CN116768779B - Small molecular compound as immunomodulator, and composition and application thereof - Google Patents

Small molecular compound as immunomodulator, and composition and application thereof Download PDF

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CN116768779B
CN116768779B CN202310643519.0A CN202310643519A CN116768779B CN 116768779 B CN116768779 B CN 116768779B CN 202310643519 A CN202310643519 A CN 202310643519A CN 116768779 B CN116768779 B CN 116768779B
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CN116768779A (en
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耿巧红
焦培福
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Qilu Normal University
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Abstract

The invention relates to a small molecular compound serving as an immunomodulator, a composition and application thereof, and belongs to the technical field of pharmaceutical chemistry. The compounds of formula (I) are shown below:

Description

Small molecular compound as immunomodulator, and composition and application thereof
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a small molecular compound serving as an immunomodulator, a composition and application thereof.
Background
The interaction between the apoptosis receptor-1/the apoptosis receptor ligand-1 (PD-1/PD-L1) results in the occurrence of tumor immune escape. PD-1/PD-L1 interaction inhibitors can mobilize the immune system against tumors, have three characteristics of specificity, memory and durability, and have been developed as important means for tumor treatment. PD-1 is expressed on the surface of activated immune cells and negatively regulates immune system function. PD-1 has two ligands: PD-L1, PD-L2. Among them, PD-L1 (also called B7-H1) is highly expressed on the surfaces of various tumor cells, while PD-L2 (also called B7-DC) is expressed only on the surfaces of Dendritic Cells (DC), so that PD-L1 becomes an important target point for tumor immunotherapy. In T cell immunity, the interaction between PD-1/PD-L1 results in phosphorylation of the PD-1 Immunoreceptor Tyrosine Inhibitory Motif (ITIM) and immunoreceptor tyrosine inhibitory motif (ITSM) within killer T cells (Tc), activating apoptosis-related interactions downstream of Tc cells, ultimately leading to Tc cell disability or depletion. Inhibiting the interaction between PD-1/PD-L1 is equivalent to releasing the immune "brake" so that Tc cells re-recognize and clear tumor cells, thereby achieving the purpose of curing tumors. Various monoclonal antibody PD-1/PD-L1 interaction inhibitors are marketed in Europe and America and in the middle, japanese and Korean batches, and the application of the monoclonal antibody PD-1/PD-L1 interaction inhibitors relates to more than 20 malignant tumors such as lung cancer, melanoma, bladder cancer and the like. However, monoclonal antibody inhibitors still suffer from a number of drawbacks: 1) Can not be taken orally; 2) The benefit crowd is small, and only 20% of PD-L1 strong positive patients benefit remarkably; 3) Immune related side effects are greater, and the like.
Small molecule antagonists may be able to overcome the above drawbacks of monoclonal antibodies, becoming a new generation of PD-1/PD-L1 interaction inhibitors, mainly because: 1) The small molecule antagonists can be orally taken, so that the antagonists are more convenient to use; 2) After structural optimization, the small molecular antagonists can also enter the inside of the cell and act on PD-1 or PD-L1 with different forms in the cell, so that the proportion of benefited people can be increased; 3) The half-life of the small molecule inhibitor in the body is short, and immune related side effects (irAEs) can be eliminated in time in a drug stopping mode, so that the use is safer. Thus, the search for small molecule immunomodulators that can efficiently block PD-1/PD-L1 interactions is an important direction in tumor immunotherapy research.
Disclosure of Invention
Aiming at the technical problems that monoclonal antibody medicines cannot be orally taken and the like, the invention provides a small molecular compound serving as an immunomodulator, a composition and application thereof.
In a first aspect, the present invention provides a compound of formula (i):
wherein X is a bond or oxygen;
y is a bond, oxygen or methylene;
a is carbon;
w is nitrogen;
R 1 is hydrogen, hydroxy, methyl,
R 2 Is hydrogen, methyl,
R 3 Is hydrogen, benzyl,
R 4 Is hydrogen,R 5 Is hydrogen or methyl;
R 1 、R 2 、R 3 、R 4 not both hydrogen.
Preferably, X is a bond;
y is methylene;
a is carbon;
w is nitrogen;
R 1 is hydroxy group,R 2 Is->R 3 Is->R 4 、R 5 Is hydrogen.
Preferably, the compound of formula (i) is selected from the following compounds:
preferably, the compound of formula (i) is selected from the following compounds:
preferably, the compound of formula (i) is selected from the following compounds:
in a second aspect, the present invention provides a composition comprising a compound of formula (I); the composition further comprises an acceptable carrier or excipient.
In a third aspect, the present invention provides the use of a compound of formula (I) for the preparation of an inhibitor of PD-1/PD-L1 interaction.
The invention has the beneficial effects that:
the existing marketed drugs are monoclonal antibodies. Because the medicines cannot be orally taken, patients need to be periodically and intravenously administrated, and therefore, the medicines cannot be used as 'bedside medicines'. The small molecular compound can be developed into different types of solid oral preparations, can be used as a 'bedside medicine', is more convenient for patients to use, is more beneficial to the treatment of diseases, and provides a new direction for the research of tumor immunotherapy.
Detailed Description
In order to better understand the technical solutions of the present invention, the following description will clearly and completely describe the technical solutions of the embodiments of the present invention, and it is obvious that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the present invention without making any inventive effort, shall fall within the scope of the present invention.
