Nitrogen-containing heterogeneous ring compound, preparation method thereof and application of nitrogen-containing heterogeneous ring compound in inhibition of kinase activity

Abstract

The invention discloses a nitrogen-containing heterogeneous ring compound, a preparation method thereof and an application of the nitrogen-containing heterogeneous ring compound in inhibition of kinase activity. The general formula of the nitrogen-containing heterogeneous ring compound is represented as a formula I or a formula I', wherein R1, R2, R3 and R4 in the formula I or the formula I' are selected from any one of hydrogen, halogen, cyanogroup, hydroxyl, amidogen and substituted or unsubstituted C1-C6 alkyl groups independently, and a 3-10-membered ring system can be formed by any two groups in R1, R2, R3 and R4; M1, M2 and M3 are selected from CRa or N independently, and at least one of M1, M2 and M3 is N; W is selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C2-C6 alkenyl, unsubstituted or halogenated 4-8-membered alkine groups, substituted or unsubstituted C3-C8 naphthenic base, substituted or unsubstituted 4-8-membered heterocyclic groups, 5-10-membered aromatic or heteroaryl groups, substituted carbonyl, substituted sulfonyl and substituted or unsubstituted amidogen. The nitrogen-containing heterogeneous ring compound can inhibit EGFR (epidermal growth factor receptor) mutant kinase activity or ALK (anaplastic lymphoma kinase) activity and is a multi-target tumor therapeutic drug with a brand-new action mechanism.

Description

technical field

[0001] The invention relates to a nitrogen-containing heterocyclic compound, a preparation method thereof and an application in inhibiting kinase activity, belonging to the technical field of medicinal chemistry. Background technique

[0002] Molecular targeted therapy of tumors is based on the key proteins closely related to the occurrence and development of tumors, and selectively acts on signaling proteins by chemical means to kill tumor cells. The characteristics of targeted therapy are: high specificity, strong selectivity, and lower toxicity and side effects compared with traditional chemotherapy drugs; when used in combination, it can enhance the efficacy of traditional chemotherapy; targeted inhibitors are prone to drug resistance in clinical practice and make the therapeutic drugs invalidated.

[0003] Lung cancer is the malignant tumor with the highest morbidity and mortality in the world, and the 5-year survival rate is only 16.8%. In 2010, the mo...

Examples

Embodiment 1

[0169] Intermediate 11 (25mg, 0.10mmol) and Intermediate 20 (35mg, 0.12mmol) were dissolved in iPrOH (1mL), concentrated hydrochloric acid (24mg, 0.25mmol) was added, microwave reaction (250w, 130°C, 120min, 300psi) . Cool to room temperature, add EA (20mL), wash with saturated sodium bicarbonate (aq) (20mL×3), wash with saturated brine (20mL×3), column chromatography (D / M / Et 3 N=10:1:0.02), to obtain Example 1: 48 mg of off-white solid with a yield of 71%.

[0170] The structure verification data is as follows: 1 H NMR (CDCl 3 )δ (ppm): 10.01 (s, 1H), 8.46 (dd, J 1 =8.4Hz,J 2 =4.4Hz,1H),8.35(s,1H),7.47(t,J=7.6Hz,1H),7.23-7.15(m,2H),7.02-6.98(m,1H),6.45(d,J= 8.8Hz, 1H), 6.35(s, 1H), 5.87(s, 1H), 4.60(t, J=8.8Hz, 2H), 3.40(d, J=12.0Hz, 2H), 3.20(t, J= 8.8Hz, 2H), 2.67(t, J=12.0Hz, 2H), 2.33(s, 6H), 2.29-2.23(m, 1H), 1.93(d, J=12.0Hz, 2H), 1.80(s, 3H),1.74(s,3H),1.68-1.58(m,2H).HRMS(ESI):m / z,calcd for C 27 h 36 N 6 o 2 P[M+H + ]:507.2637, found 507.2646.

Embodiment 2

[0172]Using Intermediate 11 (50 mg, 0.19 mmol) and Intermediate 21 (71 mg, 0.24 mmol) as raw materials, the same method as Example 1 was used to synthesize Example 2: 84 mg of off-white solid with a yield of 84%.

[0173] The structure verification data is as follows: 1 H NMR (DMSO-d 6 )δ (ppm): 11.51 (s, 1H), 8.66 (m, 1H), 8.24 (s, 1H), 8.02 (d, J = 3.2Hz, 1H), 7.54 (dd, J 1 =13.6Hz,J 2 =7.6Hz, 1H), 7.32(t, J=7.6Hz, 1H), 7.21(d, J=8.4Hz, 1H), 7.08(t, J=7.2Hz, 1H), 6.44(d, J=8.8 Hz,1H),4.49(t,J=8.4Hz,2H),3.41-3.39(m,2H),3.16(t,J=8.0Hz,2H),3.01(m,1H),2.64(t,J =12.0Hz,2H),2.53(s,6H),2.01(d,J=10.0Hz,2H),1.80(s,3H),1.77(s,3H),1.80-1.65(m,2H).HRMS (ESI): m / z, calcd for C 27 h 35 N 6 o 2 PF[M+H + ]:525.2543, found 525.2557.

Embodiment 3

[0175] Using Intermediate 11 (40 mg, 0.15 mmol) and Intermediate 22 (54 mg, 0.19 mmol) as raw materials, the same method as in Example 1 was used to synthesize Example 3: 35 mg of an off-white solid with a yield of 45%.

