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WO2017202276A1 - 苯醚类衍生物、及其制法和药物组合物与用途 - Google Patents

苯醚类衍生物、及其制法和药物组合物与用途 Download PDF

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Publication number
WO2017202276A1
WO2017202276A1 PCT/CN2017/085420 CN2017085420W WO2017202276A1 WO 2017202276 A1 WO2017202276 A1 WO 2017202276A1 CN 2017085420 W CN2017085420 W CN 2017085420W WO 2017202276 A1 WO2017202276 A1 WO 2017202276A1
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Prior art keywords
group
substituted
bromine
alkylamino
chlorine
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PCT/CN2017/085420
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English (en)
French (fr)
Inventor
冯志强
陈晓光
杨阳
周川
来芳芳
季鸣
金小锋
薛妮娜
郑义
陈浩
李凌
Original Assignee
中国医学科学院药物研究所
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Application filed by 中国医学科学院药物研究所 filed Critical 中国医学科学院药物研究所
Priority to EP17802122.6A priority Critical patent/EP3459926B1/en
Priority to US16/303,641 priority patent/US10882833B2/en
Priority to CN201780031899.5A priority patent/CN109311792B/zh
Priority to JP2019514168A priority patent/JP7075928B2/ja
Priority to KR1020187037375A priority patent/KR102400592B1/ko
Priority to RU2018145534A priority patent/RU2744975C2/ru
Publication of WO2017202276A1 publication Critical patent/WO2017202276A1/zh

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Definitions

  • the present invention discloses a class of phenyl ether derivatives, processes for their preparation, and pharmaceutical compositions and uses. Specifically, it relates to an phenyl ether derivative of the formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a process for the preparation thereof, a composition containing one or more of the compounds, and a compound of the same Uses in diseases associated with the PD-1/PD-L1 signaling pathway, such as cancer, infectious diseases, autoimmune diseases.
  • the ability of tumor cells to evade the immune system is achieved by binding of a programmed death ligand (PD-L1) produced on its surface to the PD-1 protein of T cells.
  • PD-L1 programmed death ligand
  • the tumor microenvironment in the body induces high expression of PD-1 molecules in infiltrating T cells, and tumor cells highly express PD-1 ligands PD-L1 and PD-L2, resulting in continuous activation of the PD-1 pathway in the tumor microenvironment.
  • T cell function is inhibited and the tumor cannot be found so that it cannot deliver a treatment to the immune system that requires attacking the tumor and killing the tumor cells.
  • the PD-1 antibody is an antibody protein against PD-1 or PD-L1, which prevents the first two proteins from binding, blocks this pathway, and partially restores the function of T cells, enabling these cells to continue to kill tumor cells.
  • Immunotherapy based on PD1/PDL1 is a new generation of immunotherapy that is currently attracting attention. It aims to use the body's own immune system to resist tumors and induce apoptosis by blocking PD-1/PD-L1 signaling pathway. Tumor potential. Recently, a series of surprising studies have confirmed that PDl/PD-Ll inhibitory antibodies have strong anti-tumor activity against a variety of tumors, which is particularly eye-catching. September 4, 2014, Merck, USA (Pembrolizumab) became the first FDA-approved PD-1 mAb for the treatment of advanced or unresectable melanoma patients who were ineffective for other medications.
  • the monoclonal antibody therapeutic drug has its own defects: it is easily decomposed by proteases, so it is unstable in the body and cannot be taken orally; it is easy to produce immune cross-reaction; the product quality is not easy to control, and the production technology is high; a large amount of preparation and purification is difficult, and production is difficult. High cost; inconvenient to use, can only be injected or drip. Therefore, PDl/PD-Ll interaction small molecule inhibitors are a better choice for tumor immunotherapy.
  • the technical problem to be solved by the present invention is to provide a phenyl ether derivative having the structural formula I which inhibits the interaction of PD1/PD-L1, and a stereoisomer thereof and a pharmaceutically acceptable salt thereof, and a preparation method thereof and a pharmaceutical combination thereof And its use in the preparation of a medicament for preventing or treating diseases associated with the PD1/PD-L1 signaling pathway.
  • the present invention provides the following technical solutions:
  • a first aspect of the technical solution of the present invention is to provide a class of an phenyl ether derivative as shown in Formula I, and a stereoisomer thereof, and a pharmaceutically acceptable salt thereof.
  • R1 is selected from:
  • R2 is selected from the group consisting of a substituted or unsubstituted C1-8 aliphatic hydrocarbon group, and the substituent is selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, trifluoromethyl, hydroxy, C1-5 alkoxy, amino, C1-6.
  • R3 is selected from the group consisting of a substituted C1-8 saturated alkylamino group, a substituted C2-6 unsaturated alkylamino group, a substituted C2-6 azacyclo-1-yl group, and the substituent is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and iodine.
  • X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy.
  • R2 is selected from the group consisting of a substituted or unsubstituted C1-8 aliphatic hydrocarbon group, and the substituent is selected from the group consisting of halogen, cyano, trifluoromethyl, hydroxy, C1-5 alkoxy group, amino group, C1-6 alkylamino group, acetylamino group, methylsulfonyl group, hydroxyformyl group, hydroxycarbamoyl group;
  • R3 is selected from the group consisting of a substituted C1-8 saturated alkylamino group, a substituted C2-6 unsaturated alkylamino group, a substituted C2-6 azacyclo-1-yl group, and the substituent is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and iodine.
  • X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy.
  • R3 is selected from the group consisting of a substituted C1-8 saturated alkylamino group, a substituted C2-6 unsaturated alkylamino group, a substituted C2-6 azacyclo-1-yl group, and the substituent is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and iodine.
  • X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy.
  • R3 is selected from the group consisting of a substituted C1-8 saturated alkylamino group, a substituted C2-6 unsaturated alkylamino group, a substituted C2-6 azacyclo-1-yl group, and the substituent is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and iodine.
  • X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy.
  • R3 is selected from the group consisting of a substituted C1-8 saturated alkylamino group, a substituted C2-6 unsaturated alkylamino group, a substituted C2-6 azacyclo-1-yl group, and the substituent is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and iodine.
  • X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy.
  • R3 is selected from the group consisting of a substituted C1-8 saturated alkylamino group, a substituted C2-6 unsaturated alkylamino group, a substituted C2-6 azacyclo-1-yl group, and the substituent is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and iodine.
  • X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy.
  • R3 is selected from the group consisting of a substituted C1-8 saturated alkylamino group, a substituted C2-6 unsaturated alkylamino group, a substituted C2-6 azacyclo-1-yl group, and the substituent is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and iodine.
  • X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy.
  • R2 is selected from the group consisting of a substituted or unsubstituted C1-8 aliphatic hydrocarbon group, and the substituent is selected from the group consisting of halogen, cyano, trifluoromethyl, hydroxy, C1-5 alkoxy, amino, C1-6 alkylamino, acetylamino, A Sulfonyl, hydroxyformyl, hydroxycarbamoyl;
  • R3 is selected from the group consisting of a substituted C1-8 saturated alkylamino group, a substituted C2-6 unsaturated alkylamino group, a substituted C2-6 azacyclo-1-yl group, and the substituent is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and iodine.
  • X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy.
  • R3 is selected from the group consisting of a substituted C1-8 saturated alkylamino group, a substituted C2-6 unsaturated alkylamino group, a substituted C2-6 azacyclo-1-yl group, and the substituent is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and iodine.
  • X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy.
  • R3 is selected from the group consisting of a substituted C1-8 saturated alkylamino group, a substituted C2-6 unsaturated alkylamino group, a substituted C2-6 azacyclo-1-yl group, and the substituent is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and iodine.
  • X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy.
  • R3 is selected from the group consisting of a substituted C1-8 saturated alkylamino group, a substituted C2-6 unsaturated alkylamino group, a substituted C2-6 azacyclo-1-yl group, and the substituent is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and iodine.
  • X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy.
  • R3 is selected from the group consisting of a substituted C1-8 saturated alkylamino group, a substituted C2-6 unsaturated alkylamino group, a substituted C2-6 azacyclo-1-yl group, and the substituent is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and iodine.
  • X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy.
  • R3 is selected from the group consisting of a substituted C1-8 saturated alkylamino group, a substituted C2-6 unsaturated alkylamino group, a substituted C2-6 azacyclo-1-yl group, and the substituent is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and iodine.
  • X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy.
  • the most preferred compounds are selected from:
  • the pharmaceutically acceptable salt described above includes a salt formed by combining with an inorganic acid, an organic acid, an alkali metal ion, an alkaline earth metal ion or an organic base capable of providing a physiologically acceptable cation, and an ammonium salt;
  • the inorganic acid is selected from the group consisting of hydrochloric acid , hydrobromic acid, phosphoric acid or sulfuric acid;
  • the organic acid is selected from the group consisting of methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, citric acid, maleic acid tartaric acid, fumaric acid, citric acid or lactic acid;
  • the metal ion is selected from the group consisting of lithium ion, sodium ion and potassium ion;
  • the alkaline earth metal ion is selected from the group consisting of calcium ion and magnesium ion;
  • the organic base capable of providing a physiologically acceptable cation is selected from the group consisting
  • a second aspect of the present invention provides a method for preparing the compound of the first aspect:
  • R1, R2, R3, and X are the same as those described in the first aspect.
  • the pharmaceutically acceptable salts of the formula I include different acid addition salts, such as the acid addition salts of the following inorganic or organic acids: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, Trifluoroacetic acid, citric acid, maleic acid, tartaric acid, fumaric acid, citric acid, lactic acid.
  • the pharmaceutically acceptable salts of formula I also include various alkali metal salts (lithium, sodium, potassium salts), alkaline earth metal salts (calcium, magnesium salts) and ammonium salts, and organics which provide physiologically acceptable cations.
  • a third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, the phenyl ether derivative of the first aspect of the present invention and a stereoisomer thereof, and Pharmaceutically acceptable salts and pharmaceutically acceptable carriers or excipients.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention as an active ingredient.
