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Antiproliferative compounds

一种化合物、增生性病症的技术，应用在药物组合、有机化学、抗肿瘤药等方向

Active Publication Date: 2016-05-25
GENENTECH INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Additionally, the relatively rapid acquisition of resistance to cancer drugs remains a major obstacle to successful cancer treatment

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0248] step 1

[0249]

[0250] 3-Bromo-6-ethyl-5-methylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0251] A mixture of 4-bromo-1H-pyrazol-5-amine (16.1 g, 100.0 mmol) and ethyl 2-ethyl-3-oxobutanoate (19.0 g, 120.0 mmol) in AcOH (300 mL) was heated at reflux 4h. After solvent evaporation, the residue was washed with MTBE (200 mLx3). The resulting solid was collected by filtration and dried to give the crude title compound (17.0 g, 67% yield). It was used directly in the next step without further purification. LCMS(ESI)m / z:255.9[M+H + ].

[0252] step 2

[0253]

[0254] 3-Bromo-7-chloro-6-ethyl-5-methylpyrazolo[1,5-a]pyrimidine

[0255] POCl 3 (60.8g, 400.0mmol) was added dropwise to 3-bromo-6-ethyl-5-methylpyrazolo[1,5-a]pyrimidin-7(4H)-one (25.6g, 100.0mmol) and DIPEA (51.6 g, 400.0 mmol) in toluene (500 mL) was stirred and cooled (0 °C) in the mixture. After the addition, the mixture was allowed to warm to 90 °C and stirring was continued for 4 h, at which time LC...

Embodiment 2

[0273]

[0274] 6-Ethyl-5-methyl-3-(1-(5-methylpyrimidin-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-7( 4H)-one

[0275] In a similar procedure to that shown in Example 1, the title compound was prepared in 15% yield from 2-chloro-5-methylpyrimidine. 1 HNMR (400MHz, DMSO-d 6 ):δ11.43(s,1H),9.06(s,1H),8.70(s,2H),8.19(s,2H),2.45-2.47(m,2H),2.40(s,3H),2.29( s,3H), 1.02-0.98(m,3H). LCMS (method C): RT = 0.721min, m / z: 335.9 [M+H + ].

Embodiment 3

[0277]

[0278] 6-Ethyl-5-methyl-3-(1-(pyrimidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0279] In a similar procedure to that shown in Example 1, the title compound was prepared in 19% yield from 4-chloropyrimidine. 1 HNMR (400MHz, DMSO-d 6 ): δ9.18(s,1H),9.11(s,1H),8.87(d,J=5.210Hz,1H),8.37(s,1H),8.22(s,1H),7.95(d,J= 5.2Hz, 1H), 2.48-2.45(m, 2H), 2.42(s, 3H), 1.03(t, J=6.8Hz, 3H). LCMS (Method C): RT = 0.713min, m / z: 321.8, 665.1 [M+H + ,2M+1].

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Abstract

The present invention relates to compounds formula (I) and to salts thereof, wherein R1-R4 and A have any of the values defined in the specification, and compositions and uses thereof. The compounds are useful as inhibitors of histone demethylases, such as KDM5. Also included are pharmaceutically acceptable compositions comprising the compounds of the present invention and methods of using said compositions in the treatment of various disorders.

Description

[0001] Cross References to Related Applications [0002] This patent application claims the benefit of priority to US Application Serial No. 61 / 874,310, filed September 5, 2013, which is incorporated herein by reference. technical field [0003] The present invention relates to compounds useful as inhibitors of histone demethylases, such as KDM5. Background technique [0004] Packing the 300 million nucleotides of the human genome into the nucleus of a cell requires enormous compaction. To accomplish this feat, the DNA in our chromosomes is wrapped around spools of proteins called histones to form densely repeating protein / DNA polymers called chromatin. Far from serving as pure packaging modules, chromatin templates form the basis of a newly recognized and crucial set of genetic control mechanisms known as epigenetic regulation. By imparting specific chemical modifications to histones and DNA, epigenetic regulators regulate the structure, function, and accessibility of our...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/519A61P35/00
CPCA61K31/519A61P35/00A61P43/00C07D487/04A61K31/282A61K31/337A61K45/06A61K2300/00A61N5/10
Inventor B·K·阿尔布雷克特S·F·拜隆V·S·格林J-C·阿尔芒热Y·勒布朗J·梁S·R·马格努森V·H-W·崔B·张
Owner GENENTECH INC
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