Antitumor pharmaceutical composition for combination therapy

Abstract

The present application relates to an antitumor pharmaceutical composition for combination therapy, comprising (a) a Topo I inhibitor or a pharmaceutically acceptable salt, prodrug, hydrate, solvate or isotopically substituted analog thereof; and (b) a CHK1 inhibitor or a pharmaceutically acceptable salt, prodrug, hydrate, solvate or isotopically substituted analog thereof, or an ATR inhibitor or a pharmaceutically acceptable salt, prodrug, hydrate, solvate or isotopically substituted analog thereof, or a PARP inhibitor or a pharmaceutically acceptable salt, prodrug, hydrate, solvate or isotopically substituted analog thereof.

Description

Technical Field

[0001] This application relates to the field of medicinal chemistry, and more specifically to antitumor drug compositions for combination therapy. Background Technology

[0002] DNA is a relatively stable organic molecule, but it is still subject to constant attacks from various exogenous stresses (such as ultraviolet radiation, ionizing radiation, and chemical exposure) and endogenous factors (such as replication errors, cellular metabolism, and oxidative stress), eventually leading to single-strand DNA breaks (SSBs) or double-strand DNA breaks (DSBs). Therefore, cells have evolved a complex biochemical pathway system to deal with this threat, collectively known as the DNA-damage response (DDR), to prevent harmful mutations from being passed on.

[0003] Tumor cells are known for their rapid division rate, which typically exceeds that of normal cells. Given the significant differences between normal and tumor cells in their DNA repair mechanisms, drug intervention can disrupt the cell cycle and DNA repair mechanisms of tumor cells. These cells may then be unable to effectively repair the damage, ultimately leading to tumor cell death.

[0004] Human DNA topoisomerases, including DNA topoisomerase 1 (Topo I) and topoisomerase 2 (Topo II), are widely present in human cells and play important roles in key cellular processes such as DNA replication, transcription, and chromatin remodeling. Topo I inhibitors, as an important class of anti-tumor drugs, exert their anti-tumor activity by stabilizing the Topo I-DNA covalent complex (TopoIcc) and blocking the DNA ligation step. However, tumor cells easily develop Topo I inhibitor resistance by activating repair and checkpoint response pathways to mitigate the tumor-killing effect of Topo I inhibitors. Activated response pathways include DNA single-strand break repair and double-strand repair-related pathways, with targets including, but not limited to, CHK1, ATR, and PARP.

[0005] The pathogenesis of tumors is complex, and there are numerous drugs available for treating them, but many suffer from drawbacks such as significant side effects and the tendency for patients to develop drug resistance. The inhibitory effect of single-agent therapy is no longer sufficient to meet stringent treatment requirements. Combinations of drugs with different mechanisms of action are needed to overcome drug resistance, achieve earlier and deeper disease remission, and prolong remission time and patient survival. Actively exploring different forms of combination therapy is an inevitable direction for anti-tumor drug development. Summary of the Invention

[0006] To address the shortcomings of the prior art, the present invention aims to provide a combination of Topo I inhibitors or their pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically substituted analogs with CHK1 inhibitors, ATR inhibitors, PARP inhibitors or their pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically substituted analogs as an antitumor drug. The advantage lies in the synergistic effect of Topo I inhibitors or their pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically substituted analogs with CHK1 inhibitors, ATR inhibitors, PARP inhibitors or their pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically substituted analogs, achieving an antitumor effect superior to single-drug therapy and exhibiting a significant effect on tumor volume inhibition.

[0007] In one aspect, the present invention provides a pharmaceutical composition comprising:

[0008] (a) Topo I inhibitors or their pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically substituted analogs, and

[0009] (b) CHK1 inhibitors or their pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically substituted analogs, or

[0010] ATR inhibitors or their pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically substituted analogs, or

[0011] PARP inhibitors or their pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically substituted analogs thereof.

[0012] In some embodiments, the Topo I inhibitor or its pharmaceutical salt, prodrug, hydrate, solvate, or isotopically substituted analogue may be selected from the type I topoisomerase inhibitors disclosed in PCT / CN2024 / 123915 and PCT / CN2024 / 123886.

