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US-12617791-B2 - Triheterocyclic derivative, and pharmaceutical composition and application thereof

US12617791B2US 12617791 B2US12617791 B2US 12617791B2US-12617791-B2

Abstract

A triheterocyclic derivative, and a pharmaceutical composition and an application thereof. The triheterocyclic derivative (I), and a stereoisomer or a pharmacologically acceptable salt thereof have the following structure. The triheterocyclic derivative has good effects of inhibiting ATR levels in vivo and in vitro, and furthermore, the triheterocyclic derivative can also effectively treat diseases caused by abnormal ATR levels, such as cancers.

Inventors

  • Xiaohui Liu
  • Fengtao LIU
  • Daxin Gao

Assignees

  • Shanghai De Novo Pharmatech Co., Ltd.

Dates

Publication Date
20260505
Application Date
20211015
Priority Date
20201016

Claims (20)

  1. 1 . A compound of formula (II) or a compound of formula (III), a stereoisomer or a pharmaceutically acceptable salt thereof; in the compound of formula (II), any one of the following conditions (1)-(3) is satisfied: (1) U 1 and U 2 are C respectively: V is NR 6 : V 1 is N or CR 7a ; and V 2 is N or CR 7b ; (2) U 1 is C: U 2 is N: V is CR 7 ; V 1 is N or CR 7a ; and V 2 is N or CR 7b ; and (3) U 1 is N: U 2 is C: V is CR 7 ; V 1 is N or CR 7a ; and V 2 is N or CR 7b ; in the compound of formula (III): U 1 and U 2 are each independently C; V is CR 7 ; V 1 is N or CR 7a ; V 2 is N or CR 7b ; and V 3 is N or CR 7c ; in each of the compound of formula (II) and the compound of formula (III): X is CR 3 or NR 5 ; X 1 is CR 3a , CR 3a R 4a or NR 5a ; X 2 is CR 3b , CR 3b R 4b or NR 5b ; U is N or CH; R 1 is hydrogen or C 1-6 alkyl; R 2 is methyl; R 3 , R 3a and R 3b are each independently hydrogen, halogen, cyano, nitro, C 1-6 alkyl, C 2-6 alkynyl, C 2-6 alkenyl, C 6-10 aryl, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 6-10 aryl-C 1-6 alkyl, C 3-8 cycloalkyl-C 1-6 alkyl, 3- to 8-membered heterocycloalkyl-C 1-6 alkyl, 5- to 6-membered heteroaryl-C 1-6 alkyl, —SR a , —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR a R b , —C(O)OR a , —C(O)R a , —C(O)NR a R b , —C(O)N(R b )OR a , —C(O)NR b S(O) 2 R a , —C(═NH)R a , —NR a R b , —NR b C(O)R a , —N(R b )C(O)OR a , —N(R b )C(O)NR a R b , —NR b S(O) 2 R a , —NR b C(═NH)R a , —NR b C(═NH)NR b R a , —S(O) 1-2 R a , —S(O) 2 NR a R b , —S(O)(═NCN)R a , —S(O)(═NR b )R a or —NR b S(O) 2 NR a R b ; wherein, the C 1-6 alkyl, C 2-6 alkynyl, C 2-6 alkenyl, C 6-10 aryl, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 6-10 aryl-C 1-6 alkyl, C 3-8 cycloalkyl-C 1-6 alkyl, 3- to 8-membered heterocycloalkyl-C 1-6 alkyl, or 5- to 6-membered heteroaryl-C 1-6 alkyl is unsubstituted or optionally substituted at any position by 1 to 3 of the following substituents selected from halogen, cyano, nitro, —SR a , —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR a R b , —C(O)OR a , —C(O)R a , —C(O)NR a R b , —C(O)NR b S(O) 2 R a , —NR a R b , —NR b C(O)R a , —N(R b )C(O)OR a , —N(R b )C(O)NR a R b , —NR b C(═NH)R a , —NR b C(═NH)NR a R a , —NR b S(O) 2 R a , —NR b S(O) 2 NR a R b , —S(O) 1-2 R a , —S(O) 2 NR a R b , —S(O)(═NCN)R a and —S(O)(═NR b )R a ; R 4a and R 4b are each independently hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl or halo C 1-6 alkoxy; R 5 , R 5a and R 5b are each independently hydrogen, C 1-6 alkyl, C 2-6 alkynyl, C 2-6 alkenyl, C 6-10 aryl, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 6-10 aryl-C 1-6 alkyl, C 3-8 cycloalkyl-C 1-6 alkyl, 3- to 8-membered heterocycloalkyl-C 1-6 alkyl, 5- to 6-membered heteroaryl-C 1-6 alkyl, —SR a , —OR a , —C(O)OR a , —C(O)R a , —C(O)NR a R b , —C(O)N(R b )OR a , —C(O)NR b S(O) 2 R a , —C(═NH)R a , —S(O) 1-2 R a , —S(O) 2 NR a R b , —S(O)(═NCN)R a or —S(O)(═NR b )R a ; wherein, the C 1-6 alkyl, C 2-6 alkynyl, C 2-6 alkenyl, C 6-10 aryl, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 6-10 aryl-C 1-6 alkyl, C 3-8 cycloalkyl-C 1-6 alkyl, 3- to 8-membered heterocycloalkyl-C 1-6 alkyl, or 5- to 6-membered heteroaryl-C 1-6 alkyl is unsubstituted or optionally substituted at any position by 1 to 3 of the following substituents selected from halogen, cyano, nitro, —SR a , —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR a R b , —C(O)OR a , —C(O)R a , —C(O)NR a R b , —C(O)NR b S(O) 2 R a , —NR a R b , —NR b C(O)R a , —N(R b )C(O)OR a , —N(R b )C(O)NR a R b , —NR b C(═NH)R a , —NR b C(═NH)NR a R b , —NR b S(O) 2 R a , —NR b S(O) 2 NR a R b , —S(O) 1-2 R a , —S(O) 2 NR a R b , —S(O)(═NCN)R a and —S(O)(═NR b )R a ; R 6 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl, or 3- to 8-membered heterocycloalkyl-C 1-6 alkyl, wherein, the C 6-10 aryl or 5- to 10-membered heteroaryl is unsubstituted or optionally substituted at any position by 1 to 3 of the following substituents selected from halogen, cyano, —R c , —OR c , —NR c R d , —N(CN)R c , —N(OR d )R c , —S(O) 0-2 R c , —C(O)R c , —C(O)OR c , —C(O)NR c R d , —C(NH)NR c R d , —NR d C(O)R c , —NR d C(O)NR c R d , —NR d S(O) 2 R c and —OC(O)R c ; R 7 , R 7a , R 7b and R 7c are each independently hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, 3- to 8-member heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl or 3- to 8-membered heterocycloalkyl-C 1-6 alkyl, wherein, the C 6-10 aryl or 5- to 10-membered heteroaryl is unsubstituted or optionally substituted at any position by 1 to 3 of the following substituents selected from halogen, cyano, —R c , —OR c , —NR c R d , —N(CN)R c , —N(OR d )R c , —S(O) 0-2 R c , —C(O)R c , —C(O)OR c , —C(O)NR c R d , —C(NH)NR c R d , —NR d C(O)R c , —NR d C(O)NR c R d , —NR d S(O) 2 R c and —OC(O)R c ; each of R a , R b , R c and R d is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10 aryl, 5- to 6-membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl, 3- to 8-membered heterocycloalkyl-C 1-6 alkyl, phenyl-C 1-6 alkyl, or 5- to 6-membered heteroaryl-C 1-6 alkyl; the R a , R b , R c and R d are unsubstituted or optionally substituted at any position by 1 to 3 of the following substituents selected from halogen, hydroxyl, amino, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-6 alkenyl and C 2-6 alkynyl.
  2. 2 . The compound, the stereoisomer or the pharmaceutically acceptable salt thereof of claim 1 , wherein, the compound satisfies any one of the following conditions: (1) U is N; and (2) R 1 is hydrogen.
