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5-cyan0-4- (pyrrolo [2, 3b] pyridine-3-yl) -pyrimidine derivatives useful as protein kinase inhibitors

An alkyl and aryl technology, applied in the field of 5-cyano-4-(pyrrolo[2,3b]pyridin-3-yl)pyrimidine derivatives that can be used as protein kinase inhibitors, can solve the problem of hindering cell Centriole duplication and other issues

Inactive Publication Date: 2010-03-24
VERTEX PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Abolition of PLK2 by siRNA or transfection of a kinase-inactive mutant into cells blocks centriole replication

Method used

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  • 5-cyan0-4- (pyrrolo [2, 3b] pyridine-3-yl) -pyrimidine derivatives useful as protein kinase inhibitors
  • 5-cyan0-4- (pyrrolo [2, 3b] pyridine-3-yl) -pyrimidine derivatives useful as protein kinase inhibitors
  • 5-cyan0-4- (pyrrolo [2, 3b] pyridine-3-yl) -pyrimidine derivatives useful as protein kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0349] Example 1: 2-(Phenylamino)-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile.

[0350]

[0351] Heating 2-(methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b) in THF (2mL) at 100°C under microwave conditions ]Pyridin-3-yl)pyrimidine-5-carbonitrile (50mg, 0.096mmol) with benzylamine (21uL, 0.19mmol, 2.0Eq.) and DIPEA (50uL, 0.29mmol, 3.0Eq.) for 10 minutes. The reaction was concentrated and the residue was dissolved in THF (5 mL). Join LiOH.H 2 A solution of O (20mg, 0.48mmol, 5.0Eq.) in water (1mL) was stirred and reacted for 1 hour. The reaction mixture was concentrated and the residue was treated with MeOH. The resulting white precipitate (13 mg, 36%, over two steps) was isolated by filtration under vacuum.

[0352] MS(ES + )m / e=395. 1 H NMR (DMSO) 4.67 (2H, d), 4.74 (2H, d), 7.21-7.38 (10H, m), 8.68 (1H, s), 8.72-8.74 (5H, m), 8.86 (1H, t) , 8.93 (1H, s), 9.03 (1H, t), 9.27 (1H, s), 12.77 (2H, vbrs). [1∶1 Rotamer Mixture]

Embodiment 2

[0353] Example 2: 2-((R)-1-(6-(4-Methylpiperazin-1-yl)pyridin-3-yl)ethylamino)-4-(5-(trifluoromethyl) -1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile I-147 and 2-((S)-1-(6-(4-methylpiperazin-1-yl) )Pyridin-3-yl)ethylamino)-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (I-129 )

[0354]

[0355] step 1 : 2-(Methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile .

[0356]

[0357] The 2-(methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (1.4 g, 2.86 mmol) was suspended in ethanol (60 mL) and water (4 mL). Cool the mixture in an ice bath and slowly pour chlorine into the solution for 20 minutes. After the addition is complete, the suspension is stirred for another 30 minutes at 0°C. The reaction mixture was vented for 15 minutes, then ether (100 mL) was added and the solid was filtered off. The solid was dried under vacuum to obtain a ...

Embodiment 3

[0371] Example 3: N-((1R,4r)-4-((1R)-1-(5-cyano-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b ]Pyridin-3-yl)pyrimidin-2-ylamino)ethyl)cyclohexyl)methylsulfonamide I-202 and N-((1S,4s)-4-((1R)-1-(5-cyano Base-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-ylamino)ethyl)cyclohexyl)methylsulfonamide 1- 203

[0372]

[0373] step 1: 2-hydroxy-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile.

[0374]

[0375] To 2-(methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile DIPEA (7.421 g, 10.00 mL, 57.42 mmol) was added to a suspension of (1 g, 1.918 mmol) in acetonitrile (20 mL). The reaction mixture was stirred for 1 hour, and then water (5 mL) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum to obtain the desired product (880 mg, quantitative yield).

[0376] MS(ES + )460, (ES - )458.

[0377] Step 2: 2-Chloro-4-(1-...

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Abstract

The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

Description

[0001] cross reference [0002] This application requires U.S. Application No. 60 / 876,307 filed on December 21, 2006, U.S. Application No. 60 / 922,291 filed on April 6, 2007, and U.S. Application No. 60 / 947,707 filed on July 3, 2007 And the priority of U.S. application No. 60 / 989,014 filed on November 19, 2007. Invention field [0003] The present invention relates to compounds useful as protein kinase inhibitors. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using these compositions in the treatment of various disorders. The invention also provides methods for preparing the compounds of the invention. Background of the invention [0004] In recent years, a better understanding of the structure of disease-related enzymes and biomolecules has greatly contributed to the search for new therapeutic agents. An important class of enzymes that has been intensively studied are protein kinases. [0005] Protein ...

Claims

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Application Information

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IPC IPC(8): A61K31/506A61K31/551A61P3/00A61P5/00A61P9/00A61P11/06A61P19/00A61P25/00A61P25/28A61P29/00A61P35/00A61P37/00A61P37/08A61P43/00
CPCC07D471/04A61P1/00A61P1/02A61P1/16A61P3/00A61P3/10A61P5/00A61P5/14A61P7/00A61P9/00A61P11/06A61P19/00A61P19/02A61P19/08A61P25/00A61P25/28A61P27/02A61P29/00A61P31/12A61P31/18A61P35/00A61P35/02A61P37/00A61P37/02A61P37/04A61P37/06A61P37/08A61P43/00A61K31/506C07D403/02C07D403/04C07D487/04
Inventor M·莫蒂摩尔S·C·杨S·R·L·埃弗里特R·克内特尔J·L·平德A·P·鲁瑟福德S·杜兰G·布伦奇利J·D·沙里耶M·奥唐纳
Owner VERTEX PHARMA INC
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