Design, synthesis and evaluation of new 6-substituted-5-benzyloxy-4-oxo-4H-pyran-2-carboxamides as potential Src inhibitors

Figures & data

Figure 1 Structure of the three most advanced Src inhibitors.

Figure 2 Structure of benzoquinones I and pyranones II.

Figure 3 Illustration of a possible binding mode of BMS-354825 in the ATP binding site of active Src kinase.

Figure 4 Possible interactions of pyranones II with Src.

Scheme 1 Synthesis of 5-benzyloxy-4-oxo-4H-pyran-2-carboxamide and [6-aminocarbonyl-3-benzyloxy-4-oxo-4H-pyran-2-yl]methyl diethyl phosphate derivatives 18-37. Reagents and conditions: (i) DHP, PTSA·H₂O, CH₂Cl₂, rt, 2; (ii) HCHO, NaOH/H₂O, rt, 3; (CH₃)₂CHCHO, NaOH/H₂O, rt, 4; HCHO, NaOH/H₂O, MeOH, rt, 5; (iii) BnBr, NaOH/H₂O, MeOH, Δ, 6-9; (iv) ClP(O)(OC₂H₅)₂, pyridine, DMAP, CH₂Cl₂, rt, 10; (v) Zn/HCl, H₂O, 70°C, 11, 12; (vi) HCl 1 N, Δ, 13; (vii) CrO₃, H₂SO₄, acetone, 0°C or − 20°C, 14-17; (viii) Method A: TBTU, Et₃N, toluene/acetonitrile, rt, 18-20; Method B: DEPBT, DIEA, THF, Δ, 21, 22; Method C: CMPI, Et₃N, CH₂Cl₂, Δ, 23-37.

Table I.  Amide bond formation.

Compound	R	R6	Method	Yield (%)
18	H	H	A	85
18	H	H	B	69
18	H	H	C	traces
19	2-Cl	H	A	66
19	2-Cl	H	B	35
20	2,6-diCl	H	A	35
20	2,6-diCl	H	B	–
21	2,6-diCH3	H	A	45
21	2,6-diCH3	H	B	51
22	2,6-ClCH3	H	A	traces
22	2,6-ClCH3	H	B	23
23	H	CH3	C	62
24	2-Cl	CH3	C	58
25	2,6-diCl	CH3	C	25
26	2,6-diCH3	CH3	C	79
27	2,6-ClCH3	CH3	C	57
28	H	CH2CH(CH3)2	C	85
29	2-Cl	CH2CH(CH3)2	C	80
30	2,6-diCl	CH2CH(CH3)2	C	37
31	2,6-diCH3	CH2CH(CH3)2	C	84
32	2,6-ClCH3	CH2CH(CH3)2	C	65
33	H	CH2OP(O)(OC2H5)2	C	75
34	2-Cl	CH2OP(O)(OC2H5)2	C	78
35	2,6-diCl	CH2OP(O)(OC2H5)2	C	31
36	2,6-diCH3	CH2OP(O)(OC2H5)2	C	83
37	2,6-ClCH3	CH2OP(O)(OC2H5)2	C	74