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Pyrrolo[2,3-d]pyrimidine compounds and salts thereof, preparation method and medicinal use thereof

A compound and 3-d technology, applied in the field of pyrrolo[2,3-d]pyrimidine compounds and their salts, for the preparation of drugs for the treatment of tumors related to high expression of focal adhesion kinase

Active Publication Date: 2020-06-09
FUDAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main patents related to this type of compound are WO2008129380 and WO2010141406, etc., but so far no FAK inhibitor drugs have been approved for marketing for clinical treatment of tumors

Method used

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  • Pyrrolo[2,3-d]pyrimidine compounds and salts thereof, preparation method and medicinal use thereof
  • Pyrrolo[2,3-d]pyrimidine compounds and salts thereof, preparation method and medicinal use thereof
  • Pyrrolo[2,3-d]pyrimidine compounds and salts thereof, preparation method and medicinal use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083]

[0084] (1) 98mg (0.456mmol) N-[3-(aminomethyl)pyridin-2-yl]-N-methylmethanesulfonamide, 85mg (0.456mmol) 2,4-dichloropyrrolo[2,3 -d] Dissolve pyrimidine and 0.156mL (0.912mmol) N,N-diisopropylethylamine in 4mL ethanol, and stir under reflux in the external bath. After 1 h of reaction, the reaction was stopped, the solvent was spun off, and the obtained crude product was washed with water and diethyl ether in sequence to obtain 77 mg of a white solid with a yield of 46.1%. m.p.218-211℃. 1 H-NMR(DMSO-d6,400MHz)δ=3.14(s,3H),3.26(s,3H),4.74(d,J=5.40Hz,2H),6.59(s,1H),7.12(s,1H ), 7.41(dd, J=7.72Hz, J=4.72Hz, 1H), 7.82(d, J=7.64Hz, 1H), 8.43(d, J=4.64Hz), 8.47(s, 1H), 11.75( s,1H)ppm.ESI-MS m / z 367.1[M+H] + .

[0085] (2) 80 mg (0.22 mmol) of the solid obtained in step (1), 32 mg (0.22 mmol) of 5-aminoindol-2-one and 75 mg (0.44 mmol) of p-toluenesulfonic acid were dissolved in 1.5 mL of n-butanol, microwaved Reaction at 150°C for 3h. After the reaction was complet...

Embodiment 2

[0087]

[0088] (1) 60mg (0.299mmol) 2,4-dichloro-5-methylpyrrolo[2,3-d]pyrimidine, 77mg (0.358 mmol) N-[3-(aminomethyl)pyridin-2-yl ]-N-methylmethanesulfonamide and 0.100mL (0.585mmol) of N,N-diisopropylethylamine were dissolved in 4mL of ethanol, and the external bath was refluxed and stirred. The reaction stopped after 40 h, and a large amount of solids were precipitated out in the reaction liquid at this time. The reaction solution was transferred to an ice bath and stirred for 30 min, and filtered to obtain 75 mg of a light yellow solid with a yield of 66.0%. 1 H-NMR(DMSO-d6,400MHz)δ=2.38(s,3H),3.12(s,3H),3.28(s,3H),4.70(s,2H),6.68(s,1H),7.38(m ,2H),7.85(d,J=6.36Hz,1H),8.40(d,J=2.96Hz,1H),11.43(s,1H)ppm.ESI-MS m / z381.1[M+H] + .

[0089] (2) 150mg (0.396mmol) solid obtained in step (1), 58mg (0.395mmol) 5-aminoindol-2-one, 163.5mg (1.185mmol) potassium carbonate, 36mg (0.0395mmol) Pd 2 (dba) 3And 38mg (0.0790 mmol) of Xphos were dissolved in 6mL of tert-butanol, un...

Embodiment 3

[0091]

[0092] (1) 200mg (0.943mmol) 2,4-dichloro-5-cyanopyrrolo[2,3-d]pyrimidine, 243mg (1.132 mmol) N-[3-(aminomethyl)pyridin-2-yl ]-N-methylmethanesulfonamide and 0.322mL (1.886mmol) of N,N-diisopropylethylamine were dissolved in 8mL of ethanol, and the external bath was refluxed and stirred. The reaction stopped after 16 hours, and a large amount of solids precipitated out in the reaction solution. The reaction solution was transferred to an ice bath and stirred for 30 min, and filtered to obtain 220 mg of a light yellow solid with a yield of 60.0%. m.p.>250℃. 1 H-NMR(DMSO-d6,400MHz)δ=3.12(s,3H),3.28(s,3H),4.79(d,J=5.24Hz,2H),7.40(dd,J=7.64Hz,J= 4.54Hz,1H),7.70(t,J=5.84Hz,1H),7.86(d,J=6.16Hz,1H),8.20(s,1H),8.43(d,J=2.92Hz,1H), 12.92 (s,1H)ppm.ESI-MS m / z392.1[M+H] + .

[0093] (2) 50 mg (0.128 mmol) of the solid obtained in step (1), 19 mg (0.128 mmol) of 5-aminoindol-2-one and 66 mg (0.384 mmol) of p-toluenesulfonic acid were dissolved in 2 mL of n-butanol, and th...

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Abstract

The invention belongs to the field of organic chemistry and drug synthesis, and relates to pyrrolo[2,3-d]pyrimidine compounds and salts thereof. The compounds and salts thereof have a remarkable inhibiting effect on focal adhesion kinase, and can be used for preparing medicines for treating related diseases of the focal adhesion kinase, especially can be used for preparing medicines for treating related tumors with high expression of the focal adhesion kinase.

Description

Technical field [0001] The invention belongs to the field of organic chemistry and drug synthesis, and relates to a class of pyrrolo[2,3-d]pyrimidine compounds and their salts. The compounds and their salts have significant inhibitory effects on focal adhesion kinase and can be used to prepare and treat focal adhesion plaques. Drugs for kinase-related diseases, especially drugs for the treatment of tumors related to high expression of focal adhesion kinase. Background technique [0002] The prior art discloses that focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that plays a central role in integrin-mediated cell signaling pathways. Research shows that FAK has two conformations: activated and inactive. The conformation of FAK in the inactive state changes under the action of integrins, causing autophosphorylation of tyrosine residue Y397, and FAK changes to the activated state. After activation, FAK combines with Src family proteins to form a complex, which jo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/519A61P35/00
CPCC07D487/04
Inventor 张倩黄健谈寒一刘星龚超超
Owner FUDAN UNIV
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