CN116217556A - Polycyclic nonene compound and preparation method and application thereof - Google Patents
Polycyclic nonene compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a polycyclic nonene compound, a preparation method and application thereof. Specifically, the compound has a structure shown in a formula I, wherein the definition of each group and substituent is described in the specification. The invention also discloses a preparation method of the compound and application of the compound in promoting the secretion of IL-2 by organisms.
Description
Technical Field
The invention relates to the field of medicines, in particular to a polycyclic nonene compound, a preparation method and application thereof.
Background
Interleukin 2 (IL-2, interlukin-2) is a cell growth factor with immunomodulatory effects. IL-2 not only can promote proliferation and differentiation of T lymphocytes and B lymphocytes, but also has important biological effects of enhancing natural killer cell activity, inducing activation of lymphokines and the like, thereby having important effects in the treatment of tumors, viral infection, bacterial infection and autoimmune diseases. IL-2 is produced primarily by T cell lines, and under mitogen stimulation, either CD 4-positive or CD 8-positive T cells produce IL-2, while alloantigens primarily stimulate the secretion of IL-2 by CD 4-positive T cells. In addition, certain T cell leukemia cell lines (e.g., jurkat cell lines) can also produce high levels of IL-2 upon stimulation by mitogens, calcium ionophores, or PMA.
The research shows that IL-2 has certain curative effect on some patients infected by virus due to low cellular immunity and need to strengthen cellular immunity. IL-2 itself has no direct antiviral activity and is capable of mediating anti-viral infection by enhancing CTL cell, NK cell activity and inducing IFN-gamma production. IL-2 has shown a favorable Miao ethnome for active hepatitis and has certain curative effects on herpes simplex virus infection, AIDS, leprosy, tubercle bacillus infection and the like. If IL-2 can obviously prolong half death time of mice and guinea pigs infected by the tubercle bacillus H37RV strain, reduce death rate and reduce the number of tubercle bacillus in spleen and lung tissues of infected animals.
Although IL-2 has a positive therapeutic effect in viral or bacterial infectious diseases, the potential of IL-2 as a therapeutic drug in the anti-infective field is greatly limited due to the high production and storage costs of macromolecular drugs, and the inability to be orally administered. Therefore, the research and development of the micromolecular medicine capable of promoting the organism to generate endogenous IL-2 so as to achieve the anti-infection effect has important scientific significance and application prospect.
Tecovirimat is an orthopoxvirus VP37 envelope protein inhibitor, which was obtained by high throughput screening by us SIGA Technologies company and was FDA approved for smallpox treatment in 2018 and was then emergently approved by european drug administration EMA in 2022 for monkey pox treatment. The tecovirimate study found that tecovirimate inhibited intracellular mature particle IMV from being encapsulated by golgi to form intracellular enveloped particle IEV by targeting the orthopoxvirus VP37 envelope protein, thereby preventing release of the virus and interfering with the propagation of orthopoxvirus in the host.
Disclosure of Invention
The invention aims to provide a compound shown in a formula I, a preparation method thereof and application thereof in the aspect of stimulating endogenous IL-2 production.
In a first aspect of the invention, there is provided a compound of formula i:
wherein:
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)-;
R is selected from the group consisting of substituted or unsubstituted: 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 fused 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S, C6-C10 aryl- (C1-C6 alkylene) -, monocyclic or fused 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; wherein said substitution means substitution with 1, 2, 3 or 4 groups selected from the group consisting of: amino, hydroxy, mercapto, halogen, cyano, nitro, acyloxy, acylamino, C1-C6 alkoxy, C1-C6 alkyl-NH-, C1-C6 alkyl-S-, C1-C8 alkyl, haloC 1-C8 alkyl, hydroxy-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbamate, allyloxy, propargyloxy, sulfonyloxy, sulfonylamino;
alternatively, L is-NHC (=o) -, R is selected from the group consisting of substituted or unsubstituted: a 5-10 membered fused ring heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S, a 5-10 membered fused ring heteroaryl- (C1-C6 alkylene) -, containing 1, 2 or 3 heteroatoms selected from N, O or S; wherein said substitution means substitution with 1, 2, 3 or 4 groups selected from the group consisting of: amino, hydroxy, mercapto, halogen, cyano, nitro, acyloxy, acylamino, C1-C6 alkoxy, C1-C6 alkyl-NH-, C1-C6 alkyl-S-, C1-C8 alkyl, haloC 1-C8 alkyl, hydroxy-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbamate, allyloxy, propargyloxy, sulfonyloxy, sulfonylamino.
