Synthesis and Biological Activity in vitro of Imidazo[4,5-c]quinoline Derivatives †

doi:10.7503/cjcu20190544

Abstract

Abstract:

In search of new and efficient PI3K/mTOR inhibitor based on the imidazoquinoline structural framework, 15 novel imidazo[4,5-c] quinoline were synthesized via SNAr reaction of 4-chloroquinoline with aniline, the Traube condensation reaction of aromatic diamine with triphosgene and the Suzuki coupling reaction of bromo-compounds with 3-quinoline boronic acid. The structures of the key intermediates and target compounds were confirmed by ¹H NMR, ¹³C NMR and HRMS. Imidazo[4,5-c] quinolin analogues(8Aa—8Ae, 8Ba—8Be, 8Ca—8Ce) were evaluated for their in vitro activities against PI3Kα/mTOR by ADP-Glo kinase assay and TR-FRET assay, all compounds displayed strong activities.

Key words: Imidazoquinoline, Traube reaction, Suzuki reaction, PI3K/mTOR Dual inhibitor

CLC Number:

O626.32

TrendMD:

Yanjie LI,Ensi WANG,Xiaowei SHAO,Xingmin ZHANG,Shengxiu NIU,Lijuan YANG,Yi WU. Synthesis and Biological Activity in vitro of Imidazo[4,5-c]quinoline Derivatives ^†[J]. Chem. J. Chinese Universities, 2019, 40(12): 2502.

Figures/Tables 8

References 25

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Compd.	m. p./℃	Compd.	m. p./℃	Compd.	m. p./℃
2A	133—134	4A	214—217	6A	219—221
2B	140—142	4B	210—213	6B	213—215
2C	138—141	4C	192—195	6C	215—217
3A	166—168	5A	230—232	7A	196—198
3B	169—170	5B	225—227	7B	186—188
3C	174—177	5C	224—226	7C	227—230

Compd.	m. p./℃	Compd.	m. p./℃	Compd.	m. p./℃
2A	133—134	4A	214—217	6A	219—221
2B	140—142	4B	210—213	6B	213—215
2C	138—141	4C	192—195	6C	215—217
3A	166—168	5A	230—232	7A	196—198
3B	169—170	5B	225—227	7B	186—188
3C	174—177	5C	224—226	7C	227—230

Compd.	Appearance	Yield(%)	m. p./℃	HRMS(calcd.), m/z[M+1]⁺
8Aa	White solid	73	275—277	528.2321(528.2340)
8Ab	White solid	78	289—292	564.1991(564.1984)
8Ac	White solid	56	284—286	581.2335(581.2349)
8Ad	White solid	92	263—267	544.2270(544.2280)
8Ae	White solid	92	235—239	558.2427(558.2435)
8Ba	White solid	73	277—279	526.2165(526.2181)
8Bb	White solid	77	279—282	562.1835(562.1862)
8Bc	White solid	56	278—280	579.2179(579.2197)
8Bd	White solid	87	268—270	542.2114(542.2137)
8Be	White solid	65	235—238	556.2270(556.2288)
8Ca	White solid	65	281—283	552.2321(552.2345)
8Cb	White solid	61	286—288	588.1991(588.2014)
8Cc	White solid	60	283—285	605.2335(605.2361)
8Cd	White solid	89	279—281	568.2270(568.2294)
8Ce	White solid	47	279—281	582.2427(582.2451)

Compd.	Appearance	Yield(%)	m. p./℃	HRMS(calcd.), m/z[M+1]⁺
8Aa	White solid	73	275—277	528.2321(528.2340)
8Ab	White solid	78	289—292	564.1991(564.1984)
8Ac	White solid	56	284—286	581.2335(581.2349)
8Ad	White solid	92	263—267	544.2270(544.2280)
8Ae	White solid	92	235—239	558.2427(558.2435)
8Ba	White solid	73	277—279	526.2165(526.2181)
8Bb	White solid	77	279—282	562.1835(562.1862)
8Bc	White solid	56	278—280	579.2179(579.2197)
8Bd	White solid	87	268—270	542.2114(542.2137)
8Be	White solid	65	235—238	556.2270(556.2288)
8Ca	White solid	65	281—283	552.2321(552.2345)
8Cb	White solid	61	286—288	588.1991(588.2014)
8Cc	White solid	60	283—285	605.2335(605.2361)
8Cd	White solid	89	279—281	568.2270(568.2294)
8Ce	White solid	47	279—281	582.2427(582.2451)

