Pharmaceutical composition and application

Abstract

The invention provides a pharmaceutical composition and application thereof. The invention relates to a pharmaceutical composition, in particular to a pharmaceutical composition comprising a first therapeutic agent and a second therapeutic agent, and an application of the pharmaceutical composition in preparation of drugs for treating and / or preventing cancers.

Description

Technical Field

[0001] The present invention provides a pharmaceutical composition and its application, specifically comprising a pharmaceutical composition comprising a first therapeutic agent and a second therapeutic agent, and the application of the pharmaceutical composition in preparing a drug for treating and / or preventing cancer. Background Art

[0002] There are many relevant targets in the development and progression of tumors. Deubiquitinating enzymes (DUBs) are encoded by over 100 human genes and divided into six families. Ubiquitin-specific proteases (USPs) comprise the largest DUB family, comprising over 50 members. Ubiquitination is a reversible process. DUBs act within the ubiquitin-protease system, cleaving the isopeptide bond between lysine and the C-terminus of UBQ, affecting cell proliferation, cell cycle, apoptosis, DNA damage response, tumor suppression, development, and metastasis.

[0003] USP1 (Ubiquitin specific protease 1), a member of the USP family, is a cysteine isopeptidase containing a tripartite structure consisting of Cys90, His593, and Asp751. The human USP1 gene was cloned in 1998 and encodes a 785-amino acid protein. Normally, USP1 is relatively inactive. It becomes activated by forming a heterodimeric complex with UAF1 (USPl-associated factor 1), a cofactor containing WD40 repeats that binds and regulates USP1 activity. It functions as a deubiquitinating enzyme, stabilizes replication forks, and is localized in the nucleus.

[0004] USP1 is highly expressed in cancers such as breast and ovarian cancer, and its expression is also elevated in other cancers. USP1 overexpression is associated with BRCA1 deficiency in breast and ovarian cancer. USP1 deubiquitination is involved in various cancer-related processes, including Fanconi anemia (FA), translesion DNA synthesis (TLS), and cell differentiation. In FA, USP1 deubiquitinates FANCD2 (Fanconi anemia group D2 protein); in TLS, USP1 deubiquitinates PCNA (Proliferating cell nuclear antigen); and in cell differentiation, USP1 influences the ubiquitination of the family of inhibitors of DNA-binding proteins (IDs), regulating cell proliferation and differentiation.

[0005] These DNA damage response (DDR) pathways are crucial for the repair of DNA damage induced by DNA cross-linking agents such as cisplatin and ultraviolet radiation. In the TLS pathway, PCNA affected by USP1, together with USP1 / UAF1 and BRCA1 / 2, is involved in DNA break repair. After the replication fork stalls, RAD18-mediated monoubiquitination of PCNA promotes the conversion of PCNA binding from replicative polymerases (polδ / ε) to TLS polymerases (such as POLK). After bypassing the lesion through TLS polymerases, USP1 then deubiquitinates PCNA, promoting the conversion of PCNA binding back to replicative polymerases. Inhibition of USP1 leads to replication fork instability and is synthetically lethal with BRCA mutations.

[0006] The PARP (Poly-ADP-ribose polymerases) superfamily includes 17 members with structurally similar PARP catalytic domains, which catalyze the transfer of ADP-ribose to target proteins using NAD+ as a substrate and play important roles in DNA damage repair and maintenance of genomic integrity. Since 2014, several PARP inhibitors have been successively approved for marketing globally, and the approved indications cover ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, etc. With the widespread clinical use of PARP inhibitors, the problem of drug resistance has become increasingly prominent, greatly limiting their use in patients and leaving unmet clinical needs. Since USP1 and PARP regulate different DNA damage repair pathways, the combination of the two inhibitors has the potential to improve the efficacy of PARP inhibitors and solve some drug resistance problems. Summary of the Invention

[0007] The purpose of the present invention is to provide a composition of a tricyclic ubiquitin-specific protease 1 (USP1) inhibitor and poly ADP-ribose polymerase (PARP) and its application. The specific technical solutions are as follows:

[0008] The present invention provides a pharmaceutical composition comprising a first therapeutic agent and a second therapeutic agent, wherein the first therapeutic agent is selected from PARP inhibitors; the second therapeutic agent is selected from the compounds represented by the general formula (Ⅰ) or pharmaceutically acceptable salts thereof:

[0009]

[0010] Wherein,

[0011] X1, X2, X3, and X4 are each independently selected from N or CR ,

[0008] , ,

[0009] , , , ,

[0011] , , 2 ,

[0007] ,

[0012] , 3 , , a , 1 , ,

[0010] ;

[0012] R 1 、R 2 、R 3Each independently selected from a 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic group, 6- to 10-membered aryl or 5- to 12-membered heteroaryl optionally substituted by one or more Q1;

[0013] R 4 and R 5 Each independently selected from deuterium, hydrogen, carboxyl, cyano, nitro, amino, halogen, C 2-6 alkenyl, C 2-6 alkynyl, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl or halo C 1-6 alkoxy;

[0014] Each Q1 is independently selected from deuterium, halogen, cyano, carboxyl, hydroxy, amino, nitro, sulfonamido, C 1-6 alkylamino, di(C 1-6 alkyl)amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylaminoacyl, C 1-6 alkylacylamino, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamido, C 1-6 alkylaminosulfonyl, -(L) m -C 1-6 alkyl, -(L) m -C 2-6 alkenyl, -(L) m -C 2-6 alkynyl, -(L) m -C 1-6 alkoxy, -(L) m -6- to 10-membered aryl, -(L) m -5- to 12-membered heteroaryl, -(L) m -3- to 8-membered cycloalkyl or -(L) m -3- to 8-membered heterocyclic group, each Q2 is independently selected from deuterium, halogen, carboxyl, hydroxy, cyano, nitro, amino, C 1-6 alkyl, hydroxy C1-6 Alkyl, carboxyl C 1-6 Alkyl, C 1-6 Alkylamino, di(C 1-6 alkyl)amino, -CO-C 1-6 Alkylene-NH2, -CO-C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl or halo C 1-6 Alkoxy;

[0015] Each L is independently selected from -CO-, -O-, -S-, -SO-, -S(O)2-, -NR c -, or -CR a R b -;

[0016] Each R a 、each R b is independently selected from deuterium, hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C 2-6 alkenyl, C 2-6 alkynyl, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylaminoacyl, C 1-6 alkylacylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylaminosulfonyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl or carboxyl C 1-6 alkyl;

[0017] Each R c is independently selected from deuterium, hydrogen, optionally deuterated C 1-6 alkyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl or carboxyl C 1-6 alkyl;

[0018] Each m is independently an integer from 0 - 3;

[0019] Each n is independently an integer from 0 - 6.

[0020] In some embodiments, the pharmaceutical composition according to the foregoing embodiments, wherein,

[0021] X1, X2, X3, and X4 are each independently selected from N;

[0022] R 1 , R 2 , R 3 are each independently selected from phenyl optionally substituted with 1 - 4 Q1s or a 5 - or 6 - membered heteroaryl;

[0023] R 4 , R 5 are each independently selected from deuterium, hydrogen, C 1-4 alkyl optionally deuterated, C 1-4 alkoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, halo - C 1-4 alkyl, hydroxy - C 1-4 alkyl, amino - C 1-4 alkyl, carboxy - C 1-4 alkyl, or halo - C 1-4 alkoxy;

[0024] Each Q1 is independently selected from deuterium, halogen, C 1-4 alkoxy optionally substituted with 1 - 3 substituents Q2, C 1-4 alkylamino, di(C 1-4 alkyl)amino, halo - C 1-4 alkyl, halo - C 1-4 alkoxy, hydroxy - C 1-4 alkyl, amino - C 1-4 alkyl, carboxy - C 1-4 alkyl, -(L) m -C 1-4 alkyl, or -(L) m -3 - to 6 - membered cycloalkyl, and each Q2 is independently selected from deuterium, halogen, carboxyl, hydroxy, cyano, nitro, amino, C 1-4 alkyl, hydroxy - C 1-4 alkyl, carboxy - C 1-4 alkyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkoxy, halo - C 1-4 alkyl, or halo - C 1-4 alkoxy;

[0025] Each L is independently selected from -CR a R b - or -O-;

[0026] Each R a , each R b is independently selected from deuterium, hydrogen, C 1-4 alkyl optionally deuterated, C 1-4Alkoxy, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, halo C 1-4 Alkyl, halo C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl or carboxy C 1-4 Alkyl;

[0027] Each R c Is independently selected from deuterium, hydrogen, optionally deuterated C 1-4 Alkyl, halo C 1-4 Alkyl or halo C 1-4 Alkoxy;

[0028] Each m is independently an integer from 0 - 2;

[0029] Each n is independently an integer from 0 - 4.

[0030] In some embodiments, the pharmaceutical composition according to the foregoing embodiment, wherein,

[0031] X1, X2, X3, X4 are independently selected from N;

[0032] R 1 、R 2 、R 3 Are independently selected from phenyl, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3 - triazolyl, 1,2,4 - triazolyl, pyridyl, 2 - pyridone, 4 - pyridone, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3 - triazinyl, 1,3,5 - triazinyl or 1,2,4,5 - tetrazinyl, optionally substituted with 1 - 3 Q1;

[0033] R 4 、R 5 Are independently selected from deuterium, hydrogen, optionally deuterated methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec - butyl, tert - butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl or trifluoromethoxy;

[0034] Each Q1 is independently selected from deuterium, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, -(L) m -C 1-4 alkyl or -(L) m -3- to 6-membered cycloalkyl, and each Q2 is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl, carboxyethyl, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;

[0035] Each L is independently selected from -CR a R b -;

[0036] Each R a and each R b are independently selected from deuterium, hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy or isopropoxy optionally substituted with deuterium;

[0037] Each m is independently selected from 0, 1, 2;

[0038] Each n is independently 0, 1, 2, 3.

[0039] In some embodiments, for the pharmaceutical composition described in the foregoing embodiments, the second therapeutic agent is selected from a compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof:

[0040]

[0041] Wherein,

[0042] R 1 is selected from phenyl or a 5- or 6-membered nitrogen-containing heteroaryl optionally substituted with 1 to 3 Q1;

[0043] Each Q1 is independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy or 3- to 6-membered cycloalkyl optionally substituted with 1 to 3 substituents Q2, and each Q2 is independently selected from deuterium, C 1-6 alkyl, C1-6 Alkoxy, halo-C 1-6 alkyl or halo-C 1-6 alkoxy;

[0044] Selected from the following structures:

[0045] m is an integer of 1 or 2;

[0046] Each s is independently an integer of 0, 1, or 2.

[0047] In some embodiments, for the pharmaceutical composition described in the foregoing embodiment, the second therapeutic agent is selected from the compounds represented by the general formula (II) or pharmaceutically acceptable salts thereof:

[0048]

[0049] Wherein, R 6 is selected from hydrogen, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy;

[0050] The definitions of each Q1 and each s are as described in any one of the foregoing embodiments.

[0051] In some embodiments, for the pharmaceutical composition described in the foregoing embodiment, the second therapeutic agent is selected from the compounds represented by the general formula (II) or pharmaceutically acceptable salts thereof, wherein,

[0052] R 6 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, deuterated butyl, deuterated isobutyl, deuterated sec-butyl, deuterated tert-butyl, deuterated methoxy, deuterated ethoxy, deuterated propoxy or deuterated isopropoxy.

[0053] In some embodiments, for the pharmaceutical composition described in the foregoing embodiment, the second therapeutic agent is selected from the compounds represented by the general formula (II) or pharmaceutically acceptable salts thereof, wherein,

[0054] R 6 is selected from hydrogen, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl or halo-C 1-6 alkoxy;

[0055] Preferably, R6 Selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, deuterated butyl, deuterated isobutyl, deuterated sec-butyl, deuterated tert-butyl, deuterated methoxy, deuterated ethoxy, deuterated propoxy or deuterated isopropoxy;

[0056] Each Q1 is independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy or 3-6 membered cycloalkyl, and each Q2 is independently selected from deuterium, C 1-6 alkyl, C 1-6 [[ID=*16]]alkoxy, halo C 1-6 alkyl or halo C 1-6 alkoxy;

[0057] Each s is independently an integer of 0, 1, or 2.

[0058] In some embodiments, for the pharmaceutical composition described in the foregoing embodiments, the second therapeutic agent is selected from the following structures or pharmaceutically acceptable salts thereof:

[0059]

[0060]

[0061]

[0062] In some embodiments, a pharmaceutical composition comprises a first therapeutic agent and a second therapeutic agent, the first therapeutic agent is selected from PARP inhibitors; the second therapeutic agent is selected from the structure shown in the following formula (III) or a pharmaceutically acceptable salt thereof:

[0063]

[0064] Wherein, R 4’ is selected from deuterium, hydrogen, cyano, halogen, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl or halo C 1-6 alkoxy;

[0065] R 5’ is selected from optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy;

[0066] Each Q1’, each Q2’, and each Q3’ are each independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl, 3- to 6-membered cycloalkyl;

[0067] p’, q’, and s’ are each independently integers from 0 to 3.

[0068] In some embodiments, a pharmaceutical composition comprises a first therapeutic agent and a second therapeutic agent, the first therapeutic agent being selected from PARP inhibitors; the second therapeutic agent being selected from the structure of formula (III) below or a pharmaceutically acceptable salt thereof:

[0069] wherein, R 4’ is selected from deuterium, hydrogen, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl or halo C 1-6 alkoxy;

[0070] R 5’ is selected from optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy;

[0071] Each Q1’, each Q2’, and each Q3’ are each independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0072] p’, q’, and s’ are each independently integers 0, 1, or 2.

[0073] In some embodiments, a pharmaceutical composition comprises a first therapeutic agent and a second therapeutic agent, wherein the first therapeutic agent is selected from PARP inhibitors; and the second therapeutic agent is selected from the following structures or pharmaceutically acceptable salts thereof:

[0074]

[0075] In some embodiments, for the pharmaceutical composition described in the foregoing embodiment, the PARP inhibitor is selected from olaparib, niraparib, fluzoparib, pamiparib, rucaparib and pharmaceutically acceptable salts thereof.

[0076] In some embodiments, for the pharmaceutical composition described in the foregoing embodiment, the first therapeutic agent and the second therapeutic agent are administered sequentially or simultaneously.

[0077] In some embodiments, for the pharmaceutical composition described in the foregoing embodiment, the first therapeutic agent is administered orally; and the second therapeutic agent is administered orally.

[0078] In some embodiments, the pharmaceutical composition described in the foregoing embodiment further comprises one or more pharmaceutical carriers and / or diluents.

[0079] In some embodiments, the present invention further provides a kit, which comprises the foregoing pharmaceutical composition and a drug instruction.

[0080] In some embodiments, the use of the pharmaceutical composition described in the foregoing embodiment in the preparation of a drug for treating and / or preventing cancer, wherein the cancer is selected from brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colon cancer, colorectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, non-Hodgkin lymphoma, central nervous system tumor, prostate cancer, thyroid cancer, female genital tract cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, testicular cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, glioma, astrocytoma, neuroblastoma, sarcoma.

[0081] In some embodiments, for the use described in the foregoing embodiment, the cancer is selected from breast cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, lung cancer, colorectal cancer, prostate cancer.

[0082] In some embodiments, for the use described in the foregoing embodiment, the breast cancer is triple-negative breast cancer.

[0083] In some embodiments, for the use described in the foregoing embodiment, the lung cancer is selected from small cell lung cancer and non-small cell lung cancer.

[0084] In some embodiments, for the use described in the foregoing embodiments, wherein the cancer is a poly (ADP - ribose) polymerase inhibitor - resistant cancer.

[0085] In some embodiments, for the use described in the foregoing embodiments, wherein the cancer comprises at least one of BRCA1 mutation, BRCA2 mutation, or p53 mutation.

[0086] In some embodiments, for the use described in the foregoing embodiments, wherein the breast cancer comprises a BRCA1 mutation, a BRCA2 mutation, or both a BRCA1 mutation and a BRCA2 mutation.

[0087] In some embodiments, for the use described in the foregoing embodiments, wherein the ovarian cancer comprises a BRCA1 mutation, a BRCA2 mutation, a p53 mutation, or both a BRCA1 mutation and a BRCA2 mutation.

[0088] In some embodiments, the present invention further relates to the use of a pharmaceutical preparation containing the foregoing pharmaceutical composition in the preparation of a drug for treating and / or preventing cancer.

[0089] In some embodiments, the present invention provides a method for treating cancer, the method comprising administering an effective amount of the above - mentioned pharmaceutical composition to a patient in need; the cancer is as described above.

[0090] In some embodiments, the first therapeutic agent and the second therapeutic agent are co - administered according to a specific dosage regimen.

[0091] In some embodiments, the first therapeutic agent or a pharmaceutically acceptable salt thereof is orally administered at a dose of 10 - 1500 mg per day.

[0092] In some embodiments, the first therapeutic agent is olaparib and is orally administered at a dose of 100 - 1000 mg per day.

[0093] In some embodiments, the first therapeutic agent is olaparib and is orally administered at a dose of 100 - 800 mg per day.

[0094] In some embodiments, the first therapeutic agent is olaparib and is orally administered at a dose of 100 - 600 mg per day.

[0095] In some embodiments, the first therapeutic agent is olaparib and is orally administered at a dose of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg per day.

[0096] In some embodiments, the second therapeutic agent or a pharmaceutically acceptable salt thereof is orally administered at a dose of 100 - 5000 mg per day.

[0097] In some embodiments, the second therapeutic agent or a pharmaceutically acceptable salt thereof is administered orally at a dose of 500-5000 mg per day. Detailed Description

[0098] The present invention discloses a pharmaceutical composition comprising a first therapeutic agent and a second therapeutic agent, wherein the first therapeutic agent is a poly(ADP-ribose) polymerase (PARP) inhibitor and the second therapeutic agent is a ubiquitin-specific protease 1 (USP1) inhibitor. The present invention also discloses the use of a combination of a PARP inhibitor and a USP1 inhibitor in the preparation of a drug for treating and / or preventing cancer, and the combination of the two has a synergistic effect.

[0099] Definitions and General Terms

[0100] In the present application, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of the present invention, the definitions of some terms are provided below. When the definitions and explanations of the terms provided in the present application are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations provided in the present application shall prevail.

[0101] As used herein, "halogen" refers to fluorine, chlorine, bromine, and iodine, preferably fluorine and chlorine.

[0102] As used herein, "halo" means that any hydrogen in the substituent can be replaced by one or more identical or different halogens. "Halogen" is defined as above.

[0103] As used herein, "C 1-6 alkyl" means a straight-chain or branched-chain alkyl group containing 1-6 carbon atoms, including, for example, "C 1-5 alkyl", "C 1-4 alkyl", "C 1-3 alkyl", "C 1-2 alkyl", "C 2-6 alkyl", "C 2-5 alkyl", "C 2-4 alkyl", "C 2-3 alkyl", "C 3-6 alkyl", "C 3-5 alkyl", "C 3-4 alkyl", "C 4-6 alkyl", "C 4-5 alkyl", "C 5-6"Alkyl", etc. Specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc. The "C 1-4 alkyl" in the present invention refers to specific examples of C 1-6 alkyl containing 1-4 carbon atoms.

[0104] The "C 1-6 alkylene" in the present invention refers to the group formed by removing one hydrogen atom from the above-mentioned C 1-6 alkyl, including, for example, "C 1-5 alkylene", "C 1-4 alkylene", "C 1-3 alkylene", "C 1-2 alkylene", "C 2-6 alkylene", "C 2-5 alkylene", "C 2-4 alkylene", "C 2-3 alkylene", "C 3-6 alkylene", "C 3-5 alkylene", "C 3-4 alkylene", "C 4-6 alkylene", "C 4-5 alkylene", "C 5-6 alkylene", etc. Specific examples include, but are not limited to: methylene, ethylene, propylene, butylene, pentylene, hexylene, etc. The "C 1-4 alkylene" in the present invention refers to specific examples of C 1-6 alkylene containing 1-4 carbon atoms.

[0105] The "C 2-6 alkenyl" in the present invention refers to a straight-chain, branched-chain or cyclic alkenyl having 2-6 carbon atoms and containing at least one double bond, including, for example, "C 2-5 alkenyl", "C 2-4 alkenyl", "C 2-3"Alkenyl", etc., specific examples include but are not limited to: vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 2-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 1-methyl-2-pentenyl, 3-methyl-2-pentenyl, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-1-butenyl, 2-ethyl-1-butenyl, 2-ethyl-3-butenyl, etc.

[0106] The "C 2-6 alkynyl" referred to in the present invention means a straight-chain or branched alkynyl having 2 to 6 carbon atoms containing a triple bond, including, for example, "C 2-5 alkynyl", "C 2-4 alkynyl", "C 2-3 alkynyl", etc., specific examples include but are not limited to: ethynyl, 1-propynyl, 2-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1,1-dimethyl-3-butynyl, 2-ethyl-3-butynyl, etc.

[0107] As used herein, "C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylaminoacyl, C 1-6 alkylacylamino, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonylamino, C 1-6 alkylaminosulfonyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl" means an C 1-6 alkyl - O -, C 1-6 alkyl - NH -, (C 1-6 alkyl)2 - N -, C 1-6 alkyl - NH - C(O)-, C 1-6 alkyl - C(O)-NH -, C1-6 alkyl-S(O)2-, C 1-6 alkyl-S(O)2-NH-, C 1-6 alkyl-NH-S(O)2-, C 1-6 alkyl-C(O)-, C 1-6 alkyl-O-C(O)-formed groups, where "C 1-6 alkyl" is defined as described above.

[0108] As used herein, "C 1-4 alkoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkylaminoacyl, C 1-4 alkylacylamino, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonylamino, C 1-4 alkylaminosulfonyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl" means groups formed by C 1-4 alkyl-O-, C 1-4 alkyl-NH-, (C 1-4 alkyl)2-N-, C 1-4 alkyl-NH-C(O)-, C 1-4 alkyl-C(O)-NH-, C 1-4 alkyl-S(O)2-, C 1-4 alkyl-S(O)2-NH-, C 1-4 alkyl-NH-S(O)2-, C 1-4 alkyl-C(O)-, C 1-4 alkyl-O-C(O)-formed groups, where "C 1-4 alkyl" is defined as described above.

[0109] As used herein, "halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl, halo C 1-6 alkoxy" means groups formed by replacing one or more (e.g., 1-4, 1-3, 1-2) hydrogen atoms of C 1-6 alkyl, C 1-6 alkoxy with halogen atoms, hydroxy groups, amino groups, carboxy groups, respectively.

[0110] As used herein, "halo C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, carboxy C 1-4 alkyl, halo C1-4 "Alkoxy" refers to a group formed by replacing one or more (e.g., 1 - 4, 1 - 3, 1 - 2) hydrogen atoms in C 1-4 alkyl, C 1-4 alkoxy with halogen atoms, hydroxyl groups, or amino groups respectively.

[0111] The "3 - 12 - membered cycloalkyl" as used in the present invention refers to a saturated or partially saturated non - aromatic cyclic alkyl group containing 3 - 12 carbon atoms, including "monocyclic alkyl" and "fused - ring alkyl".

[0112] The "monocyclic alkyl" as used in the present invention refers to a saturated or partially saturated non - aromatic monocyclic alkyl group, including "3 - 8 - membered saturated cycloalkyl" and "3 - 8 - membered partially saturated cycloalkyl"; preferably "3 - 4 - membered cycloalkyl", "3 - 5 - membered cycloalkyl", "3 - 6 - membered cycloalkyl", "3 - 7 - membered cycloalkyl", "4 - 5 - membered cycloalkyl", "4 - 6 - membered cycloalkyl", "4 - 7 - membered cycloalkyl", "4 - 8 - membered cycloalkyl", "5 - 6 - membered cycloalkyl", "5 - 7 - membered cycloalkyl", "5 - 8 - membered cycloalkyl", "6 - 7 - membered cycloalkyl", "6 - 8 - membered cycloalkyl", "7 - 8 - membered cycloalkyl", "3 - 6 - membered saturated cycloalkyl", "4 - 7 - membered saturated cycloalkyl", "4 - 8 - membered saturated cycloalkyl", "5 - 8 - membered saturated cycloalkyl", "5 - 7 - membered saturated cycloalkyl", "5 - 6 - membered saturated cycloalkyl", "3 - 6 - membered partially saturated cycloalkyl", "4 - 7 - membered partially saturated cycloalkyl", "4 - 8 - membered partially saturated cycloalkyl", "5 - 8 - membered partially saturated cycloalkyl", "5 - 7 - membered partially saturated cycloalkyl", "5 - 6 - membered partially saturated cycloalkyl", etc. Specific examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohex - 1,3 - diene, cyclohex - 1,4 - diene, cycloheptenyl, cyclohept - 1,3 - dienyl, cyclohept - 1,4 - dienyl, cyclohept - 1,3,5 - trienyl, cyclooctenyl, cyclooct - 1,3 - diene, cyclooct - 1,4 - diene, cyclooct - 1,5 - diene, cyclooct - 1,3,5 - triene, cyclooctatetraene, etc.

[0113] The "fused cycloalkyl group" described in the present invention refers to a saturated or partially saturated, non-aromatic cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms with each other. One of the rings in the fused rings can be an aromatic ring, but the fused rings as a whole do not have aromaticity; the fusion mode can be: 5-6 membered cycloalkyl group fused with 5-6 membered cycloalkyl group, benzo-5-6 membered cycloalkyl group, benzo-5-6 membered saturated cycloalkyl group, etc. Examples include but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.2.0]octyl, octahydrodicyclopentadienyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthryl, bicyclo[3.1.0]hex-2-enyl, bicyclo[4.1.0]hept-3-enyl, bicyclo[3.2.0]hept-3-enyl, bicyclo[4.2.0]oct-3-enyl, 1,2,3,3a-tetrahydrodicyclopentadienyl, 2,3,3a,4,7,7a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8a-octahydronaphthyl, 1,2,4a,5,6,8a-hexahydronaphthyl, 1,2,3,4,5,6,7,8,9,10-decahydrophenanthryl, benzocyclopentyl, benzocyclohexyl, benzocyclohexenyl, benzocyclopentenyl, etc.

[0114] The "3- to 12-membered heterocyclic group" as used in the present invention refers to a saturated or partially saturated and non-aromatic monocyclic or fused-ring cyclic group having at least one heteroatom (for example, having 1, 2, 3, 4 or 5 heteroatoms) and having 3 to 12 ring atoms, wherein the heteroatom is a nitrogen atom, an oxygen atom and / or a sulfur atom. Optionally, the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the cyclic structure may be oxo-substituted. The "3- to 12-membered heterocyclic group" as used in the present invention includes a "3- to 12-membered saturated heterocyclic group" and a "3- to 12-membered partially saturated heterocyclic group". Preferably, the "3- to 12-membered heterocyclic group" as used in the present invention contains 1 to 3 heteroatoms; preferably, the "3- to 12-membered heterocyclic group" as used in the present invention contains 1 to 2 heteroatoms, and the heteroatoms are selected from nitrogen atoms and / or oxygen atoms; preferably, the "3- to 12-membered heterocyclic group" as used in the present invention contains 1 to 2 nitrogen atoms. The "3- to 12-membered heterocyclic group" is preferably a "3- to 10-membered heterocyclic group", a "3- to 8-membered heterocyclic group", a "4- to 8-membered heterocyclic group", a "3- to 6-membered heterocyclic group", a "3- to 6-membered saturated heterocyclic group", a "3- to 6-membered nitrogen-containing heterocyclic group", a "3- to 6-membered saturated nitrogen-containing heterocyclic group", a "5- to 6-membered heterocyclic group", a "5- to 6-membered saturated heterocyclic group", a "5- to 6-membered nitrogen-containing heterocyclic group", etc.Specific examples of "3- to 12-membered heterocyclic group" include, but are not limited to: aziridinyl, 2H-aziridinyl, diaziridinyl, 3H-diazirenyl, azetidinyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,4-dioxadienyl, tetrahydrofuryl, tetrahydropyranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydrothienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, 4,5-dihydrooxazolyl, 4,5-dihydroisoxazolyl, 2,3-dihydroisoxazolyl, 2H-1,2-oxazinyl, 6H-1,3-oxazinyl, 4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 2H-pyranyl, 2H-pyran-2-one group, 3,4-dihydro-2H-pyranyl, pyrrolidinylcyclopropyl, cyclopentylaziridinyl, pyrrolidinylcyclobutyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, pyrrolidinylpiperazinyl, pyrrolidinylmorpholinyl, piperidinylmorpholinyl, benzopyrrolidinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuryl, benzopyrrolidinyl, benzimidazolidinyl, benzoxazolidinyl, benzothiazolidinyl, benzisoxazolidinyl, benzisothiazolidinyl, benzopiperidinyl, benzomorpholinyl, benzopiperazinyl, benzotetrahydropyranyl, pyridinylcyclopentyl, pyridinylcyclohexyl, pyridinyltetrahydrofuryl, pyridinylpyrrolidinyl, pyridinylimidazolidinyl, pyridinyloxazolidinyl, pyridinylthiazolidinyl, pyridinylisoxazolidinyl, pyridinylisothiazolidinyl, pyridinylpiperidinyl, pyridinylmorpholinyl, pyridinylpiperazinyl, pyridinyltetrahydropyranyl, pyrimidinylcyclopentyl, pyrimidinylcyclohexyl, pyrimidinyltetrahydrofuryl, pyrimidinylpyrrolidinyl, pyrimidinylimidazolidinyl, pyrimidinyloxazolidinyl, pyrimidinylthiazolidinyl, pyrimidinylisoxazolidinyl, pyrimidinylisothiazolidinyl, pyrimidinylpiperidinyl, pyrimidinylmorpholinyl, pyrimidinylpiperazinyl, pyrimidinyltetrahydropyranyl, tetrahydroimidazo[4,5-c]pyridinyl, 3,4-dihydroquinazolinyl, 1,2-dihydroquinoxalinyl, benzo[d][1,3]dioxolanyl, 2H-chromenyl, 2H-chromen-2-one group, 4H-chromenyl, 4H-chromen-4-one group, 4H-1,3-benzoxazinyl, 4,6-dihydro-1H-furo[3,4-d]imidazolyl, 3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazolyl, 4,6-dihydro-1H-thieno[3,4-d]imidazolyl, 4,6-dihydro-1H-pyrrolo[3,4-d]imidazolyl, octahydro-benzo[d]imidazolyl, decahydroquinolinyl, hexahydrothienoimidazolyl, hexahydrofuroimidazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, octahydrocyclopentenopyrrolyl, 4H-1,3-benzoxazinyl, etc.

[0115] The "6-10 membered aryl group" described in the present invention refers to an aromatic cyclic group containing 6-10 ring carbon atoms, including "6-8 membered monocyclic aryl groups" and "8-10 membered fused ring aryl groups".

[0116] The "6-8 membered monocyclic aryl group" described in the present invention refers to a monocyclic aryl group containing 6-8 ring carbon atoms, and its examples include but are not limited to: phenyl, cyclooctatetraenyl, etc.; preferably phenyl.

[0117] The "8-10 membered fused ring aryl group" described in the present invention refers to an unsaturated, aromatic cyclic group formed by two or more cyclic structures sharing two adjacent atoms with each other and containing 8-10 ring carbon atoms, preferably "9-10 membered fused ring aryl group", and specific examples include naphthyl, etc.

[0118] The "5-12 membered heteroaryl group" described in the present invention refers to an aromatic cyclic group containing 5-12 ring atoms (wherein at least one ring atom is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom), and can be, for example, a 5-12 membered nitrogen-containing heteroaryl group, a 5-12 membered oxygen-containing heteroaryl group, a 5-12 membered sulfur-containing heteroaryl group, etc. It includes "5-8 membered monocyclic heteroaryl groups" and "8-10 membered fused heteroaryl groups".

[0119] The "5-8 membered monocyclic heteroaryl group" described in the present invention refers to a monocyclic aromatic cyclic group containing 5-8 ring atoms (wherein at least one ring atom is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom). Optionally, the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the cyclic structure can be oxo-substituted. The "5-8 membered monocyclic heteroaryl group" includes, for example, "5-7 membered monocyclic heteroaryl groups", "5-6 membered monocyclic heteroaryl groups", "5-6 membered nitrogen-containing monocyclic heteroaryl groups", "5 membered nitrogen-containing monocyclic heteroaryl groups", etc. Specific examples of the "5-8 membered monocyclic heteroaryl group" include but are not limited to furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridone group, 4-pyridone group, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, azepine, 1,3-diazepine, azocine, etc. The "5-6 membered heteroaryl group" refers to specific examples of the 5-8 membered heteroaryl group containing 5-6 ring atoms.

[0120] The "8- to 10-membered fused heteroaryl" as used in the present invention refers to an unsaturated aromatic cyclic structure formed by two or more cyclic structures sharing two adjacent atoms with each other, containing 8 to 10 ring atoms (wherein at least one ring atom is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom). Optionally, the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the cyclic structure can be oxo-substituted. It includes "9- to 10-membered fused heteroaryl", "8- to 9-membered fused heteroaryl", etc., and the fusion mode can be benzo 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl fused with 5- to 6-membered heteroaryl, etc.; specific examples include but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furanothiophene, pyrazolooxazole, benzofuranyl, benzisofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, etc.

[0121] The "optionally substituted by..." as used in the present invention includes two situations of "substituted" and "unsubstituted".

[0122] In the present application, each atom not specified as deuterium is present in its natural isotopic abundance.

[0123] The "deuterated" as used in the present invention means that one or more hydrogen atoms on the deuterated group are replaced by one or more deuterium atoms, which can be partial deuteration or complete deuteration. For example, a deuterated compound can contain only one deuterium. In some embodiments, the deuterated compound contains only two deuteriums. In some embodiments, the deuterated compound contains only three deuteriums. In some embodiments, the deuterated compound contains four deuteriums.

[0124] The "optionally deuterated" as used in the present invention includes two situations where the group is deuterated and not deuterated, wherein the "deuterated" is as defined above.

[0125] The "pharmaceutically acceptable salt" as used in the present invention refers to addition salts of pharmaceutically acceptable acids and bases, such as metal salts, ammonium salts, salts formed with organic acids, salts formed with organic bases, salts formed with inorganic acids, salts formed with acidic amino acids or basic amino acids, etc.

[0126] The "pharmaceutical composition" as used in the present invention includes a pharmaceutical preparation prepared by combining the active ingredients of a first therapeutic agent and a second therapeutic agent into the same compound preparation, and also includes a composition formed by separately preparing the active ingredients of the first therapeutic agent and the second therapeutic agent into single preparations.

[0127] The pharmaceutical composition described in the present invention can be formulated into any pharmaceutically acceptable dosage form. It is administered to patients in need of such treatment by oral, parenteral, rectal, or pulmonary administration, etc. When used for oral administration, it can be formulated into conventional solid preparations such as tablets, capsules, pills, granules, etc.; it can also be formulated into oral liquid preparations such as oral solutions, oral suspensions, syrups, etc. When formulating oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. can be added. When used for parenteral administration, it can be formulated into injections, including injection solutions, sterile powders for injection, and concentrated solutions for injection. When formulating injections, conventional methods in the existing pharmaceutical field can be used for production. When formulating injections, additives may not be added, or suitable additives can be added according to the nature of the drug. When used for rectal administration, it can be formulated into suppositories, etc. When used for pulmonary administration, it can be formulated into inhalants or sprays, etc.

[0128] The "effective amount" described in the present invention refers to the amount of the aforementioned compound, pharmaceutical preparation, or pharmaceutical composition that can at least alleviate the symptoms of the patient's disease when administered to the patient. The actual amount containing the "therapeutically effective amount" will vary according to various circumstances, including but not limited to the specific disease being treated, the severity of the disease, the physical and health conditions of the patient, and the administration route. Skilled medical practitioners can easily determine the appropriate amount using methods known in the medical field.

[0129] The pharmaceutical composition of the present invention has the following advantages:

[0130] (1) The pharmaceutical composition of the present invention has excellent anti-tumor inhibitory activity and good inhibitory activity against ovarian cancer cells, non-small cell lung cancer cells, breast cancer cells, colorectal cancer cells, etc.

[0131] (2) The combined use of the pharmaceutical composition of the present invention has a synergistic inhibitory effect on ovarian cancer cells, non-small cell lung cancer cells, breast cancer cells, and colorectal cancer cells.

[0132] (3) The pharmaceutical composition of the present invention can effectively solve the drug resistance problem of using PARP inhibitors alone.

[0133] (4) The pharmaceutical composition of the present invention has low toxicity and good safety.

[0134] The beneficial effects of the pharmaceutical composition of the present invention are further elaborated through experiments below, but it should not be understood that the pharmaceutical composition of the present invention only has the following beneficial effects.

[0135] Experimental Example 1 In vitro Cytological Inhibitory Activity Test of the Combination of the Compound and Olaparib - I

[0136] Test articles: Compound 1, Compound 1-1, Compound 22, Compound 23, the preparation methods of which are described in PCT / CN2022 / 089956 and PCT / CN2022 / 089047; Olaparib: purchased commercially.

[0137] The cell lines used in the following experiments are as follows:

[0138] Caov-3: human ovarian cancer cells; HCT-116: human colorectal cancer cells.

[0139] Experimental methods:

[0140] 1. Prepare cells

[0141] 1.1 Cell culture:

[0142] All cells are adherent cells. The culture medium for Caov-3 cells is DMEM medium + 10% FBS, and the culture medium for HCT-116 cells is McCoy's 5a medium + 10% FBS. The cells are tested in the logarithmic growth phase.

[0143] 1.2 Preparation of cell suspension:

[0144] Harvest the cells in the logarithmic growth phase and count the cells using a platelet counter. Detect the cell viability by trypan blue exclusion method to ensure that the cell viability is above 90%. Adjust to the appropriate concentration and add 80 μL of cell suspension to 96-well plates respectively. Table 1. Number of cells inoculated

[0145]

[0146] 2. Prepare the test compounds

[0147] 2.1 Prepare the DMSO stock solutions of the test compounds (each test compound, Olaparib), and the stock solution concentrations of each test compound are 10 mM. The stock solution concentration of Olaparib for Caov-3 cell experiments is 10 mM, and the stock solution concentration of Olaparib for HCT-ill6 cell experiments is 20 mM.

[0148] 2.2 Prepare the working stock solutions of the test compounds

[0149] For Caov-3 cells:

[0150] (1) The stock solution of Compound 23 is diluted 2-fold with DMSO to 5 mM, and then serially diluted 4-fold with DMSO for a total of 5 concentrations. The stock solution of Olaparib is diluted 2-fold with DMSO to 5 mM, and then serially diluted 4-fold with DMSO for a total of 4 concentrations;

[0151] (2) The stock solution of Compound 22 was diluted 2-fold with DMSO to 5 mM, and then serially diluted 4-fold with DMSO to obtain a total of 4 concentrations. The stock solution of Olaparib was diluted 2-fold with DMSO to 5 mM, and then serially diluted 4-fold with DMSO to obtain a total of 5 concentrations;

[0152] Then, 2 μL of the DMSO serially diluted compound was added to 198 μL of the culture medium to prepare the working stock solution of the test compound (the compound concentration was 10 times the final concentration).

[0153] (3) The stock solution of Compound 1 was diluted 20-fold with DMSO to 500 μM, and then serially diluted 2-fold to obtain a total of 4 concentrations. The stock solution of Olaparib was serially diluted 4-fold with DMSO to obtain a total of 5 concentrations. Then, 2 μL of the DMSO serially diluted compound was added to 198 μL of the culture medium to prepare the working stock solution of the test compound (the compound concentration was 10 times the final concentration).

[0154] HCT-116 cells: The stock solutions of Compound 1-1 / Compound 1 / Olaparib were diluted 4-fold with DMSO to 2.5 mM, and then serially diluted 4-fold with DMSO to obtain a total of 4 concentrations. The stock solution of Olaparib was serially diluted 3-fold with DMSO to obtain a total of 5 concentrations. Then, 2 μL of the serially diluted Compound 1-1 / Compound 1 / Olaparib was added to 198 μL of the culture medium to prepare the working stock solution of the test compound (the compound concentration was 10 times the final concentration).

[0155] 2.3 Compound treatment

[0156] To each well of the 96-well plate seeded with cells, the working stock solution of each test compound and 10 μL of the working stock solution of Olaparib were added.

[0157] 2.4 Control well setting

[0158] Solvent control: 0.2% DMSO.

[0159] Blank control: The reading of the 96-well plate was detected at 0 h after adding the drug.

[0160] 2.5 The 96-well plate was placed in a cell culture incubator at 37 °C and 5% CO2 for 7 days.

[0161] 3. Detection

[0162] The CTG reagent was thawed and the 96-well plate was equilibrated to room temperature for 30 minutes. 50 μL of the reagent (Celltiter Glo assay kit) was added to each well, and the plate was shaken on an oscillator for 2 min to mix evenly (protected from light), and then incubated at room temperature for 20 minutes (protected from light). The light signal value was read using a multimode microplate reader.

[0163] 4. Data Processing

[0164] 1) Inhibition rate (%) = (Reading of DMSO solvent control well - Reading of test substance well) / (Reading of DMSO solvent control well - Reading of blank control well) × 100%;

[0165] 2) Calculate the CI value using software. A CI value less than 1 indicates a synergistic effect.

[0166] Experimental Results and Conclusions

[0167] Table 2

[0168]

[0169] Table 3

[0170]

[0171] Table 4

[0172]

[0173] Table 5

[0174]

[0175]

[0176] Table 6

[0177]

[0178] From the above results, it can be seen that compounds 1, 1-1, 22, and 23 all showed strong synergistic effects when combined with the PARP inhibitor Olaparib on tumor cells of multiple different cancer types, indicating that compounds 1, 1-1, 22, and 23 have the potential for combination therapy with PARP inhibitors in clinical practice.

[0179] Experimental Example 2 In vitro Cytological Inhibitory Activity Test II of the Combination of Compounds and Olaparib

[0180] Test articles: Compound 1, the preparation method of which is described in PCT / CN2022 / 089956; Olaparib: purchased commercially.

[0181] The cell lines used in the following experiments are as follows:

[0182] NCI-H1651: human non-small cell lung cancer cells; HCC1395: human breast cancer cells

[0183] Experimental Method (CelltiterGlo assay)

[0184] 1. Prepare cells

[0185] 1.1 Cell culture

[0186] All cells are adherent cells. The culture medium for NCI-H1651 cells is ALC-4 medium + 10% FBS, and the culture medium for HCC1395 cells is RPMI-1640 medium + 20% FBS.

[0187] 1.2 Preparation of cell suspension

[0188] Harvest cells in the logarithmic growth phase and perform cell counting using a platelet counter. Detect cell viability by trypan blue exclusion method to ensure that the cell viability is above 85%. Adjust to the appropriate concentration and add 80 μL of cell suspension to each well of a 96-well plate respectively.

[0189] 2. Prepare test compounds

[0190] 2.1 Prepare DMSO stock solutions of test compounds (Compound 1, Olaparib), and the stock solution concentration of each test compound is 10 mM.

[0191] 2.2 Prepare working stock solutions of test compounds

[0192] For HCC 1395 cells: The 10 mM stock solution of each test compound is serially diluted 4-fold with DMSO for a total of 6 concentrations. Then, take 2 μL of the DMSO-diluted compound and add it to 198 μL of the culture medium to obtain the working stock solution of the test compound (the compound concentration is 10 times the final concentration, and the highest concentration is 100 μM).

[0193] For NCI-H1651 cells: The 10 mM stock solution of the test compound Olaparib is diluted 10-fold with DMSO to 1 mM. The diluted Olaparib stock solution (1 mM) and the compound stock solution (10 mM) are serially diluted 4-fold with DMSO for a total of 6 concentrations. Then, take 2 μL of the DMSO-diluted compound and add it to 198 μL of the culture medium to obtain the working stock solution of the test compound (the compound concentration is 10 times the final concentration, the highest compound concentration is 100 μM, and the highest Olaparib concentration is 10 μM).

[0194] 2.3 Compound treatment

[0195] Add 10 μL of the compound working stock solution and 10 μL of the Olaparib working stock solution (10-fold dilution, final DMSO concentration is 0.2%) to each well of the 96-well plate seeded with cells.

[0196] HCC 1395 cells:

[0197] The final concentration of the compound / Olaparib is: 10000.00 nM, 2500.00 nM, 625.00 nM, 156.25 nM, 39.06 nM, 9.77 nM.

[0198] NCI-H1651 cells:

[0199] The final concentration of the compound is: 10000.00 nM, 2500.00 nM, 625.00 nM, 156.25 nM, 39.06 nM, 9.77 nM.

[0200] The final concentration of Olaparib is: 1000.00 nM, 250.00 nM, 62.50 nM, 15.63 nM, 3.91 nM, 0.98 nM.

[0201] 2.4 Control well settings

[0202] Solvent control: 0.2% DMSO.

[0203] 2.5 Place the 96-well plate in a 37°C, 5% CO2 cell culture incubator for 72 h and then change the medium.