  3. 3 . The compound, the stereoisomer or the pharmaceutically acceptable salt thereof of claim 1 , wherein, the compound satisfies any one of the following conditions: (1) R 3 is C 1-6 alkyl, phenyl, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl, 3- to 8-membered heterocycloalkyl-C 1-6 alkyl, 5- to 6-membered heteroaryl-C 1-6 alkyl, —NR b S(O) 2 R a , —S(O) 1-2 R a , —S(O) 2 NR a R b , —S(O)(═NCN)R a or —S(O)(═NR b )R a ; wherein, the C 1-6 alkyl, phenyl, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl, or 3- to 8-membered heterocycloalkyl-C 1-6 alkyl is unsubstituted or optionally substituted at any position by 1 to 3 of the following substituents selected from halogen, —CN, —SR a , —OR a , —C(O)OR a , —C(O)R a , —C(O)NR a R b , —NR a R b , —NR b C(O)R a , —NR b S(O) 2 R a , —S(O) 1-2 R a , —S(O) 2 NR a R b , —S(O)(═NCN)R a and —S(O)(═NR b )R a ; (2) R 3a and R 3b are each independently hydrogen, halogen, cyano, C 1-6 alkyl, halo C 1-6 alkyl or halo C 1-6 alkoxy; (3) R 4a and R 4b are each independently hydrogen or C 1-6 alkyl; (4)R 5 is C 1-6 alkyl, phenyl, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl, 3- to 8-membered heterocycloalkyl-C 1-6 alkyl, 5- to 6-membered heteroaryl-C 1-6 alkyl, —S(O) 1-2 R a , —S(O) 2 NR a R b , —S(O)(═NCN)R a or —S(O)(═NR b )R a ; wherein, the C 1-6 alkyl, phenyl, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl, or 3- to 8-membered heterocycloalkyl-C 1-6 alkyl is unsubstituted or optionally substituted at any position by 1 to 3 of the following substituents selected from halogen, —CN, —SR a , —OR a , —C(O)OR a , —C(O)R a , —C(O)NR a R b , —NR a R b , —NR b C(O)R a , —NR b S(O) 2 R a , —S(O) 1-2 R a , —S(O) 2 NR a R b , —S(O)(═NCN)R a and —S(O)(═NR b )R a ; (5) R 5a and R 5b are each independently hydrogen, C 1-6 alkyl, halo C 1-6 alkyl or C 3-8 cycloalkyl; (6)R 6 and R 7 are each independently 5- to 6-membered heteroaryl; the 5- to 6-membered heteroaryl is unsubstituted or optionally substituted at any position by 1 to 3 of the following substituents selected from halogen, cyano, —R c , —OR c , —NR c R d , —N(CN)R c , —N(OR d )R c , —S(O) 0-2 R c , —C(O)R c , —C(O)OR c , —C(O)NR c R d , —C(NH)NR c R d , —NR d C(O)R c , —NR d C(O)NR c R d , —NR d S(O) 2 R c and —OC(O)R c ; (7) R 7a , R 7b and R 7c are each independently hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl or halo C 1-6 alkoxy; (8)each R a is independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl or 3- to 8-membered heterocycloalkyl; the R a is unsubstituted or optionally substituted at any position by 1 to 3 of the following substituents selected from halogen, hydroxyl, amino, C 1-6 alkoxy, C 1-6 alkylamino, halo C 1-6 alkyl and halo C 1-6 alkoxy; (9) each R b is independently hydrogen or C 1-6 alkyl; (10)each R c is independently hydrogen or C 1-6 alkyl; the C 1-6 alkyl is unsubstituted or optionally substituted at any position by 1 to 3 of the following substituents selected from halogen, hydroxyl, amino, C 1-6 alkoxy, C 1-6 alkylamino, halo C 1-6 alkyl and halo C 1-6 alkoxy; and (11) each R d is independently hydrogen or C 1-6 alkyl.
  4. 4 . The compound, the stereoisomer or the pharmaceutically acceptable salt thereof of claim 1 , wherein R 6 and R 7 are each independently pyrrolyl, pyrazolyl or isoxazolyl; the pyrrolyl, pyrazolyl or isoxazolyl is unsubstituted or optionally substituted at any position by 1 to 3 of the following substituents selected from halogen, cyano, —R c , —OR c , —NR c R d , —N(CN)R c , —N(OR d )R c , —S(O) 0-2 R c , —C(O)R c , —C(O)OR c , —C(O)NR c R d , —C(NH)NR c R d , —NR d C(O)R c , —NR d C(O)NR c R d , —NR d S(O) 2 R c and —OC(O)R c .
