CN109776377B - Indoline compound and preparation method and application thereof - Google Patents
Indoline compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and discloses indoline compounds with a structure shown in a general formula I, and a preparation method and application thereof, wherein a substituent R1、R2、R3、R4、R5Have the meanings given in the description. The indoline compound, the stereoisomer and the pharmaceutically acceptable salt thereof or the pharmaceutical composition containing the indoline compound can be used for preparing medicines for treating diseases related to PD-1/PD-L1 protein/protein interaction, such as cancers, virus infection and other diseases.
Description
The technical field is as follows:
the invention belongs to the technical field of medicines, and relates to indoline compounds, a preparation method and application thereof, in particular to indoline compounds, a preparation method thereof and a pharmaceutical composition containing the indoline compounds. The invention also relates to application of the compounds, stereoisomers and pharmaceutically acceptable salts thereof in preparing medicaments for treating diseases related to the PD-1/PD-L1 signal channel, such as cancers, infectious diseases and autoimmune diseases.
Background art:
immunotherapy is a hotspot field of tumor therapy in recent years, and is the first of ten scientific breakthroughs by Science in 2013. Programmed death receptor 1 (PD-1) is a T cell surface receptor that, when bound to programmed death ligand 1(PD-L1), generates a negative immune regulatory signal that inhibits T cell activation, proliferation, and release of cytokines such as interleukin 2(IL-2), interferon gamma (IFN-. gamma.) (Eur. J. Immunol.,2002,32(3), 634. sup. 643.). A large number of researches show that the tumor microenvironment in a body can induce the up-regulation of PD-1 expression in infiltrated T cells, and the tumor cells highly express PD-L1, so that the signal path mediated by PD-1/PD-L1 is continuously activated, the function of tumor specific CD8+ T cells is inhibited, and the tumor cells cannot be recognized or killed, namely, the tumor cells realize immune escape. Therefore, the targeted blocking of the PD-1/PD-L1 protein/protein interaction can restore the function of the T cell, and lead the T cell to re-recognize and kill the tumor cell.
Immunotherapy based on PD-1/PD-L1 is of great interest, and currently approved commercially available PD-1/PD-L1 monoclonal antibodies include Pembrolizumab by Moshadong, Nivolumab by Baume Shinobo, Avelumab by Merck, Durvalumab by Asricon, Atezolizumab by Roche, and the like. The monoclonal antibodies have shown significant efficacy in the treatment of a variety of tumor types, and approved indications include melanoma, non-small cell lung cancer, gastric cancer, urothelial cancer, and the like. With the development of clinical research, monoclonal antibody drugs are expected to realize breakthrough in more indications.
Although monoclonal antibody drugs have shown advantages in clinical treatment, there are also significant drawbacks such as difficulty in preparation and purification, and high production cost; is easy to be decomposed by protease and has short half-life period; can not be taken orally, and can only be taken by injection; the immunogenicity of monoclonal antibodies leads to severe toxic side effects. Compared with biological macromolecular drugs, the small molecular compound is chemically modified, so that the pharmacokinetic properties of the small molecular compound are controllable, and the small molecular compound has larger exploration and optimization space in the aspects of production process, administration mode and the like. Therefore, the development of small molecule inhibitors targeting the PD-1/PD-L1 protein/protein interaction is a viable option for the realization of immunotherapy.
At present, a small-molecule PD-1/PD-L1 inhibitor is developed in an early stage, a PD-L1 inhibitor AC-170 of Curis is in a clinical I stage, and a small-molecule inhibitor of Baishi Guibao and Incyte is also in a preclinical research stage. Therefore, the development of small molecule PD-1/PD-L1 inhibitors with novel chemical structures is urgently needed.
The inventor designs and synthesizes a series of novel indoline compounds. The activity research result shows that the compound can obviously inhibit the interaction of PD-1/PD-L1 protein/protein.
The invention content is as follows:
the invention provides indoline compounds shown in a general formula I, stereoisomers and pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
R1selected from unsubstituted or substituted by 1-3R6Substituted phenyl, or
R6Independently selected from halogen, (C)1-C4) Alkyl, (C)1-C4) An alkoxy group;
R2、R3each independently selected from hydrogen, halogen, hydroxyl and (C)1-C4) Alkyl, (C)1-C4) Alkoxy radical,
R9Independently selected from cyano, methanesulfonyl, acetamido, carbamoyl;
R4、R5independently selected from hydrogen, (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, tetrahydropyran-4-yl; said (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl radicalCarboxyl group (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, tetrahydropyran-4-yl may optionally be substituted with 1-3R7Substitution;
or R4、R5And the nitrogen atom to which they are attached form a 3-to 7-membered, preferably 5-to 6-membered, nitrogen-containing heterocycle; the nitrogen-containing heterocyclic ring contains 1-3 heteroatoms of N, O or S, and is preferably a 5-6-membered heterocyclic ring containing one nitrogen atom; the nitrogen-containing heterocycle may be optionally substituted with 1 to 3R8Substitution;
R7independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino and (C)1-C4) Alkyl, hydroxy (C)1-C4) Alkyl, (C)1-C4) Alkoxy (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, (C)1-C4) An acyl group;
R8independently selected from hydrogen, hydroxy, carboxy, amino, carbamoyl, (C)1-C4) Alkyl, (C)1-C4) Alkoxy group, (C)1-C4) Alcoxyl formyl group and hydroxyl group (C)1-C4) An alkyl group.
The invention preferably relates to indoline compounds shown in the general formula I, stereoisomers and pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
R1selected from phenyl which is unsubstituted or substituted by 1 to 3 halogen, methyl, methoxy, or
R2、R3Each independently selected from hydrogen, halogen, hydroxy, methyl, ethyl, methoxy,
simultaneously, the invention also preferably relates to indoline compounds of the general formula I, stereoisomers and pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
R1selected from phenyl which is unsubstituted or substituted by 1 to 3 halogen, methyl, methoxy, or
R2、R3One of them is selected from
The other is selected from hydrogen, halogen, hydroxyl, methyl, ethyl and methoxy;
the indoline compounds of general formula I of the present invention and stereoisomers and pharmaceutically acceptable salts thereof are preferably selected from the following compounds, but these compounds are not meant to limit the present invention in any way:
in addition, the present invention also includes prodrugs of the compounds of the present invention. Prodrugs of the compounds of the present invention are derivatives of formula I which may themselves have poor or no activity, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis, or otherwise) to the corresponding biologically active form.
The indoline compound of the general formula I, the stereoisomer and the pharmaceutically acceptable salt thereof comprise salts formed by inorganic acid, organic acid and alkali metal ions; the inorganic acid is selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid; the organic acid is selected from: succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, or p-toluenesulfonic acid; the alkali metal ions are selected from lithium ions, sodium ions or potassium ions.
"halogen" in the present invention means fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl; "Nitrogen-containing heterocycle" refers to a monocyclic or polycyclic ring system containing a nitrogen atom, the ring system being non-aromatic or aromatic.
The composition can contain the indoline compound shown in the formula I, the stereoisomer and the pharmaceutically acceptable salt thereof as active ingredients, and is mixed with a pharmaceutically acceptable carrier or excipient to prepare the composition. Such carriers or excipients include diluents, binders, wetting agents, disintegrants, lubricants, glidants and the like as are well known in the art. Diluents include, but are not limited to, starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, dibasic calcium phosphate, and the like; the humectant includes water, ethanol, isopropanol, etc.; binders include, but are not limited to, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyethylene glycol, and the like; disintegrants include, but are not limited to, dry starch, microcrystalline cellulose, low substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, sodium lauryl sulfate, and the like; lubricants and glidants include, but are not limited to, talc, silicon dioxide, polyethylene glycol, and the like.
The pharmaceutical composition of the present invention can be formulated into several dosage forms including, but not limited to, injections, tablets, capsules, and the like.
The indoline compound, the stereoisomer and the pharmaceutically acceptable salt thereof can be combined with other active ingredients for use, so that a better treatment effect is achieved.
