CN116903554A - VISTA and PD-1/PD-L1 double-target small molecule inhibitor and preparation method and application thereof - Google Patents

VISTA and PD-1/PD-L1 double-target small molecule inhibitor and preparation method and application thereof Download PDF

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CN116903554A
CN116903554A CN202311179753.9A CN202311179753A CN116903554A CN 116903554 A CN116903554 A CN 116903554A CN 202311179753 A CN202311179753 A CN 202311179753A CN 116903554 A CN116903554 A CN 116903554A
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蔡适
王天雨
刘春河
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Beijing Kexiang Zhongsheng Pharmaceutical Technology Co ltd
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Abstract

The application discloses a compound shown in a formula I, or pharmaceutically acceptable salts, isomers, metabolites, prodrugs and solubles thereofDosage or hydrate, pharmaceutical compositions and uses thereof. The deuterated isoquinoline-aminopyrimidine compound shown in the formula I has obvious effect on blocking the VISTA and PD-1/PD-L1 signal paths, can effectively treat and relieve diseases such as cancers, is simple to prepare as a small molecule inhibitor, and is convenient for industrial production.

Description

VISTA and PD-1/PD-L1 double-target small molecule inhibitor and preparation method and application thereof
Technical Field
The application relates to the technical field of chemical medicines, in particular to a compound for blocking VISTA and PD-1/PD-L1 signal paths, and a preparation method and application thereof.
Background
Malignant tumor is one of the most complex and difficult diseases in the world today, and seriously threatens human health and life. The tumor treatment modes mainly comprise operation, radiotherapy, chemotherapy, targeted therapy and the like. Tumor immunotherapy refers to a therapeutic method for inhibiting and killing tumor cells by stimulating the immune system of the body to enhance the anti-tumor immune effect. With the comprehensive development and cross penetration of oncology, immunology and molecular biology, intensive research on tumor pathogenesis has achieved various achievements in immunotherapy, bringing new hopes for tumor treatment.
Immune checkpoint inhibitors in tumor immunotherapy are currently the immunotherapeutic agents that compare the heat of fire. Tumor cells can inhibit the activity of T cells of immune cells by up-regulating the expression of immune checkpoint receptors, thereby completing the immune escape of the tumor cells. The immune checkpoint inhibitor can inhibit immune checkpoint passage, relieve the inhibition of immune cell T cells, activate the immune killing of organism to tumor cells, and realize tumor treatment effect. Presently, immune checkpoints have been found to be CTLA-4 (cytotoxic T lymphocyte-associated antigen-4), PD-1 (Programmed cell death 1) and TIM3 (T cell membrane 3) and the like (see Drew M.Pardol, nature Review Cancer, 2012, 12, 252).
Programmed death receptor 1 (PD-1) is a type I transmembrane protein of 288 amino acids consisting of an immunoglobulin (Ig) superfamily domain comprising an immunoreceptor tyrosine motif inhibitory motif (ITIM) and immunoreceptor tyrosine opening Guan Jixu (ITSM), a stem of about 20 amino acids, a transmembrane domain and an intracellular domain of about 95 amino acid residues. PD-1 is expressed primarily on T cells, B cells, natural killer T cells, activated monocytes and dendritic cells. PD-1 has two types of natural ligands: PD-L1 and PD-L2; can interact with PD-1, transmit inhibitory signals, and regulate the balance between T cell activation, tolerance and immunopathology. However, tumor cells can express PD-L1 and act with PD-1 on T cells, so that the immunocompetence of the T cells is inhibited and immune escape occurs. Therefore, the inhibition of the interaction between PD-1 and PD-L1 can activate the anti-tumor immune response of the organism, thereby achieving the effect of killing tumors. Currently, a plurality of monoclonal antibody drugs targeting PD-1/PD-L1 signal paths are approved to be marketed and used for treating tumor patients; in addition, small molecule inhibitors of PD-1/PD-L1 are also currently under active development, with the fastest progression also entering phase II clinical. However, with the intensive treatment of clinical tumor patients, studies have found that inhibition of the PD-1/PD-L1 pathway promotes increased expression of other immune checkpoints, such as VISTA, TIM3, etc., and thus drug toleration occurs.
T cell activation inhibitor immunoglobulin variable region domains (VISTA) are a class of immune checkpoints that are expressed primarily in hematopoietic tissues. In addition, VISTA is also highly expressed in bone marrow cells, neural cells, and neutrophils. Unlike other immune checkpoints, which induce expression after immune response activation, VISTA is stably expressed during immune cell homeostasis. Various studies have shown that VISTA also has an inhibitory effect on the immune system. Thus, inhibition of VISTA signaling pathway can also restore the anti-tumor immune activity of the body.
In order to better play the anti-tumor immunity of the organism, the research of the double-target small molecule inhibitor is an effective method. To date, no small molecule inhibitors that target both the PD1/PD-L1 and VISTA signaling pathways have been marketed. Therefore, the development of a novel double-target small molecule inhibitor with good anti-tumor activity has great significance.
Disclosure of Invention
The application aims to: aiming at the current situation that the dual-target inhibitor drugs without VISTA and PD-1/PD-L1 signal paths in the existing market are marketed, the application provides a small molecular compound for simultaneously targeting the VISTA and the PD-1/PD-L1 signal paths, and a preparation method and application thereof.
The technical scheme is as follows: in order to achieve the above object, the present application discloses a compound represented by the following formula I, a pharmaceutically acceptable salt thereof:
wherein X is 1 Independently CH 2 O, NH or S;
R 1 independently an aldehyde group, a hydroxyl group, a substituted or unsubstituted amino group, or an amino acid;
R 2 independently is hydrogen, deuterium, halogen, cyano, morpholinyl, tetrahydropyranyl, substituted or unsubstituted hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted pyrrolidone group, substituted or unsubstituted piperidyl, substituted or unsubstituted piperazinyl;
R 3 、R 4 each hydrogen, deuterium, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy;
m is 0, 1, 2 or 3;
n is 0, 1, 2,3, 4 or 5.
Further, the present application discloses a compound represented by the following formula I, each R 1 Wherein the substituent in the substituted amino group is one or more of the following groups: c (C) 1-4 Alkyl, C 1-4 Amide group, C 1-4 Ester group, C 1-4 Carboxyl, C 1-4 A hydroxyl group; wherein said C 1-4 Alkyl, C 1-4 Amide group, C 1-4 Ester group, C 1-4 Carboxyl, C 1-4 The hydroxyl group may optionally be substituted with one or more of the following substituents: hydroxy, carboxyl, cyano, amino, C 3-6 Cycloalkyl, C 6-10 Aryl, C 6-10 Heterocyclyl, C 2-4 Alkenyl, C 2-4 Alkynyl; when there are plural substituents, the substituents may be the same or different.
Further, the present application discloses a compound represented by the following formula I, each R 2 Wherein said substituted hydroxy, substituted amino,Substituted alkyl, substituted alkenyl, substituted alkynyl, substituted alkoxy, substituted C 3 -C 6 The substituents in cycloalkyl, substituted pyrrolidinonyl, substituted piperidinyl and substituted piperazinyl may be one or more of the following: halogen, cyano, hydroxy, trifluoromethyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Carboxyl, C 1-4 Ester group or C 1-4 An amide group; wherein said C 1-4 Alkyl, C 1-4 Amide group, C 1-4 Ester group, C 1-4 Carboxyl, C 1-4 The hydroxyl group may optionally be substituted with one or more of the following substituents: hydroxy, carboxyl, cyano, amino, C 3-6 Cycloalkyl, C 6-10 Aryl, C 6-10 Heterocyclyl, C 2-4 Alkenyl, C 2-4 Alkynyl; when there are plural substituents, the substituents may be the same or different.
The compound shown in the formula I is specifically selected from the following compounds:
。
further, the above specific compounds also include pharmaceutically acceptable salts, racemates, optical isomers or solvent compounds thereof.
The preparation method of the compound comprises the steps that when X is O, NH, S and R 1 When m is 1, which is a substituted or unsubstituted amino group, the synthetic route of the compound is as follows:
wherein R is 2 , R 3 , R 4 N is as defined in formula I, and the synthesis steps are as follows:
(1) The compound II and the compound III are subjected to condensation ring closure reaction to obtain a compound IV;
(2) Reacting the compound IV with the pinacol biborate to obtain a compound V;
(3) Carrying out nucleophilic substitution reaction on the compound VI to obtain a compound VII;
(4) Carrying out Suzuki coupling reaction on the compound V and the compound VII to obtain a compound VIII;
(5) The compound VIII is subjected to reduction reaction to obtain the compound IX.
(6) The compound IX is subjected to oxidation reaction to obtain a compound X.
(7) The compound X is subjected to reductive amination reaction to obtain a compound XI.
A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds having the structure depicted in formula I or a pharmaceutically acceptable salt, racemate, optical isomer or solvent compound thereof as an active ingredient and a pharmaceutically acceptable carrier.
The pharmaceutical composition is in the form of capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalant, ointment, suppository or patch.
The application of the compound with the structure shown in the formula I in preparing an immune checkpoint inhibitor, an inhibitor with VISTA and PD-1/PD-L1 signal path inhibition activity, an anti-tumor drug and an anti-infection drug.
