(R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide Chemical Properties

Density 

1.619±0.06 g/cm3(Predicted)

storage temp. 

Store at -20°C

solubility 

DMF:30.0(Max Conc. mg/mL);79.31(Max Conc. mM)
DMSO:68.33(Max Conc. mg/mL);180.65(Max Conc. mM)
DMSO:PBS (pH 7.2) (1:5):0.16(Max Conc. mg/mL);0.42(Max Conc. mM)
Ethanol:3.0(Max Conc. mg/mL);7.93(Max Conc. mM)

form 

A solid

pka

14.25±0.40(Predicted)

color 

Light yellow to yellow

InChI

InChI=1S/C16H20BrN5O/c17-11-6-19-15-13(14(11)22-5-1-2-10(18)8-22)12(7-20-15)21-16(23)9-3-4-9/h6-7,9-10H,1-5,8,18H2,(H,19,20)(H,21,23)/t10-/m1/s1

InChIKey

BAZRWWGASYWYGB-SNVBAGLBSA-N

SMILES

C1(C(NC2C3=C(N4CCC[C@@H](N)C4)C(Br)=CN=C3NC=2)=O)CC1

(R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide Usage And Synthesis

Uses

GDC-0575 (ARRY-575, RG7741) is a highly-selective oral small-molecule Chk1 inhibitor with an IC50 of 1.2 nM.

Synthesis

(0010) To a 1 L inert jacketed reactor equipped with a mechanical stirrer, nitrogen/vacuum manifold, thermocouple, and condenser was added (R)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-nitro-1H-pyrrolo[2,3-b]pyridine (1:1 toluene solvent compound) (30.0 g, 1.00 equiv) and tetrahydrofuran ( 180 mL, 6.00 mL/g). Subsequently, 4.5 M piperazine aqueous solution (42.4 g dissolved in 190 mL of water) was slowly added to the reaction mixture while maintaining the temperature at 0 °C. Next, sulfuric acid (36.1 mL, 3.00 eq.) was added and the reaction mixture was stirred at 25 °C for 2 hours. Upon completion of the reaction, 15.0 mL of saturated brine was added and the aqueous phase was separated. The organic phase was stirred for 5 minutes at 20 °C before water (22.0 mL) was added and subjected to continuous distillation at 50 °C. The ethanol feed rate was adjusted to match the distillation rate by adjusting the ethanol feed rate until a total of 260 mL of ethanol was added. Subsequently, water (340 mL) was added over a period of 1 hour at 50 °C. The resulting solid was separated by filtration and washed with 20% aqueous ethanol (2 x 60 mL). Finally, drying in a vacuum oven at 50 °C overnight gave 16.4 g (78% corrected yield) of (R)-5-bromo-4-(3-aminopiperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine as a light yellow solid. Note: The 1H NMR and 13C NMR spectra of the free base product have broader signals, so the spectra shown are after conversion of the free base to the bis-HCl salt.1H NMR (300 MHz, DMSO-d6): δ 11.98 (br, 1H), 9.78 (s, 1H), 8.44 (br, 3H), 8.25 (s, 1H), 7.45 (d, J = 2.4 Hz, 1H), 3.57 (m, 1H), 3.43 (m, 1H), 3.41 (m, 1H), 3.28 (m, 1H), 3.14 (m, 1H), 2.15 (m, 1H), 1.90 (penta, J = 6.5 Hz, 1H), 1.81 (m, 1H), 1.72 (m, 1H), 1.52 (m, 1H ), 0.83 (m, 4H).13C NMR (75 MHz, DMSO-d6): δ 172.9, 149.5, 145.9, 145.1, 121.9, 114.2, 113.1, 107.8, 53.8, 51.1, 47.5, 28.6, 24.37, 14.7, 7.55, 7.45.HRMS- ESI (m/z): [M + H]+ calculated value C16H21BrN5O, 378.0924; measured value, 378.0912.

in vivo

References

[1] Oo ZY, et al. Endogenous Replication Stress Marks Melanomas Sensitive to CHEK1 Inhibitors In Vivo. Clin Cancer Res. 2018 Mar 13. doi: 10.1158/1078-0432.CCR-17-2701. DOI:10.1158/1078-0432.CCR-17-2701
[2] Laroche-Clary A, et al. CHK1 inhibition in soft-tissue sarcomas: biological and clinical implications. Ann Oncol. 2018 Apr 1;29(4):1023-1029. DOI:10.1093/annonc/mdy039
[3] Di Tullio A, et al. The combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human acute myeloid leukemia. Nat Commun. 2017 Nov 22;8(1):1679. DOI:10.1038/s41467-017-01834-4

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