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MNK inhibitors

One-NH2, compound technology, applied in the field of novel MNK inhibitors

Pending Publication Date: 2020-06-09
SHANGHAI DE NOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although the research on MNKs continues to deepen, and some small molecule entities have entered the clinical research stage, there is no real MNK inhibitor that has entered the market. With the continuous in-depth research on the structure-activity relationship of MNK inhibitors, the present invention discloses a new class of MNK inhibitor with good inhibitory effect on MNK1 and MNK2

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0442] Example 1: 7'-((6-aminopyrimidin-4-yl)amino)-5'-methylspiro[cyclohexane-1,2'-pyrido[2,1-f][1,2 ,4]Triazine]-4',8'(1'H,3'H)-dione hydrochloride (compound 1-1) synthesis

[0443]

[0444] Step 1: Intermediate 1.1 (100 mg, 0.3 mmol), tert-butyl 6-aminopyrimidine-4-carbamate (77.3 mg, 0.37 mmol), Pd 2 (dba) 3 (15mg), Xantphos (15mg), Cs 2 CO 3 (200 mg, 0.61 mmol) and 1,4-dioxane (2.5 mL) were replaced with nitrogen three times, and then the reaction system was heated to 85° C. and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, the residue was slurried with ethanol (2.5mL), filtered, the filter cake was rinsed with a small amount of cold ethanol, and the filter cake was vacuum-dried to obtain (6-((5'-methyl-4',8' -Dicarbonyl-1',3',4',8'-tetrahydrospiro[cyclohexane-1,2'-pyridine[2,1-f][1,2,4]triazine]-7' -yl)amino)pyrimidin-4-yl)tert-butyl carbamate (200 mg, crude) as a yellow solid. m / z:[M+H] + 456.0.

[0445] Step 2: Under ice...

Embodiment 2

[0446] Example 2: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5'-methylspiro[cyclohexane-1,2'-pyrido[2, Synthesis of 1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (compound 1-2)

[0447]

[0448] Intermediate 1.1 (50mg, 0.15mmol), 7H-pyrrolo[2,3-d]pyrimidin-4-amine (25mg, 0.18mmol), Pd 2 (dba) 3 (10mg), Xantphos (10mg), Cs 2 CO 3 (100 mg, 0.3 mmol) and 1,4-dioxane (1.2 mL) were replaced with nitrogen three times, and then the reaction system was heated to 95° C. and stirred for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by prep-HPLC (separation condition 2) to obtain compound 1-2 (20 mg, yield: 34%) as a yellow solid. m / z:[M+H] + 380.0; 1 H NMR (400MHz, DMSO-d 6 ):δ12.42(s,1H),9.75(br.s,1H),9.03(s,1H),8.45(s,1H),8.21(s,1H),7.46(s,1H),6.89( s,1H),2.49(s,3H),1.75-1.25(m,10H).

Embodiment 3

[0449] Example 3: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5'-chlorospiro[cyclohexane-1,2'-pyrido[2,1 Synthesis of -f][1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (compound 1-3)

[0450]

[0451] Using the synthesis method of compound 1-2, intermediate 1.1 was replaced by 1.2 to obtain compound 1-3 as a white solid. m / z:[M+H] + 400.0; 1 H NMR (400MHz, DMSO-d 6 ):δ12.27(s,1H),9.25(br.s,1H),9.12(s,1H),8.64(s,1H),8.51(s,1H),7.44(s,1H),6.89( s,1H),1.84-1.16(m,10H).

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PUM

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Abstract

The invention discloses a novel MNK inhibitor with a structure represented by a formula I or I'. The MNK inhibitor disclosed by the invention has a good effect of inhibiting the level of MNK1 and / or MNK2 in vivo and in vitro, and can be used for effectively treating MNK1 and / or MNK2 mediated diseases, such as cancer.

Description

technical field [0001] The present invention relates to a novel MNK inhibitor, its pharmaceutical composition and its use as a cancer therapeutic agent. Background technique [0002] MAP-interacting kinases 1 and 2 (MNK1 and MNK2) are a class of serine / threonine protein kinases that can be activated by ERK or p38 and can phosphorylate eukaryotic initiation factor 4E (eIF4E), which is involved in protein synthesis and essential for the stability of cell function. eIF4E is involved in cap-dependent translation initiation. The eIF4E protein binds to the 5'cap structure of mRNA and is necessary for cap-dependent translation initiation. Multiple lines of evidence suggest that eIF4E exhibits a genuine carcinogenesis-promoting role in vivo. eIF4E is overexpressed in various types of human cancers and is associated with poor prognosis of tumor patients (MamaneY, et al. Oncogene, 2004 23:3172-79; Graff JR, et al., Cancer Res, 2009 69:3866- 73; Ruggero D, et al. Nat Med, 2004 10: ...

Claims

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Application Information

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IPC IPC(8): C07D471/10C07D519/00C07D471/14C07D491/20C07D487/04C07D487/10C07D403/12A61K31/53A61K31/519A61K31/527A61P35/00A61P35/02
CPCC07D471/10C07D519/00C07D471/14C07D491/20C07D487/04C07D487/10C07D403/12A61P35/00A61P35/02A61K31/53A61K31/519A61K31/527A61K31/437A61K31/52C07D471/04
Inventor 杨和平高大新
Owner SHANGHAI DE NOVO PHARMA
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