EXAMPLE 1 preparation of Compound PF-2001 (1- ((2, 2 '-dimethyl- [1,1' -biphenyl ] -3-yl) methyl) -6-methoxy-1H-indole)
3-bromo-2-methylbenzyl alcohol (MW=201, 201g,1.0 mol), 2-methylbenzoboric acid (MW=136, 136g,1.0 mol), sodium carbonate (MW=106, 212g,2.0 mol) were dispersed in 1, 4-dioxane (2000 mL) under nitrogen protection, deionized (500 mL) was added, and PdCl was added 2 (dppf) (0.4 g), was reacted at 110℃for 12 hours. Cooled to room temperature, filtered with suction, the 1, 4-dioxane was concentrated off, and the mixture was extracted with dichloromethane (300 ml×2). The dichloromethane phase was washed twice with aqueous sodium carbonate (0.5 mol/L,300 mL. Times.2), dried over anhydrous magnesium sulfate, filtered off with suction, and the filter cake was washed twice with dichloromethane (100 mL. Times.2). The dichloromethane phases were combined and concentrated to dryness to give compound PF-200101 (mw=212, 193 g) in 91% yield.
MS(ESI,m/z):213.1[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ7.41(d,J＝7.5Hz,1H),7.31–7.17(m,4H),7.09–7.00(m,1H),6.95(d,J＝7.2Hz,1H),5.18(t,J＝5.4Hz,1H),4.56(d,J＝5.4Hz,2H),1.97(s,3H),1.91(s,3H)。
PF-200101 (MW=212, 212g,1.0 mol) was dispersed in dichloromethane (2500 mL), thionyl chloride (MW=119, 143g,1.2 mol) was added and reacted at room temperature for 3 hours. The reaction mixture was washed twice with water (3000 mL. Times.2), dried over anhydrous magnesium sulfate, filtered off with suction and the filter cake washed twice with dichloromethane (100 mL. Times.2). The dichloromethane phases were combined and concentrated to dryness to give compound PF-200102 (mw=230, 219 g) in 95% yield. MS (ESI, m/z): 231.1[ M+H ]] + 。
6-methoxyindole (MW=147, 14.7g,0.1 mol) was dissolved in N, N-dimethylformamide (200 mL) at 0-5℃and 60% sodium hydride (MW=24, 6.0g,0.15 mol) was added in portions and reacted for 30 minutes, and PF-200102 (MW=230, 25.3g,0.11 mol) was added dropwise. The reaction was continued for 6 hours at 0-25 ℃. Water (400 mL) was slowly added and extracted with dichloromethane (300 mL. Times.2). The dichloromethane phase was washed twice with saturated aqueous sodium carbonate (0.5 mol/L,300 mL. Times.2), dried over anhydrous magnesium sulfate, filtered off with suction, and the filter cake was washed twice with dichloromethane (100 mL. Times.2). The dichloromethane phases were combined and concentrated to dryness to give compound PF-2001 (mw=341, 25 g), 74% yield.
MS(ESI,m/z):342.1[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ7.47(d,J＝8.6Hz,1H),7.34–7.21(m,3H),7.18(d,J＝3.1Hz,1H),7.12(t,J＝7.6Hz,1H),7.07(d,J＝6.8Hz,1H),6.98(dd,J＝11.3,4.6Hz,2H),6.71(dd,J＝8.6,2.2Hz,1H),6.54(d,J＝7.6Hz,1H),6.45(d,J＝3.0Hz,1H),5.43(d,J＝2.3Hz,2H),3.74(s,3H),2.00(d,J＝1.7Hz,6H)。
13 C NMR(101MHz,DMSO-d 6 )δ156.15(s),142.02(s),141.61(s),137.45(s),137.15(s),135.76(s),133.52(s),130.23(s),129.58(s),128.61(s),128.14(s),127.77(s),126.39–125.72(m),122.75(s),121.51(s),109.58(s),101.61(s),94.17(s),55.79(s),48.02(s),40.63(s),40.43(s),40.22(s),40.01(s),39.80(s),39.59(s),39.38(s),19.99(s),15.74(s)。
EXAMPLE 2 preparation of the Compound PF-2002 (3-benzyl-1- ((2, 2 '-dimethyl- [1,1' -biphenyl ] -3-yl) methyl) -6-methoxy-1H-indole)
Triethylsilane (mw=116, 34.8g,0.3 mol) was dissolved in dichloromethane (300 mL) at 0-5 ℃, PF-2001 (mw=341, 34.1g,0.1 mol) was added, benzaldehyde (mw=106, 11.7g,0.11 mol) was added, and trifluoroacetic acid (mw=114, 17.1g,0.15 mol) was added. After the addition, the reaction was continued at 25℃for 2 hours. Methanol (300 mL) was slowly added to precipitate a solid. And (3) heating and refluxing to dissolve the solid, and cooling the solution to 25 ℃ to precipitate the solid. Suction filtration and washing of the solid with methanol (150 ml×2) gave PF-2002 (mw=431, 36 g) as a white solid in 84% yield.