  • the pharmaceutical composition can be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be prepared by combining a compound of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
  • the content of the compound of the present invention in its pharmaceutical composition is usually from 0.1 to 95% by weight.
  • the dosage form can be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
  • Liquid dosage forms can be solutions (including true and colloidal solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including water injection, powder injection and infusion), eye drops, nasal drops, lotions and tinctures;
  • solid dosage forms can be tablets (including ordinary tablets, enteric tablets, lozenges, dispersible tablets, chewable tablets, Effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric capsules), granules, powders, pellets, dropping pills, suppositories, films, patches, gas (powder) aerosols A spray or the like;
  • the semisolid dosage form may be an ointment, a gel, a paste or the like.
  • diluents may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • wetting agent may be water, ethanol, or different Propyl alcohol, etc.
  • the binder may be starch syrup, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic, gelatin syrup, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl group
  • disintegrant can be dry starch, microcrystalline cellulose, low-
  • Tablets may also be further formed into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets.
  • the active ingredient compound of the present invention may be mixed with a diluent, a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule.
  • the active ingredient can also be formulated into a granule or pellet with a diluent, a binder, a disintegrant, and then placed in a hard or soft capsule.
  • the various diluents, binders, wetting agents, disintegrants, glidants of the formulations used to prepare the tablets of the present invention are also useful in the preparation of capsules of the compounds of the invention.
  • water, ethanol, isopropanol, propylene glycol or a mixture thereof may be used as a solvent, and an appropriate amount of a solubilizing agent, a solubilizing agent, a pH adjusting agent, and an osmotic pressure adjusting agent which are commonly used in the art may be added.
  • the solubilizing agent or co-solvent may be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.; the pH adjusting agent may be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure regulating agent may It is sodium chloride, mannitol, glucose, phosphate, acetate, and the like.
  • mannitol, glucose or the like may also be added as a proppant.
  • coloring agents may also be added to the pharmaceutical preparations as needed.
  • the pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of administration and enhancing the therapeutic effect.
  • the pharmaceutical composition of the present invention can be administered in a wide range of dosages depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, and the like.
  • a suitable daily dose of the compound of the invention will range from 0.001 to 150 mg/kg body weight, preferably from 0.01 to 100 mg/kg body weight.
  • the above dosages may be administered in one dosage unit or in divided dose units depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
  • the compounds or compositions of the invention may be administered alone or in combination with other therapeutic or symptomatic agents.
  • the compound of the present invention synergizes with other therapeutic agents, its dosage should be adjusted according to the actual situation.
  • a fourth aspect of the present invention provides a phenyl ether derivative, a stereoisomer thereof, and a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for preventing and/or treating a disease associated with the PD-1/PD-L1 signaling pathway.
  • the disease associated with the PD-1/PD-L1 signaling pathway is selected from the group consisting of cancer, infectious diseases, and autoimmune diseases.
  • the cancer is selected from the group consisting of skin cancer, lung cancer, urinary tumor, hematological tumor, breast cancer, glioma, digestive system tumor, reproductive system tumor, lymphoma, nervous system tumor, brain tumor, head and neck cancer.
  • the infectious disease is selected from the group consisting of a bacterial infection and a viral infection.
  • the autoimmune disease is selected from the group consisting of an organ-specific autoimmune disease, a systemic autoimmune disease, wherein the organ-specific autoimmune disease comprises chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, Myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, pulmonary hemorrhagic nephritis syndrome, primary biliary cirrhosis, multiple cerebrospinal sclerosing, acute idiopathic polyneuritis, the system described Sex autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia.
  • the compound of the present invention has high inhibitory activity against PD-1/PD-L1 interaction, and has relatively good solubility; has strong binding ability with PD-L1 protein; and has the effect of releasing PD-L1 inhibition.
  • Measuring instrument Nuclear magnetic resonance spectroscopy was performed using a Vaariaan Mercury 300 nuclear magnetic resonance apparatus. Mass spectrometry was performed using a ZAD-2F and VG300 mass spectrometer.
  • 2-bromo-3-iodotoluene (350 mg) was placed in a 50 ml single-mouth bottle, stirred with dioxane/water, and argon was blown for 10 min to remove dissolved oxygen in the solution, and then phenylboric acid (172.65 mg) was added separately.
  • Ruthenium (961.2 mg), triphenylphosphine palladium (40.91 mg).
  • Argon protection stirring at 80-100 ° C for 12 h. The reaction was stopped, cooled to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure and extracted with water and ethyl acetate three times.
  • 2,4-Dihydroxy-5-chlorobenzaldehyde (73.94 mg) was weighed and placed in a 50 ml single-mouth bottle, dissolved in 6 ml of anhydrous acetonitrile, and then sodium hydrogencarbonate (98.88 mg) was added. After stirring at room temperature for 40 min, 2-bromo-3-bromomethyl-1,1'-biphenyl (192 mg) was dissolved in 8 ml of DMF, and slowly added to the reaction system using a constant pressure dropping funnel, and heated to reflux until the reaction was completed. After cooling to room temperature, water and ethyl acetate were added for extraction.
  • Example 2 The same procedure as in Example 1 was carried out by substituting 3-bromopropene for bromoacetamide and acetylethylenediamine for the ethyl acetate.
  • Example 2 The same procedure as in Example 1 was carried out by substituting 3-bromopropyne for bromoacetamide and acetylethylenediamine for the ethyl acetate.
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 8.50 (s, 1H, -NH-), 8.08 (t, 1H, -CONH-), 7.63 (dd, 1H, -ArH), 7.57 (s, 1H) , -ArH), 7.49 (t, 1H, -ArH), 7.44 (m, 1H, -ArH), 7.42 (s, 1H, -ArH), 7.41 - 7.37 (m, 1H, -ArH), 7.36 (m , 2H, -ArH), 7.34 (q, 1H, -ArH), 7.09 (s, 1H, -ArH), 5.31 (s, 2H, -CH 2 -), 4.93 (d, 2H
  • Example 2 The same procedure as in Example 1 was carried out by substituting cyclopropylpropanylmethyl bromide for bromoacetamide and acetylethylenediamine for the ethyl acetate.
  • Example 2 The same procedure as in Example 1 was carried out by using methyl methoxycarbamoyl bromide instead of bromoacetamide to give a white solid.
  • Example 2 The same procedure as in Example 1 was carried out using morpholinylmethyl bromide instead of bromoacetamide to give a white solid.
  • Example 2 The same procedure as in Example 1 was carried out using cyclopropylmethyl bromide instead of bromoacetamide to give a white solid.
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 7.68 - 7.58 (m, 1H, -ArH), 7.55 - 7.47 (m, 3H, -ArH), 7.47 - 7.41 (m, 2H, -ArH), 7.38 (m, 3H, -ArH), 6.93 (m, 1H, -ArH), 5.34-5.20 (m, 2H, -CH 2 -), 4.20 - 4.02 (m, 1H, -CH 2 -), 3.94 (m , 2H, -CH 2 -), 3.93 - 3.91 (m, 1H, -CH 2 -), 3.76 - 3.62 (m, 2H, -CH 2 -), 3.25 - 3.17 (m, 1H, -CH 2 -) , 1.26
  • PD-1 protein carries HIS tag
  • PD-1 ligand PD-L1 carries hFc tag
  • Eu-labeled anti-hFc antibody and XL665-labeled anti-HIS antibody are combined with two tag proteins, laser After excitation, energy can be transferred from donor Eu to receptor XL665, causing XL665 to emit light, and after addition of inhibitor (compound or antibody), blocking the binding of PD-1 to PD-L1, making Eu and XL665 far apart The energy cannot be transferred and the XL665 does not emit light.
  • Example IC 50 (M) Example IC 50 (M) 1 3.12 ⁇ 10 -7 10 1.00x10 -6 2 7.32 ⁇ 10 -7 11 1.41x10 -6 3 1.26 ⁇ 10 -7 12 1.91x10 -7 4 1.80 ⁇ 10 -6 13 4.13 ⁇ 10 -8 5 1.15 ⁇ 10 -6 14 4.17 ⁇ 10 -8 6 4.25 ⁇ 10 -8 15 1.83 ⁇ 10 -7 7 1.82 ⁇ 10 -8 16 1.82 ⁇ 10 -7 8 1.02 ⁇ 10 -8 17 4.05 ⁇ 10 -8 9 8.16 ⁇ 10 -8
  • Example compounds release the ability of ligand PD-L1 to inhibit IFN ⁇
  • the expression level of IFN ⁇ can reflect the proliferative activity of T lymphocytes.
  • PBMC human mononuclear cells
  • the ligand PD-L1 was added to inhibit T lymphocytes, and the inhibition of ligand inhibition by the test compound was investigated. ability.
  • PBMC in human whole blood was extracted by Daktronics human lymphocyte separation solution (Cat. No. DKW-KLSH-0100), and PBMC was inoculated into 96-well plates, and the number of inoculation per well was 3 ⁇ 10 5 .
  • Human PD-L1 protein final concentration 5 ⁇ g/ml
  • anti-CD3/anti-CD28 antibody final concentration 1 ⁇ g/ml
  • an equivalent dilution of the example compound were added, respectively.
  • the expression level of IFN ⁇ in the supernatant was detected by Cisbio IFN ⁇ detection kit.
  • the experimental results showed that the compound of the example partially abolished the inhibitory effect of PD-L1 on IFN ⁇ at 10 nM.
  • the subcutaneous transplantation tumor method is as follows: the specific tumor cells cultured are digested, and the cells are collected by centrifugation, washed twice with sterile physiological saline, counted, adjusted to a cell concentration of 5 ⁇ 10 6 /ml with physiological saline, and 0.2 ml of the cell suspension. Inoculated into the right side of the C57BL/6 or Bablc mice. The animals were randomly divided into the next day after inoculation, 6-7 in each group, and then weighed and administered. The test compound was administered once a day to monitor the tumor volume of the mice. After the tumor volume reached a certain size, the weight of the mice was weighed.