Compd.	¹H NMR(CDCl₃, 400 MHz), δ
2A	10.68(s, 1H), 9.44(s, 1H), 7.84(d, J=8.8 Hz, 1H), 7.73—7.71(m, 1H), 7.60(s, 1H), 7.38—7.33(m, 5H), 7.25(d, J=8.4 Hz, 2H), 7.11(d, J=8.4 Hz, 2H), 5.29(s, 1H), 5.16(s, 2H), 4.36(s, 2H), 2.91(s, 2H), 2.78—2.71(m, 1H), 1.88(d, J=12.0 Hz, 2H), 1.66(d, J=10.8 Hz, 2H)
2B	10.45(s, 1H), 9.31(s, 1H), 7.76(d, J=8.0 Hz, 1H), 7.69(s, 1H), 7.63(d, J=8.4 Hz, 1H), 7.32—7.25(m, 7H), 7.04(d, J=7.4 Hz, 2H), 6.02(s, 1H), 5.12(s, 2H), 4.12(s, 2H), 3.68(s, 2H), 2.49(s, 2H)
2C	10.52(s, 1H), 9.44(s, 1H), 7.86(d, J=8.8 Hz, 1H), 7.78—7.74(m, 2H), 7.37(s, 5H), 7.34(s, 2H), 7.07(d, J=8.0 Hz, 2H), 6.47(s, 1H), 5.19—5.12(m, 2H), 4.63(s, 2H), 3.17—3.05(m, 1H), 2.26(d, J=16.8 Hz, 2H), 2.04(s, 2H), 1.78—1.68(m, 1H)
3A	8.56(s, 1H), 7.95(s, 1H), 7.85(d, J=8.2 Hz, 1H), 7.48(d, J=8.4 Hz, 1H), 7.37—7.26(m, 5H), 7.03(d, J=8.2 Hz, 2H), 6.60(d, J=8.2 Hz, 2H), 6.08(s, 1H), 5.16(s, 2H), 4.30(s, 2H), 4.13(s, 2H), 2.84(s, 2H), 2.56(t, J=11.9 Hz, 1H), 1.78(d, J=12.4 Hz, 2H), 1.61—1.51(m, 2H)
3B	8.55(s, 1H), 7.92(d, J=2.0 Hz, 1H), 7.82(d, J=8.8 Hz, 1H), 7.47(dd, J=2.0, 8.8 Hz, 1H), 7.36—7.29(m, 5H), 7.20(d, J=8.8 Hz, 2H), 6.58(d, J=8.8 Hz, 2H), 6.01(s, 1H), 5.87(s, 1H), 5.16(s, 2H), 4.11(s, 4H), 3.67(t, J=5.6 Hz, 2H), 2.46(s, 2H)
3C	8.55(s, 1H), 7.94(s, 1H), 7.82(d, J=8.9 Hz, 1H), 7.48—7.46(m, 1H), 7.32—7.26(m, 5H), 7.17(d, J=7.6 Hz, 2H), 6.56(d, J=8.3 Hz, 2H), 6.29—6.21(m, 2H), 5.13(d, J=12.9 Hz, 2H), 4.58(s, 2H), 4.16(s, 2H), 3.11—2.96(m, 1H), 2.16(d, J=9.4 Hz, 2H), 1.94(d, J=8.0 Hz, 2H), 1.68(s, 1H)
4A	11.87(s, 1H), 9.03(s, 1H), 8.15(d, J=9.2 Hz, 1H), 7.85—7.80(m, 5H), 7.64—7.59(m, 4H), 7.28(s, 1H), 5.85(s, 2H), 5.37(s, 2H), 4.49(d, J=13.2 Hz, 2H), 3.18—3.12(m, 3H), 2.14(d, J=12.3 Hz, 2H), 1.92(s, 1H)
4B	9.09(s, 1H), 8.55(s, 1H), 7.92(d, J=2.4 Hz, 1H), 7.82(d, J=9.2 Hz, 1H), 7.47(dd, J=2.4, 9.2 Hz, 1H), 7.36—7.29(m, 5H), 7.25(d, J=8.4 Hz, 2H), 6.64(d, J=8.4 Hz, 2H), 6.04(s, 1H), 5.38(s, 2H), 3.93(s, 2H), 3.64(t, J=5.6 Hz, 2H), 2.90(s, 2H)