MS(ESI,m/z):432.2[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ7.41–7.21(m,8H),7.21–7.09(m,2H),7.06(d,J＝6.7Hz,1H),6.99(d,J＝7.2Hz,1H),6.97–6.89(m,2H),6.72–6.54(m,2H),5.43–5.30(m,2H),4.02(s,2H),3.72(s,3H),1.97(d,J＝7.4Hz,6H)。
13 C NMR(101MHz,DMSO-d 6 )δ156.33(s),142.03(s),141.62(s),137.97(s),137.21(s),135.76(s),133.63(s),130.22(s),129.56(s),128.75(d,J＝19.7Hz),127.76(s),126.12(t,J＝8.6Hz),125.82(s),122.24(s),120.04(s),114.61(s),109.01(s),94.18(s),55.81(s),47.89(s),40.64(s),40.43(s),40.22(s),40.01(s),39.80(s),39.59(s),39.38(s),31.44(s),19.97(s),15.73(s)。
EXAMPLE 3 preparation of the Compound PF-2003 (1-benzyl-3- ((2, 2 '-dimethyl- [1,1' -biphenyl ] -3-yl) methyl) -5-methoxy-1H-indole)
PF-200101 (MW=212, 21.2g,0.1 mol) was dissolved in dichloromethane (300 mL) at 0-5℃and pyridinium chlorochromate PCC (MW=216, 21.6g,0.1 mol) was slowly added. After the addition, the reaction was continued at 0-5℃for 2 hours. The solid was filtered off with suction, the dichloromethane (150 mL. Times.2) phase was washed with 3N hydrochloric acid (100 mL. Times.6), with water (100 mL. Times.3), dried over anhydrous magnesium sulfate, filtered off with suction, and the filter cake was washed twice with dichloromethane (100 mL. Times.2). The dichloromethane phases were combined and concentrated to dryness to give PF-200301 (mw=210, 15 g) as a black solid in 71% yield. MS (ESI, m/z): 211.2[ M+H ]] + 。
Triethylsilane (mw=116, 34.8g,0.3 mol) was dissolved in dichloromethane (300 mL) at 0-5 ℃, 1-benzyl-5-methoxy-1H-indole (mw=237, 23.7g,0.1 mol) was added, PF-200301 (mw=210, 21.0g,0.1 mol) was added, and trifluoroacetic acid (mw=114, 17.1g,0.15 mol) was added. After the addition, the reaction was continued at 25℃for 2 hours. Methanol (300 mL) was slowly added to precipitate a solid. And (3) heating and refluxing to dissolve the solid, and cooling the solution to 25 ℃ to precipitate the solid. Suction filtration and washing of the solid with methanol (150 ml×2) gave PF-2003 (mw=431, 33 g) as a white solid in 77% yield.
MS(ESI,m/z):432.2[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ7.25(ddt,J＝13.0,10.0,8.0Hz,8H),7.19–7.08(m,3H),7.08–7.02(m,1H),7.02–6.96(m,2H),6.93(d,J＝6.3Hz,1H),6.74(dd,J＝8.9,2.4Hz,1H),5.31(s,2H),4.06(d,J＝3.7Hz,2H),3.72(s,3H),1.95(d,J＝3.5Hz,6H)。
EXAMPLE 4 preparation of Compound PF-2004 (3- ((2, 2 '-dimethyl- [1,1' -biphenyl ] -3-yl) methyl) -6-methoxy-1- (2-methylbenzyl) -1H-indole)
Triethylsilane (mw=116, 34.8g,0.3 mol) was dissolved in dichloromethane (300 mL) at 0-5 ℃, 1- (2-methylbenzyl) -6-methoxy-1H-indole (mw=251, 25.1g,0.1 mol) was added, PF-200301 (mw=210, 21.0g,0.1 mol) was added, and trifluoroacetic acid (mw=114, 17..1g,0.15 mol) was added. After the addition, the reaction was continued at 25℃for 2 hours. Methanol (300 mL) was slowly added to precipitate a solid. And (3) heating and refluxing to dissolve the solid, and cooling the solution to 25 ℃ to precipitate the solid. Suction filtration and washing of the solid with methanol (150 ml×2) gave PF-2004 (mw=445, 35 g) as a white solid in 79% yield.
MS(ESI,m/z):446.2[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ7..38(d,J＝8.6Hz,1H),7.25(ddd,,J＝9.0,6.0,1.8Hz,3H),7.21–7.13(m,4H),7.04(dd,J＝14.3,7.4Hz,2H),6.92(dd,J＝9.7,4.7Hz,2H),6.70–6.64(m,2H),6.60(d,J＝7.6Hz,1H),5.30(s,2H),4.05(d,J＝3.6Hz,2H),3.72(s,3H),2.25(s,3H),1.92(s,6H)。
EXAMPLE 5 preparation of Compound PF-2005 (1-benzyl-5-methoxy-3- ((2-methyl-4 '- (trifluoromethoxy) - [1,1' -biphenyl ] -3-yl) methyl) -1H-indole)
PF-200501 (MW=282, 28.2g,0.1 mol) was dissolved in methylene chloride (300 mL) at 0-5℃and pyridinium chlorochromate PCC (MW=216, 21.6g,0.1 mol) was slowly added. After the addition, the reaction was continued at 0-5℃for 2 hours. The solid was filtered off with suction, the dichloromethane (150 mL. Times.2) phase was washed with 3N hydrochloric acid (100 mL. Times.6), with water (100 mL. Times.3), dried over anhydrous magnesium sulfate, filtered off with suction, and the filter cake was washed twice with dichloromethane (100 mL. Times.2). The dichloromethane phases were combined and concentrated to dryness to give PF-200502 (mw=280, 23 g) as a black solid in 82% yield. MS (ESI, m/z): 281.1[ M+H ]] + 。
Triethylsilane (mw=116, 34.8g,0.3 mol) was dissolved in dichloromethane (300 mL) at 0-5 ℃, 1-benzyl-5-methoxy-1H-indole (mw=237, 23.7g,0.1 mol) was added, PF-200502 (mw=280, 28.0g,0.1 mol) was added, and trifluoroacetic acid (mw=114, 17.1g,0.15 mol) was added. After the addition, the reaction was continued at 25℃for 2 hours. Methanol (300 mL) was slowly added to precipitate a solid. And (3) heating and refluxing to dissolve the solid, and cooling the solution to 25 ℃ to precipitate the solid. Suction filtration and washing of the solid with methanol (150 ml×2) gave PF-2005 (mw=501, 29 g) as a white solid in 58% yield.
