Pyridopyrimidine compound and application thereof

A pyridopyrimidine and compound technology, applied in the field of pyridopyrimidine compounds, can solve problems such as underdeveloped value, narrow indications, and high toxicity of idelalisib

Active Publication Date: 2022-04-12
XI AN JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the value of PI3Kδ inhibitors has not been fully developed, and the indications are relatively narrow, and the approved PI3Kδ inhibitor idelalisib is highly toxic, accompanied by a black box mark

Method used

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  • Pyridopyrimidine compound and application thereof
  • Pyridopyrimidine compound and application thereof
  • Pyridopyrimidine compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049]

[0050] (S)-4-(1-tert-butoxycarbonylpyrrolidin-3-yl)amino-6-chloropyrido[3,2-d]pyrimidine (Intermediate 1-c)

[0051] Weigh 4,6-dichloropyrido[3,2-d]pyrimidine (1.00g, 5.17mmol) into a 50mL round bottom flask, then add (S)-1-Boc-3-amino-pyrrolidine ( 1.40g, 7.51mmol) and DIPEA (1.94g, 15.34mmol), isopropanol (20mL) as solvent. After stirring and heating under reflux for 2.5 hours, TLC detection showed that the reaction was complete. The system was evaporated to dryness under reduced pressure, ethyl acetate was added, washed with water, saturated sodium bicarbonate solution, and saturated NaCl solution in sequence, and the organic phase was collected. 2 SO 4 Drying, column chromatography (CH 2 Cl 2 :CH 3 OH=20:1) 1.50 g of light yellow solid was obtained with a yield of 85.2%. mp:146.6~147.9℃.MS(ESI)m / z:[M+H] + =350.1. 1 H-NMR (600MHz, CDCl 3 )δ9.03(s,1H,Ar-H),8.71(d,J=14.2Hz,1H,Ar-H),8.09(d,J=55.2Hz,1H,NH),7.24-7.30(m, 1H, Ar-H), 4.94 (d, J=28.2Hz, 1H, CH),...

Embodiment 2

[0057]

[0058] (S)-4-((1-cyclopentylformylpyrrolidinyl)-3-yl)amino-6-(2-methoxy-3-cyanopyridin-5-yl)pyrido[3,2 -d] pyrimidine (compound 2)

[0059] Compound 2 was obtained as a white solid (97 mg, 64.4%) in a similar manner to compound 1. mp: 218.6~220.9℃. 1 H-NMR (400MHz, DMSO-d 6 )δ9.58(d, J=2.1Hz, 1H, Ar-H), 9.32(dd, J=4.8, 2.5Hz, 1H, Ar-H), 8.57–8.47(m, 3H, Ar-H), 8.20(dd, J=8.8, 3.2Hz, 1H, NH), 4.91(dd, J=41.9, 7.3Hz, 1H, CH), 4.10(s, 3H, OCH 3 ), 4.00 (dd, J=10.1, 7.5Hz, 1H, CH 2 ),3.85-3.79(m,2H,CH 2 ),3.68-3.40(m,1H,CH 2 ),2.75-2.72(m,1H,CH),2.27-2.15(m,2H,CH 2 ),1.62-1.21(m,8H,CH 2 ×4). 13 C-NMR (100MHz, DMSO-d 6 )δ174.2, 174.2, 164.5, 156.2, 150.9, 142.9, 137.3, 131.44 HRMS C 24 h 25 N 7 o 3 , calculated value [M+H]+: 444.21425, measured value: 444.21485.

Embodiment 3

[0061]

[0062] (S)-4-((1-cyclohexylformylpyrrolidinyl)-3-yl)amino-6-(2-methoxy-3-cyanopyridin-5-yl)pyrido[3,2- d] pyrimidine (compound 3)

[0063] Compound 3 (97 mg, 62.3%) could be prepared in a similar manner to compound 1. mp: 232.1~233.1℃. 1 H-NMR (400MHz, DMSO-d 6 )δ9.54(s,1H,Ar-H),9.29(s,1H,Ar-H),8.51-8.48(m,3H,Ar-H),8.18(dd,J=8.2,4.2Hz,1H , NH), 4.90 (dd, J=46.4, 7.0Hz, 1H, CH), 4.10 (s, 3H, OCH 3 ),3.80-3.44(m,4H,CH 2 ×2),2.43(s,1H,CH),2.26-2.16(m,2H,CH 2 ),1.70-1.19(m,10H,CH 2 ×5). 13 C-NMR (100MHz, DMSO-d 6 )δ174.0, 164.4, 159.6, 156.1, 151.6, 142.8, 137.1, 131.4, 127.4, 125.1, 115.7, 96.2, 55.4, 49.3, 44.9, 44.3, 42.0, 41.6, 39.9, 31.5, 259.6, 20, 12.5.77. .ESI-HRMS C 25 h 27 N 7 o 2 , calculated value [M+H] + : 458.22990, measured value: 458.23348.

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Abstract

The invention discloses a pyridopyrimidine compound and application thereof, and belongs to the technical field of biological medicine. The pyridopyrimidine compound disclosed by the invention is a novel compound capable of being used as a PI3K delta inhibitor, and the determination on the activity of PI3K delta kinase and the selective activity of PI3K delta kinase proves that the compound disclosed by the invention has an obvious inhibiting effect on the activity of PI3K delta kinase and has an obvious selective effect on the activity of PI3K delta. In-vitro cell proliferation determination of a leukemia cell line shows that the compound disclosed by the invention has different inhibition effects on leukemia cells. The compounds disclosed by the invention, or pharmaceutically acceptable salts, deuterated compounds, hydrates, solvates, chemically protected prodrugs or combinations thereof, can be used as PI3K delta inhibitors, and play a role in treating and / or preventing inflammatory diseases or tumors.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a pyridopyrimidine compound and an application thereof. Background technique [0002] Phosphatidylinositol-3-kinase (PI3K) is a member of the lipid kinase family and an important part of the PI3K / AKT / mTOR signaling pathway. PI3K can be divided into three categories according to the structure and function. The most widely studied class I PI3Ks are heterodimers consisting of a regulatory subunit and a catalytic subunit. The regulatory subunit contains SH2 and SH3 domains and interacts with target proteins that contain corresponding binding sites, and this subunit is commonly referred to as p85. There are four catalytic subunits, namely p110α, p110β, p110δ, and p110γ (where p110α, p110β, and p110δ belong to the RTK family, and p110γ belongs to the GPCR family). PI3K can be divided into PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ according to their catalytic subunits. Among the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61P19/02A61P35/02A61P35/00A61P11/06A61P37/00
Inventor 辛敏行张三奇孙佳佳段伟明冯奕凡
Owner XI AN JIAOTONG UNIV
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