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Pyridine derivatives as KIF18A inhibitors

The technology of a compound, -CR1, is applied in the field of KIF18A inhibitory activity, compounds and compositions that regulate KIF18A, manage cell proliferation and treat cancer, and prepare compounds of formula I

Pending Publication Date: 2022-04-22
AMGEN INC
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  • 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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  • Pyridine derivatives as KIF18A inhibitors
  • Pyridine derivatives as KIF18A inhibitors
  • Pyridine derivatives as KIF18A inhibitors

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0359] Ring Ar 1 Preparation of intermediates

[0360] Intermediate 1: 3-Amino-N-(tert-butyl)-5-methylbenzenesulfonamide.

[0361]

[0362] step 1: To ice-cold 1-methyl-3-nitrobenzene (2.0 g, 14.58 mmol) was slowly added chlorosulfonic acid (14.57 mL, 219 mmol) over 15 min. The resulting mixture was heated at 80 °C for 3 h. The reaction mixture was quenched with crushed ice and extracted with EtOAc (50 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-methyl-5-nitrobenzenesulfonyl chloride as a brown liquid. The crude sample was used immediately in the next step. 1 H NMR (400MHz, chloroform-d) δ8.70(t, J=1.9Hz, 1H), 8.52-8.39(m, 1H), 8.18(t, J=1.7Hz, 1H), and 2.66(s, 3H ).

[0363] step 2 : To an ice-cold solution of 2-methylpropan-2-amine (1.09 g, 14.94 mmol) and DIPEA (3.56 mL, 20.37 mmol) in DCM (50 mL) was slowly added 3-methyl-5-nitrobenzene- A solution o...

example 100

[0450] Example 100: 2-(4,4-Dimethylpiperidin-1-yl)-N-(3-(piperidin-1-ylsulfonyl)phenyl)nicotinamide.

[0451]

[0452] To a solution of 2-fluoro-N-(3-(piperidin-1-ylsulfonyl)phenyl)nicotinamide (44 mg, 0.12 mmol, Intermediate 14) in ACN (1 mL) was added 4,4-bis Methylpiperidine hydrochloride (33 mg, 0.22 mmol) and DIPEA (50 μL, 0.29 mmol). The reaction mixture was stirred at 85 °C for 4 h, then allowed to cool to RT. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2x5 mL). The combined organic extracts were concentrated in vacuo and absorbed onto a plug of silica gel and chromatographed through a silica gel column (eluting with 0%-60% EtOAc in heptane) to provide 2-(4,4-di Methylpiperidin-1-yl)-N-(3-(piperidin-1-ylsulfonyl)phenyl)nicotinamide (35 mg, 0.08 mmol, 33% yield). 1 H NMR (chloroform-d) δ: 12.27 (brs, 1H), 8.42-8.61 (m, 2H), 8.14 (d, J=7.0Hz, 1H), 7.91-8.04 (m, 1H), 7.63 (d, J=5.9Hz,1H),7.48-7.57(m,2H),3.20(br s,4H),3.06(br s,4H),...

example 101

[0459] Example 101 : N-(3-(N-Cyclopropylsulfamoyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide.

[0460]

[0461] 3-(2-(6-azaspiro[2.5]oct-6-yl)nicotinamido)benzene-1-sulfonyl chloride (0.049g, 0.12mmol, intermediate 15), cyclopropylamine (0.01g, 0.19 mmol) and DCM (1 mL) into a glass vial. To the reaction mixture was added DIPEA (0.065 mL, 0.37 mmol) and the mixture was stirred at rt for 2 h. The mixture was concentrated and the crude product was purified by silica gel chromatography (EtOAc in heptane 10%-70%) to afford N-(3-(N-cyclopropylsulfamoyl)phenyl) as a white solid - 2-(6-Azaspiro[2.5]oct-6-yl)nicotinamide (43 mg, 84% yield). 1H NMR (400MHz, chloroform-d) δ = 12.15 (br s, 1H), 8.50 (d, J = 6.3Hz, 2H), 8.39 (s, 1H), 7.94 (d, J = 8.0Hz, 1H), 7.69(d, J=7.8Hz, 1H), 7.61-7.53(m, 1H), 7.24(t, J=6.0Hz, 1H), 5.00(s, 1H), 3.28(t, J=5.3Hz, 4H ), 2.32 (d, J = 4.1 Hz, 1H), 1.63 (s, 4H), 0.75-0.59 (m, 4H), 0.43 (s, 4H). MS (ESI, cation) m / z: 427.1 [M+1].

[0462] T...

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Abstract

Amide 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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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D401/14C07D405/14C07D413/14A61K31/635A61K31/63A61K31/455A61K31/5377A61P35/00A61P35/02A61P37/02A61P19/02A61P17/00A61P9/10A61P21/00A61P21/04A61P1/00
CPCC07D401/04C07D401/14C07D405/14C07D413/14A61P35/00A61P35/02A61P37/02A61P19/02A61P17/00A61P9/10A61P21/00A61P21/04A61P1/00C07D498/08C07D409/14C07D417/14
Inventor N·A·塔马约J·G·艾伦A·班纳吉J·J·陈M·J·弗罗恩M·R·卡勒T·T·阮N·尼施穆拉Q·M·薛
Owner AMGEN INC
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