disease is selected from the following group: rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, scleroderma, multiple sclerosis, myasthenia gravis, demyelinating lesions, primary adrenal cortical atrophy, chronic thyroiditis, ulcerative colitis, active hepatitis, pernicious anemia, atrophic gastritis, glomerulonephritis, pulmonary-renal hemorrhagic syndrome, autoimmune hemolysis, idiopathic thrombocytopenic purpura, idiopathic leukopenia.

[0063] In another preferred embodiment, the IL-2 related disease is selected from the following group: active hepatitis, herpes simplex virus infection, monkeypox virus infection, cowpox virus infection, smallpox virus infection, AIDS, tubercular leprosy, and Mycobacterium tuberculosis infection.

[0064] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Figure 1 This is the in vitro cell proliferation activity test result obtained in Example 2.

[0066] Figure 2 This is the result of the induction effect of the compound obtained in Example 3 on IL-2. DETAILED DESCRIPTION

[0067] After long-term and in-depth research, the inventor unexpectedly prepared a compound of formula I with excellent safety and better effect of promoting the secretion of IL-2 by the body through structural optimization. On this basis, the inventor completed the present invention.

[0068] the term

[0069] In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

[0070] In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0071] In the present invention, "C1-C6 alkyl" refers to a straight or branched alkyl group including 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like. The term "C1-C8 alkyl" has a similar meaning.

[0072] In the present invention, the term "C2-C6 alkenyl" refers to a straight or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, including but not limited to vinyl, propenyl, allyl, butenyl, isobutenyl, pentenyl and hexenyl, etc. The term "C2-C8 alkenyl" has a similar meaning.

[0073] In the present invention, the term "C2-C6 alkynyl" refers to a straight or branched alkynyl group having 2-6 carbon atoms and containing one triple bond, including but not limited to ethynyl, propynyl, propargyl, butynyl, isobutynyl, pentynyl and hexynyl, etc. The term "C2-C8 alkynyl" has a similar meaning.

[0074] In the present invention, the term "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

[0075] In the present invention, the term "C3-C8 cycloalkenyl group" refers to a cyclic alkenyl group having 3 to 8 carbon atoms in the ring and containing one double bond.

[0076] In the present invention, the term "acylamino" refers to a group or substituent containing -C(O)NR1R2, wherein R1 and R2 represent hydrogen or alkyl, such as -C(O)NH2, -C(O)NHCH3, etc.

[0077] In the present invention, the term "acyloxy" refers to a group or substituent containing -C(O)OR, wherein R represents an alkyl group, such as -C(O)OCH3 and the like.

[0078] In the present invention, the term "allyloxy" refers to CH2=CH-CH2-O-.

[0079] In the present invention, the term "propargyloxy" refers to CH≡C-CH2-O-.

[0080] In the present invention, the term "sulfonyloxy" refers to RS(=O)2-O-, wherein R represents an alkyl group.

[0081] In the present invention, the term "sulfonylamino" refers to RS(=O)2-NH-, wherein R represents an alkyl group.

[0082] In the present invention, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. Preferably, it is a C1-C4 alkoxy group.

[0083] In the present invention, the term "heterocyclyl" or "heterocycloalkyl" refers to a 5-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S, including (but not limited to) the following groups:

[0084] In the present invention, the term "aromatic ring" or "aryl group" has the same meaning, preferably "C6-C10 aryl group". The term "C6-C10 aryl group" refers to an aromatic ring group having 6-10 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl, etc.

[0085] In the present invention, the term "aromatic heterocycle" or "heteroaryl" has the same meaning and refers to a heteroaromatic group containing one to multiple heteroatoms. For example, "5-10 membered heteroaryl" refers to an aromatic heterocycle containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen and 2 to 9 carbon atoms. Non-limiting examples include: furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted.

[0086] In the present invention, the term "halo" means substituted with halogen.

[0087] In the present invention, the term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is the substituent described above, or the substituent appearing in each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position. It should be understood by those skilled in the art that the combination of substituents contemplated by the present invention is those stable or chemically feasible combinations. The substituents include, for example (but not limited to): halogen, hydroxyl, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic radical, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, etc.