[0204] 2.5.1 Aspirate 70 μL of the cell supernatant from each well of the 96-well plate and discard it, then add 70 μL of the corresponding cell culture medium;

[0205] 2.5.2 Add the corresponding compound to each well again according to the above compound preparation and treatment method, and continue to culture for 96 h before detection.

[0206] 3. Detection

[0207] Melt the CTG reagent and equilibrate the 96-well plate to room temperature for 30 minutes. Add 50 μL of the reagent (Celltiter Glo assay kit) to each well, shake on a shaker for 2 min to mix (protected from light), and incubate at room temperature for 20 minutes (protected from light). Read the light signal value with a multifunctional microplate reader.

[0208] 4. Data processing

[0209] 1) Inhibition rate (%) = (Reading of DMSO solvent control well - Reading of test substance well) / (Reading of DMSO solvent control well - Reading of solvent control well) × 100%;

[0210] 2) Analyze the data using CrownSyn software and calculate the synergy index.

[0211] Table 7. Synergy index of the compound combined with Olaparib

[0212]

[0213] The Bliss independence model was used to calculate the synergy score. A score higher than 5 indicates synergy, and a score lower than -5 indicates antagonism. Through analysis, it was found that the synergy indices of Compound 1 combined with Olaparib in the NCI-H1651 and HCC1395 models were both greater than 5, indicating that Compound 1 showed strong synergy when combined with the PARP inhibitor Olaparib on tumor cells of multiple different cancer types, suggesting that Compound 1 has the potential for combination therapy with PARP inhibitors clinically.

Claims

1. A pharmaceutical composition comprising a first therapeutic agent and a second therapeutic agent, wherein the first therapeutic agent is selected from PARP inhibitors; The second therapeutic agent is selected from the compounds represented by the general formula (I) or pharmaceutically acceptable salts thereof: Wherein, X1, X2, X3, and X4 are each independently selected from N or CR a ; R 1 、R 2 、R 3 are each independently selected from a 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic group, 6- to 10-membered aryl or 5- to 12-membered heteroaryl optionally substituted by one or more Q1; R 4 and R 5 are each independently selected from deuterium, hydrogen, carboxyl, cyano, nitro, amino, halogen, C 2-6 alkenyl, C 2-6 alkynyl, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl or halo C 1-6 alkoxy; Each Q1 is independently selected from deuterium, halogen, cyano, carboxyl, hydroxyl, amino, nitro, sulfonamido, C 1-6 alkylamino, di(C 1-6 alkyl)amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylaminoacyl, C 1-6 alkylamido, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamido, C 1-6 alkylaminosulfonyl, -(L) m -C 1-6 alkyl, -(L) m -C 2-6 alkenyl, -(L) m -C 2-6 alkynyl, -(L) m -C 1-6 alkoxy, -(L) m -6-10-membered aryl, -(L) m -5-12-membered heteroaryl, -(L) m -3-8-membered cycloalkyl or -(L) m -3-8-membered heterocyclic group, each Q2 is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, hydroxy C 1-6 alkyl, carboxy C 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, -CO-C 1-6 alkylene-NH2, -CO-C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl or halo C 1-6 alkoxy; Each L is independently selected from -CO-, -O-, -S-, -SO-, -S(O)2-, -NR c -, or -CR a R b -; Each R a 、each R b is independently selected from deuterium, hydrogen, halogen, amino, hydroxy, carboxy, cyano, C 2-6 alkenyl, C 2-6 alkynyl, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylaminoacyl, C 1-6 alkylacylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylaminosulfonyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl or carboxy C 1-6 alkyl; Each R c is independently selected from deuterium, hydrogen, optionally deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl or carboxy C 1-6 alkyl; Each m is independently an integer from 0 to 3; Each n is independently an integer from 0 to 6.

2. The pharmaceutical composition according to claim 1, wherein the second therapeutic agent is selected from the compounds represented by the general formula (II) or pharmaceutically acceptable salts thereof: Among them, R 6 selected from hydrogen, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl or halo C 1-6 alkoxy; Preferably, R 6 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, deuteromethyl, deuteroethyl, deuteropropyl, deuteroisopropyl, deuterobutyl, deuteroisobutyl, deuterosec-butyl, deuterotert-butyl, deuteromethoxy, deuteroethoxy, deuteropropoxy or deuteroisopropoxy; Each Q1 is independently selected from deuterium, a halogen, a C 1-6 alkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkyl group, a halogenated C 1-6 alkoxy group or a 3- to 6-membered cycloalkyl group, and each Q2 is independently selected from deuterium, a C 1-6 alkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkyl group or a halogenated C 1-6 alkoxy group; Each s is independently an integer of 0, 1, or 2.

3. The pharmaceutical composition according to claim 1 or 2, wherein the second therapeutic agent is selected from the following structure or pharmaceutically acceptable salts thereof:

4. A pharmaceutical composition comprising a first therapeutic agent and a second therapeutic agent, wherein the first therapeutic agent is selected from PARP inhibitors; The second therapeutic agent is selected from the following structure represented by formula (III) or pharmaceutically acceptable salts thereof: Among them, R 4’ selected from deuterium, hydrogen, cyano, halogen, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl or halo C 1-6 alkoxy; R 5’ selected from optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy; Each of Q1', each of Q2', and each of Q3' is independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, carboxy-C 1-6 alkyl, 3-6 membered cycloalkyl; p’, q’, and s’ are independently integers from 0 to 3.

5. The pharmaceutical composition according to any one of claims 1-4, wherein the PARP inhibitor is selected from olaparib, niraparib, fluzoparib, pamiparib, rucaparib, and pharmaceutically acceptable salts thereof.

6. The pharmaceutical composition according to any one of claims 1-5, wherein the first therapeutic agent and the second therapeutic agent are administered sequentially or simultaneously.

7. The pharmaceutical composition according to any one of claims 1-4, wherein the first therapeutic agent is administered orally; the second therapeutic agent is administered orally.

8. Use of the pharmaceutical composition according to any one of claims 1-7 in the preparation of a medicament for the treatment and / or prevention of cancer, wherein the cancer is selected from brain cancer, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colon cancer, colorectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, non-Hodgkin lymphoma, central nervous system tumors, prostate cancer, thyroid cancer, female genital tract cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, testicular cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, glioma, astrocytoma, neuroblastoma, sarcoma; Preferably, the cancer is selected from breast cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, lung cancer, colorectal cancer, prostate cancer.

9. The use according to claim 8, wherein The cancer contains at least one of BRCA1 mutation, BRCA2 mutation, or p53 mutation.

10. The use according to claim 8 or 9, wherein, The cancer is a poly ADP-ribose polymerase inhibitor-resistant cancer.

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