Pyridopyrimidine or pyrimidopyrimidine compound, prepration method, pharmaceutical composition, and use thereof

Patent metadata

Field	Value
Publication number	US-9796732-B2
Application number	US-201514842682-A
Country	US
Kind code	B2
Filing date	Sep 1, 2015
Priority date	Mar 4, 2013
Publication date	Oct 24, 2017
Grant date	Oct 24, 2017

Abstract

The present invention belongs to the field of pharmaceutical Chemistry. In particular, the present invention relates to a pyridopyrimidine or pyrimidopyrimidine compound as represented by general formula (I), or an isomer thereof or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, a preparation method, a pharmaceutical composition and uses thereof in preparing a mTOR inhibitor. As a mTOR inhibitor, the compound or the pharmaceutical composition thereof can be used for treating a disease or condition due to PI3K-AKT-mTOR signalling pathway malfunction.

First claim

The invention claimed is:

1. A compound represented by formula (Ia), or the isomer, the pharmaceutically acceptable salt, the ester or the solvate thereof:

wherein
R 1 and R 2 are each independently 3-oxa-8-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, or NR A R B , and at least one of R 1 and R 2 is 3-oxa-8-azabicyclo[3.2.1]octanyl or 8-oxa-3-azabicyclo[3.2.1]octanyl;
wherein R A and R B are each independently H, C1-C6 alkyl unsubstituted or substituted by C1-C6 alkoxy or halogen, or C1-C6 alkoxy unsubstituted or substituted by halogen, or R A and R B , together with N to which they are linked, form a nitrogen-containing saturated heterocycle having 4 to 8 ring atoms which is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkoxy or halogen, the nitrogen-containing saturated heterocycle is piperidine ring, a morpholine ring, a piperazine ring, an N-methylpiperazine ring, a homomorpholine ring, or a homopiperazine ring; and
R 3 is

wherein Rc is H or C1-C3 alkyl.

2. The compound of claim 1 , or the isomer, the pharmaceutically acceptable salt, the ester or the solvate thereof, wherein,
R 1 and R 2 are each independently 3-oxa-8-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, or NR A R B , and at least one of R 1 and R 2 is 3-oxa-8-azabicyclo[3.2.1]octanyl or 8-oxa-3-azabicyclo[3.2.1]octanyl;
wherein R A and R B are each independently H, C1-C3 alkyl unsubstituted or substituted by C1-C3 alkoxy or halogen, or C1-C3 alkoxy unsubstituted or substituted by halogen, or R A and R B , together with N to which they are linked, form a nitrogen-containing saturated heterocycle having 6 to 7 ring atoms which is unsubstituted or substituted by C1-C3 alkyl, C1-C3 alkoxy or halogen.

3. The compound of claim 1 , or the isomer, the pharmaceutically acceptable salt, the ester or the solvate thereof, wherein
R 1 and R 2 are each independently 3-oxa-8-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, or NR A R B , and at least one of R 1 and R 2 is 3-oxa-8-azabicyclo[3.2.1]octanyl or 8-oxa-3-azabicyclo[3.2.1]octanyl;
wherein R A and R B , together with N to which they are linked, form a morpholine ring unsubstituted or substituted by C1-C3 alkyl, C1-C3 alkoxy or halogen.

4. The compound of claim 1 , or the isomer, the pharmaceutically acceptable salt, the ester or the solvate thereof according to claim 1 , wherein
R 1 is

R 2 is

or,
R 2 is

R 1 is

5. The compound of claim 1 , or the isomer, the pharmaceutical acceptable salt, the ester or the solvate thereof, wherein
Rc is H or methyl.

6. The compound of claim 1 , or the isomer, the pharmaceutical acceptable salt, the ester or the solvate thereof, wherein the compound represented by formula (Ia) is selected from the group consisting of:

7. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 , or the isomer, the pharmaceutical acceptable salt, the ester or the solvate thereof, and optionally, a pharmaceutically acceptable carrier or excipient.

8. The compound of claim 1 , or the isomer, the pharmaceutically acceptable salt, the ester or the solvate thereof, wherein
R 1 is

9. The compound of claim 1 , or the isomer, the pharmaceutically acceptable salt, the ester or the solvate thereof, wherein
R 2 is

10. The compound of claim 1 , selected from the group consisting of

11. The pharmaceutical composition of claim 7 , wherein the compound of claim 1 is selected from the group consisting of

12. A method for treating a disease or condition in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of claim 1 , or the isomer, the pharmaceutically acceptable salt, the ester or the solvate thereof, wherein the disease or condition is caused by dysfunction of PI3K-AKT-mTOR signaling pathway, wherein the disease or condition is selected from the group consisting of:
liver cancer, non-small cell lung cancer, skin cancer, colon cancer, breast cancer, brain cancer, kidney cancer, prostate cancer, and pancreatic cancer.

13. The method of claim 12 , wherein the compound of claim 1 is selected from the group consisting of

Assignees

• Shanghai Inst Materia Medica Cas
• Univ Fudan
• Shandong Luoxin Pharmacy Stock

Inventors

• Shen Jingkang
• Yu Ke
• Meng Tao
• Ma Lanping
• Zask Arie
• Meng Lanfang
• Wang Xin
• Chen Yiyi

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title