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Thiophene[3,2-d]pyrimidine compound as well as preparation method and application thereof

A compound, C1-C6 technology, applied in the field of chemical medicine to achieve the effect of low cytotoxicity, strong immunosuppressive activity, and high kinase selectivity

Inactive Publication Date: 2018-11-02
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is worth noting that in addition to the common side effects of anti-tumor targeted drugs, most BTK inhibitors have other side effects, which may be caused by targeting a variety of other tyrosine kinases

Method used

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  • Thiophene[3,2-d]pyrimidine compound as well as preparation method and application thereof
  • Thiophene[3,2-d]pyrimidine compound as well as preparation method and application thereof
  • Thiophene[3,2-d]pyrimidine compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Synthesis of Step 1 Compound A

[0062]

[0063] 6-Bromo-4-chlorothien[3,2-D]pyrimidine (24.9g, 100mmol), m-nitrophenol (13.9g, 100mmol) and cesium carbonate (65.2g, 200mmol) were dissolved in 200ml of anhydrous N, N-dimethylformamide was stirred at room temperature for one hour. After the reaction, the system was poured into cold water and filtered to obtain compound A (30 g, 86%). 1 H NMR (400MHz, DMSO-d 6 )δ8.72(s,1H),8.31(s,1H),8.22(d,J=8.1Hz,1H),7.99(s,1H),7.89(d,J=8.2Hz,1H),7.82( d, J=8.2Hz, 1H).

[0064] Synthesis of Step 2 Compound 1-I

[0065]

[0066] 352 mg of compound A (1 mmol), 212 mg of sodium carbonate (2 mmol), 321 mg of 4-phenoxyphenylboronic acid (1.5 mmol) and 41 mg of 1,1'-bis(diphenylphosphino)ferrocene dichloride Palladium (II) dichloromethane complex (0.05mmol) mixture is placed in a nitrogen atmosphere, 10 milliliters of tetrahydrofuran and 1 milliliter of deionized water are added, nitrogen gas is filled and discharged several times, ...

Embodiment 2

[0074] Synthesis of Compound 2-I

[0075]

[0076] Compound A and 4-(2-methoxyethoxy)phenylboronic acid were used as raw materials, and compound 2-I was obtained according to the method of step 2 in Example 1, which was directly used in the next step.

[0077] Synthesis of compound 2-II

[0078]

[0079] Compound 2-I was used as a starting material. Compound 2-II was obtained according to the method of step 3 in Example 1. 1 H NMR (400MHz, CDCl 3 )δ8.70(s,1H),7.70(d,J=7.8Hz,2H),7.59(s,1H),7.23(s,1H),7.03(d,J=7.7Hz,2H),6.62( dd,J=18.1,7.7Hz,3H), 4.19(s,2H), 3.80(s,4H), 3.48(s,3H).

[0080] Synthesis of compound 2

[0081]

[0082] Compound 2-II was used as the raw material, and compound 2 was obtained according to the method of step 4 in Example 1. 1 H NMR (400MHz, CDCl 3)δ8.69(s,1H),7.73(s,2H),7.71(s,1H),7.61(s,1H),7.49(s,1H),7.41(s,2H),7.04(d,J =8.2Hz, 3H), 6.43(d, J=16.7Hz, 1H), 6.23(dd, J=16.8, 10.2Hz, 1H), 5.78(d, J=10.2Hz, 1H), 4.20(s, 2H ), 3.80(s,2H), 3...

Embodiment 3

[0084] Synthesis of compound 3-I

[0085]

[0086] Compound A and 4-morpholine phenylboronic acid were used as raw materials, and compound 3-I was obtained according to the method of step 2 in Example 1, which was directly used in the next step.

[0087] Synthesis of compound 3-II

[0088]

[0089] Compound 3-I was used as a starting material. Compound 3-II was obtained according to the method of Step 3 in Example 1. 1 H NMR (400MHz, CDCl 3 )δ8.69(s,1H),7.69(d,J=8.8Hz,2H),7.58(s,1H),7.22(d,J=8.0Hz,1H),6.97(d,J=8.8Hz, 2H), 6.62 (ddd, J=17.2, 7.2, 1.7Hz, 3H), 3.95–3.84 (m, 4H), 3.80 (s, 2H), 3.31–3.24 (m, 4H).

[0090] Synthesis of compound 3

[0091]

[0092] Compound 3-II was used as the raw material, and compound 3 was obtained according to the method of step 4 in Example 1. 1 H NMR (400MHz, DMSO-d 6 )δ10.35(s,1H),8.64(s,1H),7.91(s,1H),7.80(d,J=8.7Hz,2H),7.76(s,1H),7.52(d,J=8.3 Hz, 1H), 7.43(t, J=8.1Hz, 1H), 7.06(d, J=8.9Hz, 3H), 6.43(dd, J=17.0, 10.1Hz, 1H), ...

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Abstract

The invention provides a thiophene[3,2-d]pyrimidine compound as shown in a structural formula I as well as a preparation method and application thereof. The compound or pharmaceutically acceptable salt has remarkable inhibition effect on Bruton tyrosine kinase (BTK), has high BTK inhibition activity and high kinase selectivity, and has strong immunosuppressive activity effect. The compound or pharmaceutically acceptable salt has low cytotoxicity on mouse primary lymphocytes, has remarkable inhibition activity on lipopolysaccharide (LPS)-induced B lymphocyte activation and proliferation, has alarge administration window and high safety, and can be widely applied in the field of treatment of inflammation, immune system diseases and malignant tumor. (The formula is as shown in the description).

Description

technical field [0001] The present invention relates to the field of chemical medicine, in particular to a class of thieno[3,2-d]pyrimidine compounds, a preparation method and application of the compounds, which can selectively inhibit Bruton's tyrosine kinase ( BTK) can be used in the treatment or prevention of acute and chronic inflammation, treatment or prevention of immune disorders, or anti-tumor. Background technique [0002] Bruton's tyrosine kinase (BTK) is a member of the non-receptor tyrosine kinase Tec family, which plays a crucial role in the B cell receptor signal transduction pathway (BCR), and the BCR signaling pathway participates in mediating It regulates the activation, proliferation, differentiation and apoptosis of normal B cells. In recent years, studies have found that the abnormality of BCR signaling pathway is related to many diseases, such as inflammatory response, cancer and so on. BTK is an important signaling molecule in the BCR signaling pathwa...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61K31/519A61P29/00A61P35/00A61P37/02A61P11/00A61P11/06A61P37/08A61P19/02A61P17/06
CPCC07D495/04
Inventor 左建平吕伟唐炜张秋萌何世君张璐瑶李恒林泽民
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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