Compd.	¹H NMR(CDCl₃, 400 MHz), δ
4C	8.14(t, J=7.5 Hz, 2H), 7.93(s, 2H), 7.83(d, J=8.8 Hz, 3H), 7.58(s, 2H), 7.52(t, J=7.3 Hz, 2H), 7.49(s, 2H), 6.97(d, J=5.1 Hz, 1H), 4.81—4.74(m, 2H), 3.70(s, 1H), 3.31(s, 1H), 3.07(s, 1H), 2.90(s, 1H), 2.63(d, J=13.2 Hz, 1H), 2.41(s, 1H), 2.21(s, 2H), 2.01(s, 1H)
5A	8.88(s, 1H), 8.08(d, J=9.0 Hz, 1H), 7.70(d, J=17.8 Hz, 1H), 7.61(d, J=8.2 Hz, 4H), 7.56—7.45(m, 6H), 5.31(s, 2H), 4.53(s, 2H), 3.78(s, 3H), 3.08(s, 2H), 3.01(t, J=12.2 Hz, 1H), 2.11(d, J=11.4 Hz, 2H), 1.89(d, J=10.8 Hz, 2H)
5B	7.94(d, J=9.2 Hz, 1H), 7.59(d, J=8.4 Hz, 2H), 7.54(dd, J=2.4, 9.2 Hz, 1H), 7.43(d, J=8.4 Hz, 2H), 7.35(dd, J=7.6, 15.6 Hz, 5H), 7.32—7.26(m, 2H), 6.16(s, 1H), 5.18(s, 2H), 4.21(s, 2H), 3.77(t, J=5.6 Hz, 2H), 3.62(s, 3H), 2.62(s, 2H)
5C	8.71(s, 1H), 7.90(d, J=9.0 Hz, 1H), 7.53(d, J=9.0 Hz, 3H), 7.40(d, J=8.4 Hz, 2H), 7.31(d, J=9.6 Hz, 5H), 7.27(d, J=7.0 Hz, 2H), 6.56(s, 1H), 5.12(t, J=12.4 Hz, 2H), 4.65(s, 2H), 3.61(s, 3H), 3.11(s, 1H), 2.28(d, J=17.1 Hz, 2H), 2.04(s, 2H), 1.78(s, 1H)
6A	8.80(s, 2H), 8.23(d, J=8.8 Hz, 1H), 8.07—8.04(m, 2H), 7.89(d, J=8.6 Hz, 1H), 7.76(d, J=8.1 Hz, 1H), 7.67(t, J=7.6 Hz, 1H), 7.41—7.35(m, 5H), 7.34(s, 1H), 7.31(s, 1H), 5.17(s, 2H), 4.36(s, 2H), 3.68(s, 3H), 2.91(s, 2H), 2.86—2.79(m, 1H), 1.89(s, 2H), 1.71(d, J=9.5 Hz, 2H)
6B	8.86(s, 1H), 8.75(s, 1H), 8.17(d, J=8.8 Hz, 1H), 8.03(d, J=8.4 Hz, 1H), 7.91(s, 1H), 7.84(d, J=8.8 Hz, 1H), 7.65—7.58(m, 4H), 7.48(d, J=8.4 Hz, 3H), 7.41—7.31(m, 6H), 6.11(d, J=22.4 Hz, 1H), 5.20(d, J=13.6 Hz, 2H), 4.20(s,2H), 3.76(s, 2H), 3.63(s, 3H), 2.60(s, 2H)
6C	9.01(s, 1H), 8.89(s, 1H), 8.34—8.18(m, 2H), 8.06(s, 1H), 8.00(s, 1H), 7.79(s, 2H), 7.73—7.65(m, 3H), 7.64(s, 2H), 7.56(s, 1H), 7.47—7.44(m, 5H), 6.72(s, 1H), 5.31(s, 2H), 4.82(s, 2H), 3.77(s, 3H), 2.48—2.44(m, 2H), 2.21(s, 2H), 1.96(s, 1H), 1.38(s, 1H)
