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Biphenyl derivative containing cyclopropane structure as well as preparation method and application of biphenyl derivative

A technology of derivatives and biphenyls, applied in the field of biphenyl derivatives and their preparation, can solve the problems of long half-life, poor bioavailability and high immunogenicity, and achieve the effect of novel structure

Pending Publication Date: 2022-02-25
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite the remarkable therapeutic success of these antibodies, there are still major drawbacks such as poor bioavailability, long half-life, immunogenicity, and high cost of large-scale production due to the fact that antibodies are macromolecular substances

Method used

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  • Biphenyl derivative containing cyclopropane structure as well as preparation method and application of biphenyl derivative
  • Biphenyl derivative containing cyclopropane structure as well as preparation method and application of biphenyl derivative
  • Biphenyl derivative containing cyclopropane structure as well as preparation method and application of biphenyl derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] The synthesis of embodiment 1 compound A-1:

[0067] The synthetic route is as follows:

[0068]

[0069]

[0070] Among them, a:Pd(PPh 3 ) 2 Cl 2 ,CuI,Et 3 N, rt; b: Pd 3 (dba) 2 , Na 2 CO 3 , Dioxane, X-phos, 70°C; c: K 2 CO 3 , MeOH, rt; d: CuCl, NaOtBu, DPEphos rt; e: CH 2 I 2 ,ZnEt 2 , CF 3 COOH,CH 2 Cl 2 ,0℃-rt; f:Pd(PPh 3 ) 4 ,Cs 2 CO 3 , Toluene, 100°C; g: NaBH 3 CN, AcOH, DMF, rt.

[0071] Concrete synthetic method comprises the following steps:

[0072] (1) Synthesis of compound 1-2:

[0073] Bistriphenylphosphine palladium dichloride (Pd(PPh 3 ) 2 Cl 2 , 0.56g, 0.8mmol) and cuprous iodide (CuI, 0.76g, 4mmol) dissolved in 100mL triethylamine (Et 3 N), added 2-chloro-6-iodotoluene (10 g, 40 mmol) under the protection of argon, cooled to 0 ° C, then slowly added trimethylsilylacetylene (12 mL, 80 mmol) with a syringe, and raised to room temperature until The response is complete. After the reaction, suction filtration was perfor...

Embodiment 2

[0085] The synthesis of embodiment 2 compound A-2

[0086] The synthetic route is as follows:

[0087]

[0088] The specific synthesis method is:

[0089] The synthesis of compound A-2 was the same as that of compound A-1 except that the compound ethanolamine was used instead of N-(2-aminoethyl)acetamide. The spectrum information of compound A-2 is as follows:

[0090] 1 H NMR (500MHz, CDCl 3 )δ7.42–7.35(m,3H),7.34–7.27(m,3H),7.20(t,J=7.5Hz,1H),7.16–7.08(m,2H),6.80(d,J=7.3Hz ,1H),3.94(s,3H),3.73(d,J=2.5Hz,2H),3.66(t,J=5.1Hz,2H),2.81–2.71(m,2H),2.60–2.56(m, 1H), 2.21(s,3H), 2.13–2.05(m,1H), 1.75–1.68(m,1H), 1.53–1.43(m,1H).

Embodiment 3

[0091] The synthesis of embodiment 3 compound A-3

[0092] The synthetic route is as follows:

[0093]

[0094] The specific synthesis method is:

[0095] The synthesis of compound A-3 was the same as that of compound A-1, except that compound 2-amino-2-methylpropionic acid was used instead of N-(2-aminoethyl)acetamide. The spectrum information of compound A-3 is as follows:

[0096] 1 H NMR (400MHz, CDCl 3 )δ7.58(d, J=7.5Hz, 1H), 7.37(t, J=7.3Hz, 2H), 7.31(d, J=7.1Hz, 1H), 7.28-7.23(m, 2H), 7.14( t,J=7.5Hz,1H),7.07(t,J=7.6Hz,2H),6.79(d,J=7.3Hz,1H),3.92(s,3H),3.89–3.75(m,2H), 2.59-2.54(m,1H),2.15(s,3H),2.09–1.98(m,1H),1.64(m,1H),1.39(s,6H),0.93–0.77(m,1H).

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Abstract

The invention belongs to the technical field of medicinal chemistry, particularly relates to a biphenyl derivative containing a cyclopropane structure and a preparation method and application of the biphenyl derivative. The invention provides the biphenyl derivative containing the cyclopropane structure in order to develop a small-molecule inhibitor for inhibiting a PD-1 / PD-L1 signal passage. The biphenyl derivative has a structure as shown in a general formula (I) which is described in the specification. The biphenyl derivative is novel in structure, and in vitro activity screening experiments prove that the biphenyl derivative has a strong PD-1 / PD-L1 signal passage inhibition effect, and can be used for preparing drugs for treating and / or preventing diseases caused by abnormal expression of PD-1 / PD-L1, especially drugs for treating and / or preventing cancers.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to biphenyl derivatives containing cyclopropane structure and a preparation method and application thereof. Background technique [0002] Tumor immunity is currently a powerful strategy for treating cancer. With the in-depth study of tumor immunity, it has been found that the tumor microenvironment can protect tumor cells from being recognized and killed by the body's immune system, and the immune escape of tumor cells plays a very important role in the occurrence and development of tumors. In 2013, Science magazine listed tumor immunotherapy as the first of the top ten breakthroughs, which once again made immunotherapy the focus of the field of tumor treatment. Several approaches to activate antitumor immunity, in particular modulation of immune checkpoint receptors, have recently been developed. [0003] Immune checkpoints are co-regulated or co-inhibited...

Claims

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Application Information

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IPC IPC(8): C07D213/64C07D213/30C07D401/06C07D405/10C07C255/54C07C309/14C07D309/14C07D207/12C07D207/16C07D295/205C07D211/46C07D319/18C07D317/58C07C229/14C07D271/12A61P35/00A61P31/04A61P31/12A61P5/16A61P3/10A61P1/04A61P25/00A61P29/00A61P19/02A61P7/06A61K31/198A61K31/216A61K31/277A61K31/4245A61K31/4406A61K31/445A61K31/40A61K31/495A61K31/351A61K31/4433A61K31/4427A61K31/4439A61K31/541A61K31/5377A61K31/4545A61K31/496A61K31/44
CPCC07D213/64C07D213/30C07D401/06C07D405/10C07C255/54C07C309/14C07D309/14C07D207/12C07D207/16C07D295/205C07D211/46C07D319/18C07D317/58C07C229/14C07D271/12A61P35/00A61P31/04A61P31/12A61P5/16A61P3/10A61P1/04A61P25/00A61P29/00A61P19/02A61P7/06C07C2601/02C07C2601/14Y02P20/55
Inventor 胡文浩荆同飞张小雷邱晃王元相岳晓彤
Owner SUN YAT SEN UNIV
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