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N1-(4-(5-(cyclopropylmethyl)-1 -methyl-1 h-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1,4-diamine derivatives and related compounds as ck1 and/or iraki inhibitors for treating cancer

A technology of C1-C5, C5-C15, applied in a field of use in a method

Active Publication Date: 2019-11-19
YISSUM RES DEV CO OF THE HEBREWUNIVERSITY OF JERUSALEM LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is thought that overexpression of TLRs or essential cofactors in MDS clones may lead to chronic IRAK1 activation even in the absence of infection

Method used

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  • N1-(4-(5-(cyclopropylmethyl)-1 -methyl-1 h-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1,4-diamine derivatives and related compounds as ck1 and/or iraki inhibitors for treating cancer
  • N1-(4-(5-(cyclopropylmethyl)-1 -methyl-1 h-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1,4-diamine derivatives and related compounds as ck1 and/or iraki inhibitors for treating cancer
  • N1-(4-(5-(cyclopropylmethyl)-1 -methyl-1 h-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1,4-diamine derivatives and related compounds as ck1 and/or iraki inhibitors for treating cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0197] Example 1: 5-(Cyclopropylmethyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2- (Base)-1H-pyrazole (1) synthesis

[0198]

[0199] Step 1: Cyclopropyl(1-methyl-1H-pyrazol-5-yl)methanol (1-2): Add compound N-methylpyrazole (1-1,8.00g, 97.44mmol, 1.00eq) in THF (160mL) was added dropwise n-BuLi (2.5M, 46.77mL, 1.20eq). After 1 hour at -78°C, a solution of cyclopropanecarboxaldehyde (8.20 g, 116.93 mmol, 1.20 eq) in THF (80 mL) was added dropwise. Stir the resulting mixture at 20°C for 16 hours and pour into NH 4 Cl aqueous solution (300 mL), and stir for 10 minutes. The aqueous phase was extracted with ethyl acetate (100 mL×2). The combined organic phase was washed with brine (100 mL), and subjected to anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. Column chromatography (SiO 2 ) The residue was purified to obtain compound 1-2 (12.00 g, 78.85 mmol, yield 80.9%, purity 100%) as a colorless oil. LCMS: RT=0.118min, m / z 153.1[M+H] + .

[0200] Step 2: 5-(Cyclop...

Embodiment 2

[0203] Example 2: (1r, 4r)-N1-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyridin-2-yl) Synthesis of cyclohexane-1,4-diamine (A104)

[0204]

[0205] Step 1: 2,5-Dichloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyridine (104-2): to 2,5-di Chloro-4-iodopyridine (104-1, 523.13mg, 1.91mmol, 1.00eq) and compound 1 (500.8mg, 1.91mmol, 1.0eq) are added to the mixture in DME (10mL) 2 CO 3 (2M, 2.87mL, 3.00eq) and bis(di-tert-butyll(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (67.62mg, 95.50μmol, 67.62μL, 0.05eq). The resulting mixture was stirred at 80°C under nitrogen for 2 hours, cooled to room temperature, concentrated, and purified by column chromatography to obtain 104-2 (200 mg, 659.3 μmol, yield 34.5%, purity 93.0) as a yellow oil %). LCMS: RT=0.825min, m / z282.0[M+H] + .

[0206] Step 2: (1r, 4r)-N1-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyridin-2-yl) ring Hexane-1,4-diamine (A104): To 104-2 (180.00mg, 637.91μmol, 1.00eq)...

Embodiment 3

[0207] Example 3: (1r,4r)-N1-(6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexane- Synthesis of 1,4-diamine (A105)

[0208]

[0209] Step 1: 2-Chloro-6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyridine (105-2): To 2,6-dichloropyridine ( 562mg, 3.81mmol, 1.00eq) and compound 1 (1.00g, 3.81mmol, 1.0eq) in DME (20mL) was added Na 2 CO 3 (2M, 5.72mL, 3.00eq) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (134.89mg, 190.5umol, 134.89uL, 0.05eq). The mixture was stirred at 80°C for 2 hours, cooled to room temperature, concentrated, and purified by column chromatography to obtain 105-2 (500 mg, 1.32 mmol, yield 34.6%, purity 74.5%) as a yellow oil. LCMS: RT=0.835min, m / z 248.1[M+H] + .

[0210] Step 2: (1r,4r)-N1-(6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1 ,4-Diamine (A105): To 105-2 (400.00mg, 1.61mmol, 1.00eq) and (1r,4r)-cyclohexane-1,4-diamine (275.77mg, 2.42mmol, 1.50eq) Add tertiary BuON...

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Abstract

The present invention provides pyrazole derivatives of Formula (I), and in particular N1-(4-(5-(cyclopropylmethyl)-1-methyl-lH-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1,4-diamine derivatives and relatedcompounds as casein kinase 1 (CK1) and / or interleukin 1 receptor associated kinase 1 (IRAKI) inhibitors for treating cancer, inflammatory and immune related disorders.

Description

[0001] Cross references to related applications [0002] This application claims the priority of U.S. Provisional Application No. 62 / 453,192 filed on February 1, 2017; the entire disclosure of which is incorporated herein by reference. Technical field [0003] The present invention provides pyrazole derivatives and their use in methods for the treatment of malignant diseases and disorders and their use in methods for the treatment of inflammatory diseases and disorders. Background technique [0004] The casein kinase 1 family (CK1 or CKI) is a serine / threonine kinase with six members (isoforms) in humans: α, γ1, γ2, γ3, δ, and ε. They differ in length and N-terminal sequence (9-76 amino acids) and especially the C-terminal (24-200 amino acids) non-catalytic domain (Schittek and Sinnberg, Mol. Cancer 2014, 13:231). [0005] CK1δ and CK1ε are 98% identical in their kinase domains and 53% in their C-terminal regulatory domains (Fish et al., J. Biol. Chem. 1995, 270: 14875-14883). Howev...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D403/04C07D417/04A61K31/4439A61K31/506A61K31/4155A61K31/427A61P35/00
CPCC07D401/04C07D403/04C07D417/04A61P35/00A61P35/02A61P37/00A61P43/00A61K31/4439A61K31/4155A61K31/427A61K31/506C07D403/14
Inventor 李丹素艾里特·思尼尔-奥克利约瑟夫·瓦卡伊农·本-内里艾阿万西卡·文卡塔克-艾拉姆
Owner YISSUM RES DEV CO OF THE HEBREWUNIVERSITY OF JERUSALEM LTD
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