Substituted heteroaryl compounds, compositions and uses thereof
A compound and alkyl technology, which can be used in drug combinations, medical preparations containing active ingredients, metabolic diseases, etc., and can solve problems such as defects in tumor surveillance and high sensitivity to infection
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Embodiment 1
[0513] Example 16-(4-((5-chloro-2-(pyrazolo[1,5-a]pyridin-6-ylamino)pyrimidin-4-yl)(methyl)ammonia Base) piperidin-1-yl) nicotinonitrile
[0514]
[0515] Step 1) N-(diphenylmethylene)pyrazolo[1,5-a]pyridin-6-amine
[0516] in N 2 Under protection, to 6-bromopyrazolo[1,5-a]pyridine (1g, 5.0754mmol), Pd 2 (dba) 3 (403.5 mg, 0.4406 mmol), BINAP (312.4 mg, 0.5017 mmol), t-BuONa (982.6 mg, 10.22 mmol) and benzophenone imine (1.842 g, 10.17 mmol) were added toluene (25 mL). The reaction mixture was heated to 80° C. and stirred for 6.5 hours. After the reaction was completed, the reaction was quenched with water (80 mL). The resulting mixture was extracted with EtOAc (100 mL×3), and the combined organic phases were washed with anhydrous Na 2 SO 4 After drying, filtration and concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (PE / EtOAc (v / v)=15 / 1) to obtain the title compound as a yellow solid (1.42 g, yield 94%)....
Embodiment 2
[0536] Example 2 6-(4-((5-chloro-2-((3-methylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl) Amino)-3-ethylpiperidin-1-yl)nicotinonitrile
[0537]
[0538] Step 1) 2-Chloropropanal
[0539] To a suspension of propionaldehyde (5.00 g, 86.11 mmol) in chloroform (50 mL) was added pyrrolidine-2-carboxylic acid (1.98 g, 17.24 mmol) and NCS (12.67 g, 94.82 mmol) at 0°C. The resulting mixture was stirred at 0°C for 1 hour, then moved to room temperature and stirred overnight, then n-hexane (100 mL) was added to the mixture and stirring was continued for 30 minutes. After the reaction, the reaction mixture was filtered, the filtrate was washed with water (100mL×2), and the organic phase was washed with anhydrous Na 2 SO 4 After drying and filtering, the filtrate was obtained as 150 mL colorless solution, which was directly used in the next reaction without further treatment.
[0540] GC-MS m / z(EI):92.0[M] + .
[0541] Step 2) 7-Bromo-3-methylimidazo[1,2-a]pyridine
...
Embodiment 3
[0582] Example 3 6-(4-((5-chloro-2-((3-methylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl) Amino)-3-ethylpiperidin-1-yl)pyridazine-3-carbonitrile
[0583]
[0584] to 5-chloro-N 4 -(3-Ethylpiperidin-4-yl) -N 2 -(3-Methylimidazo[1,2-a]pyridin-7-yl)pyrimidine-2,4-diamine (0.13g, 0.34mmol) in DCM (10.0mL) suspension was added 6-chloropyrid Oxazine-3-carbonitrile (0.095 g, 0.68 mmol) and TEA (0.15 mL, 1.10 mmol). The reaction system was stirred overnight at room temperature and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (DCM / NH 3 MeOH solution (3M) (v / v)=50 / 1 to 30 / 1) to obtain the title compound as a yellow solid (0.12 g, yield 73%).
[0585] MS(ESI,pos.ion)m / z:489.4[M+H] + ;
[0586] 1 H NMR (400MHz, CDCl 3 )δ(ppm): 8.20(s, 1H), 7.95(s, 1H), 7.76(d, J=7.4Hz, 1H), 7.41(d, J=9.6Hz, 1H), 7.29(s, 1H) ,6.95-6.83(m,2H),5.12(d,J=8.1Hz,1H),4.80-4.65(m,1H),4.50-4.37(m,1H),4.32-4.19(m,1H),3.48 -3....
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