Substituted morpholines as ATR kinase inhibitors

Patent metadata

Field	Value
Publication number	US-12559488-B2
Application number	US-202017778632-A
Country	US
Kind code	B2
Filing date	Nov 20, 2020
Priority date	Nov 21, 2019
Publication date	Feb 24, 2026
Grant date	Feb 24, 2026

Abstract

Disclosed is a pyrazolo-heteroaryl derivative, a preparation method therefor, and medical use thereof. In particular, the present invention relates to a pyrazolo-heteroaryl derivative as shown in the general formula (I), a preparation method therefor, a pharmaceutical composition containing the derivative, and a use thereof as a therapeutic agent, particularly as ATR kinase inhibitor and in the preparation of drugs for the treatment and/or prevention of hyperproliferative diseases. The definition of each group in the general formula (I) is identical as in the specification.

First claim

The invention claimed is:

1 . A compound of formula (I):

or a pharmaceutically acceptable salt or tautomer thereof,
wherein:

R 1 is alkyl or cyclopropyl, wherein the alkyl or cyclopropyl is substituted with one or more CN substituents;
R 2 is H or alkyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , NH 2 , OH, O(alkyl), cycloalkyl, heterocyclyl, aryl, and heteroaryl;
ring A is pyrazolyl;
each R 3 is independently H, halogen, CN, alkyl, alkenyl, NH 2 , OH, O(alkyl), O(haloalkyl), cycloalkyl, heterocyclyl, aryl, or heteroaryl;
wherein each alkyl and O(alkyl) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , NH 2 , OH, O(alkyl), cycloalkyl, heterocyclyl, aryl, and heteroaryl; and
wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , alkyl, haloalkyl, hydroxyalkyl, NH 2 , OH, O(alkyl), cycloalkyl, heterocyclyl, aryl, and heteroaryl; and

n is 0, 1, 2, or 3.

2 . The compound according to claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein R 1 is C(CH 3 ) 2 CN or 1-cyanocyclopropyl.

3 . The compound according to claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein R 2 is H, CH 3 , or CH 2 CH 3 .

4 . The compound according to claim 1 , wherein the compound is of formula (II):

or a pharmaceutically acceptable salt or tautomer thereof.

5 . The compound according to claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein each R 3 is independently H.

6 . The compound according to claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt or tautomer thereof.

7 . The compound according to claim 6 , wherein the compound is:

or a pharmaceutically acceptable salt or tautomer thereof.

8 . The compound according to claim 6 , wherein the compound is:

or a pharmaceutically acceptable salt or tautomer thereof.

9 . A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, diluent, or excipient and the compound according to claim 1 , or a pharmaceutically acceptable salt or tautomer thereof.

10 . A method for inhibiting ataxia-telangiectasia and rad3-related (ATR) kinase activity in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of the pharmaceutical composition according to claim 9 .

11 . The method according to claim 10 , wherein the subject has a cancer.

12 . The method according to claim 11 , wherein the cancer is selected from the group consisting of B-cell lymphoma, bladder cancer, bone cancer, a brain tumor, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastric cancer, a head and neck tumor, kidney cancer, leukemia, liver cancer, lung cancer, a melanoma, multiple myeloma, neuroblastoma, neuroglioma, ovarian cancer, pancreatic cancer, prostate cancer, a sarcoma, skin cancer, and a thyroid tumor.

13 . The method according to claim 10 , wherein the subject has a hyperproliferative disease.

14 . A process for preparing a compound of formula (I) according to claim 1 :

wherein:

R 1 is alkyl or cyclopropyl, wherein the alkyl or cyclopropyl is substituted with one or more CN substituents;
R 2 is H or alkyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , NH 2 , OH, O(alkyl), cycloalkyl, heterocyclyl, aryl, and heteroaryl;
ring A is pyrazolyl;
each R 3 is independently H, halogen, CN, alkyl, alkenyl, NH 2 , OH, O(alkyl), O(haloalkyl), cycloalkyl, heterocyclyl, aryl, or heteroaryl;
wherein each alkyl and O(alkyl) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , NH 2 , OH, O(alkyl), cycloalkyl, heterocyclyl, aryl, and heteroaryl; and
wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , alkyl, haloalkyl, hydroxyalkyl, NH 2 , OH, O(alkyl), cycloalkyl, heterocyclyl, aryl, and heteroaryl; and

n is 0, 1, 2, or 3;

wherein the process comprises the following step:
reacting a compound of formula (IA):

wherein:

R 1 is alkyl or cyclopropyl, wherein the alkyl or cyclopropyl is substituted with one or more CN substituents;
R 2 is H or alkyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , NH 2 , OH, O(alkyl), cycloalkyl, heterocyclyl, aryl, and heteroaryl; and
X is halogen;

with a compound of formula (IB):

wherein:
ring A is pyrazolyl;

each R 3 is independently H, halogen, CN, alkyl, alkenyl, NH 2 , OH, O(alkyl), O(haloalkyl), cycloalkyl, heterocyclyl, aryl, or heteroaryl;
wherein each alkyl and O(alkyl) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , NH 2 , OH, O(alkyl), cycloalkyl, heterocyclyl, aryl, and heteroaryl; and
wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , alkyl, haloalkyl, hydroxyalkyl, NH 2 , OH, O(alkyl), cycloalkyl, heterocyclyl, aryl, and heteroaryl; and

n is 0, 1, 2, or 3;

to obtain the compound of formula (I) above.

15 . A process for preparing a compound of formula (II) according to claim 4 :

Assignees

• Jiangsu Hengrui Medicine Co
• Shanghai hengrui pharmaceutical co ltd

Inventors

• Li Xin
• Dong Huaide
• Bai Dongdong
• He Feng
• Tao Weikang

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• Y02P20/55

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

• C07D471/04 Primary

  Ortho-condensed systems · CPC title