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

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

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

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Warning

Hazard statements

H315Causes skin irritation

H317May cause an allergic skin reaction

H319Causes serious eye irritation

H335May cause respiratory irritation

Precautionary statements

P261Avoid breathing dust/fume/gas/mist/vapours/spray.

P264Wash hands thoroughly after handling.

P264Wash skin thouroughly after handling.

P271Use only outdoors or in a well-ventilated area.

P272Contaminated work clothing should not be allowed out of the workplace.

P280Wear protective gloves/protective clothing/eye protection/face protection.

P302+P352IF ON SKIN: wash with plenty of soap and water.

P304+P340IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.

P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

P312Call a POISON CENTER or doctor/physician if you feel unwell.

P321Specific treatment (see … on this label).

P333+P313IF SKIN irritation or rash occurs: Get medical advice/attention.

P337+P313IF eye irritation persists: Get medical advice/attention.

P363Wash contaminated clothing before reuse.

P403+P233Store in a well-ventilated place. Keep container tightly closed.

P405Store locked up.

P501Dispose of contents/container to..…

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

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