  5. 5 . The compound, the stereoisomer or the pharmaceutically acceptable salt thereof of claim 1 , wherein, the compound satisfies any one of the following conditions: (1) in the compound of formula (II), the group and (2) in the compound of formula (III), the group
  6. 6 . The compound, the stereoisomer or the pharmaceutically acceptable salt thereof of claim 5 , wherein, the compound satisfies any one of the following conditions: 1) R 3a , R 3b , R 4a and R 4b are each independently hydrogen; (2) R 7a and R 7b are each independently hydrogen; and (3) R 6 and R 7 are each independently pyrrolyl, pyrazolyl or isoxazolyl.
  7. 7 . The compound, the stereoisomer or the pharmaceutically acceptable salt thereof of claim 1 , wherein, in the compound of formula (II): U 1 and U 2 are C respectively; V is NR 6 ; V 1 is N or CR 7a ; V 2 is N or CR 7b ; U is N; R 6 is pyrrolyl, pyrazolyl or isoxazolyl; the pyrrolyl, pyrazolyl or isoxazolyl is unsubstituted or optionally substituted at any position by 1 to 3 of the following substituents selected from halogen, cyano, —R c , —OR c , —NR c R d , —N(CN)R c , —N(OR d )R c , —S(O) 0-2 R c , —C(O)R c , —C(O)OR c , —C(O)NR c R d , —C(NH)NR c R d , —NR d C(O)R c , —NR d C(O)NR c R d , —NR d S(O) 2 R c and —OC(O)R c ; R 7a and R 7b are each independently hydrogen; R c and R d are each independently hydrogen or C 1-6 alkyl; in the compound of formula (III): U is N; R 7 is pyrrolyl, pyrazolyl or isoxazolyl; the pyrrolyl, pyrazolyl or isoxazolyl is unsubstituted or optionally substituted at any position by 1 to 3 of the following substituents selected from halogen, cyano, —R c , —OR c , —NR c R d , —N(CN)R c , —N(OR d )R c , —S(O) 0-2 R c , —C(O)R c , —C(O)OR c , —C(O)NR c R d , —C(NH)NR c R d , —NR d C(O)R c , —NR d C(O)NR c R d , —NR d S(O) 2 R c and —OC(O)R c ; R 7a , R 7b and R 7c are each independently hydrogen; R c and R d are each independently hydrogen or C 1-6 alkyl.
  8. 8 . The compound, the stereoisomer or the pharmaceutically acceptable salt thereof of claim 1 , wherein, the compound of formula (II) is a compound of formula (IIA), wherein, is a double bond or a single bond; the compound of formula (III) is a compound of formula (IIIA), wherein, is a double bond or a single bond.
  9. 9 . The compound, the stereoisomer or the pharmaceutically acceptable salt thereof of claim 8 , wherein, the compound satisfies any one of the following conditions: (1) X 1 and X 2 are each independently N or CH; and (2) X 1 and X 2 are each independently CH 2 .
  10. 10 . The compound, the stereoisomer or the pharmaceutically acceptable salt thereof of claim 8 , wherein, R 5 is C 1-6 alkyl, phenyl, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl, 3- to 8-membered heterocycloalkyl-C 1-6 alkyl, 5- to 6-membered heteroaryl-C 1-6 alkyl, —S(O) 1-2 R a , —S(O) 2 NR a R b , —S(O)(═NCN)R a or —S(O)(═NR b )R a ; wherein, the C 1-6 alkyl, phenyl, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl, or 3- to 8-membered heterocycloalkyl-C 1-6 alkyl is unsubstituted or optionally substituted at any position by 1 to 3 of the following substituents