USP1 inhibitor and pharmaceutical use thereof

Abstract

The present invention relates to a USP1 inhibitor and pharmaceutical use thereof. Specifically, the present invention relates to a combination product comprising the USP1 inhibitor and an anti-tumor drug other than the USP1 inhibitor, and pharmaceutical use thereof. The USP1 inhibitor has a structure represented by formula I.

Description

USP1 inhibitors and their pharmaceutical uses Technical Field

[0001] This invention relates to the field of cancer treatment. Specifically, this invention relates to the use of a novel USP1 in the treatment of cancer. Background Technology

[0002] Ubiquitin-specific protease 1 (USP1) is a well-defined member of the deubiquitinating enzyme family, capable of cleaving ubiquitin from a variety of target proteins. Dysregulation of USP-1 expression is present in many cancers, where it acts as an oncogenic driver in various DNA damage repair processes, including translesion synthesis and the Fanconi anemia pathway. USP1 deficiency leads to reduced cell viability and replication fork degradation, suggesting that USP1 inhibitors may be particularly useful against BRCA-deficient tumors.

[0003] The poly(ADP-ribose) polymerase (PARP) family of enzymes plays a role in DNA repair and genome integrity. PARP is crucial for single-strand break repair and base excision repair pathways. A key enzymatic activity involves the addition of ADP-ribose to substrate proteins via NAD+ cleavage and nicotinamide release. DNA strand breaks activate this polymerization (“PARation”) activity, thereby adding Par to PARP itself and other DNA repair enzymes. PARP is essential for the recruitment of DNA repair proteins to damage sites. Although the use of PARP inhibitors (PARPi) has shown clinical benefit in individuals with BRCA mutations (BRCAm) or homologous recombination defects (HRD+), some patients either do not respond to treatment or develop resistance. USP1 inhibitors may have the potential to address this unmet clinical need. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides a combination product comprising a USP1 inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, isotope substitute, or stereoisomer thereof; and other antitumor drugs besides the USP1 inhibitor, wherein the USP1 inhibitor has the structure shown in Formula I:

[0005] Among them, ring A and ring B are each independently selected from C. 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein ring A and ring B are each independently and optionally substituted by one or more R1 groups;

[0006] L is selected from chemical bonds, -O-, -S-, and -C.1-6 Alkylene-, -OC 1-6 alkylene-, -C 1-6 Alkylene-O-, -SC 1-6 alkylene- and -C 1-6 Alkylene-S-;

[0007] R a and R b Each is independently selected from H atoms, -CN, and C atoms. 1-6 Alkyl, -OH, halogen, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy; or R a and R b Together they form oxygen groups, C 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0008] R2 is selected from H atom, -OH, -CN, C 1-6 Alkyl, C 2-6 alkynyl group, -C 1-6 Alkyl-C 6-10 Aryl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-6 cycloalkyl and 5-7 membered heterocyclic groups, wherein the C 1-6 Alkyl or -C 1-6 Alkyl-C 6-10 The aryl group may be optionally substituted by one or more R1s;

[0009] Preferably, R2 is selected from H atom, -CN, methyl, trideuteryl, ethynyl, propynyl, tetrahydrofuranyl, cyclopropyl, methoxy, and hydroxyl;

[0010] R3 is selected from H atom, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, 5-7 membered heterocyclic groups and -C 1-6 Alkylene-C(O)-OC 1-6 Alkyl, wherein the C 1-6 The hydroxyalkyl group and the 5-7 membered heterocyclic group are each independently optionally constituting one or more C groups. 1-6Alkyl substitution;

[0011] Preferably, R3 is selected from H atom, methoxy group, trifluoromethyl group, Cl atom, -CN group, isopropoxy group, ethynyl group, difluoromethoxy group, morpholinyl group, etc. -OH、 F atom, hydroxymethyl and

[0012] More preferably, R3 is selected from H atom, -OH, -COOH, -NH2, -CN, halogen, C 1-6 alkyl;

[0013] More preferably, R3 is selected from H atoms, C atoms 1-6 alkyl;

[0014] R4 is selected from H atom, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Hydroxyalkyl;

[0015] Preferably, R4 is a H atom;

[0016] R5 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, and C fused with 5-10 heteroaryl 6-10 Aryl groups, C fused with 3-8 membered heterocyclic groups 6-10 Aryl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally substituted by one or more R1 groups;

[0017] R1 is independently selected from D atom, -OH, -COOH, -NH2, -CN, oxo group, halogen, C at each occurrence. 1-6Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -OC 1-6 Alkylene-OC 1-6 Alkyl, wherein the C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently selected from the D atom, -OH, -COOH, -NH2, -CN, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 One or more substituents of the hydroxyalkyl group are substituted, and

[0018] n is an integer between 0 and 8.

[0019] In one embodiment of the combined product of the present invention, wherein

[0020] Ring A and ring B are each independently selected from phenyl, piperidinyl, cyclohexyl, cyclopropyl, cyclobutyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, bicyclo[2.2.2]octyl, 2-oxabicyclo[2.2.2]octyl, pentacyclooctyl, isoindolone, imidazo[1,2-a]pyrazinyl, piperidin-2,6-diketone, thienyl, furanyl, cyclopentyl, pyranyl, pyrrolidinyl, piperazinyl, Morpholinyl, naphthyl, pyrroleyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, indolyl, isoindolyl, indololinyl, isoindololinyl, indololinone, pyrido[3,2-d]pyrimidinyl, pteridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, and cubic alkyl, wherein ring A and ring B are each optionally substituted independently by one or more R1s, wherein R1 is as defined in claim 1;

[0021] L is selected from chemical bonds, -O-, -OC. 1-6 alkylene- and -C 1-6 Alkylene-O-;

[0022] In particular, Selected from

[0023] Furthermore, ring A and ring B can each be independently and arbitrarily replaced by one or more R1s, as defined in claim 1;

[0024] More specifically, Selected from

[0025] According to the present invention, the combined product wherein R5 is selected from C 6-10 Aryl, 5-6 membered heteroaryl, C fused with 5-6 membered heterocyclic group 6-10 Aryl groups and C groups fused with 5-6 heteroaryl groups 6-10 The aryl group, preferably selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, indolyl, indololinyl, and isoxazolyl, wherein C 6-10 Aryl, 5-6 membered heteroaryl, C fused with 5-6 membered heterocyclic group 6-10 Aryl groups and C groups fused with 5-6 heteroaryl groups 6-10 Each aryl group is independently selected from -OH, -COOH, -NH2, -CN, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl and C 3-6 One or more substituents of the cycloalkyl group are used for substitution;

[0026] Specifically, R5 is selected from

[0027] More specifically, R5 is

[0028] The combined product according to the invention, wherein n is 0 or 1;

[0029] R a and R b Each is independently selected from H atoms, -CN, and C atoms. 1-6 Alkyl groups, -OH groups, and halogens;

[0030] Preferably, R a and R b Each is an independent H atom.

[0031] In one embodiment, the present invention provides a combination product comprising:

[0032] USP1 inhibitors, or pharmaceutically acceptable salts, hydrates, solvates, isotopic substitutes, or stereoisomers thereof; and

[0033] Other anti-tumor drugs besides USP1 inhibitors;

[0034] The USP1 inhibitors mentioned above are selected from:

[0035] Specifically, the present invention provides the use of the combined product of the present invention for the treatment of cancer.

[0036] In the specific implementation plan, the cancer is selected from: breast cancer, lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, uterine cancer, peritoneal cancer, and endometrial cancer.

[0037] On the other hand, the present invention provides the use of the USP1 inhibitor having the structure shown in Formula I in combination with other antitumor drugs besides the USP1 inhibitor in the preparation of a medicament for treating cancer.

[0038] In the specific implementation plan, the anti-tumor drugs other than the USP1 inhibitors mentioned in this article are immune checkpoint inhibitors;

[0039] Specifically, the immune checkpoint inhibitor is selected from TIGIT inhibitors, PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, and IDO1 inhibitors;

[0040] More specifically, the immune checkpoint inhibitor is a TIGIT inhibitor.

[0041] In the specific implementation plan, the anti-tumor drugs other than the USP1 inhibitors mentioned in this article are anti-angiogenic drugs.

[0042] Anti-angiogenic drugs mainly work by blocking angiogenesis-related pathways, inhibiting the formation of new blood vessels in tumors, thereby limiting the supply of nutrients and oxygen to the tumor and inhibiting its growth and metastasis.

[0043] In specific implementation plans, the anti-angiogenic drugs are selected from VEGF / VEGFR pathway inhibitors and drugs with other anti-angiogenic mechanisms.

[0044] In the specific implementation plan, the VEGF / VEGFR pathway inhibitor is selected from monoclonal antibodies, including but not limited to bevacizumab and ramucirumab; and

[0045] Small molecule tyrosine kinase inhibitors (TKIs), including but not limited to sorafenib, sunitinib, apatinib, fruquintinib, regorafenib, cabozantinib, and lenvatinib.

[0046] In a specific implementation plan, the anti-angiogenic drug is selected from carboplatin, fruquintinib, gemcitabine, bevacizumab, ramucirumab, sorafenib, sunitinib, apatinib, regorafenib, cabozantinib, and lenvatinib.

