Pyrazolopyridine derivatives for inhibiting activity of insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase

A C5-C10, C6-C10 technology, applied in the field of pyridopyrazole derivatives that inhibit IGF-1R tyrosine kinase activity, can solve the problems of weakened ability to inhibit IGF-1R, lack of transcriptional activity of BRCAI, etc.

Active Publication Date: 2013-01-30
JIANGSU SIMCERE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

BRCAI is a tumor suppressor gene. Qin et al. (Qin H, Sun Y, Benveniste EN.J Biol Chem, 1999, 274 (41): 29130-29137) showed that it inhibits IGF-1R activity on the surface of some cells, suggesting that BRCAI The activity of BRCAI can inhibit the expression of IGF-1R, and the mutant BRCAI lacks transcriptional activity, and its ability to inhibit IGF-1R is also weakened

Method used

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  • Pyrazolopyridine derivatives for inhibiting activity of insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase
  • Pyrazolopyridine derivatives for inhibiting activity of insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase
  • Pyrazolopyridine derivatives for inhibiting activity of insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Example 1: 1-(3-(5-bromo-1-p-toluenesulfonyl-1H-pyrazol[3,4-b]pyridin-3-yl)phenyl)-3-(2-phenoxy Phenyl)urea (I-c-1)

[0085]

[0086] step 1

[0087] 2.00g (6.17mmol) of 5-bromo-3-iodo-1H-pyrazol[3,4-b]pyridine was dissolved in 25mL of dichloromethane, and 1.41g (7.4mmol) of p-toluenesulfonyl chloride and 1g of 50% NaOH aqueous solution were added , then add 10mL water, 0.1g (0.31mmol) tetrabutylammonium bromide, react at room temperature for 24 hours, pour into water, separate the liquids, extract the water phase with dichloromethane once, combine the organic phases, add anhydrous Dry over sodium sulfate, filter, add 100~200 mesh silica gel to the filtrate to make sand, perform column chromatography, and elute with petroleum ether: ethyl acetate = 1:1 to obtain 2.55g (86%) of 5-bromo-3-iodo-1 - p-toluenesulfonyl-1H-pyrazol[3,4-b]pyridine (I-a) as a white solid. 1 H NMR (400MHz, DMSO-d 6 )δ8.89(d,1H,-ArH),8.37(d,1H,-ArH),7.94(d,2H,2×-ArH),7.46(d,2H,2×-ArH),2.36(s...

Embodiment 2

[0097] Example 2: N,N-Dimethyl-3-(3-(3-(3-(2-phenoxyphenyl)ureido)phenyl)-1H-pyrazol[3,4-b] Pyridin-5-yl)benzamide (I-1)

[0098]

[0099] step 1

[0100] To 30mg (0.045mmol) 1-(3-(5-bromo-1-p-toluenesulfonyl-1H-pyrazol[3,4-b]pyridin-3-yl)phenyl)-3-(2-benzene Oxyphenyl) urea (I-c-1), 10 mg (0.052 mmol) 3-(dimethylcarbamoyl) phenylboronic acid, 3 mg (4.27 μmol) bis(triphenylphosphine) palladium dichloride in a mixture of 5 ml DMF (N,N-dimethylformamide, the same below), 0.1ml 2M.Na 2 CO 3 Aqueous solution, react at 120°C for 0.5 hours, concentrate to remove DMF, add appropriate amount of water to the residue, extract with dichloromethane, dry over anhydrous sodium sulfate, filter, add 100~200 mesh silica gel to the filtrate, concentrate to make sand, column chromatography, and dichloromethane Methane:methanol=100:1 eluted to give 30 mg (91%) N,N-dimethyl-3-(3-(3-(3-(2-phenoxyphenyl)ureido)phenyl)- 1-p-Toluenesulfonyl-1H-pyrazol[3,4-b]pyridin-5-yl)benzamide (I-d-1), as a...

Embodiment 3

[0106] Example 3: 1-(3-(5-(4-fluorophenyl)-1H-pyrazol[3,4-b]pyridin-3-yl)phenyl)-3-(2-phenoxybenzene base) urea (I-2)

[0107]

[0108] step 1

[0109]Using the method of Example 3, step 1, 30 mg (0.045 mmol) 1-(3-(5-bromo-1-p-toluenesulfonyl-1H-pyrazol[3,4-b]pyridin-3-yl)benzene Base)-3-(2-phenoxyphenyl)urea (I-c-1) reacted with 8mg (0.055mmol) 4-fluorophenylboronic acid to give 18mg (60%) of 1-(3-(5-(4- Fluorophenyl)-1-p-toluenesulfonyl-1H-pyrazol[3,4-b]pyridin-3-yl)phenyl)-3-(2-phenoxyphenyl)urea (I-d-2) , as a white solid.

[0110] step 2

[0111] Using the method of Example 3, Step 2, 18 mg (0.027 mmol) 1-(3-(5-(4-fluorophenyl)-1-p-toluenesulfonyl-1H-pyrazol[3,4-b]pyridine -3-yl)phenyl)-3-(2-phenoxyphenyl)urea (I-d-2) was reacted to give 11 mg (79%) of the title compound (I-2) as a white solid.

[0112] 1 H NMR (500MHz, DMSO-d 6 )δ13.88(s,1H,-NH-),9.44(s,1H,-NH-),8.87(s,1H,-ArH),8.71(s,1H,-ArH),8.48(s,1H ,-NH-),8.34(d,1H,-ArH),8.28(s,1H,-ArH),7.89(t,2H,2×-ArH)...

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Abstract

The invention relates to pyrazolopyridine derivatives with the structure of formula (I) or pharmaceutically acceptable salts and application of the pyrazolopyridine derivatives or pharmaceutically acceptable salts. The invention also relates to a method for preparing compounds and an intermediate of the compounds.

Description

technical field [0001] The present invention relates to some novel pyridopyrazole derivatives or their pharmaceutically acceptable salts and their use. The invention also relates to the preparation method of the compound and the intermediate of the compound. Background technique [0002] Protein tyrosine kinases (Protein Tyrosine Kinases, PTKs) play an important role in the signal transduction mechanism of normal cells, and their abnormal expression will lead to many diseases, especially tumors, so by inhibiting the activity of PTKs, the physiological balance can be restored It can be used as a new treatment method. In the past ten years, people have successfully developed a number of new cancer treatment drugs based on the tyrosine kinase signaling pathway. At the same time, Tyrosine Kinase Inhibitors (TKIs) have small molecular weight, oral efficacy and tolerance Good sex characteristics, has been approved for the treatment of many types of tumors, such as: lung cancer, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/437A61K31/5377A61K31/4545A61P35/00A61P3/10A61P9/00A61P29/00A61P37/00
Inventor 吴刚沈晗朱新荣
Owner JIANGSU SIMCERE PHARMA
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