CN111909107B - IDO/HDAC dual inhibitor and pharmaceutical composition and application thereof - Google Patents
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Abstract
The invention discloses a heterocyclic hydroximes compound with a specific structure, a pharmaceutically acceptable salt, an isomer, a prodrug or a solvate thereof, and a pharmaceutical composition containing the heterocyclic hydroximes compound as an active ingredient, and further experiments prove that the compound and the pharmaceutical composition have double inhibition effects on indoleamine-2,3-dioxygenase and histone deacetylase, can be applied to preparation of drugs for treating diseases related to abnormal regulation of 2, 3-indoleamine dioxygenase and histone deacetylase, wherein the diseases comprise cancer, neurodegenerative diseases, AIDS, senile dementia, malaria, diabetes and the like, and have wide application prospects.
Description
Technical Field
The invention belongs to the field of chemical medicine, and particularly relates to a heterocyclic hydroximic compound with a specific structure, pharmaceutically acceptable salts, isomers, prodrugs or solvates thereof, a pharmaceutical composition containing the compound, and application of the compound and the pharmaceutical composition in preparation of medicines.
Background
Indoleamine-2,3-dioxygenase (IDO) is a monomeric enzyme containing heme outside the liver, and catalyzes the rate-limiting step of tryptophan kynurenine metabolic pathway, so that tryptophan is subjected to oxidation reaction and converted into N-formyl kynurenine, the N-formyl kynurenine is hydrolyzed to generate kynurenine, and then enters the canine uric acid metabolic pathway to generate metabolites such as quinolinic acid and kynurenine. Over expression of IDO causes local tryptophan depletion, and metabolites such as canine uric acid and the like are increased, so that proliferation of T cells is inhibited, regulatory T cells are activated, and an immune-tolerant tumor microenvironment is caused, so that an organism cannot recognize and remove the tumor cells. In addition, numerous studies have shown that IDO is highly expressed in a variety of tumors and antigen presenting cells, and is closely associated with poor prognosis and low survival in patients. Therefore, inhibiting the activity of IDO can effectively prevent the degradation of tryptophan around tumor cells and promote the proliferation of T cells, thereby enhancing the attack capability of the body on the tumor cells. However, IDO inhibitors have only moderate activity when used alone, but have better efficacy when used in combination with chemotherapeutic agents or other immune checkpoint inhibitors. However, the drug combination may have the problems of complicated pharmacokinetics, failure to reach the action target point and drug-drug interaction, etc. The double-target or multi-target medicament can reduce the occurrence of medicament resistance, enhance the medicament activity and improve the therapeutic index.
Histone Deacetylases (HDACs) catalyze the deacetylation of amino-terminal lysines of histones, causing chromatin condensation and transcriptional repression. At present, it is known that there are 18 different subtypes of histone deacetylase,classified into 4 categories by species: class I includes HDAC1, HDAC2, HDAC3, and HDAC8, and is present only in the nucleus; class II includes HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, HDAC10 and HDAC11, shuttled between the nucleus and cytoplasm during signal transduction; class iv is HDAC11; the III group is SIRT1-SIRT7 which is greatly different from the I, II and IV groups, and the activity of the III group is independent of Zn 2+ But rather on coenzyme I (NAD), which is not inhibited by class I and II HDAC inhibitors. HDAC inhibitors are capable of inducing apoptosis, differentiation and autophagy of tumor cells, inhibiting proliferation of tumor cells, inhibiting adhesion and metastasis of tumor cells, and inhibiting angiogenesis. Currently, four HDAC inhibitors are on the market for the treatment of various hematological tumors. It is worth mentioning that recent studies have shown that HDAC inhibitors can enhance the tumor recognition ability of the immune system and can reverse tumor immunosuppression. Therefore, the IDO/HDAC dual inhibitor can effectively combine the advantages of the tumor immune checkpoint inhibitor and the epigenetic drug, and improve the anti-tumor curative effect.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the problems of inaccurate curative effect, larger toxic and side effect and the like of the existing medicines, the invention provides a dual inhibitor of indoleamine-2,3-dioxygenase and histone deacetylase of heterocyclic hydroximes, and also provides a preparation method of the dual inhibitor of indoleamine-2, 3-dioxygenase/histone deacetylase, a pharmaceutical composition containing the inhibitor, and pharmaceutical applications of the inhibitor and the histone deacetylase.