The application of the pharmaceutical composition in preparing inhibitors serving as immune checkpoint inhibitors, inhibitors with VISTA and PD-1/PD-L1 signal path inhibition activities, anti-tumor drugs and anti-infection drugs.
The beneficial effects are that: the compound disclosed by the application is novel in structure, can be orally administered, has an obvious effect on blocking the VISTA and PD-1/PD-L1 signal paths, can effectively treat and relieve diseases such as cancers, is simple to prepare as a small molecule inhibitor, and is convenient for industrial production.
Detailed Description
The technical solutions of the present application will be clearly and completely described below in connection with specific embodiments, and it is obvious that the described embodiments are only some embodiments of the present application, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application. In addition, the raw materials related to the application are common commercial products unless otherwise specified.
Example 1 preparation of Compound 1
The synthetic route is as follows:
synthesis of Compound I-2
Raw material I-1 (5 g, 26.59 mmol) and methyl 3-carbaldehyde benzoate (4.54 g, 27.66 mmol) were dissolved in absolute ethanol (40 mL), reflux reacted at 80 ℃ in an oil bath for 3 h, after which the reaction solution was cooled to room temperature, the solvent was concentrated to dryness, and then dissolved with absolute dichloromethane (40 mL), after which 6.04g of 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ) was added, and reacted at room temperature under nitrogen protection for 1h, tlc detected complete reaction of raw material, extracted with ethyl acetate, washed with saturated sodium thiosulfate solution and saturated sodium bicarbonate solution, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to sand, purified by column chromatography (petroleum ether: ethyl acetate=20:1) to give compound 2 (7.2 g, 82%).
Synthesis of Compound I-3
Compound I-2 (2 g, 6.02 mmol), pinacol diboronate (2.29 g, 9.03 mmol), 1' -bis-diphenylphosphino ferrocene palladium dichloride (220 mg, 0.301 mmol), potassium acetate (1.77 g, 18.06 mmol) were dissolved in 1, 4-dioxane (20 mL), protected with a nitrogen balloon and stirred for 12h at 80℃in an oil bath. TLC detection, complete reaction of the starting material, filtration through celite, extraction with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate to give sand, purification by column chromatography (petroleum ether: ethyl acetate=20:1) gave compound 3 (1.5 g, 71%).
Synthesis of Compound I-4
M-bromophenol (2 g, 11.56 mmol) was dissolved in acetonitrile (20 mL), 1-bromo-3-chloropropane (2.18 g, 13.87 mmol) and potassium carbonate (2.4 g, 17.34 mmol) were added, and stirred for 18h under oil bath 55 ℃. TLC monitoring, starting material was complete. Extraction with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate to give sand, and purifying by column chromatography (petroleum ether) to give compound 4 (2.5 g, 87%).
Synthesis of Compound I-5
Compound I-4 (1 g, 4.01 mmol), compound 3 (1.82 g, 4.81 mmol), 1' -bis-diphenylphosphino ferrocene palladium dichloride (147 mg, 0.2 mmol), potassium carbonate (1.11 g, 8.02 mmol) were dissolved in 1, 4-dioxane (15 mL) and water (3 mL), protected with a nitrogen balloon, and stirred for 12h under 80℃in an oil bath. TLC detection, complete reaction of raw materials, filtration through celite, extraction through ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate into sand, purification by column chromatography (petroleum ether: ethyl acetate=20:1) gave compound 3 (1.3 g, 77%).
Synthesis of Compound I-6
Compound I-5 (800 mg, 1.90 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (216 mg, 5.69 mmol) was added in portions under ice-bath conditions and reacted at 0℃for 1h. TLC monitoring, starting material was complete. The reaction was quenched by dropwise addition of methanol, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give sand, which was purified by column chromatography (petroleum ether: ethyl acetate=2:1) to give compound 6 (670 mg, 90%).
Synthesis of Compound I-7
Compound I-6 (600 mg, 1.52 mmol) was dissolved in 10mL of dichloromethane, sodium bicarbonate (256 mg, 3.05 mmol) and dessert-Martin reagent (969 mg, 2.29 mmol) were added under ice-bath conditions, the reaction was allowed to proceed to room temperature for 1h after which time the TLC was monitored, quenched by the addition of saturated sodium thiosulfate solution and saturated sodium bicarbonate solution, extracted with dichloromethane, washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated to give a sand, and purified by column chromatography (petroleum ether: ethyl acetate=4:1) to give compound 7 (580 mg, 97%).
Synthesis of Compound I-8
Compound I-7 (100 mg, 0.255 mmol) was dissolved in 3mL of N, N-dimethylformamide, morpholine (44 mg, 0.51 mmol), potassium carbonate (71 mg, 0.51 mmol) and potassium iodide (8 mg, 0.051 mmol) were added in this order, stirred under an oil bath at 80℃for 12h, after completion of the TLC monitoring reaction, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give sand, which was purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give compound 7 (86 mg, 76%).
Synthesis of Compound 1
