Hetero-aromatic ring and derivative type tyrosine kinase inhibitor thereof

A technology of heteroaryl and amino groups, applied in the field of preparation and treatment of blood cancer related to B cells

Inactive Publication Date: 2014-03-26
KBP BIOSCIENCES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] At present, there is no selective Btk inhibitor on the market. The fastest-developing drug is AVL-292 (structure not yet published), which is in phase I clinical research. It irreversibly selectively inhibits Btk and is used for the treatment of leukemia and autoimmune diseases.

Method used

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  • Hetero-aromatic ring and derivative type tyrosine kinase inhibitor thereof
  • Hetero-aromatic ring and derivative type tyrosine kinase inhibitor thereof
  • Hetero-aromatic ring and derivative type tyrosine kinase inhibitor thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0141] The preparation of step 1 intermediate 1

[0142] Mix 5-bromouracil (1 equivalent) with raw material 1 (at least 5 equivalents), without solvent, or add a small amount of polar solvent (water, ethanol, n-butanol, etc.) and heat (100-150 degrees) and stir for several hours Until 5-bromouracil disappears. After cooling, a solid precipitated out and was filtered to obtain Intermediate 1. When the raw material 1 is mercaptan, it is necessary to add an equivalent amount of alkali (such as sodium hydroxide) during the reaction.

[0143] Step 2 Preparation of Intermediate 2

[0144] Mix Intermediate 1 (1 equivalent) with the solvent amount of phosphorus oxychloride (at least 10 equivalents), add about two equivalents of N,N-dimethylaniline, heat (90-110 degrees) and stir for several hours to reach Intermediate 1 disappear. Cooled, poured into ice water, precipitated solid, filtered and dried to obtain Intermediate 2. Or concentrate the reaction system and perform column c...

Embodiment 1

[0217] Preparation of Example 14-(4-(6-(3-acrylamidoanilino)pyrazin-2-ylamino)phenoxy)-N-methylpyridine-2-carboxamide (compound 1)

[0218]

[0219] (1) Preparation of tert-butyl 3-(6-chloropyrazin-2-ylamino)phenylcarbamate

[0220]

[0221] Weigh 2,6-dichloropyrazine (3.0g, 20mmol), tert-butyl 3-aminophenylcarbamate (4.165g, 20mmol), tris(dibenzylideneacetone) dipalladium (0.183g, 0.2mmol ), 1,1′-binaphthyl-2,2′-bisdiphenylphosphine (0.436g, 0.7mmol), potassium tert-butoxide (4.49g, 40mmol), add 50mL of toluene as solvent, and protect under nitrogen at 90°C Light reaction for 4 hours, after stopping the reaction, cool down, directly measure 1 / 2 of the reaction solution and directly put it into the next reaction.

[0222] (2) Preparation of tert-butyl 3-(6-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)anilino)pyrazin-2-ylamino)phenylcarbamate

[0223]

[0224] Measure the reaction solution of 1 / 2 of the previous step, add 4-(4-aminophenoxy)-N-methylpyridine-2-carboxamide...

Embodiment 2

[0233] Example 2 Preparation of 4-(4-(6-(3-acrylamidoanilino)pyridin-2-ylamino)phenoxy)-N-methylpyridine-2-carboxamide (compound 2)

[0234]

[0235] (1) Preparation of tert-butyl 3-(6-bromopyridin-2-ylamino)phenylcarbamate

[0236]

[0237] Weigh 2,6-dibromopyridine (3.0g, 12.7mmol), tert-butyl 3-aminophenylcarbamate (3.17g, 15.2mmol), palladium acetate (57mg, 0.25mmol), 1,1′-linked Naphthalene-2,2′-bisdiphenylphosphine (0.16g, 0.26mmol), potassium carbonate (6.0g, 43.4mmol), add 20mL of toluene as solvent, microwave reaction at 116°C for 0.5 hours, stop the reaction, concentrate, silica gel Column chromatography (petroleum ether-petroleum ether:ethyl acetate=5:1) gave 1.9 g of a yellow solid with a yield of 41.1%.

[0238] (2) Preparation of tert-butyl 3-(6-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)anilino)pyridin-2-ylamino)phenylcarbamate

[0239]

[0240]Weigh 3-(6-bromopyridin-2-ylamino)phenylcarbamate tert-butyl ester (1.9g, 5.22mmol), 4-(4-aminophenoxy)-N-meth...

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PUM

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Abstract

The invention belongs to the technical field of medicaments, and in particular relates to a hetero-aromatic ring shown by a general formula (I) as well as a derivative type tyrosine kinase inhibitor, a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X, Z, W, R1, R2, R3, L1, L2, a, b, c, d, e, p, q, A and B are as defined in the specification. The invention also relates to preparation methods of these compounds, a pharmaceutical preparation containing these compounds, and important functions of these compounds in preparation of medicaments for treating B cell related leukemia (such as B cell chronic lymphocytic carcinoma and non-hodgkin lymphoma) and autoimmune diseases (such as rheumatoid arthritis, systemic lupus erythematosus and the like).

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to heteroaryl rings and derivatives thereof, tyrosine kinase inhibitors, pharmaceutically acceptable salts or stereoisomers thereof, preparation methods of these compounds, and pharmaceutical preparations containing these compounds , and these compounds play a role in the preparation and treatment of B cell-related blood cancers (such as B cell chronic lymphocytic carcinoma, non-Hodgkin's lymphoma), and autoimmune diseases (such as rheumatoid arthritis, systemic lupus erythematosus, etc.) play an important role. 2. Background technology [0002] Protein kinases constitute one of the largest families of human enzymes and regulate many different signaling processes by adding phosphate groups to proteins (T Hunter, Cell 1987 50:823-829). In particular, tyrosine kinases phosphorylate the phenolic moieties of proteins at tyrosine residues. The tyrosine kinase family incl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D213/81A61K31/497A61K31/501A61K31/444A61P35/00A61P35/02A61P37/06A61P29/00
CPCC07D401/12C07D213/81
Inventor 罗浩贤张艳
Owner KBP BIOSCIENCES CO LTD
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