MS(ESI,m/z):502.2[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ7.43(s,4H),7.32–7.17(m,6H),7.15–7.10(m,2H),7.08(d,J＝4.6Hz,2H),6.99(d,J＝2.4Hz,1H),6.74(dd,J＝8.9,2.4Hz,1H),5.32(s,2H),4.08(s,2H),3.72(s,3H),2.17(s,3H)。
EXAMPLE 6 preparation of Compound PF-2006 (5-methoxy-3- ((2-methyl-4 '- (trifluoromethoxy) - [1,1' -biphenyl ] -3-yl) methyl) -1- (2-methylbenzyl) -1H-indole)
Triethylsilane (mw=116, 34.8g,0.3 mol) was dissolved in dichloromethane (300 mL) at 0-5 ℃, 1- (2-methylbenzyl) -5-methoxy-1H-indole (mw=251, 25.1g,0.1 mol) was added, PF-200502 (mw=280, 28.0g,0.1 mol) was added, and trifluoroacetic acid (mw=114, 17..1g,0.15 mol) was added. After the addition, the reaction was continued at 25℃for 2 hours. Methanol (300 mL) was slowly added to precipitate a solid. And (3) heating and refluxing to dissolve the solid, and cooling the solution to 25 ℃ to precipitate the solid. Suction filtration and washing of the solid with methanol (150 ml×2) gave PF-2006 (mw=515, 35 g) as a white solid, yield 68%.
MS(ESI,m/z):516.2[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ7.40(t,J＝5.0Hz,3H),7.22(dd,J＝9.6,6.4Hz,3H),7.20–7.11(m,3H),7.09–6.99(m,4H),6.90(s,1H),6.74(dd,J＝8.9,2.4Hz,,1H),6.48(d,J＝7.5Hz,1H),5.32(s,2H),4.08(s,2H),3.73(s,3H),2.26(s,3H),2.15(s,3H)。
EXAMPLE 7 preparation of Compound PF-2007 (1-benzyl-5-methoxy-3- (2-methylbenzyl) -1H-indole)
Triethylsilane (mw=116, 34.8g,0.3 mol) was dissolved in dichloromethane (300 mL) at 0-5 ℃, 1-benzyl-5-methoxy-1H-indole (mw=237, 23.7g,0.1 mol) was added, 2-methylbenzaldehyde (mw=120, 12.0g,0.1 mol) was added, and trifluoroacetic acid (mw=114, 17..1g,0.15 mol) was added. After the addition, the reaction was continued at 25℃for 2 hours. Methanol (300 mL) was slowly added to precipitate a solid. And (3) heating and refluxing to dissolve the solid, and cooling the solution to 25 ℃ to precipitate the solid. Suction filtration and washing of the solid with methanol (150 ml×2) gave PF-2007 (mw=341, 24 g) as a white solid in 70% yield.
MS(ESI,m/z):342.2[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ7.32–7.25(m,3H),7.24–7.14(m,3H),7.14–7.07(m,4H),7.04(s,1H),6.94(d,J＝2.3Hz,1H),6.73(dd,J＝8.8,2.4Hz,1H),5.31(s,2H),3.99(s,2H),3.70(s,3H),2.29(s,3H)。
Example 8 preparation of Compound PF-2008 (6-methoxy-1- ((2-methyl-4 '- (trifluoromethoxy) - [1,1' -biphenyl ] -3-yl) methyl) -1H-indole)
PF-200501 (MW=282, 28.2g,0.1 mol) was dispersed in methylene chloride (250 mL) at 25℃and thionyl chloride (MW=119, 14.3g,0.12 mol) was added thereto for reaction at 25℃for 3 hours. The reaction mixture was washed twice with water (300 mL. Times.2), dried over anhydrous magnesium sulfate, filtered off with suction, and the filter cake was washed twice with dichloromethane (100 mL. Times.2). The dichloromethane phases were combined and concentrated to dryness to give compound PF-200801 (mw=300, 28 g) in 93% yield. MS (ESI, m/z): 301.1 [ M+H ]] + 。
6-methoxyindole (MW=147, 14.7g,0.1 mol) was dissolved in N, N-dimethylformamide (200 mL) at 0-5℃and 60% sodium hydride (MW=24, 6.0g,0.15 mol) was added in portions and reacted for 30 minutes, and PF-200801 (MW=300, 33.0g,0.11 mol) was added dropwise. The reaction was continued for 6 hours at 0-25 ℃. Water (400 mL) was slowly added and extracted with dichloromethane (300 mL. Times.2). The dichloromethane phase was washed twice with saturated aqueous sodium carbonate (300 ml×2), dried over anhydrous magnesium sulfate, suction filtered and the filter cake was washed twice with dichloromethane (100 ml×2). The dichloromethane phases were combined and concentrated to dryness to give compound PF-2008 (mw=411, 29 g), yield 71%.
MS(ESI,m/z):412.1[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ7.50–7.42(m,5H),7.20(d,J＝3.1Hz,1H),7.14(d,J＝4.5Hz,2H),6.99(d,J＝1.7Hz,1H),6.72(dd,J＝8.6,2.2Hz,1H),6.46(q,J＝3.2Hz,2H),5.45(s,2H),3.74(s,3H),2.22(s,3H)。
EXAMPLE 9 preparation of Compound PF-2009 (3-benzyl-6-methoxy-1- (2-methylbenzyl) -1H-indole)
Triethylsilane (mw=116, 34.8g,0.3 mol) was dissolved in dichloromethane (300 mL) at 0-5 ℃, 1- (2-methylbenzyl) -6-methoxy-1H-indole (mw=251, 25.1g,0.1 mol) was added, benzaldehyde (mw=106, 10.6g,0.1 mol) was added, and trifluoroacetic acid (mw=114, 17..1g,0.15 mol) was added. After the addition, the reaction was continued at 25℃for 2 hours. Methanol (300 mL) was slowly added to precipitate a solid. And (3) heating and refluxing to dissolve the solid, and cooling the solution to 25 ℃ to precipitate the solid. Suction filtration and washing of the solid with methanol (150 ml×2) gave PF-2009 (mw=341, 27 g) as a white solid in 80% yield.