Compound I-7 (60 mg) and ethanolamine (17 mg) were dissolved with methanol (2 mL) and methylene chloride (2 mL), 1 drop of glacial acetic acid was added, stirred at room temperature for 1h, then sodium cyanoborohydride (26 mg) was added, stirring at room temperature was continued for 12h, tlc was continued to monitor the completion of the reaction, washing with saturated sodium bicarbonate solution, extraction with methylene chloride, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate to give sand, and column chromatography (methylene chloride: methanol=20:1) gave compound JC-1 (56 mg, 85%). 1 H NMR (400 MHz, Chloroform-d) δ 8.23 (s, 1H), 8.14 (d, J = 7.0 Hz, 1H), 7.82 – 7.72 (m, 2H), 7.59 (d, J = 8.3 Hz, 1H), 7.49 (d, J = 7.8 Hz, 2H), 7.37 (t, J = 7.8 Hz, 1H), 7.24 – 7.15 (m, 2H), 6.96 – 6.88 (m, 1H), 4.10 (t, J = 6.3 Hz, 2H), 3.92 (s, 2H), 3.72 (q, J = 6.4, 5.7 Hz, 6H), 2.85 (t, J = 5.1 Hz, 2H), 2.55 (t, J = 7.3 Hz, 4H), 2.48 (t, J = 4.7 Hz, 2H), 2.01 (p, J = 6.5 Hz, 2H)；MS(ESI, m/z): 488.6 [M+H] + 。
Example 2 preparation of Compound 2
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.26 – 8.19 (m, 1H), 8.17 – 8.08 (m, 1H), 7.89 – 7.82 (m, 1H), 7.74 (t, J = 8.2 Hz, 1H), 7.68 – 7.50 (m, 3H), 7.41 – 7.30 (m, 1H), 7.27 – 7.14 (m, 2H), 6.97 – 6.87 (m, 1H), 4.38 (dp, J = 8.7, 3.1 Hz, 1H), 4.09 (t, J = 6.1 Hz, 2H), 3.92 (d, J = 5.5 Hz, 2H), 3.71 (t, J = 5.6 Hz, 2H), 2.98 – 2.56 (m, 8H), 2.22 – 2.09 (m, 1H), 2.09 – 1.97 (m, 2H), 1.76 (dddd, J = 13.1, 8.0, 5.3, 2.9 Hz, 1H)；MS(ESI, m/z): 488.4 [M+H] + 。
Example 3 preparation of Compound 3
The synthesis method is described in example 1. 1 H NMR (400 MHz, Chloroform-d) δ 8.23 (d, J = 1.9 Hz, 1H), 8.14 (dt, J = 6.9, 1.9 Hz, 1H), 7.81 – 7.71 (m, 2H), 7.58 (dd, J = 8.3, 1.7 Hz, 1H), 7.54 – 7.46 (m, 2H), 7.36 (t, J = 7.9 Hz, 1H), 7.23 – 7.11 (m, 2H), 6.90 (dd, J = 8.2, 2.5 Hz, 1H), 4.08 (t, J = 6.2 Hz, 2H), 3.92 (s, 2H), 3.72 (q, J = 5.2, 4.6 Hz, 3H), 2.84 (dt, J = 8.9, 4.8 Hz, 4H), 2.72 (s, 3H), 2.58 (t, J = 7.4 Hz, 2H), 2.23 (t, J = 10.1 Hz, 2H), 2.09 – 1.90 (m, 4H), 1.63 (dtd, J = 13.0, 9.2, 3.6 Hz, 2H)；MS(ESI, m/z): 502.8 [M+H] + 。
Example 4 preparation of Compound 4
The synthesis method is described in example 1. 1 H NMR (400 MHz, Chloroform-d) δ 8.25 (d, J = 1.7 Hz, 1H), 8.16 (dt, J = 7.2, 1.8 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.57 – 7.46 (m, 3H), 7.31 (dd, J = 8.1, 1.6 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 6.90 (t, J = 8.4 Hz, 2H), 4.09 (t, J = 6.1 Hz, 2H), 3.94 (s, 2H), 3.73 (dt, J = 10.3, 4.9 Hz, 6H), 2.91 – 2.83 (m, 2H), 2.64 – 2.54 (m, 4H), 2.49 (t, J = 4.6 Hz, 4H), 2.16 (s, 3H), 2.10 – 1.98 (m, 2H)；MS(ESI, m/z): 502.5 [M+H] + 。
Example 5 preparation of Compound 5
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.30 (d, J = 7.1 Hz, 1H), 8.19 (t, J = 6.5 Hz, 1H), 7.74 (dd, J = 8.0, 3.4 Hz, 1H), 7.66 (d, J= 7.4 Hz, 1H), 7.63 – 7.50 (m, 2H), 7.31 (td, J = 8.7, 8.1, 3.0 Hz, 1H), 7.20 (q, J = 7.8, 7.1 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 7.5 Hz, 1H), 4.48 (tt, J = 5.3, 2.4 Hz, 1H), 4.20 – 4.00 (m, 4H), 3.77 (t, J = 5.5 Hz, 2H), 3.28 – 2.88 (m, 8H), 2.30 – 2.14 (m, 3H), 2.13 (d, J = 2.8 Hz, 3H), 1.91 (p, J = 6.5, 5.4 Hz, 1H)；MS(ESI, m/z): 502.2 [M+H] + 。
EXAMPLE 6 preparation of Compound 6
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.31 – 8.24 (m, 1H), 8.17 (tt, J = 7.5, 1.8 Hz, 1H), 7.75 (dd, J = 9.2, 4.2 Hz, 1H), 7.69 – 7.50 (m, 3H), 7.33 (ddd, J = 9.7, 6.6, 1.7 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 4.08 (q, J = 6.1, 4.6 Hz, 2H), 3.97 (d, J = 6.6 Hz, 2H), 3.74 (t, J = 5.6 Hz, 2H), 3.68 (dt, J = 9.8, 5.4 Hz, 1H), 2.92 (dt, J = 10.0, 4.5 Hz, 2H), 2.83 (t, J = 5.5 Hz, 2H), 2.66 (t, J = 7.8 Hz, 2H), 2.31 (d, J = 11.0 Hz, 2H), 2.14 (d, J = 3.6 Hz, 3H), 2.09 – 2.01 (m, 2H), 1.91 (dt, J = 13.5, 4.1 Hz, 2H), 1.63 (qd, J = 9.6, 4.7 Hz, 2H)；MS(ESI, m/z): 516.1 [M+H] + 。
EXAMPLE 7 preparation of Compound 7
The synthesis method is described in example 1. 1 H NMR (400 MHz, Chloroform-d) δ 8.25 (d, J = 1.8 Hz, 1H), 8.17 (dt, J = 6.8, 1.9 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.57 – 7.46 (m, 3H), 7.31 (dd, J = 8.2, 1.5 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 6.90 (ddd, J = 12.5, 8.0, 1.1 Hz, 2H), 4.08 (t, J = 6.1 Hz, 2H), 3.94 (s, 2H), 3.76 – 3.69 (m, 2H), 3.51 (d, J = 6.4 Hz, 2H), 3.04 (dt, J = 11.7, 3.3 Hz, 2H), 2.90 – 2.83 (m, 2H), 2.62 (dd, J = 13.4, 6.2 Hz, 5H), 2.17 (s, 3H), 2.12 – 1.97 (m, 4H), 1.82 – 1.73 (m, 2H), 1.58 – 1.48 (m, 1H), 1.36 (td, J = 12.4, 3.8 Hz, 2H)；MS(ESI, m/z): 530.5 [M+H] + 。
Example 8 preparation of Compound 8
The synthesis method is described in example 1. 1 H NMR (400 MHz, Chloroform-d) δ 8.24 (d, J = 2.0 Hz, 1H), 8.16 (dt, J = 6.5, 2.0 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.56 – 7.45 (m, 3H), 7.30 (dd, J = 8.2, 1.6 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 6.88 (dd, J = 17.3, 7.9 Hz, 2H), 4.46 (p, J = 5.8 Hz, 1H), 4.05 (t, J = 6.1 Hz, 2H), 3.93 (s, 2H), 3.79 – 3.60 (m, 4H), 3.05 – 2.93 (m, 2H), 2.90 – 2.82 (m, 2H), 2.72 (t, J = 7.3 Hz, 2H), 2.51 (s, 3H), 2.15 (s, 3H), 1.91 (p, J = 6.6 Hz, 2H)；MS(ESI, m/z): 488.7 [M+H] + 。
Example 9 preparation of Compound 9
The synthesis method is described in example 1. 1 H NMR (400 MHz, Chloroform-d) δ 8.24 (d, J = 1.8 Hz, 1H), 8.16 (dt, J = 6.8, 1.9 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.55 – 7.47 (m, 3H), 7.30 (dd, J = 8.2, 1.5 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 6.94 – 6.84 (m, 2H), 4.38 (ddt, J = 7.4, 4.9, 2.2 Hz, 1H), 4.09 (t, J = 6.1 Hz, 2H), 3.93 (s, 2H), 3.76 – 3.67 (m, 2H), 3.01 (td, J = 8.7, 5.1 Hz, 1H), 2.90 – 2.79 (m, 3H), 2.75 (t, J = 7.5 Hz, 2H), 2.63 – 2.59 (m, 4H), 2.39 (td, J = 9.0, 6.5 Hz, 1H), 2.27 – 2.18 (m, 1H), 2.15 (s, 3H), 2.12 – 2.05 (m, 2H), 1.85 – 1.76 (m, 1H)；MS(ESI, m/z): 502.5 [M+H] + 。
Example 10 preparation of Compound 10
