CXCR4 inhibitors and uses thereof

An unsaturated, independent technology, applied in the field of CXCR4 inhibitors and its use, can solve the problems of deletion, loss of response, etc.

Pending Publication Date: 2022-03-18
X4 PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In addition, existing evidence suggests that the CXCL12/CXCR4 axis causes loss or

Method used

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  • CXCR4 inhibitors and uses thereof
  • CXCR4 inhibitors and uses thereof
  • CXCR4 inhibitors and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0462] Example 1: Synthesis of I-9

[0463] Synthetic scheme of I-9

[0464]

[0465] Synthesize 1-0.

[0466]

[0467] 3-Methyl picoline aldehyde (1-a; 10.0g, 82.55mmol), acetone (60mL) and K 2 CO 3 (17.11g, 123.83mmol) in toluene-EtOH-H2 The mixture in O solvent (150 mL+60 mL+30 mL) was stirred at 70 °C for 16 hours. After cooling to rt, the solvent was evaporated in vacuo. The resulting residue was partitioned between DCM and H 2 Between O. The aqueous phase was further extracted twice with DCM. The combined organic phases were washed with brine and washed with anhydrous Na 2 SO 4 Dry and filter. The filtrate was concentrated in vacuo and the residue was purified by column chromatography to obtain 1-0 (9.20 g, 69.1%) as a light green solid. LCMS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50mm * 4.6mm * 3.5 μ m); Column temperature: 40 ℃; Flow rate: 2.0 milliliters / minute; Mobile phase: within 1.6 minutes 90% [( Total 10mM AcONH 4 ) water / CH 3...

example 2

[0483] Example 2: Synthesis of I-1, I-5, I-6 and I-7

[0484] Synthetic scheme of I-1, I-7, I-5 and I-6

[0485]

[0486] Synthesis 2-1.

[0487]

[0488] 2-0 (9g, 41.66mmol), palladium diacetate (935mg, 4.17mmol), P (o-tolyl) 3 (2.5g, 8.34mmol), acrylonitrile (22g, 416.60mmol) and triethylamine (12g, 125mmol) in DMF (20mL) was stirred in a sealed tube at 130°C for 4 hours. Then, the suspension was filtered; the filtrate was poured into water and extracted with dichloromethane (50 mL×3), the separated organics were concentrated in vacuo and the residue was purified by column chromatography (PE / EA=10 / 1) to give 2-1 (2 g, yield: 26%). LCMS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50mm * 4.6mm * 3.5μm); Column temperature: 40 ℃; Flow rate: 2.0 ml / min; Mobile phase: 90% [water in 0.5 minutes +10mM NH 4 HCO 3 ] and 10% [CH 3 CN] to 5% [water + 10mM NH 4 HCO 3 ] and 95% [CH 3 CN], then continued under these conditions for 1.5 minutes, and finally becam...

example 3

[0513] Example 3: Synthesis of I-2 and I-3

[0514] Synthetic scheme of I-2 and I-3

[0515]

[0516] Synthetic schemes of I-2 and I-3 (continued)

[0517]

[0518] Synthesis 3-2.

[0519]

[0520] 3-0 (10.0g, 46.3mmol), 3-a (13.6g, 138.9mmol), CuI (1.8g, 9.3mmol), Pd(PPh 3 ) 2 Cl 2 (3.2g, 4.6mmol) and DIPEA (25mL) in THF (250mL) mixture in N 2 Stirring was carried out at 60° C. for 2 hours under an atmosphere. After LCMS indicated that the reaction was complete, the mixture was cooled to room temperature, treated with TBAF (56 mL, 1 M) in THF and stirred at room temperature for 1 hour. After TLC indicated that the reaction was complete, the reaction mixture was filtered through celite. The filtrate was concentrated in vacuo and the residue was purified by silica column chromatography to afford 3-2 (6.5 g, 87%) as a black solid. LCMS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50mm * 4.6mm * 3.5μm); Column temperature: 40 ℃; Flow rate: 2.0 ml / min; ...

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PUM

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Abstract

The present invention relates to compounds and methods for inhibiting the C-X-C receptor type 4 (CXCR4). The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various diseases.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 867,003, filed June 26, 2019; the entire contents of said application are hereby incorporated by reference. technical field [0003] The present invention provides compounds useful as inhibitors of C-X-C receptor type 4 (CXCR4). The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compounds to treat various diseases. Background technique [0004] C-X-C chemokine receptor type 4 (CXCR4), also known as fusin or cluster of differentiation 184 (CD184), is a seven-spanmembrane G protein-coupled receptor (GPCR) belonging to class I GPCR or rhodopsin-like GPCR family. Under normal physiological conditions, CXCR4 fulfills multiple roles and is mainly expressed in the hematopoietic and immune systems. CXCR4 was initially discovered as one of the coreceptors involved in human...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D519/00
CPCA61P35/00A61P31/00C07D401/14
Inventor E·M·J·布尔克R·斯克尔利
Owner X4 PHARMA INC
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