MS(ESI,m/z):342.2[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ7.32–7.24(m,4H),7.24–7.12(m,4H),7.09–7.02(m,2H),6.95(d,J＝2.3Hz,1H),6.72(dd,J＝8.8,2.4Hz,1H),6..55(d,J＝7.6Hz,1H),5.32(s,2H),4.03(s,2H),3.71(s,3H),2.28(s,3H)。
EXAMPLE 10 preparation of Compound PF-2010 (1-benzyl-3- (3-bromo-2-methylbenzyl) -6-methoxy-1H-indole)
Triethylsilane (mw=116, 34.8g,0.3 mol) was dissolved in dichloromethane (300 mL) at 0-5 ℃, 1-benzyl-6-methoxy-1H-indole (mw=237, 23.7g,0.1 mol) was added, 3-bromo-2-methylbenzaldehyde (mw=198, 19.8g,0.1 mol) was added, and trifluoroacetic acid (mw=114, 17..1g,0.15 mol) was added. After the addition, the reaction was continued at 25℃for 2 hours. Methanol (300 mL) was slowly added to precipitate a solid. And (3) heating and refluxing to dissolve the solid, and cooling the solution to 25 ℃ to precipitate the solid. Suction filtration and washing of the solid with methanol (150 ml×2) gave PF-2010 (mw=419, 30 g) as a white solid in 72% yield.
MS(ESI,m/z):419.1[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ7.45(d,J＝7.9Hz,1H),7.31(dd,J＝14.3,8.0Hz,3H),7.26–7.18(m,2H),7.15(d,J＝7.1Hz,2H),7.05(t,J＝7.8Hz,1H),6.98–6.91(m,2H),6.65(dd,J＝8.6,2.2Hz,1H),5.31(s,2H),4.07(s,2H),3.73(s,3H),2.35(s,3H)。
EXAMPLE 11 preparation of Compound PF-2011 (3- (3-bromo-2-methylbenzyl) -5-methoxy-1- (2-methylbenzyl) -1H-indole)
Triethylsilane (mw=116, 34.8g,0.3 mol) was dissolved in dichloromethane (300 mL) at 0-5 ℃, 1- (2-methylbenzyl) -5-methoxy-1H-indole (mw=251, 25.1g,0.1 mol) was added, 3-bromo-2-methylbenzaldehyde (mw=198, 19.8g,0.1 mol) was added, and trifluoroacetic acid (mw=114, 17.1g,0.15 mol) was added. After the addition, the reaction was continued at 25℃for 2 hours. Methanol (300 mL) was slowly added to precipitate a solid. And (3) heating and refluxing to dissolve the solid, and cooling the solution to 25 ℃ to precipitate the solid. Suction filtration and washing of the solid with methanol (150 ml×2) gave PF-2010 (mw=433, 29 g) as a white solid in 67% yield.
MS(ESI,m/z):434.1[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ7.46(d,J＝7.9Hz,1H),7.18(ddd,J＝21.8,15.1,7.2Hz,4H),7.10–7.00(m,2H),6.98(d,J＝2.3Hz,1H),6.88(s,1H),6.74(dd,J＝8.8,2.3Hz,1H),6.46(d,J＝7.6Hz,1H),5.31(s,2H),4.09(s,2H),3.72(s,3H),2.35(s,3H),2.26(s,3H)。
Example 12 preparation of Compound PF-2012 (1- ((2, 2 '-dimethyl- [1,1' -biphenyl ] -3-yl) methyl) -5-methoxy-1H-indole)
5-methoxyindole (MW=147, 14.7g,0.1 mol) was dissolved in N, N-dimethylformamide (200 mL) at 0-5℃and 60% sodium hydride (MW=24, 6.0g,0.15 mol) was added in portions and reacted for 30 minutes, and PF-200102 (MW=230, 25.3g,0.11 mol) was added dropwise. The reaction was continued for 6 hours at 0-25 ℃. Water (400 mL) was slowly added and extracted with dichloromethane (300 mL. Times.2). The dichloromethane phase was washed twice with saturated aqueous sodium carbonate (300 ml×2), dried over anhydrous magnesium sulfate, suction filtered and the filter cake was washed twice with dichloromethane (100 ml×2). The dichloromethane phases were combined and concentrated to dryness to give compound PF-2012 (mw=341, 25 g), 73% yield.
MS(ESI,m/z):342.1[M+H] + 。
EXAMPLE 13 preparation of Compound PF-2013 (1-benzyl-3- ((2, 2 '-dimethyl- [1,1' -biphenyl ] -3-yl) methyl) -1H-indol-5-ol)
PF-2003 (MW=431, 43.1g,0.1 mol) was dissolved in methylene chloride (400 mL) at 0-5℃and boron tribromide (MW=248, 27.3g,0.11 mol) was added. The reaction was continued for 2 hours at 0-5 ℃. Methanol (100 mL) was slowly added, stirred for 30 min, saturated aqueous sodium bicarbonate (400 mL) was added, the solution was separated, the dichloromethane phase was washed with saturated brine (150 ml×2), the dichloromethane phase was dried over anhydrous magnesium sulfate, suction filtered, and concentrated to dryness to give brown solid PF-2013 (mw=417, 40 g), 96% yield.