In another preferred embodiment, L is absent, or L is selected from the group consisting of: NH, -C (=o) -, -C (=s) -, -C (=o) NH-, -NHC (=s) -;
r is selected from the group consisting of substituted or unsubstituted: C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, monocyclic or bicyclic 5-to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S, C6-C10 aryl- (C1-C6 alkylene) -, monocyclic or bicyclic 5-to 10-membered heteroaryl- (C1-C6 alkylene) -, containing 1, 2 or 3 heteroatoms selected from N, O or S; wherein said substitution means substitution with 1, 2, 3 or 4 groups selected from the group consisting of: 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;
alternatively, L is-NHC (=o) -, R is selected from the group consisting of substituted or unsubstituted: a 5-10 membered fused ring heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S, a 5-10 membered fused ring heteroaryl- (C1-C6 alkylene) -, containing 1, 2 or 3 heteroatoms selected from N, O or S; wherein said substitution means substitution with 1, 2, 3 or 4 groups selected from the group consisting of: 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.
In another preferred embodiment, L is absent;
r is selected from the following groups substituted: C6-C10 aryl, and 8-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; wherein said substitution means substitution with 1, 2, 3 or 4 groups selected from the group consisting of: halogen, C1-C8 alkyl, halogenated C1-C8 alkyl;
the additional conditions are:
1) When R is a substituted C6-C10 aryl, at least 1 substituent of R is halogen;
2) When R is a substituted and cyclic 8-10 membered heteroaryl containing only 2N, at least 1 substituent of R is halogen.
In another preferred embodiment, the fused 8-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S isWherein (1)>Is a 5 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S,is phenyl orIs a 6 membered heteroaryl group containing 1 or 2 heteroatoms selected from N, O or S;
X 1 、X 2 、X 3 、X 4 each independently selected from the group consisting of: CH. S, C, N, NH.
In another preferred embodiment, the fused 8-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S has a structure selected from the group consisting of:
in another preferred embodiment, L is-NHC (=o) -, R is selected from the group consisting of substituted or unsubstituted: 8-10 membered fused ring heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S, 8-10 membered fused ring heteroaryl- (C1-C6 alkylene) -, containing 1, 2 or 3 heteroatoms selected from N, O or S; wherein said substitution means substitution with 1, 2, 3 or 4 groups selected from the group consisting of: halogen, C1-C8 alkyl, halogenated C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl;
the additional conditions are:
1) The 8-10 membered fused ring heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S contains at least 1N heteroatom.
In another preferred embodiment, the 8-10 membered bicyclic heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S isWherein (1)>Is 6 membered aryl, ">Is a 5 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S or a 5 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S;
X 5 、X 8 、X 9 CH;
X 6 、X 7 、X 10 is C;
X 11 、X 12 、X 13 each independently selected from the group consisting of: o, CH 2 、N、CH、NH。
In another preferred embodiment, the 8-10 membered fused ring heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S has a structure selected from the group consisting of:
in another preferred embodiment, the compound is selected from the group consisting of:
in a second aspect of the invention there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of a compound of the first aspect of the invention, or a pharmaceutically acceptable salt thereof.
In another preferred embodiment, the pharmaceutical composition is for the treatment of IL-2 related disorders.
In a third aspect of the present invention, there is provided a process for the preparation of a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, comprising the steps of:
1) Will beAnd->Reacting to obtain a compound of the first aspect of the invention, or a pharmaceutically acceptable salt thereof;
l, R is as defined in the first aspect of the invention.
In a fourth aspect of the invention there is provided the use of a compound of the first aspect of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in promoting endogenous IL-2 production by the body.
In another preferred embodiment, the medicament is for stimulating IL-2 secretion by human T cell leukemia cell line Jurkat cells.
In another preferred embodiment, the drug is an immunopotentiator.
In another preferred embodiment, the medicament is for the prevention and/or treatment of IL-2 related diseases.