[0047] In the specific implementation plan, drugs with other anti-angiogenic mechanisms are selected from:

[0048] Integrin inhibitors, such as ceritinib;

[0049] Platelet-derived growth factor receptor (PDGFR) inhibitors, such as sunitinib and sorafenib;

[0050] HIF (hypoxia-inducible factor) inhibitors, such as belinostat, and

[0051] Endothelin receptor antagonists, such as bosentan.

[0052] In a specific implementation plan, the anti-tumor drug other than the USP1 inhibitor is selected from olatinib.

[0053] In a specific embodiment of the combination product provided by the present invention, the other anti-tumor drugs besides the USP1 inhibitor are selected from: carboplatin, fruquintinib, olaparib, gemcitabine, bevacizumab, ramucirumab, sorafenib, sunitinib, apatinib, regorafenib, cabozantinib, and lenvatinib.

[0054] In a specific embodiment of the combination product provided by the present invention, the other anti-tumor drugs besides the USP1 inhibitor are selected from carboplatin, fruquintinib, olaparib, gemcitabine, and bevacizumab.

[0055] In another aspect, the present invention provides the use of a novel, effective, and selective USP1 inhibitor in the preparation of a medicament for treating cancer:

[0056] 4'-Cyclopropyl-5,6'-Dimethoxy-N-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]oct-1-yl)methyl)-[2,5'-bipyrimidine]-4-amine, referred to herein as 104, has the following structure:

[0057] Our study confirms that 104 is an effective selective USP1 inhibitor with an IC50 value of 104. 50 It has a concentration of approximately 9 nM and exhibits selectivity for USP1 that is more than 1000 times greater than that for USP12 and USP46. It effectively inhibits the growth of tumor cell lines in vitro and demonstrates potent anti-tumor activity in BRCA1m and HRD in vivo models. 104 also showed potent anti-proliferative activity (IC50) in the BRCA1m triple-negative breast cancer (TNBC) cell line MDA-MB-436. 50(30 nM). The MDA-MB-436CDX model confirmed the dose-dependent monotherapy inhibitory activity of 104, with a tumor growth inhibition (TGI) of 78% at 100 mg / kg QD, and its efficacy was higher than that of KSQ-4279. The efficacy was consistent with the increase of ub-PCNA.

[0058] In a first aspect, the present invention provides the use of a USP1 inhibitor in the preparation of a medicament for treating cancer, said USP1 inhibitor having a structure as shown in the following formula:

[0059] On the other hand, the present invention provides the use of a USP1 inhibitor in combination with Avastin (bevacizumab) in the preparation of a medicament for treating cancer, wherein the USP1 inhibitor has the structure shown in the following formula:

[0060] In a specific implementation plan, the USP1 inhibitor is co-administered with Avastin (bevacizumab) in the same formulation or different formulations.

[0061] In a specific implementation plan, the USP1 inhibitor is administered to the subject via the same or different routes as Avastin (bevacizumab).

[0062] In a specific implementation plan, the USP1 inhibitor and Avastin (bevacizumab) are administered to the subject via parenteral or oral administration.

[0063] In a specific implementation plan, the USP1 inhibitor, along with Avastin (bevacizumab), is used to treat breast cancer and / or ovarian cancer.

[0064] On the other hand, the present invention provides the use of a USP1 inhibitor in combination with gemcitabine in the preparation of a medicament for treating cancer, wherein the USP1 inhibitor has the structure shown in the following formula:

[0065] In a specific implementation plan, the USP1 inhibitor is co-administered with gemcitabine in the same formulation or different formulations.

[0066] In a specific implementation plan, the USP1 inhibitor is administered to the subject via the same or different routes as gemcitabine.

[0067] In a specific implementation plan, the USP1 inhibitor and gemcitabine are administered to the subject via parenteral or oral administration.

[0068] In a specific implementation, the USP1 inhibitor, along with gemcitabine, is used to treat breast cancer and / or ovarian cancer.

[0069] On the other hand, the present invention provides the use of a USP1 inhibitor in combination with olaparib in the preparation of a medicament for treating cancer, wherein the USP1 inhibitor has the structure shown in the following formula:

[0070] In a specific implementation plan, the USP1 inhibitor is co-administered with olaparib in the same formulation or in different formulations.

[0071] In a specific implementation plan, the USP1 inhibitor is administered to the subject via the same or different routes as olaparib.

[0072] In a specific implementation plan, the USP1 inhibitor and olaparib are administered to the subject via parenteral or oral administration.

[0073] In a specific implementation, the USP1 inhibitor, along with olaparib, is used to treat breast cancer and / or ovarian cancer.

[0074] In another aspect, the present invention provides the use of a USP1 inhibitor in combination with carboplatin in the preparation of a medicament for treating cancer, wherein the USP1 inhibitor has a structure as shown in the following formula:

[0075] In a specific implementation, the USP1 inhibitor is co-administered with carboplatin in the same formulation or in different formulations.

[0076] In a specific implementation plan, the USP1 inhibitor is administered to the subject via the same or different routes as carboplatin.

[0077] In a specific implementation, the USP1 inhibitor and carboplatin are administered to the subject via parenteral or oral administration.

[0078] In a specific implementation, the USP1 inhibitor, together with carboplatin, is used to treat breast cancer and / or ovarian cancer.

[0079] On the other hand, the present invention provides the use of a USP1 inhibitor in combination with olaparib in the preparation of a medicament for treating cancer, wherein the USP1 inhibitor has the structure shown in the following formula:

[0080] In a specific implementation plan, the USP1 inhibitor is co-administered with olaparib in the same formulation or in different formulations.

[0081] In a specific implementation plan, the USP1 inhibitor is administered to the subject via the same or different routes as olaparib.

[0082] In a specific implementation plan, the USP1 inhibitor and olaparib are administered to the subject via parenteral or oral administration.

[0083] In a specific implementation, the USP1 inhibitor, along with olaparib, is used to treat breast cancer and / or ovarian cancer.

[0084] On the other hand, the present invention provides the use of a USP1 inhibitor in combination with fruquintinib in the preparation of a medicament for treating cancer, wherein the USP1 inhibitor has the structure shown in the following formula:

[0085] In a specific implementation plan, the USP1 inhibitor is co-administered with fruquintinib in the same formulation or in different formulations.

[0086] In a specific implementation plan, the USP1 inhibitor is administered to the subject via the same or different routes as fruquintinib.

[0087] In a specific implementation plan, the USP1 inhibitor and fruquintinib are administered to the subject via parenteral or oral administration.

[0088] In a specific implementation plan, the USP1 inhibitor, along with fruquintinib, is used to treat breast cancer and / or ovarian cancer.

[0089] On the other hand, the present invention provides a drug combination comprising a USP1 inhibitor having the structure shown in Formula I and Avastin (bevacizumab).

[0090] In a specific implementation, the present invention provides a drug combination for treating cancer, comprising a USP1 inhibitor having the structure shown in Formula I and Avastin (bevacizumab).

[0091] In a specific implementation plan, the USP1 inhibitor is co-administered with Avastin (bevacizumab) in the same formulation or different formulations.

[0092] In a specific implementation plan, the USP1 inhibitor is administered to the subject via the same or different routes as Avastin (bevacizumab).

[0093] In a specific implementation plan, the USP1 inhibitor and Avastin (bevacizumab) are administered to the subject via parenteral or oral administration.

[0094] On the other hand, the present invention provides a drug combination comprising a USP1 inhibitor having the structure shown in Formula I and fruquintinib.

[0095] In a specific implementation, the present invention provides a drug combination for treating cancer, comprising a USP1 inhibitor having the structure shown in Formula I and fruquintinib.

[0096] In a specific implementation plan, the USP1 inhibitor is co-administered with fruquintinib in the same formulation or in different formulations.

[0097] In a specific implementation plan, the USP1 inhibitor is administered to the subject via the same or different routes as fruquintinib.

[0098] In a specific implementation plan, the USP1 inhibitor and fruquintinib are administered to the subject via parenteral or oral administration.

[0099] In another aspect, the present invention provides a method for treating cancer, the method comprising administering to a subject in need a therapeutically effective amount of a USP1 inhibitor having the structure shown in Formula I or a combination of a USP1 inhibitor having the structure shown in Formula I and Avastin (bevacizumab).

[0100] In another aspect, the present invention provides a method for treating cancer, the method comprising administering to a subject in need a therapeutically effective amount of a USP1 inhibitor having the structure shown in Formula I or a combination of a USP1 inhibitor having the structure shown in Formula I and fruquintinib.

[0101] In specific implementation schemes, the cancers described in this invention are selected from: breast cancer, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, uterine cancer, peritoneal cancer, and endometrial cancer.

[0102] In the specific implementation plan, the cancer is breast cancer.

[0103] In the specific implementation plan, the cancer is triple-negative breast cancer (TNBC).

[0104] In a specific implementation plan, the breast cancer is a BRCA1-mutated cancer, a BRCA2-mutated cancer, or a BRCA1-mutated and BRCA2-mutated cancer.

[0105] In the specific implementation plan, the cancer is ovarian cancer.