[0013] In some implementations, Topo I inhibitors have the following structure:

[0014]

[0015] in,

[0016] Y is selected from S, O, and -CR. 10a R 10b or -NR 10a , where R 10a and R 10b Independently selected from hydrogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0017] Z is selected from S, O, and -CR. 11a R11b or -NR 11a , where R 11a and R 11b Independently selected from hydrogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0018] n is 0, 1, 2, or 3; m is 0, 1, 2, or 3;

[0019] X 1 Selected from N or C(R) 1 ), where R 1 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclic, -OR 1a -SR 1a -NR 1a R 1b -COR 1a -SOR 1a -SO2R 1a -COOR 1a -CONR 1a R 1b -NR 1a COR 1b -OCOR 1a -SONR 1a R 1b -SO2NR 1a R 1b -NR 1a SOR 1b -NR 1a SO2R 1b and -Si(R 1a (R) 1b (R) 1c ), where R 1a R 1b and R 1c Independently selected from hydrogen, deuterium, -Boc, -Cbz, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

[0020] X 2 Selected from N or C(R) 2 ), where R 2 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclic, -OR 2a -SR 2a -NR 2aR 2b -COR 2a -SOR 2a -SO2R 2a -COOR 2a -CONR 2a R 2b -NR 2a COR 2b -OCOR 2a -SONR 2a R 2b -SO2NR 2a R 2b -NR 2a SOR 2b -NR 2a SO2R 2b and -Si(R 2a (R) 2b (R) 2c ), where R 2a R 2b and R 2c Independently selected from hydrogen, deuterium, -Boc, -Cbz, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

[0021] Or R 1 and R 2 Together with the atoms they are attached to, they form cyclic structures with optional substitutions;

[0022] X 3 Selected from N or C(R) 3 ), where R 3 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclic, -OR 3a -SR 3a -NR 3a R 3b -COR 3a -SOR 3a -SO2R 3a -COOR 3a -CONR 3a R 3b -NR 3a COR 3b -OCOR 3a -SONR 3a R 3b -SO2NR 3a R 3b -NR3a SOR 3b -NR 3a SO2R 3b and -Si(R 3a (R) 3b (R) 3c ), where R 3a R 3b and R 3c Independently selected from hydrogen, deuterium, -Boc, -Cbz, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

[0023] Or R 2 and R 3 Together with the atoms they are attached to, they form cyclic structures with optional substitutions;

[0024] X 4 Selected from N or C(R) 4 ), where R 4 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclic, -OR 4a -SR 4a -NR 4a R 4b -COR 4a -SOR 4a -SO2R 4a -COOR 4a -CONR 4a R 4b -NR 4a COR 4b -OCOR 4a -SONR 4a R 4b -SO2NR 4a R 4b -NR 4a SOR 4b -NR 4a SO2R 4b and -Si(R 4a (R) 4b (R) 4c ), where R 4a R 4b and R 4c Independently selected from hydrogen, deuterium, -Boc, -Cbz, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

[0025] Or R 3 and R 4 Together with the atoms they are attached to, they form cyclic structures with optional substitutions;

[0026] R 5 Selected from hydrogen, deuterium, hydroxyl, amino, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, -OR 5a -SR 5a -NR 5a R 5b -COR 5a -SOR 5a -SO2R 5a -COOR 5a -CONR 5a R 5b -NR 5a COR 5b -OCOR 5a -SONR 5a R 5b -SO2NR 5a R 5b -NR 5a SOR 5b -NR 5a SO2R 5b and -Si(R 5a (R) 5b (R) 5c ), where R 5a R 5b and R 5c Independently selected from hydrogen, deuterium, -Boc, -Cbz, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

[0027] R 6 and R 6’ Independently selected from hydrogen, deuterium, hydroxyl, amino, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclic, -OR 6a -SR 6a -NR 6a R 6b -COR 6a -SOR 6a -SO2R 6a -COOR 6a -CONR 6a R 6b -NR 6b COR6a -OCOR 6a -SONR 6a R 6b -SO2NR 6a R 6b -NR 6a SOR 6b -NR 6a SO2R 6b and -Si(R 6a (R) 6b (R) 6c ), where R 6a R 6b and R 6c Independently selected from hydrogen, deuterium, -Boc, -Cbz, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