In another preferred embodiment, the IL-2 related disorder is selected from the group consisting of: tumors, viral infections, bacterial infections, autoimmune diseases.
In another preferred embodiment, the tumor is selected from the group consisting of: thyroid cancer, lymphoma, leukemia, prostate cancer, renal cancer, bladder cancer, brain glioma, nasopharyngeal cancer, neuroblastoma, head and neck squamous cell carcinoma, cervical cancer, ovarian cancer, breast cancer, colorectal cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, osteosarcoma, interstitial sarcoma, choriocarcinoma, malignant grape embryo, malignant teratoma, gastric cancer, lung cancer, liver cancer, melanoma, undifferentiated carcinoma, benign tumor.
In another preferred embodiment, the viral infection is an 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, infant acute rash virus, varicella virus, herpes zoster virus, herpes simplex virus, japanese encephalitis virus, dengue virus, hepatitis virus, AIDS virus, monkey pox virus, vaccinia virus, variola virus, camel pox virus, murine poxvirus, parapoxvirus, rabbit poxvirus, raccoon poxvirus, skunky poxvirus, gerbilpoxvirus.
In another preferred embodiment, the bacterial infection is an infection with a bacterium selected from the group consisting of: staphylococcus aureus, streptococcus pneumoniae, streptococcus pyogenes, escherichia coli, haemophilus influenzae, staphylococcus aureus, staphylococcus epidermidis, enterococcus, klebsiella, aerobacter, pseudomonas aeruginosa, tubercle bacillus, leprosy bacillus.
In another preferred embodiment, the autoimmune disease is selected from the group consisting of: rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, scleroderma, multiple sclerosis, myasthenia gravis, demyelinating lesions, primary adrenocortical atrophy, chronic thyroiditis, ulcerative colitis, active hepatitis, pernicious anemia, atrophic gastritis, glomerulonephritis, pulmonary and renal hemorrhagic syndrome, autoimmune hemolysis, idiopathic thrombocytopenic purpura, idiopathic leukopenia.
In another preferred embodiment, the IL-2 related disorder is selected from the group consisting of: active hepatitis, herpes simplex virus infection, monkey pox virus infection, vaccinia virus infection, smallpox virus infection, AIDS disease, leprosy, and tubercle bacillus infection.
In a fifth aspect of the invention, there is provided the use of Tecovirimat for the manufacture of a medicament for promoting endogenous IL-2 production by the body.
In another preferred embodiment, the medicament is for stimulating IL-2 secretion by human T cell leukemia cell line Jurkat cells.
In another preferred embodiment, the drug is an immunopotentiator.
In another preferred embodiment, the medicament is for the prevention and/or treatment of IL-2 related diseases.
In another preferred embodiment, the IL-2 related disorder is selected from the group consisting of: tumors, viral infections, bacterial infections, autoimmune diseases.
In another preferred embodiment, the tumor is selected from the group consisting of: thyroid cancer, lymphoma, leukemia, prostate cancer, renal cancer, bladder cancer, brain glioma, nasopharyngeal cancer, neuroblastoma, head and neck squamous cell carcinoma, cervical cancer, ovarian cancer, breast cancer, colorectal cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, osteosarcoma, interstitial sarcoma, choriocarcinoma, malignant grape embryo, malignant teratoma, gastric cancer, lung cancer, liver cancer, melanoma, undifferentiated carcinoma, benign tumor.
In another preferred embodiment, the viral infection is an 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, infant acute rash virus, varicella virus, herpes zoster virus, herpes simplex virus, japanese encephalitis virus, dengue virus, hepatitis virus, AIDS virus, monkey pox virus, vaccinia virus, variola virus, camel pox virus, murine poxvirus, parapoxvirus, rabbit poxvirus, raccoon poxvirus, skunky poxvirus, gerbilpoxvirus.
In another preferred embodiment, the bacterial infection is an infection with a bacterium selected from the group consisting of: staphylococcus aureus, streptococcus pneumoniae, streptococcus pyogenes, escherichia coli, haemophilus influenzae, staphylococcus aureus, staphylococcus epidermidis, enterococcus, klebsiella, aerobacter, pseudomonas aeruginosa, tubercle bacillus, leprosy bacillus.