The technical scheme is as follows: the heterocyclic hydroximes are selected from compounds shown in formulas I to VII as follows:
and pharmaceutically acceptable salts, isomers, prodrugs or solvates thereof.
The preparation method of the heterocyclic hydroximes compound comprises the following steps:
(1) Reacting a compound shown in a formula (A) with isocyanate in an organic solvent to obtain a compound shown in a formula (B), wherein the reaction process is as follows:
(2) Deprotecting the compound shown in the formula (B) under the action of alkali to obtain a compound shown in the formula (C), wherein the reaction process is as follows:
further, in the step (1), the organic solvent is selected from one or more of dichloromethane, tetrahydrofuran (THF), N-Dimethylformamide (DMF), ethylene glycol dimethyl ether, 1, 2-dichloroethane, dimethyl phthalate (DMP), methanol, ethanol, petroleum ether, N-hexane and diethyl ether.
In the step (2), the base is one or more selected from potassium carbonate, sodium bicarbonate, magnesium carbonate, calcium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, magnesium hydroxide, imidazole hydroxide, triethylamine, diisopropylethylamine, piperidine, lutidine, N-methylmorpholine, DABCO and pyridine.
The invention also provides a pharmaceutical composition, which contains an effective amount of the heterocyclic hydroximes or the pharmaceutically acceptable salt, prodrug or solvate thereof and a pharmaceutically acceptable carrier.
The invention also provides application of the heterocyclic hydroximes compound and the pharmaceutically acceptable salt thereof or prodrug molecules thereof in preparing medicines for treating or preventing tumors.
The tumor comprises transitional proliferative diseases such as lymphoma, non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, gastric cancer, pancreatic cancer, breast cancer, prostatic cancer, liver cancer, skin cancer, epithelial cell cancer, leukemia, cervical cancer and the like.
The heterocyclic hydroximes compound and the pharmaceutically acceptable salt thereof can effectively inhibit the growth of various tumor cells, have double inhibition effects on 2, 3-indoleamine dioxygenase and histone deacetylase, and can be used for preparing corresponding antitumor drugs. As understood by those in the art, the compounds and pharmaceutically acceptable salts thereof referred to in the present application can be used for the preparation of a medicament for treating hyperproliferative diseases such as tumors in humans and other mammals.
The heterocyclic hydroximes compound and the medicine prepared from the pharmaceutically acceptable salt thereof can be used for treating mammal diseases related to abnormal regulation of 2, 3-indoleamine dioxygenase and histone deacetylase, including cancer, neurodegenerative diseases, AIDS, senile dementia, malaria, diabetes and the like.
Those of ordinary skill in the art will know the meanings of the following terms or abbreviations.
The term "pharmaceutically acceptable salt" refers to salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, such as the medically acceptable salts of amines, carboxylic acids, and other types of compounds, are well known in the art.
The term "solvate" refers to a mixture of a compound and a solvent, e.g., a crystal is a solvate.
The term "prodrug" refers to a compound that is rapidly converted in vivo by hydrolysis in blood to yield the parent compound having the above formula.
Has the beneficial effects that: the invention provides a heterocyclic hydroximes compound with a specific structure, a pharmaceutically acceptable salt, an isomer, a prodrug or a solvate thereof, and a pharmaceutical composition containing the heterocyclic hydroximes compound as an active ingredient, and further experiments prove that the compound and the pharmaceutical composition have double inhibition effects on indoleamine-2,3-dioxygenase and histone deacetylase, can be applied to preparation of drugs for treating diseases related to abnormal regulation of 2, 3-indoleamine dioxygenase and histone deacetylase, wherein the diseases comprise cancer, neurodegenerative diseases, AIDS, senile dementia, malaria, diabetes and the like, and have wide application prospects.
Detailed Description
The present application will be described in detail with reference to specific examples.
