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: 2018-03-27
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

[0274] 2-(4-(4-(isopropylamino)-6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-3-yl)-1H-1,2,3- Triazol-1-yl)ethanol

[0275]

[0276] Intermediate 1A: ethyl 4-(isopropylamino)-6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)nicotinate

[0277]

[0278] In a 5 mL vial, ethyl 6-chloro-4-(isopropylamino)nicotinate (0.72 g, 2.97 mmol), 7H-pyrrolo[2,3-d]pyrimidine (0.424 g, 3.56 mmol) and carbonic acid A mixture of potassium (0.820 g, 5.93 mmol) in DMA (5 mL) was degassed by bubbling nitrogen for 5 min. Mixture with Xantphos (0.343g, 0.593mmol) and Pd 2 (dba) 3 (0.271 g, 0.297 mmol), degas an additional 5 minutes, and seal the vial. The reaction mixture was heated with stirring at 140 °C for 60 min, at which point it was judged complete by LCMS. The solids were removed by filtration and rinsed 3 times with DMF (5 mL), and the combined filtrate and rinses were concentrated in vacuo. The residue was taken up in ethyl acetate (75 mL), and the solution was washed twice with 10% lithium chlo...

Embodiment 10

[0301] 1-(5-(1-Isopentyl-1H-1,2,3-triazol-4-yl)-4-(isopropylamino)pyridin-2-yl)-1H-pyrazolo[3 ,4-b]pyridine-5-carbonitrile TFA

[0302]

[0303] Intermediate 10A: ethyl 6-chloro-4-(isopropylamino)nicotinate

[0304]

[0305] In a thick-walled flask equipped with a Teflon screw cap, a mixture of ethyl 4,6-dichloronicotinate (12.3 g, 55.9 mmol) and isopropylamine (14.37 mL, 168 mmol) in ethanol (100 mL) was dissolved in Stirred at 80°C for 18 hours, at which point the reaction was judged complete by LCMS. The mixture was concentrated to dryness and the crude material was chromatographed via MPLC on a 330 g silica gel column eluting with 0-10% ethyl acetate / hexanes. Fractions containing product were pooled and concentrated in vacuo to afford ethyl 6-chloro-4-(isopropylamino)nicotinate (12.3 g, 90% yield) as a colorless solid. 1 H NMR (400MHz, chloroform-d) δ8.69(s, 1H), 8.11(br.s., 1H), 6.56(s, 1H), 4.36(q, J=7.1Hz, 2H), 3.71(dq , J=13.3, 6.5Hz, 1H), 1.41(t, J=7.2Hz, 3H...

Embodiment 30

[0327] 1-(4-(isopropylamino)-5-(1-propyl-1H-1,2,3-triazol-4-yl)pyridin-2-yl)-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile

[0328]

[0329] Intermediate 30A: 2-Chloro-N-isopropyl-5-(1-propyl-1H-1,2,3-triazol-4-yl)pyridin-4-amine

[0330]

[0331] A stirred solution of sodium azide (401 mg, 6.16 mmol) in water (0.8 mL) was treated with a solution of 1-bromopropane (0.421 mL, 4.62 mmol) in THF (0.2 mL). The reaction mixture was heated at 80 °C for 1 hour, then allowed to reach room temperature and allowed to stand until the organic and aqueous layers were separated. The top phase was transferred via pipette to a mixture containing 2-chloro-5-ethynyl-N-isopropylpyridin-4-amine (60 mg, 0.308 mmol), sodium ascorbate (12.21 mg, 0.062 mmol) and 1:1 tBuOH / water (1 mL) in a vial of the mixture. The mixture was treated with copper(II) sulfate (4.92 mg, 0.031 mmol), the vial was sealed, and the reaction mixture was stirred at 60 °C for 2 h, at which point it was complete as judged...

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Abstract

Disclosed are compounds of Formula (I) or salts thereof, wherein HET is a heteroaryl selected from pyrrolo[2,3 b]pyridinyl, pyrrolo[2,3 d]pyrimidinyl, pyrazolo[3,4 b]pyridinyl, pyrazolo[3,4 d]pyrimidinyl, imidazolo[4,5 b]pyridinyl, and imidazolo[4,5 d]pyrimidinyl, wherein said heteroaryl is attached to the pyridinyl group in the compound of Formula (I) by a nitrogen ring atom in said heteroaryl and wherein said heteroaryl is substituted with zero to 2 Rb; A is pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxadiazolyl or dihydroisoxazolyl, each substituted with zero or 1 Ra; and R3, Ra, and Rbare 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 1877 / 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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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D487/04A61K31/437A61K31/519A61P29/00
CPCC07D471/04C07D487/04A61P1/04A61P1/12A61P11/00A61P11/06A61P11/08A61P13/12A61P17/00A61P17/06A61P19/02A61P19/06A61P25/04A61P25/28A61P29/00A61P37/00A61P37/02A61P37/06
Inventor D·S·加德纳J·B·桑特拉V·R·派迪吴红J·V·丹奇亚S·K·奈尔J·海因斯X·朱
Owner BRISTOL MYERS SQUIBB CO
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