selected from halogen, —CN, —SR a , —OR a , —C(O)OR a , —C(O)R a , —C(O)NR a R b , —NR a R b , —NR b C(O)R a , —NR b S(O) 2 R a , —S(O) 1-2 R a , —S(O) 2 NR a R b , —S(O)(═NCN)R a and —S(O)(═NR b )R a ; each R a is independently hydrogen or C 1-6 alkyl; the C 1-6 alkyl is unsubstituted or optionally substituted at any position by 1 to 3 of the following substituents selected from halogen, hydroxyl, amino, C 1-6 alkoxy, C 1-6 alkylamino, halo C 1-6 alkyl and halo C 1-6 alkoxy; each R b is independently hydrogen or C 1-6 alkyl.
  11. 11 . The compound, the stereoisomer or the pharmaceutically acceptable salt thereof of claim 8 , wherein, in the compound of formula (IIA): V 1 and V 2 are each independently N or CH.
  12. 12 . The compound, the stereoisomer or the pharmaceutically acceptable salt thereof of claim 8 , wherein, in the compound of formula (IIIA): V 1 , V 2 and V 3 are each independently N or CH.
  13. 13 . The compound, the stereoisomer or the pharmaceutically acceptable salt thereof of claim 1 , which is any one of the following structures: or a pharmaceutically acceptable salt thereof.
  14. 14 . A pharmaceutical composition, comprising a therapeutically effective amount of an active component and a pharmaceutically acceptable excipient; the active component comprises the compound, the stereoisomer or the pharmaceutically acceptable salt thereof of claim 1 .
  15. 15 . A method for inhibiting ATR in a subject in need thereof, comprising: administering the compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof of claim 1 to the subject.
  16. 16 . A method for treating cancer in a subject in need thereof, comprising: administering the compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof of claim 1 to the subject; wherein the cancer is selected from colon cancer, ovarian cancer, lung cancer, prostate cancer, lymphoblastic leukemia and non-Hodgkin's lymphoma.
  17. 17 . A method for treating cancer in a subject in need thereof, comprising: administering the pharmaceutical composition of claim 14 to the subject; wherein the cancer is selected from colon cancer, ovarian cancer, lung cancer, prostate cancer, lymphoblastic leukemia and non-Hodgkin's lymphoma.
  18. 18 . A method for treating cancer in a subject in need thereof, comprising: administering the compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof of claim 1 to the subject in combination with one or more other kinds of therapeutic agents or treatment methods for treating cancer; wherein the cancer is selected from colon cancer, ovarian cancer, lung cancer, prostate cancer, lymphoblastic leukemia and non-Hodgkin's lymphoma.
  19. 19 . A method for treating cancer in a subject in need thereof, comprising: administering the compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof of claim 1 to the subject; wherein the cancer is selected from colon cancer and diffuse large B-Cell lymphoma.
  20. 20 . A method for treating cancer in a subject in need thereof, comprising: administering the compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof of claim 1 to the subject in combination with one or more other kinds of therapeutic agents or treatment methods for treating cancer; wherein the cancer is selected from colon cancer and diffuse large B-Cell lymphoma.