[0088] In the present invention, the term 1-6 refers to 1, 2, 3, 4, 5 or 6. Other similar terms independently have similar meanings. The term "plurality" refers to 2-6, such as 2, 3, 4, 5 or 6.

[0089] In the present invention, the term "carbamate group" has Structure, wherein Ra and Rb are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, and C6-C10 aryl.

[0090] It should be understood that when a group is present in multiple different positions of a compound at the same time, its definition at each position is independent of each other and may be the same or different. That is, the term "selected from the following group:" has the same meaning as the term "each independently selected from the following group:".

[0091] Compound

[0092] Recently, we have found that Tecovirimat can also act as an immunopotentiator, stimulating Jurkat cells, a human T-cell leukemia cell line, to secrete IL-2, thereby potentially enhancing the host immune response.

[0093]

[0094] Based on the structure of Tecovirimat, this study obtained a class of novel polycyclic nonene compounds through rational drug design. Compared with Tecovirimat, this class of compounds has higher activity in stimulating Jurkat cell lines to produce IL-2, and thus has better application potential.

[0095] Specifically, the present invention provides a compound represented by Formula I, or a pharmaceutically acceptable salt thereof:

[0096]

[0097] Wherein, L and R are as defined above.

[0098] In another preferred embodiment, in the compound, any one of L and R is independently a corresponding group in the specific compound of the present invention.

[0099] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by a compound of the present invention and an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, camphorsulfonic acid, citric acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0100] Another preferred salt is a salt of the compound of the present invention and a base, such as an alkali metal salt (e.g., sodium salt or potassium salt, specifically, sodium hydroxide, potassium hydroxide), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts (e.g., ammonium hydroxide)), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, lysine, and piperidine, respectively.

[0101] The compounds of the present invention and their pharmaceutically acceptable salts may also exist in the form of variants including stereoisomers, enantiomers, diastereomers, atropisomers, optical isomers, racemates, polymorphs, solvates or isotope-labeled compounds, and these variants are also included in the present invention.

[0102] The term "solvate" refers to a complex in which the compound of the present invention is coordinated with solvent molecules to form a specific ratio.

[0103] Preparation method

[0104] The preparation method of the compound of formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combination can be easily carried out by a technician in the field to which the present invention belongs.

[0105] Typically, the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.

[0106]

[0107] The definitions of R and L are as above.

[0108] The method comprises the following steps,

[0109] Step 1: In xylene solvent, the raw material cycloheptatriene (I-1) and maleic anhydride undergo Diels Alder reaction under heating reflux conditions to generate intermediate I-2;

[0110] Step 2: In an ethanol solvent, the intermediate I-2 reacts with an amine derivative to generate a compound of formula I.

[0111] Pharmaceutical compositions and methods of administration

[0112] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0113] Since the compounds of the present invention have excellent anti-tumor activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate tumor-related diseases.

[0114] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0115] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0116] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0117] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0118] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0119] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0120] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0121] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0122] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0123] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0124] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0125] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0126] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0127] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0128] Compared with the prior art, the present invention has the following main advantages:

[0129] (1) Compared with Tecovirimat, the compound of the present invention has a better effect of promoting the secretion of IL-2 by the body;

[0130] (2) The compounds of the present invention have excellent safety.

[0131] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or under conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0132] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0133] Example 1 Preparation of Compounds

[0134] Preparation of compound S1:

[0135]

[0136] Cycloheptatriene (100 mg, 1.09 mmol), maleic anhydride (160 mg, 1.64 mmol) and xylene (2 mL) were added to a 25 mL round-bottom flask. The mixture was refluxed for 12 hours under argon protection, and then petroleum ether (5 mL) was added to precipitate a yellow solid, which was filtered and dried to obtain a yellow solid I-2 (90 mg) with a yield of 43%. 1 H NMR (400MHz, CDCl3): δ5.88(t,J=3.4Hz,2H),3.46(s,2H),3.24(s,2H),1.11(d,J=4.4Hz,2H),0.40-0.12(m,2H).