  • mice After taking blood from the eyelids, the mice were sacrificed by cervical dislocation, and the tumor tissue, thymus tissue and spleen tissue were stripped and weighed separately. Finally, the tumor inhibition rate was calculated, and the tumor inhibition rate was used to evaluate the antitumor effect intensity.
  • the B16F10 lung metastasis model was as follows: the cultured B16F10 tumor cells were digested and centrifuged, washed twice with sterile saline, counted, adjusted to a cell concentration of 2.5 ⁇ 10 6 /ml with physiological saline, and 0.2 ml of cells were injected through the tail vein.
  • tumor cells will accumulate in the lungs of mice.
  • the animals were randomly divided into the next day after inoculation, 6-7 in each group, and then weighed and administered.
  • the test compound was administered once a day. After 3 weeks, the body weight of the mice was weighed, the animals were sacrificed, and the lung tissue of the mice was removed and weighed. Heavy, the number of lung tumors was counted after the pack solution was fixed. Finally, the inhibition rate of the compound on the tumor was calculated, and the antitumor effect intensity was evaluated by the tumor inhibition rate.
  • the Lewis lung cancer pleural effusion model was as follows: the mouse subcutaneous Lewis transplanted tumor was homogenized, washed twice with sterile saline, counted, adjusted to a cell concentration of 2.5 ⁇ 10 5 /ml with physiological saline, and injected into 0.2 ml of cells. Into the chest of C57BL/6 mice. The animals were randomly divided into the next day after inoculation, 6-7 in each group, and then weighed and administered. The test compound was administered once a day. When the mice in the control group suddenly dropped in weight, the animals were sacrificed, and the effusion in the thoracic cavity was extracted with a syringe. , record the volume of the effusion.
  • the test method of each type of T cells in the total cell ratio is performed by flow cytometry.
  • the specific steps are as follows: firstly, the sample is processed, and for the blood tissue, when the mouse is treated, the eyelid of the mouse is taken. Blood, first remove the red blood cells with red blood cell lysate, then rinse the cells with PBS solution to collect the cells; for the tumor and spleen organs of mice, first grind the tissue with a homogenizer, then add PBS buffer to dilute, then use 300 mesh sieve Web filtering. After counting the number of cells in each sample, 1 ⁇ 10 6 cells were added to an EP tube, and then flow-type antibody was stained.
  • the cells were rinsed twice with PBS solution.
  • Cell population analysis was performed using BD's VERSE flow instrument. Among them, the total number of cells in the tumor tissue was 1 ⁇ 10 5 , and the total number of cells in the blood and spleen tissues was 1 ⁇ 10 4 .
  • the ratio of each type of T cell to the total number of injected cells was analyzed after circled on a flow instrument.
  • the compounds of the examples increased the proportion of lymphocytes infiltrating the tumor, and the compounds of the examples increased the proportion of lymphocytes in the spleen.
  • the example compounds significantly inhibited the number of lung metastases.
  • the example compounds increased the number of lymphocytes in the blood of mice.
  • the example compounds For the mouse breast cancer EMT6 subcutaneous xenograft model, the example compounds have a certain anti-tumor effect.
  • the compound of the example can increase the tumor inhibition rate of cyclophosphamide after administration of cyclophosphamide.
  • the example compounds have a certain anti-tumor effect on the mouse Lewis lung cancer pleural fluid model.
  • the compounds of the examples reduce the incidence of pleural fluid.
  • the example compounds have significant anti-tumor effects in the mouse colon cancer MC38 subcutaneous xenograft model. After administration of cyclophosphamide CTX, it has a good synergistic effect.
  • SPR Surface-plasmon resonance
  • SPR angle is an optical phenomenon that occurs on the surface of two media, which can be induced by photons or electrons.
  • SPR Surface-plasmon resonance
  • the evanescent wave of total reflection meets the plasma wave on the metal surface, resonance may occur, the energy of the reflected light decreases, and a resonance peak appears on the energy spectrum of the reflected light. This resonance is called surface plasmon resonance, causing surface plasmon resonance.
  • the angle of incidence is called the SPR angle.
  • SPR biosensors provide a sensitive, real-time monitoring of non-labeled detection techniques in which molecules interact.
  • the sensor detects changes in the SPR angle, which in turn is related to the refractive index of the metal surface.
  • an analyte is bound to the surface of the chip, it causes a change in the refractive index of the chip surface, which causes a change in the SPR angle.
  • This is the basic principle for the SPR biosensor to detect intermolecular interactions in real time. At the time of the interaction analysis, the change in the SPR angle is recorded in real time on the sensorgram.
  • the PD-L1 protein was captured by the capture method on the Fc4 channel of the NTA chip; the binding buffer system was PBS-P+, pH 7.4, 0.01% DMSO. A set of concentrations of the compound and PD-L1 antibody were flowed through the surface of the chip for interaction assay.
  • the binding protein of the compound of the example was initially determined to be PD-L1, and it was further confirmed by Biacore experiments that the compound of the example had strong binding ability to PD-L1.

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Abstract

一种苯醚类衍生物、及其制法和药物组合物与用途。具体而言，涉及通式I所示的苯醚类衍生物，其可药用盐，其立体异构体及其制备方法，含有一个或多个这化合物的组合物，和该类化合物在治疗与PD-1/PD-L1信号通路有关的疾病如癌症、感染性疾病、自身免疫性疾病方面的用途。

Description

苯醚类衍生物、及其制法和药物组合物与用途 发明领域
本发明公开了一类苯醚类衍生物、及其制法和药物组合物与用途。具体而言，涉及通式I所示的苯醚类衍生物，其可药用盐，其立体异构体及其制备方法，含有一个或多个这化合物的组合物，和该类化合物在治疗与PD-1/PD-L1信号通路有关的疾病如癌症、感染性疾病、自身免疫性疾病方面的用途。
发明背景