[0028] R 7 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclic, -OR 7a -SR 7a -NR 7a R 7b -COR 7a -SOR 7a -SO2R 7a -COOR 7a -CONR 7a R 7b -NR 7a COR 7b -OCOR 7a -SONR 7a R 7b -SO2NR 7a R 7b -NR 7a SOR 7b -NR 7a SO2R 7b and -Si(R 7a (R) 7b (R) 7c ), where R 7a R 7b and R 7c Independently selected from hydrogen, deuterium, -Boc, -Cbz, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

[0029] R8 Selected from hydrogen, deuterium, halogens, and -OR 8a -OCOR 8a -SR 8a -OR 8a -SR 8b or -NR 8a R 8b , where R 8a and R 8b Independently selected from hydrogen, deuterium, optionally substituted alkyl groups and optionally substituted cycloalkyl groups;

[0030] R 9 Selected from -CH2R 9a -CF2R 9a -CHFR 9a -CD2R 9a -CDHR 9a -CDFR 9a -OR 9a -SR 9a and -NR 9a R 9b , where R 9a and R 9b It is independently selected from hydrogen, deuterium, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl.

[0031] In some implementations, Topo I inhibitors have the following structure:

[0032] (II)

[0033] in,

[0034] Y is selected from S, O, and -CR. 10a R 10b or -NR 10a , where R 10a and R 10b Independently selected from hydrogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0035] Z is selected from S, O, and -CR. 11a R 11b or -NR 11a , where R 11a and R 11b Independently selected from hydrogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0036] n is 0, 1, 2, or 3;

[0037] X 1 Selected from N or C(R)1 ), where R 1 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclic, -OR 1a -SR 1a -NR 1a R 1b -COR 1a -SOR 1a -SO2R 1a -COOR 1a -CONR 1a R 1b -NR 1a COR 1b -OCOR 1a -SONR 1a R 1b -SO2NR 1a R 1b -NR 1a SOR 1b -NR 1a SO2R 1b and -Si(R 1a (R) 1b (R) 1c ), where R 1a R 1b and R 1c Independently selected from hydrogen, deuterium, -Boc, -Cbz, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

[0038] X 2 Selected from N or C(R) 2 ), where R 2 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclic, -OR 2a -SR 2a -NR 2a R 2b -COR 2a -SOR 2a -SO2R 2a -COOR 2a -CONR 2a R 2b -NR 2a COR 2b -OCOR 2a -SONR 2aR 2b -SO2NR 2a R 2b -NR 2a SOR 2b -NR 2a SO2R 2b and -Si(R 2a (R) 2b (R) 2c ), where R 2a R 2b and R 2c Independently selected from hydrogen, deuterium, -Boc, -Cbz, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

[0039] Or R 1 and R 2 Together with the atoms they are attached to, they form cyclic structures with optional substitutions;

[0040] X 3 Selected from N or C(R) 3 ), where R 3 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclic, -OR 3a -SR 3a -NR 3a R 3b -COR 3a -SOR 3a -SO2R 3a -COOR 3a -CONR 3a R 3b -NR 3a COR 3b -OCOR 3a -SONR 3a R 3b -SO2NR 3a R 3b -NR 3a SOR 3b -NR 3a SO2R 3b and -Si(R 3a (R) 3b (R) 3c ), where R 3a R 3b and R 3cIndependently selected from hydrogen, deuterium, -Boc, -Cbz, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

[0041] Or R 2 and R 3 Together with the atoms they are attached to, they form cyclic structures with optional substitutions;

[0042] X 4 Selected from N or C(R) 4 ), where R 4 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclic, -OR 4a -SR 4a -NR 4a R 4b -COR 4a -SOR 4a -SO2R 4a -COOR 4a -CONR 4a R 4b -NR 4a COR 4b -OCOR 4a -SONR 4a R 4b -SO2NR 4a R 4b -NR 4a SOR 4b -NR 4a SO2R 4b and -Si(R 4a (R) 4b (R) 4c ), where R 4a R 4b and R 4c Independently selected from hydrogen, deuterium, -Boc, -Cbz, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

[0043] Or R 3 and R 4 Together with the atoms they are attached to, they form cyclic structures with optional substitutions;