In another preferred embodiment, the autoimmune disease is selected from the group consisting of: rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, scleroderma, multiple sclerosis, myasthenia gravis, demyelinating lesions, primary adrenocortical atrophy, chronic thyroiditis, ulcerative colitis, active hepatitis, pernicious anemia, atrophic gastritis, glomerulonephritis, pulmonary and renal hemorrhagic syndrome, autoimmune hemolysis, idiopathic thrombocytopenic purpura, idiopathic leukopenia.
In another preferred embodiment, the IL-2 related disorder is selected from the group consisting of: active hepatitis, herpes simplex virus infection, monkey pox virus infection, vaccinia virus infection, smallpox virus infection, AIDS disease, leprosy, and tubercle bacillus infection.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Drawings
FIG. 1 shows the results of in vitro cell proliferation activity test obtained in example 2.
FIG. 2 shows the results of IL-2 induction by the compound obtained in example 3.
Detailed Description
The present inventors have conducted long and intensive studies to unexpectedly prepare a compound of formula I having excellent safety and more excellent effect of promoting secretion of IL-2 by the body through structural optimization. On this basis, the inventors completed the present invention.
Terminology
In the present invention, unless otherwise indicated, terms used have the ordinary meanings known to those skilled in the art.
In the present invention, the term "halogen" refers to F, cl, br or I.
In the present invention, "C1-C6 alkyl" means a straight-chain or branched alkyl group comprising 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, neopentyl, t-pentyl, or the like. The term "C1-C8 alkyl" has a similar meaning.
In the present invention, the term "C2-C6 alkenyl" refers to a straight or branched alkenyl group having 2 to 6 carbon atoms containing one double bond, including without limitation ethenyl, propenyl, allyl, butenyl, isobutenyl, pentenyl, hexenyl and the like. The term "C2-C8 alkenyl" has a similar meaning.
In the present invention, the term "C2-C6 alkynyl" refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms containing one triple bond, and includes, without limitation, ethynyl, propynyl, propargyl, butynyl, isobutynyl, pentynyl, hexynyl and the like. The term "C2-C8 alkynyl" has similar meanings.
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, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
In the present invention, the term "C3-C8 cycloalkenyl" refers to a cyclic alkenyl group having 3 to 8 carbon atoms in the ring and containing one double bond.
In the present invention, the term "amido" means that it contains-C (O) NR 1 R 2 Wherein R is a group or substituent of 1 And R is 2 Represents hydrogen or alkyl, e.g. -C (O) NH 2 、-C(O)NHCH 3 Etc.
In the present invention, the term "acyloxy" refers to a group OR substituent containing-C (O) OR, where R represents an alkyl group, e.g., -C (O) OCH 3 Etc.
In the present invention, the term "allyloxy" refers to ch2=ch—ch2—o-.
In the present invention, the term "propargyloxy" means CH.ident.C-CH 2-O-.
In the present invention, the term "sulfonyloxy" means R-S (=O) 2-O-, wherein R represents an alkyl group.
In the present invention, the term "sulfonylamino" means R-S (=O) 2-NH-, wherein R represents an alkyl group.
In the present invention, the term "C1-C6 alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like. Preferably C1-C4 alkoxy.
In the present invention, the term "heterocyclyl" or "heterocycloalkyl" is a 5-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O, S, including, but not limited to, the following groups:
in the present invention, the term "aromatic ring" or "aryl" has the same meaning, preferably "C6-C10 aryl". The term "C6-C10 aryl" refers to an aromatic cyclic group having 6 to 10 carbon atoms, such as phenyl, naphthyl, and the like, which does not contain heteroatoms in the ring.
In the present invention, the term "aromatic heterocycle" or "heteroaryl" has the same meaning and refers to a heteroaromatic group containing one to more 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: furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring. Heteroaryl groups may be optionally substituted or unsubstituted.
In the present invention, the term "halo" refers to substitution with halogen.
In the present invention, the term "substituted" means that one or more hydrogen atoms on a particular group are replaced with a particular substituent. The specific substituents are those described in the foregoing for each of the examples or are those found in each of the examples. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, which may be the same or different at each position. Those skilled in the art will appreciate that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Such as (but not limited to): halogen, hydroxy, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, and the like.
