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Heteroaryl substituted aminopyridine compounds

A compound, heteroaryl technology, applied in the field of aminopyridine compounds, can solve problems such as signal loss

Active Publication Date: 2018-05-11
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., J. Immunol., 163:978-984 (1999); Swantek, J.L. et al., J. Immunol., 164:4301-4306 (2000)) or IRAK2 (Wan , Y. et al., J.Biol.Chem., 284:10367-10375 (2009)) leading to partial loss of signal

Method used

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  • Heteroaryl substituted aminopyridine compounds
  • Heteroaryl substituted aminopyridine compounds
  • Heteroaryl substituted aminopyridine compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0183] 3-(5-(4-(2-hydroxyprop-2-yl)-1H-pyrazol-1-yl)-4-(isopropylamino)pyridin-2-yl)pyrazolo[1,5 -a]pyrimidine-6-carbonitrile

[0184]

[0185] Intermediate 1A: ethyl 1-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1H-pyrazole-4-carboxylate

[0186]

[0187] To a stirred solution of 2-chloro-5-iodo-N-isopropylpyridin-4-amine (400 mg, 1.35 mmol) in 1,4-dioxane (10 mL) was added 1H-pyrazole-4-carboxy Ethyl acetate (189mg, 1.35mmol), CuI (51mg, 0.27mmol), K 2 CO 3 (373mg, 2.7mmol) and trans-N,N'-dimethylcyclohexyl-1,2-diamine (115mg, 0.81mmol). The mixture was sealed and heated at 110 °C for 14 hours. The solvent was removed and the mixture was partitioned between EtOAc and water. The organic layer was washed with Na 2 SO 4 Dry, filter, and concentrate. The product was purified by column chromatography (15% EtOAc / petroleum ether) to afford ethyl 1-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1H-pyrazole-4-carboxylate ( 300 mg, 72% yield). LCMS 309.4 (M+H).

[0188] Inte...

Embodiment 2

[0200] 2-(7-Chlorimidazo[1,2-b]pyridazin-3-yl)-N-isopropyl-5-(4-(tetrahydro-2H-pyran-4-yl)-1H- Pyrazol-1-yl)pyridin-4-amine

[0201]

[0202] Intermediate 2A: 2-Chloro-5-iodopyridin-4-amine

[0203]

[0204] To a stirred solution of 2-chloropyridin-4-amine (5 g, 39 mmol) in DMF (50 mL) was added NIS (8.75 g, 39 mmol). The reaction mixture was then heated at 80°C for 3 hours. The mixture was cooled and DMF was removed in vacuo. The residue was partitioned between EtOAc and water and the layers were separated. The organic layer was washed with Na 2 SO 4 Dry, filter, and concentrate. The product was purified via column chromatography (10% EtOAc / petroleum ether) to afford 2-chloro-5-iodopyridin-4-amine (4 g, 39% yield). 1 H NMR (400MHz, DMSO-d 6 )δ8.20(s,1H),6.64(s,1H),6.50(br s,2H); LC / MS: 254.8(M + ). Further elution with 12% EtOAc / petroleum ether afforded 2-chloro-3-iodopyridin-4-amine (4 g, 39% yield).

[0205] Intermediate 2B: 2-Chloro-5-iodo-N-isopropylpyrid...

Embodiment 11

[0230] 2-(6-Chloropyrazolo[1,5-a]pyrimidin-3-yl)-N-isopropyl-5-(4-propyl-1H-1,2,3-triazole-1- base) pyridin-4-amine

[0231]

[0232] Intermediate 11A: 5-Bromo-2-chloro-N-isopropylpyridin-4-amine

[0233]

[0234] 5-Bromo-2,4-dichloropyridine (3.0 g, 13.22 mmol), isopropylamine (1.7 mL, 19.83 mmol) and Huenig base (11.6 mL, 66.1 mmol) in DMF (5 mL) were stirred at room temperature The solution in was then heated behind a hood at 120° C. for 4 hours, at which point it was judged complete by LCMS. The reaction mixture was diluted with ethyl acetate and washed with 10% LiCl (3 times). The organic layer was washed with Na 2 SO 4 Dry, filter and concentrate to give crude material. The product was purified by column chromatography (hexane / EtOAc) to give 5-bromo-2-chloro-N-isopropylpyridin-4-amine (1.29 g, 37% yield) as a colorless oil. LCMS m / z 249.0 (M+H).

[0235] Intermediate 11B: 2-Chloro-N-isopropyl-5-(4-propyl-1H-1,2,3-triazol-1-yl)pyridin-4-amine

[0236]

[...

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Abstract

Disclosed are compounds of Formula (I) or salts thereof, wherein: HET is a heteroaryl selected from imidazo[1,2-b]pyridazinyl and pyrazolo[1,5-a]pyrimidinyl, wherein said heteroaryl is attached to thepyridinyl group in the compound of Formula (I) by a carbon ring atom in the heteroaryl and wherein said heteroaryl is substituted with zero to 2 Rb; A is pyrazolyl, imidazolyl, or triazolyl, each substituted with zero or 1 Ra; and R3, Ra, and Rb are define herein. Also disclosed are methods of using such compounds as modulators of IRAK4, and pharmaceutical compositions comprising such compounds.These compounds are useful in treating, preventing, or slowing inflammatory and autoimmune diseases, or in the treatment of cancer.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of Indian Provisional Patent Application 1880 / DEL / 15 filed on June 24, 2015, the entire contents of which are incorporated into this application. technical field [0003] The present invention generally relates to heteroaryl-substituted aminopyridine compounds useful as kinase inhibitors, including modulation of IRAK-4. The application provides heteroaryl-substituted aminopyridine compounds, compositions comprising the compounds, and methods of use thereof. 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 kinase modulation and methods of inhibiting the activity of kinases, including IRAK-4, in mammals. Background technique [0004] Members of the Toll / IL-1 receptor family are important regulators of inflammation and host resistance. The Toll-like receptor...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/5025A61K31/519A61P37/00
CPCC07D487/04A61P1/04A61P1/12A61P11/00A61P11/06A61P11/08A61P13/12A61P17/00A61P17/06A61P19/02A61P19/06A61P25/00A61P25/04A61P25/28A61P29/00A61P35/00A61P37/00A61P37/02A61P37/06A61P43/00
Inventor J·V·丹奇亚D·S·加德纳J·海因斯J·E·马科尔J·B·桑特拉吴红S·K·奈尔V·R·派迪K·萨库纳姆R·K·西斯特拉S·R·波利梅拉
Owner BRISTOL MYERS SQUIBB CO
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