The invention also provides an indoline compound shown in the general formula I, a stereoisomer and a pharmaceutically acceptable salt thereof, and application of the indoline compound in preparation of a medicine for preventing and/or treating diseases related to a PD-1/PD-L1 signal channel. The diseases related to the PD-1/PD-L1 signal channel are selected from cancers, infectious diseases and autoimmune diseases. The cancer is selected from lung cancer, skin cancer, blood tumor, glioma, digestive system tumor, breast cancer, lymphoma, nervous system tumor, and melanoma; the infectious diseases are selected from bacterial infection and viral infection; the autoimmune disease is selected from organ specific and systemic autoimmune diseases. Wherein the organ-specific autoimmune disease comprises chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, ulcerative colitis and acute idiopathic polyneuritis, and the systemic autoimmune disease comprises rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis and autoimmune hemolytic anemia.
The positive progress effects of the invention are as follows: the indoline compound has a novel chemical structure, has high inhibitory activity on PD-1/PD-L1 interaction in vitro research, and can be used for treating and preventing various diseases such as cancer and the like.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations are not intended to limit the scope of the invention in any way.
The following synthetic schemes outline and describe the preparation of the compounds of formula I of the present invention, and all starting materials are prepared by the procedures described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry, or are commercially available. All of the final derivatives of the invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry.
Route one:
(a) 4-bromo-1H-indole and benzene, substituted benzene or heteroaromatic boric acid or borate are taken as raw materials, and an intermediate 2 is obtained through a Suzuki coupling reaction;
(b) taking the intermediate 2 as a raw material, and preparing an indoline intermediate 3 under the action of a reducing agent such as sodium cyanoborohydride;
(c) taking the intermediate 3 and substituted benzoic acid as raw materials, and carrying out amidation reaction under the condition of a condensing agent to obtain an intermediate 4 containing formyl;
(d) the intermediate 4 is used as a raw material, condensed with an amine compound and reduced under the action of sodium cyanoborohydride or sodium triacetoxyborohydride to prepare the target compound with the general formula I.
And a second route:
(e) taking indoline intermediate 3 and substituted benzoic acid as raw materials, and carrying out amidation reaction under the condition of a condensing agent to obtain intermediate 5 containing chlorine or bromine;
(f) taking the intermediate 5 as a raw material, and carrying out Suzuki coupling reaction on the intermediate 5 and vinyl boronic acid pinacol ester to obtain an intermediate 6;
(g) preparing intermediate 4 containing formyl under the action of oxidant such as sodium periodate by using intermediate 6 as raw material;
(h) the intermediate 4 is used as a raw material, condensed with an amine compound and reduced under the action of sodium cyanoborohydride or sodium triacetoxyborohydride to prepare the target compound with the general formula I.
And a third route:
(i) taking indoline intermediate 3 and substituted benzoic acid as raw materials, and carrying out amidation reaction under the condition of a condensing agent to obtain intermediate 7 containing hydroxyl and formyl;
(j) taking the intermediate 7 as a raw material, and carrying out nucleophilic substitution reaction with halogenated hydrocarbon under an alkaline condition to obtain an intermediate 4;
(k) the intermediate 4 is used as a raw material, condensed with an amine compound and reduced under the action of sodium cyanoborohydride or sodium triacetoxyborohydride to prepare the target compound with the general formula I.
And a fourth route:
(l) Taking the intermediate 3 and substituted benzoic acid as raw materials, and carrying out amidation reaction under the condition of a condensing agent to obtain an intermediate 8 containing hydroxyl and chlorine or bromine;
(m) taking the intermediate 8 as a raw material, and carrying out nucleophilic substitution reaction with halogenated hydrocarbon under an alkaline condition to obtain an intermediate 5;
(n) taking the intermediate 5 as a raw material, and carrying out Suzuki coupling reaction on the intermediate 5 and vinyl boronic acid pinacol ester to obtain an intermediate 6;
(o) preparing intermediate 4 containing formyl radicals from intermediate 6 under the action of an oxidizing agent such as sodium periodate;
(p) taking the intermediate 4 as a raw material, condensing with an amine compound, and reducing under the action of sodium cyanoborohydride or sodium triacetoxyborohydride to obtain the target compound shown in the general formula I.
In the above scheme, R is1、R2、R3、R4、R5Is as defined in the claims. In intermediates 5 and 8, Y represents chloro or bromo. The indoline compound with the general formula I can be prepared according to the reaction route.
The specific implementation mode is as follows:
in the following examples, methods of preparing some of the compounds are depicted. It is to be understood that the following methods, as well as other methods known to those of ordinary skill in the art, can be applied to the preparation of all of the compounds described herein. The examples are intended to illustrate, but not to limit, the scope of the invention.
Example 1: (4- (((2-hydroxyethyl) amino) methyl) phenyl) (4-phenylindolin-1-yl) formyl
Step 1: 4-phenyl-1H-indoles
4-bromo-1H-indole (10g, 51.29mmol), phenylboronic acid (6.26g, 51.29mmol), palladium tetratriphenylphosphine (1.78g, 1.54mmol), and potassium carbonate (21.23g, 153.94mmol) were dissolved in a mixed solvent of dioxane and water (volume ratio 4:1, 250mL) at room temperature. Under the protection of nitrogen, the temperature is raised to 60 ℃ for reaction for 10 hours. Cooling to room temperature, suction-filtering with celite, extracting the filtrate with dichloromethane, washing the organic layer with saturated saline, concentrating under reduced pressure, and separating by column chromatography to obtain white solid 6.66g with yield 67.2%.
Step 2: 4-phenylindolines
4-phenyl-1H-indole (1.5g, 7.77mmol) was dissolved in glacial acetic acid (9mL) at room temperature, and sodium cyanoborohydride (1.47g, 23.32mmol) was slowly added and reacted at room temperature for 2 hours. Adjusting pH to 9-10 with 40% NaOH solution in ice bath, extracting with ethyl acetate, washing organic layer with saturated saline solution, concentrating under reduced pressure, and separating by column chromatography to obtain white solid 1.08g with yield 71.3%.
And step 3: 4- (4-phenylindoline-1-formyl) benzaldehyde
4-phenylindoline (0.1g, 0.51mmol), 4-formylbenzoic acid (0.08g, 0.56mmol) and HATU (0.29g, 0.76mmol) were dissolved in DMF (5mL) at room temperature, stirred at room temperature for 20min, added DIPEA (0.33g, 2.56mmol) and reacted at room temperature for 4 hours. Pouring the reaction solution into water to separate out light yellow solid, stirring at room temperature for 20min, filtering, and pulping with diethyl ether to obtain white solid 0.149g with yield of 89.5%.
And 4, step 4: (4- (((2-hydroxyethyl) amino) methyl) phenyl) (4-phenylindolin-1-yl) formyl (example 1)
4- (4-Phenylindoline-1-formyl) benzaldehyde (0.08g, 0.24mmol) and glacial acetic acid (0.02g, 0.33mmol) were dissolved in methanol (5mL) at room temperature, stirred at room temperature for 0.5 hour, ethanolamine (0.07g, 1.14mmol) was added, the mixture was reacted at room temperature for 5 hours, and sodium cyanoborohydride (0.08g, 1.27mmol) was added and the reaction was reacted at room temperature for 10 hours. After the reaction, methanol was distilled off, water was added, and the mixture was extracted with methylene chloride, washed with saturated brine, concentrated under reduced pressure, and separated by column chromatography to obtain a pale yellow solid 0.023g with a yield of 26.2%.
ESI-MS m/z:373.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ7.61–7.20(m,11H),7.09(d,J＝6.8Hz,1H),4.53(s,1H),4.00(t,J＝7.8Hz,2H),3.79(s,2H),3.49(t,J＝5.5Hz,2H),3.12(t,J＝8.0Hz,2H),2.60(t,J＝5.6Hz,2H),1.23(s,1H).
According to the synthesis method of the embodiment 1,4- (4-phenylindoline-1-formyl) benzaldehyde is used as a raw material, and the compound of the embodiment 2-3 is prepared by reacting with different amine compounds and reducing by sodium cyanoborohydride.
Example 2: n- (2- ((4- (4-phenylindoline-1-formyl) benzyl) amino) ethyl) acetamide
ESI-MS m/z:414.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ7.81(s,1H),7.54(d,J＝7.8Hz,2H),7.46(dd,J＝11.5,6.0Hz,6H),7.41–7.35(m,1H),7.29(s,1H),7.09(d,J＝7.0Hz,1H),4.00(t,J＝8.0Hz,2H),3.76(s,2H),3.18–3.09(m,4H),2.56(t,J＝6.4Hz,2H),1.79(s,3H),1.23(s,1H).
