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Nitrogen-containing heteroaromatic derivatives as tyrosine kinase inhibitors

A kind of compound and imino technology, applied in the field of nitrogen-containing heteroaromatic ring derivatives as tyrosine kinase inhibitors

Active Publication Date: 2018-08-17
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 research drug is CC-292 (also known as AVL-292), which is in phase I clinical research. Its irreversible selective inhibition of Btk is used for the treatment of leukemia and autoimmune diseases

Method used

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  • Nitrogen-containing heteroaromatic derivatives as tyrosine kinase inhibitors
  • Nitrogen-containing heteroaromatic derivatives as tyrosine kinase inhibitors
  • Nitrogen-containing heteroaromatic derivatives as tyrosine kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0171] The preparation of step 1 intermediate 1

[0172] 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 ° C) to react 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.

[0173] Step 2 Preparation of intermediate 2

[0174] 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°C) and stir for several hours to obtain 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 chromatogr...

Embodiment 1

[0368] Example 1 4-(4-(4-(3-acrylamidoanilino)-5-(methylthio)pyrimidin-2-ylamino)phenoxy)- Preparation of N-methylpyridine-2-carboxamide (Compound 1)

[0369]

[0370] (1) Preparation of 5-(methylthio)pyrimidine-2,4(1H,3H)-dione

[0371]

[0372] Mix 5-bromouracil (3g, 15.7mmol) and 20% aqueous solution of sodium methyl mercaptide (10mL), heat to 100°C for 5h, cool to room temperature, filter to obtain 1.5g of solid, yield: 60.5%.

[0373] (2) Preparation of 2,4-dichloro-5-(methylthio)pyrimidine

[0374]

[0375] Mix 5-(methylthio)pyrimidine-2,4(1H,3H)-dione (1.5g, 9.5mmol), N,N-dimethylaniline (2.3g, 19mmol), add phosphorus oxychloride (15g, 97.8mmol), reacted at 100°C for 4h, cooled, poured into ice water (100mL), precipitated solid, filtered, dried to obtain 1.1g of solid, yield: 59.4%.

[0376] (3) Preparation of tert-butyl 3-(2-chloro-5-(methylthio)pyrimidin-4-ylamino)phenylcarbamate

[0377]

[0378] 2,4-Dichloro-5-(methylthio)pyrimidine (0.5 g, 2.56 mmo...

Embodiment 2

[0390] Example 2 4-(4-(4-(3-acrylamidoanilino)-5-(methylsulfonyl)pyrimidin-2-ylamino)phenoxy base)-N-methylpyridine-2-carboxamide (compound 8)

[0391]

[0392] (1) 3-(2-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenylamino)-5-(methylsulfonyl)pyrimidin-4-ylamino)phenylamino Preparation of tert-butyl formate

[0393]

[0394] 3-(2-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenylamino)-5-(methylthio)pyrimidin-4-ylamino)phenylcarbamate Butyl ester (0.32g, 0.56mmol) was dissolved in 15mL of methanol and 5mL of water, then potassium hydrogen peroxide sulfate (oxone) (0.857g, 1.39mmol) was added, the system was stirred overnight at room temperature, and extracted with 50mL of dichloromethane , washed twice with 200 mL of water, and the organic phase was spin-dried to obtain 0.34 g of light yellow oil, which was directly used in the next step.

[0395] (2) Preparation of 4-(4-(4-(3-aminoanilino)-5-(methylsulfonyl)pyrimidin-2-ylamino)phenoxy)-N-methylpyridine-2-carboxamide

[0...

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PUM

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Abstract

The present invention relates to the compounds represented by the general formula (I) as tyrosine kinase inhibitors, the preparation method of these compounds, the pharmaceutical composition containing these compounds, and the prevention and / or treatment of B cell-related blood cancers in individuals , inflammatory and autoimmune diseases. Wherein ring A, ring B, L1, L2, R1, R2, R3, a, b, c, d, e, p and q are as defined in the specification.

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to nitrogen-containing heteroaromatic ring derivatives as tyrosine kinase inhibitors, pharmaceutically acceptable salts or stereoisomers thereof, preparation methods of these compounds, and medicines containing these compounds Compositions, using these compounds to prevent and / or treat B-cell-related blood cancers (such as B-cell chronic lymphocytic carcinoma, non-Hodgkin's lymphoma), inflammatory and autoimmune diseases (such as rheumatoid arthritis, systemic lupus erythematosus, etc.), and these compounds are used in the preparation of prevention and / or treatment of B cell-related blood cancer (such as B cell chronic lymphocytic carcinoma, non-Hodgkin's lymphoma), inflammatory and autoimmune diseases (such as rheumatoid arthritis, systemic lupus erythematosus, etc.) drug application. 2. Background technology [0002] Protein kinases constitute one of the largest f...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D401/02C07D403/12C07D239/48A61K31/505A61K31/506A61P29/00A61P35/00A61P37/00
CPCC07D239/48C07D401/04C07D401/12C07D401/14C07D403/12C07D405/12C07D413/12A61K31/337A61K31/4025A61K31/58A61P29/00A61P35/00A61P37/00A61K2300/00
Inventor 罗浩贤张艳张倩
Owner KBP BIOSCIENCES CO LTD
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