[0176] The structure verification data is as follows: 1 H NMR (DMSO-d 6 )δ(ppm):10.95(s,1H),8.51-8.50(m,1H),8.11(s,1H),7.95(d,J=5.6Hz,1H),7.52(d,J 1 =12.8Hz,J 2 =6.4Hz, 1H), 7.31(t, J=7.6Hz, 1H), 7.25(d, J=8.4Hz, 1H), 7.04(d, J=7.6Hz, 1H), 6.43(d, J=8.8 Hz,1H),5.96(d,J=5.6Hz,1H),4.49(t,J=8.4Hz,2H),3.39(m,2H),3.17-3.13(m,3H),2.63(t,J =12.0Hz,2H),2.43(s,6H),1.97-1.94(m,2H),1.78(s,3H),1.75(s,3H),1.62-1.59(m,2H).HRMS(ESI) :m / z, calcd for C 27 h 36 N 6 o 2 P[M+H + ]:507.2637, found 507.2634.

technical field

[0001] The invention relates to a nitrogen-containing heterocyclic compound, a preparation method thereof and an application in inhibiting kinase activity, belonging to the technical field of medicinal chemistry. Background technique

[0002] Molecular targeted therapy of tumors is based on the key proteins closely related to the occurrence and development of tumors, and selectively acts on signaling proteins by chemical means to kill tumor cells. The characteristics of targeted therapy are: high specificity, strong selectivity, and lower toxicity and side effects compared with traditional chemotherapy drugs; when used in combination, it can enhance the efficacy of traditional chemotherapy; targeted inhibitors are prone to drug resistance in clinical practice and make the therapeutic drugs invalidated.

[0003] Lung cancer is the malignant tumor with the highest morbidity and mortality in the world, and the 5-year survival rate is only 16.8%. In 2010, the mo...

Examples

Embodiment 1

[0169] Intermediate 11 (25mg, 0.10mmol) and Intermediate 20 (35mg, 0.12mmol) were dissolved in iPrOH (1mL), concentrated hydrochloric acid (24mg, 0.25mmol) was added, microwave reaction (250w, 130°C, 120min, 300psi) . Cool to room temperature, add EA (20mL), wash with saturated sodium bicarbonate (aq) (20mL×3), wash with saturated brine (20mL×3), column chromatography (D / M / Et 3 N=10:1:0.02), to obtain Example 1: 48 mg of off-white solid with a yield of 71%.

[0170] The structure verification data is as follows: 1 H NMR (CDCl 3 )δ (ppm): 10.01 (s, 1H), 8.46 (dd, J 1 =8.4Hz,J 2 =4.4Hz,1H),8.35(s,1H),7.47(t,J=7.6Hz,1H),7.23-7.15(m,2H),7.02-6.98(m,1H),6.45(d,J= 8.8Hz, 1H), 6.35(s, 1H), 5.87(s, 1H), 4.60(t, J=8.8Hz, 2H), 3.40(d, J=12.0Hz, 2H), 3.20(t, J= 8.8Hz, 2H), 2.67(t, J=12.0Hz, 2H), 2.33(s, 6H), 2.29-2.23(m, 1H), 1.93(d, J=12.0Hz, 2H), 1.80(s, 3H),1.74(s,3H),1.68-1.58(m,2H).HRMS(ESI):m / z,calcd for C 27 h 36 N 6 o 2 P[M+H + ]:507.2637, found 507.2646.

Embodiment 2

[0172]Using Intermediate 11 (50 mg, 0.19 mmol) and Intermediate 21 (71 mg, 0.24 mmol) as raw materials, the same method as Example 1 was used to synthesize Example 2: 84 mg of off-white solid with a yield of 84%.

[0173] The structure verification data is as follows: 1 H NMR (DMSO-d 6 )δ (ppm): 11.51 (s, 1H), 8.66 (m, 1H), 8.24 (s, 1H), 8.02 (d, J = 3.2Hz, 1H), 7.54 (dd, J 1 =13.6Hz,J 2 =7.6Hz, 1H), 7.32(t, J=7.6Hz, 1H), 7.21(d, J=8.4Hz, 1H), 7.08(t, J=7.2Hz, 1H), 6.44(d, J=8.8 Hz,1H),4.49(t,J=8.4Hz,2H),3.41-3.39(m,2H),3.16(t,J=8.0Hz,2H),3.01(m,1H),2.64(t,J =12.0Hz,2H),2.53(s,6H),2.01(d,J=10.0Hz,2H),1.80(s,3H),1.77(s,3H),1.80-1.65(m,2H).HRMS (ESI): m / z, calcd for C 27 h 35 N 6 o 2 PF[M+H + ]:525.2543, found 525.2557.

Embodiment 3

[0175] Using Intermediate 11 (40 mg, 0.15 mmol) and Intermediate 22 (54 mg, 0.19 mmol) as raw materials, the same method as in Example 1 was used to synthesize Example 3: 35 mg of an off-white solid with a yield of 45%.

[0176] The structure verification data is as follows: 1 H NMR (DMSO-d 6 )δ(ppm):10.95(s,1H),8.51-8.50(m,1H),8.11(s,1H),7.95(d,J=5.6Hz,1H),7.52(d,J 1 =12.8Hz,J 2 =6.4Hz, 1H), 7.31(t, J=7.6Hz, 1H), 7.25(d, J=8.4Hz, 1H), 7.04(d, J=7.6Hz, 1H), 6.43(d, J=8.8 Hz,1H),5.96(d,J=5.6Hz,1H),4.49(t,J=8.4Hz,2H),3.39(m,2H),3.17-3.13(m,3H),2.63(t,J =12.0Hz,2H),2.43(s,6H),1.97-1.94(m,2H),1.78(s,3H),1.75(s,3H),1.62-1.59(m,2H).HRMS(ESI) :m / z, calcd for C 27 h 36 N 6 o 2 P[M+H + ]:507.2637, found 507.2634.

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