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2, 6-diamino-pyrimidin- 5-yl-carboxamides as SRK or JAK kinases inhibitors

A compound, aminocarbonyl technology, applied in anti-inflammatory agents, drug combinations, organic chemistry, etc., can solve the problem of Src kinase inactivity

Active Publication Date: 2011-05-18
PORTOLA PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Interestingly, this ATP-competitive inhibitor of Syk is also active against Flt3, cKit and JAK kinases, but not against Src kinase (Braselmann, Taylor et al. 2006)

Method used

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  • 2, 6-diamino-pyrimidin- 5-yl-carboxamides as SRK or JAK kinases inhibitors
  • 2, 6-diamino-pyrimidin- 5-yl-carboxamides as SRK or JAK kinases inhibitors
  • 2, 6-diamino-pyrimidin- 5-yl-carboxamides as SRK or JAK kinases inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0216] a. Compound

[0217] In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0218]

[0219] in:

[0220] D. 1 selected from the following groups:

[0221] (a)C 3-8 Cycloalkyl, which is optionally substituted by 1-4 substituents independently selected from the following groups: C 1-8 Alkyl, amino, hydroxyl, C 1-8 Alkylcarbonyl, aminocarbonyl, C 1-8 Alkoxycarbonylamino, aryl C 1-8 Alkoxycarbonylamino, phenyl and heterocyclyl C 1-8 alkylene;

[0222] (b)C 1-8 Alkyl; which is optionally substituted by 1-4 substituents independently selected from the following groups: amino, oxo, C 1-8 Alkoxy, C 2-8 Alkynyl, cyano, aminocarbonyl, C 1-8 Haloalkyl, Hydroxy, Halogen, C3-8 Cycloalkyl and phenyl;

[0223] (c)C 1-8 Alkyl C 3-8 Heterocyclyl, which is optionally substituted by 1-4 substituents independently selected from the following groups: C 1-8 Alkyl, C 1-8 Alkylcarbonyl, C 1-8 Alkylsulfonyl...

Embodiment 1

[0525] Example 1.2-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(cyclobutylamino)pyrimidine-5-carboxamide 1

[0526] Process 1:

[0527]

[0528] Step 1: To a stirred solution of carboxylic acid 1.1 (85 g, 540 mmol) in thionyl chloride (425 mL) was slowly added pyridine (8.5 mL, 0.11 mmol). The reaction was stirred overnight at 75 °C, then it was concentrated and dried in vacuo to obtain a pale yellow powder which was used immediately in the next step.

[0529] Step 2: The yellow solid obtained in the previous step was slowly diluted with 750 mL of ethanol and refluxed overnight. The next day, the reaction was complete as determined by HPLC, then cooled in an ice bath, and the solid was filtered and washed with ether to afford the desired ethyl ester (1.3) as an off-white powder (91 g, 87% for two steps). C 7 h 8 N 2 o 4 The MS measured value is (M+H) + 185.0.

[0530] Step 3: Ester 1.3 (22g, 120mmol) was dissolved in phosphorus oxychloride (60mL, 600mmol), the mixt...

Embodiment 32

[0541] Example 32.2,4-bis(4-(4-acetylpiperazin-1-yl)phenylamino)pyrimidine-5-carboxamide

[0542] Process 2:

[0543]

[0544] Step 1: Compound 1.4 (Example 1, 1.05 g, 4.8 mmol) was dissolved in 40 mL of acetonitrile. Sodium thiomethoxide (0.74 g, 10.5 mmol) was added thereto. It was stirred overnight, diluted with ethyl acetate, washed 3 times with brine, dried and concentrated in vacuo. It was then placed in 20 mL of dioxane and 10 mL of water. 500 mg of LiOH hydrate was added thereto. The mixture was stirred for 4 hours. 1N HCl was added to the mixture until the pH reached 3. It was concentrated and extracted 3 times with ethyl acetate. The organic phases were combined, dried and concentrated in vacuo to obtain a white solid. The solid was then dissolved in 30 mL of anhydrous DMF. EDC hydrochloride (1.10 g, 5.7 mmol) and HOBt (0.77 g, 5.7 mmol) were added thereto. The mixture was stirred for 30 min, to which was added ammonia (obtained from a commercial 0.5N sol...

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PUM

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Abstract

The present invention is directed to compounds of formula I-II and pharmaceutically acceptable tautomers, salts, or stereoisomers thereof which are inhibitors of syk and / or JAK kinase. The present invention is also directed to intermediates used in making such compounds, the preparation of such a compound, pharmaceutical compositions containing such a compound, methods of inhibition syk and / or JAK kinase activity, methods of inhibition the platelet aggregation, and methods to prevent or treat a number of conditions mediated at least in part by syk and / or JAK kinase activity, such as cardiovascular disease, inflammatory disease, autoimmune disease and cell proliferative disorder, thrombosis, allergy, asthma, rheumatoid arthritis, leukemia, or non-Hodgkin's lymphoma. The formula I-II is shown in the description.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Patent Application No. 61 / 120,348, filed December 5, 2008, U.S. Provisional Patent Application No. 61 / 120,344, filed December 5, 2008, U.S. Provisional Patent Application No. 61 / 120,344, filed December 5, 2008 61 / 045,406 and the rights of US Provisional Patent Application No. 61 / 045,417, filed April 16, 2008, the entire contents of which are incorporated herein by reference. technical field [0003] The present invention relates to pyrimidine-5-carboxamide compounds useful as inhibitors of spleen tyrosine kinase (syk) and / or JAK kinase. The invention also relates to pharmaceutical compositions comprising pyrimidine-5-carboxamide compounds and methods of using the compounds or compositions to treat conditions characterized by undesired thrombosis. Background technique [0004] Protein kinases constitute a large family of structurally related enzymes that are responsible for the ...

Claims

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Application Information

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IPC IPC(8): C07D239/48C07D401/12C07D403/12C07D413/12C07D417/12A61P35/00A61P9/00A61K31/506
CPCC07D239/48C07D403/12C07D401/12C07D413/12C07D417/12A61P1/04A61P3/06A61P7/00A61P7/06A61P9/00A61P9/10A61P11/00A61P11/06A61P13/12A61P17/06A61P19/00A61P25/00A61P29/00A61P35/00A61P35/02A61P37/04A61P37/08A61P43/00
Inventor S·M·鲍尔Z·J·贾宋永红徐亲M·梅赫罗特拉J·W·罗斯黄沃林C·文卡塔拉曼尼A·潘迪
Owner PORTOLA PHARMA INC
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