In the present invention, the term 1-6 refers to 1, 2, 3, 4, 5 or 6. Other similar terms each independently have similar meanings. The term "plurality" refers to 2-6, such as 2, 3, 4, 5 or 6.
In the present invention, the term "urethane group" hasStructure, wherein Ra, rb are each independentlyIs selected from H, C-C6 alkyl, halogenated C1-C6 alkyl, and C6-C10 aryl.
It will be understood that when a group is present in a compound in a plurality of different positions at the same time, the definition of each position is independent of the other and may be the same or different. That is, the term "selected from the group consisting of: the "and the term" are each independently selected from the group consisting of: "has the same meaning.
Compounds of formula (I)
Recently, it has been found that Tecovirimat also acts as an immunopotentiator, stimulating IL-2 secretion by Jurkat cells, a human T cell leukemia cell line, and thus has the potential to enhance the host immune response.
Based on the Tecovirimat structure, the research obtains a polycyclic nonene compound with a novel structure through reasonable drug design, and the compound has higher activity of stimulating Jurkat cell lines to produce IL-2 compared with Tecovirimat, thereby having better application potential.
Specifically, the present invention provides a compound represented by formula i:
wherein L, R is as defined above.
In another preferred embodiment, any of the compounds L, R is, independently of each other, a group corresponding to the particular compound of the invention.
As used herein, the term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention with acids or bases that are suitable for use as medicaments. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is the salts of the compounds of the present invention with acids. Suitable salts forming acids include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and the like; 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; amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.
Another preferred class of salts are salts of the compounds of the invention with bases, for example alkali metal salts (e.g. sodium or potassium salts, such as sodium hydroxide, potassium hydroxide in particular), alkaline earth metal salts (e.g. magnesium or calcium salts), ammonium salts (e.g. lower alkanolammonium salts and other pharmaceutically acceptable amine salts (e.g. ammonium hydroxide)), such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, tert-butylamine, ethylenediamine, hydroxyethylamine, dihydroxyethylamine, triethylamine, and amine salts formed from morpholine, piperazine, lysine, piperidine, respectively.
The compounds of the present invention and pharmaceutically acceptable salts thereof may also exist as variants including stereoisomers, enantiomers, diastereomers, atropisomers, optical isomers, racemates, polymorphs, solvates or isotopically-labeled compounds, and the like, as such variants are encompassed within the present invention.
The term "solvate" refers to a complex of the compound of the invention coordinated to a solvent molecule to form a specific ratio.
Preparation method
The following more particularly describes the preparation method of the compound of the formula I, but these specific methods do not limit the present invention. The compounds of the present invention may also be conveniently prepared by optionally combining the various synthetic methods described in this specification or known in the art, such combinations being readily apparent to those skilled in the art to which the present invention pertains.
Typically, the compounds of the present invention are prepared by the following process wherein the starting materials and reagents used, unless otherwise specified, are commercially available.
Wherein R, L is defined as described above,
the method comprises the steps of,
step 1: in a dimethylbenzene solvent, raw material cycloheptatriene (I-1) and maleic anhydride undergo Diels Alder reaction under the condition of heating reflux to generate an intermediate I-2;
step 2: intermediate I-2 is reacted with amine derivatives in ethanol solvent to form the compound of formula I.
Pharmaceutical compositions and methods of administration
The invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compounds of the invention, or pharmaceutically acceptable salts thereof.
Because the compound of the present invention has excellent antitumor activity, the compound of the present invention and various crystalline forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compound of the present invention as a main active ingredient are useful for the treatment, prevention and alleviation of diseases associated with tumors.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically 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. Typically, the pharmaceutical compositions contain 1-2000mg of the compound of the invention per dose, more preferably 10-1000mg of the compound of the invention per dose. Preferably, the "one dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatibility" means herein that the components of the composition are capable of blending with and with the compounds of the invention without significant reduction in their compatibilityDrug effect of the compound. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulphate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. tween) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The pharmaceutical composition is injection, capsule, tablet, pill, powder or granule.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise 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 nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration 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 which may be required if necessary.
The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., antineoplastic agents).
