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New compounds inhibitors of the YAP/TAZ-TEAD interaction and their use in the treatment of malignant mesothelioma

一种化合物、O-R11的技术，应用在新化合物抑制剂领域，能够解决未报道抑制活性等问题

Active Publication Date: 2018-08-03
INVENTIVA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Two hydrogenated benzothiazole derivatives are disclosed that are different from the compounds disclosed in this application, but no YAP / TAZ-TEAD interaction inhibitory activity, let alone specific anticancer activity is reported

Method used

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  • New compounds inhibitors of the YAP/TAZ-TEAD interaction and their use in the treatment of malignant mesothelioma
  • New compounds inhibitors of the YAP/TAZ-TEAD interaction and their use in the treatment of malignant mesothelioma
  • New compounds inhibitors of the YAP/TAZ-TEAD interaction and their use in the treatment of malignant mesothelioma

Examples

Experimental program
Comparison scheme
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preparation example Construction

[0106] Such dosage forms, excipients and methods for their preparation are well known in the art, for example in (Handbook of pharmaceutical Excipients, Rowe et al., Seventh Edition, June 2012; Rules and Guidance For Pharma Manufacturers and distributors 205, Medecines and Healthcare products Regulatory Agency, UK, London).

[0107] Accordingly, the present invention also relates to inhibitors of the YAP / TAZ-TEAD interaction, and the use thereof of compounds of formula (I) as described herein, for therapy; in particular for the therapy in which YAP is localized in the nucleus of tumor cells For any cancer indication (such as lung cancer, thyroid cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, esophageal cancer, liver cancer, breast cancer and skin cancer); more particularly for the treatment of malignant mesothelioma use.

[0108] The present invention also relates to a method for the treatment of cancer in a patient in need thereof, comprising ...

Embodiment 1

[0208] Example 1: 4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-methyl-hydrazono]methyl]-2-methoxy -phenol

[0209] Step A: 3-Chloro-1,2-benzothiazole-1,1-dioxide

[0210]

[0211] A mixture of saccharin (4.00 g, 21.84 mmol, 1 equiv), thionyl chloride (2.38 mL, 32.75 mmol, 1.5 equiv) and a catalytic amount of DMF (120 μL) in 1,4-dioxane (20 mL) Heated at reflux for 24h. The reaction mixture was concentrated and the residue was recrystallized from toluene, filtered, washed with cold toluene and dried under vacuum at 50 °C to give a crushed white solid. The filtrate was concentrated under reduced pressure and recrystallized from toluene, filtered and washed with cold toluene. The combined solids were washed by cold toluene and dried under vacuum at 50 °C to yield 3-chloro-1,2-benzothiazole-1,1-dioxide (3.28 g, 74%). 1 H NMR (DMSO-d 6 , 300MHz): δ8.19 (dd, J = 1Hz, J = 7Hz, 1H); 7.99 (m, 3H).

[0212] Step B: 2-Methoxy-[4-(E)-(methylhydrazono)methyl]phenol

[0213]

[02...

Embodiment 2

[0218] Example 2: 4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-(2-hydroxyethyl)-hydrazono]methyl]- 2-methoxy-phenol

[0219] Step A: 4[(E)-(2-Hydroxyethylhydrazono)methyl]-2-methoxy-phenol

[0220]

[0221] Starting with 4-hydroxy-3-methoxybenzaldehyde (1.00 g, 6.57 mmol, 1 equiv) and 2-hydroxyethylhydrazine (446 μL, 6.57 mmol, 1 equiv), using the same method as detailed in Example 1, Step B The compound was prepared by the same procedure as above to give 4-[(E)-(2-hydroxyethylhydrazono)methyl]-2-methoxy-phenol (1.84 g, 89%) as a yellow solid. 1 H NMR (DMSO-d 6 , 300MHz): δ7.54(s, 1H); 7.08(d, J=1.8Hz, 1H); 6.82(dd, J=1.8Hz, J=8.4Hz, 1H); 6.74(d, J=8.4Hz ,1H); 3.79(s,3H); 3.54(t,J=6Hz,2H); 3.13(m,2H).

[0222] Step B: 4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-(2-hydroxyethyl)hydrazono]methyl]-2- Methoxy-phenol

[0223]

[0224] From 4-[(E)-(2-hydroxyethylhydrazono)methyl]-2-methoxy-phenol (800.0 mg, 3.81 mmol, 1.1 equivalents) and 3-chloro-1,2-benzo Starting with thi...

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Abstract

The invention relates to compounds of formula (I) wherein R1, R2, R3, R4, R5 and R6 are as defined in the description. The compounds of formula (I) are inhibitors of the YAP / TAZ-TEAD interaction.

Description

technical field [0001] The present invention relates to novel compound inhibitors of the YAP / TAZ-TEAD interaction and their use in therapy, especially in the treatment of malignant mesothelioma. Background technique [0002] The Hippo pathway regulates cell proliferation, cell death, and cell differentiation in multicellular organisms to ensure normal tissue development (Tumaneng K et al., Curr Biol, 2013, 22: R368-379; Yu Fx et al., Genes Dev, 2013, 27 : 355-371). Over the past few years, various genetic and biochemical studies in Drosophila and mammals have identified a highly conserved core hippo signaling module (Huang et al., Cell, 2005, 122:421-434; Zeng et al., Cancer Cell, 208, 13:188-192; Badouel et al., Curr Opin Cell Biol, 2009, 21:837-843). [0003] Essentially, the core hippo signaling module consists of the following members: Ste20-like kinase (MST1 / 2) and large tumor suppressor 1 / 2 (LATS1 / 2), and MOB activator 1A (MOB1A) and MOB1B and AGC (protein Kinase A ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12A61K31/428C07D275/06A61P35/00
CPCC07D417/12C07D275/06A61P35/00A61K31/428
Inventor 马丁·巴斯西尔维·孔塔尔克里斯蒂安·蒙塔尔贝蒂吕克·施皮策尔
Owner INVENTIVA
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