MS(ESI,m/z):416.2[M-H] - 。
EXAMPLE 14 preparation of the Compound PF-2014 (1-benzyl-3- ((2, 2 '-dimethyl- [1,1' -biphenyl ] -3-yl) methyl) -6- ((dimethylamino) methyl) -1H-indol-5-ol)
PF-2013 (MW=417, 41.7g,0.1 mol) was dissolved in N, N-dimethylformamide (200 mL) at 0-5℃and aqueous dimethylamine (40%, MW=45, 13..5g,0.12 mol) was added, followed by dropwise addition of aqueous formaldehyde (37%, MW=30, 9.7g,0.12 mol). After the completion of the dropwise addition, the reaction was continued at 25℃for 4 hours. Slowly adding water (1000 mL), precipitating brown solid, suction filtering, and oven drying to obtain brown solid PF-2014 (MW=474, 36 g), yield 76%.
MS(ESI,m/z):475.2[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ7..29(dtd,J＝9.7,7.1,3.7Hz,6H),,7.19(d,J＝8.6Hz,3H),7.06(dd,J＝7.6,5.4Hz,3H),6.92(d,J＝7.4Hz,1H),6.81(d,,J＝7.3Hz,1H),6.59(d,J＝8.7Hz,1H),5.30(s,2H),4.15(q,J＝16.9Hz,2H),3.63(d,J＝4.9Hz,2H),2.02(d,J＝5.8Hz,12H)。
Example 15 preparation of the Compound PF-2015 (3- ((1-benzyl-3- ((2, 2 '-dimethyl- [1,1' -biphenyl ] -3-yl) methyl) -6- ((dimethylamino) methyl) -1H-indol-5-yl) oxy) methyl) benzonitrile
PF-2014 (MW=474, 4.74g,0.01 mol) was dissolved in 1, 4-dioxane (50 mL) at 25℃and potassium tert-butoxide (MW=112, 1.23g,0.01 mol) was added and m-cyanobenzyl bromide (MW=195, 2.34g,0.012 mol) was added. After the addition, the reaction was continued at 90℃for 12 hours. Slowly adding water (250 mL), precipitating a white solid, carrying out suction filtration and drying to obtain white solid PF-2015 (MW=589, 3.20 g) with a yield of 54%.
MS(ESI,m/z):590.2[M+H] + 。
EXAMPLE 16 preparation of the Compound PF-2016 (1-benzyl-5-methoxy-3- ((2-methyl- [1,1' -biphenyl ] -3-yl) methyl) -1H-indole)
Triethylsilane (mw=116, 34.8g,0.3 mol) was dissolved in dichloromethane (300 mL) at 0-5 ℃, 1-benzyl-5-methoxy-1H-indole (mw=237, 23.7g,0.1 mol) was added, 3-phenyl-2-methylbenzaldehyde (mw=196, 19.6g,0.1 mol) was added, and trifluoroacetic acid (mw=114, 17.1g,0.15 mol) was added. After the addition, the reaction was continued at 25℃for 2 hours. Methanol (300 mL) was slowly added to precipitate a solid. And (3) heating and refluxing to dissolve the solid, and cooling the solution to 25 ℃ to precipitate the solid. Suction filtration and washing of the solid with methanol (150 ml×2) gave PF-2016 (mw=417, 36 g) as a white solid in 86% yield.
MS(ESI,m/z):418.2[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ7.44(t,J＝7.3Hz,2H),7.39–7..32(m,1H),7.29(dt,J＝10.6,6.0Hz,5H),7.25–7.10(m,5H),7.10–7.03(m,2H),7.00(d,J＝2.4Hz,1H),6.74(dd,J＝8.8,2.4Hz,1H),5.32(s,2H),4.07(s,2H),3.72(s,3H),2.17(s,3H)。
EXAMPLE 17 preparation of Compound PF-2017 (1-benzyl-3- ((2-methyl- [1,1' -biphenyl ] -3-yl) methyl) -1H-indol-5-ol)
PF-2016 (MW=417, 41.7g,0.1 mol) was dissolved in methylene chloride (400 mL) at 0-5℃and boron tribromide (MW=248, 27.3g,0.11 mol) was added. The reaction was continued for 2 hours at 0-5 ℃. Methanol (100 mL) was slowly added, stirred for 30 minutes, saturated aqueous sodium bicarbonate (400 mL) was added, the solution was separated, the dichloromethane phase was washed with saturated brine (150 ml×2), the dichloromethane phase was dried over anhydrous magnesium sulfate, suction filtered, and concentrated to dryness to give brown solid PF-2017 (mw=403, 38 g) in 94% yield.
MS(ESI,m/z):402.2[M-H] - 。
Example 18 preparation of the Compound PF-2018 (1-benzyl-6- ((dimethylamino) methyl) -3- ((2-methyl- [1,1' -biphenyl ] -3-yl) methyl) -1H-indol-5-ol)
PF-2017 (MW=403, 40.3g,0.1 mol) was dissolved in N, N-dimethylformamide (200 mL) at 0-5℃and aqueous dimethylamine (40%, MW=45, 13..5g,0.12 mol) was added, followed by dropwise addition of aqueous formaldehyde (37%, MW=30, 9.7g,0.12 mol). After the completion of the dropwise addition, the reaction was continued at 25℃for 4 hours. Slowly adding water (1000 mL), precipitating brown solid, suction filtering, and oven drying to obtain brown solid PF-2018 (MW=460, 36 g), yield 76%.
MS(ESI,m/z):461.2[M+H] + 。
Example 19 preparation of Compound PF-2019 (3- ((1-benzyl-6- ((dimethylamino) methyl) -3- ((2-methyl- [1,1' -biphenyl ] -3-yl) methyl) -1H-indol-5-yl) oxy) methyl) benzonitrile
PF-2018 (MW=460, 4.60g,0.01 mol) was dissolved in 1, 4-dioxane (50 mL) at 25℃and potassium tert-butoxide (MW=112, 1.23g,0.01 mol) was added and m-cyanobenzyl bromide (MW=195, 2.34g,0.012 mol) was added. After the addition, the reaction was continued at 90℃for 12 hours. Slowly adding water (250 mL), precipitating white solid, suction filtering, and oven drying to obtain white solid PF-2019 (MW=575, 2.63 g) with 46% yield.
