Substituted tricyclic compounds as FGFR inhibitors

A technology of compounds and substituents, applied in the field of tricyclic compounds

Active Publication Date: 2015-04-08
INCYTE HLDG & INCYTE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Aberrant activation of this pathway by overexpression of FGF ligands or FGFR or mutations that activate FGFR can lead to tumor development, progression and resistance to conventional cancer therapies

Method used

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  • Substituted tricyclic compounds as FGFR inhibitors
  • Substituted tricyclic compounds as FGFR inhibitors
  • Substituted tricyclic compounds as FGFR inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0449] 3-(3,5-Dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4 ,3-d]pyrimidin-2-one

[0450]

[0451] Step 1: 4-(Methylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

[0452]

[0453] Heated 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (CAS No. 958230-19-8) (from Adesis, Cat. No. 4-263; Synnovator, Cat. No. PBN2011188: 2.71 g, 15 mmol ) and methylamine (33 wt.% in ethanol, 24 mL, 200 mmol) in 2-methoxyethanol (6 mL) to 110 °C and stirred overnight in a sealed pressure flask. The reaction mixture was then cooled to room temperature and concentrated. The residue was dissolved in HCl solution (1 N, 25 mL) and heated to 50 °C. After stirring for 2 hours, the reaction mixture was cooled to room temperature and washed with saturated NaHCO 3 Solution neutralization. The pale yellow precipitate was collected by filtration, washed with water and hexanes, then dried in vacuo to afford the desired product (2.54 g, 97%) as a pale yellow solid. C...

Embodiment 2

[0460] 3-(3,5-Dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d] pyrimidin-2-one

[0461]

[0462] This compound was prepared using a procedure similar to that described for Example 1, substituting ammonium hydroxide solution for methylamine and raising the reaction temperature in Step 1 to 130°C. C 17 h 17 N 4 o 3 LC-MS calculated value: [M+H] + m / z: 325.1; found value: 325.1.

Embodiment 3

[0464] 3-(3,5-Dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4 ,3-d]pyrimidin-2-one

[0465]

[0466] This compound was prepared using a procedure similar to that described for Example 1, substituting ethylamine (2M in THF) for methylamine and raising the reaction temperature in Step 1 to 130°C. C 19 h 21 N 4 o 3 LC-MS calculated value: [M+H] + m / z: 353.2; Found: 353.1. 1 H NMR (500MHz,DMSO)δ12.18(s,1H),8.12(s,1H),7.58–7.53(m,1H),6.75(d,J=2.9Hz,1H),6.56(d,J= 2.2Hz, 2H), 6.42(t, J=2.2Hz, 1H), 4.86(s, 2H), 4.21(q, J=6.9Hz, 2H), 3.75(s, 6H), 1.38(t, J= 6.9Hz, 3H).

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Abstract

The present invention relates to tricyclic compounds, and pharmaceutical compositions of the same, that are inhibitors of one or more FGFR enzymes and are useful in the treatment of FGFR-associated diseases such as cancer.

Description

field of invention [0001] The present invention relates to tricyclic compounds which are inhibitors of one or more FGFR enzymes and are useful in the treatment of FGFR-related diseases such as cancer and pharmaceutical compositions comprising said tricyclic compounds. Background of the invention [0002] Fibroblast growth factor receptor (FGFR) is a receptor tyrosine kinase that binds fibroblast growth factor (FGF) ligand. There are four FGFR proteins (FGFR1-4) that are capable of binding ligands and are involved in the regulation of many physiological processes including tissue development, angiogenesis, wound healing and metabolic regulation. Following ligand binding, receptors undergo dimerization and phosphorylation, resulting in the stimulation of protein kinase activity and the recruitment of a number of intracellular docking proteins. These interactions contribute to the activation of a series of intracellular signaling pathways important for cell growth, proliferati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/14C07D471/22C07D491/22C07D495/14C07D498/14A61K31/519A61K31/4375A61P35/00
CPCC07D495/14C07D471/20C07D498/22C07D491/22C07D498/14C07D471/14C07D471/22A61P1/16A61P11/00A61P19/02A61P35/00A61K31/4375A61K31/519A61K31/5377A61P7/00
Inventor 吴亮星张丰雷何春红孙亚平路良钱定权徐美忠卓金聪姚文庆
Owner INCYTE HLDG & INCYTE
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