7A	8.90(s, 1H), 8.84(s, 1H), 8.25(d, J=8.9 Hz, 1H), 8.20(s, 1H), 8.09(d, J=8.4 Hz, 1H), 7.99(d, J=1.7 Hz, 1H), 7.90(d, J=8.0 Hz, 1H), 7.81(s, 1H), 7.69—7.66(m, 1H), 7.64—7.60(m, 4H), 7.39(s, 1H), 3.78(s, 3H), 3.25(d, J=12.2 Hz, 2H), 2.95—2.91(m, 1H), 2.87(t, 2H), 1.96(d, J=12.5 Hz, 2H), 1.78(t, J=15.4 Hz, 2H)
7B	8.54(s, 2H), 7.90(d, J=8.9 Hz, 1H), 7.79—7.75(m, 2H), 7.66(d, J=8.8 Hz, 1H), 7.47(t, J=8.0 Hz, 2H), 7.43(d, J=8.4 Hz, 2H), 7.33(d, J=7.4 Hz, 1H), 7.31—7.26(m, 2H), 7.13(s, 1H), 6.03(s, 1H), 4.33(s, 1H), 3.43(s, 3H), 3.32(s, 2H), 2.89(d, J=5.6 Hz, 2H), 2.32(s, 2H)
7C	8.61(s, 2H), 8.00(d, J=8.9 Hz, 1H), 7.86(d, J=8.4 Hz, 2H), 7.73(d, J=8.9 Hz, 1H), 7.60—7.54(m, 2H), 7.47(d, J=8.7 Hz, 2H), 7.38(t, J=7.5 Hz, 1H), 7.33(d, J=8.7 Hz, 2H), 7.21(s, 1H), 6.42(d, J=5.2 Hz, 1H), 4.21(s, 1H), 3.76—3.70(m, 2H), 3.51(s, 3H), 2.83—2.78(m, 1H), 2.15(d, J=17.2 Hz, 1H), 2.00(d, J=9.0 Hz, 1H), 1.91—1.83(m, 2H), 1.57(m, 1H)
8Aa	8.71(d, J=20.0 Hz, 2H), 8.16(d, J=8.4 Hz, 1H), 8.07(s, 1H), 8.04(d, J=8.4 Hz, 1H), 7.88(d, J=8.4 Hz, 1H), 7.78(d, J=12.2 Hz, 1H), 7.73(t, J=7.4 Hz, 1H), 7.58(t, J=7.0 Hz, 1H), 7.48(s, 4H), 7.26(s, 1H), 4.27(s, 1H), 3.94(d, J=12.8 Hz, 1H), 3.66(s, 3H), 3.23(t, J=12.6 Hz, 1H), 2.91(t, J=12.4 Hz, 1H), 2.69(t, J=12.4 Hz, 1H), 2.11(s, 3H), 1.96(t, J=12.8 Hz, 2H), 1.65(t, J=12.2 Hz, 2H)
8Ab	8.76(s, 1H) , 8.70(s, 1H), 8.16(d, J=8.6 Hz, 1H), 8.07(s, 1H), 8.01(d, J=8.6 Hz, 1H,), 7.89(d, J=8.3 Hz, 1H), 7.78(d, J=7.6 Hz, 1H), 7.71(t, J=6.8 Hz, 1H), 7.58(t, J=6.9 Hz, 1H), 7.48(s, 4H), 7.26(s, 1H), 4.13(s, 2H), 3.87(d, J=10.5 Hz, 2H), 3.65(s, 3H), 2.82—2.76(m, 4H), 1.96(d, J=11.7 Hz, 2H), 1.83(t, J=10.9 Hz, 2H)