The synthesis method is described in example 1. 1 H NMR (400 MHz, Chloroform-d) δ 8.25 (d, J = 1.8 Hz, 1H), 8.18 (dt, J = 6.7, 1.7 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.58 – 7.46 (m, 3H), 7.28 (dd, J = 8.0, 1.4 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 6.96 – 6.83 (m, 2H), 4.28 (ddt, J = 7.2, 4.5, 2.0 Hz, 1H), 4.06 (t, J = 6.0 Hz, 2H), 3.91 (s, 2H), 3.78 – 3.63 (m, 2H), 3.39 (s, 3H), 3.00 (td, J = 8.5, 5.0 Hz, 1H), 2.91 – 2.77 (m, 3H), 2.73 (t, J = 7.2 Hz, 2H), 2.62 – 2.55 (m, 3H), 2.40 (td, J = 9.1, 6.4 Hz, 1H), 2.25 – 2.15 (m, 1H), 2.15 (s, 3H), 2.11 – 2.03 (m, 2H), 1.83 – 1.73 (m, 1H)；MS(ESI, m/z): 544.6 [M+H] + 。
EXAMPLE 11 preparation of Compound 11
The synthesis method is described in example 1. 1 H NMR (400 MHz, Chloroform-d) δ 8.24 (d, J = 1.8 Hz, 1H), 8.17 (dt, J = 6.7, 1.7 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.57 – 7.45 (m, 3H), 7.26 (dd, J = 8.0, 1.4 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 6.95 – 6.83 (m, 2H), 4.27 (ddt, J = 7.2, 4.4, 2.0 Hz, 1H), 4.05 (t, J = 6.1 Hz, 2H), 3.90 (s, 2H), 3.77 – 3.63 (m, 2H), 3.39 (s, 3H), 3.01 (td, J = 8.4, 5.0 Hz, 1H), 2.91 – 2.78 (m, 3H), 2.72 (t, J = 7.2 Hz, 2H), 2.62 – 2.57 (m, 3H), 2.41 (td, J = 9.0, 6.4 Hz, 1H), 2.23 – 2.15 (m, 1H), 2.15 (s, 3H), 2.11 – 2.03 (m, 2H), 1.83 – 1.72 (m, 1H)；MS(ESI, m/z): 544.5 [M+H] + 。
EXAMPLE 12 preparation of Compound 12
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.30 – 8.24 (m, 1H), 8.16 (tt, J = 7.5, 1.8 Hz, 1H), 7.74 (dd, J = 9.1, 4.2 Hz, 1H), 7.68 – 7.50 (m, 3H), 7.33 (ddd, J = 9.7, 6.6, 1.7 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 7.3 Hz, 1H), 4.08 (q, J = 6.1, 4.6 Hz, 2H), 3.97 (d, J = 6.5 Hz, 2H), 3.76 (t, J = 5.6 Hz, 2H), 3.66 (dt, J = 9.8, 5.3 Hz, 1H), 3.37 (s, 3H), 2.93 (dt, J = 9.8, 4.5 Hz, 2H), 2.84 (t, J = 5.5 Hz, 2H), 2.66 (t, J = 7.8 Hz, 2H), 2.30 (d, J = 11.0 Hz, 2H), 2.15 (d, J = 3.6 Hz, 3H), 2.09 – 2.00 (m, 2H), 1.91 (dt, J = 13.5, 4.1 Hz, 2H), 1.63 (qd, J = 9.6, 4.7 Hz, 2H)；MS(ESI, m/z): 558.2 [M+H] + 。
EXAMPLE 13 preparation of Compound 13
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.24 (d, J = 1.8 Hz, 1H), 8.18 (dt, J = 6.5, 1.7 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.56 – 7.46 (m, 3H), 7.26 (dd, J = 8.0, 1.5 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 6.94 – 6.81 (m, 2H), 4.26 (ddt, J = 7.1, 4.3, 2.0 Hz, 1H), 4.04 (t, J = 6.0 Hz, 2H), 3.91 (s, 2H), 3.78 – 3.63 (m, 2H), 3.00 (td, J = 8.5, 5.0 Hz, 1H), 2.87 – 2.74 (m, 3H), 2.71 (t, J = 7.2 Hz, 2H), 2.60 – 2.53 (m, 2H), 2.40 (td, J = 9.1, 6.4 Hz, 1H), 2.25 – 2.13 (m, 1H), 2.15 (s, 3H), 2.11 – 2.03 (m, 1H), 1.81 – 1.72 (m, 1H)；MS(ESI, m/z): 530.1 [M+H] + 。
EXAMPLE 14 preparation of Compound 14
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.24 (d, J = 1.8 Hz, 1H), 8.18 (dt, J = 6.5, 1.7 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.55 – 7.44 (m, 3H), 7.26 (dd, J = 8.0, 1.5 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 6.93 – 6.80 (m, 2H), 4.25 (ddt, J = 7.0, 4.3, 2.0 Hz, 1H), 4.02 (t, J = 6.0 Hz, 2H), 3.93 (s, 2H), 3.76 – 3.63 (m, 2H), 3.02 (td, J = 8.5, 5.0 Hz, 1H), 2.87 – 2.72 (m, 3H), 2.71 (t, J = 7.2 Hz, 2H), 2.63 – 2.53 (m, 2H), 2.40 (td, J = 9.1, 6.4 Hz, 1H), 2.25 – 2.12 (m, 1H), 2.15 (s, 3H), 2.10 – 2.03 (m, 1H), 1.81 – 1.71 (m, 1H)；MS(ESI, m/z): 530.3 [M+H] + 。
EXAMPLE 15 preparation of Compound 15
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.30 – 8.24 (m, 1H), 8.15 (tt, J = 7.5, 1.8 Hz, 1H), 7.73 (dd, J = 9.1, 4.1 Hz, 1H), 7.65 – 7.50 (m, 3H), 7.32 (ddd, J = 9.7, 6.5, 1.7 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 7.3 Hz, 1H), 4.06 (q, J = 6.0, 4.4 Hz, 2H), 3.97 (d, J = 6.5 Hz, 2H), 3.75 (t, J = 5.6 Hz, 2H), 3.64 (dt, J = 9.6, 5.3 Hz, 1H), 2.93 (dt, J = 9.8, 4.5 Hz, 2H), 2.84 (t, J = 5.5 Hz, 2H), 2.66 (t, J = 7.8 Hz, 2H), 2.30 (d, J = 11.0 Hz, 2H), 2.15 (d, J = 3.6 Hz, 3H), 2.14 – 2.03 (m, 2H), 1.91 (dt, J = 13.5, 4.1 Hz, 2H), 1.64 (qd, J = 9.6, 4.6 Hz, 2H)；MS(ESI, m/z): 544.6 [M+H] + 。
EXAMPLE 16 preparation of Compound 16
The synthesis method is described in example 1. 1 H NMR (400 MHz, Chloroform-d) δ 8.25 (d, J = 1.7 Hz, 1H), 8.15 (dt, J = 7.1, 1.6 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.55 – 7.44 (m, 3H), 7.30 (dd, J = 8.0, 1.4 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 6.91 (t, J = 8.3 Hz, 2H), 4.09 (t, J = 6.1 Hz, 2H), 3.93 (s, 2H), 3.72 (dt, J = 10.2, 4.6 Hz, 6H), 2.90 – 2.80 (m, 3H), 2.65 – 2.51 (m, 4H), 2.51 (t, J = 4.6 Hz, 4H), 2.15 (s, 3H), 2.10 – 1.98 (m, 2H)；MS(ESI, m/z): 501.6 [M+H] + 。
EXAMPLE 17 preparation of Compound 17
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.31 – 8.25 (m, 1H), 8.16 (tt, J = 7.3, 1.8 Hz, 1H), 7.71 (dd, J = 9.3, 4.1 Hz, 1H), 7.63 – 7.47 (m, 3H), 7.30 (ddd, J = 9.4, 6.2, 1.6 Hz, 1H), 7.16 (t, J = 7.2 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 7.3 Hz, 1H), 4.04 (q, J = 6.3, 4.1 Hz, 2H), 3.94 (d, J = 6.3 Hz, 2H), 3.72 (t, J = 5.5 Hz, 2H), 3.63 (dt, J = 9.5, 5.3 Hz, 1H), 2.92 (dt, J = 9.6, 4.4 Hz, 2H), 2.83 (t, J = 5.6 Hz, 2H), 2.64 (t, J = 7.8 Hz, 2H), 2.30 (d, J = 11.0 Hz, 2H), 2.15 (d, J = 3.6 Hz, 3H), 2.27 – 2.18 (m, 2H), 1.91 (dt, J = 13.5, 4.1 Hz, 2H), 1.64 (qd, J = 9.6, 4.6 Hz, 2H)；MS(ESI, m/z): 515.7 [M+H] + 。
EXAMPLE 18 preparation of Compound 18
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.29 (d, J = 7.0 Hz, 1H), 8.18 (t, J = 6.5 Hz, 1H), 7.76 (dd, J = 8.0, 3.3 Hz, 1H), 7.68 (d, J= 7.4 Hz, 1H), 7.65 – 7.51 (m, 2H), 7.31 (td, J = 8.7, 8.1, 3.0 Hz, 1H), 7.22 (q, J = 7.9, 7.3 Hz, 1H), 6.95 (d, J = 8.1 Hz, 1H), 6.86 (d, J = 7.5 Hz, 1H), 4.50 (tt, J = 5.4, 2.6 Hz, 1H), 4.22 – 4.05 (m, 4H), 3.76 (t, J = 5.4 Hz, 2H), 3.32 – 2.92 (m, 8H), 2.31 – 2.13 (m, 3H), 2.14 (d, J = 2.8 Hz, 3H), 1.95 (p, J = 6.4, 5.4 Hz, 1H)；MS(ESI, m/z): 501.6 [M+H] + 。
EXAMPLE 19 preparation of Compound 19
