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Heterocyclic compounds and uses thereof

A technology of compounds and compositions, applied in the field of treatment of various diseases, can solve problems such as dose-limiting toxicity

Active Publication Date: 2013-08-28
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Current drugs in development, including second-generation covalent inhibitors such as BIBW2992, HKI-272, and PF-0299804, are effective against the T790M resistance mutation but exhibit dose-limiting toxicity due to simultaneous inhibition of WT EGFR

Method used

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  • Heterocyclic compounds and uses thereof
  • Heterocyclic compounds and uses thereof
  • Heterocyclic compounds and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0208] Intermediate 1

[0209] Process 1

[0210]

[0211] step 1:

[0212] Pre-equipped with magnetic stirrer, thermal bag and CaCl 2 N-Boc-1,3-diaminobenzene (0.96 g) and n-butanol (9.00 mL) were fed into the 25 mL three-neck RBF of the protective tube. The reaction mixture was cooled to 0°C. At 0°C, 2,4-dichloro-5-trifluoromethylpyrimidine (1.0 g) was added dropwise to the above reaction mixture. At 0°C, DIPEA (0.96 mL) was added dropwise to the above reaction mixture and the reaction mixture was stirred at 0°C to 5°C for 1 hour. Finally, the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred for another 4 hours at room temperature. Using hexane:ethyl acetate (7:3), the completion of the reaction was monitored by TLC. The precipitated solid was filtered off and washed with 1-butanol (2 mL). The solid was dried at 40°C under reduced pressure for 1 hour. 1 H-NMR (DMSO-d6, 400MHz) δ 1.48 (S, 9H), 7.02 (m, 1H), 7.26 (m, 2H), 7.58 (S, 1H)...

example 2

[0218] Compound I-2N-(3-(2-(2-methoxy-4-morpholinylphenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)phenyl)acrylamide)

[0219]

[0220] In order to obtain the title compound I-2, the intermediate 1 (16 mg) and 2-methoxy-4-morpholinoaniline in Example 1 were mixed in dioxane (1.0) with catalytic trifluoroacetic acid at 50°C. mL) was stirred overnight. The crude material was concentrated under reduced pressure and purified using HPLC (TFA modifier) ​​to give the title compound as a TFA salt. 1 H-NMR (DMSO-d6, 400MHz) δ 10.4 (S, 1H), 9.72 (br, 1H), 9.18 (br, 1H), 8.49 (br, 1H), 7.83 (S, 1H), 7.59 (d , J=8.4Hz, 1H), 7.31-7.48(m, 2H), 7.41(t, J=15.2Hz, 1H), 7.12(br, 1H), 6.67(S, 1H), 6.49(dd, J= 10.0, 16.8 Hz, 1H), 6.25 (dd, J = 2.0, 16.8 Hz, 1H), 5.77 (dd, J = 2.0, 10.0 Hz, 1H), 3.7-3.9 (m, 7H), 3.1 (br, 4H) ); C 25 H 25 F 3 N 6 O 3 Calculated value of the mass: 514.2, experimental value: 515.5 (M+H + ).

example 3

[0222] Compound I-4N-(3-(2-(4-(4-acetylpiperazin-1-yl)-2-methoxyphenylamino)-5-(trifluoromethyl)pyrimidin-4-yl Amino) phenyl) acrylamide)

[0223]

[0224] The title compound 1-4 was prepared as described in Example 2 using 2-methoxy-4-(4-acetylpiperazinyl)aniline and Intermediate 1 in Example 1. 1 H-NMR (DMSO-d6, 400MHz) δ 10.2 (S, 1H), 8.2 (br, 1H), 8.30 (S, 1H), 7.73 (br, 1H), 7.52 (d, J = 7.8 Hz, 1H ), 7.45 (d, J = 7.8 Hz, 1H), 7.26 (J = 8.2 Hz, 1H), 7.14 (be, 1H), 6.60 (S, 1H), 6.42 (dd, J = 11.4, 16.9 Hz, 1H) ), 6.24 (d, J = 16.9 Hz, 1H), 5.75 (d, J = 11.4 Hz, 1H), 3.76 (S, 3H), 3.04 (br, 4H), 2.04 (S, 3H); C 27 H 28 F 3 N 7 O 3 Calculated value of the mass: 555.2, experimental value: 556.2 (M+H + ).

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Abstract

Heterocyclic pyrimidine compounds that modulate mutant-selective epidermal growth factor receptor (EGFR) kinase activity are disclosed. Selectivity in inhibition of various mutant-EGFR is disclosed. Pharmaceutical compositions containing the pyrimidine derivatives, and methods of treating diseases associated with EGFR kinase activity comprising administration of the pyrimidine derivatives or pharmaceutical compositions containing the pyrimidine derivative, are described.

Description

[0001] Cross reference of related applications [0002] This application claims U.S. Provisional Application No. 61 / 409,080 filed on November 1, 2010, No. 61 / 411,829 filed on November 9, 2010, No. 61 / 412,330 filed on November 10, 2010, and The priority of No. 61 / 534,323 filed on September 13, 2011, the entire content of each application is incorporated herein by reference. Technical field [0003] The present invention relates to compounds suitable for use as mutant selective epidermal growth factor receptor (EGFR) kinase inhibitors. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions to treat various disorders. Background technique [0004] Protein tyrosine kinases are a class of enzymes that catalyze the transfer of phosphate groups from ATP or GTP to tyrosine residues located on protein substrates. Receptor tyrosine kinases activate the second message-transmitting effector through p...

Claims

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Application Information

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IPC IPC(8): A61K31/506A61K31/16
CPCC07D403/14C07D239/34C07D239/42C07D239/48A61K31/506A61K31/5377A61K31/541A61K31/551C07D239/47A61P35/00A61P43/00C07D413/12C07D403/12A61K31/16
Inventor 李洸镐牛德强拉塞尔·C·彼得马修·弗兰克·贝威斯基尤斯温德·辛格
Owner BRISTOL MYERS SQUIBB CO
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