随着对肿瘤免疫研究的深入，人们发现肿瘤微环境可以保护肿瘤细胞不被机体免疫系统识别和杀伤，肿瘤细胞的免疫逃逸在肿瘤发生、发展中扮演了非常重要的角色。2013年Science杂志将肿瘤免疫治疗列为十大突破之首，再次让免疫治疗成为肿瘤治疗领域的“焦点”。机体免疫细胞的激活或抑制是通过正性信号和负性信号来调节，其中程序性死亡分子1(programmed death 1，PD-1)/PD-1配体(PD-1 ligand，PD-L1)便是负性免疫调节信号，抑制了肿瘤特异性CD8+T细胞的免疫活性，介导了免疫逃逸。
肿瘤细胞所具有的逃避免疫系统的能力，是通过在其表面产生的程序性死亡配体(PD-L1)结合到T细胞的PD-1蛋白上实现的。机体内的肿瘤微环境会诱导浸润的T细胞高表达PD-1分子，肿瘤细胞会高表达PD-1的配体PD-L1和PD-L2，导致肿瘤微环境中PD-1通路持续激活，T细胞功能被抑制而不能发现肿瘤以至于不能向免疫系统发出需要攻击肿瘤和杀伤肿瘤细胞的治疗。PD-1抗体是针对PD-1或者PD-L1的一种抗体蛋白，使得前两种蛋白不能发生结合，阻断这一通路，部分恢复T细胞的功能，使这些细胞能够继续杀伤肿瘤细胞。
基于PD1/PDL1的免疫疗法是当前备受瞩目的新一代免疫疗法，旨在利用人体自身的免疫系统抵御肿瘤，通过阻断PD-1/PD-L1信号通路诱导凋亡，具有治疗多种类型肿瘤潜力。最近，一系列令人惊喜的研究结果证实PDl/PD-Ll抑制性抗体对多种肿瘤具有强大的抗瘤活性，格外引人注目。2014年9月4日美国默克的
Figure PCTCN2017085420-appb-000001
(pembrolizumab)成为FDA批准的首例PD-1单抗用于治疗对其它药物治疗无效的晚期或无法切除的黑色素瘤患者。目前，默沙东正在30多种不同类型 的癌症中调查Keytruda的潜力，包括各类血液癌症、肺癌、乳腺癌、膀胱癌、胃癌、头颈部癌症。2014年12月22日，制药巨头百时美施贵宝公司不负重望，率先发力，获得美国食品药品监督管理局(FDA)加速批准，其研发的抗癌免疫疗法药物nivolumab以Opdivo的商品名上市，用于治疗对其它药物没有应答的不可切除的或转移性黑色素瘤患者，是继默沙东Keytruda之后第二个在美国上市的PD-1抑制剂。FDA于2015年3月4日批准了nivolumab用于治疗在经铂为基础化疗期间或化疗后发生疾病进展的转移性鳞性非小细胞肺癌。根据默沙东公布的Keytruda(pembrolizumab)治疗实体瘤的一项Ib期KEYNOTE-028研究数据，Keytruda治疗在25例胸膜间皮瘤(pleuralmesothelioma，PM)患者中取得了28％的总缓解率(ORR)，并有48％的患者病情稳定，疾病控制率达到了76％。对当前任何已获批药物均无治疗反应的晚期霍奇金淋巴瘤(HL)患者，接受默沙东Keytruda和百时美Opdvio治疗后，能够达到完全缓解。在2015AACR年会上，约翰霍普金斯基梅尔癌症中心(Kimmel Cancer Center)的肿瘤内科学副教授Leisha A.Emens,MD,PhD做出的报道指出，罗氏的MPDL3280A这一具有抗PD-L1作用的单克隆抗体，在晚期三阴性乳腺癌中表现出了持久的疗效。
虽然肿瘤免疫治疗被认为是靶向治疗后癌症治疗的革命。但是，单抗治疗药物有其本身的缺陷：易被蛋白酶分解，因而在体内不稳定，不能口服；易产生免疫交叉反应；产品质量不易控制，制作技术要求高；大量制备和纯化比较困难，生产成本高；使用不方便，只能注射或点滴。所以，PDl/PD-Ll相互作用小分子抑制剂是肿瘤免疫治疗的更佳选择。
发明内容
本发明解决的技术问题是提供一种具有抑制PDl/PD-Ll相互作用的结构通式I的苯醚类衍生物，以及其立体异构体及其可药用盐，其制备方法、药物组合物和其在制备预防或治疗与PDl/PD-Ll信号通路有关疾病药物中的用途。
Figure PCTCN2017085420-appb-000002
为解决本发明的技术问题，本发明提供如下技术方案：
本发明技术方案的第一方面是提供一类如通式I所示的苯醚类衍生物及其立体异构体以及其可药用盐，
Figure PCTCN2017085420-appb-000003
式中
R1选自:
Figure PCTCN2017085420-appb-000004
R2选自：取代或未取代的C1-8脂烃基，取代基选自氟、氯、溴、碘、、氰基、三氟甲基、羟基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、甲磺酰基、羟基甲酰基、羟氨甲酰基；
R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
Figure PCTCN2017085420-appb-000005
所述的取代基包括单取代、双取代、三取代、四取代；
X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IA)所示：
Figure PCTCN2017085420-appb-000006
R2选自：取代或未取代的C1-8脂烃基，取代基选自卤素、氰基、三氟甲基、羟基、 C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、甲磺酰基、羟基甲酰基、羟氨甲酰基；
R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
Figure PCTCN2017085420-appb-000007
所述的取代基包括单取代、双取代、三取代、四取代；
X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IA-1)所示：
Figure PCTCN2017085420-appb-000008
R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
Figure PCTCN2017085420-appb-000009
所述的取代基包括单取代、双取代、三取代、四取代；
X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物 如式(IA-2)所示：
Figure PCTCN2017085420-appb-000010
R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
Figure PCTCN2017085420-appb-000011
所述的取代基包括单取代、双取代、三取代、四取代；
X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IA-3)所示：
Figure PCTCN2017085420-appb-000012
R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、 噁唑基、四氮唑基、
Figure PCTCN2017085420-appb-000013
所述的取代基包括单取代、双取代、三取代、四取代；
X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IA-4)所示：
Figure PCTCN2017085420-appb-000014
R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
Figure PCTCN2017085420-appb-000015
所述的取代基包括单取代、双取代、三取代、四取代；
X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IA-5)所示：
Figure PCTCN2017085420-appb-000016
Figure PCTCN2017085420-appb-000017
R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
Figure PCTCN2017085420-appb-000018
所述的取代基包括单取代、双取代、三取代、四取代；
X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IB)所示：
Figure PCTCN2017085420-appb-000019
R2选自：取代或未取代的C1-8脂烃基，取代基选自卤素、氰基、三氟甲基、羟基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、甲磺酰基、羟基甲酰基、羟氨甲酰基；
R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
Figure PCTCN2017085420-appb-000020
所述的取代基包括单取代、双取代、三取代、四取代；
X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IB-1)所示：
Figure PCTCN2017085420-appb-000021
R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
Figure PCTCN2017085420-appb-000022
所述的取代基包括单取代、双取代、三取代、四取代；
X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IB-2)所示：
Figure PCTCN2017085420-appb-000023
R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、 噁唑基、四氮唑基、
Figure PCTCN2017085420-appb-000024
所述的取代基包括单取代、双取代、三取代、四取代；
X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IB-3)所示：
Figure PCTCN2017085420-appb-000025
R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
Figure PCTCN2017085420-appb-000026
所述的取代基包括单取代、双取代、三取代、四取代；
X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IB-4)所示：
Figure PCTCN2017085420-appb-000027
Figure PCTCN2017085420-appb-000028
R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
Figure PCTCN2017085420-appb-000029
所述的取代基包括单取代、双取代、三取代、四取代；
X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IB-5)所示：
Figure PCTCN2017085420-appb-000030
R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
Figure PCTCN2017085420-appb-000031
所述的取代基包括单取代、双取代、三取代、四取代；
X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
最优选的化合物选自：
(S)-N-[2-(氨基甲酰甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
Figure PCTCN2017085420-appb-000032
N-(乙酰胺乙基)-2-甲氧基-4-(2-溴-3-苯基苄氧基)-5-氯苄胺盐酸盐
Figure PCTCN2017085420-appb-000033
N-(乙酰胺乙基)-2-烯丙氧基-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
Figure PCTCN2017085420-appb-000034
N-(乙酰胺乙基)-2-炔丙氧基-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
Figure PCTCN2017085420-appb-000035
N-(乙酰胺乙基)-2-环丙甲氧基-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
Figure PCTCN2017085420-appb-000036
N-[2-(二甲胺甲酰甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
Figure PCTCN2017085420-appb-000037
N-[2-(3-甲基丁烯-2-氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
Figure PCTCN2017085420-appb-000038
N-[2-(环丙基甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]苏氨酸
Figure PCTCN2017085420-appb-000039
N-[2-(环丙基甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸酰胺
Figure PCTCN2017085420-appb-000040
N-乙酰氨基乙基-2-(环丙基甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
Figure PCTCN2017085420-appb-000041
N-[2-(环丙基甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]瓜氨酸
Figure PCTCN2017085420-appb-000042
N-[2-(甲基甲氧氨基甲酰甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
Figure PCTCN2017085420-appb-000043
N-[2-(吗啉甲酰甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
