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Inhibitor compounds

A technology of compound, alkyl, applied in the field of compound of spindle checkpoint function

Active Publication Date: 2015-08-12
CANCER RES TECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This observation has led to the hypothesis that inhibition of Mps1 could have therapeutic benefit

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0878] (4-((5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)-3-methoxyphenyl )(3-methoxyazetidin-1-yl)methanone

[0879]

[0880] method 1

[0881] Make 2-(4-(3-chloroisoquinolin-5-yl)-1H-pyrazol-1-yl)-N,N-dimethylethylamine (preparation 1, 10mg, 0.033mmol), (4 -Amino-3-methoxyphenyl)(3-methoxyazetidin-1-yl)methanone (Formulation 28, 15.7 mg, 0.066 mmol), xantphos (11.5 mg, 0.02 mmol), Pd 2 (dba) 3 (3mg, 0.003mmol) and Cs 2 CO 3 (87 mg, 0.27 mmol) in toluene / DMF (3 / 1 mL) was stirred at 160 °C for 2 hours under microwave irradiation. The reaction mixture was filtered, diluted with NaCl solution and extracted with EtOAc. The organic layer was washed with 2M NH 3 Purified on an SCX-2 column eluting with / MeOH and concentrated in vacuo. The residue was purified by Biotage silica gel column chromatography eluting with 0-4% MeOH in EtOAc, followed by preparative HPLC to afford the title compound (5 mg, 30%).

[0882] 1 H NMR (500MHz, CDCl 3 ):δ9.07...

Embodiment 19

[0899] (3-methoxy-4-((5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)phenyl )(3-methoxyazetidin-1-yl)methanone

[0900]

[0901] To (3-methoxy-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)phenyl)(3 A solution of -methoxyazetidin-1-yl)methanone (Example 20, 18 mg, 0.035 mmol) in DCM / MeOH (4 / 2 mL) was added with acetic acid (2.5 μL, 0.044 mmol) and aqueous formaldehyde solution (38% w / w, 6.0 μL, 0.073 mmol), followed by sodium triacetoxyborohydride (11.2 mg, 0.053 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was washed with 2M NH 3 Purification by SCX-2 column eluting with / MeOH afforded the title compound (17 mg, 92%) as a yellow oil.

[0902] 1 H NMR (500MHz, CDCl 3 ): δ9.05(d, J=0.9Hz, 1H), 8.01(d, J=8.3Hz, 1H), 7.82(dt, J=8.3, 1.1Hz, 1H), 7.78(d, J=0.8Hz ,1H),7.69(d,J=0.8Hz,1H),7.54(dd,J=7.1,1.2Hz,1H),7.49(t,J=1.0Hz,1H),7.40-7.32(m,3H) ,7.20(dd,J=8.4,1.9Hz,...

Embodiment 20

[0906] (3-methoxy-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)phenyl)(3- Methoxyazetidin-1-yl)methanone

[0907]

[0908] 4-(4-(3-((2-methoxy-4-(3-methoxyazetidine-1-carbonyl)phenyl)-amino)isoquinoline-5 -yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (Example 3, 23 mg, 0.038 mmol) in DCM (8 mL) was added TFA (0.5 mL). The reaction was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was washed with 2M NH 3 Purification by SCX-2 column eluting with / MeOH afforded the title compound (19 mg, 98%) as a yellow oil.

[0909] 1 H NMR (500MHz, CDCl 3 ):δ9.05(d,J=0.9Hz,1H),8.00(d,J=8.3Hz,1H),7.81(d,J=8.1Hz,1H),7.77(s,1H),7.69(s ,1H),7.54(dd,J=7.1,1.3Hz,1H),7.50(s,1H),7.40-7.30(m,3H),7.20(dd,J=8.3,1.9Hz,1H),4.55- 4.35(m,2H),4.35-4.30(m,1H),4.29-4.20(m,2H),4.15-4.05(m,1H),3.96(s,3H),3.33(s,3H),3.32- 3.27 (m, 2H), 2.87-2.78 (m, 2H), 2.30-2.22 (m, 2H), 2.04-1.92 (m, 2H).

[0910] LCMS (ESI) Rt = ...

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Abstract

The present invention relates to compounds of formula (I), wherein R, R, Ar, W, X and Z are all as defined herein. The compounds of the present invention are known to inhibit the spindle checkpoint function of Monospindle 1 (Mps1 - also known as TTK) kinases either directly or indirectly via interaction with the Mps1 kinase itself. In particular, the present invention relates to the use of these compounds as therapeutic agents for the treatment and / or prevention of proliferative diseases, such as cancer. The present invention also relates to processes for the preparation of these compounds, and to pharmaceutical compositions comprising them.

Description

[0001] introduction [0002] The present invention relates to compounds that directly or indirectly inhibit the spindle checkpoint function of Mps1 kinase via interaction with the monopolar spindle 1 (Mps1, also known as TTK) kinase itself. In particular, the present invention relates to compounds useful as therapeutic agents for the treatment and / or prevention of proliferative diseases such as cancer. The invention also relates to processes for the preparation of these compounds, and to pharmaceutical compositions comprising these compounds. Background of the invention [0003] Cancer arises from uncontrolled and unregulated cell proliferation. Precisely what causes cells to become malignant and proliferate in an uncontrolled and unregulated manner has been the focus of intense research in recent decades. Such research has led to the targeting of surveillance mechanisms (such as those responsible for regulating the cell cycle) with anticancer agents. For example, published...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D413/14C07D401/04C07D405/04C07D471/04C07D519/00A61P35/00A61K31/4725A61K31/4375A61K31/519
CPCC07D413/14C07D519/00C07D471/04C07D405/04C07D401/04C07D401/14A61K31/519A61P35/00A61P43/00A61K31/4375A61K31/4725
Inventor 斯文·赫尔德J·布拉格萨瓦德·索兰基汉纳·伍德沃塞巴斯蒂安·诺德V·巴韦特西亚斯彼得·希德瑞克保罗·伊诺森蒂贵-明·J·张布特斯·阿特什
Owner CANCER RES TECH LTD
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