8Ac	8.76—8.72(m, 1H), 8.71(s, 1H), 8.54(s, 1H), 8.16(d,J=8.4 Hz, 1H), 8.07(s, 1H), 8.04(d, J=8.4 Hz, 1H), 7.88(d, J=8.4 Hz, 1H), 7.78(d, J=12.2 Hz, 1H), 7.73(s, 1H), 7.58(s, 1H), 7.48(s, 4H), 7.26(s, 1H), 4.27(s, 1H), 3.94(d, J=12.8 Hz, 1H), 3.66(s, 3H), 3.23(t, J=12.6 Hz, 1H), 2.91(t, J=11.4 Hz, 1H), 2.69(t, J=12.4 Hz, 1H), 1.96(t, J=16.8 Hz, 2H), 1.65(t, J=12.2 Hz, 2H)
8Ad	8.54(s, 1H), 8.47(d, J=1.6 Hz, 1H), 7.93(d, J=8.8 Hz, 1H), 7.87(s, 1H), 7.79(d, J=8.4 Hz, 1H), 7.64(d, J=9.2 Hz, 1H), 7.56(d, J=8.0 Hz, 1H), 7.51(t, J=7.7 Hz, 1H), 7.36—7.32(m, 1H), 7.26(s, 4H), 7.04(s, 1H), 4.46(d, J=13.2 Hz, 1H), 3.97(d, J=16.4 Hz, 4H), 3.40(s, 4H), 2.89(t, J=12.2 Hz, 2H), 2.70(t, J=12.2 Hz,1H), 2.55(t, J=12.4 Hz, 1H), 1.72(d, J=12.8 Hz, 2H)
Compd.	¹H NMR(CDCl₃, 400 MHz), δ
8Ae	8.63(d, J=12.4 Hz, 1H), 8.53(s, 1H), 8.01(d, J=8.8 Hz, 1H), 7.95(d, J=7.6 Hz, 1H), 7.87(d, J=9.2 Hz, 1H), 7.66—7.56(m, 3H), 7.41—7.31(m, 5H), 7.09(d, J=15.6 Hz, 1H), 4.63(s, 1H), 3.78(s, 1H), 3.69(s, 2H), 3.50(s, 3H), 3.09(t, J=11.8 Hz, 1H), 2.71—2.62(m, 2H), 1.91—1.82(m, 2H), 1.56(t, J=10.8 Hz, 2H), 1.26(d, J=6.4 Hz, 3H)
8Ba	8.72(m, 2H), 8.11(d, J=8.8 Hz, 1H), 7.98—7.94(m, 2H), 7.86—7.84(m, 1H), 7.67—7.62(m, 2H), 7.57(d, J=8.4 Hz, 2H), 7.50—7.45(m, 3H), 7.31(d, J=7.2 Hz, 1H), 6.14(d, 1H), 4.18(s, 1H), 3.88—3.74(m, 3H), 3.65—3.62(m, 1H), 3.60(s, 3H), 2.57(s, 1H), 2.50(s, 1H), 2.10—2.07(m, 2H)
8Bb	9.52(s, 2H), 8.90(d, J=8.8 Hz, 1H), 8.73(s, 2H), 8.64(d, J=8.7 Hz, 1H), 8.40(t, J=8.0 Hz, 2H), 8.36(d, J=8.0 Hz, 2H), 8.28(t, J=7.4 Hz, 1H), 8.24(d, J=8.0 Hz, 2H), 8.09(s, 1H), 6.91(s, 1H), 4.69(s, 2H), 4.39(s, 3H), 4.24(t, J=5.2 Hz, 2H), 3.58(s, 3H), 3.42(s, 2H)
8Bc	8.00(d, J=7.6 Hz, 1H), 7.94(s, 1H), 7.36(t, J=8.8 Hz, 2H), 7.18(s, 2H), 7.07(d, J=7.7 Hz, 1H), 6.94(d, J=8.1 Hz, 1H), 6.88—6.82(m, 4H), 6.70(d, J=3.0 Hz, 2H), 6.56(s, 2H), 6.45(s, 1H), 3.58(s, 1H), 3.52(s, 1H), 3.18(s, 1H), 3.11(s, 1H), 2.84(s, 3H), 1.86(d, J=22.3 Hz, 2H)