Figure PCTCN2017085420-appb-000044
(S)-N-[2-(环丙基甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
Figure PCTCN2017085420-appb-000045
(S)-N-[2-(羟胺甲酰甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]哌啶-2-甲酸
Figure PCTCN2017085420-appb-000046
(S，S)-N-[2-(氨基甲酰甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]-4-羟基脯氨酸
Figure PCTCN2017085420-appb-000047
S，S)-N-[2-(环丙基甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]-4-羟基 脯氨酸
Figure PCTCN2017085420-appb-000048
以上所述的药用盐包括与无机酸、有机酸、碱金属离子、碱土金属离子或能提供生理上可接受的阳离子的有机碱结合形成的盐以及铵盐；所述的无机酸选自盐酸、氢溴酸、磷酸或硫酸；所述的有机酸选自甲磺酸、对甲苯磺酸、三氟乙酸、枸杞酸、马来酸酒石酸、富马酸、柠檬酸或乳酸；所述的碱金属离子选自锂离子，钠离子，钾离子；所述的碱土金属离子选自钙离子，镁离子；所述的能提供生理上可接受的阳离子的有机碱选自甲胺、二甲胺、三甲胺、哌啶、吗啉或三(2－羟乙基)胺。
本发明技术方案的第二方面是提供了第一方面所述化合物的制备方法：
为了制备本发明通式I所述的化合物，依据通式I的结构，本发明制备通式I化合物将分为五步。
Figure PCTCN2017085420-appb-000049
(a)以2-溴-3-碘甲苯1和苯或取代苯的硼酸或硼酸酯为基本原料，通过suzuki偶联反应得到中间体化合物2；
(b)以中间体2为原料，通过溴代试剂使甲基溴化得到溴代物中间体3；
(c)以中间体3为原料，在碱性条件下与取代的2，4-二羟基-X取代苯甲醛反应，得到苄芳醚中间体4；
(d)以中间体4为原料，在碱性条件下与卤化物反应，得到中间体化合物5；
(e)以含醛基的中间体化合物5为原料，与含氨基或亚氨基的HR3缩合及还原得到目标化合物I；
所述的R1、R2、R3、X的定义同第一方面所述相同。
另外，上述反应中的起始原料及中间体容易得到，各步反应可依据已报道的文献或对本领域熟练技术人员来说可以用有机合成中的常规方法很容易合成。通式I所述化合物可以溶剂化物或非溶剂化物的形式存在，利用不同的溶剂进行结晶可能得到不同的溶剂化物。通式I所述药学上可接受的盐包括不同酸加成盐，如下列无机酸或有机酸的酸加成盐：盐酸，氢溴酸，磷酸，硫酸，甲磺酸，对甲苯磺酸，三氟乙酸，枸杞酸，马来酸，酒石酸，富马酸，柠檬酸，乳酸。通式I所述药学上可接受的盐还包括不同碱金属盐(锂，钠，钾盐)，碱土金属盐(钙，镁盐)及铵盐，和能提供生理上可接受的阳离子的有机碱的盐，如甲胺，二甲胺，三甲胺，哌啶，吗啉及三(2－羟乙基)胺的盐。在本发明范围内的所有这些盐都可采用常规方法制备。在所述的通式I化合物及其溶剂化物和其盐的制备过程中，不同结晶条件可能出现多晶或共晶。
本发明技术方案的第三方面是提供了一种药物组合物，所述的药物组合物包含作为有效成分的本发明第一方面所述的苯醚类衍生物及其立体异构体以及其可药用盐和药学上可接受的载体或赋形剂。
本发明还涉及以本发明化合物作为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量％。
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂 (包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本发明化合物的每天的合适剂量范围为0.001-150mg/Kg体重，优选为0.01-100mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
本发明技术方案的第四方面是提供了苯醚类衍生物及其立体异构体以及其可药用盐在制备预防和/或治疗与PD-1/PD-L1信号通路有关疾病的药物中的应用。所述的与PD-1/PD-L1信号通路有关的疾病选自癌症、感染性疾病、自身免疫性疾病。所述的癌症选自皮肤癌、肺癌、泌尿系肿瘤、血液肿瘤、乳腺癌、胶质瘤、消化系统肿瘤、生殖系统肿瘤、淋巴瘤、神经系统肿瘤、脑瘤、头颈癌。所述的感染性疾病选自细菌感染、病毒感染。所述的自身免疫性疾病选自器官特异性自身免疫病、系统性自身免疫病，其中，所述的器官特异性自身免疫病包括慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症、急性特发性多神经炎，所述的系统性自身免疫病包括类风湿关节炎、系统性红斑狼疮、系统性血管炎、硬皮病、天疱疮、皮肌炎、混合性结缔组织病、自身免疫性溶血性贫血。
有益技术效果：本发明化合物对PD-1/PD-L1相互作用具有很高的抑制活性，且溶解性相对较好；与PD-L1蛋白具有很强的结合能力；并具有解除PD-L1抑制IFNγ的能力；体内药效研究表明，本发明化合物无论从肿瘤体积还是重量上，都可显著的抑制皮下肿瘤的生长，并可明显增加小鼠血液中、脾脏中各淋巴细胞数量。
具体实施方式
以下将结合实施例对发明作进一步说明，但并不限制本发明的范围。
测定仪器：核磁共振光谱用Vaariaan Mercury 300型核磁共振仪。质谱用ZAD-2F和VG300质谱仪。
实施例1：(S)-N-[2-(氨基甲酰甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
Figure PCTCN2017085420-appb-000050
(1)2-溴-3-苯基-甲苯
置2-溴-3-碘甲苯(350mg)于50ml单口瓶中，加入二氧六环/水搅拌，鼓吹氩气10min，排除溶液中溶解的氧气，然后分别加入苯硼酸(172.65mg),碳酸铯(961.2mg)，三苯基膦合钯(40.91mg)。氩气保护，80-100℃下搅拌12h。停止反应，降至室温，用硅藻土过滤。滤液减压浓缩后，加入水和乙酸乙酯萃取3次。合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸干。通过硅胶柱层析(石油醚)，得到无色油状物221mg。1H NMR(400MHz,DMSO-d6)，δ7.49–7.29(m,7H,Ar-H),7.14(d,1H,Ar-H),2.42(s,3H,Ar-CH3)。
(2)2-溴-3-溴甲基-1,1'-联苯
称取2-溴-3-苯基-甲苯(234mg)于100ml单口瓶中，加入20ml CCl4,使之溶解完全，搅拌下加入NBS(178mg)，升温至80℃，回流，然后加入过氧化苯甲酰(4mg)，2h后再次加入过氧化苯甲酰(4mg)，继续反应2h，停止反应，冷至室温，加入适量水，用二氯甲烷进行萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸干，得到黄色油状物192mg。直接用于下一步的反应。
(3)2-羟基-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛
称取2,4-二羟基-5-氯苯甲醛(73.94mg)置于50ml单口瓶中，以6ml无水乙腈溶解，然后加入碳酸氢钠(98.88mg)。室温搅拌40min后，将2-溴-3-溴甲基-1,1'-联苯(192mg)溶于8ml DMF中，用恒压滴液漏斗缓慢加入至反应体系，加热回流至反应完全。降至室温，加入水和乙酸乙酯进行萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸干，通过硅胶柱层析得到白色固体2-羟基-4-(2-溴 -3-苯基苄氧基)-5-氯苯甲醛152mg。1H NMR(500MHz,DMSO-d6)δ11.18(s,1H,-OH),10.09(s,1H,-CHO),7.74(s,1H,-ArH),7.66(d,1H,-ArH),7.57(t,1H,-ArH),7.51(m,2H,-ArH),7.46(d,1H,-ArH),7.42(d,3H,-ArH),6.85(s,1H,-ArH),5.37(s,2H,-CH2-).
(4)2-(氨基甲酰甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛
将2-羟基-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛(100mg)置于50ml单口瓶中，用6ml DMF溶解，加入碳酸铯(127.53mg)。室温搅拌15min后，滴加溴代乙酰胺(68.25mg)的DMF(4ml)溶液。在80℃下搅拌2h后停止反应。降至室温，加入水和乙酸乙酯萃取分液，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸干，通过硅胶柱层析得到白色固体60mg。1H NMR(400MHz,DMSO)δ10.28(s,1H,-CHO),7.74(s,1H,-ArH),7.72–7.63(m,2H,-ArH),7.58–7.36(m,8H,-ArH,-CONH2),7.11(s,1H,-ArH),5.44(s,2H,-CH2-),4.75(s,2H,-CH2-).MS(FAB):476(M+1).
(5)(S)-N-[2-(氨基甲酰甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
将2-(氨基甲酰甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛(80mg)溶于5ml DMF中，加入丝氨酸乙酯(49mg)，冰醋酸(57mg)至反应体系中。室温搅拌20min后，加入氰基硼氢化钠(25mg)，25℃下搅拌14h。停止反应，加入水和乙酸乙酯萃取分离。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸干，再加乙醇回流至反应完全，蒸干，通过硅胶柱层析得到(S)-N-[2-(氨基甲酰甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸乙酯淡黄色油状物70mg，然后将其溶于甲醇/水(4ml/1ml)中，加入氢氧化锂一水合物(20mg)，室温搅拌2h后，冰浴下加入醋酸数滴调节PH值至酸性，减压过滤得到(S)-N-[2-(氨基甲酰甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸类白色固体45mg。1H NMR(400MHz,DMSO)δ8.03(s,1H,-ArH),7.62(d,J＝6.7Hz,1H,-ArH),7.56–7.35(m,9H,-ArH,-CONH2),7.00(s,1H,-ArH),5.32(s,2H,-CH2-),4.60(m,2H,-CH2-),4.03(m,2H,-CH2-),3.78–3.56(m,3H,-CH2-,-CH-).MS(FAB):565(M+1).
实施例2：N-(乙酰胺乙基)-2-甲氧基-4-(2-溴-3-苯基苄氧基)-5-氯苄胺盐酸盐
Figure PCTCN2017085420-appb-000051
1、2-甲氧基-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛
称取2-羟基-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛(100mg，0.24mmol)溶于5ml无水THF中，加入碳酸铯(93.4mg，0.29mmol)，氩气保护，在冰浴条件下搅拌15min。加入碘甲烷(110ul，1.8mmol)，移至室温反应3h，乙酸乙酯和水萃取3次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，通过硅胶柱层析得到白色固体78.2mg。1H NMR(400MHz,DMSO-d6)δ10.13(s,1H,-CHO),7.66(s,1H,-ArH),7.51(s,1H,-ArH),7.44(q,3H,-ArH),7.39(s,1H,-ArH),7.36(s,2H,-ArH),7.34(s,1H,-ArH),7.06(s,1H,-ArH),5.44(s,2H,-CH2-),3.97(s,3H,-OCH3)。
2、N-(乙酰胺乙基)-2-甲氧基-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
称取2-甲氧基-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛(50.mg，0.116mmol)溶于5ml DMF中，加入乙酰乙二胺(35.54mg，0.348mmol)，量取冰醋酸(42.11mg，0.696mmol)滴加至反应体系中，室温搅拌20min，称取氰基硼氢化钠(18mg，0.29mmol)，25℃搅拌14h，停止反应。加入水和乙酸乙酯萃取分液，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸干，通过硅胶柱层析得到粘稠产物。加入10ml HCl的饱和甲醇溶液，室温搅拌过夜，旋干溶剂，乙醚洗涤，得到淡黄色固体粉末28mg。1H NMR(400MHz,DMSO-d6)δ9.31(s,1H,HCl),9.04(s,1H,-NH-),8.33(s,1H,-CONH-),7.61(m,,2H,-ArH),7.48(s,1H,-ArH),7.42(m,2H,-ArH),7.37(m,1H,-ArH),7.33(m,3H,-ArH),6.95(s,1H,-ArH),5.32(s,2H,-CH2-),3.98(s,2H,-CH2-),3.85(s,3H,-OCH3),3.16(m,2H,-CH2-),2.86(m,2H,-CH2-),1.78(s,3H,-COCH3).MS(FAB):517(M)。
实施例3：N-(乙酰胺乙基)-2-烯丙氧基-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
