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4-aryl-2-amino-pyrimidines or 4-aryl-2-aminoalkyl-pyrimidines as jak-2 modulators and pharmaceutical compositions containing them

A kind of technology of cycloalkylalkyl, heterocycloalkylalkyl, applied in 4-aryl-2-amino-pyrimidine or 4-aryl-2-aminoalkyl-pyrimidine as JAK-2 regulator and Field of pharmaceutical compositions containing them

Inactive Publication Date: 2009-04-29
EXELIXIS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the function of the N-terminal domain is not well understood, there is some evidence that it regulates the JH1 domain to regulate catalytic activity

Method used

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  • 4-aryl-2-amino-pyrimidines or 4-aryl-2-aminoalkyl-pyrimidines as jak-2 modulators and pharmaceutical compositions containing them
  • 4-aryl-2-amino-pyrimidines or 4-aryl-2-aminoalkyl-pyrimidines as jak-2 modulators and pharmaceutical compositions containing them
  • 4-aryl-2-amino-pyrimidines or 4-aryl-2-aminoalkyl-pyrimidines as jak-2 modulators and pharmaceutical compositions containing them

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0480] N-(4-{2-[(3-aminophenyl)amino]pyrimidin-4-yl}phenyl)acetamide (Compound 58)

[0481] a) N-(4-(2-chloropyrimidin-4-yl) phenyl) acetamide (C 1 )

[0482]

[0483] Add 2,4-dichloropyrimidine A to the flask 1 (650mg, 4.4mmol), 4-acetamidophenylboronic acid B 1 (820 mg, 4.6 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocenepalladium (480 mg, 0.56 mmol, 15 mol%) and triethylamine (1.5 mL, 11 mmol). Ethylene glycol dimethyl ether (30mL) was added into the flask, and the mixture was washed with N 2 Purge for 5 minutes. The reaction mixture was heated under N 2 Stir at 80°C under atmosphere for 12 hours, then add ether and filter the reaction mixture. Product C was isolated by removing the solvent with a rotary evaporator 1 , which was used without further purification. LCMS: m / z248(M+H) + .

[0484] b) N-(4-{2-[(3-aminophenyl)amino]pyrimidin-4-yl}phenyl)acetamide (58)

[0485]

[0486] will hold C 1 (500 mg, 2.0 mmol) and 3-tert-butoxycarbonyl-amino-aniline ...

Embodiment 2

[0488] N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)phenyl]-2,6-dichlorobenzamide (Compound 7)

[0489]

[0490] A flask was charged with 58 (638 mg, 2.0 mmol), 2,6-dichlorobenzoyl chloride G (350 μL, 2.4 mmol), diisopropylethylamine (1.1 mL, 6 mmol) and THF (50 mL). The reaction mixture was stirred at 70°C for 6 hours. The crude mixture was concentrated on a rotary evaporator and the crude product was purified by HPLC using TFA / ACN as eluent. The title compound 7 was isolated by precipitation from ACN and washed with ether.

[0491] 1 H-NMR (400MHz, d 6 -DMSO): 10.718ppm (s, 1H), 10.269ppm (s, 1H), 9.678ppm (s, 1H), 8.507ppm (d, 1H), 8.419ppm (s, 1H), 8.215ppm (d, 2H ), 7.758ppm (d, 2H), 7.608ppm (d, 2H), 7.532ppm (t, 1H), 7.472ppm (d, 1H), 7.380ppm (d, 1H), 7.301ppm (t, 1H), 7.216ppm(d, 1H), 2.085ppm(s, 3H); MS(EI)C 25 h 19 Cl 2 N 5 o 2 : 492.2 (MH + ).

Embodiment 3

[0493] N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)acetamide (18)

[0494]

[0495] Add C to the flask 1 (500 mg, 2.0 mmol), 4-morpholinoaniline H (540 mg, 3.0 mmol) and nBuOH (10 mL). The flask was immersed in a 180°C oil bath for 30 minutes. The mixture was cooled to room temperature and the black residue was dissolved in DMF and MeOH. The product was purified by HPLC using TFA / ACN as eluent. The TFA salt was removed by extraction with sodium hydroxide and ethyl acetate to afford the title compound 18.

[0496] 1 H-NMR (400MHz, d 6 -DMSO): 10.533ppm (s, 1H), 9.408ppm (s, 1H), 8.447ppm (d, 1H), 8.114ppm (d, 2H), 7.813ppm (d, 2H), 7.705ppm (d, 2H ), 7.288ppm (d, 1H), 6.982ppm (brs, 2H), 4.65ppm (brs, 4H), 3.072ppm (brs, 2H), 2.108ppm (s, 3H); MS (EI) C 22 h 23 N 5 o 2 : 390.3 (MH + ).

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Abstract

This invention relates to certain pyrimidine derivative inhibitors of JAK-2, having Formula (I): wherein D, E, L, Z, R<1>, R<2>, R<25>, and n1 are as defined in the specification, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and methods of use thereof.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to: U.S. Provisional Application Serial No. 60 / 840,420, filed August 25, 2005; U.S. Provisional Application Serial No. 60 / 785,239, filed March 23, 2006; and US Provisional Application Serial No. 60 / 763,426 filed January 30. field of invention [0003] The present invention relates to certain 4-aryl-2-amino-pyrimidines and 4-aryl-2-aminoalkyl-pyrimidines as inhibitors of protein tyrosine kinases. The present invention specifically relates to JAK-2 inhibitors involved in cytokine receptor signaling pathways. Background of the invention [0004] Janus kinases (JAKs) are protein tyrosine kinases expressed ubiquitously in cells. JAKs are involved in membrane signaling events initiated by a variety of extracellular factors that interact with cell surface receptors. JAKs initiate cytoplasmic signaling cascades of cytokine receptors lacking protein tyrosine kinase domains. This signal trans...

Claims

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Application Information

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IPC IPC(8): C07D239/42C07D401/04C07D401/12C07D401/14C07D403/12C07D405/04C07D405/12C07D405/14C07D409/12C07D409/14C07D413/04C07D413/12C07D417/12C07D453/02C07D487/04
Inventor G·曼N·艾A·阿卡拉斯S·D·布朗W·K·V·陈J·陈H·杜S·埃普什泰恩T·P·富尔塞思A·A·加兰T·P·许M·A·伊布拉欣H·W·B·约翰逊B·凯恩P·基尔尼B·G·金E·S·科尔顿J·W·利希M·S·李G·L·路易斯L·E·迈尔R·T·诺古奇M·佩克B·H·里奇维X·施J·乌尔弗里P·周
Owner EXELIXIS INC
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