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KIF18A inhibitors

An alkyl, pharmaceutical technology for use in the fields of compounds and compositions modulating KIF18A, preparing compounds of formula I, KIF18A inhibiting activity, managing cell proliferation and treating cancer

Pending Publication Date: 2022-04-08
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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Experimental program
Comparison scheme
Effect test

preparation example Construction

[0348] Preparation of synthetic intermediates

[0349] Ring Ar 1 Intermediates:

[0350] Intermediate 1: (R)-3-fluoro-5-(2-methylmorpholino)aniline.

[0351]

[0352] step 1 : 1,3-difluoro-5-nitrobenzene (3.0g, 18.86mmol, ApolloScientific (ApolloScientific)), (R)-2-methylmorpholine (2.29g, 22.63mmol, Abochemical (Arbor Chemicals)) and DIPEA (6.59 mL, 37.7 mmol) in 1,4-dioxane (30 mL) was stirred under microwave at 100 °C for 2 h. The reaction mixture was concentrated and purified by silica gel column chromatography (eluting with a gradient of 0%-40% EtOAc in petroleum ether) to give (R)-4-(3-fluoro-5- Nitrophenyl)-2-methylmorpholine (1.5 g, 6.24 mmol, 33% yield). 1 H NMR (400MHz, DMSO-d 6 ): δppm 7.54 (d, J = 2.3Hz, 1H), 7.38 (dt, J = 8.4, 2.1Hz, 1H), 7.27 (dt, J = 12.3, 2.3Hz, 1H), 3.92 (ddd, J = 11.5 ,3.7,1.4Hz,1H),3.80(dt,J=12.2,2.2Hz,1H),3.68(ddt,J=12.2,3.1,1.6Hz,1H),3.53-3.67(m,2H),2.79( td,J=11.9,3.6Hz,1H), 2.41-2.49(m,1H),1.16(d,J=6.2Hz,3H). m / z(ESI):...

example 100

[0479] Example 100: N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((3-methyloxetan-3-yl)sulfonyl Base)-2-(6-azaspiro[2.5]oct-6-yl)benzamide

[0480]

[0481] To 4-((3-methyloxetan-3-yl)sulfonyl)-2-(6-azaspiro[2.5]oct-6-yl in DMF (2 mL) at RT ) benzoic acid (120 mg, 0.33 mmol, Intermediate 15) solution was added HATU (187 mg, 0.49 mmol) and DIPEA (143 μL, 0.821 mmol) and stirred for 10 min. To this reaction mixture was added 3-amino-N-(tert-butyl)benzenesulfonamide (82 mg, 0.36 mmol) and stirred at RT for 12 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3x25 mL). The combined organic extracts were washed with brine solution (20 mL), washed with Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The crude residue was purified by silica gel column chromatography using 30% EtOAc in hexanes to give the title compound (110 mg, 58% yield) as an off-white solid. 1 H NMR (400MHz, chloroform-d): δ12.33(s, 1H), 8.47(d, J=8.2Hz, 1H), 8....

example 101

[0487] Example 101: N-(3-((1-Hydroxy-2-methylpropan-2-yl)amino)phenyl)-4-(N-(3-methyloxetane Alkyl-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide

[0488]

[0489] To 4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid (0.25g, 0.66 mmol, Intermediate 12) and 2-((3-aminophenyl)amino)-2-methylpropan-1-ol (0.130 g, 0.72 mmol, Intermediate 2-2) in DMF (3 mL) 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (0.291 g, 0.986 mmol) was added and stirred at rt for 18 h . The reaction was partitioned between water and EtOAc. The organic phase was separated, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. Purification by preparative SFC afforded N-(3-((1-hydroxy-2-methylpropan-2-yl)amino)phenyl)-4-(N-(3-methyloxetane -3-yl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (0.26 g, 0.48 mmol, 73% yield). 1 H NMR (500MHz, DMSO-d6) δppm 11.61 (s, 1H) 8.16 (s, 1H) 7.87 (d, J = 8.48Hz, 1H) 7.2...

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Abstract

Amide compounds of formula (I) as defined herein: and compositions containing these compounds, as well as processes for preparing such compounds. Also provided herein are methods of treating disorders or diseases treatable by inhibition of the kinin motor protein KIF18A, such as cancer, psoriasis, atopic dermatitis, autoimmune disease, or inflammatory bowel disease, etc.

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): C07D405/12C07D221/20C07D401/12C07D401/10C07D413/10C07D413/12C07D417/10C07D409/12A61P35/00A61P35/02A61P17/06A61P37/06A61P1/00A61P1/04A61P21/04A61K31/635A61K31/438A61K31/4545A61K31/5377A61K31/4709
CPCA61P35/00C07D405/12C07D401/12C07D409/12C07D413/12C07D221/20
Inventor N·A·塔马约A·班纳吉J·J·陈M·P·布尔博M·R·卡勒J·D·罗A·E·米纳蒂T·T·阮N·尼施穆拉L·H·佩图斯M·C·瓦尔顿Q·M·薛J·G·艾伦
Owner AMGEN INC
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