Figure PCTCN2017085420-appb-000052
用3-溴丙烯代替溴代乙酰胺，乙酰基乙二胺代替丝氨酸乙酯，操作同实施例1，得 到白色固体。1H NMR(400MHz,DMSO-d6)δ8.10(s,1H,-CONH-),7.61(d,1H,-ArH),7.54(d,1H,-ArH),7.51–7.46(m,1H,-ArH),7.43(d,2H,-ArH),7.39(d,1H,-ArH),7.35(s,2H,-ArH),7.33(s,1H,-ArH),6.95(s,1H,-ArH),6.04(m,1H,-CH＝),5.39(d,1H,＝CH2),5.31(s,2H,-CH2-),5.24(d,1H,＝CH2),4.68(d,2H,-CH2-),3.98(s,2H,-CH2-),2.85(t,2H,-CH2-),1.79(s,3H,-COCH3).MS(FAB):545(M+1)。
实施例4：N-(乙酰胺乙基)-2-炔丙氧基-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
Figure PCTCN2017085420-appb-000053
用3-溴丙炔代替溴代乙酰胺，乙酰基乙二胺代替丝氨酸乙酯，操作同实施例1，得到白色固体。1H NMR(400MHz,DMSO-d6)δ8.50(s,1H,-NH-),8.08(t,1H,-CONH-),7.63(dd,1H,-ArH),7.57(s,1H,-ArH),7.49(t,1H,-ArH),7.44(m,1H,-ArH),7.42(s,1H,-ArH),7.41–7.37(m,1H,-ArH),7.36(m,2H,-ArH),7.34(q,1H,-ArH),7.09(s,1H,-ArH),5.31(s,2H,-CH2-),4.93(d,2H,-CH2-),3.95(s,2H,-CH2-),3.59(t,1H,CH),3.27-3.28(m,2H,-CH2-),2.83(m,2H,-CH2-),1.79(s,3H,-COCH3).MS(FAB):543(M+1)。
实施例5：N-(乙酰胺乙基)-2-环丙甲氧基-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
Figure PCTCN2017085420-appb-000054
用溴甲基环丙烷代替溴代乙酰胺，乙酰基乙二胺代替丝氨酸乙酯，操作同实施例1，得到白色固体。1H NMR(400MHz,DMSO-d6)δ8.06(s,1H,-CONH-),7.59(m,1H,-ArH),7.51–7.46(m,2H,-ArH),7.43(m,2H,-ArH),7.40(s,1H,-ArH),7.34(m,3H,-ArH),6.91(d,1H,-ArH),5.36–5.26(m,2H,-CH2-),3.94–3.88(m,2H,-CH2-),3.29–3.19(m,4H,-CH2-),2.76(m,2H,-CH2-),2.34(m,1H,-CH2-),2.02(m,1H,-CH2-),1.78(s,3H,-COCH3-),1.27–1.15(m,1H,-CH-),0.53(m,1H,-CH2-),0.31(m,1H,-CH2-).MS(FAB):559(M+1)。
实施例6：N-[2-(二甲胺甲酰甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
Figure PCTCN2017085420-appb-000055
用N，N-二甲基溴代乙酰胺代替溴代乙酰胺，操作同实施例1，得到白色固体。1H NMR(400MHz,DMSO)δ7.65(d,J＝7.1Hz,1H,-ArH),7.45(ddd,J＝23.8,18.3,6.8Hz,8H,-ArH),7.03(s,1H,-ArH),5.25(d,J＝42.2Hz,2H,-CH2-),5.05(s,2H,-CH2-),4.05(dd,J＝32.7,13.2Hz,2H,-CH2-),3.78–3.56(m,3H,-CH2-,-CH-),2.99(s,3H,-CH3),2.83(s,3H,-CH3).MS(FAB):593(M+1)。
实施例7：N-[2-(3-甲基丁烯-2-氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
Figure PCTCN2017085420-appb-000056
用3-甲基丁烯-2-基溴代替溴代乙酰胺，操作同实施例1，得到白色固体。1H NMR(400MHz,DMSO)δ7.64(dd,J＝7.7,1.7Hz,1H,-ArH),7.55–7.49(m,1H,-ArH),7.49–7.45(m,3H,-ArH),7.43(dt,J＝5.6,2.3Hz,1H,-ArH),7.40–7.36(m,3H,-ArH),6.92(s,1H,-ArH),5.46–5.40(m,1H,＝CH),5.33(s,2H,-CH2-),4.65(d,J＝6.5Hz,2H,-CH2-),3.88(d,J＝2.5Hz,2H,-CH2-),3.64(ddd,J＝17.3,11.0,6.2Hz,2H,-CH2-),3.15–3.09(m,1H,-CH-),1.72(d,J＝1.0Hz,6H,-CH3).MS(FAB):576(M+1)。
实施例8：N-[2-(环丙基甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]苏氨酸
Figure PCTCN2017085420-appb-000057
用环丙烷基甲基溴代替溴代乙酰胺，苏氨酸乙酯代替丝氨酸乙酯，操作同实施例1，得到白色固体。1H NMR(400MHz,DMSO-d6)δppm 7.65-6.86(m,10H,Ar-H),5.27 (s,2H,CH2),3.90-3.81(m,5H,CH2×2,CH),2.93(d,J＝4.0Hz,1H,CH),1.21(m,1H,CH),1.11(d,J＝4.0Hz,3H,CH3),0.52-0.32(m,4H,CH2×2)。MS(FAB):576(M+1)。
实施例9：N-[2-(环丙基甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸酰胺
Figure PCTCN2017085420-appb-000058
用环丙烷基甲基溴代替溴代乙酰胺，丝氨酸酰胺代替丝氨酸乙酯，操作同实施例1，得到白色固体。1H NMR(400MHz,DMSO-d6)δppm 7.63-6.82(m,12H,Ar-H,CONH2),5.26(s,2H,CH2),3.85(q,2H,J＝4.0Hz,CH2),3.66-3.40(m,4H,CH2×2),2.97(s,1H,CH),1.17(m,1H,CH),0.55-0.26(m,4H,CH2×2)。MS(FAB):561(M+1)。
实施例10：N-乙酰氨基乙基-2-(环丙基甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
Figure PCTCN2017085420-appb-000059
用环丙烷基甲基溴代替溴代乙酰胺，乙酰乙二胺代替丝氨酸乙酯，操作同实施例1，得到白色固体。1H NMR(400MHz,DMSO-d6)δppm 7.78(m,1H,CONH),7.62-6.80(m,10H,Ar-H),5.26(s,2H,CH2),3.86(d,J＝8.0Hz,2H,CH2),3.61(s,2H,CH2),3.10(q,J＝4.0Hz,2H,CH2),2.52(t,J＝4.0Hz,2H,CH2),1.75(s,3H,CH3),1.17(m,1H,CH),0.55-0.26(m,4H,CH2×2)。MS(FAB):559(M+1)。
实施例11：N-[2-(环丙基甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]瓜氨酸
Figure PCTCN2017085420-appb-000060
用环丙烷基甲基溴代替溴代乙酰胺，瓜氨酸乙酯代替丝氨酸乙酯，操作同实施例1，得到白色固体。1H NMR(400MHz,DMSO-d6)δppm 7.58-6.73(m,10H,Ar-H),5.29(s,1H,CONH),5.20(s,2H,CH2),3.82(d,J＝4.0Hz,2H,CH2),3.68(q,J＝16.0Hz, 2H,CH2),2.86(q,J＝8.0Hz,1H,CH),1.68-1.36(m,4H,CH2×2),0.81(m,2H,CH2),1.19(m,1H,CH),0.52-0.27(m,4H,CH2×2)。MS(FAB):632(M+1)。
实施例12：N-[2-(甲基甲氧氨基甲酰甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
Figure PCTCN2017085420-appb-000061
用甲基甲氧氨基甲酰甲基溴代替溴代乙酰胺，操作同实施例1，得到白色固体。
1H NMR(400MHz,DMSO-d6)δ7.66(d,J＝7.3Hz,1H,-ArH),7.52(d,J＝7.7Hz,1H,-ArH),7.49(s,1H,-ArH),7.47(s,1H,-ArH),7.45(s,1H,-ArH),7.43(s,1H,-ArH),7.38(d,J＝6.7Hz,3H,-ArH),7.14(s,1H,-ArH),5.75(d,J＝0.9Hz,1H),5.28(s,3H,-OCH3),4.69–4.52(m,3H,-NCH3),4.12(d,J＝12.5Hz,2H,-CH2-),4.00(d,J＝15.7Hz,2H,-CH2-),3.79(d,J＝12.4Hz,2H,-CH2-),3.75(d,J＝5.5Hz,2H,-CH2-).MS(FAB):609(M+1)。
实施例13：N-[2-(吗啉甲酰甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
Figure PCTCN2017085420-appb-000062
用吗啉甲酰基甲基溴代替溴代乙酰胺，操作同实施例1，得到白色固体。1H NMR(400MHz,DMSO-d6)δ7.65(dd,J＝7.7,1.7Hz,1H,-ArH),7.55–7.51(m,1H),7.50(s,1H,-ArH),7.48(t,J＝1.8Hz,1H,-ArH),7.46(q,J＝1.3Hz,1H,-ArH),7.45–7.41(m,1H,-ArH),7.40(d,J＝1.7Hz,2H,-ArH),7.38(dq,J＝4.3,1.9Hz,2H,-ArH),7.00(s,1H),5.30(s,2H,-CH2-),5.05(s,2H,-CH2-),4.19–4.02(m,2H,-CH2-),4.02–3.91(m,2H,-CH2-),3.74(dd,J＝11.2,4.5Hz,2H,-CH2-),3.67(q,J＝6.7,5.0Hz,2H,-CH2-),3.62–3.58(m,2H,-CH2-),3.55–3.52(m,2H,-CH2-),3.25–3.21(m,1H,-CH-).MS(FAB):635(M+1)。
实施例14：(S)-N-[2-(环丙基甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
Figure PCTCN2017085420-appb-000063
用环丙基甲基溴代替溴代乙酰胺，操作同实施例1，得到白色固体。1H NMR(400MHz,DMSO-d6)δ7.68–7.58(m,1H,-ArH),7.55–7.47(m,3H,-ArH),7.47–7.41(m,2H,-ArH),7.38(m,3H,-ArH),6.93(m,1H,-ArH),5.34-5.20(m,2H,-CH2-),4.20–4.02(m,1H,-CH2-),3.94(m,2H,-CH2-),3.93-3.91(m,1H,-CH2-),3.76–3.62(m,2H,-CH2-),3.25-3.17(m,1H,-CH2-),1.26(m,1H,-CH-)0.56(m,1H,-CH2-),0.42–0.28(m,1H,-CH2-).MS(FAB):562(M+1)。
实施例15：(S)-N-[2-(羟胺甲酰甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]哌啶-2-甲酸
Figure PCTCN2017085420-appb-000064
用羟胺甲酰甲基溴代替溴代乙酰胺，用哌啶-2-甲酸乙酯代替丝氨酸乙酯，操作同实施例1，得到白色固体。1H NMR(400MHz,DMSO)δ8.21(s,1H,-ArH),7.81–7.32(m,9H,-ArH),5.43–5.19(s,2H,-CH2-),4.18–4.00(m,2H,-CH2-),3.78–3.56(m,2H,-CH2-),3.16(d,J＝11.0Hz,1H,-CH-),2.94–2.86(m,1H,-CH2-),2.28–2.22(m,1H,-CH2-),1.91–1.85(m,2H,-CH2-),1.56–1.40(m,3H,-CH2-),1.36–1.30(m,1H,-CH2-).MS(FAB):605(M+1)。
实施例16：(S，S)-N-[2-(氨基甲酰甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]-4-羟基脯氨酸
Figure PCTCN2017085420-appb-000065
(1)2-溴-3-(3，4-乙二氧基苯基)甲苯
用2-(3，4-乙二氧苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷代替苯硼酸，用[1,1'-双(二苯基膦基)二茂铁]二氯化钯代替三苯基膦钯，碳酸钾代替碳酸铯，操作同实施例1，得到化合物2-溴-3-(3，4-乙二氧基苯基)甲苯，淡黄色油状物。1H NMR(400MHz,Chloroform-d)δ7.21(d,2H,-ArH),7.11(m,1H,-ArH),6.90(d,2H,-ArH),6.86(d,1H,-ArH),4.30(m,4H,-OCH2CH2O-),2.48(s,3H,-CH3).