The synthesis method is described in example 1. 1 H NMR (400 MHz, Chloroform-d) δ 8.26 (d, J = 2.0 Hz, 1H), 8.18 (dt, J = 7.1, 1.8 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.56 – 7.47 (m, 2H), 7.21 (t, J = 7.9 Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H), 6.90 (d, J= 8.1 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 4.10 (q, J = 5.9 Hz, 2H), 3.95 (s, 2H), 3.74 (dt, J = 8.1, 4.8 Hz, 6H), 2.88 (t, J = 5.1 Hz, 2H), 2.75 (s, 2H), 2.60 (t, J = 7.4 Hz, 2H), 2.51 (d, J = 4.7 Hz, 4H), 2.32 (s, 3H), 2.10 – 2.01 (m, 2H), 1.97 (s, 3H)；MS(ESI, m/z): 516.4 [M+H] + 。
EXAMPLE 20 preparation of Compound 20
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.15 (dd, J = 6.7, 2.5 Hz, 1H), 8.09 – 8.00 (m, 1H), 7.55 – 7.39 (m, 3H), 7.13 – 7.03 (m, 1H), 7.03 – 6.95 (m, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.62 (t, J = 6.7 Hz, 1H), 4.28 (ddq, J = 8.4, 5.3, 2.7 Hz, 1H), 3.99 (t, J = 5.9 Hz, 2H), 3.83 (d, J = 7.0 Hz, 2H), 3.61 (t, J = 5.6 Hz, 2H), 2.83 (dt, J = 10.5, 5.3 Hz, 1H), 2.79 – 2.63 (m, 5H), 2.62 – 2.50 (m, 2H), 2.21 – 2.10 (m, 3H), 2.10 – 1.91 (m, 3H), 1.81 (d, J = 3.4 Hz, 3H), 1.67 (m, 1H)；MS(ESI, m/z): 516.6 [M+H] + 。
EXAMPLE 21 preparation of Compound 21
The synthesis method is described in example 1. 1 H NMR (300 MHz, Methanol-d 4 ) δ 8.29 (d, J = 1.7 Hz, 1H), 8.20 (dt, J = 7.3, 1.7 Hz, 1H), 7.69 – 7.54 (m, 3H), 7.28 – 7.09 (m, 2H), 6.97 (dd, J = 8.3, 1.1 Hz, 1H), 6.75 (dd, J = 7.6, 1.0 Hz, 1H), 4.11 (t, J = 6.0 Hz, 2H), 3.99 (s, 2H), 3.80 – 3.62 (m, 3H), 2.89 (dt, J = 26.5, 6.0 Hz, 4H), 2.74 – 2.63 (m, 2H), 2.29 (s, 5H), 2.09 (dp, J = 12.1, 6.8, 6.2 Hz, 2H), 1.94 (s, 5H), 1.63 (dtd, J = 13.2, 9.5, 3.7 Hz, 2H)；MS(ESI, m/z): 530.1 [M+H] + 。
EXAMPLE 22 preparation of Compound 22
The synthesis method is described in example 1. 1 H NMR (300 MHz, Methanol-d 4 ) δ 8.28 (d, J = 1.6 Hz, 1H), 8.21 (dt, J = 7.1, 1.6 Hz, 1H), 7.68 – 7.52 (m, 3H), 7.29 – 7.07 (m, 2H), 6.98 (dd, J = 8.2, 1.0 Hz, 1H), 6.76 (dd, J = 7.5, 1.2 Hz, 1H), 4.09 (t, J = 6.2 Hz, 2H), 3.98 (s, 2H), 3.80 – 3.63 (m, 3H), 3.50 (d, J = 6.2, 2H), 2.89 (dt, J = 26.5, 6.0 Hz, 4H), 2.74 – 2.63 (m, 2H), 2.29 (s, 5H), 2.09 (m, 2H), 1.94 (s, 5H), 1.61 (dtd, J = 13.2, 9.5, 3.7 Hz, 2H)；MS(ESI, m/z): 544.6 [M+H] + 。
EXAMPLE 23 preparation of Compound 23
The synthesis method is described in example 1. 1 H NMR (400 MHz, Chloroform-d) δ 8.27 (d, J = 1.8 Hz, 1H), 8.22 (dt, J = 7.3, 1.7 Hz, 1H), 7.67 – 7.54 (m, 3H), 7.27 – 7.10 (m, 2H), 6.96 (dd, J = 8.1, 1.3 Hz, 1H), 6.74 (dd, J = 7.1, 1.0 Hz, 1H), 4.43 (p, J = 5.8 Hz, 1H), 4.02 (t, J = 6.1 Hz, 2H), 3.91 (s, 2H), 3.75 – 3.62 (m, 4H), 3.03 – 2.91 (m, 2H), 2.92 – 2.80 (m, 2H), 2.76 (t, J = 7.1 Hz, 2H), 2.34 (s, 3H), 1.96 (s, 3H), 1.96 (p, J = 6.3 Hz, 2H)；MS(ESI, m/z): 502.5 [M+H] + 。
EXAMPLE 24 preparation of Compound 24
The synthesis method is described in example 1. 1 H NMR (400 MHz, Chloroform-d) δ 8.30 (d, J = 2.0 Hz, 1H), 8.20 (dt, J = 7.0, 1.4 Hz, 1H), 7.71 – 7.60 (m, 3H), 7.23 – 7.05 (m, 2H), 6.94 (dd, J = 7.7, 1.1 Hz, 1H), 6.73 (dd, J = 7.5, 1.3 Hz, 1H), 4.37 (p, J = 5.6 Hz, 1H), 4.05 (t, J = 6.0 Hz, 2H), 3.88 (s, 2H), 3.65 – 3.59 (m, 2H), 3.01 (td, J = 8.0, 4.7 Hz, 1H), 2.84 – 2.73 (m, 3H), 2.71 (t, J = 7.2 Hz, 2H), 2.61 – 2.50 (m, 4H), 2.30 (s, 5H), 2.01 (s, 5H), 1.85 – 1.76 (m, 1H)；MS(ESI, m/z): 516.7 [M+H] + 。
EXAMPLE 25 preparation of Compound 25
The synthesis method is described in example 1. 1 H NMR (400 MHz, Chloroform-d) δ 8.25 (d, J = 1.7 Hz, 1H), 8.18 (dt, J = 6.8, 1.3 Hz, 1H), 7.64 – 7.43 (m, 3H), 7.27 – 7.10 (m, 2H), 6.96 (dd, J = 8.1, 1.3 Hz, 1H), 6.78 (dd, J = 7.1, 1.0 Hz, 1H), 4.36 (p, J = 5.3 Hz, 1H), 4.14 (t, J = 6.0 Hz, 2H), 3.95 (s, 2H), 3.81 – 3.72 (m, 2H), 3.35 (s, 3H), 3.01 (td, J = 8.5, 5.0 Hz, 1H), 2.91 – 2.77 (m, 3H), 2.73 (t, J= 7.2 Hz, 2H), 2.65 – 2.48 (m, 4H), 2.33 (s, 5H), 2.05 (s, 5H), 1.83 – 1.73 (m, 1H)；MS(ESI, m/z): 558.8 [M+H] + 。
EXAMPLE 26 preparation of Compound 26
The synthesis method is described in example 1. 1 H NMR (400 MHz, Chloroform-d) δ 8.24 (d, J = 1.7 Hz, 1H), 8.16 (dt, J = 6.6, 1.1 Hz, 1H), 7.60 – 7.41 (m, 3H), 7.24 – 7.08 (m, 2H), 6.95 (dd, J = 7.8, 1.0 Hz, 1H), 6.76 (dd, J = 7.0, 1.3 Hz, 1H), 4.34 (p, J = 5.5 Hz, 1H), 4.13 (t, J = 6.0 Hz, 2H), 3.95 (s, 2H), 3.81 – 3.71 (m, 2H), 3.35 (s, 3H), 3.00 (td, J = 8.4, 5.0 Hz, 1H), 2.91 – 2.75 (m, 3H), 2.72 (t, J= 7.2 Hz, 2H), 2.66 – 2.48 (m, 4H), 2.33 (s, 5H), 2.05 (s, 5H), 1.86 – 1.74 (m, 1H)；MS(ESI, m/z): 558.3 [M+H] + 。
EXAMPLE 27 preparation of Compound 27
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.29 – 8.23 (m, 1H), 8.15 (tt, J = 7.1, 1.5 Hz, 1H), 7.64 – 7.42 (m, 3H), 7.28 – 7.13 (m, 2H), 6.91 (d, J = 8.1 Hz, 1H), 6.83 (d, J = 7.3 Hz, 1H), 4.28 (q, J = 6.1, 4.6 Hz, 2H), 3.97 (d, J = 6.5 Hz, 2H), 3.71 (t, J = 5.6 Hz, 2H), 3.62 (dt, J= 9.8, 5.3 Hz, 1H), 3.32 (s, 3H), 2.91 (dt, J = 9.5, 4.1 Hz, 2H), 2.80 (t, J= 5.5 Hz, 2H), 2.61 – 2.43(m, 4H), 2.31 (s, 5H), 2.04 (s, 5H), 1.82 – 1.71 (m, 1H) 1.63 (qd, J = 9.3, 4.1 Hz, 1H)；MS(ESI, m/z): 558.2 [M+H] + 。
EXAMPLE 28 preparation of Compound 28
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.25 (d, J = 1.9 Hz, 1H), 8.15 (dt, J = 6.3, 1.5 Hz, 1H), 7.51 – 7.44 (m, 3H), 7.25 (dd, J = 8.1, 1.4 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 6.90 – 6.80 (m, 2H), 4.24 (m, 1H), 4.01 (t, J = 5.0 Hz, 2H), 3.88 (s, 2H), 3.75 – 3.60 (m, 2H), 3.30 (s, 3H), 2.98 (td, J = 8.3, 4.0 Hz, 1H), 2.88 – 2.72 (m, 2H), 2.67 (t, J = 6.2 Hz, 2H), 2.64 – 2.42(m, 2H), 2.34 (s, 3H), 2.07 (s, 3H), 1.81 – 1.75 (m, 1H) 1.63 (qd, J = 8.7, 4.0 Hz, 1H)；MS(ESI, m/z): 544.1 [M+H] + 。
EXAMPLE 29 preparation of Compound 29
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.25 (d, J = 1.9 Hz, 1H), 8.15 (dt, J = 6.3, 1.5 Hz, 1H), 7.52 – 7.45 (m, 3H), 7.26 (dd, J = 8.0, 1.4 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 6.92 – 6.78 (m, 2H), 4.26 (m, 1H), 4.00 (t, J = 4.8 Hz, 2H), 3.86 (s, 2H), 3.75 – 3.61 (m, 2H), 3.30 (s, 3H), 2.96 (td, J = 8.0, 4.1 Hz, 1H), 2.85 – 2.72 (m, 2H), 2.65 (t, J = 6.0 Hz, 2H), 2.60 – 2.45 (m, 2H), 2.34 (s, 3H), 2.07 (s, 3H), 1.80 – 1.75 (m, 1H) 1.64 (qd, J = 8.5, 4.1 Hz, 1H)；MS(ESI, m/z): 544.2 [M+H] + 。