[0044] R 5Selected from hydrogen, deuterium, hydroxyl, amino, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, -OR 5a -SR 5a -NR 5a R 5b -COR 5a -SOR 5a -SO2R 5a -COOR 5a -CONR 5a R 5b -NR 5a COR 5b -OCOR 5a -SONR 5a R 5b -SO2NR 5a R 5b -NR 5a SOR 5b -NR 5a SO2R 5b and -Si(R 5a (R) 5b (R) 5c ), where R 5a R 5b and R 5c Independently selected from hydrogen, deuterium, -Boc, -Cbz, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

[0045] R 4 and R 5 Together with the atoms they are attached to, they form cyclic structures with optional substitutions;

[0046] R 6 and R 6’ Independently selected from hydrogen, deuterium, hydroxyl, amino, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclic, -OR 6a -SR 6a -NR 6a R 6b -COR 6a -SOR 6a -SO2R 6a -COOR 6a -CONR 6a R 6b -NR 6b COR 6a -OCOR6a -SONR 6a R 6b -SO2NR 6a R 6b -NR 6a SOR 6b -NR 6a SO2R 6b and -Si(R 6a (R) 6b (R) 6c ), where R 6a R 6b and R 6c Independently selected from hydrogen, deuterium, -Boc, -Cbz, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

[0047] R 7 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclic, -OR 7a -SR 7a -NR 7a R 7b -COR 7a -SOR 7a -SO2R 7a -COOR 7a -CONR 7a R 7b -NR 7a COR 7b -OCOR 7a -SONR 7a R 7b -SO2NR 7a R 7b -NR 7a SOR 7b -NR 7a SO2R 7b and -Si(R 7a (R) 7b (R) 7c ), where R 7a R 7b and R 7c Independently selected from hydrogen, deuterium, -Boc, -Cbz, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

[0048] R 8Selected from hydrogen, deuterium, halogens, and -OR 8a -OCOR 8a -SR 8a -OR 8a -SR 8b or -NR 8a R 8b , where R 8a and R 8b Independently selected from hydrogen, deuterium, optionally substituted alkyl groups and optionally substituted cycloalkyl groups;

[0049] R 9 Selected from -CH2R 9a -CF2R 9a -CHFR 9a -CD2R 9a -CDHR 9a -CDFR 9a -OR 9a -SR 9a and -NR 9a R 9b , where R 9a and R 9b It is independently selected from hydrogen, deuterium, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl.

[0050] In some implementations, Topo I inhibitors have the following structure:

[0051]

[0052] (IIIa) (IIIb) (IIIc)

[0053] in,

[0054] Y is selected from S, O, and -CR. 10a R 10b or -NR 10a , where R 10a and R 10b Independently selected from hydrogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0055] Z is selected from S and O;

[0056] n is 0, 1, or 2; m is 1 or 2;

[0057] X 1 Selected from N or C(R) 1 ), where R 1Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclic, -OR 1a -SR 1a -NR 1a R 1b -COR 1a -SOR 1a -SO2R 1a -COOR 1a -CONR 1a R 1b -NR 1a COR 1b -OCOR 1a -SONR 1a R 1b -SO2NR 1a R 1b -NR 1a SOR 1b -NR 1a SO2R 1b and -Si(R 1a (R) 1b (R) 1c ), where R 1a R 1b and R 1c Independently selected from hydrogen, deuterium, -Boc, -Cbz, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

[0058] X 2 Selected from N or C(R) 2 ), where R 2 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclic, -OR 2a -SR 2a -NR 2a R 2b -COR 2a -SOR 2a -SO2R 2a -COOR 2a -CONR 2a R 2b -NR 2a COR 2b -OCOR 2a -SONR 2a R 2b -SO2NR2a R 2b -NR 2a SOR 2b -NR 2a SO2R 2b and -Si(R 2a (R) 2b (R) 2c ), where R 2a R 2b and R 2c Independently selected from hydrogen, deuterium, -Boc, -Cbz, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

[0059] Or R 1 and R 2 Together with the atoms they are attached to, they form cyclic structures with optional substitutions;

