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Prc2 inhibitors

A CR5, -COOR5 technology, applied in the field of compounds that inhibit polycomb protein inhibitory complex 2, can solve problems such as large recurrence risk

Pending Publication Date: 2020-11-27
MIRATI THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is also a greater risk of recurrence after prostatectomy in tumors expressing high levels of EZH2 (Varambally et al., (2008) Science 322:1695-1699)

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0573] 8-(1,3-Dimethyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazole And[1,2-c]pyrimidine-2-carboxylic acid

[0574]

[0575] 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylic acid ethyl ester ( 0.100g, 230μmol, 1.00 equivalent), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) pyrazole (81.6mg, 368μmol, 1.60 equivalent), sodium bicarbonate (77.2mg, 919μmol, 4.00 equivalent), Pd(dppf)Cl 2 (16.8 mg, 23.0 μmol, 0.100 equiv) in dioxane (2.10 mL) and water (0.700 mL) were purged three times with nitrogen. Subsequently, the mixture was stirred at 105 °C under nitrogen atmosphere for 1 h. The reaction mixture was filtered and concentrated in vacuo. The crude material was purified by prep-TLC (SiO 2 , PE:EA=2:3) to obtain 8-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran -4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylic acid ethyl ester (60.0 mg, 47.9% ...

Embodiment 2

[0579] 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methylpyridin-3-yl)imidazo[1,2-c ]pyrimidine-2-carboxylic acid

[0580]

[0581] To 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylic acid ethyl ester ( 50.0mg, 115μmol, 1.00 equivalent), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine ( 37.8 mg, 172 μmol, 1.50 eq) in dioxane (3.00 mL) were added water (1.00 mL) followed by Pd(dppf)Cl 2 (8.41 mg, 11.5 μmol, 0.100 equiv) and sodium bicarbonate (29.0 mg, 345 μmol, 3.00 equiv). The reaction mixture was stirred at 105 °C under nitrogen for 1 h. The mixture was cooled to 25 °C and filtered. The filtrate was concentrated in vacuo to provide a residue. The crude material was purified by prep-TLC (dichloromethane / methanol=10 / 1) to give 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8 -(2-Methylpyridin-3-yl)imidazo[1,2-c]pyrimidine-2-carboxylic acid ethyl ester (40.0 mg, 75.0% yield, 96....

Embodiment 3

[0585] 5-(((5-fluorobenzofuran-4-yl)methyl)amino)-8-(2-methylpyridin-3-yl)imidazo[1,2-c]pyrimidine-2-carboxylic acid

[0586]

[0587] 8-Bromo-5-(((5-fluorobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylic acid ethyl ester (120 mg, 274 μmol, 1.00 equiv) , 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (120 mg, 548 μmol, 2.00 equivalents), Sodium bicarbonate (69.0 mg, 822 μmol, 32.0 μL, 3.00 equiv) and Pd(dppf)Cl 2 (22.4 mg, 27.4 μmol, 0.100 equiv) in dioxane (3.00 mL) and water (0.600 mL) was purged with nitrogen and stirred at 105 °C under nitrogen atmosphere for 1 h. The mixture was concentrated under reduced pressure to obtain a residue. The crude material was purified by prep-TLC (DCM / methanol=20 / 1) to give 5-(((5-fluorobenzofuran-4-yl)methyl)amino)-8-(2-methylpyridine-3 -yl) Imidazo[1,2-c]pyrimidine-2-carboxylic acid ethyl ester (100 mg, 78.9% yield, 96.3% purity) as a brown solid. LCMS[M+1]: 446.2.

[0588]To 5-(((5-fluorobenzof...

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Abstract

The present invention relates to compounds that inhibit Polycomb Repressive Complex 2 (PRC2) activity. In particular, the present invention relates to compounds, pharmaceutical compositions and methods of use, such as methods of treating cancer using the compounds and pharmaceutical compositions of the present invention (Formula (I)).

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Application No. 62 / 624,176, filed January 31, 2018, U.S. Provisional Application No. 62 / 672,701, filed May 17, 2018, and U.S. Provisional Application No. 62 / 747,736, the entire contents of their respective applications are hereby incorporated by reference in their entirety. technical field [0003] The present invention relates to compounds that inhibit Polycomb Repressive Complex 2 (Polycomb Repressive Complex 2, PRC2). In particular, the invention relates to compounds, pharmaceutical compositions comprising the compounds and methods of their use. Background technique [0004] Polycomb repressive complex 2 (PRC2) is a multiprotein complex that contributes to the epigenetic silencing of target genes, thereby regulating development and homeostasis. The PRC2 complex is composed of three core subunits: enhancer of zeste homolog 2 (EZH2), embryonic ectoderm development protein (E...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61P35/00A61K31/519
CPCC07D487/04A61P35/00A61K31/519
Inventor M.A.马克斯M.R.李T.P.博宾斯基A.C.伯恩斯N.阿罗拉J.G.克里斯坦森J.M.凯查姆
Owner MIRATI THERAPEUTICS INC
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