The methods of treatment of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 50 to 1000mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
Compared with the prior art, the invention has the following main advantages:
(1) Compared with Tecovirimat, the compound has better effect of promoting the secretion of the organism to produce IL-2;
(2) The compounds of the present invention have excellent safety.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedure, which does not address the specific conditions in the examples below, is generally followed by routine conditions such as Sambrook et al, molecular cloning: conditions described in the laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989) or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
Example 1 preparation of Compounds
Preparation of compound S1:
in a 25mL round bottom flask was added cycloheptatriene (100 mg,1.09 mmol), maleic anhydride (160 mg,1.64 mmol) and xylene (2 mL). Reflux reaction for 12 hours under the protection of argon, petroleum ether (5 mL) is added to precipitate yellow solid, and the yellow solid I-2 (90 mg) is obtained after suction filtration and drying, and the yield is 43%. 1 H NMR(400MHz,CDCl 3 ):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).
In a 25mL round bottom flask was added intermediate I-2 (40 mg,0.21 mmol), starting material I-3 (38 mg,0.21 mmol), ethanol (1 mL) and 1 drop of DIPEA. Reflux was performed for 4.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, ice water was added to precipitate a solid, which was filtered and dried to obtain a pale yellow solid S1 (90 mg), and the yield was 81%. 1 H NMR(400MHz,CDCl 3 ):δ7.99(s,1H),7.38(dd,J=8.2,1.6Hz,1H),6.81(d,J=8.1Hz,1H),6.03(s,2H),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).
Preparation of compound S2:
in a 25mL round bottom flask was added intermediate I-2 (40 mg,0.21 mmol), starting material I-4 (40 mg,0.21 mmol), ethanol (1 mL) and 1 drop of DIPEA. Reflux was performed for 4.5 hours. After the reaction was completed, the solution was cooled to room temperature, water was added, extraction was performed three times with ethyl acetate, and the organic phase was combined, washed once with saturated brine and dried over anhydrous sodium sulfate. Column chromatography (PE/EA 1:1) after rotary evaporation concentration gave S2 (38 mg) as a white solid in 47% yield. 1 H NMR(400MHz,DMSO-d 6 ):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).
Preparation of compound S3:
the synthesis was similar to S1, giving S3 as a pale yellow solid in 13% yield. 1 H NMR(400MHz,DMSO-d 6 ):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).
Preparation of compound S4:
the synthesis was analogous to S1, giving S4 as a white solid in 40% yield. 1 H NMR(400MHz,Methanol-d 4 ):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).
Preparation of compound S5:
the synthesis was similar to S1, giving S5 as a pale yellow solid in 34% yield. 1 H NMR(400MHz,Methanol-d 4 ):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).
Preparation of compound S6:
the synthesis was analogous to S1, giving S6 as a white solid in 45% yield. 1 H NMR(400MHz,Methanol-d 4 ):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).
Preparation of compound S7:
the synthesis was analogous to S1, giving S7 as a white solid in 42% yield. 1 H NMR(400MHz,DMSO-d 6 ):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).
Preparation of compound S8:
the synthesis was analogous to S1, giving S8 (40 mg) as a white solid in 58% yield. 1 H NMR(400MHz,DMSO-d 6 ):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).
Preparation of compound S9:
the synthesis was analogous to S1, giving S9 as a white solid in 45% yield. 1 H NMR(400MHz,CDCl 3 ):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).
Preparation of compound S10:
the synthesis was analogous to S1, giving S10 as a white solid in 49% yield. 1 H NMR(400MHz,CDCl 3 ):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).
Preparation of compound S11:
the synthesis was analogous to S1, giving S11 as a white solid in 36% yield. 1 H NMR(400MHz,DMSO-d 6 ):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).
Preparation of compound S12:
the synthesis was similar to S2, giving S12 as a pale yellow solid in 32% yield. 1 H NMR(400MHz,CDCl 3 ):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),3.53-3.50(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).
Preparation of compound S13:
the synthesis was analogous to S2, giving S13 as a pale yellow solid in 41% yield. 1 H NMR(400MHz,CDCl 3 ):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).
Preparation of compound S14:
the synthesis was analogous to S2, giving S14 as a pale yellow solid in 42% yield. 1 H NMR(400MHz,CDCl 3 ):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).
