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Azaindazole bipyridine derivative myeloid cell proliferation inhibitor and preparation method and application in pharmacy

A technology of heteroindazole bipyridine and proliferation inhibition, applied in the directions of active ingredients of heterocyclic compounds, drug combinations, anti-tumor drugs, etc. The effect of clinical research value

Active Publication Date: 2022-04-01
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, the indazole or azaindazole related derivatives disclosed in the prior art are not applicable to the treatment of myeloid cells and related diseases

Method used

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  • Azaindazole bipyridine derivative myeloid cell proliferation inhibitor and preparation method and application in pharmacy
  • Azaindazole bipyridine derivative myeloid cell proliferation inhibitor and preparation method and application in pharmacy
  • Azaindazole bipyridine derivative myeloid cell proliferation inhibitor and preparation method and application in pharmacy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0176] Example 1N-{2-chloro-5-[3-(6-morpholine pyridin-3-yl)-1H-7-azaindazol-5-yl]pyridin-3-yl}benzenesulfonamide

[0177]

[0178] Nitrogen-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)pyridin-3-yl)benzenesulfonamide (0.10g, 0.253mmol), 4-(5-(5-bromo-1H-7-azaindazol-3-yl)pyridin-2-yl)morpholine (0.10g, 0.279 mmol), anhydrous potassium carbonate (0.087g, 0.633mmol), water (0.50mL), 1,4-dioxane (1.50mL) and PdCl 2 (dppf) (0.0055 g, 7.59×10 -3 mmol), then reacted at 100°C for 12 hours, cooled to room temperature, diluted the reaction solution with ethyl acetate, spin-dried the solvent under reduced pressure, and purified by column chromatography to obtain light brown solid 1 (yield: 39%). 1 H NMR (400MHz, DMSO-d 6)δ3.51 (t, J = 4.4Hz, 4H), 3.75 (t, J = 4.4Hz, 4H), 6.98 (d, J = 8.8Hz, 1H), 7.61 (t, J = 7.2Hz, 2H) ,7.69(t,J=7.2Hz,1H),7.79(d,J=7.6Hz,2H),7.90(d,J=2.0Hz,1H),7.94(d,J=1.6Hz,1H),7.99 (dd, J 1 =2.0Hz,J 2 =6.4Hz,1H),8.50(s,1H),8.61(d,J=2.4Hz,1H),8....

Embodiment 2

[0179] Example 2N-{2-methoxy-5-[3-(1-methyl-1H-pyrazol-4-yl)-1H-7-azaindazol-5-yl]pyridin-3-yl }Benzenesulfonamide

[0180]

[0181] Add N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)pyridin-3-yl)benzenesulfonamide (0.10g, 0.256mmol), 5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-1H-7-azaind Azole (0.077g, 0.279mmol), anhydrous potassium carbonate (0.087g, 0.633mmol), water (0.50mL), toluene (2.00mL) and Pd(PPh 3 ) 4 (0.0088 g, 7.59×10 -3 mmol), then reacted at 110°C for 8 hours, then cooled to room temperature, the reaction solution was diluted with ethyl acetate, the solvent was spin-dried under reduced pressure, purified by column chromatography, and concentrated to obtain a brown solid 2 (yield: 46%) . 1 H NMR (400MHz, DMSO-d 6 )δ3.83 (s, 3H), 3.91 (s, 3H), 7.59 (t, J = 7.2Hz, 2H), 7.68 (t, J = 7.2Hz, 1H), 7.77 (d, J = 7.2Hz, 3H),7.91(s,1H), 8.25(s,1H),8.40(s,1H),8.45(s,1H),8.70(s,1H),10.45(s,1H),11.89(s,1H ).

Embodiment 3

[0182] Example 3 (S)-5-chloro-N-{1-[2-methoxy-5-(3-morpholine-1H-7-azaindazol-5-yl)pyridin-3-yl] Propyl}-2,6-dimethylpyrimidin-4-amine

[0183]

[0184] Add (S)-5-chloro-N-(1-(2-methoxy-5-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)pyridin-3-yl)propyl)-2,6-dimethylpyrimidin-4-amine (0.10g, 0.23mmol), 4-(5- Bromo-1H-7-azaindazol-3-yl)morpholine (0.079g, 0.279mmol), anhydrous potassium carbonate (0.087g, 0.633mmol), water (0.50mL), toluene (2.00mL) and Pd (PPh 3 ) 4 (0.0088g, 7.59×10 - 3 mmol), then reacted at 110°C for 8 hours, cooled to room temperature, the reaction solution was diluted with ethyl acetate, the solvent was spin-dried under reduced pressure, purified by column chromatography, and concentrated to obtain a brown solid 3 (yield: 36%) . 1 H NMR (400MHz, DMSO-d 6 )δ0.94(t,J=8.0Hz,3H),1.79-1.93(m,2H),2.39(s,3H),2.42(s,3H),2.83(t,J=4.4Hz,4H), 3.72(t,J=4.4Hz,4H),3.81(t,J=7.2Hz,1H),4.03(s,3H),6.79(s,1H),6.86(s,1H),8.09(s,1H ),8.22(s,1H),9.24(s,1H),9.5(s,1...

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Abstract

The present invention provides the azaindazole bipyridine derivative myeloid cell proliferation inhibitor shown in formula I, wherein R 1 , R 2 , R 3 All have the meaning defined in the description of the present invention. The compound of formula I can significantly inhibit myeloid cell proliferation represented by MOLM-16, HL-60, MV-4-11 and related diseases. The formula I or its salt or related drug combination provided by the present invention has excellent in vivo and in vitro inhibitory activity, good druggability, high bioavailability, and no obvious damage to organs. Therefore, formula I or its salts and related drug combinations have great prospects for clinical application.

Description

technical field [0001] The invention relates to the technical field of chemical medicines, in particular to an azaindazole bipyridine derivative inhibitor applied to myeloid cell proliferation and related diseases, a preparation method thereof, and an application in pharmacy. Background technique [0002] Myeloid cells are produced by myeloid progenitor cells, usually including: granulocytes, monocytes, macrophages, myeloid dendritic cells, etc., which together constitute an important branch of the immune system. Studies have shown that myeloid cells are key to regulating cancer cell-related activities, including: immune evasion, and affect the treatment of nearly all types of cancer. Therefore, the development of related inhibitors around myeloid cell proliferation is beneficial to overcome the limitations of current cancer treatment (Nature reviews Cancer, 2016, 16, 447-462). The candidate drug CAL-101 (Idelalisib) developed by Calistoga around targeting PI3K kinases, stu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04C07D519/00A61K31/5377A61K31/444A61K31/506A61K31/519A61K31/52A61K31/501A61K45/06A61P35/00A61P37/06A61P35/02
CPCC07D471/04C07D519/00A61P35/00A61P37/06A61P35/02
Inventor 周亚明凌云贾瑜杨永泰刘小锋陈珍霞邓名莉杨成斌
Owner FUDAN UNIV