The invention includes the free forms of formulae (I) to (VII) as well as pharmaceutically acceptable salts and stereoisomers. Some specific exemplary compounds herein are protonated salts of amine-based compounds. The term "free form" refers to the amine compound in a non-salt form. Inclusion of pharmaceutically acceptable salts includes not only exemplary salts of the particular compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of formulas (I) - (VII). The free form of a particular salt of the compound may be isolated using techniques known in the art. For example, the free form is regenerated by treating the salt with a suitable dilute aqueous base such as dilute aqueous sodium hydroxide, dilute aqueous sodium carbonate, dilute aqueous ammonia and dilute aqueous potassium bicarbonate. The free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
Pharmaceutically acceptable salts of the invention can be synthesized from compounds of the invention containing a basic or acidic moiety by conventional chemical methods. In general, salts of basic compounds are prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric amount or excess of an inorganic or organic acid in the form of the desired salt in an appropriate solvent or combination of solvents. Similarly, salts of the compounds are formed by reaction with a suitable inorganic or organic base.
Thus, pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts of the compounds of the present invention formed by the reaction of a basic compound of the present invention and an inorganic or organic acid. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, acetic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, fumaric acid, 2-acetoxy-benzoic acid, fumaric acid, p-toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.
Example 1
The reaction formula is as follows;
step 1.1- (4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazole-3-substituted) -1,2, 5-oxadiazole-3-substituted) -3- (3-methoxyphenyl) urea
A tetrahydrofuran solution (1 mL) of m-methoxyphenylisocyanate (14.9mg, 0.10mmol) was slowly dropped into a tetrahydrofuran solution (1 mL) of a raw material (30mg, 0.0877mmol) at 0 ℃ under the protection of argon, the temperature was raised to room temperature to react for 16 hours, the reaction solution was concentrated, water (1 mL) was added, ethyl acetate (1 mL) was further added, the layers were separated, the aqueous phase was extracted with ethyl acetate (2X 2 mL), the organic phases were combined, washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, concentrated, and column chromatography was performed to obtain a target product (32 2mg, 66%). MS (EI, M/z): 491 (M) + +1).
Step 2. (Z) - (N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- (3- (3-methoxyphenyl) ureido) -1,2, 5-oxadiazole-3-carboximidamide
Dissolving the above raw materials (20 mg) in tetrahydrofuran (1 mL), adding NaOH aqueous solution (0.5 mL, 2M) to react for 2h, adding water (1 mL), ethyl acetate (5 mL), separating, extracting the aqueous phase with ethyl acetate (2X 5 mL), combining the organic phases, washing with saturated saline (2 mL), drying over anhydrous sodium sulfate, concentrating, and performing column chromatographyThe target compound I (18mg, 95%) was obtained. 1 H NMR(400MHz,DMSO):δ11.53(s,1H),9.85(s,1H),9.55(s，1H),9.01(s,1H),7.33(s,1H), 7.28-7.26(m,2H),7.16-7.05(m,1H),6.94(t,J＝8.2Hz,1H),6.77(d,J＝6.2Hz,1H),6.65-6.60 (m,1H),3.65(s,3H)ppm. 13 C NMR(125MHz,DMSO):δ163.9,162.3,158.3,154.1,148.3, 146.1,136.6,133.8,128.7,119.6,118.2,117.8,115.8,113.2,110.8,109.3,58.3ppm.MS(EI,m/z): 465(M + +1).
Example 2
(Z) - (N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- (3- (2-methoxyphenyl) ureido) -1,2, 5-oxadiazole-3-carboximidamide
The synthesis method is referred to example 1.
1 H NMR(400MHz,DMSO):δ11.56(s,1H),9.70(s,1H),9.50(s,1H),8.95(s,1H),7.89(t,J ＝8.5Hz,1H),7.12-7.06(m,1H),6.87(t,J＝8.3Hz,1H),6.87(d,J＝6.2Hz,1H),6.69-6.63(m, 1H),3.78(s,3H)ppm. 13 C NMR(125MHz,DMSO):δ 13 C NMR(125MHz,DMSO):δ163.1, 156.3,152.1,149.3,147.1,141.3,135.8,128.7,124.1,121.2,120.3,113.2,110.8,109.3,58.4ppm. MS(EI,m/z):465(M + +1).