Preparation of compound S15:
the synthesis was analogous to S2, giving S15 as a pale yellow solid in 42% yield. 1 H NMR(400MHz,CDCl 3 ):δ7.79-7.74(m,2H),7.18-7.13(m,1H),5.84(m,2H),3.55(s,2H),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).
Preparation of compound S16:
the synthesis was analogous to S2, giving S16 as a pale yellow solid in 37% yield. 1 H NMR(400MHz,CDCl 3 ):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).
Preparation of compound S17:
the synthesis was similar to S2, giving S17 as a pale yellow solid in 51% yield. 1 H NMR(400MHz,CDCl 3 ):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).
Preparation of compound S18:
the synthesis was analogous to S2, giving S18 as a white solid in 47% yield. 1 H NMR(400MHz,DMSO-d 6 ):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),5.80(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).
Preparation of compound S19:
the synthesis was analogous to S1, giving S19 as a pale yellow solid in 29% yield. 1 H NMR(400MHz,DMSO-d 6 ):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).
Preparation of compound S20:
the synthesis was analogous to S1, giving S20 as a white solid in 47% yield. 1 H NMR(400MHz,DMSO-d 6 ):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).
Preparation of compound S21:
the synthesis was analogous to S1, giving S21 as a white solid in 38% yield. 1 H NMR(400MHz,DMSO-d 6 ):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).
Preparation of compound S22:
the synthesis was analogous to S1, giving S22 as a white solid in 34% yield. 1 H NMR(400MHz,DMSO-d 6 ):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,2H),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).
Preparation of compound S23:
the synthesis was analogous to S1, giving S23 as a yellow solid in 48% yield. 1 H NMR(400MHz,CDCl 3 ):δ8.05(s,1H),7.91(d,J=9.5Hz,1H),7.08(d,J=9.5Hz,1H),5.90-5.84(m,2H),3.51(s,2H),3.20-3.15(m,2H),1.17-1.11(m,2H),0.37-0.23(m,2H).
Preparation of compound S24:
the synthesis was analogous to S2, giving S24 as a yellow solid in 38% yield. 1 H NMR(400MHz,CDCl 3 ):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).
Preparation of compound S25:
the synthesis was analogous to S2, giving S25 as a yellow solid in 47% yield. 1 H NMR(400MHz,CDCl 3 ):δ8.51(dd,J=2.9,2.2Hz,1H),7.77(dd,J=7.9,2.2Hz,1H),5.94(dd,J=4.8,3.4Hz,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).
Preparation of compound S26:
the synthesis was analogous to S2, giving S26 as a yellow solid in 13% yield. 1 H NMR(400MHz,CDCl 3 ):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).
Preparation of compound S27:
the synthesis was analogous to S2, giving S27 as a yellow solid in 34% yield. 1 H NMR(400MHz,CDCl 3 ):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).
Example 2 in vitro cell proliferation Activity test of Compounds
The present study uses the CCK8 (Cell Counting Kit-8) method to test compounds for cytotoxicity. Taking logarithmic phase human leukemia T cell line Jurkat cells, processing, inoculating into 96-well plate, and inoculating into 5% CO at 37deg.C 2 Is cultured for 24 hours under the condition of (2). Two concentrations of the test compound were added. Culturing was continued for 48 hours under the same conditions, and then cytopathy was treated with CCK8 kit (Beyotime) according to the manufacturer's instructionsThe death was quantified and the cell viability was calculated. Three complex wells were set up for each concentration gradient and the detection was repeated three times. The activity results are shown in Table 1 and FIG. 1.
Wherein: normal cell proliferation activity in vitro of the compounds was determined by CCK8 assay kit and the final data taken as the average of three measurements.
Results of in vitro cell proliferation Activity of the compounds of Table 1
Example 3 experiment for inducing IL-2 secretion in Jurkat cells
The logarithmic phase of human leukemia T cell line Jurkat cells was taken, the cell concentration was first adjusted to one million per ml, and a fraction was taken as a control group (without PMA and PHA). PMA and PHA were added to the medium at concentrations of 20ng/mL and 20. Mu.g/mL, respectively, and after mixing by blow, 200. Mu.L/well was added to a 48-well plate. The test compound was added at a single concentration, tecovirimat was used as a positive control, and 5% CO at 37℃ 2 Is cultured for 48 hours under the condition of (2). Cells were first blown evenly, cells and medium were collected into an EP tube, centrifuged for 10 minutes, supernatant was collected and stored at-20℃and then the IL-2 content was measured using an IL-2ELISA kit, and the results are shown in Table 2 and FIG. 2.