[0137] In a 25 mL round-bottom flask, add intermediate I-2 (40 mg, 0.21 mmol), raw material I-3 (38 mg, 0.21 mmol), ethanol (1 mL) and 1 drop of DIPEA. Heat and reflux for 4.5 hours. After the reaction is complete, cool the reaction solution to room temperature, add ice water to precipitate the solid, filter and dry to obtain a light yellow solid S1 (90 mg), with a yield of 81%. 1 H NMR (400MHz, CDCl3): δ7.99(s,1H),7.38(dd,J=8.2,1.6Hz,1H),6.81(d,J=8.1Hz,1H),6.03(s,2 H),5.86-5.78(m,2H),3.45(s,2H),3.12(s,2H),1.13(dd,J=6.2,2.4Hz,2H),0.34-0.22(m,2H).

[0138] Preparation of compound S2:

[0139]

[0140] In a 25 mL round-bottom flask, add intermediate I-2 (40 mg, 0.21 mmol), raw material I-4 (40 mg, 0.21 mmol), ethanol (1 mL) and 1 drop of DIPEA. Heat and reflux for 4.5 hours. After the reaction is complete, the liquid is cooled to room temperature, water is added, and extracted three times with ethyl acetate. The organic phases are combined and washed once with saturated brine and dried over anhydrous sodium sulfate. After rotary evaporation and concentration, column chromatography separation (PE / EA 1:1) is performed to obtain white solid S2 (38 mg) with a yield of 47%. 1 H NMR (400MHz, DMSO-d6): δ11.17(s,1H),10.90(s,0H),7.85-7.74(m,2H),7.55(d,J=8.5Hz,1H),5.75 (d,J=18.0Hz,2H),3.21(d,J=23.8Hz,4H),1.18-1.09(m,2H),0.26-0.18(m,1H),0.06-0.03(m,1H).

[0141] Preparation of compound S3:

[0142]

[0143] The synthesis method was similar to that of S1, and a light yellow solid S3 was obtained with a yield of 13%. 1 H NMR (400MHz, DMSO-d6): δ11.12(s,1H),8.22(s,1H),8.13(s,1H),7.85(d,J=8.7Hz,1H),7.59(d,J=7.2Hz,1H),5.77(d,J =13.6Hz,2H),4.08(s,3H),3.27(s,2H),3.20(s,1H),3.14(d,J=5.4Hz,1H),1.16(s,2H),0.33-0.17(m,1H),0.05(s,1H).

[0144] Preparation of compound S4:

[0145]

[0146] The synthesis method was similar to that of S1, and white solid S4 was obtained with a yield of 40%. 1 H NMR (400MHz, Methanol-d4): δ8.12(s,2H),7.87(d,J=8.5Hz,1H),7.61(d,J=9.1Hz ,1H),5.82(s,2H),3.36(s,2H),3.23(s,2H),1.23-1.17(m,2H),0.35-0.21(m,2H).

[0147] Preparation of compound S5:

[0148]

[0149] The synthesis method was similar to that of S1, and a light yellow solid S5 was obtained with a yield of 34%. 1 H NMR (400MHz, Methanol-d4): δ8.27(s,1H),8.21(s,1H),7.78(d,J=10.2Hz,1H),7.51(d,J=9.2Hz, 1H),5.82(d,J=3.9Hz,2H),4.24(s,3H),3.36(s,2H),3.22(s,2H),1.20(s,2H),0.33-0.21(m,2H).

[0150] Preparation of compound S6:

[0151]

[0152] The synthesis method was similar to that of S1, and white solid S6 was obtained with a yield of 45%. 1 H NMR (400MHz, Methanol-d4): δ8.25-8.22(m,1H),7.96-7.88(m,2H),7.41(dd,J=8.6,0.7Hz,1H),5.80(s ,2H),3.83(s,3H),3.40(ddq,J=6.5,4.8,2.3Hz,2H),3.12(s,2H),1.12-1.07(m,2H),0.28-0.17(m,2H).