EXAMPLE 30 preparation of Compound 30
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.32 – 8.26 (m, 1H), 8.16 (tt, J = 7.0, 1.6 Hz, 1H), 7.62 – 7.46 (m, 3H), 7.32 (m, 1H), 7.21 (t, J = 7.7 Hz, 1H), 6.93 – 6.74 (m, 2H), 4.10 (q, J = 5.6, 4.0 Hz, 2H), 3.95 (d, J = 6.0 Hz, 2H), 3.70 (t, J = 5.6 Hz, 2H), 3.60 (dt, J = 9.0, 5.1 Hz, 1H), 2.92 (dt, J = 9.3, 4.8 Hz, 2H), 2.82 (t, J = 5.0 Hz, 2H), 2.62 (t, J = 7.2 Hz, 2H), 2.35 (s, 5H), 2.09 (s, 5H), 1.91 (dt, J = 12.5, 4.1 Hz, 2H), 1.64 (qd, J = 9.2, 4.6 Hz, 2H)；MS(ESI, m/z): 558.6 [M+H] + 。
EXAMPLE 31 preparation of Compound 31
The synthesis method is described in example 1. 1 H NMR (400 MHz, Chloroform-d) δ 8.26 (d, J = 1.6 Hz, 1H), 8.15 (dt, J = 7.0, 1.6 Hz, 1H), 7.58 – 7.41 (m, 3H), 7.28 (dd, J = 8.2, 1.3 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 6.91 (t, J = 8.1 Hz, 2H), 4.05 (t, J = 6.0 Hz, 2H), 3.95 (s, 2H), 3.76 (dt, J = 10.0, 4.8 Hz, 6H), 2.95 – 2.75 (m, 3H), 2.62 – 2.51 (m, 4H), 2.51 (t, J = 4.6 Hz, 4H), 2.32 (s, 3H), 2.12 (s, 5H)；MS(ESI, m/z): 515.2 [M+H] + 。
EXAMPLE 32 preparation of Compound 32
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.29 – 8.24 (m, 1H), 8.14 (tt, J = 7.0, 1.5 Hz, 1H), 7.63 – 7.47 (m, 3H), 7.30 (ddd, J = 9.4, 6.2, 1.6 Hz, 1H), 7.16 (t, J = 7.2 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 7.3 Hz, 1H), 4.04 (q, J = 6.3, 4.1 Hz, 2H), 3.92 (d, J = 6.0 Hz, 2H), 3.75 (t, J = 5.2 Hz, 2H), 3.62 (dt, J = 9.5, 5.3 Hz, 1H), 2.96 (dt, J = 9.6, 4.1 Hz, 2H), 2.81 (t, J = 5.0 Hz, 2H), 2.64 (t, J = 7.5 Hz, 2H), 2.36 (s, 5H), 2.27 – 2.18 (m, 2H), 2.14 (s, 5H), 1.64 (qd, J = 9.6, 4.6 Hz, 2H)；MS(ESI, m/z): 515.7 [M+H] + 。
EXAMPLE 33 preparation of Compound 33
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.26 (d, J = 7.4 Hz, 1H), 8.15 (t, J = 6.2 Hz, 1H), 7.67 (d, J = 7.4 Hz, 1H), 7.62 – 7.51 (m, 2H), 7.32 (td, J = 8.5, 8.0, 3.2 Hz, 1H), 7.20 (q, J = 7.3, 6.3 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 4.48 (tt, J = 5.0, 2.6 Hz, 1H), 4.25 – 4.08 (m, 4H), 3.72 (t, J = 5.4 Hz, 2H), 3.38 – 3.01 (m, 8H), 2.31 (m, 5H), 2.14 (s, 3H), 1.96 (p, J = 6.0, 5.4 Hz, 1H)；MS(ESI, m/z): 515.1 [M+H] + 。
EXAMPLE 34 preparation of Compound 34
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.28 (d, J = 7.0 Hz, 1H), 8.14 (t, J = 6.1 Hz, 1H), 7.70 (dd, J = 8.0, 3.5 Hz, 1H), 7.62 (d, J= 7.7 Hz, 1H), 7.60 – 7.48 (m, 2H), 7.30 (td, J = 8.5, 8.0, 3.3 Hz, 1H), 7.16 (q, J = 7.4, 7.0 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.83 (d, J = 7.2 Hz, 1H), 4.45 (tt, J = 5.1, 2.4 Hz, 1H), 4.15 – 4.02 (m, 4H), 3.75 (t, J = 5.5 Hz, 2H), 3.27 – 2.90 (m, 8H), 2.32 – 2.16 (m, 3H), 1.93 (p, J = 6.0, 5.1 Hz, 1H)；MS(ESI, m/z): 566.3 [M+H] + 。
EXAMPLE 35 preparation of Compound 35
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.27 (d, J = 7.1 Hz, 1H), 8.14 (t, J = 6.0 Hz, 1H), 7.71 (dd, J = 8.0, 3.6 Hz, 1H), 7.63 (d, J= 7.8 Hz, 1H), 7.61 – 7.48 (m, 2H), 7.31 (td, J = 8.4, 8.0, 3.3 Hz, 1H), 7.14 (q, J = 7.4, 7.0 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 7.2 Hz, 1H), 4.41 (tt, J = 5.1, 2.3 Hz, 1H), 4.15 – 4.03 (m, 4H), 3.76 (t, J = 5.6 Hz, 2H), 3.26 – 2.89 (m, 8H), 2.31 – 2.12 (m, 3H), 1.92 (p, J = 6.0, 5.0 Hz, 1H)；MS(ESI, m/z): 566.6 [M+H] + 。
EXAMPLE 36 preparation of Compound 36
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.24 (d, J = 7.1 Hz, 1H), 8.11 (t, J = 6.3 Hz, 1H), 7.74 (dd, J = 7.9, 3.4 Hz, 1H), 7.65 (d, J= 7.3 Hz, 1H), 7.62 – 7.48 (m, 2H), 7.33 (td, J = 8.1, 7.3, 3.5 Hz, 1H), 7.16 (q, J = 7.9, 6.7 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 7.2 Hz, 1H), 4.40 (tt, J = 5.1, 2.3 Hz, 1H), 4.15 – 4.04 (m, 4H), 3.76 (t, J = 5.5 Hz, 2H), 3.23 – 2.86 (m, 8H), 2.30 – 2.16 (m, 3H), 1.90 (p, J = 5.6, 4.8 Hz, 1H)；MS(ESI, m/z): 566.1 [M+H] + 。
EXAMPLE 37 preparation of Compound 37
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.28 (m, 1H), 8.17 (tt, J = 7.5, 1.8 Hz, 1H), 7.75 (dd, J = 9.2, 4.2 Hz, 1H), 7.69 – 7.50 (m, 3H), 7.33 (ddd, J = 9.7, 6.6, 1.7 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 4.09 (q, J = 6.1, 4.6 Hz, 2H), 3.95 (d, J = 6.5 Hz, 2H), 3.73 (t, J = 5.6 Hz, 2H), 3.66 (dt, J = 9.3, 5.1 Hz, 1H), 2.93 (dt, J = 10.1, 4.5 Hz, 2H), 2.82 (t, J = 5.5 Hz, 2H), 2.68 (t, J = 7.8 Hz, 2H), 2.30 (d, J = 11.2 Hz, 2H), 2.16 (d, J = 3.6 Hz, 3H), 2.11 – 2.01 (m, 2H), 1.89 (dt, J = 13.5, 4.1 Hz, 2H), 1.65 (qd, J = 9.6, 4.6 Hz, 2H)；MS(ESI, m/z): 580.7 [M+H] + 。
EXAMPLE 38 preparation of Compound 38
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.27 (m, 1H), 8.16 (tt, J = 7.3, 1.7 Hz, 1H), 7.74 (dd, J = 9.2, 4.1 Hz, 1H), 7.65 – 7.51 (m, 3H), 7.30 (ddd, J = 9.4, 6.5, 1.7 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.83 (d, J = 7.5 Hz, 1H), 4.04 (q, J = 6.0, 4.1 Hz, 2H), 3.93 (d, J = 6.3 Hz, 2H), 3.72 (t, J = 5.5 Hz, 2H), 3.67 (dt, J = 9.3, 5.1 Hz, 1H), 2.92 (dt, J = 10.0, 4.5 Hz, 2H), 2.86 (t, J = 5.5 Hz, 2H), 2.69 (t, J = 7.8 Hz, 2H), 2.32 (d, J = 11.0 Hz, 2H), 2.16 (d, J = 3.5 Hz, 3H), 2.11 – 2.00 (m, 2H), 1.90 (dt, J = 13.4, 4.1 Hz, 2H), 1.65 (qd, J = 9.6, 4.5 Hz, 2H)；MS(ESI, m/z): 536.5 [M+H] + 。
EXAMPLE 39 preparation of Compound 39
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.27 (m, 1H), 8.16 (tt, J = 7.2, 1.7 Hz, 1H), 7.75 (dd, J = 9.2, 4.3 Hz, 1H), 7.65 – 7.52 (m, 3H), 7.30 (ddd, J = 9.0, 6.0, 1.7 Hz, 1H), 7.24 (t, J = 7.2 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.83 (d, J = 7.5 Hz, 1H), 4.04 (q, J = 6.0, 4.1 Hz, 2H), 3.92 (d, J = 6.4 Hz, 2H), 3.75 (t, J = 5.0 Hz, 2H), 3.64 (dt, J = 9.0, 5.1 Hz, 1H), 2.92 (dt, J = 10.2, 4.3 Hz, 2H), 2.82 (t, J = 5.5 Hz, 2H), 2.65 (t, J = 7.8 Hz, 2H), 2.27 (d, J = 10.0 Hz, 2H), 2.16 (d, J = 3.2 Hz, 3H), 2.11 – 2.05 (m, 2H), 1.95 (dt, J = 13.0, 4.1 Hz, 2H), 1.69 (qd, J = 9.6, 4.0 Hz, 2H)；MS(ESI, m/z): 520.4 [M+H] + 。