[0060] X 3 Selected from N or C(R) 3 ), where R 3 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclic, -OR 3a -SR 3a -NR 3a R 3b -COR 3a -SOR 3a -SO2R 3a -COOR 3a -CONR 3a R 3b -NR 3a COR 3b -OCOR 3a -SONR 3a R 3b -SO2NR 3a R 3b -NR 3a SOR 3b -NR 3a SO2R 3b and -Si(R 3a (R) 3b (R) 3c ), where R 3a R 3b and R 3cIndependently selected from hydrogen, deuterium, -Boc, -Cbz, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

[0061] Or R 2 and R 3 Together with the atoms they are attached to, they form cyclic structures with optional substitutions;

[0062] X 4 Selected from N or C(R) 4 ), where R 4 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted partially unsaturated carbocyclic, optionally substituted aryl, optionally substituted heteroaryl, -OR 4a -SR 4a -NR 4a R 4b -COR 4a -SOR 4a -SO2R 4a -COOR 4a -CONR 4a R 4b -NR 4a COR 4b -OCOR 4a -SONR 4a R 4b -SO2NR 4a R 4b -NR 4a SOR 4b -NR 4a SO2R 4b and -Si(R 4a (R) 4b (R) 4c ), where R 4a R 4b and R 4c Independently selected from hydrogen, deuterium, -Boc, -Cbz, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted partially unsaturated carbocyclic, optionally substituted aryl and optionally substituted heteroaryl.

[0063] Or R 3 and R 4 Together with the atoms they are attached to, they form cyclic structures with optional substitutions;

[0064] R 5 and R6 Independently selected from hydrogen, deuterium, hydroxyl, amino, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclic, -OR 6a -SR 6a -NR 6a R 6b -COR 6a -SOR 6a -SO2R 6a -COOR 6a -CONR 6a R 6b -NR 6b COR 6a -OCOR 6a -SONR 6a R 6b -SO2NR 6a R 6b -NR 6a SOR 6b -NR 6a SO2R 6b and -Si(R 6a (R) 6b (R) 6c ), where R 6a R 6b and R 6c Independently selected from hydrogen, deuterium, -Boc, -Cbz, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

[0065] R 7 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclic, -OR 7a -SR 7a -NR 7a R 7b -COR 7a -SOR 7a -SO2R 7a -COOR 7a -CONR 7a R 7b -NR 7a COR 7b -OCOR 7a -SONR 7a R 7b -SO2NR 7a R 7b -NR 7aSOR 7b -NR 7a SO2R 7b and -Si(R 7a (R) 7b (R) 7c ), where R 7a R 7b and R 7c Independently selected from hydrogen, deuterium, -Boc, -Cbz, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

[0066] R 8 Selected from hydrogen, deuterium, halogens, and -OR 8a -OCOR 8a -SR 8a -OR 8a -SR 8b or -NR 8a R 8b , where R 8a and R 8b Independently selected from hydrogen, deuterium, optionally substituted alkyl groups and optionally substituted cycloalkyl groups;

[0067] R 9 Selected from -CH2R 9a -CF2R 9a -CHFR 9a -CD2R 9a -CDHR 9a -CDFR 9a -OR 9a -SR 9a and -NR 9a R 9b , where R 9a and R 9b Independently selected from hydrogen, deuterium, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted ynyl and optionally substituted cycloalkyl;

[0068] R 10 Selected from hydrogen, deuterium, F, hydroxyl, amino, and -OCH3;

[0069] R 11 and R 12 It is independently selected from hydrogen, deuterium, and F.

[0070] In some implementations, Topo I inhibitors have the following structure:

[0071]

[0072] (I)(III).

[0073] In some implementations, the Topo I inhibitor is selected from the following compounds:

[0074] .

[0075] In some implementations, the CHK1 inhibitor is selected from: Rabusertib (LY2603618), Prexasertib (LY2606368), CCT245737, SCH900776 (MK-8776), BEBT-260, XCCS605B, AZD-7762, Gartisertib (VX-803), PF477736, GDC-0575, LY2880070, SAR-020106, PD-321852, SB-218078.

[0076] In some implementations, the CHK1 inhibitor is Rabusertib.