Results of Compounds of Table 2 for inducing IL-2 secretion in Jurkat cells
As can be seen from table 1 and fig. 1: the compound and Tecovirimat have no obvious proliferation inhibition effect on Jurkat cells at the concentration of 1 mu M and 10 mu M, show lower cytotoxicity, and show that the compound has good safety.
As can be seen from table 2 and fig. 2: most of the compounds can obviously promote Jurkat cells to produce IL-2 at the concentration of 1 mu M, and the activity is higher than that of Tecovirimat, which proves that the compounds have obvious immunity enhancement effect on organisms and potential application value for treating infectious diseases.
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.
Claims (10)
1. A compound of formula i, or a pharmaceutically acceptable salt thereof:
wherein:
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)-;
R is selected from the group consisting of substituted or unsubstituted: 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 fused 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S, C6-C10 aryl- (C1-C6 alkylene) -, monocyclic or fused 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; wherein said substitution means substitution with 1, 2, 3 or 4 groups selected from the group consisting of: amino, hydroxy, mercapto, halogen, cyano, nitro, acyloxy, acylamino, C1-C6 alkoxy, C1-C6 alkyl-NH-, C1-C6 alkyl-S-, C1-C8 alkyl, haloC 1-C8 alkyl, hydroxy-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbamate, allyloxy, propargyloxy, sulfonyloxy, sulfonylamino;
alternatively, L is-NHC (=o) -, R is selected from the group consisting of substituted or unsubstituted: a 5-10 membered fused ring heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S, a 5-10 membered fused ring heteroaryl- (C1-C6 alkylene) -, containing 1, 2 or 3 heteroatoms selected from N, O or S; wherein said substitution means substitution with 1, 2, 3 or 4 groups selected from the group consisting of: amino, hydroxy, mercapto, halogen, cyano, nitro, acyloxy, acylamino, C1-C6 alkoxy, C1-C6 alkyl-NH-, C1-C6 alkyl-S-, C1-C8 alkyl, haloC 1-C8 alkyl, hydroxy-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbamate, allyloxy, propargyloxy, sulfonyloxy, sulfonylamino.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof,
l is absent;
r is selected from the following groups substituted: C6-C10 aryl, and 8-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; wherein said substitution means substitution with 1, 2, 3 or 4 groups selected from the group consisting of: halogen, C1-C8 alkyl, halogenated C1-C8 alkyl;
the additional conditions are:
1) When R is a substituted C6-C10 aryl, at least 1 substituent of R is halogen;
2) When R is a substituted and cyclic 8-10 membered heteroaryl containing only 2N, at least 1 substituent of R is halogen.
3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the fused 8-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S isWherein (1)>Is a 5 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S, -/-, and>is phenyl or is 6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S;
X 1 、X 2 、X 3 、X 4 each independently selected from the group consisting of: CH. S, C, N, NH.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof,
l is-NHC (=o) -, R is selected from the group consisting of substituted or unsubstituted: 8-10 membered fused ring heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S, 8-10 membered fused ring heteroaryl- (C1-C6 alkylene) -, containing 1, 2 or 3 heteroatoms selected from N, O or S; wherein said substitution means substitution with 1, 2, 3 or 4 groups selected from the group consisting of: halogen, C1-C8 alkyl, halogenated C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl;
the additional conditions are:
1) The 8-10 membered fused ring heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S contains at least 1N heteroatom.
5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein the 8-10 membered fused ring heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O or S isWherein (1)>Is 6 membered aryl, ">Is a 5 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S or a 5 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S;
X 5 、X 8 、X 9 CH;
X 6 、X 7 、X 10 is C;
X 11 、X 12 、X 13 each independently selected from the group consisting of: o, CH 2 、N、CH、NH。
7. a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of a compound of claim 1, or a pharmaceutically acceptable salt thereof.
9. Use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for promoting endogenous IL-2 production by the body.
Use of tecovirimat, for the preparation of a medicament for promoting endogenous IL-2 production by the body.
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