Example 3: (S) - (4- ((2- (hydroxymethyl) pyrrolidin-1-yl) methyl) phenyl) (4-phenylindolin-1-yl) formyl
ESI-MS m/z:413.2[M+H]+；
Example 4: (4- (((2-hydroxyethyl) amino) methyl) -3-methylphenyl) (4-phenylindolin-1-yl) formyl
Step 1: (4-bromo-3-methylphenyl) (4-phenylindolin-1-yl) formyl
4-phenylindoline (0.09g, 0.46mmol), 4-bromo-3-methylbenzoic acid (0.1g, 0.47mmol) and HATU (0.26g, 0.68mmol) were dissolved in anhydrous DMF (5mL) at room temperature, stirred well and then DIPEA (0.11g, 0.92mmol) was added and reacted at room temperature for 2 hours. The reaction solution was poured into cold water, stirred for 15 minutes, and filtered to obtain 0.16g of a white solid with a yield of 90.2%.
Step 2: (3-methyl-4-vinylphenyl) (4-phenylindolin-1-yl) formyl
(4-bromo-3-methylphenyl) (4-phenylindolin-1-yl) formyl (0.1g, 0.26mmol), vinyl boronic acid pinacol ester (0.04g, 0.26mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.02g, 0.027mmol) and cesium carbonate (0.18g, 0.55mmol) were dissolved in a mixed solvent of 1, 4-dioxane/water (volume ratio 3:1, 8mL) at room temperature and reacted at 90 ℃ for 1.5 hours under nitrogen protection. The reaction solution was cooled to room temperature, 1, 4-dioxane was distilled off, water was added to the system, and extraction was performed with ethyl acetate. The white solid is obtained by column chromatography separation, and the yield is 61.3 percent.
And step 3: 2-methyl-4- (4-phenylindoline-1-formyl) benzaldehyde
(3-methyl-4-vinylphenyl) (4-phenylindolin-1-yl) formyl (0.23g, 0.68mmol) was dissolved in a mixed solution of 1, 4-dioxane/water (volume ratio 5: 1, 10mL) at room temperature, and 2% OsO was rapidly added4After stirring the aqueous solution (1.3mL) for 5 minutes, sodium periodate (0.58g, 2.7mmol) was added and the reaction was stirred at room temperature for 3 hours. The reaction solution was poured into water, filtered under suction, and dried to obtain a white-like solid of 0.21 with a yield of 91.5%.
And 4, step 4: (4- (((2-hydroxyethyl) amino) methyl) -3-methylphenyl) (4-phenylindolin-1-yl) formyl (example 4)
2-methyl-4- (4-phenylindoline-1-formyl) benzaldehyde (0.08g, 0.23mmol) was dissolved in dry dichloromethane (5mL), glacial acetic acid (0.02g, 0.35mmol) was added and stirred for 10min, ethanolamine (0.056g, 0.92mmol) was added and the reaction stirred for 2 h. Sodium triacetoxyborohydride (0.25g, 1.18mmol) was added to the reaction solution, and the reaction was continued at room temperature for 10 hours. Adding water into the reaction solution, evaporating the organic layer, and carrying out column chromatography to obtain 0.027g of white solid with the yield of 30.2%.
ESI-MS m/z:387.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ8.03(s,1H),7.56–7.44(m,5H),7.40(s,3H),7.28(s,1H),7.09(s,1H),3.99(m,2H),3.87(s,2H),3.58(s,2H),3.12(m,2H),2.76(s,2H),2.37(s,3H),1.91(s,1H).
According to the synthesis method of the embodiment 4, the compound of the embodiment 5-10 is prepared by reacting 2-methyl-4- (4-phenylindoline-1-formyl) benzaldehyde serving as a raw material with different amine compounds and reducing the amine compounds by sodium triacetoxyborohydride.
Example 5: n- (2- ((2-methyl-4- (4-phenylindoline-1-formyl) benzyl) amino) ethyl) acetamide
ESI-MS m/z:428.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ7.87(s,1H),7.43(d,J＝52.1Hz,9H),7.10(s,1H),4.00(s,2H),3.75(s,2H),3.20(s,2H),3.12(s,2H),2.65(s,2H),2.35(s,3H),1.82(s,3H).
Example 6: 2- ((2-methyl-4- (4-phenylindoline-1-formyl) benzyl) amino) ethane-1-sulfonamide
ESI-MS m/z:450.2[M+H]+；
Example 7: n- (2- ((2-methyl-4- (4-phenylindoline-1-formyl) benzyl) amino) ethyl) methanesulfonamide
ESI-MS m/z:464.2[M+H]+；
Example 8: (S) - (4- ((2- (hydroxymethyl) pyrrolidin-1-yl) methyl) -3-methylphenyl) (4-phenylindolin-1-yl) formyl
ESI-MS m/z:427.2[M+H]+；
Example 9: (2-methyl-4- (4-phenylindoline-1-formyl) benzyl) -L-proline
ESI-MS m/z:441.2[M+H]+；
Example 10: (3-methyl-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) (4-phenylindolin-1-yl) formyl
ESI-MS m/z:427.2[M+H]+；
The compounds of examples 11-20 were prepared by amidation with 4-bromo-3-methoxybenzoic acid, Suzuki coupling of vinylboronic acid pinacol ester, sodium periodate oxidation, reductive amination with sodium cyanoborohydride starting from 4-phenylindoline in analogy to the synthesis of example 4.
Example 11: (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) (4-phenylindolin-1-yl) formyl
ESI-MS m/z:403.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ8.08(s,1H),7.64–7.24(m,7H),7.23–7.03(m,3H),4.58(s,1H),4.12–3.96(m,2H),3.84(s,3H),3.79(s,2H),3.51(s,2H),3.15(dd,J＝17.6,10.1Hz,2H),2.65(s,2H),1.25(s,1H).
Example 12: n- (2- ((2-methoxy-4- (4-phenylindoline-1-formyl) benzyl) amino) ethyl) acetamide
ESI-MS m/z:444.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ7.87(s,1H),7.47(dd,J＝17.2,5.9Hz,5H),7.39(dt,J＝8.4,4.3Hz,1H),7.30(s,1H),7.19–7.14(m,2H),7.11(d,J＝7.0Hz,1H),4.02(t,J＝8.0Hz,2H),3.84(s,3H),3.78(s,2H),3.18(dd,J＝12.1,6.1Hz,2H),3.14(t,J＝8.1Hz,2H),2.63(t,J＝6.2Hz,2H),1.81(s,3H),1.24(s,1H).
Example 13: 2- ((2-methoxy-4- (4-phenylindoline-1-formyl) benzyl) amino) ethane-1-sulfonamide
ESI-MS m/z:466.2[M+H]+；
Example 14: n- (2- ((2-methoxy-4- (4-phenylindoline-1-formyl) benzyl) amino) ethyl) methanesulfonamide
ESI-MS m/z:480.2[M+H]+；
Example 15: (2-methoxy-4- (4-phenylindoline-1-formyl) benzyl) -D-serine
ESI-MS m/z:447.2[M+H]+；
Example 16: (2-methoxy-4- (4-phenylindoline-1-formyl) benzyl) -D-alanine
ESI-MS m/z:431.2[M+H]+；
Example 17: (S) -3-hydroxy-4- ((2-methoxy-4- (4-phenylindoline-1-formyl) benzyl) amino) butanoic acid
ESI-MS m/z:461.2[M+H]+；
Example 18: (S) - (4- ((2- (hydroxymethyl) pyrrolidin-1-yl) methyl) -3-methoxyphenyl) (4-phenylindolin-1-yl) formyl
ESI-MS m/z:443.2[M+H]+；
Example 19: (2-methoxy-4- (4-phenylindoline-1-formyl) benzyl) -L-proline
ESI-MS m/z:456.2[M+H]+；
Example 20: (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) (4-phenylindolin-1-yl) formyl
ESI-MS m/z:443.2[M+H]+；
The compounds of examples 21 to 23 were prepared analogously to the synthesis of example 11, starting from 4-phenylindoline by amidation with 4-bromo-3, 5-dimethoxybenzoic acid, Suzuki coupling of vinylboronic acid pinacol ester, oxidation with sodium periodate and reductive amination with sodium cyanoborohydride.
