Novel biphenyl derivative as well as preparation method and medical application thereof

Abstract

The invention relates to the field of medicinal chemistry, and discloses a biphenyl derivative with PD-1 / PD-L1 inhibitory activity as well as a preparation method and application thereof. The invention further discloses a composition containing the biphenyl derivative with the PD-1 / PD-L1 inhibitory activity or the pharmaceutically acceptable salt of the biphenyl derivative and a pharmaceutically acceptable carrier of the biphenyl derivative, and an application of the composition in preparation of a PD-1 / PD-L1 inhibitor. The compound can be used for treating tumors.

Description

technical field

[0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of biphenyl derivatives with PD-1 / PD-L1 inhibitory activity, a preparation method, a pharmaceutical composition containing these compounds and their use in treating tumors.

[0002] technical background

[0003] In recent years, tumor immunotherapy has become the focus in the field of tumor treatment. Unlike traditional treatments that directly target tumor cells, tumor immunotherapy uses the body's own immune system to kill tumor cells. The activation of the immune checkpoint pathway will inhibit the activation of T cells, prevent the excessive activation of the human immune system, maintain the immune tolerance of the normal body, and avoid the occurrence of autoimmune diseases. Tumors lead to tumor immune escape by overactivating immune checkpoint pathways by themselves and some lymphocytes. Among these immune checkpoints, the overactivation of PD-1 / PD-L1 ...

Examples

Embodiment 1

[0073] (4-((3'-(3-(4-(((1-carboxy-2-hydroxyethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propane Oxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl) Methoxy)benzyl)serine (II-1:R 1 and R 2 for R 3 and R 4 for -CH 3 , R 5 for Cl, R 6 for n=3) Synthesis

[0074] Synthesis of 3-bromo-2-methylphenol (IV-1)

[0075] Add 3-bromo-2-methylaniline (5.00g, 26.9mmol) into the three-necked flask, slowly drop into sulfuric acid solution (65mL, 1mmol / L) while stirring, and a large amount of insoluble white solids precipitate out. After dropping, lower the internal temperature of the reaction solution to 0-5°C, slowly add 30% sodium nitrite solution (2.23g, 32.3mmol) dropwise, yellow insoluble matter is formed, after dropping, lower the temperature to 0-5°C and stir for 30 minute. Toluene (30 mL) was added, and the temperature was raised to 100° C. to react for 1 hour. Stop the reaction after the reaction solution is clear and transparent, cool to ro...

Embodiment 2

[0113] 5-((4-chloro-2-(((2-hydroxyethyl)amino)methyl)-5-((3'-(3-(4-(((2-hydroxyethyl)amino)methyl Base)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy ) phenoxy) methyl) nicotinonitrile (II-2: R 1 and R 2 for R 3 and R 4 for -CH 3 , R 5 for Cl, R 6 for n=3) Synthesis

[0114] Dissolve compound XVI-1 (0.20g, 0.31mmol) and ethanolamine (57μL, 0.95mmol) in a mixed solution of dichloromethane (4mL) and methanol (2mL), stir at room temperature for 30min, and slowly add NaBH(OAc) 3 (0.81g, 3.80mmol), react at room temperature for 2 hours. TLC monitors that the reaction of raw materials is complete, and the reaction is stopped. Adjust the pH to 7 with saturated sodium bicarbonate solution, extract with dichloromethane (10mL×2), combine the organic phases, wash with water (10mL×2) and saturated sodium chloride solution (10mL×2), and anhydrous sodium sulfate Dry, filter with suction, and remove the solvent under reduced pressure to obtain a ligh...

Embodiment 3

[0117] N-(2-((4-((3'-(3-(4-(((2-acetylaminoethyl)amino)methyl)-1H-1,2,3-triazole-1- base)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridine-3 -yl) methoxy) benzyl) amino) ethyl) acetamide (II-3: R 1 and R 2 for R 3 and R 4 for -CH 3 , R 5 for Cl, R 6 for n=3) Synthesis

[0118] Compound XVI-1 (0.20g, 0.31mmol) and N-acetylethylenediamine (0.10g, 0.95mmol) were dissolved in dichloromethane (5mL) and added to the reaction flask successively, stirred at room temperature for 30min, and NaBH(OAc ) 3 (0.81g, 3.80mmol), react at room temperature for 2 hours. TLC monitors that the reaction of raw materials is complete, and the reaction is stopped. Adjust the pH to 7 with saturated sodium bicarbonate solution, extract with dichloromethane (10 mL×2), combine the organic phases, wash with water (10 mL×2) and saturated sodium chloride (10 mL×2), and dry over anhydrous sodium sulfate. Suction filtration, the solvent was removed under reduced pr...

technical field

[0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of biphenyl derivatives with PD-1 / PD-L1 inhibitory activity, a preparation method, a pharmaceutical composition containing these compounds and their use in treating tumors.

