CN-120699015-B - Pyridopyrimidine compound containing morpholine structure, and preparation method and application thereof

Abstract

The invention discloses a pyridopyrimidine compound containing a morpholine structure, and a preparation method and application thereof, and belongs to the technical field of medicines. The pyridopyrimidine compound containing the morpholine structure provided by the invention has stronger capability of inhibiting PI3K alpha kinase, so that the pyridopyrimidine compound can be used as an active ingredient for preparing a therapeutic drug for diseases caused by abnormal activation of PI3K alpha kinase, and has potential application value in preparing a drug for treating and/or preventing proliferative diseases and cancers. The invention provides important technical support for developing anticancer drugs with high efficiency and better selectivity.

Inventors

• XU SHAN
• WANG CHUHANG
• CHEN HUIJING
• WEN JIE
• PAN QINGSHAN
• WANG RAN
• WANG LINXIAO
• LI MIN
• PAN LINA
• CHEN LU

Assignees

• 江西科技师范大学

Dates

Publication Date

20260512

Application Date

20250609

Claims (7)

1. 1. The pyridopyrimidine compound containing the morpholine structure is characterized by having a structural formula shown in a formula I: ; In the formula I, when R 1 is When R 2 is selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) ; When R 1 is When R 2 is selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) 。
2. 2. A process for preparing a pyridopyrimidine compound having a morpholine structure as claimed in claim 1, When R 1 is In this case, the compounds of formula I are prepared as follows: ; In the above route, compound 2 is prepared by Miyaura boration reaction, compound 4 is prepared by nucleophilic substitution reaction, compound 5 is prepared by debroc reaction, compound 6-a is prepared by aromatic nucleophilic substitution reaction, compound 6-a and compound 2 are prepared by Suzuki coupling reaction to prepare compound 7-a, and compound 8-a is prepared by amidation reaction; When R 1 is In this case, the compounds of formula I are prepared as follows: ; in the above route, compound 2 is prepared by Miyaura boronation, compound 4 is prepared by nucleophilic substitution reaction, compound 5 is prepared by debrac reaction, compound 6-b is prepared by aromatic nucleophilic substitution reaction, compound 6-b and compound 2 are prepared by Suzuki coupling reaction to obtain compound 7-b, and compound 8-b is prepared by amidation reaction.
3. 3. A pharmaceutically acceptable salt of a pyridopyrimidine compound having a morpholino structure according to claim 1.
4. 4. A pharmaceutical preparation, characterized in that the active ingredient is a pyridopyrimidine compound containing a morpholine structure according to claim 1 or a pharmaceutically acceptable salt of a pyridopyrimidine compound containing a morpholine structure according to claim 3.
5. 5. The use of a pyridopyrimidine compound having a morpholine structure according to claim 1 for the preparation of a medicament for the treatment and/or prophylaxis of cancer, wherein the cancer is breast cancer.
6. 6. Use of a pharmaceutically acceptable salt of a pyridopyrimidine compound having a morpholino structure according to claim 3 for the manufacture of a medicament for the treatment and/or prophylaxis of cancer, wherein the cancer is breast cancer.
7. 7. Use of a pharmaceutical formulation according to claim 4 for the manufacture of a medicament for the treatment and/or prophylaxis of cancer, wherein the cancer is breast cancer.

Description

Pyridopyrimidine compound containing morpholine structure, and preparation method and application thereof Technical Field The invention belongs to the technical field of medicines, and particularly relates to a pyridopyrimidine compound containing a morpholine structure, and a preparation method and application thereof. Background In terms of cancer type, lung cancer, female breast cancer and colorectal cancer are the first three cancers with the greatest number of new diagnoses worldwide. The data reveals a serious threat to human health by cancer, especially breast and lung cancer, the most common cancer for women and men. Breast cancer has a particularly pronounced effect on female health worldwide, accounting for one fourth of new cancer cases diagnosed by women worldwide and one sixth of cancer deaths. To address the challenges of breast cancer, improving the prevention and treatment ability of breast cancer is a current focus of attention by governments and health organizations of various countries. The development of new drugs for the treatment of breast cancer using molecular targeted therapeutic strategies is currently the focus of work. The individual targeting therapy applied clinically at present mainly aims at abnormal activation of PI3K signal channels to treat breast cancer, and the clinical curative effect is obviously improved through definite molecular targets, target detection technology and targeted drugs on the market. Phosphatidylinositol 3-kinase (Phosphatidylinositol-kinase) is a family of enzymes with serine/threonine (Ser/Thr) kinase activity and is widely involved in regulating key biological processes such as cell growth, differentiation, proliferation, endocytosis, etc. PI3Ks are classified into three major classes, type I, type II and type III, based on their sequence homology, structural features and substrate specificity, with type I PI3Ks being the most studied. Type I PI3ks can be further divided into class IA and class IB, class IA including pi3kα, pi3kβ and pi3kδ, whereas class IB contains pi3kγ alone. Class IA PI3ks are heterodimers consisting of the p110α, p110β or p110δ catalytic subunit and the p85 regulatory subunit, whereas class IB PI3ks consist of the catalytic subunit p110γ together with the regulatory subunit p101 or p 87. The activation mechanism of PI3 ks is complex and diverse. Class IA PI3 ks transmit signals primarily through receptor tyrosine kinases (Receptor Tyrosine Kinase). When insulin or other growth factors bind to the RTK, autophosphorylation of tyrosine residues in the intracellular domain of the receptor is triggered, thereby activating PI3K. In contrast, activation of PI3K gamma is primarily dependent on the interaction of GN- β (guanine nucleotide binding protein- β) and GN- γ (guanine nucleotide binding protein- γ) in a G protein-coupled receptor. In addition, PI3K activation can also be achieved through the GTPase activity of the Ras protein. Insulin also indirectly activates PI3K through insulin receptor substrate 1 (Insulin Receptor Substrate 1). Meanwhile, cytokines can also mediate activation of PI3 ks by Janus Kinase 1 (Janus Kinase 1). These diverse activation mechanisms make PI3 ks play an important role in the cell signaling network. Studies have shown that the PI3K-AKTmTOR signaling pathway is a critical signaling network within cells that plays a central role in many aspects of human life activities. Abnormal activation of this pathway is closely related to the occurrence, progression and resistance to treatment of a variety of tumors. The PI3K-AKT-mTOR pathway prevents cell death by promoting cell survival and inhibiting apoptosis, which is particularly important in tumor progression. Tumors may utilize the PI3K-AKT-mTOR pathway to suppress immune system attacks, effecting immune escape. Continued activation of the PI3K-AKT-mTOR pathway may lead to tumor resistance to chemotherapy and targeted therapies, and interaction with other signaling pathways such as MAPK, JAK, etc., may further promote tumor progression. Aberrant activation of the PI3K-AKT-mTOR pathway is associated with a variety of tumor types including breast, colorectal, lung, prostate, ovarian, and the like. Because of its critical role in tumor development, the PI3K-AKT-mTOR pathway has become an important target for cancer treatment. There are different problems with the drugs currently marketed, and there is still a need to further improve the efficacy. Disclosure of Invention In order to solve the problems, the invention provides a pyridopyrimidine compound containing a morpholine structure, and a preparation method and application thereof. In order to achieve the above purpose, the present invention provides the following technical solutions: according to one of the technical schemes, the invention provides a pyridopyrimidine compound containing a morpholine structure, wherein the structural formula of the pyridopyrimidine compound is shown as formula I: In the fo