[0106] In a specific implementation plan, the ovarian cancer is a BRCA1-mutated cancer, a BRCA2-mutated cancer, a BRCA wild-type ovarian cancer with CCNE1 amplification, or a p53-mutated cancer.

[0107] In the specific implementation plan, the ovarian cancer is a BRCA1-mutated cancer and a p53-mutated cancer.

[0108] In the specific implementation plan, the ovarian cancer is a BRCA1 and BRCA2 mutated cancer.

[0109] In the specific implementation plan, the ovarian cancer is a BRCA2-mutated cancer.

[0110] In the specific implementation plan, the ovarian cancer is prostate cancer.

[0111] In the specific implementation plan, the cancer is PARP inhibitor-resistant cancer.

[0112] In the specific implementation plan, the cancer is olaparib-resistant cancer. Attached Figure Description

[0113] Figure 1 shows the inhibition of 104 in mice of subcutaneous tumor MDA-MB-436 (triple-negative breast cancer cell line, BRCA1 mutation).

[0114] Figure 2A shows the tumor-suppressive effect of 215 in combination with carboplatin, fruquintinib, and olaparib in the CAOV3 subcutaneous tumor model.

[0115] Figure 2B shows the changes in body weight in mice in the caov3 subcutaneous tumor model.

[0116] Figure 3A shows the tumor-suppressive effects of 104 monotherapy and in combination with gemcitabine, olaparib, and avastin (bevacizumab injection) in the CAVO3 subcutaneous tumor model.

[0117] Figure 3B shows the changes in body weight in mice in the caov3 subcutaneous tumor model. Detailed Implementation

[0118] In one specific embodiment, the present invention provides a combination product comprising a USP1 inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, isotope substitute, or stereoisomer thereof; and another antitumor drug other than the USP1 inhibitor, wherein the USP1 inhibitor has a structure shown in Formula I:

[0119] Among them, ring A and ring B are each independently selected from C. 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein ring A and ring B are each independently and optionally substituted by one or more R1 groups;

[0120] L is selected from chemical bonds, -O-, -S-, and -C. 1-6 Alkylene-, -OC 1-6 alkylene-, -C 1-6 Alkylene-O-, -SC 1-6 alkylene- and -C 1-6 Alkylene-S-;

[0121] Ra and R b Each is independently selected from H atoms, -CN, and C atoms. 1-6 Alkyl, -OH, halogen, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy; or R a and R b Together they form oxygen groups, C 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0122] R2 is selected from H atom, -OH, -CN, C 1-6 Alkyl, C 2-6 alkynyl group, -C 1-6 Alkyl-C 6-10 Aryl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-6 cycloalkyl and 5-7 membered heterocyclic groups, wherein the C 1-6 Alkyl or -C 1-6 Alkyl-C 6-10 The aryl group may be optionally substituted by one or more R1s;

[0123] Preferably, R2 is selected from H atom, -CN, methyl, trideuteryl, ethynyl, propynyl, tetrahydrofuranyl, cyclopropyl, methoxy, and hydroxyl;

[0124] R3 is selected from H atom, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, 5-7 membered heterocyclic groups and -C 1-6 Alkylene-C(O)-OC 1-6 Alkyl, wherein the C 1-6 The hydroxyalkyl group and the 5-7 membered heterocyclic group are each independently optionally constituting one or more C groups. 1-6 Alkyl substitution;

[0125] Preferably, R3 is selected from H atom, methoxy group, trifluoromethyl group, Cl atom, -CN group, isopropoxy group, ethynyl group, difluoromethoxy group, morpholinyl group, etc. -OH、 F atom, hydroxymethyl and

[0126] More preferably, R3 is selected from H atom, -OH, -COOH, -NH2, -CN, halogen, C 1-6 alkyl;

[0127] More preferably, R3 is selected from H atoms, C atoms 1-6 alkyl;

[0128] R4 is selected from H atom, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Hydroxyalkyl;

[0129] Preferably, R4 is a H atom;

[0130] R5 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, and C fused with 5-10 heteroaryl 6-10 Aryl groups, C fused with 3-8 membered heterocyclic groups 6-10 Aryl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally substituted by one or more R1 groups;

[0131] R1 is independently selected from D atom, -OH, -COOH, -NH2, -CN, oxo group, halogen, C at each occurrence. 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8Cycloalkyl, 3-8 membered heterocyclic groups, -OC 1-6 Alkylene-OC 1-6 Alkyl, wherein the C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently selected from the D atom, -OH, -COOH, -NH2, -CN, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 One or more substituents of the hydroxyalkyl group are substituted; and

[0132] n is an integer between 0 and 8.

[0133] In a specific embodiment of Formula I shown in this invention, ring A and ring B are each independently selected from phenyl, piperidinyl, cyclohexyl, cyclopropyl, cyclobutyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, bicyclo[2.2.2]octyl, 2-oxabicyclo[2.2.2]octyl, pentacyclooctyl, isoindolinone, imidazo[1,2-a]pyrazinyl, piperidin-2,6-diketone, thiophene, furanyl, cyclopentyl, pyranyl The compounds are alkyl, pyrrolyl, piperazinyl, morpholinyl, naphthyl, pyrrolyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, indolyl, isoindolyl, indololinyl, isoindololinyl, indololinone, pyrido[3,2-d]pyrimidinyl, pteridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, and cubic, wherein ring A and ring B are each independently and optionally substituted by one or more R1s, as defined above;

[0134] L is selected from chemical bonds, -O-, -OC. 1-6 alkylene- and -C 1-6 Alkylene-O-;

[0135] In particular, Selected from

[0136] Furthermore, rings A and B can each be independently and arbitrarily replaced by one or more R1s, as defined above;

[0137] More specifically, Selected from

[0138] In a specific embodiment of Formula I shown in this invention, R5 is selected from C. 6-10Aryl, 5-6 membered heteroaryl, C fused with 5-6 membered heterocyclic group 6-10 Aryl groups and C groups fused with 5-6 heteroaryl groups 6-10 The aryl group, preferably selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, indolyl, indololinyl, and isoxazolyl, wherein C 6-10 Aryl, 5-6 membered heteroaryl, C fused with 5-6 membered heterocyclic group 6-10 Aryl groups and C groups fused with 5-6 heteroaryl groups 6-10 Each aryl group is independently selected from -OH, -COOH, -NH2, -CN, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl and C 3-6 One or more substituents of the cycloalkyl group are used for substitution;

[0139] Specifically, R5 is selected from

[0140] In a specific embodiment of Formula I shown in this invention, n is 0 or 1;

[0141] R a and R b Each is independently selected from H atoms, -CN, and C atoms. 1-6 Alkyl groups, -OH groups, and halogens;

[0142] Preferably, R a and R b Each is an H atom or -CN independently.

[0143] In a specific embodiment, the present invention provides a combination product comprising a USP1 inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, isotope substitute, or stereoisomer thereof; and other antitumor drugs besides the USP1 inhibitor, wherein the USP1 inhibitor is selected from:

[0144] In one embodiment, the present invention provides the use of a USP1 inhibitor in combination with other antitumor drugs besides the USP1 inhibitor in the preparation of a medicament for treating cancer, wherein the USP1 inhibitor has the structure shown in Formula I:

[0145] Among them, ring A and ring B are each independently selected from C. 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein ring A and ring B are each independently and optionally substituted by one or more R1 groups;

[0146] L is selected from chemical bonds, -O-, -S-, and -C. 1-6 Alkylene-, -OC 1-6 alkylene-, -C 1-6 Alkylene-O-, -SC 1-6 alkylene- and -C 1-6 Alkylene-S-;

[0147] R a and R b Each is independently selected from H atoms, -CN, and C atoms. 1-6 Alkyl, -OH, halogen, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy; or R a and R b Together they form oxygen groups, C 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0148] R2 is selected from H atom, -OH, -CN, C 1-6 Alkyl, C 2-6 alkynyl group, -C 1-6 Alkyl-C 6-10 Aryl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-6 cycloalkyl and 5-7 membered heterocyclic groups, wherein the C 1-6 Alkyl or -C 1-6 Alkyl-C 6-10 The aryl group may be substituted by one or more R1s, as defined above;

[0149] Preferably, R2 is selected from H atom, -CN, methyl, trideuteryl, ethynyl, propynyl, tetrahydrofuranyl, cyclopropyl, methoxy, and hydroxyl;

[0150] R3 is selected from H atom, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, 5-7 membered heterocyclic groups and -C 1-6 Alkylene-C(O)-OC 1-6 Alkyl, wherein the C1-6 The hydroxyalkyl group and the 5-7 membered heterocyclic group are each independently optionally constituting one or more C groups. 1-6 Alkyl substitution;

[0151] Preferably, R3 is selected from H atom, methoxy group, trifluoromethyl group, Cl atom, -CN group, isopropoxy group, ethynyl group, difluoromethoxy group, morpholinyl group, etc. -OH、 F atom, hydroxymethyl and

[0152] R4 is selected from H atom, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Hydroxyalkyl;

[0153] Preferably, R4 is a H atom;

[0154] R5 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, and C fused with 5-10 heteroaryl 6-10 Aryl groups, C fused with 3-8 membered heterocyclic groups 6-10 Aryl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally substituted by one or more R1 groups; and

[0155] n is an integer between 0 and 8.