MS(ESI,m/z):576.2[M+H] + 。
Example 20
Preparation of the Compound PF-2020 (1-benzyl-3- ((2-methyl-4 '- (trifluoromethoxy) - [1,1' -biphenyl ] -3-yl) methyl) -1H-indol-5-ol)
PF-2005 (MW=501, 50.1g,0.1 mol) was dissolved in dichloromethane (400 mL) at 0-5℃and boron tribromide (MW=248, 27.3g,0.11 mol) was added. The reaction was continued for 2 hours at 0-5 ℃. Methanol (100 mL) was slowly added, stirred for 30 minutes, saturated aqueous sodium bicarbonate (400 mL) was added, the solution was separated, the dichloromethane phase was washed with saturated brine (150 ml×2), the dichloromethane phase was dried over anhydrous magnesium sulfate, suction filtered, and concentrated to dryness to give brown solid PF-2020 (mw=487, 36 g) in 74% yield.
MS(ESI,m/z):486.2[M-H] - 。
EXAMPLE 21 preparation of Compound PF-2021 (((1-benzyl-5-hydroxy-3- ((2-methyl-4 '- (trifluoromethoxy) - [1,1' -biphenyl ] -3-yl) methyl) -1H-indol-6-yl) methyl) -L-proline)
PF-2020 (MW=487, 48.7g,0.1 mol) was dissolved in N, N-dimethylformamide (200 mL) at 0-5℃and L-proline (MW=115, 13.8g,0.12 mol) was added thereto, and an aqueous formaldehyde solution (37%, MW=30, 9.7g,0.12 mol) was added dropwise. After the completion of the dropwise addition, the reaction was continued at 25℃for 4 hours. Water (1000 mL) was slowly added to precipitate a white solid, which was suction filtered and dried to give PF-2021 (MW=614, 39 g) as a white solid in 64% yield.
MS(ESI,m/z):613.2[M-H] - 。
EXAMPLE 22 preparation of the Compound PF-2022 (methyl ((1-benzyl-5-hydroxy-3- ((2-methyl-4 '- (trifluoromethoxy) - [1,1' -biphenyl ] -3-yl) methyl) -1H-indol-6-yl) methyl) -L-proline)
PF-2021 (MW=614, 6.14g,0.01 mol) was dispersed in methanol (60 mL) at 0-5℃and thionyl chloride (MW=119, 2.38g,0.02 mol) was added. After the completion of the dropwise addition, the reaction mixture was heated to 40℃and the reaction was continued for 6 hours. Concentrating to dryness to obtain white solid. The white solid was dissolved in ethyl acetate (60 mL) and washed with saturated aqueous sodium bicarbonate (60 mL. Times.3). The ethyl acetate phase was dried over anhydrous magnesium sulfate, filtered off with suction and concentrated to dryness to give compound PF-2022 (mw=628, 4.30 g) in 68% yield.
MS(ESI,m/z):629.2[M+H] + 。
Example 23
Preparation of the Compound PF-2023 (methyl ((1-benzyl-3- ((2-methyl-4 '- (trifluoromethoxy) - [1,1' -biphenyl ] -3-yl) methyl) -5- ((4- (trifluoromethyl) benzyl) oxy) -1H-indol-6-yl) methyl) -L-proline)
PF-2022 (MW=628, 6.28g,0.01 mol) was dissolved in 1, 4-dioxane (50 mL) at 25℃and potassium tert-butoxide (MW=112, 1.23g,0.01 mol) was added and p-trifluoromethylchlorobenzyl (MW=195, 2.34g,0.012 mol) was added. After the addition, the reaction was continued at 90℃for 12 hours. Water (250 mL) was slowly added to precipitate a white solid, which was suction filtered and dried to give PF-2023 (MW=786, 4.36 g) as a white solid in 55% yield.
MS(ESI,m/z):787.2[M+H] + 。
EXAMPLE 24 preparation of Compound PF-2024 ((R) - ((1- ((1-benzyl-3- ((2-methyl-4 '- (trifluoromethoxy) - [1,1' -biphenyl ] -3-yl) methyl) -5- ((4- (trifluoromethyl) benzyl) oxy) -1H-indol-6-yl) methyl) pyrrolidin-2-yl) - λ3-oxy) - λ3-methanone)
PF-2023 (MW=786, 0.786g,0.001 mol) was dissolved in methanol (10 mL) at 25℃and sodium hydroxide (MW=40, 0.044g,0.0011 mol) was added and water (MW=18, 1.8g,0.10 mol) was added. After the addition, the reaction was continued at 70℃for 12 hours. Ph=6.5 was adjusted with 6N hydrochloric acid and concentrated to dryness to give a white solid. The white solid was washed with water (5 ml×2), suction filtered and dried to give compound PF-2024 (mw=772, 0.693 g) in 55% yield.
