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Inhibitors of bruton's tyrosine kinase

An amino, solvate technology, applied in the field of medicines for the treatment of diseases and disorders, can solve problems such as adverse reactions

Inactive Publication Date: 2019-08-27
JOINT CO BIOCAD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, off-target interactions of ibrutinib with EGFR and other TEC family kinases can cause adverse drug reactions (ADRs) such as bleeding, rash, diarrhea, and atrial fibrillation (Wu et al. (2016), Journal of Hematology & Oncology, 9 :80)

Method used

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  • Inhibitors of bruton's tyrosine kinase
  • Inhibitors of bruton's tyrosine kinase
  • Inhibitors of bruton's tyrosine kinase

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0414] Example 1. General Synthesis of Compounds of Formula I.

[0415]

[0416] where V 1 , V 2 , L, R 1 , R 3 , R 4 , R 11 , n, k have the above meanings.

[0417] General Synthetic Procedures for Compounds of Formula III.

[0418]

[0419] where V 1 , V 2 , L, R 1 , R 3 , R 4 , R 11 , n, k have the above meanings.

[0420] Step 1: Synthesis of compound B(E). In a three-necked flask equipped with a stirrer and thermometer, mix under nitrogen in the indicated order: 20 mL of 1,4-dioxane; (0.002 mol) the necessary compound X1, X2 or X3; 0.759 g (0.003 mol) ) of bis(pinacolate) diboron; 0.190 g (0.0004 mol) of XPhos; 0.588 g (0.006 mol) of dried potassium acetate; 0.067 g (0.0002 mol) of palladium(II) acetate. While stirring, an inert gas (argon or nitrogen) was passed through the mixture for 15 minutes. The resulting reaction was stirred at 80-90° C. for 3-5 hours under inert gas; TLC method was used to ensure completion of the reaction. When the reactio...

Embodiment 2

[0427] Example 2. The general synthesis method of compounds X1, X2, X3.

[0428]

[0429] where A 1 、A 2 、A 3 、A 4 、A 5 、A 6 、A 7 、A8 、A 9 , R 5 has the above meaning.

[0430] Compound X1. In a round bottom flask equipped with a stirrer, thermometer and reflux condenser, mix in the indicated order: 200 mL of DMF, 0.1 mol of the corresponding dihalogenated benzene X1-2, 0.1 mol of the corresponding hydroxypyridine X1-1 and 0.2 mol of cesium carbonate or potassium carbonate. The mixture was stirred at 100° C. for 2-6 hours under inert gas; TLC method was used to ensure completion of the reaction. Then, most of the solvent was distilled off using a rotary evaporator; 200 mL of ethyl acetate was added, and the resulting suspension was filtered through celite. The filtrate was evaporated. The resulting product was purified by column chromatography, eluent: ethyl acetate:methanol (9:1). The product obtained is the compound of formula X1 in 60% to 80% yield.

[0431...

Embodiment 3

[0433] Example 3. Method for Synthesizing Intermediates.

[0434] 1)

[0435]

[0436] BCD-BTK-4-11. In a round bottom flask equipped with a stirrer, thermometer and reflux condenser, dissolve 20.6g (0.158mol) of 2-amino-4-chloropyridine in tert-butanol, add 38.5 g (0.175 mol) of BOC anhydride. The mixture was stirred at 40°C for 5 hours. Excess solvent was distilled off by rotary evaporator at 40°C; the residue was treated with hexane. The resulting suspension was cooled to 0°C and the precipitate was filtered off. Yield: 28 g (77%).

[0437] BCD-BTK-4-10. In a round bottom flask equipped with stirrer, thermometer, and reflux condenser, mix in the order indicated: 135 mL of dry tetrahydrofuran (THF), 20 g (0.169 mol) of N,N,N' , N'-tetramethylethylenediamine and 15.7 g (0.068 mol) of BCD-BTK-4-11. The reaction mixture was cooled to -78°C; 68 mL of 2.5M n-butyllithium in hexanes was added dropwise, maintaining the temperature. Then, the reaction mass was allowed to s...

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PUM

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Abstract

The present invention relates to a new compound of formula I: or pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: V1 is C or N, V2 is C(R2) or N, whereby if V1 is C then V2is N, if V1 is C then V2 is C(R2), or if V1 is N then V2 is C(R2); each n, k is independently 0, 1; each R2, R11 is independently H, D, Hal, CN, NR'R", C(O)NR'R", C1-C6 alkoxy; R3 is H, D, hydroxy, C(O)C1-C6 alkyl, C(O)C2-C6 alkenyl, C(O)C2-C6 alkynyl, C1-C6 alkyl; R4 is H, Hal, CN, CONR'R", hydroxy, C1-C6 alkyl, C1-C6 alkoxy; L is CH2, NH, O or chemical bond; R1 is selected from the group of thefragments, comprising: Fragment 1, Fragment 2, Fragment 3 each A1, A2, A3, A4 is independently CH, N, CHal; each A5, A6, A7, A8, A9 is independently C, CH or N; R5 is H, CN, Hal, CONR'R", C1-C6 alkyl,non-substituted or substituted by one or more halogens; each R' and R" is independently selected from the group, comprising H, C1-C6 alkyl, C1-C6 cycloalkyl, aryl; R6 is selected from the group: [formula II] each R7, R8, R9, R10 is independently vinyl, methylacetylenyl; Hal is CI, Br, I, F, which have properties of inhibitor of Bruton's tyrosine kinase (Btk), to pharmaceutical compositions containing such compounds, and their use as pharmaceuticals for treatment of diseases and disorder.

Description

technical field [0001] The present invention relates to novel inhibitors of Bruton's tyrosine kinase, their preparation, pharmaceutical compositions comprising such compounds and the use of such compounds or such compositions as medicaments for the treatment of diseases and disorders. Background technique [0002] Bruton's tyrosine kinase (Btk), a member of the Tec family of non-receptor tyrosine kinases, is a key signaling enzyme expressed in all hematopoietic cell types except T lymphocytes and natural killer cells. Btk plays a crucial role in B cell signaling pathways linking cell surface B cell receptor (BCR) stimulation with downstream intracellular responses. [0003] Btk is a key regulator of B cell development, activation, signaling and survival (Kurosaki, Curr. Op. Imm., 2000, 276-281; ​​Schaeffer and Schwartzberg, Curr. Op. Imm. 2000, 282-288). In addition, Btk plays a role in numerous other hematopoietic cell signaling pathways, for example, Toll-like receptor (T...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12C07D401/14C07D401/04C07D403/04C07D471/04A61K31/416A61K31/4162
CPCC07D401/04C07D401/14C07D403/04C07D403/12C07D471/04A61P11/06A61P17/00A61P19/02A61P29/00A61P35/00A61P35/02A61P37/02A61P37/06A61P37/08A61P43/00A61K31/437A61K31/4439A61K31/444
Inventor 阿列克谢·谢尔盖耶维奇·加夫里洛夫帕韦尔·亚历山德罗维奇·阿勒苏宁斯韦特兰娜·利昂尼多夫纳·戈布诺娃米哈伊尔·弗拉基米罗维奇·雷哈斯基纳塔利亚·弗拉迪米洛夫娜·柯哲米亚基纳安娜·亚历山德罗芙娜·库库什基纳安娜·谢尔盖夫娜·库沙科娃列昂尼德·埃夫根维奇·米哈伊洛夫亚历山大·摩尔多夫斯基亚历山德拉·弗拉基米罗芙娜·波普科娃谢尔盖·亚历山德罗维奇·西罗诺夫斯韦特兰娜·谢尔盖夫纳·斯米尔诺娃帕韦尔·阿列克谢维奇·伊科夫列夫
Owner JOINT CO BIOCAD
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