Example 21: (4- (((2-hydroxyethyl) amino) methyl) -3, 5-dimethoxyphenyl) (4-phenylindolin-1-yl) formyl
ESI-MS m/z:433.2[M+H]+；
Example 22: n- (2- ((2, 6-dimethoxy-4- (4-phenylindoline-1-formyl) benzyl) amino) ethyl) acetamide
ESI-MS m/z:474.2[M+H]+；
Example 23 (S) - (4- ((2- (hydroxymethyl) pyrrolidin-1-yl) methyl) -3, 5-dimethoxyphenyl) (4-phenylindolin-1-yl) formyl
ESI-MS m/z:473.2[M+H]+；
The compounds of examples 24 and 25 were prepared analogously to the synthesis of example 4, starting from 4-phenylindoline by amidation with 4-bromo-3-chlorobenzoic acid, Suzuki coupling of pinacol ester vinylborate, oxidation with sodium periodate and reductive amination with sodium cyanoborohydride.
Example 24 (3-chloro-4- (((2-hydroxyethyl) amino) methyl) phenyl) (4-phenylindolin-1-yl) formyl
ESI-MS m/z:407.1[M+H]+；1H NMR(600MHz,DMSO-d6)δ8.08(s,1H),7.65(s,2H),7.56(d,J＝6.6Hz,1H),7.47(d,J＝2.6Hz,4H),7.42–7.24(m,2H),7.11(d,J＝5.0Hz,1H),4.54(s,1H),4.01(s,2H),3.86(s,2H),3.50(d,J＝4.4Hz,2H),3.13(t,J＝7.3Hz,2H),2.63(s,2H),1.23(s,1H).
Example 25N- (2- ((2-chloro-4- (4-phenylindoline-1-formyl) benzyl) amino) ethyl) acetamide
ESI-MS m/z:448.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ8.10(s,1H),7.84(s,1H),7.66(s,2H),7.58(s,1H),7.48(s,4H),7.37(d,J＝39.1Hz,2H),7.13(s,1H),4.01(s,2H),3.84(s,2H),3.16(dd,J＝15.6,7.5Hz,4H),2.61(s,2H),1.81(s,3H),1.24(s,1H).
Example 26: (3-hydroxy-4- (((2-hydroxyethyl) amino) methyl) phenyl) (4-phenylindolin-1-yl) formyl
Step 1: 2-hydroxy-4- (4-phenylindoline-1-formyl) benzaldehyde
4-phenylindoline (1.51g, 7.74mmol), 4-formyl-3-hydroxybenzoic acid (1.31g, 7.89mmol) were dissolved in dichloromethane (20mL) at room temperature, EDCI (1.78g, 9.31mmol) was added and the reaction was continued for 3 h. The reaction mixture was washed with water, saturated brine and the solvent was evaporated to dryness to give a pale yellow solid (2.27 g) with a yield of 85.6%.
Step 2: (3-hydroxy-4- (((2-hydroxyethyl) amino) methyl) phenyl) (4-phenylindolin-1-yl) formyl (example 26)
Similar to the synthesis method of example 1, the compound is prepared by taking 2-hydroxy-4- (4-phenylindoline-1-formyl) benzaldehyde as a raw material and performing reductive amination on the benzaldehyde and ethanolamine through sodium cyanoborohydride.
ESI-MS m/z:389.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ7.48(d,J＝4.1Hz,4H),7.42–7.36(m,1H),7.29(s,1H),7.23(d,J＝7.6Hz,1H),7.16(t,J＝7.8Hz,1H),7.09(d,J＝7.1Hz,1H),6.96(d,J＝7.4Hz,1H),6.90(s,1H),6.77(t,J＝8.4Hz,1H),4.00(t,J＝8.0Hz,2H),3.92(s,2H),3.53(t,J＝5.6Hz,2H),3.13(t,J＝8.1Hz,2H),2.65(t,J＝5.5Hz,2H),1.25(s,1H).
The compound of example 27 was prepared by reductive amination of 2-hydroxy-4- (4-phenylindoline-1-formyl) benzaldehyde, starting with N- (2-aminoethyl) acetamide, using sodium cyanoborohydride in analogy to the procedure for the synthesis of example 26.
Example 27N- (2- ((2-hydroxy-4- (4-phenylindoline-1-formyl) benzyl) amino) ethyl) acetamide
ESI-MS m/z:430.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ7.86(s,1H),7.48(d,J＝4.2Hz,4H),7.39(dt,J＝8.6,4.4Hz,1H),7.29(s,1H),7.22(d,J＝7.7Hz,1H),7.16(t,J＝7.8Hz,1H),7.09(d,J＝7.4Hz,1H),6.96(d,J＝7.4Hz,1H),6.90(s,1H),6.76(d,J＝8.3Hz,1H),4.00(t,J＝8.1Hz,2H),3.86(s,2H),3.18(dd,J＝12.2,6.2Hz,2H),3.13(t,J＝8.2Hz,2H),2.60(t,J＝6.4Hz,2H),1.81(s,3H),1.24(s,1H).
Example 28: (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-yl) (4- (((2-hydroxyethyl) amino) methyl) phenyl) formyl
Step 1: 4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -1H-indole
4-bromo-1H-indole (10g, 51.29mmol), 2- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (13.45g, 51.29mmol), palladium tetratriphenylphosphine (1.78g, 1.54mmol) and potassium carbonate (21.23g, 153.94mmol) were dissolved in a mixed solvent of dioxane and water (volume ratio 4:1, 250mL) at room temperature. Under the protection of nitrogen, the temperature is raised to 60 ℃ for reaction for 13 hours. Cooling to room temperature, suction-filtering with celite, extracting the filtrate with dichloromethane, washing the organic layer with saturated brine, concentrating under reduced pressure, and separating by column chromatography to obtain white solid 8.68g with yield 67.4%.
Step 2: 4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indoline
4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -1H-indole (2g, 7.97mmol) was dissolved in glacial acetic acid (10mL) at room temperature, and sodium cyanoborohydride (1.51g, 23.90mmol) was slowly added and reacted at room temperature for 3 hours. In an ice bath, the pH was adjusted to 9 with NaOH solution, extraction was performed with dichloromethane, the organic layer was washed with saturated brine, the organic layer was evaporated, and column chromatography was performed to obtain 1.42g of a white solid with a yield of 70.4%.
And step 3: 4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indoline-1-formyl) benzaldehyde
4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indoline (0.5g, 1.98mmol), 4-formylbenzoic acid (0.33g, 2.17mmol) and HATU (1.13g, 2.96mmol) were dissolved in DMF (10mL) at room temperature, stirred at room temperature for 20min, DIPEA (1.28g, 9.88mmol) was added, and the reaction was carried out at room temperature for 5 hours. Pouring the reaction solution into water to separate out light yellow solid, stirring at room temperature for 30min, filtering, and pulping with diethyl ether to obtain white solid 0.70g with yield of 92.5%.
And 4, step 4: (4- (2, 3-Dihydrobenzo [ b ] [1,4] Dioxin-6-yl) indolin-1-yl) (4- (((2-hydroxyethyl) amino) methyl) phenyl) formyl (example 28)
4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-yl) benzaldehyde (0.08g, 0.21mmol) and glacial acetic acid (0.02g, 0.31mmol) were dissolved in DMF (5mL) at room temperature, stirred at room temperature for 0.5 hour, ethanolamine (0.06g, 1.04mmol) was added, and reacted at room temperature for 5 hours, followed by addition of sodium cyanoborohydride (0.07g, 1.04mmol) and reaction at room temperature for 10 hours. After the reaction, the reaction solution was poured into water, extracted with dichloromethane, and separated by column chromatography to obtain a white-like solid 0.025g, with a yield of 28.2%.
ESI-MS m/z:431.2[M+H]+；
The compound of example 29 was prepared analogously to the synthesis of example 28, starting from 4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) benzaldehyde and N- (2-aminoethyl) acetamide under reductive amination conditions with sodium cyanoborohydride.
Example 29: n- (2- ((4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) benzyl) amino) ethyl) acetamide
ESI-MS m/z:472.2[M+H]+；
Example 30: (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-yl) (4- (((2-hydroxyethyl) amino) methyl) -3-methylphenyl) formyl
Step 1: (4-bromo-3-methylphenyl) (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-yl) formyl
4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indoline (0.9g, 3.56mmol), 4-bromo-3-methylbenzoic acid (0.76g, 3.56mmol), HATU (2.03g, 5.33mmol) were dissolved in anhydrous DMF (10mL) at room temperature, and after stirring well, DIPEA (0.92g, 7.12mmol) was added and reacted at room temperature for 3 hours. The reaction solution was poured into cold water, stirred for 15 minutes, and filtered by suction to obtain 1.37g of a white solid with a yield of 85.5%.