[0077] In some implementations, the ATR inhibitor is selected from: Ceralasertib (AZD6738), VE-821, Elimusertib (BAY-1895344), Berzosertib (VE-822), AD1058, Camonsertib (RP-3500), M-1774, ATRN-119 (Atrin Pharmaceuticals), RP-3500, ART-0380, and IMP9064.

[0078] In some implementations, the ATR inhibitor is selected from limusertib (BAY-1895344) and VE-821.

[0079] In some implementations, the PARP inhibitor is selected from: Veliparib (ABT-888), Rucaparib (AG014699), Olaparib, Niraparib, Fluzoparib, Pamiparib, Talazoparib, Senaparib, TQB3823, Saruparib, and AZD5305.

[0080] In some implementations, the PARP inhibitor is selected from Veliparib (ABT-888), Rucaparib (AG014699), or Olaparib.

[0081] In one aspect, the present invention also relates to a pharmaceutical composition comprising: (a) a Topo I inhibitor or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, or isotopically substituted analogue thereof; and (b) a CHK1 inhibitor, ATR inhibitor, PARP inhibitor, TDP1 inhibitor, ATM inhibitor, WEE1 inhibitor, MAT2A inhibitor, PRMT5 inhibitor, PI3K inhibitor, CDK4 / 6 inhibitor, PKMYT1 inhibitor, mTOR inhibitor, MYC inhibitor or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, or isotopically substituted analogue thereof; and its use as an antitumor drug.

[0082] In some embodiments, the pharmaceutical compositions of the present invention may also contain additional medicaments for the prevention and / or treatment of cancer or tumors (such as small molecules, peptides, nucleic acids, antibodies, and antibody-drug conjugates).

[0083] In some implementations, the drug for the prevention and / or treatment of cancer or tumors is selected from antibody-drug conjugates, and representative examples may include, but are not limited to, trastuzumab emtansine, brentuximab vedotin, brentuximab vedotin (BV), disitamab vedotin, sacituzumab govitecan, trastuzumab deruxtecan, or any combination thereof.

[0084] In another aspect, the present invention also provides a method for treating a disease, the method comprising administering the pharmaceutical composition of the present invention to a patient in need.

[0085] In another aspect, the present invention also provides the use of the above-described pharmaceutical composition in the preparation of a medicament for treating diseases.

[0086] In some implementations, the disease is selected from cancer or tumors. Representative examples of cancers and tumors include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer, familial adenomatous polyposis, colorectal cancer, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, kidney cancer, renal parenchymal carcinoma, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary tract cancer, melanoma, and brain tumors (such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumors). Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, leukemia, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmacytoma.

[0087] In some implementations, cancer and tumor are selected from intermediate and advanced tumors, relapsed and refractory tumors, tumors that have failed chemotherapy and / or relapsed, tumors that have failed radiotherapy and / or relapsed, tumors that have failed targeted therapy and / or relapsed, and tumors that have failed immunotherapy and / or relapsed.

[0088] As the most preferred technical solution of this invention, the combination therapy involves combining a Topo I inhibitor or its pharmaceutical salt, prodrug, hydrate, solvate, or isotopically substituted analogue with a CHK1 inhibitor, ATR inhibitor, PARP inhibitor or its pharmaceutical salt, prodrug, hydrate, solvate, or isotopically substituted analogue, which can inhibit the activity of many viruses with carcinogenic effects. Furthermore, as nucleotide analogues, the combination therapy exhibits stronger inhibition of cancer cell growth and active proliferation compared to monotherapy, penetrating the synthesized nucleic acid chain and causing chain termination, thereby inducing apoptosis of tumor cells. Simultaneously, the combination therapy has high biocompatibility, stronger antitumor activity than monotherapy, overcomes drug resistance to single drugs, and provides new strategies and ideas for cancer treatment. Detailed Implementation

[0089] definition

[0090] As used herein, the term "combination" refers to the administration of at least one dose of a Topo I inhibitor or its pharmaceutical salt, prodrug, hydrate, solvate, or isotopically substituted analogue thereof, along with at least one dose of a CHK1 inhibitor, ATR inhibitor, PARP inhibitor or its pharmaceutical salt, prodrug, hydrate, solvate, or isotopically substituted analogue thereof, and / or at least one dose of a PD-1 blocker, PD-L1 blocker, or CTLA-4 blocker, wherein two or three substances exhibit pharmacological activity. The time period may be within a dosing cycle, preferably within 4 weeks, 3 weeks, 2 weeks, 1 week, or less than 24 hours, more preferably within 12 hours. A Topo I inhibitor or its pharmaceutical salt, prodrug, hydrate, solvate, or isotopically substituted analogue, along with a CHK1 inhibitor, ATR inhibitor, PARP inhibitor or its pharmaceutical salt, prodrug, hydrate, solvate, or isotopically substituted analogue, and / or a PD-1 blocker, PD-L1 blocker, or CTLA-4 blocker, may be administered simultaneously or sequentially. This duration includes treatment in which a Topo I inhibitor or its pharmaceutical salt, prodrug, hydrate, solvate, or isotopically substituted analogue, along with a CHK1 inhibitor, ATR inhibitor, PARP inhibitor or its pharmaceutical salt, prodrug, hydrate, solvate, or isotopically substituted analogue, and / or a PD-1 blocker, PD-L1 blocker, or CTLA-4 blocker, is administered via the same or different routes of administration. The combined administration methods of this invention are selected from simultaneous administration, independently formulated and co-administered, or independently formulated and sequentially administered.

[0091] As used herein, the term "medicinal salt" refers to a derivative of the disclosed compound, wherein the parent compound is modified by converting an existing acid or base portion into its salt form. Examples of medicinal salts include, but are not limited to, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid, and salts with organic carboxylic acids and sulfonic acids such as acetic acid, trifluoroacetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, and naphthalenedisulfonic acid; or salts with conventional bases, such as alkali metal salts (e.g., sodium and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), and ammonium salts derived from ammonia and organic amines (e.g., diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabiethylamine, methylpiperidine, L-arginine, creatine, choline, L-lysine, ethylenediamine, N,N-dibenzylethylenediamine, ethanolamine, meglumine, and tromethamine).

[0092] As used herein, the term "prodrug" refers to a compound that undergoes biotransformation before exhibiting its pharmacological effects. Prodrugs can be prepared using well-known methods, such as those described in Burgers Medicinal Chemistry and Drug Development (1995) 172-178, 949-982 (Manfred E. Wolff).

[0093] As used herein, the term "solvent" refers to a complex formed by coordination with a solvent molecule. When the solvent molecule is water, the solvate is a hydrate.

[0094] Compounds as described herein can be isotopically substituted, that is, one or more atoms therein are replaced by atoms with different atomic masses or mass numbers. Such isotopically substituted compounds are considered to be within the scope of this invention. Examples of isotopes that can be incorporated into compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, etc. 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I.

[0095] Example

[0096] The invention is illustrated below by way of the following non-limiting embodiments.

[0097] Example 1. Cell proliferation inhibitory activity of the compound combination was determined by CTG (CELLTITER-GLO) luminescence assay.

[0098] Assay Principle: The CellTiter-Glo™ luciferase kit from Promega was used. This method uses luciferase as the detection substance. Luciferase requires ATP during luminescence, and metabolically active cells generate ATP through respiration and other life processes. An equal volume of CellTiter-Glo™ reagent was added to the cell culture medium, and the luminescence value was measured. The light signal is directly proportional to the amount of ATP in the system, and ATP is positively correlated with the number of viable cells; therefore, it is used to detect the inhibitory effect of compounds on cell proliferation activity. This combination experiment was designed to detect whether compounds with different mechanisms of action have an additive or synergistic effect when used in combination.

