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KIF18A inhibitors

A technology of -NR8-, -NR11SO2NR11, applied in the field of pharmaceutical reagents

Pending Publication Date: 2022-04-26
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
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Effect test

preparation example Construction

[0321] Ring Ar 1 Compound preparation: Ring Ar 1 An example of a compound includes Compound D-1, having the formula:

[0322]

[0323] In step D-1, compound D-1 (wherein W 4 is halogen, such as fluorine or chlorine) and R 2 The reagents react to form compound D-2. Examples of compound D-1 include, but are not limited to, 3-fluorobenzoic acid or 3-fluoro-3-methylbenzoic acid. R 2 Examples of reagents include, but are not limited to, (1) (R)-2-methylmorpholine, (2) 4,4-difluoropiperidine hydrochloride, or (3) 3,3-difluoroazetidine alkane hydrochloride. Examples of bases include, but are not limited to, diisopropylethylamine, potassium carbonate.

[0324] Step D-2: Ring Ar 2 Compound preparation:

[0325]

[0326] In step D-2, compound D-3 (wherein W 7 and W 8 Each of which is independently halo, such as fluorine, chlorine, bromine or iodine) and R X Reagents (e.g. (1) 6-azaspiro[2.5]octane hydrochloride, (2) 4,4-dimethylpiperidine hydrochloride, (3) 3,4,4-tri...

example 100

[0404] Example 100: N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-5-((1-hydroxy-2-methylpropan-2-yl)amino)-3-(6- Azaspiro[2.5]oct-6-yl)pyrazine-2-carboxamide.

[0405]

[0406] Step 1: N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-3,5-dichloropyrazine-2-carboxamide (3.71g, 9.20mmol, intermediate 10), A mixture of DIPEA (2.12 mL, 11.96 mmol) and 2-amino-2-methyl-1-propanol (0.97 mL, 10.12 mmol) in ACN:DMSO (4:1, 50 mL) was stirred at RT for 16 h. Then, water was added and extracted with DCM (2x20 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (0-30% EtOAc / EtOH (3:1) in heptane) to give N-(3-(N-(tert-butyl)sulfamoyl)phenyl) -5-Chloro-3-((1-hydroxy-2-methylpropan-2-yl)amino)pyrazine-2-carboxamide (1.50 g, 3.29 mmol, 36% yield). 1 H NMR (DMSO-d 6 )δ:10.85(s,1H),9.03(s,1H),8.44(s,1H),7.87-7.94(m,2H),7.50-7.61(m,3H),5.05(t,J=5.5Hz , 1H), 3.53 (d, J=5.5Hz, 2H), 1.39 (s, 6...

example 101

[0415] Example 101: N-(3-(N-(tert-Butyl)sulfamoyl)-5-methylphenyl)-5-((1-hydroxy-2-methylpropan-2-yl)amino)- 3-(6-azaspiro[2.5]oct-6-yl)pyrazine-2-carboxamide.

[0416]

[0417] Step 1: Add 5-(4,4-dimethyl-2-oxooxazolidin-3-yl)-3-(6-azaspiro[2.5]oct-6 to a 50-mL round bottom flask -yl)pyrazine-2-carboxylic acid (111 mg, 0.320 mmol, Intermediate 8) and DCM (4 mL). Then oxalyl chloride (0.24 mL, 0.48 mmol, 2M in DCM) was added, followed by two drops of DMF. The reaction mixture was stirred at RT for 30 min and the solvent was removed under vacuum. The residue was redissolved in DCM (4 mL) and washed with 3-amino-N-(tert-butyl)-5-methylbenzenesulfonamide (78 mg, 0.32 mmol, Intermediate 1) and DIPEA (0.17 mL, 0.96 mmol )deal with. The reaction mixture was stirred at RT for 18 h and the solvent was removed under vacuum. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (eluting with a gradient of 0%-50% EtOA...

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Abstract

Provided are compounds of formula (I) as defined herein, 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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IPC IPC(8): C07D401/04A61P35/00A61P17/06A61P17/00A61P29/00A61P1/00A61P19/02A61P37/02A61P21/04A61P25/00A61P1/04A61K31/497
CPCC07D401/04A61P35/00A61P17/06A61P17/00A61P29/00A61P1/00A61P19/02A61P37/02A61P21/04A61P25/00A61P1/04C07D241/28C07D401/14
Inventor N·A·塔马约M·R·卡勒T·T·阮N·尼施穆拉Q·M·薛J·G·艾伦
Owner AMGEN INC
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