[0153] Preparation of compound S7:

[0154]

[0155] The synthesis method was similar to that of S1, and white solid S7 was obtained with a yield of 42%. 1 H NMR (400MHz, DMSO-d6): δ11.00(s,1H),8.35(s,1H),8.15(d,J=9.9Hz,1H),7.73(d,J=5.9Hz,2H),5.77(d,J= 14.6Hz,2H),3.87(s,3H),3.25(s,3H),3.19(s,1H),1.19-1.11(m,2H),0.30-0.20(m,1H),0.10-0.01(m,1H).

[0156] Preparation of compound S8:

[0157]

[0158] The synthesis method was similar to that of S1 to obtain white solid S8 (40 mg) with a yield of 58%. 1 H NMR (400MHz, DMSO-d6): δ7.81(d,J=8.2Hz,2H),7.35(d,J=8.2Hz,2H),5.80(t,J=3.6Hz, 2H),3.26(s,2H),3.19(s,2H),1.16(s,2H),0.23(q,J=6.6Hz,1H),0.05(d,J=3.8Hz,1H).

[0159] Preparation of compound S9:

[0160]

[0161] The synthesis method was similar to that of S1, and white solid S9 was obtained with a yield of 45%. 1 H NMR (400MHz, CDCl3): δ7.41(d,J=2.1Hz,1H),7.39(d,J=2.0Hz,1H),7.14(d,J=2.1Hz,1H),7.12(d,J= 1.9Hz,1H),5.88-5.83(m,2H),3.49(s,2H),3.16-3.12(m,2H),1.19-1.13(m,2H),0.37-0.25(m,2H).

[0162] Preparation of compound S10:

[0163]

[0164] The synthesis method was similar to that of S1, and white solid S10 was obtained with a yield of 49%. 1 H NMR (400MHz, CDCl3): δ7.74(d,J=8.4Hz,1H),7.43(s,1H),7.28(d,J=8.3Hz,1H),5.87( s,2H),3.51(s,2H),3.17(s,2H),1.17(s,2H),0.35(q,J=6.9Hz,1H),0.30-0.27(m,1H).

[0165] Preparation of compound S11:

[0166]

[0167] The synthesis method was similar to that of S1, and white solid S11 was obtained with a yield of 36%. 1H NMR (400MHz, DMSO-d6): δ7.74(d,J=8.6Hz,1H),7.43(d,J=2.3Hz,1H),7.16(dd,J=8.6,2.3Hz,1H),5.82( p,J=4.6Hz,2H),3.27(s,2H),3.21-3.18(m,2H),1.19-1.15(m,2H),0.27-0.24(m,1H),0.09-0.05(m,1H).

[0168] Preparation of compound S12:

[0169]

[0170] The synthesis method was similar to that of S2, and a light yellow solid S12 was obtained with a yield of 32%. 1 H NMR (400MHz, CDCl3): δ8.04(s,1H),7.98(s,1H),7.82(d,J=8.4Hz,1H),7.56-7.54(m,1H),5.80(dt,J=5.9,3.1Hz,2H),3.5 3-3.50(m,2H),3.18(dt,J=6.1,2.8Hz,2H),1.25(m,1H),1.17-1.13(m,1H),0.36-0.31(m,1H),0.26(dq,J=6.4,3.2Hz,1H).

[0171] Preparation of compound S13:

[0172]

[0173] The synthesis method was similar to that of S2, and a light yellow solid S13 was obtained with a yield of 41%. 1 H NMR (400MHz, CDCl3): δ7.96(s,1H),7.68(dd,J=7.9,0.9Hz,1H),7.44(dd,J=7.7,0.9Hz,1H),7.21(t,J=7.8Hz,1H),5.80(dd,J=4.8,3.3Hz,2H),3. 51(ddp,J=6.6,4.5,2.0Hz,2H),3.18(t,J=1.8Hz,2H),1.16(ddt,J=8.3, 3.9, 2.4Hz, 2H), 0.33 (td, J=7.4, 5.9Hz, 1H), 0.26 (dt, J=5.9, 3.7Hz, 1H).

