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4-substituted pyrrolo[2,3-b]pyridine as erbb modulators useful for treating cancer

A technology represented by -C3H5, applied to medical preparations containing active ingredients, compounds of group 4/14 elements of the periodic table, drug combinations, etc., can solve problems such as increasing EGFR kinase activity

Pending Publication Date: 2021-03-30
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These mutations increase the kinase activity of EGFR, leading to hyperactivation of downstream pro-survival signaling pathways (Pao et al. NatRev Cancer 2010,10:760-774)

Method used

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  • 4-substituted pyrrolo[2,3-b]pyridine as erbb modulators useful for treating cancer
  • 4-substituted pyrrolo[2,3-b]pyridine as erbb modulators useful for treating cancer
  • 4-substituted pyrrolo[2,3-b]pyridine as erbb modulators useful for treating cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0343] N-(5-(4-chloro-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3- Base)-2-methylphenyl)acrylamide 2,2,2-trifluoroacetate (trifluoroacetate) (A1)

[0344]

[0345] Step 1: 4-Chloro-3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-b] Pyridine (A1)

[0346]

[0347] in N 2 4-Chloro-3-iodopyridin-2-amine (5.0 g, 19.0 mmol, 1.0 equiv), trimethyl ((4-methyl-3- Nitrophenyl)ethynyl)silane (5.7g, 25.0mmol, 1.25eq), 1,4-diazabicyclo[2.2.2]octane (3.6g, 32.3mmol, 1.7eq) and dichlorobis( Triphenylphosphine)palladium(II) (1.4 g, 2.0 mmol, 0.1 equiv) was divided into three microwave vials. Each vial was heated in the microwave at 145°C for 2h. EtOAc (250 mL) was added and the organic phase was washed with saturated NaHCO 3 Wash with aqueous solution 3 times. The organic phase was subjected to MgSO 4 Dry and remove solvent in vacuo. The crude product was purified by flash chromatography on silica gel (cHex / EtOAc = 100:0 to 1:1) t...

Embodiment 44

[0374] N-(5-(4-chloro-2-(3-(4-methylpiperazine-1-carbonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)- 2-Methylphenyl)acrylamide 2,2,2-trifluoroacetate (B2)

[0375]

[0376] Step 1: 3-(3-(3-acrylamido-4-methylphenyl)-4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl) Benzoic acid (B1)

[0377]

[0378] N-(5-(4-chloro-2-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide A4 (500mg, 1.14mmol, 1.0 equivalent), 3-carboxyphenylboronic acid (284mg, 1.71mmol, 1.5 equivalent) and K 3 PO 4 (483mg, 2.28mmol, 2.0 equivalents) in two Alkane / H 2 The mixture in O (15mL / 3mL) was replaced with N 2 Air flow degassed for 5min. Add [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane addition compound (93mg, 0.11mmol, 0.1eq) and heat the reaction mixture in a microwave oven to 130°C for 2h. The solvent was removed and the crude was purified by flash chromatography on silica gel (DCM / MeOH=100:0 to 0:100) to yield the desired product B1 (200 mg, 0.46 mmol, 41...

Embodiment 55

[0387] 1-(6-(4-chloro-2-(4-(1-methylpiperidin-4-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indole Lin-1-yl)prop-2-en-1-one 2,2,2-trifluoroacetate (C5)

[0388]

[0389] Step 1: 6-(4-Chloro-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indoline-1- tert-butyl formate (C1)

[0390]

[0391] Following the general procedure reported in Preparative Example 1, Step 1, from 4-chloro-3-iodopyridin-2-amine and 6-((trimethylsilyl)ethynyl)indoline-1-carboxylic acid tert Butyl ester Preparation C1 (1.0 g, 2.26 mmol, 76%, beige solid). MS(ES)C 23 h 28 ClN 3 o 2Si requirement: 441, measured: 442 (M+H) + .

[0392] Step 2: 4-Chloro-3-(indolin-6-yl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine (C2)

[0393]

[0394] 6-(4-Chloro-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine-3 in 30% TFA in DCM (60 mL) at room temperature -yl) tert-butyl indoline-1-carboxylate C1 (1.0 g, 2.26 mmol) was stirred for 2 h. Evaporation of the solvent gave the desired product C2 as a beige...

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Abstract

The present invention relates to certain 4-substituted 1H-pyrrolo[2,3-b]pyridine compounds of the formula (I) and pharmaceutically acceptable salts thereof. These compounds is useful in the treatmentor prevention of a disease or medical condition mediated through certain mutated forms of ErbB receptor, especially of Exon20 Her2 and EGFR mutations.

Description

[0001] The present invention relates to certain 4-substituted 1H-pyrrolo[2,3-b]pyridine compounds of formula (I) and pharmaceutically acceptable salts thereof. These compounds are useful in the treatment or prevention of diseases or medical conditions mediated by certain mutant forms of the ErbB receptor, especially exon 20 Her2 and EGFR mutations. technical field [0002] The present invention relates to certain 4-substituted 1H-pyrrolo[2,3-b]pyridine compounds of formula (I) and pharmaceutically acceptable salts thereof. These compounds are useful in the treatment or prevention of diseases or medical conditions mediated by certain mutant forms of the ErbB receptor, especially exon 20 Her2 and EGFR mutations. [0003] Background technique [0004] Receptor tyrosine kinases (RTKs) are cell surface receptors that transmit signals from the extracellular environment to control cell growth, differentiation and survival. Dysregulation of expression of protein kinases by gene ...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61P35/00A61K31/437C07F7/08
CPCC07D471/04A61P35/00C07F7/0814A61K31/496A61K31/5377A61K31/437C07D471/10A61K31/4545A61K31/4709A61K31/506A61K31/538A61K45/06
Inventor C·舒尔茨-法德姆雷希特B·克勒布尔P·努斯鲍默C·德根哈特M·鲍曼
Owner LEAD DISCOVERY CENT
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