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Pyrazolo [3, 4-b] pyridine derivative, preparation method thereof and application of pyrazolo [3, 4-b] pyridine derivative as HPK1 inhibitor

A compound and alkylene technology, which is applied in the field of medicine, can solve the problems of HPK1 regulatory activity that needs to be improved, and achieve the effect of simple synthesis and convenient operation

Active Publication Date: 2021-12-31
ZHEJIANG MEDICAL COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005]Although WO 2018049214A1 and WO 2008124849 disclose that pyrazolo[3,4-b]pyridine can be used as an HPK1 regulator, its HPK1 regulation activity needs to be improved

Method used

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  • Pyrazolo [3, 4-b] pyridine derivative, preparation method thereof and application of pyrazolo [3, 4-b] pyridine derivative as HPK1 inhibitor
  • Pyrazolo [3, 4-b] pyridine derivative, preparation method thereof and application of pyrazolo [3, 4-b] pyridine derivative as HPK1 inhibitor
  • Pyrazolo [3, 4-b] pyridine derivative, preparation method thereof and application of pyrazolo [3, 4-b] pyridine derivative as HPK1 inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1: 3-(3-fluoro-4-methoxyphenyl)-5-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4 -b]pyridine (compound 1)

[0052]

[0053] Step 1: 5-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridine (compound 1-1)

[0054]

[0055] To 5-bromo-1H-pyrazolo[3,4-b]pyridine (1.97g, 1.0eq.) and (4-(4-methylpiperazin-1-yl)phenyl)boronic acid (2.2g, 1.0eq.) To a mixture of dioxane (100mL) and water (50mL) was added K 2 CO 3 (4.14g, 3.0eq.) and Pd(dppf)Cl 2 (731 mg, 0.1 eq.). The reaction mixture was stirred at 100 °C for 4 h under nitrogen. The mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:MeOH=20:1) to obtain compound 1-1 (2.1 g, 85%). 1 H NMR (400MHz, DMSO-d6) δ13.65(s, 1H), 8.79(d, J=2.2Hz, 1H), 8.36(d, J=2.1Hz, 1H), 8.16(s, 1H), 7.60 (d, J = 8.8Hz, 2H), 7.05 (d, J = 8.8Hz, 2H), 3.29–3.00 (m, 4H), 2.50–2.42 (m, 4H), 2.24 (s, 3H). LC-MS(M+...

Embodiment 2

[0061]Example 2: 3-(4-isopropoxyphenyl)-5-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b] Pyridine (Compound 2)

[0062]

[0063] Compound 2 (60 mg, 50%) was prepared from (4-isopropoxyphenyl)boronic acid and Compound 1-2 (100 mg, 1.0 eq.) in a similar manner to that described in Example 1, Step 3. 1 H NMR (400MHz, DMSO-d6) δ13.68(s, 1H), 8.81(d, J=1.9Hz, 1H), 8.55(d, J=1.7Hz, 1H), 8.01(d, J=8.7Hz ,2H),7.68(d,J=8.7Hz,2H),7.06(t,J=8.2Hz,4H),4.69(dt,J=12.0,6.0Hz,1H),3.42-3.32(m,4H) , 3.25–3.10 (m, 4H), 2.23 (s, 3H), 1.31 (d, J=6.0Hz, 6H). LC-MS(M+H) + = 428.22, Rt = 10.793 min.

Embodiment 3

[0064] Example 3: 5-(4-(4-methylpiperazin-1-yl)phenyl)-3-(3,4,5-trifluorophenyl)-1H-pyrazolo[3,4- b] pyridine (compound 3)

[0065]

[0066] Compound 3 (25 mg, 30%) was prepared from (3,4,5-trifluorophenyl)boronic acid and Compound 1-2 (100 mg, 1.0 eq) in a similar manner to that described in Step 3 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ13.94(s,1H), 8.82(d, J=1.9Hz,,1H), 8.63(d,J=1.6Hz,,1H), 8.12–7.85(m, 2H), 7.69(d, J=8.0Hz, 2H), 7.04(d, J=8.0Hz, 2H), 3.19-3.24(m, 4H), 2.46-2.53(m, 4H), 2.24(s, 3H ). LC-MS(M+H) + = 424.14, Rt = 11.088 min.

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Abstract

The invention relates to a pyrazolo [3, 4-b] pyridine derivative, a preparation method thereof and an application of the pyrazolo [3, 4-b] pyridine derivative as an HPK1 inhibitor, and discloses a compound with a structure as shown in a formula (I) (each group is defined in the specification), or a stereoisomer of the compound, or a pharmaceutically acceptable salt of the compound, and a pharmaceutical composition containing the compound. The invention further discloses a preparation method of the compound with the structure as shown in the formula (I). In addition, the invention also discloses application of the compound with the structure as shown in the formula (I) as the HPK1 inhibitor in preparation of drugs for treating HPK1 related disorders or diseases.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a pyrazolo[3,4-b]pyridine derivative, a preparation method thereof and an application as an HPK1 inhibitor. Background technique [0002] HPK1 regulates diverse functions of various immune cells, and its kinase activity has been shown to be active in T cell receptor (TCR) [Liou J., et al., Immunity, 2000.12(4):p.399-408], B cell receptor (BCR) [Liou J., et al., Immunity, 2000.12(4): p.399-408], transforming growth factor receptor (TGF-βR) [Wang, W., et al., JBiolChem, 1997.272(36) : page 22771-5; Zhou, G., et al., J Biol Chem, 1999.274 (19): page 13133-8], or the PGE2 receptor (EP2 and EP4) of Gs coupling [Ikegami, R., et al., J Immunol, 2001.166(7): p. 4689-96] is induced following activation. Overexpression of HPK1 inhibits TCR-induced activation of AP-1-dependent gene transcription in a kinase-dependent manner, suggesting that HPK1 is required to inhibit the Erk MAPK pathwa...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07F7/08A61P35/00A61K31/496A61K31/5377A61K31/695
CPCC07D471/04C07F7/0812A61P35/00Y02P20/55
Inventor 曾申昕黄文海潘有禄沈正荣章迟啸梁美好王尊元
Owner ZHEJIANG MEDICAL COLLEGE
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