Example 3
(Z) - (N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- (3- (4-hydroxyphenyl) ureido) -1,2, 5-oxadiazole-3-carboximidamide
Synthetic methods refer to example 1.
1 H NMR(400MHz,DMSO):δ11.23(s,1H),9.88(s,1H),9.55(s，1H),9.43(s,1H),9.21(s, 1H),7.38(d,J＝5.3Hz,2H),6.93(t,J＝8.2Hz,1H),6.87(d,J＝6.2Hz,1H),6.75(d,J＝5.3Hz, 2H)ppm. 13 C NMR(125MHz,DMSO):δ162.9,155.3,153.1,150.2,147.5,142.1,134.6,132.2, 123.5,119.5,117.5,117.8,116.8,115.2,109.9ppm.MS(EI,m/z):451(M + +1).
Example 4
(Z) - (N- (3-bromo-4-fluorophenyl) -4- (3, 4-dimethoxyphenyl) ureido) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboximidamide
The synthesis method is referred to example 1.
1 H NMR(400MHz,DMSO):δ11.38(s,1H),9.88(s,1H),9.65(s,1H),9.05(s,1H),7.23(s, 1H),6.94-6.89(m,2H),6.83(d,J＝6.2Hz,1H),6.69-6.62(m,1H),3.88(s,3H),3.62(s,3H)ppm. 13 C NMR(125MHz,DMSO):δ 13 C NMR(125MHz,DMSO):δ163.1,155.3,152.1,150.1,147.3, 146.1,142.0,134.3,129.8,119.7,118.2,116.5,114.2,111.9,110.8,107.2,58.4,56.9ppm.MS(EI, m/z):495(M + +1).
Example 5
(Z) - (N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- (3- (4-trifluoromethoxy) phenyl) ureido) -1,2, 5-oxadiazole-3-carboxamido)
Synthetic methods refer to example 1.
1 H NMR(400MHz,DMSO):δ11.23(s,1H),9.89(s,1H),9.54(s,1H),9.02(s,1H),7.22(m, 2H),6.96-6.93(m,3H),6.83(t,J＝8.5Hz,1H),6.72(m,1H)ppm. 13 C NMR(125MHz,CDCl 3 ):δ 165.4,155.8,151.2,148.0,146.4,142.3,134.6,132.6,130.2,119.3,118.0,117.2,114.5,110.8ppm. MS(EI,m/z):518(M + +1).
Example 6
(Z) - (N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- (3- (3-trifluoromethoxy) phenyl) ureido) -1,2, 5-oxadiazole-3-carboximidamide
The synthesis method is referred to example 1.
1 H NMR(400MHz,DMSO):δ11.28(s,1H),9.89(s,1H),9.43(s,1H),9.12(s,1H),7.34(s, 1H),7.23-7.20(m,2H),6.93(t,J＝8.5Hz,1H),6.83-6.79(m,2H),6.68-6.65(m,1H)ppm. 13 C NMR(125MHz,DMSO):δ163.2,160.8,155.3,151.9,147.4,142.3,136.6,134.8,129.2,119.8, 118.0,117.2,113.5,110.8,110.2,109.3ppm.MS(EI,m/z):518(M + +1).
Example 7
(Z) - (N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- (3- (piperidinyl-4-yl) ureido) -1,2, 5-oxadiazole-3-carboximidamide
The synthesis method is referred to example 1.
1 H NMR(400MHz,DMSO):δ11.27(s,1H),9.88(s,1H),9.33(s,1H),9.09(s,1H),7.32(s, 1H),7.23-7.20(m,2H),3.60(m,1H),2.80-2.77(m,2H),2.60-2.57(m,2H),1.87-1.83(m,2H), 1.45-1.42(m,2H)ppm. 13 C NMR(125MHz,DMSO):δ163.1,156.3,154.9,147.3,142.3,134.6, 120.8,118.8,117.2,110.7,49.5,48.5,32.9,31.2ppm.MS(EI,m/z):442(M + +1).