[0156] In a specific embodiment of Formula I shown in this invention, ring A and ring B are each independently selected from phenyl, piperidinyl, cyclohexyl, cyclopropyl, cyclobutyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, bicyclo[2.2.2]octyl, 2-oxabicyclo[2.2.2]octyl, pentacyclooctyl, isoindolinone, imidazo[1,2-a]pyrazinyl, piperidin-2,6-diketone, thiophene, furanyl, cyclopentyl, pyranyl The compounds are alkyl, pyrrolyl, piperazinyl, morpholinyl, naphthyl, pyrrolyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, indolyl, isoindolyl, indololinyl, isoindololinyl, indololinone, pyrido[3,2-d]pyrimidinyl, pteridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, and cubic, wherein ring A and ring B are each independently and optionally substituted by one or more R1s, as defined above;

[0157] L is selected from chemical bonds, -O-, -OC. 1-6 alkylene- and -C 1-6 Alkylene-O-;

[0158] In particular, Selected from

[0159] Furthermore, rings A and B are each independently and arbitrarily assigned to one or more R... 1 Replace, R 1 As defined above;

[0160] More specifically, Selected from

[0161] In a specific embodiment of Formula I shown in this invention, R5 is selected from C. 6-10 Aryl, 5-6 membered heteroaryl, C fused with 5-6 membered heterocyclic group 6-10 Aryl groups and C groups fused with 5-6 heteroaryl groups 6-10 The aryl group, preferably selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, indolyl, indololinyl, and isoxazolyl, wherein C 6-10 Aryl, 5-6 membered heteroaryl, C fused with 5-6 membered heterocyclic group 6-10 Aryl groups and C groups fused with 5-6 heteroaryl groups 6-10 Each aryl group is independently selected from -OH, -COOH, -NH2, -CN, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6Hydroxyalkyl and C 3-6 One or more substituents of the cycloalkyl group are used for substitution;

[0162] Specifically, R5 is selected from

[0163] In a specific embodiment of Formula I shown in this invention, n is 0 or 1;

[0164] R a and R b Each is independently selected from H atoms, -CN, and C atoms. 1-6 Alkyl groups, -OH groups, and halogens;

[0165] Preferably, R a and R b Each is an H atom or -CN independently.

[0166] In a specific embodiment, the present invention provides the use of a combination of a USP1 inhibitor selected from the following antitumor drugs other than USP1 inhibitors in the preparation of a medicament for treating cancer:

[0167] In a specific embodiment of the present invention, the cancer is selected from: breast cancer, lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, uterine cancer, peritoneal cancer, and endometrial cancer.

[0168] In a specific embodiment of the present invention, the cancer is selected from: BRCA1-mutated breast cancer, BRCA2-mutated breast cancer, BRCA1-mutated and BRCA2-mutated breast cancer, BRCA1-mutated ovarian cancer, BRCA2-mutated ovarian cancer, or p53-mutated ovarian cancer.

[0169] In a specific embodiment of the present invention, the anti-tumor drugs other than the USP1 inhibitor are selected from antibody-drug conjugates, immune checkpoint inhibitors, and anti-angiogenic drugs.

[0170] Specifically, the immune checkpoint inhibitor is selected from TIGIT inhibitors, PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, and IDO1 inhibitors.

[0171] In a specific implementation scheme, the anti-angiogenic drug is selected from VEGF / VEGFR pathway inhibitors, integrin inhibitors, platelet-derived growth factor receptor inhibitors, HIF inhibitors, and endothelin receptor antagonists.

[0172] More specifically, anti-angiogenic drugs are selected from monoclonal antibodies and small molecule tyrosine kinase inhibitors.

[0173] In a specific implementation plan, the anti-angiogenic drug is selected from fruquintinib, bevacizumab, ramucirumab, sorafenib, sunitinib, apatinib, regorafenib, cabozantinib, and lenvatinib.

[0174] definition

[0175] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0176] As used herein, the terms "combination product" or "composition" refer to a combination of products that are provided as a single dose unit or as part of a kit for combined administration. Combination products can be administered simultaneously, separately, or sequentially.

[0177] The term "simultaneous" administration as used in this article refers to the administration of USP1 inhibitors and other anti-tumor drugs other than USP1 inhibitors via the same route and at the same time.

[0178] In this article, “separate” administration refers to the administration of USP1 inhibitors and other anti-tumor drugs other than USP1 inhibitors to each other via different routes, at the same time or substantially at the same time.

[0179] In this article, "sequential" administration refers to the administration of USP1 inhibitors and other anti-tumor drugs other than USP1 inhibitors at different times via the same or different routes.

[0180] The term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20) carbon atoms, preferably C14. 1-10 Alkyl, more preferably C 1-6 Alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-3-ethylhexyl, n-decyl, and 3,3-diethylhexyl.

[0181] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group having 2 to 6 (e.g., 2, 3, 4, 5, and 6) carbon atoms and at least one carbon-carbon double bond, wherein the carbon-carbon double bond can be located at any position within the alkenyl group, preferably C. 2-5 Alkenyl groups. Examples of alkenyl groups include, but are not limited to, -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CH-CH2-CH3, -CH2-CH=CH-CH3, -CH=CH-CH=CH2, -CH=C(CH3)-CH3 and -CH2-C(CH3)=CH2.

[0182] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group having 2 to 6 (e.g., 2, 3, 4, 5, and 6) carbon atoms and at least one carbon-carbon triple bond, wherein the carbon-carbon triple bond can be located at any position within the alkynyl group, preferably C. 2-5 Alkyne groups. Examples of alkynyl groups include, but are not limited to, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -C≡C-CH2-CH3, -CH2-CH2-C≡CH, -CH(CH3)C≡CH, and -CH2-C≡C-CH3.

[0183] The term "cycloalkyl" includes two categories: conventional cycloalkyl and heterocyclic cycloalkyl.

[0184] Conventional cycloalkyl groups refer to aliphatic saturated or partially unsaturated monovalent cycloalkyl groups having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20) carbon atoms, preferably C4. 3-12 Conventional cycloalkyl, more preferably C 3-10 Conventional cycloalkyl, more preferably C 3-8 Conventional cycloalkyl groups, with C4 being the most preferred. 3-6 Conventional cycloalkyl groups. Conventional cycloalkyl groups optionally contain one or more double or triple bonds.

[0185] Conventional cycloalkyl groups can be monocycloalkyl groups, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptanetrienyl, and cyclooctyl. Conventional cycloalkyl groups can also be polycycloalkyl groups (e.g., bicycloalkyl, tricycloalkyl, tetracycloalkyl, and pentacycloalkyl groups), including spirocycloalkyl, fused-ring alkyl, and bridged-ring alkyl groups.

[0186] The term "spirocycloalkyl" refers to a 5-20 quintone (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 quintone) spirocycloalkyl, preferably a 6-14 quintone spirocycloalkyl, and more preferably a 7-10 quintone spirocycloalkyl. The spirocycloalkyl can be monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl, preferably monospirocycloalkyl, and more preferably 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocycloalkyl. Examples of spirocycloalkyl include, but are not limited to:

[0187] The term "fused cycloalkyl" refers to a 5-20 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 membered) fused cycloalkyl, preferably a 6-14 membered fused cycloalkyl, more preferably a 7-10 membered fused cycloalkyl. The fused cycloalkyl can be bicyclic, tricyclic, tetracyclic, or pentacyclic or more, preferably bicyclic or tricyclic fused cycloalkyl, more preferably a 5-membered / 5-membered or 5-membered / 6-membered fused cycloalkyl. Examples of fused cycloalkyl include, but are not limited to:

[0188] The term "bridged cycloalkyl" refers to a 5-20 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 membered) bridged cycloalkyl, preferably a 6-14 membered bridged cycloalkyl, more preferably a 7-10 membered bridged cycloalkyl. The bridged cycloalkyl can be bicyclic, tricyclic, tetracyclic, or pentacyclic or more, preferably bicyclic, tricyclic, or tetracyclic bridged cycloalkyl, more preferably bicyclic or tricyclic bridged cycloalkyl. Examples of bridged cycloalkyl include, but are not limited to:

[0189] The term "heterocyclic cycloalkyl" includes monocyclic alkyl, spirocyclic alkyl, fused cycloalkyl, and bridged cycloalkyl groups fused to any one selected from conventional aryl, conventional heteroaryl, and conventional heterocyclic groups, with the linkage site located on the corresponding conventional cycloalkyl group (referring to monocyclic alkyl, spirocyclic alkyl, fused cycloalkyl, or bridged cycloalkyl). Examples of heterocyclic cycloalkyl groups include, but are not limited to:

[0190] The term "heterocyclic group" includes two categories: conventional heterocyclic groups and heterostructure heterocyclic groups.

[0191] Conventional heterocyclic groups refer to aliphatic saturated or partially unsaturated monovalent cyclic hydrocarbon groups having 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20) ring atoms, wherein one or more ring atoms are substituted by one or more elements selected from nitrogen, oxygen, S, S(O), and S(O)2, and the substitution does not form -OO-, -OS-, or -SS-; preferably C. 3-12 A conventional heterocyclic group, wherein 1-4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, C. 3-8 A conventional heterocyclic group, wherein 1-3 (e.g., 1, 2, and 3) are heteroatoms; the most preferred is C. 5-7 A conventional heterocyclic group, in which 1-2 or 1-3 are heteroatoms.

