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Pyrrolo[2,3-b]pyridines as hpk1 inhibitor and uses thereof

A kind of -NO2, pharmaceutical technology, applied in the field of pyrrolo[2,3-b]pyridine and its application as HPK1 inhibitor

Pending Publication Date: 2021-07-23
BEIGENE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although WO 2008124849 discloses pyrrolo[2,3-b]pyridine as Abelson tyrosine kinase, Ron receptor tyrosine kinase, Met receptor tyrosine kinase, Fms-like tyrosine kinase-3, Aurora kinase, p21-activated kinase-4, or 3-phosphoinositide-dependent kinase-1, no pyrrolo[2,3-b]pyridine derivatives have been reported as HPK1 modulators

Method used

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  • Pyrrolo[2,3-b]pyridines as hpk1 inhibitor and uses thereof
  • Pyrrolo[2,3-b]pyridines as hpk1 inhibitor and uses thereof
  • Pyrrolo[2,3-b]pyridines as hpk1 inhibitor and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0173] Example 1: N,N-Dimethyl-4-(5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridine-3 -yl) benzamide (compound 1)

[0174]

[0175] Step 1-1: tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (Compound 1-1)

[0176]

[0177] 7-Bromo-1,2,3,4-tetrahydroisoquinoline (1 g, 4.72 mmol, 1 eq), di-tert-butyl dicarbonate (1.23 g, 5.66 mmol, 1.2 eq) and Et 3 A solution of N (1.36 mL, 9.44 mmol, 2 eq) in THF (30 mL) was stirred at r.t for 5 hr. The reaction mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column with PE / EA (10 / 1 ) to give the title compound (1.45 g, 98.6%) as a light yellow oil.

[0178] Step 1-2: tert-butyl 7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (compound 1 -2)

[0179]

[0180] Under nitrogen atmosphere, tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.45g, 4.65mmol, 1eq) and 5-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrro...

example 2

[0193] Example 2: N,N-dimethyl-4-(5-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3- b] pyridin-3-yl) benzamide (compound 2)

[0194]

[0195] At r.t., to N,N-dimethyl-4-(5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridine- To a solution of 3-yl)benzamide (100 mg, 0.25 mmol, 1 eq) in DCM (20 mL) was added 37% HCHO solution (126 mg, 1.26 mmol, 5 eq) and NaBH(OAc) 3 (160 mg, 0.75 mmol, 3 eq). The mixture was stirred for 1 h. Pass the reaction mixture through aqueous K 2 CO 3 (20 mL) and stirred for 5 hrs, then extracted with DCM (3x30 mL). The combined organic layers were washed with brine, washed with anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure. The residue was purified by preparative TLC (dichloromethane / methanol=10 / 1) to give the title compound (16 mg, 15.5%). 1H NMR (400MHz, DMSO-d6) δ12.07(s, 1H), 8.54(d, J=1.8Hz, 1H), 8.44(d, J=1.9Hz, 1H), 8.00(s, 1H), 7.85 (d,J=8.1Hz,2H),7.59-7.41(m,4H),7.22(d,J=7.8Hz,1H),3.58(s,2H...

example 3

[0196] Example 3: (3-Hydroxyazetidin-1-yl)(4-(5-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H- Pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone (compound 3)

[0197]

[0198] Step 3-1: tert-butyl 7-(3-(4-(methoxycarbonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydro Isoquinoline-2(1H)-carboxylate (Compound 3-1)

[0199]

[0200] In the same manner as described in compound 1, steps 1-5, from tert-butyl 7-(1-(tert-butoxycarbonyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine-5- (4-(methoxycarbonyl)phenyl)boronic acid) to prepare the title compound. 650mg, 86%, white solid. LCMS(M+H) + = 483.9.

[0201] Step 3-2: Methyl 4-(5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzene Ester (compound 3-2)

[0202]

[0203] In the same manner as described in compound 1, steps 1-6, from tert-butyl 7-(3-(4-(methoxycarbonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine- 5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate and TFA to prepare the title compound. 500mg, 96%, yellow...

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Abstract

Disclosed herein is a compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising thereof. Also disclosed is a method of treating HPK1 related disorders or diseases by using the compound disclosed herein.

Description

technical field [0001] The present disclosure provides compounds and compositions and methods of use thereof. Compounds disclosed herein modulate (eg, inhibit) hematopoietic progenitor kinase 1 (HPK1 ) activity and are useful in the treatment of various diseases, including cancer. Background technique [0002] HPK1 regulates different functions of various immune cells and has been shown to be active in T cell receptor (TCR) [Liou J. et al., Immunity [immunity], 2000.12(4): pp. 399-408], B cell receptor (BCR) [Liou J. et al., Immunity [immunity], 2000.12 (4): 399-408 pages], transforming growth factor receptor (TGF-βR) [Wang, W. et al., J Biol Chem [ Journal of Biochemistry], 1997.272 (36): page 22771-5; Zhou, G. et al., J Biol Chem [Journal of Biochemistry], 1999.274 (19): page 13133-8], or Gs-coupled PGE2 receptor The kinase activity of HPK1 is induced following activation of the N-body (EP2 and EP4) [Ikegami, R. et al., J Immunol, 2001. 166(7): p. 4689-96]. Overexpressi...

Claims

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Application Information

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IPC IPC(8): C07D471/02A61K31/407A61P35/00
CPCA61P35/00C07D471/04C07D519/00
Inventor 李菁王志伟
Owner BEIGENE
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