Compounds and preparing method and applications thereof

Abstract

The invention provides compounds and a preparing method and applications thereof. The compounds are compounds shown as a formula I or stereoisomers, tautomers, medicine active metabolites, medicinal salts, hydrates, solvates or prodrugs of the compounds shown as the formula I, wherein X, R1 and R2 are defined in the specification. The compounds can be adopted as kinase inhibitors.

Description

technical field

[0001] The present invention relates to the field of medicine. Specifically, the present invention relates to compounds and their preparation methods and uses. More specifically, the present invention relates to compounds and their preparation methods, pharmaceutical compositions, and the use of compounds and pharmaceutical compositions in the preparation of medicines. Background technique

[0002] Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase of the Tec kinase family, which is a key regulator of B cell development, activation, signal transduction and survival. ) play an important role in signal transduction. When BCR is activated, BTK is first activated by other tyrosine kinases (such as Lyn and SYK), leading to the activation of transcription factors essential for B cell proliferation and differentiation. In addition, BTK is also involved in receptor signal transduction related to B cell migration and adhesion, including chemokine recept...

Examples

Embodiment 1

[0053] Embodiment 1: compound (intermediate) shown in preparation formula 3

[0054] Add the compound shown in formula 1 (17.0 grams, 0.1 moles), the compound shown in formula 2 (11.1 grams, 0.11 moles) and tetrahydrofuran (800 milliliters) in the there-necked flask, then add cesium carbonate (39.1 grams, 0.12 moles), Refluxed for 15 hours, after the reaction was over, concentrated to obtain an oily liquid, which was first dissolved with methanol (60 milliliters), then stirred and recrystallized with acetone (180 milliliters), and a solid was precipitated, filtered, and dried to obtain the compound shown in formula 3 (18.7 grams, recovered Yield 74.0%) without further purification.

Embodiment 2

[0055] Embodiment 2: compound (intermediate) shown in preparation formula 3

[0056] Add the compound shown in formula 1 (17.0 grams, 0.1 moles), the compound shown in formula 2 (15.2 grams, 0.15 moles) and tetrahydrofuran (800 milliliters) in the there-necked flask, then add cesium carbonate (48.9 grams, 0.15 moles), Refluxed for 12 hours, after the reaction was finished, concentrated to obtain an oily liquid, which was first dissolved with methanol (60 milliliters), then stirred and recrystallized with acetone (180 milliliters), and a solid was precipitated, filtered, and dried to obtain the compound shown in formula 3 (18.2 grams, recovered Yield 72.1%) without further purification.

Embodiment 3

[0057] Embodiment 3: compound (intermediate) shown in preparation formula 3

[0058] Add the compound shown in formula 1 (17.0 grams, 0.1 moles), the compound shown in formula 2 (10.6 grams, 0.105 moles) and tetrahydrofuran (800 milliliters) in the there-necked flask, then add cesium carbonate (39.1 grams, 0.12 moles), Refluxed for 24 hours, after the reaction was finished, concentrated to obtain an oily liquid, which was first dissolved with methanol (60 ml), then stirred and recrystallized with acetone (180 ml), the solid was precipitated, filtered, and dried to obtain the compound shown in formula 3 (18.4 g, recovered Yield 72.8%) without further purification.

technical field

[0001] The present invention relates to the field of medicine. Specifically, the present invention relates to compounds and their preparation methods and uses. More specifically, the present invention relates to compounds and their preparation methods, pharmaceutical compositions, and the use of compounds and pharmaceutical compositions in the preparation of medicines. Background technique

[0002] Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase of the Tec kinase family, which is a key regulator of B cell development, activation, signal transduction and survival. ) play an important role in signal transduction. When BCR is activated, BTK is first activated by other tyrosine kinases (such as Lyn and SYK), leading to the activation of transcription factors essential for B cell proliferation and differentiation. In addition, BTK is also involved in receptor signal transduction related to B cell migration and adhesion, including chemokine recept...

Examples

Embodiment 1

[0053] Embodiment 1: compound (intermediate) shown in preparation formula 3

[0054] Add the compound shown in formula 1 (17.0 grams, 0.1 moles), the compound shown in formula 2 (11.1 grams, 0.11 moles) and tetrahydrofuran (800 milliliters) in the there-necked flask, then add cesium carbonate (39.1 grams, 0.12 moles), Refluxed for 15 hours, after the reaction was over, concentrated to obtain an oily liquid, which was first dissolved with methanol (60 milliliters), then stirred and recrystallized with acetone (180 milliliters), and a solid was precipitated, filtered, and dried to obtain the compound shown in formula 3 (18.7 grams, recovered Yield 74.0%) without further purification.

Embodiment 2

[0055] Embodiment 2: compound (intermediate) shown in preparation formula 3

[0056] Add the compound shown in formula 1 (17.0 grams, 0.1 moles), the compound shown in formula 2 (15.2 grams, 0.15 moles) and tetrahydrofuran (800 milliliters) in the there-necked flask, then add cesium carbonate (48.9 grams, 0.15 moles), Refluxed for 12 hours, after the reaction was finished, concentrated to obtain an oily liquid, which was first dissolved with methanol (60 milliliters), then stirred and recrystallized with acetone (180 milliliters), and a solid was precipitated, filtered, and dried to obtain the compound shown in formula 3 (18.2 grams, recovered Yield 72.1%) without further purification.

Embodiment 3

[0057] Embodiment 3: compound (intermediate) shown in preparation formula 3

[0058] Add the compound shown in formula 1 (17.0 grams, 0.1 moles), the compound shown in formula 2 (10.6 grams, 0.105 moles) and tetrahydrofuran (800 milliliters) in the there-necked flask, then add cesium carbonate (39.1 grams, 0.12 moles), Refluxed for 24 hours, after the reaction was finished, concentrated to obtain an oily liquid, which was first dissolved with methanol (60 ml), then stirred and recrystallized with acetone (180 ml), the solid was precipitated, filtered, and dried to obtain the compound shown in formula 3 (18.4 g, recovered Yield 72.8%) without further purification.

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