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Heteroaryl compound and application thereof

A technology of heteroaryl compounds, applied in the field of heteroaryl compounds, can solve the problems of insufficient research on inhibition

Pending Publication Date: 2021-03-30
LONGTAISHEN MEDICAL TECH NANJING CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the compounds provided in WO2018011138 and WO2016124553 only disclose that they have certain inhibitory activity on peripheral blood mononuclear cells (PBMC) of patients with chronic lymphocytic leukemia (CLL)
However, it has been found that its inhibitory effect on other cancer cells is insufficient, and there is still room for improvement in its pharmacokinetic properties and toxicological characteristics.

Method used

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  • Heteroaryl compound and application thereof
  • Heteroaryl compound and application thereof
  • Heteroaryl compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0409] Compound 1: 2-(4-(6-chloro-7-((1-((6-methoxypyridin-3-yl)methylene)piperidin-4-yl)amine)-3hydro-imidazole [4,5-b]pyridin-2-yl)phenoxy)-N-methylacetamide

[0410]

[0411] General Method E: Related Compound 5-Chloro-N 4 -(1-((6-methoxypyridin-3-yl)methylene)piperidin-4-yl)-3-nitropyridine-2,4-diamine (I-27, 50mg, 1eq) and 2-(4-formylphenoxy)-N-methylacetamide (I-1, 25 mg, 1 eq).

[0412] 1 H NMR (400MHz, DMSO-d 6 )δ13.15(s,1H),8.17–8.02(m,4H),7.92(s,1H),7.66(dd,J=8.5,2.4Hz,1H),7.17–7.07(m,2H),6.81 (d,J=8.4Hz,1H),5.81(d,J=8.8Hz,1H),5.04–4.85(m,1H),4.57(s,2H),3.84(s,3H),3.47(s, 2H), 2.86(d, J=11.1Hz, 2H), 2.68(d, J=4.6Hz, 3H), 2.15(t, J=11.5Hz, 2H), 1.98(d, J=8.7Hz, 3H) ,1.67(q,J=10.7,9.9Hz,2H).MS:ESI(+)[M+1] + 536.0.

Embodiment 2

[0414] Compound 2: 2-(4-(6-chloro-7-((1-((5-methoxypyridin-2-yl)methylene)piperidin-4-yl)ammonia)-3hydro-imidazole [4,5-b]pyridin-2-yl)phenoxy)-N-methylacetamide

[0415]

[0416] General Method E: Related Compound 5-Chloro-N 4 -(1-((5-methoxypyridin-2-yl)methylene)piperidin-4-yl)-3-nitropyridine-2,4-diamine (I-28,1eq) and 2 -(4-Formylphenoxy)-N-methylacetamide (I-1, 1 eq).

[0417] 1 H NMR (400MHz, DMSO-d 6)δ13.15(s,1H),8.24(s,1H),8.08(d,J=8.6Hz,3H),7.92(s,1H),7.48–7.31(m,2H),7.21–7.06(m ,2H),5.84(d,J=8.6Hz,1H),4.98(s,1H),4.57(s,2H),3.83(s,3H),3.65(s,2H),2.94(s,2H) ,2.68(d,J=4.6Hz,3H),2.31(d,J=20.6Hz,2H),2.02(d,J=11.6Hz,2H),1.72(d,J=12.2Hz,2H); MS :ESI(+)[M+1] + 536.0.

Embodiment 3

[0419] Compound 3: 2-(4-(6-chloro-7-((1-(4-(trimethylsilyl)benzyl)piperidin-4-yl)amino)-3hydro-imidazol[4,5 -b]pyridin-2-yl)phenoxy)-N-methylacetamide

[0420]

[0421] General Method E: Related Compound 5-Chloro-3-nitro-N 4 -(1-(4-(trimethylsilyl)benzyl)piperidin-4-yl)pyridine-2,4-diamine (I-29,1eq) and 2-(4-formylphenoxy )-N-methylacetamide (I-1, 1 eq).

[0422] 1 H NMR (400MHz, DMSO-d 6 )δ7.95–7.77(m,3H),7.67(s,1H),7.25(d,J=7.5Hz,2H),7.09(d,J=7.6Hz,2H),6.95–6.80(m,2H ),5.53(d,J=8.8Hz,1H),4.73(d,J=10.9Hz,1H),4.32(s,2H),3.27(s,3H),2.63(d,J=11.0Hz,2H ), 2.44(d, J=4.6Hz, 3H), 1.91(t, J=11.4Hz, 2H), 1.75(d, J=11.3Hz, 2H), 1.44(td, J=12.8, 9.3Hz, 2H ); MS:ESI(+)[M+1] + 576.9.

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Abstract

The invention discloses a heteroaryl compound and application thereof, and provides a heteroaryl compound as shown in a formula I, a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof. The compound has good tumor inhibition activity, especially on human chronic lymphocytic leukemia, lung adenocarcinoma, breast cancer, ovarian cancer, breast cancer or pancreatic cancer, and hasgood inhibitory activity on drug-resistant breast cancer, lung cancer, ovarian cancer or leukemia.

Description

technical field [0001] The invention relates to a heteroaryl compound and its application. Background technique [0002] Chronic lymphocytic leukemia (CLL) arises from B lymphocytes that differ in stages of activation and maturation from antigen-experienced B cells with different immunoglobulin chain variable (IgVH) gene mutations (Chiorazzi Net al., N. Engl. J. Med., 2005, 352, 804-15). Patients with mutated IgHV genes have a better prognosis than patients with unmutated genes (Damle RN et al., Blood 1999,94,1840-7; Hamblin TJ et al., Blood, 1999,94,1848 -54). Global gene expression profiling studies have shown partially distinct but overall overlapping expression profiles in mutated and unmutated leukemic B cells, indicating common phenotypes (Klein Uet.al., J. Exp. Med., 2001, 194, 1625-38; Rosenwald A et al., J. Exp. Med., 2001, 194, 1639-47). [0003] Gene expression profiling studies demonstrated a 43.8-fold increase in the orphan receptor kinase tyrosine kinase (R...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D401/14C07D471/04C07D473/34C07F7/10A61P35/02A61P35/00A61K31/454A61K31/52A61K31/4545A61K31/437A61K31/695
CPCC07F7/0812C07D471/04C07D473/34C07D401/12C07D401/14A61P35/00A61P35/02A61K31/437A61K31/454A61K31/4545A61K31/52A61K31/695C07F7/10A61K31/506
Inventor 杨磊
Owner LONGTAISHEN MEDICAL TECH NANJING CO LTD
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