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Substituted diaminopyrimidine compound

A compound, haloalkyl technology, applied in the field of substituted diaminopyrimidine compounds, can solve problems such as limited application range, no curative effect, and poor patient compliance

Active Publication Date: 2019-06-07
SHENZHEN TARGETRX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, although these second-generation inhibitors can effectively overcome most crizotinib-resistant mutations, they are still ineffective against some mutations, such as ceritinib for F1174C / V, alectinib for I1171N / T / S and They are still not effective against G1202R
[0006] Furthermore, poor absorption, distribution, metabolism and / or excretion (ADME) properties are known to be a major reason for the failure of many drug candidates in clinical trials
Many currently marketed drugs also limit their application range due to poor ADME properties
The rapid metabolism of drugs will cause many drugs that can treat diseases with high efficiency to be eliminated from the body too quickly, making it difficult to become a drug
Although frequent or high-dose medication may solve the problem of rapid drug clearance, this method will bring problems such as poor patient compliance, side effects caused by high-dose medication, and increased treatment costs
In addition, rapidly metabolizing drugs may also expose patients to undesirable toxic or reactive metabolites

Method used

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  • Substituted diaminopyrimidine compound
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  • Substituted diaminopyrimidine compound

Examples

Experimental program
Comparison scheme
Effect test

specific Embodiment approach

[0061] compound

[0062] In one embodiment, the invention relates to compounds of formula (I):

[0063]

[0064] in:

[0065] R 1 and R 2 independently selected from H, D, halogen, -CN, -OH, -OC 1-6 Alkyl, -NH 2 , -NHC 1-6 Alkyl, -N(C 1-6 alkyl) 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or R 1 and R 2 Atoms attached to them form C 6-10 Aryl or 5-10 membered heteroaryl, preferably pyrrolyl; wherein said group is optionally replaced by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 D replacements;

[0066] R 3 selected from H, D, halogen, -CN or C 1-6 Alkoxy; wherein said C 1-6 Alkoxy is optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 Ds;

[0067] R 4 selected from H, D, halogen, -CN or C 1-6 Alkoxy; wherein said C 1-6 Alkoxy is optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 Ds;

[0068] R 5 selected from:

[0069]

[0070] which is optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8...

Embodiment 1

[0215] Example 1 (2-((2-((4-(4-(two (methyl-d 3 )amino)piperidin-1-yl)-2-methoxyphenyl)amino)-Preparation of 5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (compound T-1)

[0216]

[0217] Synthesize using the following route:

[0218]

[0219] Synthesis of Step 1 Compound 3

[0220] Add compound 1 (1.71g, 10mmol) and acetonitrile (30mL) to a 50mL single-necked flask equipped with magnetic stirring successively, stir to dissolve, add compound 2 (2.6g, 13mmol) and potassium carbonate (2.07g, 15mmol), react The temperature of the mixture was raised to 70° C. under a nitrogen atmosphere, and the mixture was kept stirring for 3 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, water (60 mL) was added, a large amount of yellow solid was precipitated, filtered, washed with water (10 mL), and dried to obtain 2.5 g of the yellow solid with a yield of 71.2%. LC-MS(APCI):m / z=352.2(M+1) + .

[0221] Synthesis of Step 2 ...

Embodiment 2

[0229] Example 2 (2-((5-chloro-2-((4-(4-(dimethylamino)piperidin-1-yl-3,3,5,5-d 4 )-2-methoxy Preparation of phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (compound T-2)

[0230]

[0231] Synthesize using the following route:

[0232]

[0233] Synthesis of step 1 compound 8

[0234] Add compound 1 (1.71g, 10mmol) and acetonitrile (20mL) to a 50mL single-necked flask equipped with magnetic stirring successively, stir to dissolve, add monohydrate 4-piperidone hydrochloride (2.0g, 13mmol) and DIPEA ( N,N-diisopropylethylamine, 3.90 g, 30 mmol), the temperature of the reaction mixture was raised to 80° C. under a nitrogen atmosphere, and the temperature was kept and stirred overnight. Cool to room temperature, distill off the solvent under reduced pressure, add water (60 mL), precipitate a large amount of yellow solid, filter, wash with water (100 mL), and dry to obtain 2.1 g of the yellow solid, yield 84.0%. LC-MS(APCI):m / z=251.2(M+1) + . 1 H NMR...

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PUM

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Abstract

The present invention provides a substituted diaminopyrimidine compound represented by a formula (I), or a pharmaceutically acceptable salt, a crystal form, a prodrug, a metabolite, a hydrate, a solvate, a stereoisomer or an isotope derivative thereof, as well as a pharmaceutical composition and uses thereof. The compound provided by the invention can be used for treating ALK-mediated related diseases, such as non-small cell lung cancer, breast cancer, neural tumor, esophageal cancer, soft tissue cancer, lymphoma and leukemia.

Description

field of invention [0001] The invention belongs to the technical field of medicine. In particular, the present invention relates to substituted diaminopyrimidine compounds having an inhibitory effect on protein tyrosine kinases, pharmaceutical compositions comprising the compounds, methods of preparing the compounds and the use of the compounds in therapy. The compounds described herein can be used as a new generation of ALK inhibitors and can be used to treat cancers mediated by ALK, and these compounds have better pharmacokinetic properties. Background technique [0002] Anaplastic lymphoma kinase (ALK) is a receptor-type protein tyrosine kinase that belongs to the insulin receptor superfamily. In 1994, it was discovered by Morris and Shiota from anaplastic large cell lymphoma (ALCL) as a product of chromosomal rearrangement. The most common fusion method is the NPM (Nucleophosmin) gene on chromosome 5 and ALK gene fusion on chromosome 2. NPM-ALK fusion protein is detec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6558C07F9/6561A61K31/675A61K45/06A61P35/00A61P35/02
CPCA61K31/675A61K45/06A61P35/00A61P35/02C07F9/6558C07F9/6561C07D401/12C07D239/42
Inventor 王义汉李焕银
Owner SHENZHEN TARGETRX INC