Example 8
Determination of HDAC enzyme Activity
The determination principle is as follows: the biochemical activity of a compound is determined by its degree of deacetylation that inhibits HDAC enzymes. After acting on the fluorescently labeled substrate containing the acetylated lysine side chains and the HDAC enzyme, the fluorescent substrate is deacetylated. The deacetylated fluorescently labelled substrate is cleaved by the enzyme, releasing the fluorescent species which, upon excitation with 360nm light, produces 460nm emission.
The method comprises the following specific steps: HDAC substrate is diluted to 200M (reaction concentration is 20M) by using reaction buffer, HDAC enzyme is diluted to proper concentration, heterocyclic urea compound prepared by the invention with different concentration is added, reaction is carried out for 30 minutes at 37 ℃, then 2 times concentration substrate development solution (developer) with the same volume is added, incubation is carried out for 15 minutes at room temperature, finally reading is measured by a microplate reader, exciting light is 360nm, emitting light is 460nm, and data is processed by Prime 4 software. The results are shown in Table 1.
Example 9
Determination of IDO1 enzymatic Activity
Firstly, adding 15 mul of buffer solution (pH: 7-8) of sodium hydrogen phosphate into pores of a microporous plate, adding 5 mul of reaction buffer solution containing a proper amount of IDO1 enzyme and the heterocyclic urea compound prepared by the invention, uniformly mixing, reacting for 3 hours at room temperature, detecting the light absorption value with the wavelength of 320nm by using an Envision multilabel reader multifunctional enzyme-linked immunosorbent assay instrument of PE company, calculating the inhibition rate of the heterocyclic urea compound on the enzyme reaction according to the absorption ratio, and analyzing and calculating the IC of the heterocyclic urea compound by using GraphPad software 50 The value is obtained. The results are shown in Table 1.
TABLE 1
IC in the above table 50 Refers to the concentration of inhibitor that is inhibited by half (50% inhibition concentration).
From the results in the table above, it can be seen that: compared with SAHA, the compound has certain HDAC enzyme inhibitory activity and stronger IDO1 inhibitory activity compared with INCB 24360.
Example 10
Determination of IDO1 enzyme Activity at cellular level
Hela cells were cultured and passaged in DMEM medium containing antibiotics in a carbon dioxide incubator at 37 ℃ overnight in a 96-well plate, and then 1. Mu.l of a heterocyclic urea compound and 100. Mu.l of interferon-. Gamma.were added to each well (final concentration: 100 ng/ml). After further culturing the cells for 72 hours, 70. Mu.l of the cell culture supernatant was added to a 96-well sharp bottom plate, 5. Mu.l of trichloroacetic acid (6.1N) was added to each well, incubated at 50 ℃ for 30min and then taken out, and centrifuged at 25000rpm for 10min. Transferring 20 mul/hole of the centrifuged supernatant into a 384 micro-porous plate, adding 20 mul of 2% dimethylaminobenzaldehyde acetic acid solution into each hole, shaking and uniformly mixing, measuring light absorption at 480nm, and measuring the value. The results are shown in Table 2.
TABLE 2
| sample | IC 50 (μM) |
| INCB24360 | 0.055 |
| I | 0.043 |
| II | 0.046 |
| III | 0.033 |
| IV | 0.039 |
| V | 0.021 |
| VI | 0.032 |
| VII | 0.018 |
Example 11
Test for detecting Activity of Compound on cancer cell
The experimental principle is as follows: inhibition of cancer cell growth by compounds was measured by the MTT method. The principle of the MTT method is that yellow thiazole blue can penetrate a cell membrane to enter a cell, amber dehydrogenase in mitochondria of a living cell can reduce exogenous MTT into bluish purple needle-shaped Formazan crystals which are difficult to dissolve in water and deposit the crystals in the cell, the crystals can be dissolved by dimethyl sulfoxide (DMSO), an enzyme linked immunosorbent assay detector is used for detecting the light absorption value of the crystals at the wavelength of 490nm/570nm, and the cell number can be indirectly reflected.