[0192] Conventional heterocyclic groups can be monocyclic heterocyclic groups, examples of which include, but are not limited to, oxoheterobutyl, 3-pyrrolinyl, pyrrolylalkyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazoleyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl, preferably 1,2,5-oxadiazolyl, pyranyl, or morpholinyl. Conventional heterocyclic groups can also be polycyclic heterocyclic groups, including spirocyclic heterocyclic groups, fused-ring heterocyclic groups, and bridged-ring heterocyclic groups.

[0193] The term "spiroheterocyclic group" refers to a 5-20 ternary (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 ternary) spiroheterocyclic group, preferably a 6-14 ternary spiroheterocyclic group, and more preferably a 7-10 ternary spiroheterocyclic group. The spiroheterocyclic group can be a monospirocyclic, bispirocyclic, or multispirocyclic group, preferably a monospirocyclic or bispirocyclic group, and more preferably a 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocyclic group. Examples of spiroheterocyclic groups include, but are not limited to:

[0194] The term "fused heterocyclic group" refers to a 5-20 member (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 member) fused heterocyclic group, preferably a 6-14 member fused heterocyclic group, and more preferably a 7-10 member fused heterocyclic group. The fused heterocyclic group can be bicyclic, tricyclic, tetracyclic, or more than five-ring fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, and more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Examples of fused heterocyclic groups include, but are not limited to:

[0195] The term "bridged heterocyclic group" refers to a 5-14 quinary (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 quinary) bridged heterocyclic group, preferably a 6-14 quinary bridged heterocyclic group, and more preferably a 7-10 quinary bridged heterocyclic group. The bridged heterocyclic group can be bicyclic, tricyclic, tetracyclic, or more quinary or higher, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Examples of bridged heterocyclic groups include, but are not limited to:

[0196] The term "heterogeneous heterocyclic group" includes monocyclic, spirocyclic, fused-ring, and bridged-ring heterocyclic groups fused to any one selected from conventional aryl, conventional heteroaryl, and conventional cycloalkyl groups, with the linkage site located on the corresponding conventional heterocyclic group (referring to monocyclic, spirocyclic, fused-ring, or bridged-ring heterocyclic groups). Examples of heterocyclic heterocyclic groups include, but are not limited to:

[0197] The term "aryl" includes two categories: conventional aryl and heterostructure aryl.

[0198] Conventional aryl refers to 6-14 membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14 membered) aromatic hydrocarbon groups, preferably C. 6-10 Conventional aryl groups, more preferably phenyl, naphthyl, phenanthryl or anthracene.

[0199] The term "heteroaryl" includes a conventional aryl group fused to any one selected from conventional heteroaryl, conventional heterocyclic, and conventional cycloalkyl groups, with the linkage site located on the conventional aryl group. Examples of heteroaryl groups include, but are not limited to:

[0200] The term "heteroaryl" includes two categories: conventional heteroaryl and heterostructure heteroaryl.

[0201] Conventional heteroaryl refers to a 5-14 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 membered) aromatic hydrocarbon group in which 1-4 (e.g., 1, 2, 3, and 4) carbon atoms are replaced with heteroatoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Preferably, the number of ring atoms is 5-10, including 1-3 (e.g., 1, 2, and 3) heteroatoms. More preferably, the number of ring atoms is 5 or 6, including 1-2 heteroatoms. Examples of conventional heteroaryl include, but are not limited to, imidazolyl, furanyl, thiophenel, thiazolyl, pyrazolyl, oxazolyl, pyrrololyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, and pyrazinyl, preferably imidazolyl, thiazolyl, pyrazolyl, pyrimidinyl, or thiazolyl, more preferably pyrazolyl or thiazolyl.

[0202] The term "hybrid heteroaryl" includes a conventional heteroaryl group fused to any one selected from conventional aryl, conventional cycloalkyl, and conventional heterocyclic groups, with the linkage site located on the conventional heteroaryl group. Examples of heteroaryl groups include, but are not limited to:

[0203] The term "alkoxy" includes -O-alkyl and -O-cycloalkyl, wherein "alkyl" and "cycloalkyl" are as defined above. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

[0204] The term "haloalkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0205] The term "haloalkoxy" refers to an alkoxy group that is substituted with one or more halogens, wherein the alkoxy group is as defined above.

[0206] The term "hydroxyl group" refers to -OH.

[0207] The term "halogen" refers to -F, -Cl, -Br, or -I.

[0208] The term "amino" refers to -NH2.

[0209] The term "cyano" refers to -CN.

[0210] The term "nitro" refers to -NO2.

[0211] The term "oxo" refers to =O.

[0212] The term "carboxyl group" refers to -C(=O)OH.

[0213] The term "thiol" refers to -SH.

[0214] The term "ester group" refers to -C(=O)O-alkyl or -C(=O)O-cycloalkyl, where alkyl and cycloalkyl are as defined above.

[0215] The term "acyl" refers to -C(=O)R, where R is selected from alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

[0216] The term "hydroxyl protecting group" refers to a group introduced onto a hydroxyl group that is easily removed, used to block or protect the hydroxyl group so that reactions can occur on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.

[0217] symbol This refers to the connection site.

[0218] As used in this article, other anti-tumor drugs besides USP1 inhibitors include, but are not limited to, PARP inhibitors, antimetabolites, platinum coordination complexes, etc.

[0219] As used herein, the terms “PARPi” and “PARP inhibitor” are used interchangeably and refer to reagents that can inhibit the poly(ADP-ribose) polymerase (PARP) of an enzyme, including but not limited to niraparib, pamipanib, olaparib, farruzopanib, rucaparib, saruparib, and tapazoparib.

[0220] Antimetabolite antitumor drugs are antitumor drugs that act on the S phase of the cell cycle (DNA synthesis). They limit DNA synthesis by inhibiting DNA synthesis, or by inhibiting the synthesis of purine or pyrimidine bases. Therefore, the S phase cannot continue, and cell death occurs. Examples of antimetabolite antitumor drugs include, but are not limited to, fluorouracil, methotrexate, cytarabine, mercaptopurine, thioguanine, and gemcitabine.

[0221] Gemcitabine, 2'-deoxy-2',2'-difluorocytidine hydrochloride (β-isomer), is commercially available. Gemcitabine exhibits cell phase specificity in the S-phase by blocking cell development across the G1 / S boundary. Gemcitabine can be used in combination with cisplatin for the treatment of locally advanced non-small cell lung cancer, or alone for the treatment of locally advanced pancreatic cancer. Platinum coordination complexes are anticancer agents that interact with DNA. Platinum complexes enter tumor cells, hydrate, and form internal and external cross-links with DNA, leading to adverse biological effects on the tumor. Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.

[0222] As used herein, the term “pharmaceutically acceptable” means, to a reasonable extent of medical judgment, that a compound, substance, composition, and / or dosage form is suitable for use in human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and is commensurate with a reasonable benefit / risk ratio.

[0223] As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt. Exemplary salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucurons, glycosides, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and bis(hydroxynaphthyl) salts (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthyl)carbamate).

[0224] As used herein, the term "treatment" is a method for achieving a beneficial or desired clinical outcome. For the purposes of this invention, a beneficial or desired clinical outcome includes (but is not limited to) any one or more of the following: relief of one or more symptoms, reduction of disease severity, prevention or delay of disease spread (e.g., metastasis), prevention or delay of disease recurrence, delay or slowing of disease progression, improvement of disease condition, inhibition of disease or disease progression, inhibition or slowing of disease or its progression, prevention of its development, and symptom relief (whether partial or overall). "Treatment" also encompasses the pathological outcome of reducing proliferative diseases. The methods provided herein cover any one or more of these therapeutic aspects. Based on the foregoing, the term "treatment" does not necessarily require the complete elimination of all aspects of the condition.

[0225] In the case of cancer, the term "treatment" includes (but is not limited to): inhibiting cancer cell growth, inhibiting cancer cell replication, reducing total tumor burden and delaying, stopping or slowing tumor growth, progression or metastasis.

[0226] As used herein, “cancer” refers to a physiological condition in mammals typically characterized by uncontrolled cell growth. Examples of cancer include, but are not limited to, blood-borne tumors (e.g., multiple myeloma, lymphoma, and leukemia) and solid tumors. Non-limiting examples of blood cancers include non-Hodgkin lymphoma, Hodgkin lymphoma, multiple myeloma, leukemia, lymphoma, myelodysplastic syndromes, acute lymphoblastic leukemia, acute myeloid leukemia, and chronic myeloid leukemia. Non-limiting examples of solid tumors include breast cancer (especially triple-negative breast cancer), gastric cancer, kidney cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, lung cancer, colon cancer, breast cancer, melanoma, and pancreatic cancer.

[0227] As used herein, “patient,” “subject,” and “subject” refer to an animal, such as a mammal. In some embodiments, the patient is a human. In other embodiments, the patient is a non-human animal, such as a dog, cat, livestock (e.g., a horse, pig, or donkey), chimpanzee, or monkey.

[0228] The anticancer effect of anticancer drugs can be inferred from specific data, such as the tumor growth inhibition rate (TGI). The tumor growth inhibition rate is calculated using the following formula: TGI = 100 - (TV) Dn给药组 TV D0给药组 ) / (TV Dn对照组 TV D0对照组 )*100

[0229] Calculate the tumor growth inhibition rate (TGI%).

[0230] In specific implementations, the tumor growth inhibition rate of the 104 monotherapy or the combination of 104 monotherapy and olaparib is 30% or higher, preferably 35% or higher, 40% or higher, 45% or higher, 50% or higher, 55% or higher, 60% or higher, 65% or higher, 70% or higher, 75% or higher, 80% or higher, 85% or higher, 90% or higher, 95% or higher, or 100% or higher.

[0231] Example

[0232] Preparation Example 1. Preparation of compound 4'-cyclopropyl-5,6'-dimethoxy-N-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]oct-1-yl)methyl)-[2,5'-bipyrimidine]-4-amine (hereinafter referred to as 104).

[0233] The preparation method of the compounds is as described in CN116496252A for the preparation of compound 104, and the entire contents of that description are incorporated herein by reference. The intermediate compounds BB2C35 and A2-7 are identical to those in CN116496252A.

[0234] In short, the intermediate compound BB2C35 (125.0 mg, 0.36 mmol, 1.00 eq), compound A2-7 (118.1 mg, 0.72 mmol, 2.00 eq), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos-Pd-G2, 56.58 mg, 0.072 mmol, 0.20 eq), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos, 68.65 mg) were sequentially added. 0.144 mmol (0.40 eq) and potassium phosphate (229.3 mg, 1.08 mmol, 3.00 eq) were added to dioxane (2.5 mL) and water (0.5 mL). The mixture was purged with nitrogen three times and stirred at 95 °C for 16 hours under nitrogen protection. Water (15.0 mL) and ethyl acetate (30.0 mL) were added for extraction three times. The organic layers were combined, washed twice with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-0 / 1) to obtain a white solid compound 104.

[0235] Preparation Example 2. Example 215: Synthesis of compound (4'-cyclopropyl-5,6'-dimethoxy-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)chicol-1-yl)methyl)-[2,5'-bispyrimidine]-4-amine) (hereinafter referred to as compound 215)

[0236] For details on the synthesis of the compound, please refer to International Patent Application PCT / CN2023 / 091270; the entire contents of which are incorporated herein by reference.

[0237] In short, the synthetic steps of compound 215 are as follows:

[0238] Compound 215 (7.77 mg, 14.0 μM, 11.9% yield), a white solid, was prepared from compound 207-5 (500 mg, 1.61 mmol, 1.0 eq) and 7 M ammonia-methanol (40.0 mL, 173 eq). LC-MS: m / z = 538.3 (M+H) + .

[0239] In vivo testing Example 1.104: Role of monotherapy in an MDA-MB-436 (BRCA1 mutation) subcutaneous tumor model

[0240] This method evaluates the efficacy of 104 monotherapy drugs in an MDA-MB-436 (BRCA1 mutation) subcutaneous tumor model.

[0241] Experimental methods:

[0242] 1. Cell preparation

[0243] 1.1 Cell Culture

[0244] MDA-MB-436: Human breast cancer cells (BRCA1 mutation) were adherent cells purchased from the American Type Culture Collection (ATCC), catalog number: HTB-130. The complete culture medium consisted of DMEM + 10% FBS + 1% ITS-G + 1% PS. Cells were tested during the logarithmic growth phase.

[0245] 1.2 Preparation of cell suspension:

[0246] Harvest cells in the logarithmic growth phase and count them using a Thermo Countess 2. Ensure cell viability is above 95%. Adjust the cell suspension concentration to 5 × 10⁻⁶. 7 1 cell / mL, each mouse was inoculated with cell suspension and 0.2 mL of Matrigel (1:1).

[0247] 2. Preparation of laboratory animals

[0248] 2.1 Eighty 6-8 week old female BALB / c nude mice were ordered from Zhejiang Vital River for the experiment.

[0249] 3. Experimental Design

[0250] After the tumors grew to a certain size following inoculation, the drugs were administered to different groups. The average tumor size in this experiment was 196 mm. 3 The grouping and dosing regimens are as follows.

[0251] Table 1 Pharmacodynamic Experimental Design Note: Dosage volume: 10 mL / kg based on mouse body weight.

[0252] po: oral administration.

[0253] QD: Once a day.

[0254] Blank control: 0.5% CMC-Na+ 0.5% Tween-80

[0255] 4. Preparation of test compounds

[0256] 4.1 Compound Information

[0257] Compound name and batch number: 104 / 20220057-05-P1

[0258] Purity: 99.2%

[0259] Calculation formula: Volume = Weight × Purity / Concentration

[0260] Solvent: 0.5% CMC-Na+0.5% Tween-80

[0261] Compound name and batch number: KSQ-4279 / 20210081-024-1; see details for the specific structure. Website, Directory Number: HY-145471

[0262] Purity: 99.0%

[0263] Calculation formula: Volume = Weight × Purity / Concentration

[0264] Solvent: 0.5% CMC-Na+0.5% Tween-80

[0265] 4.2 Compound Preparation

[0266] Table 2. Preparation of compounds

[0267] 5. Measurement of tumor size and mouse body weight

[0268] Tumor volume was measured twice a week using calipers, and the calculation formula was V = 0.5a × b. 2 Where a is the long diameter of the tumor (mm) and b is the short diameter of the tumor (mm). Body weight is recorded using a scale twice a week.

[0269] 6. Data Analysis

[0270] 6.1 According to the formula TGI = 100 - (TV) Dn给药组 TV D0给药组 ) / (TV Dn对照组 TV D0对照组 The tumor growth inhibition rate (TGI%) is calculated by multiplying the result by 100. TGI: Tumor inhibition rate. Dn给药组： The average tumor volume on the day of administration in the treatment group; TV D0给药组 : Average tumor volume on the day of treatment group assignment. TV Dn对照组 The average tumor volume on the day of tumor measurement was measured in the blank control group. (TV) D0对照组 The average tumor volume on the day of grouping in the blank control group.

[0271] 6.2 Two-way ANOVA was used to analyze the statistical differences in tumor volume among different tumor-bearing mice after grouping. A p-value less than 0.05 was considered statistically significant.

[0272] 7. Experimental Results

[0273] The experiment ended after 21 days. The 104-drug monotherapy group showed good efficacy at 100 mpk, with a TGI% of 78%, which was significantly different from the blank control group. However, no efficacy was observed at 30 mpk and 10 mpk, with TGI% of 4% and 18%, respectively. The results are shown in Figure 1.

[0274] In vivo testing Example 2.215: Effect of combination with carboplatin, fruquintinib, and olaparib in a CAOV3 subcutaneous tumor model.

[0275] This method evaluates the efficacy of compound 215 as a monotherapy and in combination with carboplatin, fruquintinib, and olaparib in a cov3 (HRD+, homologous recombination defective) subcutaneous tumor model.

[0276] Experimental methods:

[0277] 1. Cell preparation

[0278] 1.1 Cell Culture

[0279] Caov3: Human ovarian cancer cells, adherent cells, were purchased from the American Type Culture Collection (ATCC), catalog number: HTB-75. The complete culture medium was DMEM + 10% FBS + 1% PS. Cells were tested during the logarithmic growth phase.

[0280] 1.2 Preparation of cell suspension:

[0281] Harvest cells in the logarithmic growth phase and count them using a Thermo Countess 2. Ensure cell viability is above 95%. Adjust the cell suspension concentration to 5 × 10⁻⁶. 7 1 cell / mL, each mouse was inoculated with cell suspension and 0.2 mL of Matrigel (1:1).

[0282] 2. Preparation of laboratory animals

[0283] 2.1 155 female NOG mice aged 6-8 weeks were ordered from Zhejiang Vital River for the experiment.

[0284] 3. Experimental Design

[0285] After the tumors grew to a certain size following inoculation, the drugs were administered to different groups. The average tumor size in this experiment was 176 mm. 3 The grouping and dosing regimens are as follows.

[0286] Table 3. Pharmacodynamic experimental design Note: Dosage volume: 10 mL / kg based on mouse body weight.

[0287] 4. Preparation of test compounds

[0288] 4.1 Compound Information

[0289] Compound name and batch number: 215 / EW5066731-P1 / DC230025-0329

[0290] Purity: 98.80%

[0291] Solvent: 0.5% CMC-Na+0.5% Tween-80

[0292] Compound name and batch number: Olaparib / 279339

[0293] Purity: 99.61%

[0294] Solvent: 10% DMSO+90% 10% HP-β-CD

[0295] Compound name and batch number: Fruquintinib / 95759

[0296] Purity: 99.09%

[0297] Solvent: 10% DMSO+90% 20% SBE-β-CD

[0298] Compound name and batch number: Carboplatin / 3M131CA4

[0299] purity: /

[0300] Media: saline

[0301] 4.2 Compound Preparation

[0302] Table 4. Compound Formulation

[0303] 5. Measurement of tumor size and mouse body weight

[0304] Tumor volume was measured twice a week using calipers, and the calculation formula was V = 0.5a × b. 2 Where a is the long diameter of the tumor (mm) and b is the short diameter of the tumor (mm). Body weight is recorded using a scale twice a week.

