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KIF18A inhibitors

A pharmaceutical, alkyl technology, applied in the field of managing cell proliferation and treating cancer, preparing compounds of formula I, regulating KIF18A compounds and compositions, and KIF18A inhibitory activity

Pending Publication Date: 2022-04-01
AMGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In particular, inhibition of KIF18A has been found to induce mitotic cell arrest, a known vulnerability that can promote mitotic cell death through apoptosis, mitotic catastrophe, or heterogeneously driven lethality or death following mitotic slippage in interphase

Method used

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Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0340] Preparation of synthetic intermediates

[0341] Preparation of ring Ar 1 intermediate

[0342] Intermediate 1: 3-(4,4-Difluoropiperidin-1-yl)-5-methylaniline

[0343]

[0344] step 1 : To a solution of 1-bromo-3-methyl-5-nitrobenzene (10 g, 46.3 mmol) and 4,4-difluoropiperidine hydrochloride (10.9 g, 69.4 mmol) in toluene (50 mL) was added Sodium tert-butoxide (13.3g, 139mmol), Pd 2 (dba) 3 (4.24g, 4.63mmol) and xantphos (2.68g, 4.63mmol). The reaction mixture was heated at 100 °C for 1.5 h and allowed to cool to room temperature. The reaction mixture was diluted with water, after bed and washed with EtOAc. The organic extract was washed with brine, washed with Na 2 SO 4 Dry, filter, and concentrate in vacuo. The crude product was purified by flash column chromatography (eluting with 10% to 20% EtOAc in petroleum ether) to afford 4,4-difluoro-1-(3-methyl-5-nitro as a gray solid Phenyl)piperidine (2.3 g, 9.0 mmol, 19% yield). 1 H NMR (400MHz, DMSO...

example 100

[0393] Example 100: N-(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-5-(6-azaspiro [2.5] Oct-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide

[0394]

[0395] At rt, to 7-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-5-(6-azaspiro[2.5]octyl- To a solution of 6-yl)quinazolin-4-amine (0.125 g, 0.230 mmol, intermediate 12) and 2-hydroxyethane-1-sulfonamide (0.058 g, 0.461 mmol) in DMF (2 mL) was added Tripotassium phosphate (0.147g, 0.691mmol), copper(I) iodide (0.088g, 0.461mmol) and (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (0.033 g, 0.230mmol) and heated at 95°C for 16h. Pass the reaction mixture through Pad filtered and washed with EtOAc. The combined organic extracts were washed with brine, washed with Na 2 SO 4 Drying, filtration and evaporation gave crude compound. The crude product was passed through preparative HPLC [Sun fireC-18 (150x19) mm, 5.0 μm, CH 3 CN / H 2 0.1% TFA in O] purified to give N-(4-((3-(4,4-difluoropiperidin-1-...

preparation example 100

[0397]

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Abstract

Provided are compounds of Formula (I) as defined herein: (I) and synthetic intermediates thereof, which are capable of modulating the KIF18A protein, thereby affecting the cell cycle and cell proliferation processes to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions comprising the compounds and methods for treating conditions associated with KIF18A activity.

Description

[0001] The present invention relates to the field of pharmaceutical agents, and more particularly, to compounds and compositions for modulating KIF18A and uses and methods for managing cell proliferation and treating cancer. Background technique [0002] Cancer is one of the most prevalent diseases that afflict mankind and is the leading cause of death worldwide. In the effort to find an effective treatment or cure for one or more of many different cancers, many groups have devoted considerable time, energy and financial resources over the past few decades. However, of the available cancer treatments and therapies to date, only a few offer a significant degree of success. [0003] Cancer is often characterized by unregulated cell proliferation. Disruption of one or more genes responsible for cellular pathways that control the progression of proliferation through the cell cycle and centrosomal cycling can result in a loss of normal regulation of cell proliferation. These dysr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D401/04A61K31/517A61K31/502A61P35/00A61P35/02
CPCC07D401/04C07D401/14A61P35/00C07D405/14C07D413/14C07D471/04C07D471/08
Inventor N·A·塔马约A·班纳吉M·P·布尔博
Owner AMGEN INC
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