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Bruton tyrosine kinase inhibitor with spiro or bridge ring structure and preparation method thereof

A technology of tyrosine kinase and bridged ring structure, applied in the field of medicinal chemistry, can solve the problems of large clinical dosage, easy to be metabolized, low bioavailability, etc., and achieve the effect of strong inhibitory activity and high utilization rate

Active Publication Date: 2016-07-06
CHENGDU BRILLIANT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the process of administration, there are still problems such as being easily metabolized, low bioavailability (only 7-23%), and large clinical dosage (560mg / day).

Method used

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  • Bruton tyrosine kinase inhibitor with spiro or bridge ring structure and preparation method thereof
  • Bruton tyrosine kinase inhibitor with spiro or bridge ring structure and preparation method thereof
  • Bruton tyrosine kinase inhibitor with spiro or bridge ring structure and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: 1-(3-(amino-3-(4-phenoxyphenyl)-3a,7a-1H-pyrazol[3,4-d]pyrimidin-1-yl)-2,3- Preparation of dihydrospiro[indene-1,4'-piperidin]-1'-yl)prop-2-en-1-one,

[0039] The synthesis steps are as follows:

[0040]

[0041] Step 1: Preparation of N,N-bis(2-chloroethyl)carbamate tert-butyl ester (1b)

[0042] Under ice-bath condition, add two (2-chloroethyl) amine hydrochloride (19.99g, 0.112mmol) and (Boc) 2 Slowly add TEA (34.00g, 0.336mmol) into 300mL DCM solution of O (26.84g, 0.123mmol), wait for the reaction mixture to naturally rise to room temperature and continue to stir for 5h, TLC shows that after the reaction of raw materials is completed, the reaction solution is saturated with water and washed with brine, and the organic phase was washed with anhydrous Na 2 SO 4 Fully dried, evaporated in vacuo and purified by flash chromatography (PE:EA=100:1) to obtain 24.4 g of the target compound as a colorless oil;

[0043] Step 2: Preparation of spiro[indene-1...

Embodiment 2

[0057] Endo-1-((1R,3s,5S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazol[3,4-d]pyrimidin-1-yl) -8-Azabridge[3.2.1]octane-8-yl)prop-2-en-1-one and exo-1-((1R,3s,5S)-3-(4-amino-3 -(4-phenoxyphenyl)-1H-pyrazol[3,4-d]pyrimidin-1-yl)-8-azabridge[3.2.1]octane-8-yl)prop-2- Preparation of en-1-ones

[0058]

[0059] Step 1: Preparation of N-tert-butoxycarbonyl-nortropinone

[0060]

[0061] To a solution of nortropinone hydrochloride (4.8 g, 29.70 mmol) and TEA (4.50 g, 44.55 mmol) in DCM (150 mL) was slowly added (Boc) under nitrogen. 2 O (56mg, 44.55mmol), the reaction mixture was stirred at room temperature overnight, after the reaction was completed, water (50mL) was added to quench the reaction, the organic phase was separated, and the aqueous phase was extracted with DCM (30mLx3), and the above organic phases were combined for Anhydrous Na 2 SO 4 Fully dried, evaporated in vacuo and purified by chromatography (PE:EA=5:1~1:1) to obtain 5.0 g of the target compound as a whit...

Embodiment 3

[0090] 1-((1R,5S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazol[3,4-d]pyrimidin-1-yl)-9-aza Preparation of bridge [3.3.1] nonan-9-yl) prop-2-en-1-one

[0091] The synthesis steps are as follows:

[0092]

[0093] Step 1: Preparation of 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one

[0094] Add 1,3-acetonedicarboxylic acid to 20 mL of water containing benzylamine hydrochloride (3.8 g, 26.46 mmol), glutaraldehyde (25% aqueous glutaraldehyde, 8.8 mL, 21.90 mmol) under ice bath (3.2g, 21.90mmol) and 10% sodium acetate (7.5mL), after which the ice bath was removed, the reaction mixture was stirred at room temperature for 2h, then at 50°C for 12h, then solid NaHCO was added slowly 3 When the pH was greater than 7, the organic phase was separated, the aqueous phase was extracted with DCM (20mLx3), and the above organic phases were combined with anhydrous Na 2 SO 4 Fully dried, evaporated in vacuo and purified by chromatography (PE:EA=10:1) to obtain 2.3 g of the target compound as a whi...

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Abstract

The invention discloses a Bruton tyrosine kinase inhibitor with spiro or endo structure and a preparation method thereof. The inhibitor comprises Formula (I). The inhibitor has an obvious inhibiting action on BTK activity, and the inhibition activity for DOHH2 cells is enhanced by approximately 8 times. The spiro or endo compound can be used as a BTK inhibitor, and has wide application prospects in resisting malignant tumors.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a Bruton's tyrosine kinase inhibitor with a spiro ring or bridge ring structure, a preparation method of such compounds, and a method and application of using these novel compounds to inhibit BTK activity. Background technique [0002] In recent years, the treatment of hematological malignancies is gradually changing from conventional chemoimmunotherapy to targeted therapy. Unlike traditional chemotherapy drugs, targeted therapy can precisely target fast-growing cancer cells while avoiding damage to normal cells. Harm, reduce the toxic and side effects of traditional chemotherapy drugs such as hair loss, gastrointestinal reactions, and bone marrow suppression; The production of tinib-based drugs against kinases has brought more attention to small molecule covalent inhibitor drugs. Small molecule covalent inhibitors (covalent inhibitors), also known as irreversible i...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D519/00A61K31/519A61K31/55A61P29/00A61P35/00A61P35/02A61P19/02A61P7/06A61P37/00A61P11/00A61P11/02A61P15/02A61P13/12A61P1/00A61P13/08A61P27/02A61P15/00
CPCC07D487/04C07D519/00A61K31/519A61K31/55
Inventor 李英富黄浩喜刘冠峰陈垌辉杜振军
Owner CHENGDU BRILLIANT PHARMA CO LTD
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