[0174] Preparation of compound S14:

[0175]

[0176] The synthesis method was similar to that of S2, and a light yellow solid S14 was obtained with a yield of 42%. 1 H NMR (400MHz, CDCl3): δ8.18-8.14(m,2H),7.72-7.69(m,1H),5.86-5.84(m,2H),3.58-3.54(m,2H),3. 25(dd,J=2.1,1.5Hz,2H),1.20-1.16(m,2H),0.35(td,J=7.4,6.0Hz,1H),0.27(dt,J=6.0,3.7Hz,1H).

[0177] Preparation of compound S15:

[0178]

[0179] The synthesis method was similar to that of S2, and a light yellow solid S15 was obtained with a yield of 42%. 1 H NMR (400MHz, CDCl3): δ7.79-7.74(m,2H),7.18-7.13(m,1H),5.84(m,2H),3.55(s,2 H), 3.22 (s, 2H), 1.15 (d, J = 5.4Hz, 2H), 0.34 (q, J = 7.0Hz, 1H), 0.26 (q, J = 4.2Hz, 1H).

[0180] Preparation of compound S16:

[0181]

[0182] The synthesis method was similar to that of S2, and a light yellow solid S16 was obtained with a yield of 37%. 1 H NMR (400MHz, CDCl3): δ8.26(d,J=6.1Hz,1H),7.59(d,J=7.6Hz,1H),5.83(tt,J=5.1,2.5Hz,2H),3.55(ddq,J=4.6,2.9 ,1.7Hz,2H),3.23(dd,J=2.2,1.5Hz,2H),1.18-1.14(m,2H),0.34(td,J=7.4,6.0Hz,1H),0.26(dt,J=6.0,3.7Hz,1H).

[0183] Preparation of compound S17:

[0184]

[0185] The synthesis method was similar to that of S2 to obtain pale yellow solid S17 with a yield of 51%. 1H NMR (400MHz, CDCl3): δ8.38(s,1H),7.99(d,J=8.3Hz,1H),7.64(d,J=8.4Hz,1H),5.91-5.83(m,2H) ,3.58(s,2H),3.31-3.24(m,2H),1.23-1.17(m,2H),0.37(q,J=7.4,6.7Hz,1H),0.31-0.26(m,1H).

[0186] Preparation of compound S18:

[0187]

[0188] The synthesis method was similar to that of S2, and white solid S18 was obtained with a yield of 47%. 1 H NMR (400MHz, DMSO-d6): δ8.14(dd,J=8.6,0.4Hz,1H),8.07(dd,J=2.1,0.4Hz,1H),7.50(dd,J=8.6,2.1Hz,1H),5.8 0(dd,J=4.5,3.0Hz,2H),3.34-3.30(m,3H),1.20(s,2H),0.26(td,J=7.3,5.5Hz,1H),0.04(dt,J=5.5,3.7Hz,1H).

[0189] Preparation of compound S19:

[0190]

[0191] The synthesis method was similar to that of S1, and a light yellow solid S19 was obtained with a yield of 29%. 1 H NMR (400MHz, DMSO-d6): δ7.93(s,1H),7.74(d,J=8.6Hz,1H),7.53(d,J=9.7Hz,1H),5. 88-5.79(m,2H),3.32(s,4H),1.23-1.13(m,2H),0.31-0.22(m,1H),0.11-0.04(m,1H).

[0192] Preparation of compound S20:

[0193]

[0194] The synthesis method was similar to that of S1, and white solid S20 was obtained with a yield of 47%. 1H NMR (400MHz, DMSO-d6): δ12.90 (d, J=19.1Hz, 1H), 7.85-7.67 (m, 1H), 7.59-7.44 (m, 1H), 7.40 -7.31(m,1H),5.85-5.81(m,2H),3.32-3.30(m,4H),1.20-1.14(m,2H),0.26(td,J=7.4,5.5Hz,1H),0.10-0.03(m,1H).

