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Cnoline compound PI3K kinase inhibitor as well as preparation method and application thereof in pharmacy

A technology of kinase inhibitors and compounds, applied in the field of medicinal chemistry, can solve the problems of not being able to treat PI3K kinase, not having PI3K kinase targeting, and achieving good therapeutic effect and safety effect

Inactive Publication Date: 2021-06-01
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, none of the above-mentioned cinnoline derivatives have PI3K kinase targeting, so they cannot be used to treat diseases related to PI3K kinase overexpression

Method used

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  • Cnoline compound PI3K kinase inhibitor as well as preparation method and application thereof in pharmacy
  • Cnoline compound PI3K kinase inhibitor as well as preparation method and application thereof in pharmacy
  • Cnoline compound PI3K kinase inhibitor as well as preparation method and application thereof in pharmacy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0153] Example 1: 4-morpholino-6-(2-methoxy-3-benzenesulfonylaminopyridin-5-yl)cinnoline

[0154]

[0155] With 0.43g (1.10mmol) 2-methoxy-3-benzenesulfonylaminopyridine-5-boronic acid pinacol ester, 0.29g (1.00mmol) 4-morpholino-6-bromocinnoline, 0.35g ( 2.50mmol) anhydrous K 2 CO 3 , 0.04g (5% mol) PdCl 2 (dppf), 10mL 1,4-dioxane, 2mL water into a 100mL flask, N 2 Reflux under protection for 8h. After the completion of the reaction was confirmed by TLC, 1,4-dioxane was removed by rotary evaporation, and an appropriate amount of EA was added to mix with silica gel to pass through the column to obtain 0.25 g of 4-morpholinyl-6-(2-methoxy-3-benzenesulfonylamino pyridin-5-yl)cinnoline (49%). 1 H-NMR (400MHz, DMSO-d6): δppm 3.39 (t, J = 4.48Hz, 4H), 3.75 (s, 3H), 3.95 (t, J = 4.26Hz, 4H), 7.59 (t, J = 7.66 Hz, 2H), 7.68(t, J=7.46Hz, 1H), 7.73(d, J=7.32Hz, 2H), 7.91(s, 1H), 8.15(d, J=8.88Hz, 1H), 8.20( s,1H),8.24(s,1H),8.53(d,J=8.88Hz,1H),8.62(s,1H),9.02(s,1H),10.03(brs,...

Embodiment 2

[0156] Example 2: 4-morpholino-6-(2-chloro-3-benzenesulfonylaminopyridin-5-yl)cinnoline

[0157]

[0158] 0.43g (1.10mmol) 2-chloro-3-benzenesulfonylaminopyridine-5-boronic acid pinacol ester, 0.29g (1.00mmol) 4-morpholino-6-bromocinnoline, 0.27g (2.50mmol ) Anhydrous Na 2 CO 3 , 0.05g (6% mol) PdCl 2 (dppf), 12mL 1,4-dioxane, 3mL water into a 100mL flask, N 2 Reflux under protection for 8h. After the completion of the reaction was confirmed by TLC, 1,4-dioxane was removed by rotary evaporation, and an appropriate amount of EA was added and mixed with silica gel to pass through the column to obtain 0.36 g of 4-morpholinyl-6-(2-chloro-3-benzenesulfonylaminopyridine- 5-yl)cinnoline (75%). 1 H-NMR (400 MHz, DMSO-d6): δppm 3.48 (t, J = 4.38Hz, 4H), 3.90 (t, J = 4.24Hz, 4H), 7.59 (t, J = 7.62Hz, 2H), 7.68 (t, J=7.50Hz,1H),7.78(d,J=7.64Hz,2H),8.14(d,J=8.92Hz,1H),8.14(s,1H),8.18(s,1H),8.44 (d,J=8.56Hz,1H),8.73(s,1H),9.04(s,1H),10.71(brs,1H)

Embodiment 3

[0159] Example 3: 4-phenylamino-6-(2-methoxy-3-benzenesulfonylaminopyridin-5-yl)cinnoline

[0160]

[0161] With 0.43g (1.10mmol) 2-methoxy-3-benzenesulfonylaminopyridine-5-boronic acid pinacol ester, 0.30g (1.00mmol) 4-phenylamino-6-bromocinnoline, 0.35g ( 2.50mmol) anhydrous K 2 CO 3 , 0.04g (5% mol) PdCl 2 (dppf), 10mL 1,4-dioxane, 2mL water into a 100mL flask, N2 Reflux for 16h under protection. After the completion of the reaction was confirmed by TLC, 1,4-dioxane was removed by rotary evaporation, and an appropriate amount of EA was added to mix with silica gel to pass through the column to obtain 0.19 g of 4-phenylamino-6-(2-methoxy-3-benzenesulfonylamino pyridin-5-yl)cinnoline (39%). 1 H-NMR (400MHz, DMSO-d6): δppm 3.54(s, 3H), 7.25(t, J=7.70Hz, 1H), 7.40(d, J=7.46Hz, 2H), 7.50(t, J=7.80 Hz,2H),7.56(t,J=7.68Hz,2H),7.71(t,J=7.50Hz,1H),7.77(d,J=7.76Hz,2H),8.13(s,1H),8.19( d,J=8.88Hz,1H),8.29(s,2H),8.48(s,2H),8.78(s,1H)

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Abstract

The invention provides a cinnoline compound PI3K kinase inhibitor as shown in a formula I. In the cinnoline compound PI3K kinase inhibitor, and R1, R2 and R3 are defined in the specification. The invention also provides a pharmaceutical composition of the formula I or the salt thereof, a preparation method of the pharmaceutical composition and application of the pharmaceutical composition to treatment of inflammation caused by overexpression of PI3K kinase, immune diseases, cardiovascular diseases, cancers and other diseases related to PI3K kinase.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to the preparation and drug combination of cinnoline compounds or salts thereof, and the application to diseases, diseases or conditions related to PI3K kinases. Background technique [0002] Phosphatidylinositol 3-kinase (PI3K) is an important signal transduction molecule in cells. PI3K participates in the regulation of cell proliferation, differentiation and apoptosis by phosphorylating the 3-hydroxyl group on the phosphatidylinositol ring. Physiological processes such as death. The abnormal activation of PI3K caused by the mutation of the upstream gene of PI3K (such as PIK3CA) or the inactivation mutation of its negative regulatory gene PTEN have been observed in cancer cells. It can be said that PI3K is closely related to the occurrence and development of various cancers and non-cancerous diseases (Vivanco, I.; Sawyers, C.L., Nat. Rev. Cancer 2002, 2, 489.). PI3K k...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D401/14C07D473/34A61K31/502A61K31/5377A61P35/02A61P35/00A61P37/00A61P9/00A61P7/04
CPCA61P7/04A61P9/00A61P35/00A61P35/02A61P37/00C07D401/04C07D401/14C07D473/34Y02P20/55
Inventor 周亚明贾瑜凌云杨永泰刘小锋邓名莉陈珍霞田承泽
Owner FUDAN UNIV
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