Experimental materials: the cancer cell lines used were Hela (human cervical carcinoma cells), MCF-7 (human breast carcinoma cells), BGC-823 (human gastric carcinoma cells), A549 (human lung carcinoma cells), HT1080 (human fibrosarcoma cells), A431 (human epidermal squamous cell carcinoma cells), DU145 (human prostate carcinoma cells), U937 (human leukemia cells), pac-1 (human pancreatic carcinoma cells), MOLT-4 (human acute lymphoblastic leukemia cells); cultured with DMEM +10% FBS medium or with 1640+10% FBS, respectively.
Experimental methods and analysis of results:
experimental groups: 190. Mu.l cell suspension + 10. Mu.l drug at different concentrations (final concentration 10) -5 ～10 -10 M)
Blank control group: 200 μ l PBS
Negative control group: 190. Mu.l cell suspension + 10. Mu.l 2% DMSO (final DMSO concentration is 0.1%)
Positive control group: 190. Mu.l cell suspension + 10. Mu.l of different concentrations of the compound
a) The cells were seeded in 96-well plates at 1500/well, 190. Mu.l/well, 5% CO at 37 ℃ 2 Culturing in an incubator overnight;
b) Adding 10 μ l of different drugs into each well the next day to obtain a final concentration of 10 -5 ～10 -10 M, arranging three parallel holes; 37 ℃ and 5% CO 2 Incubating in an incubator for 72 hours;
c) Mu.l of 5mg/ml MTT, 5% CO at 37 ℃ were added to each well 2 Incubating in an incubator for 4 hours;
d) Discarding the supernatant, adding 100 μ l DMSO into each well, and oscillating;
e) Reading at 570nm, calculating cell survival rate, and calculating cell survival rate according to the resultCalculating GI 50 The following Table 3 was obtained.
TABLE 3
GI of the above table 50 Expressed is the concentration of drug required for 50% growth inhibition of the cells (50% growth inhibition).
From the results in the table above, it can be seen that: the above drugs have a certain cytotoxicity compared to positive control (SAHA).
Claims (2)
1. A heterocyclic hydroximic compound is selected from compounds shown in formulas I to VI:
and pharmaceutically acceptable salts thereof;
the application of the heterocyclic hydroximes compound in preparing medicines for treating diseases related to abnormal regulation of 2, 3-indoleamine dioxygenase and histone deacetylase; the diseases include hyperproliferative diseases, neurodegenerative diseases, AIDS, senile dementia, malaria and diabetes;
the hyperproliferative diseases include lymphoma, non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, gastric cancer, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, leukemia and cervical cancer.
2. A pharmaceutical composition comprising an effective amount of the heterocyclic hydroxamic compounds or pharmaceutically acceptable salts thereof according to claim 1, and a pharmaceutically acceptable carrier.
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| CN106866571A (en) * | 2017-01-20 | 2017-06-20 | 中国药科大学 | Heterocyclic urea compound and its pharmaceutical composition and application |
| CN108003111A (en) * | 2017-12-14 | 2018-05-08 | 华东理工大学 | Double target spot inhibitor of a kind of HDAC1 and IDO1 and its preparation method and application |
| WO2019057123A1 (en) * | 2017-09-20 | 2019-03-28 | 杭州英创医药科技有限公司 | Polycyclic compound acting as ido inhibitor and/or ido-hdac dual inhibitor |
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| CN101212967A (en) * | 2005-05-10 | 2008-07-02 | 因塞特公司 | Modulators of indoleamine 2,3-dioxygenase and methods of using the same |
| CN106866571A (en) * | 2017-01-20 | 2017-06-20 | 中国药科大学 | Heterocyclic urea compound and its pharmaceutical composition and application |
| WO2019057123A1 (en) * | 2017-09-20 | 2019-03-28 | 杭州英创医药科技有限公司 | Polycyclic compound acting as ido inhibitor and/or ido-hdac dual inhibitor |
| CN108003111A (en) * | 2017-12-14 | 2018-05-08 | 华东理工大学 | Double target spot inhibitor of a kind of HDAC1 and IDO1 and its preparation method and application |
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