[0195] Preparation of compound S21:

[0196]

[0197] The synthesis method was similar to that of S1, and white solid S21 was obtained with a yield of 38%. 1 H NMR (400MHz, DMSO-d6): δ7.55(dd,J=8.9,4.8Hz,1H),7.38-7.35(m,1H),7.08(td,J=9.4,2.6Hz,1H),5.83(t ,J=3.8Hz,2H),3.32(s,4H),1.17(dq,J=7.2,3.4Hz,2H),0.26(td,J=7.4,5.4Hz,1H),0.07(q,J=3.8Hz,1H).

[0198] Preparation of compound S22:

[0199]

[0200] The synthesis method was similar to that of S1, and white solid S22 was obtained with a yield of 34%. 1 H NMR (400MHz, DMSO-d6): δ7.62(d,J=2.1Hz,1H),7.56(d,J=8.6Hz,1H),7.23(dd,J=8.6,2.0Hz,1H),5.83(t,J=3.7Hz,2 H),3.31-3.28(m,4H),1.17(ddq,J=7.6,3.9,2.4,1.9Hz,2H),0.26(td,J=7.4,5.4Hz,1H),0.07(dt,J=5.4,3.6Hz,1H).

[0201] Preparation of compound S23:

[0202]

[0203] The synthesis method was similar to that of S1 to obtain yellow solid S23 with a yield of 48%. 1H NMR (400MHz, CDCl3): δ8.05(s,1H),7.91(d,J=9.5Hz,1H),7.08(d,J=9.5Hz,1H),5.9 0-5.84(m,2H),3.51(s,2H),3.20-3.15(m,2H),1.17-1.11(m,2H),0.37-0.23(m,2H).

[0204] Preparation of compound S24:

[0205]

[0206] The synthesis method is similar to that of S2, and yellow solid S24 is obtained with a yield of 38%. 1 H NMR (400MHz, CDCl3): δ8.21(dd,J=1.9,0.9Hz,1H),7.66(s,1H),7.52(d,J=9.6Hz,1H),7.26-7.23(m,1H),5.85(dd,J=4.8,3.3Hz,2H) ,3.52-3.48(m,2H),3.16(t,J=1.8Hz,2H),1.13(ddt,J=6.1,4.1,2.3Hz,2H),0.31(td,J=7.4,5.8Hz,1H),0.25(dt,J=5.9,3.7Hz,1H).

[0207] Preparation of compound S25:

[0208]

[0209] The synthesis method was similar to that of S2 to obtain yellow solid S25 with a yield of 47%. 1 H NMR (400MHz, CDCl3): δ8.51 (dd, J=2.9, 2.2Hz, 1H), 7.77 (dd, J=7.9, 2.2Hz, 1H), 5.94 (dd, J=4.8, 3.4 Hz,2H),3.54-3.49(m,2H),3.23-3.20(m,2H),1.14(ddd,J=9.4,3.9,2.3Hz,2H),0.37-0.27(m,2H).

[0210] Preparation of compound S26:

[0211]

[0212] The synthesis method was similar to that of S2 to obtain yellow solid S26 with a yield of 13%. 1H NMR (400MHz, CDCl3): δ8.71(d,J=7.3Hz,1H),8.07(s,1H),7.27(dd,J=7.2,1.7Hz,1H),5.95-5.91 (m,2H),3.55-3.50(m,2H),3.26-3.21(m,2H),1.15(dq,J=5.8,3.8,3.0Hz,2H),0.38-0.26(m,2H).

[0213] Preparation of compound S27:

[0214]

[0215] The synthesis method was similar to that of S2 to obtain yellow solid S27 with a yield of 34%. 1 H NMR (400MHz, CDCl3): δ8.48(d,J=7.9Hz,1H),7.75(d,J=2.7Hz,1H),7.06(dd,J=7.3,2.2Hz,1H),5.93(dd ,J=4.8,3.4Hz,2H),3.55-3.49(m,2H),3.24-3.20(m,2H),1.14(dq,J=7.7,2.4Hz,2H),0.36-0.26(m,2H).