EXAMPLE 40 preparation of Compound 40
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.26 (d, J = 7.1 Hz, 1H), 8.15 (t, J = 6.5 Hz, 1H), 7.71 (dd, J = 8.0, 3.4 Hz, 1H), 7.63 (d, J= 7.4 Hz, 1H), 7.60 – 7.48 (m, 2H), 7.25 (td, J = 8.4, 7.7, 3.0 Hz, 1H), 7.17 (q, J = 7.8, 7.0 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 7.5 Hz, 1H), 4.48 (tt, J = 5.3, 2.4 Hz, 1H), 4.15 – 4.00 (m, 2H), 3.73 (t, J = 5.0 Hz, 2H), 3.27 – 2.84 (m, 8H), 2.35 – 2.18 (m, 3H), 2.11 (d, J = 2.8 Hz, 3H), 1.90 (p, J = 6.0, 5.4 Hz, 1H)；MS(ESI, m/z): 488.4 [M+H] + 。
EXAMPLE 41 preparation of Compound 41
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.25 (d, J = 7.5 Hz, 1H), 8.12 (t, J = 6.1 Hz, 1H), 7.75 (dd, J = 7.9, 3.2 Hz, 1H), 7.60 (d, J= 7.0 Hz, 1H), 7.58 – 7.41 (m, 2H), 7.23 (td, J = 8.4, 7.2, 3.2 Hz, 1H), 7.10 (q, J = 7.5, 7.0 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 7.2 Hz, 1H), 4.43 (tt, J = 5.7, 2.0 Hz, 1H), 4.25 – 4.05 (m, 6H), 3.70 (t, J = 5.1 Hz, 2H), 3.27 – 2.81 (m, 8H), 2.39 – 2.14 (m, 3H), 2.10 (d, J = 2.8 Hz, 3H), 1.88 (m, 1H)；MS(ESI, m/z): 516.2 [M+H] + 。
EXAMPLE 42 preparation of Compound 42
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.23 (d, J = 7.5 Hz, 1H), 8.10 (t, J = 5.5 Hz, 1H), 7.71 (dd, J = 7.8, 3.0 Hz, 1H), 7.60 (d, J= 6.5 Hz, 1H), 7.55 – 7.40 (m, 2H), 7.21 (td, J = 8.0, 7.1, 3.2 Hz, 1H), 7.08 (q, J = 7.9, 7.0 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.80 (d, J = 7.2 Hz, 1H), 4.47 (tt, J = 5.2, 2.4 Hz, 1H), 4.25 – 4.05 (m, 6H), 3.74 – 3.58 (m, 4H), 3.30 – 2.94 (m, 8H), 2.34 – 2.14 (m, 3H), 2.12 (d, J = 2.8 Hz, 3H), 1.85 (m, 1H)；MS(ESI, m/z): 530.3 [M+H] + 。
EXAMPLE 43 preparation of Compound 43
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.27 (m, 1H), 8.15 (tt, J = 7.3, 1.6 Hz, 1H), 7.73 (dd, J = 8.8, 4.1 Hz, 1H), 7.69 – 7.52 (m, 3H), 7.35 (ddd, J = 9.3, 6.2, 1.4 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.82 (d, J = 7.5 Hz, 1H), 4.11 (q, J = 6.0, 4.3 Hz, 2H), 3.95 (d, J = 6.6 Hz, 2H), 3.71 (t, J = 5.1 Hz, 2H), 3.65 (dt, J = 9.3, 5.0 Hz, 1H), 2.92 (dt, J = 10.1, 4.5 Hz, 2H), 2.63 (t, J = 7.8 Hz, 2H), 2.33 (d, J = 11.0 Hz, 2H), 2.14 (d, J = 3.2 Hz, 3H), 2.09 – 2.01 (m, 2H), 1.92 (dt, J= 13.5, 4.1 Hz, 2H), 1.65 (qd, J = 9.2, 4.7 Hz, 2H)；MS(ESI, m/z): 502.2 [M+H] + 。
EXAMPLE 44 preparation of Compound 44
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.26 (m, 1H), 8.15 (tt, J = 7.2, 1.6 Hz, 1H), 7.72 (dd, J = 8.6, 4.7 Hz, 1H), 7.66 – 7.50 (m, 3H), 7.36 (ddd, J = 9.3, 6.1, 1.4 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.82 (d, J = 7.5 Hz, 1H), 4.12 (q, J = 6.0, 4.5 Hz, 2H), 3.92 (d, J = 6.8 Hz, 2H), 3.65 (m, 4H), 2.82 – 2.63 (m, 4H), 2.35 (m, 4H), 2.14 (d, J = 3.1 Hz, 3H), 2.12 – 2.02 (m, 3H), 1.94 (dt, J = 13.0, 4.2 Hz, 2H), 1.67 (qd, J = 9.2, 4.7 Hz, 2H)；MS(ESI, m/z): 530.5 [M+H] + 。
EXAMPLE 45 preparation of Compound 45
The synthesis method is described in example 1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.27 (m, 1H), 8.12 (tt, J = 7.0, 1.6 Hz, 1H), 7.75 (dd, J = 8.6, 4.7 Hz, 1H), 7.65 – 7.51 (m, 3H), 7.37 (ddd, J = 9.0, 6.2, 1.4 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.80 (d, J = 7.5 Hz, 1H), 4.13 (q, J = 6.5, 4.0 Hz, 2H), 3.95 (d, J = 6.8 Hz, 2H), 3.66 (m, 4H), 2.83 – 2.62 (m, 4H), 2.35 (m, 4H), 2.15 (d, J = 3.0 Hz, 3H), 2.17 – 2.00 (m, 5H), 1.95 (dt, J = 13.0, 4.2 Hz, 2H), 1.65 (qd, J = 9.2, 4.7 Hz, 2H)；MS(ESI, m/z): 544.3 [M+H] + 。
Example 46
Preparation of tablets
Compound 1 (50 g), hydroxypropylmethyl cellulose E (150 g), starch (200 g), a proper amount of povidone K30 and magnesium stearate (1 g) prepared in example 1 were mixed, granulated and tableted.
In addition, the compounds prepared in examples 1 to 45 may be formulated into capsule, powder, granule, pill, injection, syrup, oral preparation, inhalant, ointment, suppository or patch etc. by adding various pharmaceutical excipients according to conventional preparation method of pharmacopoeia 2020.
Application examples
Pharmacological tests prove that the VISTA and PD-1/PD-L1 inhibitory activities can be used for preparing antitumor drugs. The following are pharmacological test results for the compounds of the present application:
1. compound binding ability assay for VISTA protein
Experimental facility and reagent
1. Model used in this experiment: biacore S200.
2. S series CM5 chip. Cargo number: 29-1049-88 (one-piece), BR-1005-30 (three-piece), 29-1496-03 (ten-piece), purchased as GE Healthcare.
3. Amino coupling kit. Cargo number: BR-1000-50 purchased as GE Healthcare.
4. Buffer solution: 10 x PBS-P+ (cat# 28-9950-84), purchased from GE Healthcare.
5. Analytically pure DMSO, deionized water (0.22 μm membrane filtration).
6. Protein: glycosylation modified VISTA proteins.
7. Other consumables: a capless 1.5 ml EP tube (cat# BR-1002-87), rubber bottle cap type 2 (cat# BR-1004-11), 96 well plate (cat# BR-1005-03), 96 well plate sealing film (cat# 28-9758-16), purchased as GE Healthcare.
(II) Experimental procedure
Compounds were tested for binding capacity to VISTA proteins using Biacore S200 system and CM5 chip, 10mM compounds were diluted with 1.05 x pbs-PThe method comprises the steps of testing mother liquor to 10 concentration gradients (5 [ mu ] M, 2.5 [ mu ] M, 1.25 [ mu ] M, 0.625 [ mu ] M, 0.3125 [ mu ] M, 0.156 [ mu ] M, 0.078 [ mu ] M, 0.039 [ mu ] M, 0.0195 [ mu ] M and 0.00975 [ mu ] M), obtaining affinity data of different concentrations, and fitting to obtain a compoundK D Numerical values.
(III) results of experiments
The following table shows the binding of the example compounds to VISTA proteinK D Numerical values.