Step 2: (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-yl) (3-methyl-4-vinylphenyl) formyl
(4-bromo-3-methylphenyl) (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-yl) formyl (0.1g, 0.22mmol), vinyl boronic acid pinacol ester (0.04g, 0.26mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.016g, 0.025mmol) and cesium carbonate (0.14g, 0.44mmol) were dissolved in a mixed solvent of 1, 4-dioxane/water (volume ratio 3:1, 8mL) at room temperature, and reacted at 95 ℃ for 10 hours under nitrogen protection. The reaction solution was cooled to room temperature, 1, 4-dioxane was distilled off, water was added to the system, extraction was performed with dichloromethane, and column chromatography separation was performed to obtain 0.042g of a white solid with a yield of 47.6%.
And step 3: 4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2-methylbenzaldehyde
Reacting (4- (2, 3-dihydrobenzo [ b ]) at room temperature][1,4]Dioxin-6-yl) indolin-1-yl) (3-methyl-4-vinylphenyl) formyl (0.2g, 0.50mmol) was dissolved in 1, 4-dioxane/water (volume ratio 5: 1, 10mL), 2% of OsO was rapidly added4After stirring the aqueous solution (1.1mL) for 5 minutes, sodium periodate (0.43g, 2.0mmol) was added and the reaction was stirred at room temperature for 5 hours. The reaction solution was poured into water, filtered under suction, and dried to obtain 0.19g of off-white solid with a yield of 95.5%.
And 4, step 4: (4- (2, 3-Dihydrobenzo [ b ] [1,4] Dioxin-6-yl) indolin-1-yl) (4- (((2-hydroxyethyl) amino) methyl) -3-methylphenyl) formyl (example 30)
4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2-methylbenzaldehyde (0.07g, 0.18mmol) was dissolved in dry dichloromethane (5mL), glacial acetic acid (0.016g, 0.27mmol) was added thereto, and the mixture was stirred for 10min, ethanolamine (0.055g, 0.90mmol) was added thereto, and the reaction was stirred for 2 hours. Sodium triacetoxyborohydride (0.19g, 0.90mmol) was added to the reaction solution, and the reaction was continued at room temperature for 12 hours. Adding water into the reaction solution, evaporating the organic layer, and carrying out column chromatography to obtain 0.028g of white solid with the yield of 34.4%.
ESI-MS m/z:445.2[M+H]+；
The compounds of examples 31-35 were prepared by reductive amination of 4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2-methylbenzaldehyde as the starting material with an amine compound via sodium cyanoborohydride in a similar manner to the synthesis of example 30.
Example 31: n- (2- ((4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2-methylbenzyl) amino) ethyl) acetamide
ESI-MS m/z:486.2[M+H]+；
Example 32: n- (2- ((4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2-methylbenzyl) amino) ethyl) methanesulfonamide
ESI-MS m/z:522.2[M+H]+；
Example 33: (4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2-methylbenzyl) -D-serine
ESI-MS m/z:489.2[M+H]+；
Example 34: (4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2-methylbenzyl) -D-alanine
ESI-MS m/z:473.2[M+H]+；
Example 35: (S) - (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-yl) (4- ((2- (hydroxymethyl) pyrrolidin-1-yl) methyl) -3-methylphenyl) formyl
ESI-MS m/z:485.2[M+H]+；
Example 36: 3- ((2- (((2-hydroxyethyl) amino) methyl) -5- (4-phenylindoline-1-formyl) phenoxy) methyl) benzonitrile
Step 1: 3- ((2-formyl-5- (4-phenylindoline-1-formyl) phenoxy) methyl) benzonitrile
2-hydroxy-4- (4-phenylindoline-1-formyl) benzaldehyde (0.6g, 1.75mmol), 3- (bromomethyl) benzonitrile (0.41g, 2.1mmol) and cesium carbonate (1.14g, 3.5mmol) were dissolved in DMF (10mL) at room temperature, and the temperature was raised to 75 ℃ for reaction for 1.5 hours. The reaction solution was cooled to room temperature, poured into water, and a white solid precipitated, stirred at room temperature for 20min, filtered to obtain 0.65g of a white solid with a yield of 81.2%.
Step 2: 3- ((2- (((2-hydroxyethyl) amino) methyl) -5- (4-phenylindoline-1-formyl) phenoxy) methyl) benzonitrile (example 36)
3- ((2-formyl-5- (4-phenylindoline-1-formyl) phenoxy) methyl) benzonitrile (0.07g, 0.15mmol) and glacial acetic acid (0.01g, 0.167mmol) were dissolved in dichloromethane (5mL) at room temperature, stirred at room temperature for 0.5 hour, ethanolamine (0.05g, 0.82mmol) was added, reaction was carried out at room temperature for 3 hours, sodium triacetoxyborohydride (0.16g, 0.75mmol) was added, and reaction was carried out at room temperature for 10 hours. The reaction solution was washed with water and brine, concentrated under reduced pressure, and subjected to column chromatography to obtain 0.013g of a white solid with a yield of 16.3%.
ESI-MS m/z:504.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ8.01(d,J＝74.6Hz,2H),7.83(dd,J＝13.5,7.8Hz,2H),7.63(t,J＝7.7Hz,1H),7.48(d,J＝4.1Hz,5H),7.40(dd,J＝8.5,4.2Hz,1H),7.26(s,2H),7.17(d,J＝7.4Hz,1H),7.10(d,J＝6.8Hz,1H),5.28(s,2H),4.53(s,1H),3.92(s,2H),3.83(s,2H),3.51(s,2H),3.11(t,J＝8.0Hz,2H),2.63(t,J＝5.4Hz,2H),1.24(s,1H).
The compound of example 37 was prepared in analogy to the synthesis of example 36, starting from 4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2-methylbenzaldehyde and reductive amination with (S) -piperidine-2-carboxylic acid over sodium cyanoborohydride.
Example 37: (S) -1- (2- ((3-cyanobenzyl) oxy) -4- (4-phenylindoline-1-formyl) benzyl) piperidine-2-carboxylic acid
ESI-MS m/z:572.3[M+H]+；1H NMR(600MHz,DMSO-d6)δ8.02(d,J＝88.8Hz,2H),7.82(dd,J＝13.6,7.5Hz,2H),7.62(t,J＝7.4Hz,1H),7.50(dd,J＝26.4,5.2Hz,5H),7.40(d,J＝3.6Hz,1H),7.28(d,J＝28.8Hz,2H),7.19(d,J＝7.1Hz,1H),7.11(d,J＝4.8Hz,1H),5.28(s,2H),3.94–3.83(m,3H),3.73(d,J＝14.4Hz,1H),3.24(s,1H),3.13–3.08(m,2H),2.95(s,1H),2.32(s,1H),1.81(s,2H),1.52(s,3H),1.42(s,1H).
Example 38: 5- ((2- (((2-hydroxyethyl) amino) methyl) -5- (4-phenylindoline-1-formyl) phenoxy) methyl) pyridine-3-carbonitrile
Step 1: 5- ((2-formyl-5- (4-phenylindoline-1-formyl) phenoxy) methyl) pyridine-3-carbonitrile
2-hydroxy-4- (4-phenylindoline-1-formyl) benzaldehyde (0.6g, 1.75mmol), 5- (chloromethyl) pyridine-3-carbonitrile (0.35g, 2.3mmol) and cesium carbonate (1.14g, 3.5mmol) were dissolved in DMF (10mL) at room temperature, and the temperature was raised to 30 ℃ for reaction for 3 hours. The reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate, and the organic layer was washed with saturated brine, and the solvent was distilled off to obtain 0.58g of a pale yellow solid in a yield of 72.6%.