[0216] Example 2 In vitro cell proliferation activity test of compounds

[0217] This study used the CCK8 (Cell Counting Kit-8) method to test the cytotoxicity of the compounds. Jurkat cells, a human leukemia T cell line in the logarithmic growth phase, were treated and inoculated in a 96-well plate and cultured for 24 hours at 37°C and 5% CO2. Two concentrations of the test compound were added. The culture was continued for 48 hours under the same conditions, and then the CCK8 kit (Beyotime) was used according to the manufacturer's instructions to quantitatively analyze cell pathological death and calculate the cell survival rate. Three replicate wells were set for each concentration gradient, and the test was repeated three times. The activity results are shown in Tables 1 and Figure 1 shown.

[0218] Among them: The in vitro normal cell proliferation activity of the compound was determined by CCK8 detection kit, and the final data was taken as the average value of three measurements.

[0219] Table 1 Results of in vitro cell proliferation activity of compounds

[0220]

[0221] Example 3 Experiment on inducing IL-2 secretion in Jurkat cells

[0222] Take Jurkat cells, a human leukemia T cell line in the logarithmic growth phase, and first adjust the cell concentration to one million per milliliter, and take a portion as a control group (without PMA and PHA). Add PMA and PHA to the culture medium to make their concentrations 20ng / mL and 20μg / mL, respectively. After pipetting and mixing, add 200μL / well to a 48-well plate. Add a single concentration of the test compound, use Tecovirimat as a positive control, and culture for 48 hours at 37°C and 5% CO2. First, pipette the cells evenly, collect the cells and culture medium into an EP tube, centrifuge for 10 minutes, collect the supernatant, and store at -20°C. Then use the IL-2ELISA kit to detect the IL-2 content. The results are shown in Table 2 and Figure 2 shown.

[0223] Table 2 Results of compounds inducing IL-2 secretion in Jurkat cells

[0224]

[0225] From Table 1 and Figure 1 It can be seen that the compounds of the present invention and Tecovirimat have no obvious proliferation inhibition effect on Jurkat cells at two concentrations of 1 μM and 10 μM, showing low cytotoxicity, indicating that the compounds of the present invention have good safety.

[0226] From Table 2 and Figure 2 It can be seen that most of the compounds of the present invention can significantly promote the production of IL-2 by Jurkat cells at a concentration of 1 μM, and the activity is higher than that of Tecovirimat, indicating that the compounds of the present invention have a significant immune enhancement effect and have potential application value in the treatment of infectious diseases.

[0227] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound represented by formula I or a pharmaceutically acceptable salt thereof: in: L is absent; R is a substituted structure selected from the following group: Wherein, the substitution refers to substitution by 1, 2, 3 or 4 groups selected from the group consisting of halogen, C1-C8 alkyl, halogenated C1-C8 alkyl; Alternatively, L is -NHC(=O)-, and R is a substituted structure selected from the following group: Wherein, the substitution refers to substitution by 1, 2, 3 or 4 groups selected from the group consisting of halogen, C1-C8 alkyl, halogenated C1-C8 alkyl; Furthermore, the compound is not the following compound:

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: L is absent; R is a substituted structure selected from the following group:

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: L is -NHC(=O)-, R is substituted The substitution refers to substitution by 1, 2, 3 or 4 groups selected from the following group: C1-C8 alkyl, halogenated C1-C8 alkyl.

4. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the group consisting of:

5. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the group consisting of:

6. A pharmaceutical composition, characterized in that It comprises a pharmaceutically acceptable carrier and a safe and effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

7. A method for preparing the compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The steps include: 1) and Reaction to obtain the compound according to claim 1 or a pharmaceutically acceptable salt thereof; L, R are as defined in claim 1.

8. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: Used for preparing medicine, wherein the medicine is used for promoting the body to produce endogenous IL-2.

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