[0305] 6. Data Analysis

[0306] 6.1 According to the formula TGI = 100 - (TV) Dn给药组 TV D0给药组 ) / (TV Dn对照组 TV D0对照组 )×100 to calculate the tumor growth inhibition rate (TGI%).

[0307] 6.2 Two-way ANOVA was used to analyze the statistical differences in tumor volume among different tumor-bearing mice after grouping. A p-value less than 0.05 was considered statistically significant.

[0308] 7. Experimental Results

[0309] The experiment concluded after 32 days. The combination of 215 at 30 mpk (D1-D5) and 50 mpk (D6-D32) with carboplatin 30 mpk demonstrated efficacy, with a TGI% of 75.80%, significantly better than the 215 and carboplatin 30 mpk monotherapy groups (TGIs of 23.4% and 40.11%, respectively). Similarly, the combination of 215 at 30 mpk (D1-D5) and 50 mpk (D6-D32) with fruquintinib 3 mpk also demonstrated efficacy, with a TGI% of 74.59%, significantly better than the 215 and fruquintinib 3 mpk groups (TGIs of 23.4% and 35.92%, respectively).

[0310] The results are shown in Figures 2A and 2B and Table 5.

[0311] Table 5 *p<0.05**p<0.01***p<0.001****p<0.0001,versus Vehicle,ANOVA

[0312] In vivo testing Example 3.104: Effect of combination with gemcitabine, olaparib, and avastin (bevacizumab injection) in a CAOV3 subcutaneous tumor model.

[0313] This method evaluates the efficacy of 104 monotherapy and in combination with gemcitabine, olaparib, and avastin (bevacizumab injection) in a caov3 (HRD+, homologous recombination defective) subcutaneous tumor model.

[0314] Experimental methods:

[0315] 1. Cell preparation

[0316] 1.1 Cell Culture

[0317] Caov3: Human ovarian cancer cells, adherent cells, were purchased from the American Type Culture Collection (ATCC), catalog number: HTB-75. The complete culture medium was DMEM + 10% FBS + 1% PS. Cells were tested during the logarithmic growth phase.

[0318] 1.2 Preparation of cell suspension:

[0319] Harvest cells in the logarithmic growth phase and count them using a Thermo Countess 2. Ensure cell viability is above 95%. Adjust the cell suspension concentration to 5 × 10⁻⁶. 7 1 cell / mL, each mouse was inoculated with cell suspension and 0.2 mL of Matrigel (1:1).

[0320] 2. Preparation of laboratory animals

[0321] 2.1 One hundred female NCG mice aged 6-8 weeks were ordered from Jicui Yaokang for the experiment.

[0322] 3. Experimental Design

[0323] After the tumors grew to a certain size following inoculation, the drugs were administered to different groups. The average tumor size in this experiment was 162 mm. 3 The grouping and dosing regimens are as follows.

[0324] Table 6. Pharmacodynamic Experimental Design Note: Dosage volume: 10 mL / kg based on mouse body weight.

[0325] 4. Preparation of test compounds

[0326] 4.1 Compound Information

[0327] Compound name and batch number: 104 / 231102R

[0328] Purity: 97.90%

[0329] Solvent: 0.5% CMC-Na+0.5% Tween-80

[0330] Compound name and batch number: Gemcitabine / 263166

[0331] Purity: 99.83%

[0332] Solvent: Saline

[0333] Compound name and batch number: Olaparib / 279339

[0334] Purity: 99.61%

[0335] Solvent: 10% DMSO+90% 10% HP--CD

[0336] Compound name and batch number: Avastin (bevacizumab injection) / H0392B01

[0337] purity: /

[0338] Solvent: Saline

[0339] 4.2 Compound Preparation

[0340] Table 7. Compound Formulation

[0341] 5. Measurement of tumor size and mouse body weight

[0342] Tumor volume was measured twice a week using calipers, and the calculation formula was V = 0.5a × b. 2 Where a is the long diameter of the tumor (mm) and b is the short diameter of the tumor (mm). Body weight is recorded using a scale twice a week.

[0343] 6. Data Analysis

[0344] 6.1 According to the formula TGI = 100 - (TV) Dn给药组 TV D0给药组 ) / (TV Dn对照组 TV D0对照组 )×100 to calculate the tumor growth inhibition rate (TGI%).

[0345] 6.2 Two-way ANOVA was used to analyze the statistical differences in tumor volume among different tumor-bearing mice after grouping. A p-value less than 0.05 was considered statistically significant.

[0346] 7. Experimental Results

[0347] The experiment ended after 35 days. 104 showed efficacy in the combination of 300 mpk and gemcitabine 5 mpk, with a TGI% of 85.13%, which was significantly better than that of 104 and gemcitabine monotherapy groups (TGIs of 38.64% and 47.55%, respectively), showing a significant difference.

[0348] 104 showed efficacy in the combination of 300 mpk and olaparib 100 mpk, with a TGI% of 122.15%, which was significantly better than that of the 104 and Avastin monotherapy groups (TGIs of 38.64% and 19.95%, respectively). However, the mice in this combination therapy group had poor tolerance, and the treatment was discontinued on day 25, resulting in the death of 3 mice.

[0349] 104 showed efficacy in the combination of 300 mpk and Avastin 5 mpk, with a TGI% of 98.10%, which was significantly better than that of 104 and Avastin monotherapy groups (TGIs of 38.64% and 64.36%, respectively), showing a significant difference.

[0350] The results are shown in Table 8 and Figures 3A and 3B.

[0351] Table 8 *p<0.05**p<0.01***p<0.001****p<0.0001, versus blank control, ANOVA

[0352] The differences between the single-drug group and the combination-drug group are shown in Table 9 below:

[0353] Table 9 *p<0.05**p<0.01***p<0.001****p<0.0001, versus blank control, ANOVA

