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Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
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A compound, dihydrogen technology, applied in the field of new compounds of ene and diseases, can solve problems such as outstanding medical needs
Active Publication Date: 2019-03-29
DECIPHERA PHARMA LLC
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This complex heterogeneity of c-KIT mutations within individual patients highlights the unmet medical need to identify c-KIT kinase inhibitors effective against a broad spectrum of c-KIT primary and secondary mutations
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[0184] The present disclosure is further illustrated by the following examples, which should not be construed to limit the scope or spirit of the present disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments and are thus not intended to limit the scope of the present disclosure. It is further to be understood that various other embodiments, modifications and their equivalents may occur to those skilled in the art without departing from the spirit of the disclosure and / or the scope of the appended claims.
[0185]General procedure A: To a stirred solution of formic acid (0.50 mmol, 1.00 eq) and DPPA (0.75 mmol, 1.50 eq) in 1,4-dioxane (5.0 mL) was added TEA (1.5 mmol, 3.00 eq) at room temperature ). After stirring at room temperature for 30 minutes, the appropriate amine (0.76 mmol, 1.50 eq) was added and the mixture was heated at 100°C. After 2 hours, the completed reaction was cooled ...
Embodiment A1
[0188] Example A1: Combine Example A6 (1.61 g, 4.85 mmol), 4-methoxy-N-methylbenzylamine (1.10 g, 7.28 mmol) and DBU (1.09 mL, 7.28 mmol) in NMP (20 mL) and heated at 180 °C overnight under Ar. The mixture was cooled to room temperature, poured into H 2 O (200 mL) and the resulting solid was collected by filtration and washed with H 2 O Rinse well. The solid was dried to wet on the filter, dissolved in EtOAc, dried (MgSO 4 ) and evaporated to give 3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl-7-((4-methoxybenzyl)( Methyl)amino)-1,6-naphthyridin-2(1H)-one (2.06 g), which was slightly contaminated with EtOAc and NMP. It was used as such in the next reaction.
[0189]
Embodiment A2
[0190] Example A2: Using a procedure similar to Example A8, Example A1 (2.06 g, 4.61 mmol) was converted to 3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl- 7-(Methylamino)-1,6-naphthyridin-2(1H)-one (1.16 g, 73% yield over 2 steps). 1 H NMR (400MHz, DMSO-d 6 ):δ8.36(s,1H),7.58(s,1H),6.94-6.92(m,1H),6.83(d,J=12.0Hz,1H),6.57(d,J=9.6Hz,1H) ,4.87(br s,2H),4.12(q,J=6.8Hz,2H),2.84(d,J=4.8Hz,3H),1.94(s,3H),1.19(t,J=7.2Hz,3H ); MS(ESI) m / z:327.2[M+H] + .
[0191]
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Abstract
The present invention relates to dihydronaphthyridines and related compounds; compositions comprising an effective amount of dihydronaphthyridines or related compounds; and methods for treating or preventing proliferative diseases comprising administering an effective amount of dihydronaphthyridines or related compounds compound. The present invention discloses the unexpected utility of compounds that inhibit cKIT kinase against a broad range of c-KIT mutations, including primary mutations (KIT exon 9) that can occur in individual patients with refractoryGIST or 11) and the combined presence of secondary KIT mutations (exons 13, 14, 17, and 18). Also unexpected is the utility of compounds of the invention to inhibit the problematic exon 17D816V c-KIT mutation, for which there is currently no effective therapy.
Description
Background of the invention [0001] c-KIT (also known as KIT, CD117 and stem cell factor receptor) is a 145 kDa transmembrane tyrosinekinaseprotein that acts as a type III receptor (Pereira et al., J. Carcin. 2005, 4, p. 19). The c-KIT proto-oncogene located on chromosome 4q11-21 encodes the c-KIT receptor, and its ligand is stem cell factor (SCF, steel factor, kit ligand, mast cellgrowth factor; Morstyn, G. et al., Oncology 1994, 51(2), p. 205; Yarden, Y. et al., Embo. J. 1987, 6(11), p. 3341). The receptor has tyrosineproteinkinase activity and binding of the ligand SCF results in autophosphorylation of c-KIT and its association with substrates such as phosphatidylinositol 3-kinase (PI3K). Phosphorylation of tyrosine by protein tyrosine kinases is particularly important in cell signaling and can mediate signals for major cellular processes such as proliferation, survival, differentiation, apoptosis, ligation, invasion and migration. c-KIT deficiency is the cause of pie...
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