8Bd	7.98(s, 2H), 7.36(d, J=8.9 Hz, 1H), 7.26—7.19(m, 2H), 7.11(d, J=8.8 Hz, 1H), 6.94—6.89(m, 2H), 6.84(d, J=8.0 Hz, 2H), 6.76—6.72(m, 3H), 6.58—6.56(m, 1H), 5.42—5.34(m, 1H), 3.42(d, J=21.2 Hz, 2H), 3.22(s, 2H), 3.05(t, J=5.2 Hz, 1H), 2.87(s, 3H), 2.75(t, J=5.2 Hz, 1H), 2.49(s, 1H), 1.83(s, 2H)
8Be	8.62(s, 2H), 8.00(d, J=8.8 Hz, 1H), 7.89—7.82(m, 2H), 7.74(d, J=8.6 Hz, 1H), 7.56—7.49(m, 5H), 7.40—7.36(m, 3H), 7.19(d, J=6.2 Hz, 1H), 6.01(d, J=18.6 Hz, 1H), 4.43—4.41(m, 1H), 4.10(s, 2H), 3.57(s, 2H), 3.50(s, 3H), 2.44(d, J=21.8 Hz, 2H), 1.22—1.17(m, 3H)
8Ca	8.50—8.48(d, 2H), 7.83(d, J=8.4 Hz, 2H), 7.69(t, J=8.9 Hz, 2H), 7.61(d, J=8.2 Hz, 2H), 7.44—7.32(m, 4H), 7.22(s, 2H), 6.26(dd, J=4.6, 16.5 Hz, 1H), 4.68—4.58(m, 1H), 4.34(s, 3H), 3.36(s, 3H), 2.91—2.76(m, 1H), 2.03(d, J=16.6 Hz, 1H), 1.83—1.79(m, 5H)
8Cb	8.55(s, 2H), 7.94(d, J=8.8 Hz, 1H), 7.78(d, J=8.1 Hz, 2H), 7.68(d, J=8.6 Hz, 1H), 7.52—7.46(m, 2H), 7.39(d, J=8.0 Hz, 2H), 7.33(t, J=7.4 Hz, 1H), 7.28(d, J=8.0 Hz, 2H), 7.16(s, 1H), 6.32(d, J=5.0 Hz, 1H), 4.26(d, J=5.1 Hz, 2H), 3.70(s, 1H), 3.43(s, 3H), 2.91(d, J=15.8 Hz, 1H), 2.69(s, 3H), 2.19(d, J=17.2 Hz, 1H), 2.08(d, J=9.5 Hz, 1H), 1.92—1.84(m, 2H)
8Cc	8.66—8.63(d, 2H), 8.15—8.02(m, 1H), 7.99(d, J=8.8 Hz, 1H), 7.83—7.75(m, 3H), 7.53—7.50(m, 4H), 7.33(d, J=7.7 Hz, 3H), 7.25(s, 1H), 6.42(d, J=4.3 Hz, 1H), 4.24(s, 2H), 3.49(s, 3H), 3.13(m, 2H), 2.28(t, J=16.8 Hz, 1H), 2.17—2.10(m, 1H), 1.99—1.88(m, 2H)
8Cd	8.59(s, 2H), 8.00(d, J=8.8 Hz, 1H), 7.84(d, J=5.6 Hz, 2H), 7.70(d, J=8.7 Hz, 1H), 7.52(d, J=4.1 Hz, 2H), 7.43—7.36(m, 3H), 7.31(d, J=7.9 Hz, 2H), 7.20(d, J=4.4 Hz, 1H), 6.37—6.33(m, 1H), 4.18(d, J=5.1 Hz, 1H), 4.10—4.02(m, 1H), 3.47(s, 3H), 3.44(s, 2H), 3.06—2.90(m, 2H), 2.32—2.11(m, 2H), 1.94—1.78(m, 3H)
8Ce	8.62(d, 2H), 8.01—7.93(d, J=8.4 Hz, 4H), 7.41(d, J=7.6 Hz, 5H), 7.36—7.23(m, 3H), 6.39(s, 1H), 4.72(m, 1H), 4.57—4.49(m, 1H), 4.35—4.26(m, 1H), 4.20(s, 2H), 3.50(s, 3H), 3.16—2.93(m, 1H), 2.16—1.84(m, 4H), 1.23(d, J=5.8 Hz, 3H)