Numbering of compounds K D (nM) Numbering of compounds K D (nM)
1 41.6 24 16.5
2 20.5 25 25.3
3 20.8 26 27.4
4 14.8 27 28.1
5 4.8 28 9.3
6 2.3 29 13.6
7 8.5 30 9.5
8 10.4 31 8.2
9 15.2 32 8.6
10 23.0 33 7.5
11 32.2 34 12.9
12 26.3 35 15.6
13 7.3 36 17.9
14 8.5 37 21.3
15 9.1 38 16.0
16 7.1 39 12.2
17 9.9 40 27.1
18 10.2 41 24.0
19 17.8 42 26.3
20 8.7 43 19.3
21 7.6 44 18.2
22 10.4 45 19.3
23 12.3
2. Compound binding ability assay for VISTA protein
Experimental facility and reagent
1. Centrifuge Eppendorf 5430
2. Microplate reader Perkein Elmer EnVision
3、PD-1-Eu、PD-L1-Biotin、Dye labeled acceptor (BPS Bioscience)
4、384 well microplate (Perkin Elmer)
(II) Experimental methods
The inhibition of the PD-1/PD-L1 pathway by the compounds of the examples was determined by the TR-FRET method, and the procedure is as follows:
(1) Preparing 1X modified TR-FRET assay buffer;
(2) Preparation of compound concentration gradient: test compound test concentration was 1.0 μm starting with 3-fold dilution 9 times, 10 concentration points. The solution was diluted 100 times to final concentration in 384 well plates and transferred 200 nL to 384 well plates for reaction. 200 nL DMSO is added to each of the negative control well and the positive control well;
(3) Preparing PD-L1-Biotin solution with 4 times of final concentration by using 1X modified TR-FRET assay buffer prepared in advance;
(4) Adding 5.0 mu L of PD-L1-Biotin solution with a final concentration of 4 times to the compound hole and the positive control hole respectively; add 5.0. Mu.L of 1 Xmodified TR-FRET assay buffer to the negative control wells;
(5) Centrifuging at 1000 rpm for 0.5min, shaking, mixing, and incubating at room temperature for 15min;
(6) Preparing a Dye labeled acceptor mixed solution of PD-1-Eu with a final concentration of 4 times and a final concentration of 2 times by using 1X modified TR-FRET assay buffer prepared in advance;
(7) 15. Mu.L of a mixed solution of PD-1-Eu and Dye labeled acceptor (Dye labeled acceptor having a final concentration of 4 times that of PD-1-Eu of 5.0. Mu.L and a final concentration of 2 times that of 10. Mu.L) was added;
(8) Centrifuging at 1000 rpm for 0.5min, shaking, mixing, and incubating at room temperature for 90min;
(9) Centrifuging the 384-well plate at 1000 rpm for 0.5min, shaking, mixing uniformly, reading fluorescence intensities of 665 nm and 620 nm by using an enzyme-labeled instrument, and calculating a TR-FRET ratio (665 nm emision/620 nm emision);
(10) Calculating inhibition rates at different concentration points, and using GraphPad Prism 6.0 software to fit a quantitative response curve to obtain IC for calculating enzyme activity of each compound 50 Values.
(III) results of experiments
The following table shows the IC of the compounds of the examples for PD-1/PD-L1 interaction inhibitory activity 50 Values.
Numbering of compounds IC 50 (nM) Numbering of compounds IC 50 (nM)
1 112 24 19.1
2 201 25 74.2
3 303 26 78.2
4 20.5 27 83.5
5 15.2 28 24.5
6 10.9 29 10.2
7 25.4 30 12.1
8 37.2 31 21.2
9 43.2 32 36.0
10 79.8 33 21.4
11 63.2 34 92.3
12 56.6 35 73.6
13 31.9 36 26.4
14 6.3 37 80.2
15 9.8 38 57.3
16 25.2 39 37.1
17 18.2 40 204
18 24.5 41 185
19 63.9 42 137
20 15.3 43 235
21 8.4 44 167
22 15.7 45 132
23 22.3
Finally, it should be noted that the above description is only for illustrating the technical solution of the present application, and not for limiting the scope of the present application, and that the simple modification and equivalent substitution of the technical solution of the present application can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present application.

Claims (9)

1. A compound of formula I and pharmaceutically acceptable salts thereof:
；
wherein X is 1 Independently CH 2 O, NH or S;
R 1 independently an aldehyde group, a hydroxyl group, a substituted or unsubstituted amino group, or an amino acid;
R 2 independently is hydrogen, deuterium, halogen, cyano, morpholinyl, tetrahydropyranyl, substituted or unsubstituted hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted pyrrolidone group, substituted or unsubstituted piperidyl, substituted or unsubstituted piperazinyl;
R 3 、R 4 each hydrogen, deuterium, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy;
m is 0, 1, 2 or 3;
n is 0, 1, 2,3, 4 or 5.
2. The compound of claim 1, wherein each R 1 Wherein the substituent in the substituted amino group is one or more of the following groups: c (C) 1-4 Alkyl, C 1-4 Amide group, C 1-4 Ester group, C 1-4 Carboxyl, C 1-4 A hydroxyl group; wherein said C 1-4 Alkyl, C 1-4 Amide group, C 1-4 Ester group, C 1-4 Carboxyl, C 1-4 The hydroxyl group may optionally be substituted with one or more of the following substituents: hydroxy, carboxyl, cyano, amino, C 3-6 Cycloalkyl, C 6-10 Aryl, C 6-10 Heterocyclyl, C 2-4 Alkenyl, C 2-4 Alkynyl; when there are plural substituents, the substituents may be the same or different.
3. The compound of claim 1, wherein each R 2 In (a), the substituted hydroxy, substituted amino, substituted C 1-4 Alkyl, substituted C 2-4 Alkenyl, substituted C 2-4 Alkynyl, substituted C 1-4 Alkoxy, substituted C 3 -C 6 The substituents in cycloalkyl, substituted pyrrolidone groups, substituted piperidine groups and substituted piperazine groups are selected from one or more of the following groups: halogen, cyano, hydroxy, trifluoromethyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Carboxyl, C 1-4 Ester group or C 1-4 An amide group; wherein said C 1-4 Alkyl, C 1-4 Amide group, C 1-4 Ester group, C 1-4 Carboxyl, C 1-4 The hydroxyl group may optionally be substituted with one or more of the following substituents: hydroxy, carboxyl, cyano, amino, C 3-6 Cycloalkyl, C 6-10 Aryl, C 6-10 Heterocyclyl, C 2-4 Alkenyl, C 2-4 Alkynyl; when there are plural substituents, the substituents may be the same or different.
4. The compound of claim 1, which is any one of the following:
；
。
5. the method for producing a compound according to claim 1, wherein when X is O, NH, S, R 1 When m is 1, which is a substituted or unsubstituted amino group, the synthetic route of the compound is as follows:
；
wherein R is 2 , R 3 ,R 4 N is as defined in formula I, and the synthesis steps are as follows:
(1) The compound II and the compound III are subjected to condensation ring closure reaction to obtain a compound IV;
(2) Reacting the compound IV with the pinacol biborate to obtain a compound V;
(3) Carrying out nucleophilic substitution reaction on the compound VI to obtain a compound VII;
(4) Carrying out Suzuki coupling reaction on the compound V and the compound VII to obtain a compound VIII;
(5) The compound VIII is subjected to reduction reaction to obtain a compound IX;
(6) The compound IX is subjected to oxidation reaction to obtain a compound X;
(7) The compound X is subjected to reductive amination reaction to obtain a compound XI.
6. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, as an active ingredient and a pharmaceutically acceptable carrier.
7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is selected from the group consisting of capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories, and patches.
8. Use of a compound according to any one of claims 1-4 for the preparation of an inhibitor having VISTA and PD-1/PD-L1 signaling pathway inhibitory activity, an anti-tumor drug, an anti-infective drug as an immune checkpoint inhibitor.
9. Use of a pharmaceutical composition according to claim 6 or 7 for the preparation of an inhibitor having VISTA and PD-1/PD-L1 signaling pathway inhibitory activity as an immune checkpoint inhibitor, an anti-tumor drug, an anti-infective drug.
CN202311179753.9A 2023-09-13 2023-09-13 VISTA and PD-1/PD-L1 double-target small molecule inhibitor and preparation method and application thereof Pending CN116903554A (en)

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JP2003221386A (en) * 2001-11-26 2003-08-05 Takeda Chem Ind Ltd Bicylic derivative, method for producing the same, and use of the same
CN105061325A (en) * 2015-08-21 2015-11-18 洛阳师范学院 Synthesis method for biaryl benzimidazole compounds
CN111909108A (en) * 2019-09-02 2020-11-10 中国药科大学 Biphenyl compound and preparation method and medical application thereof
CN114524778A (en) * 2022-02-22 2022-05-24 药康众拓(江苏)医药科技有限公司 Benzo five-membered nitrogen-containing heterocyclic compound and preparation method and application thereof
CN116041277A (en) * 2023-01-18 2023-05-02 中国药科大学 Phenyl and biphenyl substituted five-membered heterocyclic compound, preparation method, pharmaceutical composition and application thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003221386A (en) * 2001-11-26 2003-08-05 Takeda Chem Ind Ltd Bicylic derivative, method for producing the same, and use of the same
CN105061325A (en) * 2015-08-21 2015-11-18 洛阳师范学院 Synthesis method for biaryl benzimidazole compounds
CN111909108A (en) * 2019-09-02 2020-11-10 中国药科大学 Biphenyl compound and preparation method and medical application thereof
CN114524778A (en) * 2022-02-22 2022-05-24 药康众拓(江苏)医药科技有限公司 Benzo five-membered nitrogen-containing heterocyclic compound and preparation method and application thereof
CN116041277A (en) * 2023-01-18 2023-05-02 中国药科大学 Phenyl and biphenyl substituted five-membered heterocyclic compound, preparation method, pharmaceutical composition and application thereof

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