Step 2: 5- ((2- (((2-hydroxyethyl) amino) methyl) -5- (4-phenylindoline-1-formyl) phenoxy) methyl) pyridine-3-carbonitrile (example 38)
5- ((2-formyl-5- (4-phenylindoline-1-formyl) phenoxy) methyl) pyridine-3-carbonitrile (0.07g, 0.15mmol) was dissolved in DMF (5mL), ethanolamine (0.03g, 0.49mmol) and glacial acetic acid (0.05g, 0.83mmol) were added, and the mixture was reacted at room temperature for 2 hours, followed by addition of sodium cyanoborohydride (0.03g, 0.48mmol) and reaction at room temperature for 10 hours. The reaction solution was poured into water, extracted with ethyl acetate, washed with saturated brine, concentrated under reduced pressure, and subjected to column chromatography to obtain an off-white solid (0.0135 g) with a yield of 17.6%.
ESI-MS m/z:505.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ9.01(d,J＝10.4Hz,2H),8.44(s,1H),7.51–7.46(m,5H),7.40(dd,J＝8.7,4.3Hz,1H),7.30(s,1H),7.22–7.08(m,3H),6.76(t,J＝8.8Hz,1H),5.33(s,2H),4.57(s,1H),3.95(t,J＝7.1Hz,2H),3.86(s,2H),3.51(d,J＝4.8Hz,2H),3.12(t,J＝8.1Hz,2H),2.65(s,2H).
The compounds of examples 39-42 were prepared by reductive amination of 5- ((2-formyl-5- (4-phenylindoline-1-formyl) phenoxy) methyl) pyridine-3-carbonitrile, starting with amine compounds via sodium cyanoborohydride in analogy to the procedure for the preparation of example 38.
Example 39: n- (2- ((2- ((5-cyanopyridin-3-yl) methyleneoxy) -4- (4-phenylindolin-1-formyl) benzyl) amino) ethyl) acetamide
ESI-MS m/z:546.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ9.00(d,J＝11.1Hz,2H),8.44(s,1H),7.83(s,1H),7.48(d,J＝3.7Hz,5H),7.40(d,J＝4.2Hz,1H),7.29(s,2H),7.20(d,J＝7.1Hz,1H),7.11(d,J＝5.4Hz,1H),5.32(s,2H),3.95(s,2H),3.82(s,2H),3.17(d,J＝5.9Hz,2H),3.12(t,J＝7.7Hz,2H),2.61(t,J＝5.5Hz,2H),1.79(s,3H).
Example 40: (2- ((5-cyanopyridin-3-yl) methyleneoxy) -4- (4-phenylindolin-1-formyl) benzyl) -D-alanine
ESI-MS m/z:533.2[M+H]+；
Example 41: (S) -5- ((2- ((2- (hydroxymethyl) pyrrolidin-1-yl) methyl) -5- (4-phenylindoline-1-formyl) phenoxy) methyl) pyridine-3-carbonitrile
ESI-MS m/z:545.3[M+H]+；
Example 42: (2- ((5-cyanopyridin-3-yl) methyleneoxy) -4- (4-phenylindolin-1-formyl) benzyl) -L-proline
ESI-MS m/z:559.2[M+H]+；
Example 43: 4- ((2- (((2-hydroxyethyl) amino) methyl) -5- (4-phenylindoline-1-formyl) phenoxy) methyl) pyridine-2-carbonitrile
Step 1: 4- ((2-formyl-5- (4-phenylindoline-1-formyl) phenoxy) methyl) pyridine-2-carbonitrile
2-hydroxy-4- (4-phenylindoline-1-formyl) benzaldehyde (2g, 5.83mmol), 4- (bromomethyl) pyridine-2-carbonitrile (1.37g, 7mmol), and cesium carbonate (3.8g, 11.66mmol) were dissolved in DMF (15mL) and the temperature was raised to 75 ℃ to react for 1.5 hours. The reaction solution was cooled to room temperature, poured into water, and a white solid precipitated, stirred at room temperature for 1 hour, and filtered by suction to obtain 2.32g of a white solid with a yield of 86.6%.
Step 2: 4- ((2- (((2-hydroxyethyl) amino) methyl) -5- (4-phenylindoline-1-formyl) phenoxy) methyl) pyridine-2-carbonitrile (example 43)
Prepared by a method similar to the synthesis method of the example 38 and by taking 4- ((2-formyl-5- (4-phenylindoline-1-formyl) phenoxy) methyl) pyridine-2-carbonitrile as a raw material and carrying out reductive amination on ethanolamine by sodium cyanoborohydride.
ESI-MS m/z:505.2[M+H]+；
The compounds of examples 44-47 were prepared by reductive amination of 4- ((2-formyl-5- (4-phenylindoline-1-formyl) phenoxy) methyl) pyridine-2-carbonitrile, starting with amine compounds via sodium cyanoborohydride in analogy to the procedure for the preparation of example 38.
Example 44: n- (2- ((2- ((2-cyanopyridin-4-yl) methyleneoxy) -4- (4-phenylindolin-1-formyl) benzyl) amino) ethyl) acetamide
ESI-MS m/z:546.2[M+H]+；
Example 45: (2- ((2-cyanopyridin-4-yl) methyleneoxy) -4- (4-phenylindolin-1-formyl) benzyl) -D-alanine
ESI-MS m/z:533.2[M+H]+；
Example 46: (S) -4- ((2- ((2- (hydroxymethyl) pyrrolidin-1-yl) methyl) -5- (4-phenylindoline-1-formyl) phenoxy) methyl) pyridine-2-carbonitrile
ESI-MS m/z:545.3[M+H]+；
Example 47: (2- ((2-cyanopyridin-4-yl) methyleneoxy) -4- (4-phenylindolin-1-formyl) benzyl) -L-proline
ESI-MS m/z:559.2[M+H]+；
Example 48: 3- ((5- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2- (((2-hydroxyethyl) amino) methyl) phenoxy) methyl) benzonitrile
Step 1: 4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2-hydroxybenzaldehyde
4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indoline (0.57g, 2.24mmol) and 4-formyl-3-hydroxybenzoic acid (0.38g, 2.29mmol) were dissolved in anhydrous dichloromethane (10mL) at room temperature, and after stirring well, EDCI (0.51g, 2.69mmol) was added and the reaction was carried out at room temperature for 5 hours. The reaction mixture was washed with water and brine, and the solvent was distilled off to obtain 0.73g of a pale yellow solid with a yield of 80.7%.
Step 2: 3- ((5- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2-formylphenoxy) methyl) benzonitrile
4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2-hydroxybenzaldehyde (0.39g, 0.97mmol), 3- (bromomethyl) benzonitrile (0.23g, 1.16mmol), and cesium carbonate (0.63g, 1.94mmol) were dissolved in anhydrous DMF (5mL) at room temperature, and the temperature was raised to 75 ℃ for reaction for 2 hours. The reaction solution was cooled to room temperature, poured into cold water, stirred for 20 minutes, and filtered by suction to obtain 0.44g of a white solid with a yield of 88.4%.
And step 3: 3- ((5- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2- (((2-hydroxyethyl) amino) methyl) phenoxy) methyl) benzonitrile (example 48)
Prepared in a similar manner to example 36, from 3- ((5- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2-formylphenoxy) methyl) benzonitrile, and ethanolamine by reductive amination with sodium triacetoxyborohydride.
ESI-MS m/z:562.2[M+H]+；
Example 49: 5- ((5- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2- (((2-hydroxyethyl) amino) methyl) phenoxy) methyl) pyridine-3-carbonitrile
Step 1: 5- ((5- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2-formylphenoxy) methyl) pyridine-3-carbonitrile
4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2-hydroxybenzaldehyde (2g, 4.99mmol), 5- (chloromethyl) pyridine-3-carbonitrile (0.99g, 6.48mmol), and cesium carbonate (3.25g, 9.98mmol) were dissolved in DMF (20mL) at room temperature, and the temperature was raised to 30 ℃ for reaction for 5 hours. The reaction mixture was poured into water, extracted with dichloromethane, and the organic layer was washed with saturated brine, and the solvent was distilled off to obtain 1.97g of an off-white solid with a yield of 76.5%.
Step 2: 5- ((5- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2- (((2-hydroxyethyl) amino) methyl) phenoxy) methyl) pyridine-3-carbonitrile (example 49)
5- ((5- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2-formylphenoxy) methyl) pyridine-3-carbonitrile (0.078g, 0.15mmol) was dissolved in DMF (5mL), ethanolamine (0.03g, 0.49mmol) and glacial acetic acid (0.05g, 0.83mmol) were added thereto, and the mixture was reacted at room temperature for 1 hour, followed by addition of sodium cyanoborohydride (0.03g, 0.48mmol) and reaction at room temperature for 15 hours. The reaction solution was poured into water, extracted with dichloromethane, washed with saturated brine, concentrated under reduced pressure, and subjected to column chromatography to obtain 0.0188g of a white solid with a yield of 22.3%.
