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Thiazolyl- or thiadiazolyl-substituted pyridyl compounds useful as kinase inhibitors

A compound, nitro technology, applied in the field of kinase inhibitor compounds, can solve problems such as signal loss

Active Publication Date: 2014-12-31
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Conversely, deletion of IRAK1 (Thomas, J.A. et al. 1999, J. Immunol. 163:978-984; Swantek, J.L. et al., 2000, J. Immunol. 164:4301-4306) or IRAK2 (Wan, Y. et al. , 2009, J.Biol.Chem.284:10367-10375) leading to partial loss of signal

Method used

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  • Thiazolyl- or thiadiazolyl-substituted pyridyl compounds useful as kinase inhibitors
  • Thiazolyl- or thiadiazolyl-substituted pyridyl compounds useful as kinase inhibitors
  • Thiazolyl- or thiadiazolyl-substituted pyridyl compounds useful as kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0253]

[0254] Ethyl 2-amino-2-(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)nicotinoyl)hydrazinoylidene)acetate (7) (300mg, 0.679 mmol) in a sealed tube and heated at 180 °C for 1 h. The reaction was dissolved in methanol, then concentrated. The resulting crude was purified by flash column chromatography on silica gel, MeOH:CHCl 3as an eluent. The material was further purified by preparative HPLC to give N2-(benzo[d]thiazol-6-yl)-N4-isopropyl-5-(4H-1,2,4-triazol-3-yl) Pyridine-2,4-diamine. 1 H NMR: 400MHz, CD 3 OD: δ1.32(d, J=4.00Hz, 6H), 1.43(t, J=6.80Hz, 3H), 3.72-3.74(m, 1H), 4.41(q, J=6.80Hz, 2H), 6.17 (s,1H),7.48(dd,J=2.40,8.8Hz,1H),7.93(d,J=8.80Hz,1H),8.33(s,1H),8.61(s,1H),9.02(s, 1H). LC / MS: Ascentis Express C18, Solvent A=2%ACN:98%H 2 O:10mM NH 4 COOH; Solvent B=98%ACN:2%H 2 O:10mM NH 4 COOH; gradient 0-100% B over 3 min; retention time: 1.789 min; LCMS (ES-API), m / z 422.0 (M-H). HPLC: XBridge (150×4.6mm), 3.5 microns; Solvent A=5%ACN:95%H 2 O...

Embodiment 2

[0267]

[0268] Synthesis of (5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl) (2-(Hydroxymethyl)pyrrolidin-1-yl)methanone. To (5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-(hydroxymethyl)pyrrolidin-1 -yl) Methanone (27a) (50mg, 0.15mmol) in di Alkane (5mL):H 2 O (1mL) solution, add 6-aminobenzothiazole (0.18mmol, 1.2eq), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (0.07mmol, 0.5eq) and Na 2 CO 3 (0.7mmol, 3eq) and degassed for 10min. Add Pd to the reaction mixture 2 (dba) 3 (0.07 mmol, 0.5 equiv), and degassed again for 10 min and then heated at 115 °C overnight. The reaction mixture was cooled and filtered through a small pad of celite. The filtrate was concentrated and the crude was purified by column chromatography using silica gel and MeOH:CHCl as eluent 3 . This material was further purified by preparative HPLC to afford the title compound. 1 H NMR: 400MHz, CD 3 OD: δ1.38(d,J=6.40Hz,1H),2.0...

Embodiment 3

[0275] (R)-(5-(6-(Benzo[c][1,2,5]thiadiazol-5-ylamino)-4-(isopropylamino)pyridin-3-yl)-1, 3,4-Thiadiazol-2-yl)(3-hydroxypyrrolidin-1-yl)methanone

[0276]

[0277] 1 H NMR: 400MHz, DMSO-d 6:δ1.34(d,J=6.40Hz,6H),1.87-1.99(m,2H),3.59-3.70(m,2H),3.77-3.81(m,1H),3.98-4.00(m,1H) ,4.05-4.20(m,1H),4.35-4.42(m,1H),5.07(s,1H),7.61(dd,J=2.00,-78.20Hz,1H),7.97(d,J=9.20Hz, 1H), 8.46(d, J=7.20Hz, 1H), 8.63(s, 1H), 8.77(d, J=1.60Hz, 1H), 9.76(s, 1H). LC / MS: Purospherstar RP-18, 4×55mm, 3μm; Solvent A=10%ACN:90%H 2 O:20mM NH 4 OAc; solvent B = 90% ACN: 10% H 2 O:20mM NH 4 COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.91 min; LCMS (ES-API), m / z 483.0 (M+H). HPLC: Sunfire C18 (150×4.6mm), 3.5 microns; Solvent A=5%ACN:95%H 2 O: 0.05% TFA pH = 2.5; Solvent B = 95% ACN: 5% H 2 O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); flow rate: 1.0 μL / min; retention time: 6.869 min; purity: 98.5%.

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Abstract

Compounds having the following formula (I) or an enantiomer, diastereomer or a pharmaceutically-acceptable salt thereof, wherein X is N or C-R7, are useful as kinase modulators, including IRAK-4 modulation.

Description

technical field [0001] The present invention relates to compounds useful as inhibitors of kinases, including modulation of IRAK-4. Provided herein are heterocyclic substituted pyridyl compounds, compositions including these compounds, and methods of using them. The present invention also relates to pharmaceutical compositions comprising at least one compound of the present invention for use in the treatment of disorders associated with the modulation of kinases and methods of inhibiting the activity of kinases, including IRAK-4 in mammals. Background of the invention [0002] Members of the Toll / IL-1 receptor family are important regulators of inflammation and host resistance. The Toll-like receptor (TLR) family recognizes molecular features derived from infectious organisms, including bacteria, fungi, parasites, and viruses, among others (reviewed in Kawai, T., et al. 2010, Nature Immunol. 11:373-384). Ligand binding to the receptor induces dimerization of the adapter mol...

Claims

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Application Information

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IPC IPC(8): C07D417/04C07D417/14A61K31/4439A31P37/00A61P29/00
CPCC07D413/04C07D413/14C07D417/04C07D417/14C07D471/04C07D487/04A61P1/04A61P11/00A61P11/06A61P17/02A61P17/06A61P19/02A61P19/06A61P19/08A61P19/10A61P25/00A61P25/16A61P25/28A61P27/02A61P29/00A61P3/00A61P31/00A61P31/04A61P31/12A61P31/18A61P35/00A61P35/02A61P35/04A61P37/02A61P37/06A61P43/00A61P5/14A61P9/10A61P3/10
Inventor V.R.佩蒂S.R.库马S.K.奈尔A.巴纳吉R.西斯特拉W.J.皮茨J.海因斯
Owner BRISTOL MYERS SQUIBB CO
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