Tricyclic fused thiophene derivatives as JAK inhibitors

Technology of a compound, heterocycloalkyl, in the field of tricyclic fused thiophene derivatives as JAK inhibitors

Active Publication Date: 2015-09-16
INCYTE
View PDF21 Cites 11 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, JAK inhibition may benefit cancer patients for reasons other than extending potential antitumor activity

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
  • Tricyclic fused thiophene derivatives as JAK inhibitors
  • Tricyclic fused thiophene derivatives as JAK inhibitors
  • Tricyclic fused thiophene derivatives as JAK inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0622] Example 1. (1R)-1-{1-[(3S)-tetrahydro-2H-pyran-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b ]pyridin-2-yl}ethanol

[0623]

[0624] Step 1. 6-Nitrothieno[3,2-b]pyridin-7-ol

[0625]

[0626] N,N,N-tributylbutan-1-ammonium nitrate (from Aldrich, 9.1 g, 30 mmol) dissolved in dichloromethane (100 mL) was added dropwise to thieno[3,2- b] In a stirred solution of pyridin-7-ol (ex Aldrich, 3.0 g, 20 mmol) in dichloromethane (100 mL). Trifluoroacetic anhydride (4.5 mL, 32 mmol) was added maintaining the temperature below 0 °C. The resulting mixture was then stirred at -5°C for 30 minutes and at room temperature overnight. The reaction mixture was concentrated, diluted with ether, and filtered. The collected solids were washed successively with water and diethyl ether / methanol (MeOH) mixture (1 :1 ), and air-dried to give the desired product (3.3 g, 85%). C 7 h 5 N 2 o 3 LCMS calculated value of S: (M+H) + : m / z=197.0; found value: 196.9.

[0627] Step 2. 7-Chloro-6-nit...

Embodiment 2

[0638] Example 2. (trans-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl }cyclohexyl)acetonitrile

[0639]

[0640] Step 1. {trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}methanol

[0641]

[0642] 7-Chloro-6-nitrothieno[3,2-b]pyridine (0.21 g, 0.98 mmol) (Example 1, Step 2), (trans-4-aminocyclohexyl)methanol were heated at 90 °C (from J&W Pharmatech, 0.25 g, 2.0 mmol) and a mixture of N,N-diisopropylethylamine (0.51 mL, 2.9 mmol) in isopropanol (3.3 mL) for 2 hours. The resulting mixture was concentrated and purified on silica gel (eluting with 0 to 60% EtOAc in hexanes) to give the desired product (0.26 g, 86%). C 14 h 18 N 3 o 3 LCMS calculated value of S: (M+H) + : m / z=308.1; found value: 308.0.

[0643] Step 2. {trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}methyl methanesulfonate

[0644]

[0645] To {trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}methanol (0.26g, 0.84mmol) and N,N-diisopropy...

Embodiment 3

[0655] Example 3. trans-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl} Cyclohexanol

[0656]

[0657] Step 1. trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexanol

[0658] 7-Chloro-6-nitrothieno[3,2-b]pyridine (0.47 g, 2.2 mmol) (Example 1, Step 2), trans-4-aminocyclohexanol (from Aldrich, 0.50 g, 4.4 mmol) and a mixture of N,N-diisopropylethylamine (1.1 mL, 6.6 mmol) in isopropanol (7.4 mL) for 2 hours. The reaction mixture was concentrated and purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (0.266 g, 41%). C 13 h 16 N 3 o 3 LCMS calculated value of S: (M+H) + : m / z=294.1; found value: 294.0.

[0659] Step 2. trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexanol

[0660] at room temperature in H 2 Hydrogenation of trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexanol (50 mg, 0.2 mmol) and 10% palladium on carbon (7 mg) under balloon pressure The mixture in methanol...

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
densityaaaaaaaaaa
Login to view more

Abstract

The present invention provides tricyclic fused thiophene derivatives, as well as their compositions and methods of use, that modulate the activity of Janus kinase (JAK) and are useful in the treatment of diseases related to the activity of JAK including, for example, inflammatory disorders, autoimmune disorders, cancer, and other diseases.

Description

[0001] This application claims the benefit of priority of U.S. Provisional Application No. 61 / 721,308, filed November 1, 2012, and U.S. Provisional Application No. 61 / 783,850, filed March 14, 2013, which Each is incorporated herein by reference in its entirety. field of invention [0002] The present invention provides tricyclic fused thiophene derivatives that regulate Janus kinase (JAK) activity and are suitable for treating diseases associated with JAK activity, including, for example, inflammatory disorders, autoimmune disorders, cancer, and other diseases, as well as compositions and uses thereof method. Background technique [0003] Protein kinases (PKs) regulate diverse biological processes including cell growth, survival, differentiation, organ formation, morphogenesis, neovascularization, tissue repair and regeneration, among others. Protein kinases also play particular roles in many human diseases, including cancer. Cytokines, low molecular weight polypeptides or...

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(China)
IPC IPC(8): C07D495/12A61K31/4365A61K31/437A61P37/00
CPCC07D495/12C07D495/14A61K31/437A61P1/04A61P13/12A61P17/00A61P17/06A61P17/10A61P19/00A61P19/02A61P19/10A61P21/04A61P25/00A61P29/00A61P35/00A61P35/02A61P37/00A61P37/06A61P37/08A61P43/00A61P5/00A61P5/14A61P9/00A61P3/10
Inventor Y-L·李W·朱梅松J·格列
Owner INCYTE
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