Tyrosine kinase inhibitor for nitrogen hetero-aromatic ring and derivatives thereof

A heteroaryl and amino technology, applied in medical preparations containing active ingredients, anti-inflammatory agents, drug combinations, etc.

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 research drug is CC-292 (also known as AVL-292, whose structure has not yet be

Method used

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  • Tyrosine kinase inhibitor for nitrogen hetero-aromatic ring and derivatives thereof
  • Tyrosine kinase inhibitor for nitrogen hetero-aromatic ring and derivatives thereof
  • Tyrosine kinase inhibitor for nitrogen hetero-aromatic ring and derivatives thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0125] The preparation of step 1 intermediate 1

[0126] 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.

[0127] Step 2 Preparation of intermediate 2

[0128] 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

[0193] Example 14-(4-(4-(3-acrylamidoanilino)-5-aminopyrimidin-2-ylamino)phenoxy)-N-methylpyridine-2-carboxamide (compound 2) preparation

[0194]

[0195] (1) Preparation of tert-butyl 3-(2-chloro-5-nitropyrimidin-4-ylamino)phenylcarbamate

[0196]

[0197] 2,4-Dichloro-5-nitropyrimidine (1.93g, 10mmol) was dissolved in 12mL of THF, cooled to -78°C, tert-butyl 3-aminophenylcarbamate (2.08g , 10mmol) and DIEA (3.3mL, 20mmol) in THF solution 8mL, dropwise, react at this temperature for 2h. Ice water was added to the system, extracted with ethyl acetate, and spin-dried to obtain 3.4 g of a yellow solid with a yield of 93%.

[0198] (2) tert-butyl 3-(2-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)anilino)-5-nitropyrimidin-4-ylamino)phenylcarbamate Preparation of esters

[0199]

[0200] Dissolve tert-butyl 3-(2-chloro-5-nitropyrimidin-4-ylamino)phenylcarbamate (1.83g, 5.0mmol) in 15mL of DMSO, add 4-(4-amino Phenoxy)-N-methylpyridine-2-carboxamide (1.22g, 5.0mmol) and D...

Embodiment 2

[0212] Example 24-(4-(4-(3-acrylamidoanilino)-5-(dimethylamino)pyrimidin-2-ylamino)phenoxy)-N-methylpyridine-2-carboxamide (Compound 3) Preparation

[0213]

[0214] (1) Preparation of 5-(dimethylamino)pyrimidine-2,4(1H,3H)-dione

[0215]

[0216] 5-Bromouracil (10.0g, 52.4mmol) was added to 50mL of 33% dimethylamine aqueous solution, and the reaction was refluxed for 16h after addition. Cool, filter with suction, and dry to obtain 4.0 g of a light yellow solid with a yield of 49%.

[0217] (2) Preparation of 2,4-dichloro-N,N-dimethylpyrimidin-5-amine

[0218]

[0219] Add 5-(dimethylamino)pyrimidine-2,4(1H,3H)-dione (4.0g, 25.8mmol) to 50mL POCl 32mL of N,N-dimethylaniline was added dropwise, and the reaction was carried out at 110°C for 24h after the dropwise completion. Concentrate the reaction system, add 20mL toluene and spin dry the system to obtain an oily substance, pour it into ice water, and wash with Na 2 CO 3 Neutralized to neutral, extracted with ...

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PUM

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a tyrosine kinase inhibitor for nitrogen hetero-aromatic ring and derivatives thereof shown in the general formula (I), and pharmaceutically acceptable salts or stereoisomer thereof, wherein R1, R2, R3, L1, L2, a, b, c, d, e, p, q, A and B are defined in the specification. The invention further relates to a preparation method for the compounds, and pharmaceutical preparations containing the same, and the compounds play an important role in preparing drugs for preventing and/or treating blood cancers (such as B cell chronic lymphocytic leukemia, non-hodgkin lymphomas and the like) related to B cells, and autoimmune diseases (such as thrumatoid arthritis, systemic lupus erythematosus and the like).

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to nitrogen-containing heteroaromatic rings and derivatives thereof, tyrosine kinase inhibitors, pharmaceutically acceptable salts or stereoisomers thereof, methods for preparing these compounds, and tyrosine kinase inhibitors containing these compounds. Pharmaceutical preparations, and these compounds are used in the preparation for the 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 joint inflammation, systemic lupus erythematosus, etc.) plays 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 198 750:823-829). In particular, tyrosine kinases phosphory...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D239/50C07D401/14A61K31/506A61K31/505A61K31/5377A61P35/00A61P29/00A61P37/06
CPCC07D401/12C07D239/50C07D401/14
Inventor 罗浩贤张艳
Owner KBP BIOSCIENCES CO LTD
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