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Diaryl macrocycles as modulators of protein kinases

A bicyclic aryl and bicyclic heteroaryl technology, applied in the field of diaryl macrocycle derivatives, can solve problems such as the incomplete understanding of the normal function of human ROS1 kinase

Active Publication Date: 2016-11-30
TURNING POINT THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The normal function of the human ROS1 kinase is not fully understood

Method used

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  • Diaryl macrocycles as modulators of protein kinases
  • Diaryl macrocycles as modulators of protein kinases
  • Diaryl macrocycles as modulators of protein kinases

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example

[0378] The following examples are offered to illustrate, not limit, the invention. Those skilled in the art will recognize that the following synthetic reactions and schemes can be modified to obtain other compounds of formula (I) or (I-A) by selection of appropriate starting materials and reagents. Bicyclic heteroaromatics with suitable functionality for use in synthetic methods are commercially available.

[0379] abbreviation The examples described herein use a variety of materials including, but not limited to, those described by the following abbreviations known to those skilled in the art:

[0380]

[0381]

example A6

[0383]

[0384] Step 1. At 16°C in N 2 To a solution of 5-fluoro-2-hydroxybenzaldehyde (500.00 mg, 3.57 mmol, 1.00 eq.) in MeOH (20.00 mL) was added 1-methylpyrrolidin-3-amine (357.43 mg, 3.57 mmol) in one portion ,1.00eq.). The mixture was heated at 16 °C under N 2 Stirring was continued for 10 hours. Then add NaBH 4 (270.00mg, 7.14mmol, 2.00eq.) and the mixture was heated under N at 16°C 2 Stirring was continued for 6 hours. TLC (DCM:MeOH=15:1) showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with water (50 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (50 mL), washed with Na 2 SO 4 Dry, filter and concentrate under reduced pressure to obtain A6-5 (350.00 mg, 1.56 mmol, 43.71% yield) as a yellow solid. 1 HNMR (300MHz, DMSO-d 6 )δ6.94(dd, J=2.7,9.3Hz,1H),6.86(dt,J=3.0,8.6Hz,1H),6.67(dd,J=4.7,8.7Hz,1H),3.71(s,2H ),3.24-3.09(m,1H...

example A8

[0387]

[0388] To ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1.25 g, 5.54 mmol) and (R)-2-(1-aminoethyl)-4-fluorophenol HCl salt ( (available from NetChem Inc.) in EtOH (15.83 mL) was added Schoenig's base (3.58 g, 27.70 mmol) and heated to 70 °C for 1.5 hours. The reaction was rotary evaporated to dryness, suspended in water, and extracted with DCM (5 x 50 mL). The combined extracts were washed with Na 2 SO 4 Dry and concentrate under reduced pressure. Flash chromatography (ISCO system, silica (40 g), 0-5% methanol in dichloromethane) provided A8 (1.89 g, 5.49 mmol, 99% yield).

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Abstract

The present invention relates to certain diaryl macrocyclic compounds, pharmaceutical compositions containing them, and methods of using them, including methods for treating cancer, pain, neurological diseases, autoimmune diseases, and inflammation.

Description

[0001] Cross References to Related Applications [0002] This application is asserted under 35 U.S.C. § 119(e) over U.S. Provisional Application Nos. 61 / 931,506, filed January 24, 2014, 62 / 049,326, filed September 11, 2014, and January 2015. Priority No. 62 / 106,301, filed May 22, the entire contents of which are incorporated herein by reference in their entirety. technical field [0003] The present invention relates to certain diaryl macrocyclic derivatives, pharmaceutical compositions containing them and their uses for treating cancer, pain, neurological diseases, autoimmune diseases and inflammation. Background technique [0004] Protein kinases are key regulators of cell growth, proliferation and survival. Genetic and epigenetic alterations accumulate in cancer cells, which lead to aberrant activation of signal transduction pathways that drive the malignant process. Manning G. (Manning, G) et al., Science 2002, 298, 1912-1934. Pharmacological inhibition of these sign...

Claims

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Application Information

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IPC IPC(8): A61K31/5025C07D487/04A61K31/519
CPCC07D498/18C07B2200/13A61K31/519A61P19/02A61P21/00A61P25/00A61P25/04A61P25/14A61P25/16A61P25/28A61P29/00A61P3/10A61P31/00A61P35/00A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P9/10
Inventor 崔景荣李一山埃文·W·罗杰斯翟大勇
Owner TURNING POINT THERAPEUTICS INC
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