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N2-phenyl-pyrido[3,4-d]pyrimidine-2,8-diamine derivatives and their use as MPS1 inhibitors

A technology of alkyl and cyano groups, which is applied in the direction of drug combination, medical preparations containing active ingredients, organic active ingredients, etc.

Active Publication Date: 2018-04-06
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 may have therapeutic benefit

Method used

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  • N2-phenyl-pyrido[3,4-d]pyrimidine-2,8-diamine derivatives and their use as MPS1 inhibitors
  • N2-phenyl-pyrido[3,4-d]pyrimidine-2,8-diamine derivatives and their use as MPS1 inhibitors
  • N2-phenyl-pyrido[3,4-d]pyrimidine-2,8-diamine derivatives and their use as MPS1 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0806] N2-(2-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-6-methyl-N8-neopentylpyridine And[3,4-d]pyrimidine-2,8-diamine

[0807]

[0808] method 1

[0809] To 6-methyl-2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine (preparation 4, 29 mg, 0.094 mmol) in DMSO (7 mL) The solution was added N-(2-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)formamide (Product 31, 22mg, 0.094mmol) and Cs 2 CO 3 (61 mg, 0.188 mmol). The reaction was heated to 100°C for 18 hours. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The residue was washed by using MeOH followed by 1M NH in MeOH 3 Purified by elution from SCX-2 cartridges to provide title compound (13.4 mg, 33%).

[0810] 1 H NMR (500MHz, MeOH-d 4 ): δppm 9.04 (s, 1H), 8.69 (d, J = 8.5Hz, 1H), 7.84 (s, 1H), 7.23 (d, J = 2.0Hz, 1H), 7.16 (d, J = 8.5, 2.0 Hz,1H),6.71(s,1H),4.16(s,3H),4.05(s,3H),3.47(s,2H),2.4...

Embodiment 2

[0814] N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-((3-methyltetra Hydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine

[0815]

[0816] To 6-methyl-2-(methylsulfonyl)-N-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidin-8-amine (Production 5, 34 mg, 0.101 mmol) in DMSO (7 mL) was added N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)methanol Amide (Product 32, 30mg, 0.121mmol) and Cs 2 CO 3 (66 mg, 0.202 mmol). The reaction was heated to 100°C for 18 hours. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The residue was chromatographed by silica gel column eluting with 0-10% MeOH in DCM followed by MeOH followed by 1M NH in MeOH 3 Purified by elution from SCX-2 cartridges to provide Title compound (27.6 mg, 58%).

[0817] 1 H NMR (500MHz, MeOH-d 4 ): δppm 9.06(s,1H),8.82(d,J=8.5Hz,1H),8.55(s,1H),7.40-7.37(m,2H),6.74(s,1H),4...

Embodiment 3

[0821] 1-(2-((2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido [3,4-d]pyrimidin-8-yl)-3-methylazetidine-3-carbonitrile

[0822]

[0823] To 3-methyl(6-methyl-2-(methylsulfonyl)-pyrido[3,4-d]pyrimidin-8-yl)azetidine-3-carbonitrile (product 7, 64mg , 0.202 mmol) in DMSO (7 mL) was added N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)formamide (Production 32, 60mg, 0.242mmol) and Cs 2 CO 3 (131 mg, 0.403 mmol). The reaction was heated to 100°C for 18 hours. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The residue was chromatographed by silica gel column eluting with 0-10% MeOH in DCM followed by MeOH followed by 1M NH in MeOH 3 Purified by elution from SCX-2 cartridges to provide Title compound (34.6 mg, 38%).

[0824] 1 H NMR (500MHz, MeOH-d 4 ): δppm 9.10(s, 1H), 8.56(s, 1H), 8.46(d, J=8.5Hz, 1H), 7.40(dd, J=8.5, 2.0Hz, 1H), 7.39(d, J=2.0...

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Abstract

The present invention relates to compounds of formula (I), wherein R1, R2, R3 and R4 are all as defined herein. It is known that the compounds of the present invention inhibit the spindle checkpoint function of Mps1 kinase directly or indirectly by interacting with the monospindle 1 (Mps1 - also known as TTK) 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 invention also relates to processes for the preparation of these compounds, and to pharmaceutical compositions comprising these compounds.

Description

[0001] introduce [0002] The present invention relates to compounds that directly or indirectly inhibit the spindle checkpoint function of Mps1 kinase through 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, publish...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04C07D519/00A61K31/519A61P35/00
CPCC07D519/00A61K31/519C07D471/04A61P35/00A61P43/00
Inventor 汉纳·伍德沃保罗·伊诺森蒂塞巴斯蒂安·诺德J·布拉格斯文·赫尔德
Owner CANCER RES TECH LTD
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