(2)(S，S)-N-[2-(氨基甲酰甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]-4-羟基脯氨酸
用2-溴-3-(3，4-乙二氧基苯基)甲苯代替2-溴-3-甲基-1,1'-联苯，用4-羟基脯氨酸代替丝氨酸，操作同实施例1。得到产物)(S，S)-N-[2-(氨基甲酰甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]-4-羟基脯氨酸白色固体粉末。MS(FAB):633(M+1)。
实施例17：S，S)-N-[2-(环丙基甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]-4-羟基脯氨酸
Figure PCTCN2017085420-appb-000066
(1)2-溴-3-(3，4-乙二氧基苯基)甲苯
用2-(3，4-乙二氧苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷代替苯硼酸，用[1,1'-双(二苯基膦基)二茂铁]二氯化钯代替三苯基膦钯，碳酸钾代替碳酸铯，操作同实施例1，得到化合物2-溴-3-(3，4-乙二氧基苯基)甲苯，淡黄色油状物。1H NMR(400MHz,Chloroform-d)δ7.21(d,2H,-ArH),7.11(m,1H,-ArH),6.90(d,2H,-ArH),6.86(d,1H,-ArH),4.30(m,4H,-OCH2CH2O-),2.48(s,3H,-CH3).
(2)(S，S)-N-[2-(环丙基甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]-4-羟基脯氨酸
(3)用2-溴-3-(3，4-乙二氧基苯基)甲苯代替2-溴-3-甲基-1,1'-联苯，用环丙基甲基溴代替氨基甲酰甲基溴，用4-羟基脯氨酸代替丝氨酸，操作同 实施例1。得到产物(S，S)-N-[2-(环丙基甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]-4-羟基脯氨酸白色固体粉末。MS(FAB):646(M+1)。
药理活性
1、体外活性评价：体外酶学水平的检测方法采用Cisbio公司PD-1/PD-L1binding assay kit检测试剂盒。
PD-1/PD-L1小分子抑制剂的筛选原理和方法
1)原理：PD-1蛋白带HIS标签，PD-1的配体PD-L1带hFc标签，分别用Eu标记的anti-hFc抗体和XL665标记的anti-HIS抗体与两个标签蛋白结合，激光激发后，能量能够从供体Eu上转移到受体XL665，使得XL665发光，而加入抑制剂(化合物或抗体)后，阻断PD-1与PD-L1的结合，使得Eu和XL665距离较远，能量不能转移，XL665不会发光。
2)实验方法：具体方法可参考Cisbio公司的PD-1/PD-L1试剂盒(货号64CUS000C-2)。简单叙述如下，384孔白色酶标板，每孔加入2μl稀释液或者用稀释液稀释的目标化合物，然后每孔再加入4μl PD-1蛋白和4μl PD-L1蛋白，常温孵育15min，再每孔加入10μl anti-Tag1-Eu3+和anti-Tag2-XL665的混合液，室温孵育1h-4h后用Envison仪器检测665nm和620nm处的荧光信号。HTRF率＝(665nm/620nm)*104。每个化合物检测8-10个浓度，采用Graphpad软件计算IC50。3)筛选结果见表1：
表1.实施例化合物在分子水平对PD-1与PD-L1相互作用的抑制活性评价
实施例 IC50(M) 实施例 IC50(M)
1 3.12×10-7 10 1.00x10-6
2 7.32×10-7 11 1.41x10-6
3 1.26×10-7 12 1.91x10-7
4 1.80×10-6 13 4.13×10-8
5 1.15×10-6 14 4.17×10-8
6 4.25×10-8 15 1.83×10-7
7 1.82×10-8 16 1.82×10-7
8 1.02×10-8 17 4.05×10-8
9 8.16×10-8    
2、实施例化合物解除配体PD-L1抑制IFNγ的能力
IFNγ的表达水平能够反映T淋巴细胞的增殖活性。利用提取的人PBMC(人单个核细胞)，在anti-CD3/anti-CD28抗体激活T淋巴细胞的基础上，加入配体PD-L1抑制T淋巴细胞，考察待测化合物解除配体抑制作用的能力。
具体操作如下，采用达科为公司的人淋巴细胞分离液(货号DKW-KLSH-0100)提取人全血中的PBMC，将PBMC接种到96孔板中，每孔接种数为3×105个。分别加入人的PD-L1蛋白(终浓度5μg/ml)，anti-CD3/anti-CD28抗体(终浓度1μg/ml)和等比例稀释的实施例化合物。72h后采用Cisbio公司的IFNγ检测试剂盒检测上清中IFNγ的表达量。实验结果显示，实施例化合物在10nM时就能部分解除PD-L1对IFNγ的抑制作用。
3、实施例化合物体内药效
药效学研究方法如下：
皮下移植瘤方法如下：将培养的特定肿瘤细胞消化后离心收集细胞，用无菌生理盐水清洗两遍后计数，用生理盐水调整细胞浓度为5×106/ml，将0.2ml细胞混悬液接种到C57BL/6或Bablc小鼠右侧腋下。接种后次日动物随机分组，每组6-7只，称重后给药，待测化合物每天给药1次，监测小鼠肿瘤体积大小，待肿瘤体积达到一定大小后，称量小鼠体重，眼眶取血后脱颈处死小鼠，剥取肿瘤组织、胸腺组织和脾组织并分别称重。最后计算肿瘤抑制率，以肿瘤抑制率评价抗肿瘤作用强度。
B16F10肺转移模型方法如下：将培养的B16F10肿瘤细胞消化离心，用无菌生理盐水清洗两遍后计数，用生理盐水调整细胞浓度为2.5×106/ml，将0.2ml细胞通过尾静脉注射入到C57BL/6小鼠体内，肿瘤细胞将在小鼠肺部聚集。接种后次日动物随机分组，每组6-7只，称重后给药，待测化合物每天给药1次，3周后称量小鼠体重，处死动物，剥取小鼠肺组织并称重，包式液固定后计数肺部肿瘤数目。最后计算化合物对肿瘤的抑制率，以肿瘤抑制率评价抗肿瘤作用强度。
Lewis肺癌胸水模型方法如下：将小鼠皮下Lewis移植瘤肿匀浆后，用无菌生理盐水清洗两遍后计数，用生理盐水调整细胞浓度为2.5×105/ml，将0.2ml细胞注射入到C57BL/6小鼠胸腔内。接种后次日动物随机分组，每组6-7只，称重后给药，待测化合物每天给药1次，待对照组小鼠体重突然下降时处死动物，用注射器抽取胸腔内的积液，记录积液体积。
在以上各模型作用机制研究中，各类型T细胞占总细胞比例的试验方法采用流式细胞术方法，具体步骤如下：先处理样品，对于血液组织，在处理小鼠时，取小鼠的眼眶血，先用红细胞裂解液去除红细胞后，然后用PBS溶液进行漂洗后收集细胞；对于小鼠的肿瘤和脾脏器官，先用匀浆器研磨组织，再加入PBS缓冲液稀释，然后用300目的筛网过滤。计数各样本的细胞数后，取1×106的细胞加入EP管中后进行流式抗体的染色，在冰上孵育1h后，用PBS溶液漂洗2遍。用BD公司的VERSE流式仪器进行细胞群的分析。其中，肿瘤组织总上样细胞数为1×105个，血液和脾脏组织总上样细胞数为1×104个。在流式仪器上圈门后分析各类型T细胞占总进样细胞数的比例。
(1)黑色素瘤高转移株B16F10皮下移植瘤模型
对于黑色素瘤高转移株B16F10，实施例化合物无论从肿瘤体积还是重量上，都可显著的抑制皮下肿瘤的生长。
从其作用机制分析，实施例化合物可增加肿瘤浸润的各淋巴细胞比例，实施例化合物可增加脾中各淋巴细胞比例。
(2)黑色素瘤高转移株B16F10肺转移模型
对于黑色素瘤高转移株B16F10肺转移模型，实施例化合物能显著抑制肺部转移灶数量。
从其作用机制分析，实施例化合物可增加小鼠血液中各淋巴细胞数量。
(3)小鼠乳腺癌EMT6皮下移植瘤模型
对于小鼠乳腺癌EMT6皮下移植瘤模型，实施例化合物具有一定的抗肿瘤作用。另外联合环磷酰胺给药后，实施例化合物能使环磷酰胺的抑瘤率提高。
(4)小鼠Lewis肺癌胸水模型
对于小鼠Lewis肺癌胸水模型，实施例化合物具有一定的抗肿瘤作用。实施例化合物能降低胸水发生率。
(5)小鼠结肠癌MC38皮下移植瘤模型
对于小鼠结肠癌MC38皮下移植瘤模型，实施例化合物具有显著的抗肿瘤作用。联合环磷酰胺CTX给药后，具有良好的协同作用。
4、利用Biacore设备测试实施例化合物以及PD-L1抗体与PD-L1蛋白的相互作用
(1)实验原理
表面等离子体是一种金属表面的电磁波，由自由振动的光子和电子相互作用产生。表面等离子体共振(surface-plasmon resonance，SPR)是一种发生在两种介质表面的光学现象，这种现象可以由光子或电子诱导。光从光密介质射入光疏介质发生全反射现象，会形成消逝波进入光疏介质。当全反射的消逝波与金属表面的等离子波相遇时，可能会发生共振，反射光能量下降，在反射光能量谱上出现共振峰，这种共振称为表面等离子体共振，引起表面等离子体共振的入射角称为SPR角。SPR生物传感器提供了一个灵敏的、实时监测分子将相互作用的非标记检测技术。该传感器检测的是SPR角的变化，SPR又与金属表面的折射率相关。当有分析物结合到芯片表面后，导致了芯片表面折射率的改变，从而引起SPR角度变化，这就是SPR生物传感器实时检测分子间相互作用的基本原理。在相互作用分析时，SPR角度的改变被实时记录在传感图上。
(2)实验方法：
采用捕获法将PD-L1蛋白捕获于NTA芯片Fc4通道上；结合缓冲液体系为PBS-P+，pH7.4，0.01％DMSO。将配制好的一系列浓度的化合物及PD-L1抗体流经芯片表面，进行相互作用测定。
(3)实验结果：
初步确定实施例化合物的结合蛋白为PD-L1，进一步采用Biacore实验证实，实施例化合物与PD-L1具有很强的结合能力。

Claims (22)

  1. 如通式I所示的苯醚类衍生物及其立体异构体以及其可药用盐，
    Figure PCTCN2017085420-appb-100001
    式中
    R1选自:
    Figure PCTCN2017085420-appb-100002
    R2选自：取代或未取代的C1-8脂烃基，取代基选自氟、氯、溴、碘、、氰基、三氟甲基、羟基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、甲磺酰基、羟基甲酰基、氨基甲酰基、羟氨甲酰基；
    R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
    Figure PCTCN2017085420-appb-100003
    所述的取代基包括单取代、双取代、三取代、四取代；
    X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
  2. 根据权利要求1的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IA)所示：
    Figure PCTCN2017085420-appb-100004
    R2选自：取代或未取代的C1-8脂烃基，取代基选自卤素、氰基、三氟甲基、羟基、 C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、甲磺酰基、羟基甲酰基、氨基甲酰基、羟氨甲酰基；
    R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
    Figure PCTCN2017085420-appb-100005
    所述的取代基包括单取代、双取代、三取代、四取代；
    X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
  3. 根据权利要求2的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IA-1)所示：
    Figure PCTCN2017085420-appb-100006
    R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
    Figure PCTCN2017085420-appb-100007
    所述的取代基包括单取代、双取代、三取代、四取代；
    X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
  4. 根据权利要求2的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于, 所述的化合物如式(IA-2)所示：
    Figure PCTCN2017085420-appb-100008
    R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
    Figure PCTCN2017085420-appb-100009
    所述的取代基包括单取代、双取代、三取代、四取代；
    X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
  5. 根据权利要求2的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IA-3)所示：
    Figure PCTCN2017085420-appb-100010
    R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、 噁唑基、四氮唑基、
    Figure PCTCN2017085420-appb-100011
    所述的取代基包括单取代、双取代、三取代、四取代；
