Benzoheterocycle substituted tetrahydroisoquinoline compound

#The present application claims the right of the following priorities: application number: CN202011508096.4, filed on Dec. 18, 2020; application number: CN202110266745.2, filed on Mar. 11, 2021; application number: CN202111523273.0, filed on Dec. 13, 2021.

#The present disclosure relates to the field of medicinal chemistry, and in particular, relates to benzoheterocycle substituted tetrahydroisoquinoline compounds, preparation methods thereof and use thereof.

#Phosphate is an important mineral that regulates various metabolic processes including signal transduction, energy production, and mineral metabolism, and is primarily absorbed in the small intestine and filtered by the kidneys, and subsequently reabsorbed or excreted via the renal tubules. Thus, serum phosphate concentrations remain within a physiological range despite differences in daily phosphate intake. In patients with advanced chronic kidney disease (CKD), the renal phosphorus metabolism function is basically lost, which leads to hyperphosphatemia. Studies have shown that hyperphosphatemia is associated with multiple adverse clinical outcomes in CKD patients, including: induction of vascular calcification, increased incidence and risk of death of cardiovascular disease, secondary hyperparathyroidism, metabolic bone disease or ectopic calcification resulted from renal osteodystrophy, promotion of renal failure and progression of cardiovascular disease.

#FIG. 1 is a standardized correction value (nP) of urinary phosphorus excretion amount against dietary phosphorus intake amount according to embodiments of the present disclosure;

#FIG. 2 is a standardized correction value (nNa) of urinary sodium excretion amount against dietary sodium intake amount according to embodiments of the present disclosure;

#FIG. 3 is fecal form score according to embodiments of the present disclosure;

#The present application is described in detail by the embodiments below, but it does not mean that there are any adverse restrictions on the present application. The present application has been described in detail herein, wherein specific embodiments thereof are also disclosed, and it will be apparent to those skilled in the art that various variations and improvements can be made to specific embodiments of the present application without departing from the spirit and scope of the present application.

#Compound A1-1 (6.53 g, 22.0 mmol), tris(dibenzylideneacetone)dipalladium (700 mg, 0.76 mmol), xantphos (700 mg, 1.21 mmol), N,N-diisopropylethylamine (3.87 g, 30.0 mmol) were dissolved in 1,4-dioxane (50 mL) solution, then the system was heated under nitrogen atmosphere to 70° C., and the compound benzyl mercaptan (2.48 g, 20.0 mmol) was added dropwise to the reaction system, after the dropwise addition, the system was stirred at 70° C. for 3 hours. The reaction mixture was cooled to room temperature (25° C.), filtered with celite, and the filtrate was concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0-6%) to obtain compound A1-2.

#1H NMR (400 MHz, DMSO-d6) δ 7.44 (d, J=2.0 Hz, 1H), 7.41-7.36 (m, 2H), 7.35-7.29 (m, 2H), 7.29-7.23 (m, 2H), 7.13 (dd, J=8.0, 0.9 Hz, 1H), 4.27 (s, 2H), 2.18 (s, 3H).