Description

The present application is a National Stage of International Application No. PCT/CN2021/123992, filed on Oct. 15, 2021, which claims the priorities of the Chinese Patent Application NO. CN202011107416.5 filed on Oct. 16, 2020, the Chinese Patent Application NO. CN202110097827.9 filed on Jan. 25, 2021, and the Chinese Patent Application NO. CN202110929213.2 filed on Aug. 13, 2021. The contents of the above Chinese patent applications are incorporated herein by reference in their entireties. TECHNICAL FIELD The present disclosure relates to a triheterocyclic derivative, a pharmaceutical composition thereof and a use thereof as a therapeutic agent, especially as a cancer therapeutic agent. BACKGROUND Human cells suffer from hundreds of DNA damages every day. The causes of DNA damage include normal cell functions (such as oxidative metabolites), DNA metabolites (such as spontaneous errors during DNA transcription and replication), and environmental factors (such as ultraviolet light, ionizing radiation, genotoxins), etc. If the above-mentioned damages can not be repaired correctly, it will lead the loss of the activity of cells or organisms. The accumulation of DNA damages can also affect the stability and integrity of the genome and promote the formation of cancer. DNA damages may occur through oxidation or alkylation of DNA bases, DNA base mismatches and dimerization, breaks and discontinuities in the DNA backbone, intra-strand/inter-strand DNA cross-links, and general changes in DNA structure. To ensure the stability and integrity of the cellular genome, cells have a complex set of DNA damage response (DDR) mechanisms that can recognize and deal with these specific types of DNA damage in specific parts of the cell cycle to maintain genomic integrity and cell viability. It was found that multiple DDR mechanisms exist in healthy cells and these repair mechanisms can compensate each other during DNA repair. (Jackson S P, Nature, 2009, 461(7267), 1071-1078). However, many cancer cells have defects in multiple DNA repair pathways and therefore exhibit a greater dependence on undamaged DNA repair pathways. Ataxia telangiectasia mutated and Rad3-related kinase (ATR, also known as FRAP-Related Protein 1; FRP1; MEC1; SCK1; SECKL1) is a member of the phosphatidylinositol-3 kinase (PIKK) protein family, it is an important kinase that can activate cell responses after DNA damage, thereby arresting cell cycle progression, stabilizing replication forks and repairing DNA, thereby avoiding apoptosis (Cimprich K. A., Nature Rev. Mol. Cell Biol., 2008, 9:616-627). ATR acts by stabilizing stalled replication forks, regulating activation of cell cycle checkpoints and DNA damage repair. After ATR is activated, it will activate three signal transduction pathways to block cell cycle progression, promote DNA repair, and stabilize replication forks by regulating its downstream regulatory factors (mainly including Chk1, WRN, and FANCI). Although the presence of RPA-coated single-stranded DNA is a common feature of ATR activation, in some cases ATR can also be activated without uncoupling of DNA helicase and DNA polymerase, e.g., by UV radiation, platinum chemotherapy or alkylating agent, etc. Since DNA repair in tumor cells may be defective due to the presence of multiple mutations, resulting in a greater dependence on undamaged DNA repair pathways. Therefore, the theory of synthetic lethality can be used to kill specific tumor cells while preserving healthy cells. Current cancer treatments, including chemotherapy and ionizing radiation, can induce DNA damage and replication fork arrest, thereby activating cell cycle checkpoints and leading to cell cycle arrest. This response mechanism is an important mechanism that helps cancer cells survive during treatment. Broken double-strand DNA or replication stress can rapidly activate ATR, and the corresponding ATR can initiate a series of downstream targets such as Chk1 (ATR substrate), p53, DNA topoisomerase 2 binding protein (TopBP1), thereby leading to DNA repair and cell cycle arrest. Because the ATR gene rarely mutates, it is easily activated during cancer chemotherapy. In addition, several synthetic lethal interactions can be produced by inhibiting ATR, especially interactions with the ATM/p53 pathway. p53 is the most common tumor suppressor gene mutation, DNA repair of cells with ATM/p53 gene deficiency or mutation are more dependent on the activation of ATR (Reaper, P. M., Nat. Chem. Biol., 2011, 7, 428-430). Studies have shown that the loss of specific DNA repair proteins, such as X-ray cross-complementary repair gene 1, mismatch excision cross-complementary repair gene 1, can also lead to tumor cells being more sensitive to ATR inhibition (Sultana R, PLoS One, 2013, 8(2): e57098). In addition, hypoxic tumor cells may cause replication stress, making them more sensitive to ATR inhibition, and by inhibiting ATR, the sensitivity of tumor cells to ionizing radiation and chemotherapy c