Claims

A combination product comprising: USP1 inhibitors, and Other anti-tumor drugs besides USP1 inhibitors; among them The USP1 inhibitor has the structure shown in Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, isotopic substitute, or stereoisomer thereof: in, each of ring A and ring B is independently selected from C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, and each of ring A and ring B is independently optionally substituted with one or more R1; L is selected from a chemical bond, -O-, -S-, -C 1-6 alkylene-, -O-C 1-6 alkylene-, -C 1-6 alkylene-O-, -S-C 1-6 alkylene- and -C 1-6 alkylene-S-; R a and R b are each independently selected from the group consisting of an H atom, -CN, C 1-6 alkyl, -OH, halo, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy; or R a and R b together form an oxo group, C 3-8 cycloalkyl, or 3-8 membered heterocyclyl; R2is selected from the group consisting of H atom, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, -C 1-6 alkynyl, -C 6-10 aryl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl and 5-7 membered heterocyclyl, wherein said C 1-6 alkyl or -C 1-6 alkyl-C 6-10 aryl is optionally substituted with one or more R1; Preferably, R2 is selected from H atom, -CN, methyl, trideuteryl, ethynyl, propynyl, tetrahydrofuranyl, cyclopropyl, methoxy, and hydroxyl; R3 is selected from H atom, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, 5-7 membered heterocyclic groups and -C 1-6 Alkylene-C(O)-OC 1-6 Alkyl, wherein the C 1-6 The hydroxyalkyl group and the 5-7 membered heterocyclic group are each independently optionally constituting one or more C groups. 1-6 Alkyl substitution; Preferably, R3 is selected from H atom, methoxy group, trifluoromethyl group, Cl atom, -CN group, isopropoxy group, ethynyl group, difluoromethoxy group, morpholinyl group, etc. -OH、 F atom, hydroxymethyl and More preferably, R3is selected from the group consisting of H atom, -OH, -COOH, -NH2, -CN, halogen, C 1-6 alkyl; Further preferably, R3is selected from a H atom, a C 1-6 alkyl group; R4 is selected from H atom, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Hydroxyalkyl; Preferably, R4 is a H atom; R5 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, and C fused with 5-10 heteroaryl 6-10 Aryl groups, C fused with 3-8 membered heterocyclic groups 6-10 Aryl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally substituted by one or more R1 groups; R1 is independently selected from D atom, -OH, -COOH, -NH2, -CN, oxo group, halogen, C at each occurrence. 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -OC 1-6 Alkylene-OC 1-6 Alkyl, wherein the C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently selected from the D atom, -OH, -COOH, -NH2, -CN, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 One or more substituents of the hydroxyalkyl group are substituted; and n is an integer between 0 and 8. The combined product according to claim 1, wherein Ring A and ring B are each independently selected from phenyl, piperidinyl, cyclohexyl, cyclopropyl, cyclobutyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, bicyclo[2.2.2]octyl, 2-oxabicyclo[2.2.2]octyl, pentacyclooctyl, isoindolone, imidazo[1,2-a]pyrazinyl, piperidin-2,6-diketone, thienyl, furanyl, cyclopentyl, pyranyl, pyrrolidinyl, piperazinyl, Morpholinyl, naphthyl, pyrroleyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, indolyl, isoindolyl, indololinyl, isoindololinyl, indololinone, pyrido[3,2-d]pyrimidinyl, pteridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, and cubic alkyl, wherein ring A and ring B are each optionally substituted independently by one or more R1s, wherein R1 is as defined in claim 1; L is selected from chemical bonds, -O-, -OC. 1-6 alkylene- and -C 1-6 Alkylene-O-; In particular, Selected from Furthermore, ring A and ring B can each be independently and arbitrarily replaced by one or more R1s, as defined in claim 1; More specifically, Selected from The combined product according to claim 1 or 2, wherein R5 is selected from C. 6-10 Aryl, 5-6 membered heteroaryl, C fused with 5-6 membered heterocyclic group 6-10 Aryl groups and C groups fused with 5-6 heteroaryl groups 6-10 The aryl group, preferably selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, indolyl, indololinyl, and isoxazolyl, wherein C 6-10 Aryl, 5-6 membered heteroaryl, C fused with 5-6 membered heterocyclic group 6-10 Aryl groups and C groups fused with 5-6 heteroaryl groups 6-10 Each aryl group is independently selected from -OH, -COOH, -NH2, -CN, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl and C 3-6 One or more substituents of the cycloalkyl group are used for substitution; Specifically, R5 is selected from More specifically, R5 is The combined product according to any one of claims 1-3, wherein n is 0 or 1; R a and R b Each is independently selected from H atoms, -CN, and C atoms. 1-6 Alkyl groups, -OH groups, and halogens; Preferably, R a and R b Each is an independent H atom. The combined product according to any one of claims 1-4, wherein the USP1 inhibitor is selected from: The combined product according to any one of claims 1-5, wherein, Other anti-tumor drugs besides the USP1 inhibitor are selected from anti-angiogenic drugs; More preferably, the anti-angiogenic drug is selected from monoclonal antibodies and small molecule tyrosine kinase inhibitors; More preferably, the anti-angiogenic drug is selected from: carboplatin, fruquintinib, gemcitabine, bevacizumab, ramucirumab, sorafenib, sunitinib, apatinib, regorafenib, cabozantinib, and lenvatinib; Alternatively, other anti-tumor drugs besides the USP1 inhibitor may be selected from olatinib. The combination product according to any one of claims 1-6 is used for the treatment of cancer. According to the combined product of claim 7, wherein the cancer is selected from: breast cancer, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, uterine cancer, peritoneal cancer, and endometrial cancer. Preferably, the cancer is ovarian cancer. The combination product according to any one of claims 1-8, wherein the other antitumor drug besides the USP1 inhibitor is selected from carboplatin, fruquintinib, olaparib, gemcitabine, and bevacizumab. The combination product according to any one of claims 1-9, wherein the USP1 inhibitor and other antitumor drugs besides the USP1 inhibitor are administered simultaneously, separately or sequentially. The use of a USP1 inhibitor in combination with other antitumor drugs besides USP1 inhibitors in the preparation of a drug for treating cancer, wherein The USP1 inhibitor has the structure shown in Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, isotopic substitute, or stereoisomer thereof: in, Ring A and ring B are each independently selected from C. 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein ring A and ring B are each independently and optionally substituted by one or more R1 groups; L is selected from chemical bonds, -O-, -S-, and -C. 1-6 Alkylene-, -OC 1-6 alkylene-, -C 1-6 Alkylene-O-, -SC 1-6 alkylene- and -C 1-6 Alkylene-S-; R a and R b Each is independently selected from H atoms, -CN, and C atoms. 1-6 Alkyl, -OH, halogen, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy; or R a and R b Together they form oxygen groups, C 3-8 cycloalkyl or 3-8 membered heterocyclic groups; R2 is selected from H atom, -OH, -CN, C 1-6 Alkyl, C 2-6 alkynyl group, -C 1-6 Alkyl-C 6-10 Aryl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-6 cycloalkyl and 5-7 membered heterocyclic groups, wherein the C 1-6 Alkyl or -C 1-6 Alkyl-C 6-10 The aryl group may be optionally substituted by one or more R1s; Preferably, R2 is selected from H atom, -CN, methyl, trideuteryl, ethynyl, propynyl, tetrahydrofuranyl, cyclopropyl, methoxy, and hydroxyl; R3 is selected from H atom, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, 5-7 membered heterocyclic groups and -C 1-6 Alkylene-C(O)-OC 1-6 Alkyl, wherein the C 1-6 The hydroxyalkyl group and the 5-7 membered heterocyclic group are each independently optionally constituting one or more C groups. 1-6 Alkyl substitution; More preferably, R3 is selected from H atom, -OH, -COOH, -NH2, -CN, halogen, C 1-6 alkyl; More preferably, R3 is selected from H atoms, C atoms 1-6 alkyl; Preferably, R3 is selected from H atom, methoxy group, trifluoromethyl group, Cl atom, -CN group, isopropoxy group, ethynyl group, difluoromethoxy group, morpholinyl group, etc. -OH、 F atom, hydroxymethyl and R4 is selected from H atom, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Hydroxyalkyl; Preferably, R4 is a H atom; R5 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, and C fused with 5-10 heteroaryl 6-10 Aryl groups, C fused with 3-8 membered heterocyclic groups 6-10 Aryl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally substituted by one or more R1 groups; R1 is independently selected from D atom, -OH, -COOH, -NH2, -CN, oxo group, halogen, C at each occurrence. 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -OC 1-6 Alkylene-OC 1-6 Alkyl, wherein the C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently selected from the D atom, -OH, -COOH, -NH2, -CN, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 One or more substituents of the hydroxyalkyl group are substituted, and n is an integer between 0 and 8. The use according to claim 11, wherein Ring A and ring B are each independently selected from phenyl, piperidinyl, cyclohexyl, cyclopropyl, cyclobutyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, bicyclo[2.2.2]octyl, 2-oxabicyclo[2.2.2]octyl, pentacyclooctyl, isoindolone, imidazo[1,2-a]pyrazinyl, piperidin-2,6-diketone, thiophene, furanyl, cyclopentyl, pyranyl, pyrrolidinyl, piperazinyl, morphoyl, etc. The compounds are linyl, naphthyl, pyrroleyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, indolyl, isoindolyl, indololinyl, isoindololinyl, indololinone, pyrido[3,2-d]pyrimidinyl, pteridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, and cubic alkyl, wherein ring A and ring B are each optionally substituted independently by one or more R1s, wherein R1 is as defined in claim 11; L is selected from chemical bonds, -O-, -OC. 1-6 alkylene- and -C 1-6 Alkylene-O-; In particular, Selected from Furthermore, ring A and ring B can each be independently and arbitrarily replaced by one or more R1s, as defined in claim 11; More specifically, Selected from The use according to claim 11 or 12, wherein R5 is selected from C. 6-10 Aryl, 5-6 membered heteroaryl, C fused with 5-6 membered heterocyclic group 6-10 Aryl groups and C groups fused with 5-6 heteroaryl groups 6-10 The aryl group is preferably selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, indolyl, indololinyl, and isoxazolyl, wherein C 6-10 Aryl, 5-6 membered heteroaryl, C fused with 5-6 membered heterocyclic group 6-10 Aryl groups and C groups fused with 5-6 heteroaryl groups 6-10 Each aryl group is independently selected from -OH, -COOH, -NH2, -CN, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl and C 3-6 One or more substituents of the cycloalkyl group are used for substitution; Specifically, R5 is selected from More specifically, R5 is The use according to any one of claims 11-13, wherein n is 0 or 1; R a and R b Each is independently selected from H atoms, -CN, and C atoms. 1-6 Alkyl groups, -OH groups, and halogens; Preferably, R a and R b Each is an independent H atom. The use according to any one of claims 11-14, wherein the USP1 inhibitor is selected from: The use according to any one of claims 11-15, wherein, Other anti-tumor drugs besides the USP1 inhibitor are selected from anti-angiogenic drugs; More preferably, the anti-angiogenic drug is selected from monoclonal antibodies and small molecule tyrosine kinase inhibitors; More preferably, the anti-angiogenic drug is selected from carboplatin, fruquintinib, gemcitabine, bevacizumab, ramucirumab, sorafenib, sunitinib, apatinib, regorafenib, cabozantinib, and lenvatinib; Alternatively, other anti-tumor drugs besides the USP1 inhibitor may be selected from olatinib. The use according to any one of claims 11-16, wherein the USP1 inhibitor is co-administered with other antitumor drugs other than the USP1 inhibitor in the same formulation or different formulations; Preferably, the USP1 inhibitor is administered simultaneously, separately, or sequentially with other antitumor drugs besides the USP1 inhibitor; Preferably, the antitumor drugs other than the USP1 inhibitor are selected from: carboplatin, fruquintinib, olaparib, gemcitabine, and bevacizumab. The use according to any one of claims 11-17, wherein the USP1 inhibitor significantly enhances the antitumor activity of other antitumor drugs besides the USP1 inhibitor. The use according to any one of claims 11-17, wherein the cancer is selected from breast cancer, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, uterine cancer, peritoneal cancer, and endometrial cancer. Preferably, the cancer is ovarian cancer.

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