Pyrimido[5,4-b]pyrrolizin compound, optical isomer thereof, preparation method therefor and use thereof

Patent metadata

Field	Value
Publication number	US-12384795-B2
Application number	US-202017606121-A
Country	US
Kind code	B2
Filing date	Apr 24, 2020
Priority date	Apr 24, 2019
Publication date	Aug 12, 2025
Grant date	Aug 12, 2025

Abstract

The present invention relates to a pyrimido[5,4-b]pyrrolizin compound represented by general formula I, an optical isomer thereof, a preparation method therefor, a pharmaceutical composition containing same, and a use thereof. The compound according to the present invention has good inhibitory activity on the kinase BTK at both the molecular level and the cellular level. Meanwhile, the compound also has good anti-tumor activity and pharmacokinetic properties in vivo.

First claim

The invention claimed is:

1. A pyrimido[5,4-b]pyrrolizin compound represented by formula I, pharmaceutically acceptable salts, enantiomers, diastereomers, optical isomers, racemates, deuterated derivatives thereof:

wherein R 1 and R 2 are each independently H or C 1 -C 10 alkyl;
R 3 is H or C 1 -C 10 alkyl.

2. The pyrimido[5,4-b]pyrrolizin compound, pharmaceutically acceptable salts, enantiomers, diastereomers, optical isomers, racemates, deuterated derivatives thereof of claim 1 , wherein the compound of formula I is

3. A method for preparing the pyrimido[5,4-b]pyrrolizin compound of claim 1 , comprising the steps of:

wherein R 1 , R 2 , R 3 are as defined in claim 1 ,
removing the protective group T from reactant A8 or B8, and then reacting with

to obtain the compound of the formula I, wherein the protective group T comprises tert-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phthalimido, p-toluenesulfonyl, trifluoroacetyl, triphenylmethyl, 2,4-dimethoxybenzyl, p-methoxybenzyl, benzyl and the like.

4. A pharmaceutical composition comprising a therapeutically effective amount of the pyrimido[5,4-b]pyrrolizin compound, pharmaceutically acceptable salts, enantiomers, diastereomers, optical isomers, racemates, deuterated derivatives thereof of claim 1 and one or more pharmaceutically acceptable carriers.

5. The pharmaceutical composition of claim 4 , wherein the pharmaceutical composition comprises 65% to 99% by total weight ratio of the pyrimido[5,4-b]pyrrolizin compound, pharmaceutically acceptable salts, enantiomers, diastereomers, optical isomers, racemates, deuterated derivatives thereof as active ingredients.

6. The pyrimido[5,4-b]pyrrolizin compound, pharmaceutically acceptable salts, enantiomers, diastereomers, optical isomers, racemates, deuterated derivatives thereof of claim 1 , wherein the compound of formula I is a compound of formula I-1,

wherein R 1 , R 2 and R 3 are as defined in claim 1 .

7. The pyrimido[5,4-b]pyrrolizin compound, pharmaceutically acceptable salts, enantiomers, diastereomers, optical isomers, racemates, deuterated derivatives thereof of claim 1 , wherein R 1 and R 2 are each independently H or C 1 -C 6 alkyl.

8. The pyrimido[5,4-b]pyrrolizin compound, pharmaceutically acceptable salts, enantiomers, diastereomers, optical isomers, racemates, deuterated derivatives thereof of claim 1 , wherein R 1 and R 2 are each independently H or C 1 -C 3 alkyl.

9. The pyrimido[5,4-b]pyrrolizin compound, pharmaceutically acceptable salts, enantiomers, diastereomers, optical isomers, racemates, deuterated derivatives thereof of claim 1 , wherein R 3 is H or C 1 -C 6 alkyl.

10. The pyrimido[5,4-b]pyrrolizin compound, pharmaceutically acceptable salts, enantiomers, diastereomers, optical isomers, racemates, deuterated derivatives thereof of claim 1 , wherein R 3 is H or C 1 -C 3 alkyl.

11. The pyrimido[5,4-b]pyrrolizin compound, pharmaceutically acceptable salts, enantiomers, diastereomers, optical isomers, racemates, deuterated derivatives thereof of claim 1 , wherein the compound of formula I is

12. The method of claim 3 , wherein the protective group T comprises tert-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl.

13. The method of claim 3 , wherein the protective group T comprises tert-butoxycarbonyl.

14. The method of claim 3 , wherein the compound A8 is compound B8, the compound of formula I is the compound of formula I-1;

wherein R 1 , R 2 , R 3 are as defined in claim 1 .

Assignees

• Shanghai Inst Materia Medica Cas

Inventors

• Zhang Ao
• Ding Jian
• Xie Hua
• Song Zilan
• Xue Yu
• Xing Li
• Tong Linjiang
• Geng Meiyu

Classifications

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P35/02

  specific for leukemia · CPC title