ESI-MS m/z:563.2[M+H]+；
The compounds of examples 50-53 were prepared by reductive amination of 5- ((5- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2-formylphenoxy) methyl) pyridine-3-carbonitrile, starting with amine compounds via sodium cyanoborohydride in a manner analogous to the synthesis of example 49.
Example 50: n- (2- ((2- ((5-cyanopyridin-3-yl) methyleneoxy) -4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) benzyl) amino) ethyl) acetamide
ESI-MS m/z:604.3[M+H]+；
Example 51: n- (2- ((2- ((5-cyanopyridin-3-yl) methyleneoxy) -4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) benzyl) amino) ethyl) methanesulfonamide
ESI-MS m/z:640.2[M+H]+；
Example 52: (S) -5- ((5- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2- ((2- (hydroxymethyl) pyrrolidin-1-yl) methyl) phenoxy) methyl) pyridine-3-carbonitrile
ESI-MS m/z:603.3[M+H]+；
Example 53: (2- ((5-cyanopyridin-3-yl) methyleneoxy) -4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) benzyl) -L-proline
ESI-MS m/z:617.2[M+H]+；
Example 54: 4- ((5- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2- (((2-hydroxyethyl) amino) methyl) phenoxy) methyl) pyridine-2-carbonitrile
Step 1: 4- ((5- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2-formylphenoxy) methyl) pyridine-2-carbonitrile
4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2-hydroxybenzaldehyde (0.3g, 0.75mmol), 4- (bromomethyl) -2-cyanopyridine (0.19g, 0.97mmol), and cesium carbonate (0.49g, 1.50mmol) were dissolved in anhydrous DMF (3mL) at room temperature and reacted for 2 hours at 30 ℃. The reaction solution was poured into cold water, stirred for 20 minutes, extracted with ethyl acetate 3 times, washed with saturated brine 1 time, and the solvent was evaporated to dryness to give a pale yellow solid 0.31g with a yield of 79.6%.
Step 2: 4- ((5- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2- (((2-hydroxyethyl) amino) methyl) phenoxy) methyl) pyridine-2-carbonitrile (example 54)
4- ((5- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2-formylphenoxy) methyl) pyridine-2-carbonitrile (0.08g, 0.15mmol) was dissolved in dry dichloromethane (5mL), glacial acetic acid (0.02g, 0.23mmol) was added thereto, and the mixture was stirred for 10 minutes, ethanolamine (0.047g, 0.77mmol) was added thereto, and the reaction was stirred for 2 hours. Sodium triacetoxyborohydride (0.16g, 0.77mmol) was added to the reaction solution, and the reaction was continued at room temperature for 15 hours. Adding water into the reaction solution, evaporating the organic layer, and carrying out column chromatography to obtain 0.029g of white solid with the yield of 33.5%.
ESI-MS m/z:563.2[M+H]+；
The compounds of examples 55-59 were prepared by reductive amination of 4- ((5- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2-formylphenoxy) methyl) pyridine-2-carbonitrile, starting with amine compounds via sodium cyanoborohydride in a manner analogous to the synthesis of example 54.
Example 55: n- (2- ((2- ((2-cyanopyridin-4-yl) methyleneoxy) -4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) benzyl) amino) ethyl) acetamide
ESI-MS m/z:604.3[M+H]+；
Example 56: (2- ((2-cyanopyridin-4-yl) methyleneoxy) -4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) benzyl) -D-alanine
ESI-MS m/z:591.2[M+H]+；
Example 57: (S) -4- ((5- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) -2- ((2- (hydroxymethyl) pyrrolidin-1-yl) methyl) phenoxy) methyl) pyridine-2-carbonitrile
ESI-MS m/z:603.3[M+H]+；
Example 58: (2- ((2-cyanopyridin-4-yl) methyleneoxy) -4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-formyl) benzyl) -L-proline
ESI-MS m/z:617.2[M+H]+；
Example 59: (2S,4S) -1- (2- ((2-cyanopyridin-4-yl) methyleneoxy) -4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indoline-1-formyl) benzyl) -4-hydroxypyrrolidine-2-carboxylic acid
ESI-MS m/z:633.2[M+H]+；
Example 60: n- (2- ((2- ((2-cyanopyridin-4-yl) methyleneoxy) -4- (4- (3, 4-dimethoxyphenyl) indoline-1-formyl) benzyl) amino) ethyl) acetamide
Step 1: 4- (3, 4-Dimethoxyphenyl) indoline
According to the preparation method of the 4-phenylindoline, the compound is prepared by replacing phenylboronic acid with 3, 4-dimethoxyphenylboronic acid.
Step 2: 4- (4- (3, 4-dimethoxyphenyl) indoline-1-formyl) -2-hydroxybenzaldehyde
According to the preparation method of 2-hydroxy-4- (4-phenylindoline-1-formyl) benzaldehyde, 4- (3, 4-dimethoxyphenyl) indoline is used for replacing 4-phenylindoline to prepare the compound.
And step 3: 4- ((5- (4- (3, 4-dimethoxyphenyl) indoline-1-formyl) -2-formylphenoxy) methyl) pyridine-2-carbonitrile
According to the method for producing 4- ((5- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indoline-1-formyl) -2-formylphenoxy) methyl) pyridine-2-carbonitrile, 4- (4- (3, 4-dimethoxyphenyl) indoline-1-formyl) -2-hydroxybenzaldehyde was used instead of 4- (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indoline-1-formyl) -2-hydroxybenzaldehyde.
And 4, step 4: n- (2- ((2- ((2-cyanopyridin-4-yl) methyleneoxy) -4- (4- (3, 4-dimethoxyphenyl) indoline-1-formyl) benzyl) amino) ethyl) acetamide (example 60)
The compound of example 60 was prepared in analogy to the synthesis of example 54, starting from 4- ((5- (4- (3, 4-dimethoxyphenyl) indoline-1-formyl) -2-formylphenoxy) methyl) pyridine-2-carbonitrile and reductive amination with N- (2-aminoethyl) acetamide via sodium triacetoxyborohydride.
ESI-MS m/z:606.3[M+H]+；
Similar to the synthesis process in example 60, substituted phenylboronic acid as material is coupled with 4-bromoindoline Suzuki, condensed with 4-formyl-3-hydroxybenzoic acid, nucleophilic substituted with 4- (bromomethyl) pyridine-2-carbonitrile, and reductively aminated with N- (2-aminoethyl) acetamide via sodium triacetoxyborohydride to obtain the compounds of examples 61-63.
Example 61: n- (2- ((2- ((2-cyanopyridin-4-yl) methyleneoxy) -4- (4- (3-methoxy-4-methylphenyl) indoline-1-formyl) benzyl) amino) ethyl) acetamide
ESI-MS m/z:590.3[M+H]+；
Example 62: n- (2- ((4- (4- (4-chlorophenyl) indoline-1-formyl) -2- ((2-cyanopyridin-4-yl) methyleneoxy) benzyl) amino) ethyl) acetamide
ESI-MS m/z:580.3[M+H]+；
Example 63: n- (2- ((2- ((2-cyanopyridin-4-yl) methyleneoxy) -4- (4- (4-fluorophenyl) indoline-1-formyl) benzyl) amino) ethyl) acetamide
ESI-MS m/z:564.2[M+H]+；
Study of the biological Activity of the Compound of the present invention
Homogeneous Time-Resolved Fluorescence (HTRF) assays were used to examine the ability of the compounds of the invention to inhibit the PD-1/PD-L1 interaction. The Detection kit is purchased from CisBio (CAT #63ADK000 CPACPEG) and comprises Anti-Tag 1-captate, Anti-Tag2-XL665/d2, Tag1-PD-L1, Tag2-PD-1, Dilution Buffer, Detection Buffer and other reagents required by experiments.