[0002] technical background

[0003] In recent years, tumor immunotherapy has become the focus in the field of tumor treatment. Unlike traditional treatments that directly target tumor cells, tumor immunotherapy uses the body's own immune system to kill tumor cells. The activation of the immune checkpoint pathway will inhibit the activation of T cells, prevent the excessive activation of the human immune system, maintain the immune tolerance of the normal body, and avoid the occurrence of autoimmune diseases. Tumors lead to tumor immune escape by overactivating immune checkpoint pathways by themselves and some lymphocytes. Among these immune checkpoints, the overactivation of PD-1 / PD-L1 ...

Examples

Embodiment 1

[0073] (4-((3'-(3-(4-(((1-carboxy-2-hydroxyethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propane Oxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl) Methoxy)benzyl)serine (II-1:R 1 and R 2 for R 3 and R 4 for -CH 3 , R 5 for Cl, R 6 for n=3) Synthesis

[0074] Synthesis of 3-bromo-2-methylphenol (IV-1)

[0075] Add 3-bromo-2-methylaniline (5.00g, 26.9mmol) into the three-necked flask, slowly drop into sulfuric acid solution (65mL, 1mmol / L) while stirring, and a large amount of insoluble white solids precipitate out. After dropping, lower the internal temperature of the reaction solution to 0-5°C, slowly add 30% sodium nitrite solution (2.23g, 32.3mmol) dropwise, yellow insoluble matter is formed, after dropping, lower the temperature to 0-5°C and stir for 30 minute. Toluene (30 mL) was added, and the temperature was raised to 100° C. to react for 1 hour. Stop the reaction after the reaction solution is clear and transparent, cool to ro...

Embodiment 2

[0113] 5-((4-chloro-2-(((2-hydroxyethyl)amino)methyl)-5-((3'-(3-(4-(((2-hydroxyethyl)amino)methyl Base)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy ) phenoxy) methyl) nicotinonitrile (II-2: R 1 and R 2 for R 3 and R 4 for -CH 3 , R 5 for Cl, R 6 for n=3) Synthesis

[0114] Dissolve compound XVI-1 (0.20g, 0.31mmol) and ethanolamine (57μL, 0.95mmol) in a mixed solution of dichloromethane (4mL) and methanol (2mL), stir at room temperature for 30min, and slowly add NaBH(OAc) 3 (0.81g, 3.80mmol), react at room temperature for 2 hours. TLC monitors that the reaction of raw materials is complete, and the reaction is stopped. Adjust the pH to 7 with saturated sodium bicarbonate solution, extract with dichloromethane (10mL×2), combine the organic phases, wash with water (10mL×2) and saturated sodium chloride solution (10mL×2), and anhydrous sodium sulfate Dry, filter with suction, and remove the solvent under reduced pressure to obtain a ligh...

Embodiment 3

[0117] N-(2-((4-((3'-(3-(4-(((2-acetylaminoethyl)amino)methyl)-1H-1,2,3-triazole-1- base)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridine-3 -yl) methoxy) benzyl) amino) ethyl) acetamide (II-3: R 1 and R 2 for R 3 and R 4 for -CH 3 , R 5 for Cl, R 6 for n=3) Synthesis

[0118] Compound XVI-1 (0.20g, 0.31mmol) and N-acetylethylenediamine (0.10g, 0.95mmol) were dissolved in dichloromethane (5mL) and added to the reaction flask successively, stirred at room temperature for 30min, and NaBH(OAc ) 3 (0.81g, 3.80mmol), react at room temperature for 2 hours. TLC monitors that the reaction of raw materials is complete, and the reaction is stopped. Adjust the pH to 7 with saturated sodium bicarbonate solution, extract with dichloromethane (10 mL×2), combine the organic phases, wash with water (10 mL×2) and saturated sodium chloride (10 mL×2), and dry over anhydrous sodium sulfate. Suction filtration, the solvent was removed under reduced pr...

Images