MS(ESI,m/z):771.2[M-H] - 。
1 H NMR(400MHz,DMSO-d 6 )δ7.77(s,4H),7.44(d,J＝11.4Hz,5H),7.32–7.23(m,3H),7.14(dt,J＝15.8,7.9Hz,4H),7.02(dd,J＝18.6,9.3Hz,3H),5.32(d,J＝22.1Hz,4H),4.31(ddd,J＝22.1,20.3,11.1Hz,4H),2.82–2.62(m,2H),2.18(s,3H),1.91(d,J＝5.6Hz,2H),1.64(d,J＝24.8Hz,2H)。
EXAMPLE 25 preparation of Compound PF-2025 (N- ((1-benzyl-3- ((2, 2 '-dimethyl- [1,1' -biphenyl ] -3-yl) methyl) -5-hydroxy-1H-indol-6-yl) methyl) -N-methylglycine)
PF-2013 (MW=417, 41.7g,0.1 mol) was dissolved in N, N-dimethylformamide (200 mL) at 0-5℃and sarcosine (MW=89, 10.7g,0.12 mol) was added thereto, and aqueous formaldehyde solution (37%, MW=30, 9.7g,0.12 mol) was added dropwise. After the completion of the dropwise addition, the reaction was continued at 25℃for 4 hours. Water (1000 mL) was slowly added to precipitate a grey solid, which was filtered off with suction and dried to give PF-2025 (MW=518, 33 g) as a grey solid in 76% yield.
MS(ESI,m/z):517.2[M-H] - 。
1 H NMR(600MHz,DMSO-d 6 )δ7.26(ddd,J＝32.3,14.5,8.0Hz,7H),7.16(d,J＝7.4Hz,2H),7.13–7.03(m,2H),6.99–6.90(m,2H),6.86(d,J＝7.6Hz,1H),6.63(d,J＝8.7Hz,1H),5.29(s,2H),4.17(dd,J＝43.7,16.8Hz,2H),3.87(d,J＝2.7Hz,2H),3.05(s,2H),2.13(s,3H),1.99(d,J＝13.1Hz,6H)。
EXAMPLE 26 preparation of Compound PF-2026 (N- ((1-benzyl-3- ((2, 2 '-dimethyl- [1,1' -biphenyl ] -3-yl) methyl) -5- ((4- (trifluoromethyl) benzyl) oxy) -1H-indol-6-yl) methyl) -N-methylglycine)
PF-2025 (MW=518, 0.518g,0.001 mol) was dissolved in 1, 4-dioxane (10 mL) at 25℃and potassium tert-butoxide (MW=112, 0.246g,0.0022 mol) was added and p-trifluoromethylchlorobenzyl (MW=195, 0.463 g,0.0024 mol) was added. After the addition, the reaction was continued at 90℃for 12 hours. The reaction was cooled to 25 ℃, sodium hydroxide (mw=40, 0.044g,0.0011 mol) was added, and water (mw=18, 1.8g,0..10 mol) was added. After the addition, the reaction was continued at 70℃for 12 hours. Ph=6.5 was adjusted with 6N hydrochloric acid and concentrated to dryness to give a white solid. The white solid was washed with water (5 ml×2), washed with methanol (5 ml×2), suction filtered and dried to give compound PF-2026 (mw=676, 0.096g) in 14% yield.
MS(ESI,m/z):675.2[M-H] - 。
EXAMPLE 27PD-1/PD-L1 interaction inhibition Activity Studies
The ability of compounds to block PD-1/PD-L1 interactions was analyzed with the Perkin Elmer alpha LISA PD-1and PD-L1Binding Kit (Product Code: AL356 HV). The Biotin (Biotin) and the Streptavidin (strepitavidin) can be specifically combined and have strong binding force. The binding between biotin-labeled human PD-1and streptavidin-coated donor beads was performed in this manner. The 6-histidine motif (His) -tagged PD-L1 binds to the anti-His antibody-linked receptor bead. When PD-1and PD-L1 interact, the donor and acceptor beads come into proximity with each other. Under 680nm excitation light, the donor beads produced singlet oxygen. In solution, this singlet oxygen diffuses and activates the acceptor bead, and then produces strong emission light at 615 nm. If the compound is capable of blocking the interaction between PD-1/PD-L1, the emission is quenched. The specific experimental procedure was carried out according to the procedure provided by the kit, briefly described as follows: compound mother liquor (DMSO solution) was diluted with kit immunosuffer to give compound solutions of different concentrations. 10. Mu.L of compound solutions of different concentrations were added to HTRF 96 white low capacity plates; mu.L of biotin-labeled PD-1 (final concentration of 5 nM) and 10. Mu.L of 6-histidine motif (His) -labeled PD-L1 (final concentration of 5 nM) were added per well; mu.L of a mixture of streptavidin donor beads (final concentration of 20. Mu.g/mL) and Anti-6xHIS antibody acceptor beads (final concentration of 10. Mu.g/mL) was added to each well; incubation was carried out at room temperature for 90 minutes in the absence of light, and the 615nm emission was detected with an EnVision-Alpha. Compounds block the ability of PD-1/PD-L1 interactions (IC 50 Values) were calculated as Sigmaplot by linear regression analysis.
The biochemical analysis results of the compounds of the examples of the present invention are shown in table 1.
Table 1 biochemical IC of the compounds of the examples 50 Value of
In the tables, A represents 0 to 200nM, B represents 201 to 1000nM, and C represents ≡1001nM.
Although the present invention has been described in detail by way of preferred embodiments, the present invention is not limited thereto. Various equivalent modifications and substitutions may be made in the embodiments of the present invention by those skilled in the art without departing from the spirit and scope of the present invention, and it is intended that all such modifications and substitutions be within the scope of the present invention/be within the scope of the present invention as defined by the appended claims.

Claims (4)

1. A small molecule compound as an immunomodulator, characterized by being selected from the group consisting of:
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2. a small molecule compound as claimed in claim 1 as an immunomodulator selected from the following:
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3. a composition comprising the small molecule compound according to claim 1 as an immunomodulator.
4. Use of a small molecule compound according to claim 1 as an immunomodulator for the preparation of a PD-1/PD-L1 interaction inhibitor.
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