    X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
  6. 根据权利要求2的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IA-4)所示：
    Figure PCTCN2017085420-appb-100012
    R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
    Figure PCTCN2017085420-appb-100013
    所述的取代基包括单取代、双取代、三取代、四取代；
    X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
  7. 根据权利要求2的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IA-5)所示：
    Figure PCTCN2017085420-appb-100014
    Figure PCTCN2017085420-appb-100015
    R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
    Figure PCTCN2017085420-appb-100016
    所述的取代基包括单取代、双取代、三取代、四取代；
    X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
  8. 根据权利要求1的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IB)所示：
    Figure PCTCN2017085420-appb-100017
    R2选自：取代或未取代的C1-8脂烃基，取代基选自卤素、氰基、三氟甲基、羟基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、甲磺酰基、羟基甲酰基、羟氨甲酰基；
    R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
    Figure PCTCN2017085420-appb-100018
    所述的取代基包括单取代、双取代、三取代、四取代；
    X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
  9. 根据权利要求8的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IB-1)所示：
    Figure PCTCN2017085420-appb-100019
    R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
    Figure PCTCN2017085420-appb-100020
    所述的取代基包括单取代、双取代、三取代、四取代；
    X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
  10. 根据权利要求8的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IB-2)所示：
    Figure PCTCN2017085420-appb-100021
    R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、 噁唑基、四氮唑基、
    Figure PCTCN2017085420-appb-100022
    所述的取代基包括单取代、双取代、三取代、四取代；
    X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
  11. 根据权利要求8的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IB-3)所示：
    Figure PCTCN2017085420-appb-100023
    R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
    Figure PCTCN2017085420-appb-100024
    所述的取代基包括单取代、双取代、三取代、四取代；
    X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
  12. 根据权利要求8的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IB-4)所示：
    Figure PCTCN2017085420-appb-100025
    R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
    Figure PCTCN2017085420-appb-100026
    所述的取代基包括单取代、双取代、三取代、四取代；
    X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
  13. 根据权利要求8的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IB-5)所示：
    Figure PCTCN2017085420-appb-100027
    R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
    Figure PCTCN2017085420-appb-100028
    所述的取代基包括单取代、双取代、三取代、四取代；
    X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
  14. 根据权利要求1-3任一项的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述R3选自
    Figure PCTCN2017085420-appb-100029
    R＝甲基、乙基、丙基、异丙基、丁基、戊基、己基、庚基、辛基；
    X选自：氢、氟、氯、溴、甲基、乙烯基、三氟甲基。
  15. 根据权利要求1的苯醚类衍生物及其立体异构体以及其可药用盐，所述的化合物选自：
    (S)-N-[2-(氨基甲酰甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
    Figure PCTCN2017085420-appb-100030
    N-(乙酰胺乙基)-2-甲氧基-4-(2-溴-3-苯基苄氧基)-5-氯苄胺盐酸盐
    Figure PCTCN2017085420-appb-100031
    N-(乙酰胺乙基)-2-烯丙氧基-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
    Figure PCTCN2017085420-appb-100032
    N-(乙酰胺乙基)-2-炔丙氧基-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
    Figure PCTCN2017085420-appb-100033
    N-(乙酰胺乙基)-2-环丙甲氧基-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
    Figure PCTCN2017085420-appb-100034
    N-[2-(二甲胺甲酰甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
    Figure PCTCN2017085420-appb-100035
    N-[2-(3-甲基丁烯-2-氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
    Figure PCTCN2017085420-appb-100036
    N-[2-(环丙基甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]苏氨酸
    Figure PCTCN2017085420-appb-100037
    N-[2-(环丙基甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸酰胺
    Figure PCTCN2017085420-appb-100038
    N-乙酰氨基乙基-2-(环丙基甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
    Figure PCTCN2017085420-appb-100039
    N-[2-(环丙基甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]瓜氨酸
    Figure PCTCN2017085420-appb-100040
    N-[2-(甲基甲氧氨基甲酰甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
    Figure PCTCN2017085420-appb-100041
    N-[2-(吗啉甲酰甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
    Figure PCTCN2017085420-appb-100042
    (S)-N-[2-(环丙基甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
    Figure PCTCN2017085420-appb-100043
    (S)-N-[2-(羟胺甲酰甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]哌啶-2-甲酸
    Figure PCTCN2017085420-appb-100044
    (S，S)-N-[2-(氨基甲酰甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]-4-羟基脯氨酸
    Figure PCTCN2017085420-appb-100045
    S，S)-N-[2-(环丙基甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]-4-羟基脯氨酸
    Figure PCTCN2017085420-appb-100046
  16. 根据权利要求1的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于，所述的药用盐包括与无机酸、有机酸、碱金属离子、碱土金属离子或能提供生理上可接受的阳离子的有机碱结合形成的盐以及铵盐。
  17. 根据权利要求16的苯醚类衍生物及其立体异构体以及其可药用盐，其特征在于，所述的无机酸选自盐酸、氢溴酸、磷酸或硫酸；所述的有机酸选自甲磺酸、对甲苯磺酸、三氟乙酸、枸杞酸、马来酸酒石酸、富马酸、柠檬酸或乳酸；所述的碱金属离子选自锂离子，钠离子，钾离子；所述的碱土金属离子选自钙离子，镁离子；所述的能提供生理上可接受的阳离子的有机碱选自甲胺、二甲胺、三甲胺、哌啶、吗啉或三(2－羟乙基)胺。
  18. 制备权利要求1-15任一项所述的苯醚类衍生物及其立体异构体以及其可药用盐的方法：
    Figure PCTCN2017085420-appb-100047
    为了制备本发明通式I所述的化合物，依据通式I的结构，本发明制备通式I化合物分为两步：
    (a)以2-羟基-4-(2-溴-3-取代苄氧基)-X取代苯甲醛1为原料，在碱性条件下与卤化物反应得到含醛基的中间体化合物2；
    (b)以含醛基的中间体化合物2为原料，与含氨基或亚氨基的HR3缩合及还原得到目标化合物I；
    所述的R1、R2、R3、X的定义同权利要求1-15任一项所述。
  19. 一种药物组合物，其特征在于，所述的药物组合物包含作为有效成分的权利要求1-17任一项所述的苯醚类衍生物及其立体异构体以及其可药用盐和药学上可接受的载体或赋形剂。
  20. 权利要求1-17任一项所述的苯醚类衍生物及其立体异构体以及其可药用盐在制备预防和/或治疗与PD-1/PD-L1信号通路有关疾病的药物中的应用。
  21. 根据权利要求20的应用，其特征在于，所述的与PD-1/PD-L1信号通路有关的疾病选自癌症、感染性疾病、自身免疫性疾病。
  22. 根据权利要求21的应用，其特征在于，所述的癌症选自皮肤癌、肺癌、泌尿系肿瘤、血液肿瘤、乳腺癌、胶质瘤、消化系统肿瘤、生殖系统肿瘤、淋巴瘤、神经系统肿瘤、脑瘤、头颈癌；所述的感染性疾病选自细菌感染、病毒感染；所述的自身免疫性疾病选自器官特异性自身免疫病、系统性自身免疫病，其中，所述的器官特异性自身免疫病包括慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症、急性特发性多神经炎，所述的系统性自身免疫病包括类风湿关节炎、系统性红斑狼疮、系统性血管炎、硬皮病、天疱疮、皮肌炎、混合性结缔组织病、自身免疫性溶血性贫血。
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