[0099] Experimental Methods: Complete culture media were prepared according to different cell requirements. Cells were revived (ATCC), passaged approximately two times, and selected from well-growing cell lines. Cells in the logarithmic growth phase were collected and counted. Cells were resuspended to an appropriate concentration and seeded into 384-well plates, with 50 μL of cell suspension added to each well at a density of 600 cells / well. The plates were incubated overnight at 37 °C with 5% CO2. The next day, the test compound was prepared as a stock solution using DMSO. The compound was added using HPD 300e according to a predetermined arrangement (9*9 matrix). The final drug concentration started at 10 µmol, with 5-fold dilutions, resulting in 9 concentrations, the lowest being 0.3 nmol. After centrifugation at 1000 rpm for 1 minute, the mixture was incubated at 37 °C with 5% CO2 for 72 hours. 25 µL / well of CellTiter Glo was added to terminate the reaction. The mixture was incubated at room temperature in the dark for 30 minutes, gently shaken, and then analyzed using Envision. Read the luminescence values ​​and calculate the inhibition rate using the formula: Cell Growth Inhibition Rate % = (1 - As / Ac) × 100. Where As represents the sample (cells + CTG + test compound), and Ac represents the normal-growing cell control (cells + CTG + DMSO). Enter the inhibition rate Inh% (Y) corresponding to each concentration (X) in Excel. Use the XLfit plugin to calculate the half-maximum inhibitory concentration (IC50) of each compound using the built-in four-parameter fitting formula Y = Bottom + (Top - Bottom) / (1 + (IC50 / X) * HillSlope). Calculate the synergistic score (Bliss) using SynergyFinder. A score less than -10 indicates an antagonistic interaction between the two drugs, a score between -10 and 10 indicates an additive interaction, and a score greater than 10 indicates a synergistic interaction. The most synergistic region score refers to the highest synergistic score fitted by SynergyFinder among multiple concentration combinations of the two drugs.

[0100] Table 1

[0101]

[0102] Table 2. Compound concentrations corresponding to the highest synergistic fractions

[0103]

[0104] The results showed that Topo I inhibitors (compounds 2, 3, 5, and 6) exhibited synergistic effects in most test cell lines when combined with CHK1 inhibitors (Rabusertib), ATR inhibitors (Elimusertib, VE-821), and PARP inhibitors (Veliparib, olaparib, and rucaparib), respectively.

Claims

1. A pharmaceutical composition comprising: (a) Topo I inhibitors or their pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically substituted analogs, and (b) CHK1 inhibitors or their pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically substituted analogs, or ATR inhibitors or their pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically substituted analogs, or PARP inhibitors or their pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically substituted analogs thereof.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition further comprises an immunotherapeutic agent selected from PD-1 blockers, PD-L1 blockers, or CTLA-4 blockers.

3. The pharmaceutical composition according to claim 1, wherein the Topo I inhibitor is selected from the following compounds: 。 4. The pharmaceutical composition according to claim 1, wherein the CHK1 inhibitor is selected from: Rabusertib (LY2603618), Prexasertib (LY2606368), CCT245737, SCH900776 (MK-8776), BEBT-260, XCCS605B, AZD-7762, Gartisertib (VX-803), PF477736, GDC-0575, LY2880070, SAR-020106, PD-321852, SB-218078.

5. The pharmaceutical composition according to claim 1, wherein the ATR inhibitor is selected from: Ceralasertib (AZD6738), VE-821, Elimusertib (BAY-1895344), Berzosertib (VE-822), AD1058, Camonsertib (RP-3500), M-1774, ATRN-119 (Atrin Pharmaceuticals), RP-3500, ART-0380, and IMP9064.

6. The pharmaceutical composition according to claim 12, wherein the PARP inhibitor is selected from: Veliparib (ABT-888), Rucaparib (AG014699), Olaparib, Niraparib, Fluzoparib, Pamiparib, Talazoparib, Senaparib, TQB3823, Saruparib, AZD5305.

7. The pharmaceutical composition of claim 2, wherein the immunotherapeutic agent is selected from PD-1 antibody or antigen-binding fragment thereof, PD-L1 antibody or antigen-binding fragment thereof, and soluble PD-1 or CTLA-4 antibody or antigen-binding fragment thereof.

8. The pharmaceutical composition according to any one of claims 1-7, wherein the pharmaceutical composition further comprises additional medicaments for the prevention and / or treatment of cancer or tumors (such as small molecules, peptides, nucleic acids, antibodies, antibody-drug conjugates).

9. Use of the pharmaceutical composition according to any one of claims 1-8 in the preparation of a medicament for treating cancer and tumors.

10. The use according to claim 9, wherein the cancer and tumor comprise: Skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer, familial adenomatous polyposis, colorectal cancer, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, kidney cancer, renal parenchymal carcinoma, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary tract cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin's lymphoma, non-Hodgkin's lymphoma. Lymphoma, Burkitt lymphoma, leukemia, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmacytoma.

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