The experimental steps are as follows: PD-1 recombinant protein and PD-L1 recombinant protein were diluted to 500nM and 50nM, respectively, with Dilution Buffer. 4mM DMSO-solubilized small molecule compound was diluted 20-fold to 200uM with Dilution Buffer. Four-fold gradient Dilution with Dilution Buffer containing 5% DMSO. Concurrent Dilution of 600uM with Dilution Buffer the DMSO-solubilized PD-1/PD-L1 inhibitor was 20-fold to 30uM diluted in a four-fold gradient with Dilution Buffer containing 5% DMSO. To 384 wells, 2uL of diluted test compound, 4uL of diluted PD-1, and 4uL of diluted PDL-1 were added in that order. Mixing, and standing at room temperature for 15 min. Diluting anti-Tag1-Eu with Detection buffer3+(1:25) and anti-Tag2-XL665(1: 100). The diluted detection reagent was then mixed in equal volume, and 10. mu.L of antibody mixture was added to each reaction well. And (5) sealing the membrane and incubating for 2h at room temperature. Fluorescence signals (320nm stimulation, 665nm, 615nm emission) were detected with an envision (perkinelmer) instrument. 8-12 concentrations were measured per compound.
The results of the compounds' activity in inhibiting the PD-1/PD-L1 interaction are shown in Table 1.
TABLE 1 Activity Range or IC for the inhibition of the PD-1/PD-L1 interaction by the Compounds of the invention50. The ranges are as follows: a-1 nM-100 nM; b-100.01 nM-1 μ M; c ═ 1.01 μ M to 20 μ M.
HTRF test results indicate that the example compounds significantly inhibited PD-1/PD-L1 interaction at the molecular level. The compounds are expected to show positive effects in the treatment of diseases associated with the PD-1/PD-L1 interaction.
Claims (18)
1. Indoline compounds of general formula I and pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
R1selected from unsubstituted or substituted by 1-3R6Substituted phenyl, or
R6Independently selected from halogen, (C)1-C4) Alkyl, (C)1-C4) An alkoxy group;
R2、R3each independently selected from hydrogen, halogenHydroxy, (C)1-C4) Alkyl, (C)1-C4) Alkoxy radical,
R9Independently selected from cyano, methanesulfonyl, acetamido, carbamoyl;
R4、R5independently selected from hydrogen, (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, tetrahydropyran-4-yl; said (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, tetrahydropyran-4-yl may optionally be substituted with 1-3R7Substitution; r4、R5Not hydrogen at the same time;
or R4、R5And the nitrogen atom to which they are attached form a 3-to 7-membered nitrogen-containing heterocyclic ring; the nitrogen-containing heterocycle contains 1-3 heteroatoms of N, O or S; the nitrogen-containing heterocycle may be optionally substituted with 1 to 3R8Substitution;
R7independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino and (C)1-C4) Alkyl, hydroxy (C)1-C4) Alkyl, (C)1-C4) Alkoxy (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxy formyl radical(C1-C4) Alkyl, (C)1-C4) An acyl group;
R8independently selected from hydrogen, hydroxy, carboxy, amino, carbamoyl, (C)1-C4) Alkyl, (C)1-C4) Alkoxy group, (C)1-C4) Alcoxyl formyl group and hydroxyl group (C)1-C4) An alkyl group.
2. Indoline compounds of the general formula I according to claim 1 and pharmaceutically acceptable salts thereof,
R4、R5independently selected from hydrogen, (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, tetrahydropyran-4-yl; said (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, tetrahydropyran-4-yl may optionally be substituted with 1-3R7Substitution; r4、R5Not hydrogen at the same time;
or R4、R5And together with the nitrogen atom to which they are attached form a 5-6 membered nitrogen containing heterocyclic ring.
3. Indoline compounds of the general formula I and pharmaceutically acceptable salts thereof according to claim 1, wherein the nitrogen-containing heterocycle is a 5-6 membered heterocycle containing one nitrogen atom.
4. Indoline compounds of the general formula I according to any one of claims 1 to 3 and pharmaceutically acceptable salts thereof,
R1selected from phenyl which is unsubstituted or substituted by 1 to 3 halogen, methyl, methoxy, or
5. Indoline compounds of the general formula I according to any one of claims 1 to 3 and pharmaceutically acceptable salts thereof,
R2、R3each independently selected from hydrogen, halogen, hydroxy, methyl, ethyl, methoxy,
6. Indoline compounds of the general formula I according to claim 4 and pharmaceutically acceptable salts thereof,
R2、R3each independently selected from hydrogen, halogen, hydroxy, methyl, ethyl, methoxy,
7. Indoline compounds of the general formula I according to any one of claims 1-3, 6 and pharmaceutically acceptable salts thereof,
R2、R3one of them is selected from
And the other is selected from hydrogen, halogen, hydroxyl, methyl, ethyl and methoxy.
8. Indoline compounds of the general formula I according to claim 4 and pharmaceutically acceptable salts thereof,
R2、R3one of them is selected from
And the other is selected from hydrogen, halogen, hydroxyl, methyl, ethyl and methoxy.
9. Indoline compounds of the general formula I according to claim 5 and pharmaceutically acceptable salts thereof,
R2、R3one of them is selected from
And the other is selected from hydrogen, halogen, hydroxyl, methyl, ethyl and methoxy.
10. The compound of any one of claims 1-3, 6, 8, 9, and pharmaceutically acceptable salts thereof, wherein,
11. the compound of claim 4, and pharmaceutically acceptable salts thereof, wherein,
12. the compound of claim 5, and pharmaceutically acceptable salts thereof, wherein,
13. the compound of claim 7, and pharmaceutically acceptable salts thereof, wherein,
14. a compound as described below and pharmaceutically acceptable salts thereof:
15. a pharmaceutical composition comprising as an active ingredient a compound according to any one of claims 1 to 14 and pharmaceutically acceptable salts, carriers or excipients thereof.
16. Use of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, for the manufacture of a medicament for the prevention and/or treatment of diseases associated with the PD-1/PD-L1 signalling pathway.
17. The use according to claim 16, wherein the disease associated with the PD-1/PD-L1 signaling pathway is selected from the group consisting of cancer, infectious disease, and autoimmune disease.
18. The use according to claim 17, wherein the cancer is selected from the group consisting of lung cancer, skin cancer, hematological tumors, glioma, digestive system tumors, breast cancer, lymphoma, nervous system tumors, melanoma; the infectious diseases are selected from bacterial infection and viral infection; the autoimmune disease is selected from organ-specific, systemic autoimmune diseases; wherein the organ-specific autoimmune disease comprises chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, ulcerative colitis and acute idiopathic polyneuritis, and the systemic autoimmune disease comprises rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis and autoimmune hemolytic anemia.
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| WO2018200571A1 (en) | 2017-04-25 | 2018-11-01 | Arbutus Biopharma Corporation | Substituted 2,3-dihydro-1h-indene analogs and methods using same |
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| KR20220009420A (en) | 2019-05-15 | 2022-01-24 | 케모센트릭스, 인크. | Triaryl Compounds for Treatment of PD-L1 Disease |
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| CN116745301A (en) * | 2021-02-08 | 2023-09-12 | 南京明德新药研发有限公司 | Indolines |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566290A (en) * | 2014-10-30 | 2016-05-11 | 康朴生物医药技术（上海）有限公司 | Isoindoline derivative and intermediate, preparation method, pharmaceutical composition and application thereof |
| WO2017070089A1 (en) * | 2015-10-19 | 2017-04-27 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
| CN107849013A (en) * | 2015-07-14 | 2018-03-27 | 特殊治疗有限公司 | It is used for the cyanopyrrole alkanes for the treatment of cancer as DUB inhibitor |
| CN108699035A (en) * | 2016-02-18 | 2018-10-23 | 特殊治疗有限公司 | Noval chemical compound |
| WO2018195321A1 (en) * | 2017-04-20 | 2018-10-25 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
-
2019
- 2019-02-01 CN CN201910104141.0A patent/CN109776377B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566290A (en) * | 2014-10-30 | 2016-05-11 | 康朴生物医药技术（上海）有限公司 | Isoindoline derivative and intermediate, preparation method, pharmaceutical composition and application thereof |
| CN107849013A (en) * | 2015-07-14 | 2018-03-27 | 特殊治疗有限公司 | It is used for the cyanopyrrole alkanes for the treatment of cancer as DUB inhibitor |
| WO2017070089A1 (en) * | 2015-10-19 | 2017-04-27 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
| CN108699035A (en) * | 2016-02-18 | 2018-10-23 | 特殊治疗有限公司 | Noval chemical compound |
| WO2018195321A1 (en) * | 2017-04-20 | 2018-10-25 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
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