Heteroaromatic compounds useful for the treatment of prolferative diseases

a technology of heteroaromatic compounds and prolferative diseases, applied in the direction of drug compositions, organic chemistry, organic active ingredients, etc., can solve the problems of hampered discovery of selective inhibitors of cdk7 and anti-proliferative activity

Inactive Publication Date: 2016-09-15
SYROS PHARMACEUTICALIS INC +1
View PDF2 Cites 19 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, inhibition of human CDK7 kinase activity is likely to result in anti-proliferative activity.
The discovery of selective inhibitors of CDK7 has been hampered by the high sequence and structural similarities of the kinase domain of CDK family members.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Heteroaromatic compounds useful for the treatment of prolferative diseases
  • Heteroaromatic compounds useful for the treatment of prolferative diseases
  • Heteroaromatic compounds useful for the treatment of prolferative diseases

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of (E)-N-(4-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)piperidine-1-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide (Compound 100)

p-{[3-(Benzyloxycarbonylamino)-1-piperidyl]carbonyl}phenylamino 2,2-dimethylpropionate

[0170]

[0171]To a solution of 4-(tert-butoxycarbonylamino)benzoic acid (438 mg, 1.8 mmol), 3-CBz-aminopiperidine.HCl (500 mg, 1.8 mmol) and Et3N (0.89 ml, 5.5 mmol) in DMF (10 mL) was added HBTU (1.05 g, 2.8 mmol). The mixture was stirred 5 h at rt before being diluted with EtOAc (100 ml), washed with water (100 mL), brine (3×100 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The mixture was purified by SiO2 chromatography (Hex / EtOAc 20 to 100% gradient) and afforded the title compound (765 mg, 1.69 mmol, 94%) as a colorless oil.

tert-butyl 4-(3-aminopiperidine-1-carbonyl)phenylcarbamate

[0172]

[0173]To a degassed solution of p-{[3-(Benzyloxycarbonylamino)-1-piperidyl]carbonyl}phenylamino 2,2-dimethylpropionate (765 mg, 1.69 mmol) in M...

example 2

Synthesis of (E)-N-(4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)methyl)piperidine-1-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide (Compound 101)

tert-butyl 3-((5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)methyl)piperidine-1-carboxylate

[0182]

[0183]A solution of 3-(2,5-dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (300 mg, 0.74 mmol), 1-Boc-3-(aminomethyl)piperidine (159 mg, 0.74 mmol) and diisopropylethylamine (0.13 mL, 0.74 mmol) in NMP (2.0 mL) was heated 25 min at 135° C. (mW). The mixture was diluted with EtOAc (30 mL), washed with water (3×5 mL), brine (5 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by SiO2 chromatography (DCM / EtOAc 0 to 15% gradient), and afforded the title compound (355 mg, 0.67 mmol, 85%) as a white solid.

5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-N-(piperidin-3-ylmethyl)pyrimidin-2-amine

[0184]

[0185]Trifluoroacetic acid (0.93 mL, 12.2 mmol) was added to a stirring solu...

example 3

Synthesis of (E)-3-((5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-N-(4-(4-(dimethylamino)but-2-enamido)phenyl)piperidine-1-carboxamide (Compound 102)

5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-N-(piperidin-3-yl)pyrimidin-2-amine

[0194]

[0195]To a solution of 3-(2, 5-dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (402 mg) in 1, 2-dimethoxylmethanol was added tert-butyl 3-aminopiperidine-1-carboxylate (200 mg, 1.0 equiv) and diisopropylethylamine (129 mg, 1.0 equiv). The solution was heated for 2 h at 120° C. The cooled solution was diluted with 100 mL of CHCl3 and i-PrOH(4:1) and then washed with water. After removing solvent, the crude product was dissolved in 10 mL CHCl3 and treated with 5 mL TFA. After stirring for 30 min at room temperature, the solvent was removed and the product was purified byby silica gel chromatography with CH2Cl2 / methanol (10:1) to give the product (350 mg, 76%).

3-((5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amin...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
w/waaaaaaaaaa
temperatureaaaaaaaaaa
temperatureaaaaaaaaaa
Login to view more

Abstract

The present invention provides novel compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., leukemia, melanoma, multiple myeloma), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of a kinase, such as a cyclin-dependent kinase (CDK) (e.g., cyclin-dependent kinase 7 (CDK7)), and therefore, in duce cellular apoptosis and / or inhibit transcription in the subject.

Description

BACKGROUND OF THE INVENTION[0001]The members of the cyclin-dependent kinase (CDK) family play critical regulatory roles in proliferation. Unique among the mammalian CDKs, CDK7 has consolidated kinase activities, regulating both the cell cycle and transcription. In the cytosol, CDK7 exists as a heterotrimeric complex and is believed to function as a CDK1 / 2-activating kinase (CAK), whereby phosphorylation of conserved residues in CDK1 / 2 by CDK7 is required for full catalytic CDK activity and cell cycle progression. In the nucleus, CDK7 forms the kinase core of the RNA polymerase (RNAP) II general transcription factor complex and is charged with phosphorylating the C-terminal domain (CTD) of RNAP II, a requisite step in gene transcriptional initiation Together, the two functions of CDK7, i.e., CAK and CTD phosphorylation, support critical facets of cellular proliferation, cell cycling, and transcription.[0002]Disruption of RNAP II CTD phosphorylation has been shown to preferentially af...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(United States)
IPC IPC(8): C07D401/14A61K31/506A61K45/06
CPCC07D401/14A61K31/506A61K45/06A61P35/02
Inventor CIBLAT, STEPHANEDEROY, PATRICKGRAY, NATHANAELLEBLANC, MELISSAMARINEAU, JASON J.MOORE, JOELSPROTT, KEVINZHANG, TINGHUSIDDIQUI, M. ARSHADKABRO, ANZHELIKALEGER, SERGEMILLER, TOMROY, STEPHANIESCHMIDT, DARBYWINTER, DANA K.BRADLEY, MICHAEL
Owner SYROS PHARMACEUTICALIS INC
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap