Combination of AKR1C3-activated anti-cancer prodrug compound and analgesic for treating cancer patients with pain

Abstract

The invention provides a treatment method for treating a cancer patient accompanied with pain by combining an AKR1C3 activated anti-cancer prodrug compound and an analgesic drug, a pharmaceutical application, a drug combination and a drug preparation thereof, provides a reasonable selection scheme for clinical treatment of cancer, and particularly, provides a novel application of the drug combination to the treatment of cancer patients accompanied with pain. By combining the AST-3424 and the non-steroidal analgesic medicine, the effects of treating cancers and relieving pain at the same time can be achieved.

Description

AKR1C3-activating anticancer prodrug compounds combined with analgesics for the treatment of cancer patients with pain Technical Field

[0001] The present invention relates to a method for treating tumors and cancers, in particular to a method for treating cancers and tumors by combining an AKR1C3 activated anticancer prodrug compound with a non-steroidal analgesic drug, and belongs to the field of tumor treatment. Background Art

[0002] AST-3424 (WO2016145092, WO2017087428), a DNA alkylating agent prodrug targeting overexpressed aldehyde-keto reductase 1C3 (AKR1C3), has a CAS number of 2097713-69-2 and its structure is as follows:

[0003] Chemical structure of AST-3424

[0004] AST-3424 (also known as OBI-3424, TH-3424) enters cancer cells and is activated by the AKR1C3 enzyme overexpressed by cancer cells to release the metabolite AST-2660 (also known as AST-2660). AST-3424 itself has low toxicity to cancer cells. In its animal models and in vitro pharmacological experiments, its pharmacological effects are related to the expression of AKR1C3 enzyme: the prodrug AST-3424 is metabolized to AST-2660 under the action of AKR1C3 enzyme and NADPH, and the expression level of the enzyme is positively correlated with the efficacy (Meng F, Li WF, Jung D, et al. A novel selective AKR1C3-activated prodrug AST-3424 / OBI-3424 exhibits broad anti-tumor activity. Am J Cancer Res. 2021; 11(7): 3645-3659; Evans K, Duan J, Pritchard T, et al. OBI-3424, a Novel AKR1C3-Activated Prodrug, Exhibits Potent Efficacy against Preclinical Models of T-ALL. Clin Cancer Res.2019;25(14):4493-4503.doi:10.1158 / 1078-0432.CCR-19-0551;Wang Y,Liu Y,Zhou C,et al.An AKR1C3-specific prodrug with potent anti-tumor activities against T-ALL.Leuk Lymphoma.2020;61(7):1660-1668.doi:10.1080 / 10428194.2020.1728746; He P,Wang C,Wang Y,et al.A Novel AKR1C3 Specific Prodrug TH3424 With Potent Antitumor Activity in Liver Cancer[retracted in:Clin Pharmacol Ther.2021 Jul;110(1):262].Clin Pharmacol Ther. 2021, 110(1):229-237.doi:10.1002 / cpt.2171).

[0005] Chemical reaction formula for the metabolism of AST-3424 to AST-2660 (2660 in the figure)

[0006] Currently, the drug has entered Phase II clinical trials in China and the United States (US NCT03592264, castration-resistant prostate cancer and liver cancer; US NCT04315324, T-ALL T lymphocytic acute leukemia; China CTR20191399, various solid tumors; CTR20201915, T lymphocytic acute leukemia and B lymphocytic acute leukemia).

[0007] In particular, the results of a Phase I clinical trial completed in the United States also revealed that the therapeutic effect of AST-3424 is highly correlated with AKR1C3 enzyme expression, and patients with high AKR1C3 enzyme expression will have a better treatment effect. It has also been preliminarily determined that patients with an IHC score of H-score greater than or equal to 135 will be selected for the Phase II clinical trial (Tsimberidou, Apostolia & Verschraegen, Claire & Hsu, Pei & Pearce, Tillman. (2022). Safety, pharmacokinetics, and clinical activity of OBI-3424, an AKR1C3-activated prodrug, in patients with advanced or metastatic solid tumors: A phase 1 dose-escalation study.. Journal of Clinical Oncology. 40.3030-3030.10.1200 / JCO.2022.40.16_suppl.3030).

[0008] Summary of the Invention

[0009] As the sponsor of the Phase I clinical trial in China, the applicant found in some cases of advanced solid tumors reported in the clinical trial that some patients had higher AKR1C3 enzyme expression and had a better response to AST-3424; while some patients had almost the same higher AKR1C3 enzyme expression but had almost no response to AST-3424. After investigation, it was found that some of the patients who did not respond had taken non-steroidal analgesics during the AST-3424 treatment course.

[0010] Existing literature studies have revealed that nonsteroidal analgesics have AKR1C3 inhibitory effects:

[0011] Proc. Natl. Acad. Sci. USA 80 (1983), "Inhibition of a major NAD(P)-linked oxidore ductase from rat liver cytosol by steroidal and nonsteroidal anti-inflammatory agents and by prostaglandins", reported that seven drugs, including aspirin, sodium salicylate, paracetamol, diclofenac, fenoprofen, flufenamic acid, and tolmetin, had AKR1C3 inhibitory activity;

[0012] Y.Higaki et al., Chemico-Biological Interactions, 143-144 (2003) 50-513, Selective and potent inhibitors of human 20a-hydroxysteroid dehydrogenase (AKR1C1) that metabolizes neurosteroids derived from progesterone, reported that indomethacin has AKR1C3 inhibitory activity;

[0013] Biochem Pharmacol. 2008 January 15; 75(2): 484-493. "An Indomethacin Analogue, N-(4-Chlorobenzoyl)-melatonin, is a Selective Inhibitor of Aldo-keto Reductase 1C3 (Type 2 3α-HSD, Type 5 17β-HSD, and Prostaglandin F Synthase), a Potential Target for the Treatment of Hormone Dependent and Hormone Independent Malignancies". It was reported that six drugs, including naproxen, ibuprofen, flurbiprofen, zomepirac, meclofenamic acid, and sulindac, had AKR1C3 inhibitory activity.

[0014] Mol Pharmacol 67:60-68, 2005, "Development of Nonsteroidal Anti-Inflammatory Drug Analogs and Steroid Carboxylates Selective for Human Aldo-Keto Reductase Isoforms: Potential Antineoplastic Agents That Work Independently of Cyclooxygenase Isozymes", reported that celecoxib and mefenamic acid have AKR1C3 inhibitory activity.

[0015] But after these non-steroidal analgesics inhibit AKR1C3 activity, will they affect the process by which AKR1C3 enzyme metabolizes AST-3424 and other similar AKR1C3-activated anticancer prodrug compounds into effective AST2660, thereby affecting the efficacy of AST-3424?

[0016] In response to this, the applicant conducted in vivo and in vitro experiments, which demonstrated that certain non-steroidal analgesics, if used in combination with AST-3424, would affect the efficacy of AST-3424, while other non-steroidal analgesics would not.

[0017] Cancer patients often experience pain for various reasons. Clinically, pain is common in patients at any stage of cancer, but it is particularly prevalent in advanced cancer. Data show that approximately 34% of clinically cured cancer patients experience pain, while approximately 25% of newly diagnosed cancer patients experience pain. During treatment, 30% to 50% of patients experience pain, and the rate can reach 70% to 90% in advanced cancer patients. Because pain can severely impact patients' quality of life, most patients receive analgesics under the guidance of medical professionals. Symptomatic intervention and treatment are implemented according to the World Health Organization's three-step cancer pain relief ladder. In the first stage, oral analgesia is the primary treatment, primarily with common nonsteroidal anti-inflammatory drugs. In the second stage, if the first-step approach fails to alleviate pain, weaker opioids, such as codeine and extended-release tramadol, are used, as part of the second-step cancer pain treatment ladder. In the third stage, if none of the above-mentioned treatments provide pain relief, stronger opioids, such as oxycodone, morphine, and fentanyl, are used.

[0018] Considering that cancer-associated pain is very common, and that patients in clinical practice often use non-steroidal analgesics for intervention and symptomatic treatment of pain at the same time as taking cancer treatment drugs, the applicant proposed the following technical solution based on the above clinical trial results and the experimental results that some non-steroidal analgesics do not affect the efficacy of AST-3424.

[0019] The method comprises using a drug containing an AKR1C3-activating anticancer prodrug compound or its salt, ester, solvate, or isotopomer in combination with a non-steroidal analgesic drug to treat cancer patients with pain.

[0020] The invention discloses pharmaceutical uses of an AKR1C3-activated anticancer prodrug compound or its salts, esters, solvates and isotope isomers, which are used to prepare therapeutic drugs for treating cancer patients with pain in combination with non-steroidal analgesics.

[0021] The present invention also provides a pharmaceutical combination comprising the following substances as active ingredients:

[0022] AKR1C3 activating prodrug compound or its salt, ester, solvate, isotope isomer, and

[0023] nonsteroidal analgesics;

[0024] The active ingredients are formulated together or separately for combined use, simultaneous use or separate use.

[0025] The drug combination of the present invention is used for treating cancer or tumor patients with pain.

[0026] AKR1C3-activating anticancer prodrug compounds are compounds that metabolize DNA alkylating agents under conditions of AKR1C3 enzyme activation.

[0027] In general, AKR1C3 activating anticancer prodrug compounds satisfy at least one of the following conditions, but are not limited to:

[0028] A. In the presence of AKR1C3 inhibitors (e.g., compound 36 in Bioorganic and Medicinal Chemistry, 2014: 967-977) The cancer cell proliferation inhibition effect of a compound detected in the absence of an AKR1C3 inhibitor was less than that detected in the absence of an AKR1C3 inhibitor. 50 When quantifying, if the IC value of a compound against a cancer cell line in the presence of an AKR1C3 inhibitor is 50 Greater than the IC in the absence of AKR1C3 inhibitors 50 , it can be determined that the compound is an anticancer drug activated by AKR1C3 (lysis-prodrug). Specific examples are as follows:

[0029] PCT / US2016 / 021581, Publication No. WO2016145092A1, corresponding to Chinese Application No. 2016800150788, Publication No. CN107530556A;

[0030] PCT / US2016 / 062114, publication number WO2017087428, corresponding to Chinese application number 2016800446081, publication number CN108290911A;

[0031] PCT / US2016 / 025665, Publication No. WO2016161342, corresponding to Chinese Application No. 2016800200132, Publication No. CN108136214A; and

[0032] PCT / NZ2019 / 050030, publication number WO2019190331, corresponding to Chinese application number CN2019800234236, publication number CN111918864A,

[0033] PCT / CN2020 / 120281, publication number WO2021068952, corresponding to the compound disclosed in Chinese application number CN2020800716528, publication number CN114555574A.

[0034] The entire text of the above patent documents is hereby incorporated into the text of this patent application.

[0035] Among them, the compounds disclosed in patent PCT / US2016 / 021581, publication number WO2016145092A1, corresponding to Chinese application number 2016800150788, publication number CN107530556A; PCT / US2016 / 062114, publication number WO2017087428, corresponding to Chinese application number 2016800446081, publication number CN108290911A; PCT / US2016 / 025665, publication number WO2016161342, corresponding to Chinese application number 2016800200132, publication number CN108136214A are cleavage prodrugs, and the original drug that is finally cleaved and metabolized to produce the active substance is As well as drugs such as paclitaxel and camptothecin; the compound disclosed in patent PCT / NZ2019 / 050030, publication number WO2019190331, corresponding to Chinese application number CN2019800234236 and publication number CN111918864A, is a cleavage prodrug, and the ultimate cleavage metabolized prodrug is a nitrogen mustard structure drug;

[0036] B. A certain compound has significant differences in its inhibitory effect on cancer cells with different expression levels of AKR1C3 enzyme, and its inhibitory effect on cancer cells with high expression of AKR1C3 enzyme is much greater than that on cancer cells with low expression of AKR1C3 enzyme. 50 When quantifying, if a compound has an IC 50 The value is less than the IC of cancer cells with low AKR1C3 expression 50 When the value is , it can be determined that the compound is an anticancer drug activated by AKR1C3. Specifically, the compounds disclosed in patents PCT / CN2020 / 120281, publication number WO2021068952A1; PCT / IB2020 / 057285, publication number WO2021005586 (corresponding to Chinese application number 2020800538041, publication number CN114206870A). The full text of this patent document is hereby incorporated into the text of this patent application.

[0037] The drug described herein refers to a medicine or preparation, wherein the prepared medicine contains an active ingredient compound or a salt or solvate thereof within a specific dosage range, and / or the prepared medicine is in a specific dosage form and is administered by a specific administration method.

[0038] The prepared medicine, drug, preparation may also include pharmaceutically acceptable adjuvants or excipients. The medicine may be in any dosage form for clinical use, such as tablets, suppositories, dispersible tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, sugar-coated tablets, granules, dry powders, oral solutions, small needles for injection, freeze-dried powder for injection, or large infusions. Depending on the specific dosage form and mode of administration, the pharmaceutically acceptable adjuvants or excipients in the medicine may include one or more of the following: diluents, solubilizers, disintegrants, suspending agents, lubricants, adhesives, fillers, flavorings, sweeteners, antioxidants, surfactants, preservatives, wrappers, and pigments.

[0039] Monotherapy refers to single-drug therapy. Combination therapy refers to combined drug therapy. Monotherapy refers to the use of only one anticancer drug in a single course of treatment. Combination therapy refers to the use of two or more anticancer drugs simultaneously or sequentially in a single course of treatment.

[0040] Generally speaking, combination therapy requires exploring different dosages and dosing cycles based on the characteristics of the disease and the types of combined drugs. Only based on the above conditions can the combination drug treatment plan explored achieve better therapeutic effects than single drug treatment.

[0041] The drug dosage, administration cycle and administration schedule of monotherapy and combination therapy are explored through clinical trials.

[0042] Regarding the compounds described herein, if their chemical structures contain organic amine structures and P=O double bond structures, the compounds may also be administered in the form of salts. That is, the present invention provides pharmaceutically acceptable salts of the compounds, which may be basic salts, including salts formed with inorganic bases (e.g., alkali metal hydroxides, alkaline earth metal hydroxides, etc.) or with organic bases (e.g., monoethanolamine, diethanolamine, or triethanolamine, etc.). Alternatively, the salts may be acidic salts, including salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid, or phosphoric acid, etc.) or with organic acids (e.g., methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, maleic acid, citric acid, etc.). Similarly, they may react with certain acids or alcohols to form esters, and thus the compounds may also be administered in the form of esters.

[0043] Similarly, the above-mentioned compound concept also includes various crystal forms of the compound, such as PCT application PCT / CN2023 / 080261 and publication WO2023169462A1, which disclose a crystal form of an AKR1C3-activated anticancer prodrug compound:

[0044] For various reasons, these compounds may also form solvates with certain solvents, such as hydrates or alcoholates, and thus the compounds may also be administered in the form of solvates. The selection and preparation of acceptable salts, esters and solvates of compounds are well known in the art.

[0045] The term "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including but not limited to hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl), chlorine-36 ( 36 Cl), chlorine-37( 37 Cl), bromine-79( 79 Br), bromine-81( 81 Br), iodine-123 ( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I) and iodine-131( 131I). In certain embodiments, an "isotopic variant" of a compound is a stable form, i.e., non-radioactive. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including but not limited to hydrogen ( 1 H), deuterium ( 2 H), carbon-12 ( 12 C), carbon-13 ( 13 C), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), phosphorus-31 ( 31 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl), chlorine-37( 37 Cl), bromine-79( 79 Br), bromine-81( 81 Br) and iodine-127( 127 I). In certain embodiments, an "isotopic variant" of a compound is an unstable form, i.e., radioactive. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including but not limited to tritium ( 3 H), carbon-11 ( 11 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), fluorine-18 ( 18 F), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-35( 35 S), chlorine-36 ( 36 Cl), iodine-123 ( 123 I), iodine-125( 125 I), iodine-129( 129 I) and iodine-131( 131 I) It is understood that in the compounds provided herein, any hydrogen may be replaced by, for example, 2 H is D, or any carbon can be, for example 13 C, or any nitrogen may be e.g. 15 N, and any oxygen may be18 O. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of deuterium (D).

[0046] Nonsteroidal analgesics are a large class of drugs, also known as "nonsteroidal anti-inflammatory analgesics" because they often have anti-inflammatory effects. From a structural point of view, nonsteroidal antipyretic analgesics refer to a class of antipyretic analgesics that do not contain steroidal structures in their chemical structure. Some varieties also have anti-inflammatory and anti-rheumatic effects. Nonsteroidal analgesics used clinically include the following varieties:

[0047] Nonsteroidal analgesics mainly include:

[0048] 1. Salicylic acid, the representative drug is aspirin.

[0049] 2. Acetanilide, the representative drug is acetaminophen.

[0050] 3. Aromatic acid class, representative drugs include diclofenac, indomethacin, and sulindac.

[0051] 4. Arylpropionic acid class, representative drugs include ibuprofen, naproxen, and flurbiprofen axetil.

[0052] 5. Oxicams, representative drugs include flunoxicam, piroxicam, and meloxicam.

[0053] 6. Pyrazolones, representative drugs include phenylbutazone, hydroxyphenylbutazone, and metamizole.

[0054] 7. Selective COX-2 inhibitors, representative drugs include celecoxib, nimesulide, etoricoxib, and parecoxib.

[0055] The nearly 40 drugs listed above can all be classified into the above 7 categories.

[0056] The AKR1C3-activating anticancer prodrug compound is selected from the structural formulas (1) to (11):

[0057] Among them, R1, R2, R3, R4, R5, R8, R9, R 10 The definition is as described in the claims of patent application PCT / CN2020 / 089692, publication number WO2020228685A1 (corresponding to Chinese application number 2020800358890, publication number CN113853379A), and the synthesis and preparation methods of specific compounds are also described in the above application, which are hereby incorporated into this application in their entirety. The specific definitions are as follows:

[0058] in,

[0059] R1 is C6-C 10 Aryl or Z-substituted aryl, 4-15 membered heterocyclic or Z-substituted heterocyclic, 5-15 membered heteroaryl or Z-substituted heteroaryl, 7-15 membered fused ring or Z-substituted fused ring;

[0060] R2 is hydrogen, a halogen atom, a cyano group or an isocyano group, a hydroxyl group, a mercapto group, an amino group, OTs, OMS, a C1-C6 alkyl group or a Z-substituted alkyl group, a C2-C6 alkenyl group or a Z-substituted alkenyl group, a C2-C6 alkynyl group or a Z-substituted alkynyl group, a C3-C8 cycloalkyl group or a Z-substituted cycloalkyl group, a C6-C 10 Aryl or Z-substituted aryl, 4-15 membered heterocyclic or Z-substituted heterocyclic, 5-15 membered heteroaryl or Z-substituted heteroaryl, ether of 1-6 carbon atoms or Z-substituted alkoxy of 1-6 carbon atoms, -CONR 6 R 7 、-SO2NR 6 R 7 、-SO2R 6 、-OCOO-R 6 、-COOR 6 、-NR 6 COR 7 、-OCOR 6 、-NR 6 SO2R 7 、-NR 6 SO2NR 6 R 7 Or R2 and the atoms on the R1 group to which it is bonded together form a 7-15 membered fused ring or a Z-substituted fused ring;

[0061] R3 is hydrogen, halogen, cyano or isocyano, hydroxyl, mercapto, amine, OTs, OLCMS, C1-C6 alkyl or Z substituted alkyl, C2-C6 alkenyl or Z substituted alkenyl, C2-C6 alkynyl or Z substituted alkynyl, C3-C8 cycloalkyl or Z substituted cycloalkyl, C6-C 10 Aryl or Z-substituted aryl, 4-15 membered heterocyclic or Z-substituted heterocyclic, 5-15 membered heteroaryl or Z-substituted heteroaryl, C1-C6 alkoxy or Z-substituted C1-C6 alkoxy, -CONR 6 R 7 、-SO2NR 6 R 7 、-SO2R 6 、-OCO-R 6 、-OCOO-R 6 、-COOR 6 、-NR 6 COR 7, -OCOR 6 、-NR 6 SO2R 7 ;

[0062] R4 and R5 are each independently hydrogen, a halogen atom, a cyano group or an isocyano group, a hydroxyl group, a mercapto group, an amino group, OTs, OLCMS, a C1-C6 alkyl group or a Z-substituted alkyl group, a C2-C6 alkenyl group or a Z-substituted alkenyl group, a C2-C6 alkynyl group or a Z-substituted alkynyl group, a C3-C8 cycloalkyl group or a Z-substituted cycloalkyl group, a C6-C 10 Aryl or Z-substituted aryl, 4-15 membered heterocyclic or Z-substituted heterocyclic, 5-15 membered heteroaryl or Z-substituted heteroaryl, C1-C6 alkoxy or Z-substituted C1-C6 alkoxy, -CONR 6 R 7 、-SO2NR 6 R 7 、-SO2R 6 、-OCOO-R 6 、-COOR 6、 -NR 6 COR 6 、-OCOR 6 、-NR 6 SO2R 7 Or R4, R5 and the atoms on the benzene ring to which they are bonded together form a 7-15 membered fused ring or a Z-substituted fused ring;

[0063] R 6 and R 7 Each is independently hydrogen, cyano or isocyano, C1-C6 alkyl or Z substituted alkyl, C2-C6 alkenyl or Z substituted alkenyl, C2-C6 alkynyl or Z substituted alkynyl, C3-C8 cycloalkyl or Z substituted cycloalkyl, C6-C 10 Aryl or Z-substituted aryl, 4-15 membered heterocyclic or Z-substituted heterocyclic, 5-15 membered heteroaryl or Z-substituted heteroaryl, C1-C6 alkoxy or Z-substituted C1-C6 alkoxy, or R 6 、R 7 The group and the atoms to which it is bonded together form a 5-7 membered heterocyclic group or a Z-substituted 5-7 membered heterocyclic group;

[0064] R8, R 10 Each is independently hydrogen, deuterium, aryl or Z-substituted aryl, C1-C6 alkyl or Z-substituted alkyl, C2-C6 alkenyl or Z-substituted alkenyl, C2-C6 alkynyl or Z-substituted alkynyl, C3-C8 cycloalkyl or Z-substituted cycloalkyl, and at least one of them must be hydrogen or deuterium;

[0065] R9 is a substituted C6-C 10aryl, substituted 4- to 15-membered heterocyclic ring having at least one fluorine atom or nitro group, substituted 5- to 15-membered heteroaryl group having at least one fluorine atom or nitro group.

[0066] The Z substituent is a halogen atom, a cyano group or an isocyano group, a hydroxyl group, a thiol group, an amine group, OTs, OMS, a C1-C3 alkyl group or a substituted alkyl group, a C1-C3 alkoxy group or a substituted alkoxy group, a C2-C3 alkenyl group or a substituted alkenyl group, a C2-C3 alkynyl group or a substituted alkynyl group, a C3-C8 cycloalkyl group or a substituted cycloalkyl group, an aromatic ring, a heterocyclic ring, a heteroaromatic ring and a condensed ring or a substituted aromatic ring, a heterocyclic ring, a heteroaromatic ring and a condensed ring, and the substitution is monosubstitution or geminal disubstitution;

[0067] Substitution of C6-C in R9 10 The substituents of the aryl group, the substituted 4-15 membered heterocyclic ring, and the substituted 5-15 membered heteroaryl group are halogen atoms, nitro groups, cyano groups or isocyano groups, hydroxyl groups, amino groups, C1-C3 alkyl groups or alkoxy groups, alkenyl groups, alkynyl groups, cycloalkyl groups or benzene rings, substituted benzene rings, C1-C3 alkoxy groups, or halogen atom-substituted alkoxy groups.

[0068] For typical example compounds, please refer to PCT / CN2020 / 089692. For specific compounds listed in the examples section of publication number WO2020228685A1, the preparation methods and spectral data of these compounds can be found in the above-mentioned patent application text, and the full text of the application is introduced here.

[0069] Wherein, the definitions of A, E, G, X, and Y are as described in the claims of patent application PCT / NZ2019 / 050030, publication number WO2019190331A1 (corresponding to Chinese application number 2019800234236, publication number CN111918864A), and the synthesis and preparation methods of specific compounds are also described in the above application, which are hereby incorporated into this application in their entirety. Specifically as follows:

[0070] in:

[0071] A is H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, CFH2, CF2H, CF3, F, Cl, Br, I, OCF3, COR or CON(R)2;

[0072] E is SO or SO2;

[0073] X is Cl, Br, I or OSO2R;

[0074] Y is Cl, Br, I or OSO2R;

[0075] Each R is independently H or C1-C6 alkyl;

[0076] G is a radical selected from the group consisting of formula (B)-(AA):

[0077] in:

[0078] R1 is H, C1-C6 alkyl, CH2(CH2)nOH, CH2CH(OH)CH2OH, phenyl, pyridyl, benzyl or pyridylmethyl, provided that when R1 is phenyl, pyridyl, benzyl or pyridylmethyl, R1 is optionally substituted at any available position with C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, OR6, N(R6)(R7), CFH2, CF2H, CF3, F, Cl, Br, I, OCF3, COR6, CON(R6)(R7), SOR6, SON(R6)(R7), SO2R6, SO2N(R6)(R7), CN or NO2;

[0079] R2 and R3 are each independently H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, OR6, N(R6)(R7), CFH2, CF2H, CF3, F, Cl, Br, I, OCF3, COR6, CON(R6)(R7), SOR6, SON(R6)(R7), SO2R6, SO2N(R6)(R7), CN or NO2;

[0080] R4 is N(R6)(R7), OH, OCH2(CH2)nN(R6)(R7) or CH2(CH2)nN(R6)(R7);

[0081] R5 is H or a C1-C6 alkyl group;

[0082] R6 and R7 are each independently H or C1-6 alkyl, or R6 and R7 together form a substituted or unsubstituted 5-membered or 6-membered heterocyclic ring;

[0083] Z is CH or N;

[0084] W is CH2, O, S, SO or SO2;

[0085] n is 0 to 6;

[0086] * indicates the point of connection to formula (I).

[0087] For typical example compounds, please refer to the specific compounds listed in the examples section of patent application PCT / NZ2019 / 050030, publication number WO2019190331A1 (corresponding to Chinese application number 2019800234236, publication number CN111918864A). For the preparation methods and spectral data of these compounds, please refer to the above-mentioned patent application text, and the full text of the application is introduced here.

[0088] Wherein, the definition of Rw is as described in the claims of patent application PCT / CN2020 / 120281, publication number WO2021068952A1 (corresponding to Chinese application number 202080071652.8, publication number CN114555574A), and the synthesis and preparation methods of specific compounds are also described in the above application, which are hereby incorporated into this application in their entirety. The specific definitions are as follows:

[0089] Rw is

[0090] R1 is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl are optionally substituted by 1, 2 or 3 R a replaced by;

[0091] Each R a are independently H, F, Cl, Br, I, -CN, -OH, C 1-3 Alkoxy or C 1-3 alkyl;

[0092] R2 is H or C 1-6 alkyl;

[0093] Or R1 and R2 are linked together to form a 4-6 membered heterocycloalkyl group, wherein the 4-6 membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 R b replaced by;

[0094] Each R b are independently H, F, Cl, Br, I, -CN, -OH, -NH2, -OCH3, -OCH2CH3, -CH3 or -CH2CH3;

[0095] R3 is H, F, Cl, Br, I, -OH, -NH2, C 1-3 Alkoxy or C 1-3 alkyl;

[0096] Or R2 and R3 are connected together to make the structural unit for

[0097] T1 is -(CR c R d ) m -or-(CR cR d ) n -O-;

[0098] m is 1, 2, or 3;

[0099] n is 1 or 2;

[0100] T2 is N or CH;

[0101] R c and R d Each independently is H, F, C 1-3 Alkyl or C 1-3 alkoxy;

[0102] R4, R5 and R6 are each independently H, F, Cl, Br, I, C 1-3 Alkyl or C 1-3 alkoxy;

[0103] T is N or CH;

[0104] R7 and R8 are each independently H, F, Cl, Br or I;

[0105] R9 and R 10 Each independently is H, F, Cl, Br, I, -CN or

[0106] The 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl each contain 1, 2, 3 or 4 heteroatoms independently selected from N, -O- and -S-.

[0107] For typical example compounds, please refer to the specific compounds listed in the examples section of patent application PCT / CN2020 / 120281, publication number WO2021068952A1 (corresponding to Chinese application number 202080071652.8, publication number CN114555574A). For the preparation methods and spectral data of these compounds, please refer to the above-mentioned patent application text. The full text of this application is introduced here.

[0108] Among them, X, Y, Z, R, T, A and X 10 The definitions are as described in the claims of patent application PCT / US2016 / 021581, publication number WO2016145092A1 (corresponding to Chinese application number 2016800150788, publication number CN107530556A), and the synthesis and preparation methods of the specific compounds are also described in the aforementioned application, which are hereby incorporated into this application in their entirety. The specific definitions are as follows:

[0109] X 10 O, S, SO or SO2;

[0110] A is C6-C10 Aryl, 5-15 membered heteroaryl or -N=CR 1 R 2 ;

[0111] R 1 and R 2 are independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 4-15 membered heterocycle, ether, -CONR 13 R 14 or -NR 13 COR 14 ;

[0112] X, Y and Z are each independently hydrogen, CN, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 4-15 membered heterocycle, ether, -CONR 13 R 14 or -NR 13 COR 14 ;

[0113] R is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 4-15 membered heterocycle, ether, -CONR 13 R 14 or -NR 13 COR 14 ;

[0114] R 13 and R 14 are independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 4-15 membered heterocycle or ether

[0115] T comprises a phosphoramidite alkylating agent comprising one or more alkylating agents bonded to -OP(Z 1 ) part of Z 5 -X 5 -Y 5 Part of the alkylating agent, wherein Z 5 is a heteroatom containing nitrogen, sulfur or oxygen, X 5 is a substituted or unsubstituted ethylene group, Y 5 is a halo or another leaving group, or Z 5 -X 5 -Y 5 Together they form an aziridinyl (NCH2CH2) moiety and Z 1 is O or S; and

[0116] These alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, and ether groups are substituted or unsubstituted.

[0117] For typical example compounds, please refer to the specific compounds listed in the examples section of patent application PCT / US2016 / 021581, publication number WO2016145092A1 (corresponding to Chinese application number 2016800150788, publication number CN107530556A). For the preparation methods and spectral data of these compounds, please refer to the text of the above-mentioned patent application, and the full text of the application is hereby introduced.

[0118] in:

[0119] A is a substituted or unsubstituted C6-C10 aryl, biaryl or substituted biaryl, 5-15 membered heteroaryl or -N=CR 1 R 2 , wherein the substituent when substituted is selected from the group consisting of: halogen, -CN, -NO2, -O-(CH2)-O-, -CO2H and its salts, -OR 100 、-CO2R 100 、-CONR 101 R 102 、-NR 101 R 102 、-NR 100 SO2R 100 、-SO2R 100 、-SO2NR 101 R 10 2 , C1-C6 alkyl, C3-C10 heterocyclic group;

[0120] Among them, R 100 、R 101 and R 102 are independently hydrogen, C1-C8 alkyl, C6-C12 aryl; or R 101 and R 102 together with the nitrogen atom to which it is attached, form a 5-7 membered heterocyclic ring;

[0121] wherein the alkyl group and the aryl group are each substituted with 1-3 halo groups or 1-3 C1-C6 alkyl groups;

[0122] R 1 and R 2 each independently phenyl or methyl;

[0123] X, Y and Z are each independently hydrogen or halo;

[0124] R is hydrogen or C1-C6 alkyl or halogen-substituted alkyl.

[0125] For typical example compounds, please refer to the specific compounds listed in the examples section of patent application PCT / US2016 / 021581, publication number WO2016145092A1 (corresponding to Chinese application number 2016800150788, publication number CN107530556A). For the preparation methods and spectral data of these compounds, please refer to the text of the above-mentioned patent application, and the full text of the application is hereby introduced.

[0126] Among them, X, Y, Z, R, D, L 1 , A and X 10 The definition is as described in the claims of patent application PCT / US2016 / 025665, publication number WO2016161342A3 (corresponding to Chinese application number 2016800200132, publication number CN108136214A), and the synthesis and preparation methods of specific compounds are also described in the above application, which are hereby incorporated into this application in their entirety, and are specifically defined as:

[0127] X 10 O, S, SO or SO2;

[0128] A is C6-C 10 Aryl, 5- to 15-membered heteroaryl, or -N=CR 1 R 2 ;

[0129] R 1 and R 2 Each independently represents hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 4- to 15-membered heterocyclic ring, 5- to 15-membered heteroaryl, ether, -CONR 13 R 14 or -NR 13 COR 14 ;

[0130] X, Y and Z are each independently hydrogen, CN, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 4- to 15-membered heterocyclic ring, 5- to 15-membered heteroaryl, ether, -CONR 13 R 14 or -NR 13 COR 14 ;

[0131] Each R is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 4- to 15-membered heterocyclic ring, 5- to 15-membered heteroaryl, ether, -CONR 13 R14 or -NR 13 COR 14 ;

[0132] R 13 and R 14 Each independently represents hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 4- to 15-membered heterocyclic ring, 5- to 15-membered heteroaryl, or ether;

[0133] Among them L 1 and D is defined as follows:

[0134] L 1 Selected from:

[0135] R 40 and R 41 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 aryl, 4- to 15-membered heterocyclic ring, or 5- to 15-membered heteroaryl;

[0136] R 42 is a C2-C3 alkylene or heteroalkylene group which is optionally substituted with 1 to 3 C1-C6 alkyl groups;

[0137] V(-) is any anion, preferably a pharmaceutically acceptable anion;

[0138] D is a moiety such that D-OH is an anticancer drug, wherein OH is an aliphatic hydroxyl group or a phenolic hydroxyl group, or is an OH moiety attached to a phosphorus atom as provided herein; or

[0139] L 1 for:

[0140] R 40 As defined above, R 43 is hydrogen or forms a heterocyclic ring together with D, and the phenylene moiety is optionally substituted, and

[0141] D is such that D-NR 43 H is a moiety of an anticancer drug; or

[0142] L 1 For the key, -OC(R 40 R 41 )2-、-OC(R 40 R 41 )-NR 40 R 41 (+)-C(R 40 R 41 )-or

[0143] where R 40 、R 41 and V is as defined above, and

[0144] D is an anticancer drug containing a tertiary or secondary nitrogen atom, wherein the tertiary nitrogen atom or the secondary nitrogen atom is bonded to L 1 ;

[0145] and

[0146] wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, and ether groups are optionally substituted.

[0147] For typical example compounds, please refer to the specific compounds listed in the Examples section of patent application PCT / US2016 / 025665, publication number WO2016161342A3 (corresponding to Chinese application number 2016800200132, publication number CN108136214A). The preparation methods and spectral data of these compounds are shown in the text of the above-mentioned patent application, and the full text of the application is hereby incorporated by reference.

[0148] Wherein, the definitions of R1, R2, R3, R4 and T are as described in the claims of patent application PCT / CN2021 / 118597, publication number WO2022057838A1. The synthesis and preparation methods of specific compounds are also described in the above-mentioned application, which are hereby incorporated into this application in their entirety and are specifically defined as:

[0149] T is N or CH;

[0150] R1 and R2 are each independently H, F, Cl, Br, I or C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R a replaced by;

[0151] Each R a independently F, Cl, Br, I, -CN, -OH or -NH2;

[0152] R3 and R4 are each independently H, F, Cl, Br, I, CN, C 1-3 Alkyl, C 1-3 Alkoxy, Among them, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R e replaced by;

[0153] R b and R cEach independently represents H, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2;

[0154] R d It is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2;

[0155] Each R e independently F, Cl, Br, I, -CN, -OH or -NH2.

[0156] For typical example compounds, please refer to patent application PCT / CN2021 / 118597. For specific compounds listed in the examples section of publication number WO2022057838A1, the preparation methods and spectral data of these compounds can be found in the above-mentioned patent application text, and the full text of the application is introduced here.

[0157] Wherein, the definitions of R1, R2, R3, R4, G1, G2, G3, G4, E, T, Y, Z, m, n, s, t, v, w, and Ring A are as described in the claims of patent application CN202210585771.6, publication number CN115403579A. The synthesis and preparation methods of specific compounds are also described in the above-mentioned applications, which are hereby incorporated into the present application in their entirety, and are specifically defined as:

[0158] G 1 , G 2 , G 3 or G 4 The same or different, and each independently CR 5 or N atoms;

[0159] Each R 5 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, cyano, amino, nitro, -NR a R b 、-C(O)NR a R b , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, hydroxy, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0160] Y is selected from -(C(R y2 R y3 )) f -NR y1 -、-(C(Ry2 R y3 )) g -O-、-(C(R y2 R y3 )) h -S-、-(C(R y2 R y3 )) h -S(O)-、-(C(R y2 R y3 )) h -S(O)2-、-C(R y2 R y3 )-、-NR y1 -(C(R y2 R y3 )) f -、-O-(C(R y2 R y3 )) g -、-S-(C(R y2 R y3 )) h -、-S(O)-(C(R y2 R y3 )) h - and -S(O)2-(C(R y2 R y3 )) h -;

[0161] R y1 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group;

[0162] R y2 and R y3 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;

[0163] or R y2 and R y3 Together they form =O;

[0164] Z is O or OH;

[0165] is a single bond or a double bond, when When Z is OH, When it is a double bond, Z is O;

[0166] E is selected from NH, O atoms and S atoms;

[0167] T is selected from -C(R T1 R T2 )- -NR T3 -or-O-;

[0168] R T1 and R T2 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;

[0169] or R T1 and R T2 Together with the carbon atom to which it is attached, it forms a cycloalkyl group or a heterocyclic group, wherein the cycloalkyl group or the heterocyclic group are each independently substituted with one or more substituents selected from halogen, alkyl and hydroxy;

[0170] R T3 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group;

[0171] Ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group;

[0172] Each R 1 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a cyano group, a -NR a R b 、-C(O)NR a R b 、-S(O)NR a R b 、-S(O)2NR a R b 、-S(O)R c 、-S(O)2R c 、-B(OR d ) 2, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, hydroxy, oxo, cyano, -NR a R b 、-C(O)NR a R b 、-S(O)NR a R b 、-S(O)2NR a R b 、-S(O)R c 、-S(O)2R c 、-B(OR d ) 2, substituted by one or more substituents selected from nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0173] R a and R bare the same or different and are each independently selected from hydrogen atom, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, -C(O)R e , cycloalkyl and heterocyclic groups; or R a and R b Together with the nitrogen atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, hydroxy, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0174] R c is selected from alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, hydroxy, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0175] R d A hydrogen atom or C 1-6 alkyl;

[0176] R e is selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, hydroxy, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0177] Each R 2 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, an oxo group, a hydroxyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group;

[0178] Each R 3 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, an oxo group, a hydroxyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group;

[0179] R 4 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyl group, and a hydroxyalkyl group;

[0180] n is 0, 1, 2, or 3;

[0181] v is 0, 1, or 2;

[0182] w is 0, 1, or 2;

[0183] f is 0, 1, or 2;

[0184] g is 0, 1, or 2;

[0185] h is 0, 1, or 2;

[0186] m is 0, 1, 2, 3, 4 or 5;

[0187] s is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0188] t is 0, 1, 2, 3, 4, 5, or 6;

[0189] The condition is,

[0190] When Y is an -O- atom and E is an O atom, Ring A is a phenyl group or a 5- to 6-membered heteroaryl group, and G 3 CR 5 or N atom, R 5 Not a hydrogen atom;

[0191] When Y is an -O- atom and E is an S atom, ring A is a phenyl group or a 5- to 6-membered heteroaryl group;

[0192] When G 1 , G 2 , G 3 and G 4 All CR 5 , Y is NR y1 , n, v and w are all 1, and E is an O atom, 1) T is not CH2 or CD2, 2) there is at least one R 2 or R 3 is a deuterium atom, 3)R 4 is selected from alkyl, haloalkyl, hydroxyl and hydroxyalkyl, 4) one of R 1 is a 3- to 8-membered cycloalkyl group or a 5- to 8-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl group or the 5- to 8-membered heterocyclic group is optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, hydroxy, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic group, aryl and heteroaryl; 5) Ring A is R d A hydrogen atom or C 1-6 alkyl.

[0193] For typical example compounds, please refer to patent application CN202210585771.6. For specific compounds listed in the examples section of publication number CN115403579A, the preparation methods and spectral data of these compounds can be found in the above-mentioned patent application text, and the full text of the application is introduced here.

[0194] or a pharmaceutically acceptable salt thereof,

[0195] Among them, R1 、R 2a 、R 2b 、R 3 、R 4 、R 5 The definitions of n and Z are as described in the claims of patent application PCT / IB2020 / 057285, publication number WO2021005586A1 (corresponding to Chinese application number CN202080053804.1, publication number CN114206870A). The synthesis and preparation methods of specific compounds are also described in the above-mentioned application, which are hereby incorporated into this application in their entirety and are specifically defined as:

[0196] Is a single bond or a double bond;

[0197] Z when When it is a single bond, it is OH; or when When it is a double bond, it is O;

[0198] Each R 1 independently selected from the group consisting of: (C1-C6)alkyl, (C1-C6)alkoxy, (C0-C4)alkylN(R 8 ) 2, and halogen;

[0199] R 2a and R 2b are each independently selected from the group consisting of: H, (C1-C6)alkyl, and halo;

[0200] Each R 3 independently selected from the group consisting of: H, and halo;

[0201] R 4 is selected from the group consisting of: aryl, 5 to 6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O and S; and 9 to 10 membered fused bicyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O and S; wherein any of the foregoing is optionally replaced by one or more R 6 replace;

[0202] R 5 Selected from the group consisting of: H; (C1-C6)alkyl; (C2-C6)alkenyl; (C0-C4)alkyl OR 8 ; (C1-C4) alkyl (C3-C 10 )cycloalkyl; halo(C1-C6)alkyl; (C2-C3)alkynyl; (C1-C4)alkylN(R 10 )2;

[0203] Each R 6independently selected from the group consisting of: halo; (C1-C6) alkyl; (C1-C6) alkoxy; halo (C1-C6) alkyl; OH; aryl; 3 to 6 membered heterocyclic; 5 to 6 membered heteroaryl; (C0-C4) alkyl S(O) m (C1-C6)alkyl; halo(C1-C6)alkoxy; (C0-C4)alkylS(O) m N(R 8 )2; (C0-C4) alkyl N (R 8 )2; (C0-C4) alkyl (CO) OR 7 ; N(R 8 )S(O) m (C1-C6)alkyl; N(R 8 )S(O) m (C3-C6)cycloalkyl; OP(O)(OH)2; (C0-C3)alkyl (CO)NHR 11 ; (C0-C3) alkyl OR 7 , and (C3-C 10 )cycloalkyl; wherein each R 6 When not halo, OH, or OP(O)(OH)2, it is optionally substituted by one to three R 9 Substitution; or two adjacent R 6 together with the atoms to which they are attached, form a 5- to 7-membered heterocyclic ring or a (C5-C8)cycloalkyl group;

[0204] Each R 7 and R 8 independently selected from the group consisting of: H or optionally substituted by one to three R 9 substituted (C1-C6)alkyl;

[0205] Each R 9 independently selected from the group consisting of: halo; -OH; amino, (C1-C4) alkylamino, di(C1-C4) alkylamino, OP(O)(OH)2; (C1-C6) alkyl; (C1-C3) alkynyl; (C1-C6) alkoxy; halo(C1-C6) alkyl; (C0-C4) alkylS(O) m (C1-C6)alkyl; halo(C1-C6)alkoxy; 3- to 6-membered heterocyclic ring optionally substituted with oxo (=O); (C0-C4)alkylS(O) m N(R 10 )2; (C0-C4) alkyl (CO) R 10 ; (C0-C4)alkyl (CO)OR 10 ; (C0-C4) alkyl NR 10 S(O) m (C1-C6)alkyl; (C0-C4)alkyl OR10 ; (C0-C4) alkyl N(R 10 )2; (C0-C4) alkylCN; (C0-C4) alkylN(R 10 )2; and (C0-C4)alkyl (CO) N (R 10 )2;

[0206] Each R 10 independently selected from the group consisting of: H, (C1-C6)alkyl; or a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally substituted with one or more of: (C1-C6)alkyl; and oxo (═O);

[0207] Each R 11 Selected from the group consisting of: H; optionally replaced by one to four R 12 substituted 4 to 6 membered heterocyclic ring; optionally substituted by one to four R 12 Substituted (C3-C6) cycloalkyl; (C0-C3) alkyl optionally substituted by halogen (C3-C6) cycloalkyl (C1-C3) alkyl; optionally substituted by one to three R 12 substituted CH2-aryl; (C1-C6)alkyl; (C2-C6)alkenyl; or (C2-C6)alkynyl, wherein each of the (C1-C6)alkyl; (C2-C6)alkenyl; and (C2-C6)alkynyl is optionally substituted by one or more R 13 replace;

[0208] Each R 12 independently selected from the group consisting of OH, (C1-C3)alkoxy, NH2; or (C1-C3)alkyl optionally substituted with one or more OH;

[0209] Each R 13 independently selected from the group consisting of: halo, OH, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino, (C1-C3)alkoxy; and C(O)-(C3-C8)cycloalkyl;

[0210] m is 0, 1, or 2; and

[0211] n is 0, 1, or 2.

[0212] For typical example compounds, please refer to the specific compounds listed in the examples section of patent application PCT / IB2020 / 057285, publication number WO2021005586A1 (corresponding to Chinese application number CN202080053804.1, publication number CN114206870A). For the preparation methods and spectral data of these compounds, please refer to the above-mentioned patent application text. The full text of this application is introduced here.

[0213] or a pharmaceutically acceptable salt thereof,

[0214] Among them, R w ,X,R4,R 10 、R 13 、R 14 The definition is as described in the claims of patent application PCT / CN2022 / 098082, publication number WO2022258043A1, and the synthesis and preparation methods of specific compounds are also described in the above application, which are hereby incorporated into this application in their entirety, and are specifically defined as:

[0215] The two Xs are independently CR 15 or N;

[0216] R 13 、R 14 are independently hydrogen, C1-C6 alkyl, cycloalkyl, alkenyl, alkynyl, C6-C 20 Aryl, 5-20 membered heterocyclic group, halogen substituted C1-C6 alkyl, cycloalkyl, alkenyl, alkynyl, halogen substituted C6-C 20 aryl, or a 5-20 membered heterocyclic group substituted with halogen, and R 13 、R 14 Not simultaneously hydrogen;

[0217] R 10 is hydrogen, C1-C6 alkyl, cycloalkyl, alkenyl, alkynyl, C6-C 20 Aryl, 5-20 membered heterocyclic group, halogen substituted C1-C6 alkyl, cycloalkyl, alkenyl, alkynyl, halogen substituted C6-C 20 aryl, or a 5-20-membered heterocyclic group substituted with halogen;

[0218] or R 10 With R 13 or R 14 Can be in accordance with the above R 10 、R 13 、R 14 Under defined conditions, they are connected to form a 5-9 membered ring;

[0219] R4, R 15 Each is independently hydrogen, halogen, C1-C6 alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, cyano, 5-20 membered heterocyclic group, C6-C 20 Aryl, or halogen-substituted C1-C6 alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, 5-20 membered heterocyclic group, C6-C 20 aryl;

[0220] or R 10 With R 15Can be in accordance with the above R 10 、R 15 Formation of a 4-12 membered cyclic hydrocarbon or heterocycle under defined conditions;

[0221] R W yes

[0222] A is CR 16 or N, wherein the position of A can be changed on the ring;

[0223] R 16 is hydrogen, C1-C6 alkyl, cycloalkyl, alkenyl, alkynyl, C6-C 20 Aryl, 5-20 membered heterocyclic group, halogen substituted C1-C6 alkyl, cycloalkyl, alkenyl, alkynyl, halogen substituted C6-C 20 aryl, or a 5-20-membered heterocyclic group substituted with halogen;

[0224] R6 and R7 meet the following conditions:

[0225] R6 and R7 are each independently hydrogen, halogen, cyano, hydroxy, C1-C6 alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, 5-20 membered heterocyclic group, C6-C 20 Aryl, or halogen-substituted C1-C6 alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, 5-20 membered heterocyclic group, C6-C 20 Aryl, or cyano-substituted C1-C6 alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, 5-20 membered heterocyclic group, C6-C 20 Aryl, or hydroxy-substituted C1-C6 alkyl, cycloalkyl, alkoxy, 5-20 membered heterocyclic group, C6-C 20 Aryl, or -CONR 11 R 12 , or -CH2NR 11 R 12 ;

[0226] Or R6 and R7 are connected to form

[0227] A 5-8 membered monocyclic or condensed heterocyclic ring containing at least one N, S or O, or containing two or three of N, S and O at the same time;

[0228] Alternatively, a 5-8 membered monocyclic or fused heterocyclic ring containing at least one N, S, or O, or containing two or three of N, S, and O, and the monocyclic or fused heterocyclic ring is substituted with a C1-C6 alkyl group;

[0229] R6 can be used with CR 16 connected to form a 5-9 membered ring, heterocycle or aromatic heterocycle;

[0230] R11 、R 12 The following conditions are met:

[0231] R 11 、R 12 Each is independently C1-C6 alkyl, halogen-substituted C1-C6 alkyl or R 11 、R 12 Satisfy the above definition conditions and -CONR 11 R 12 The N in the form a 5-7 membered ring, with -CH2NR 11 R 12 The N in the group forms a 5-7 membered ring.

[0232] For typical example compounds, please refer to patent application PCT / CN2022 / 098082 and the specific compounds listed in the examples section of publication number WO2022258043A1. For the preparation methods and spectral data of these compounds, please refer to the text of the above-mentioned patent application, and the full text of the application is introduced here.

[0233] Furthermore, the AKR1C3-activating anticancer prodrug compound is selected from the compounds of the following structures:

[0234] Preferably, according to the experimental results in the examples, the drug containing the AKR1C3 activating anticancer prodrug compound or its salt, ester, solvate, isotopomer isomer is administered with a non-steroidal analgesic drug at intervals or simultaneously.

[0235] In the examples, experiments confirmed that some nonsteroidal analgesics reported in the literature as inhibitors of the AKR1C3 enzyme significantly affect the anti-tumor cell proliferation activity of the AKR1C3 enzyme-activated drug AST-3424, while some nonsteroidal analgesics reported in the literature as inhibitors of the AKR1C3 enzyme do not affect the anti-tumor cell proliferation activity of the AKR1C3 enzyme-activated drug AST-3424. Drugs that affect the anti-tumor cell proliferation activity of the AKR1C3 enzyme-activated drug AST-3424 can eliminate this effect after washing the cells. Based on this, it is speculated that the effect will weaken or disappear after the influencing drug disappears or is eliminated. Therefore:

[0236] Nonsteroidal analgesic drugs that do not affect the anti-tumor cell proliferation activity of AST-3424, a drug that activates AKR1C3 enzymes, can be administered simultaneously with AKR1C3-activating anticancer prodrug compounds;

[0237] Nonsteroidal analgesics that affect the anti-tumor cell proliferation activity of AST-3424, a drug that activates AKR1C3 enzymes, cannot be administered simultaneously with AKR1C3-activating anticancer prodrug compounds. They should be administered after a period of time to allow the nonsteroidal analgesics to be metabolized and eliminated.

[0238] Simultaneous administration is not strictly required. Instead, the non-steroidal analgesic drug is administered during a period when the drug containing the AKR1C3-activated anticancer prodrug compound has not been completely metabolized, that is, the drug is still in the body, and the drug containing the AKR1C3-activated anticancer prodrug compound is administered during a period when the non-steroidal analgesic drug has not been completely metabolized, that is, the drug is still in the body.

[0239] Administer at intervals, including two situations:

[0240] When the patient has been taking nonsteroidal analgesics, the drug containing the AKR1C3-activating anticancer prodrug compound or its salt, ester, solvate, or isotope isomer should be administered only after the nonsteroidal analgesics have been eliminated;

[0241] When the patient has been administered a drug containing an AKR1C3-activating anticancer prodrug compound or its salt, ester, solvate, or isotope isomer, the nonsteroidal analgesic drug should be administered only after the AKR1C3-activating anticancer prodrug compound or its salt, ester, solvate, or isotope isomer is activated.

[0242] Preferably, when the patient has been administered a drug containing an AKR1C3-activating anticancer prodrug compound or a salt, ester, solvate, or isotopomer thereof, the nonsteroidal analgesic drug should be administered 1.33-1.75 hours after the start of drug infusion.

[0243] Compounds of structural formula 1 / 2 are the same as AST-3424, both being prodrugs of AST-2660. They are activated by the AKR1C3 enzyme (involved by NADPH) to produce AST-2660 (a DNA alkylating agent) to exert anticancer effects:

[0244] The compounds of structural formula 3 are all nitrogen mustard analogs A prodrug of AKR1C3, which is activated by NADPH to produce a nitrogen mustard analogue. (a DNA alkylating agent) exerts anti-cancer effects:

[0245] The compound of structural formula 4 is the same as AST-3424, both being prodrugs of AST-2660. It is activated by the AKR1C3 enzyme (involved by NADPH) to produce AST-2660 (a DNA alkylating agent) to exert anticancer effects:

[0246] The compound of structural formula 5 is similar to AST-3424 and is a prodrug of a phosphamidonate alkylating agent. It is activated by the AKR1C3 enzyme (involving NADPH) to produce T (a phosphamidonate alkylating agent, AST-2660 is a phosphamidonate alkylating agent) to exert anticancer effects:

[0247] The compound of structural formula 6 is similar to AST-3424 and is a prodrug of AST-2660. It is activated by the AKR1C3 enzyme (involved by NADPH) to produce AST-2660, which exerts an anti-cancer effect:

[0248] The compounds of structural formula 7 / 8 / 11 are similar to AST-3424 and are activated by the AKR1C3 enzyme (with the involvement of NADPH) to produce drugs such as AST-2660, paclitaxel or camptothecin, thereby exerting anti-cancer effects.

[0249] The compound of structural formula 9 / 10 is a prodrug of a KARS inhibitor, which is activated by the action of the AKR1C3 enzyme (with the involvement of NADPH) to produce a KARS inhibitor drug and exert an anti-cancer effect.

[0250] Based on the activation reactions of the above 11 types of AKR1C3-activated anticancer prodrug compounds, it can be seen that the first stage of activation of this type of compound requires the participation of the AKR1C3 enzyme. After the activation is completed, even if non-steroidal analgesics have an inhibitory effect on the AKR1C3 enzyme, it will not affect the above activation process, that is, the AKR1C3-activated anticancer prodrug compounds can exert their efficacy.

[0251] Specifically, a drug containing AST-3424, AST-3423 or AST-2870 or a salt, ester, solvate or isotope isomer thereof is administered simultaneously with ibuprofen or celecoxib.

[0252] According to the three-step analgesic principle, nonsteroidal analgesics are generally administered in the first stage, which is aimed at mild pain. Therefore, the pain is mild pain.

[0253] The present invention actually provides a suitable dosing regimen for clinical cancer treatment, namely, achieving the effects of simultaneously treating cancer and relieving pain by combining AST-3424 with non-steroidal analgesics.

[0254] The drug combination of the present invention comprises at least two active ingredients, such as AST-3424 and celecoxib, AST-3424 and naproxen, and AST-3424 and ibuprofen. Of course, pharmaceutically acceptable excipients may also be included.

[0255] Typically, the two active ingredients that characterize the pharmaceutical combinations described herein may be formulated either together (single dosage unit) or separately (kit).

[0256] The two active ingredients, formulated together or separately, may generally be administered simultaneously; or, given the nature of their respective formulations, separately with a time interval which allows for the optimization of the synergistic effect of the two active ingredients.

[0257] The drug combination can be a compound drug comprising a pharmaceutical composition comprising, as one active ingredient, the aforementioned AKR1C3-activating prodrug compound or its salts, esters, solvates, or isotopic isomers, and as another active ingredient, a non-steroidal analgesic. In this case, the aforementioned active ingredients are co-formulated and administered simultaneously.

[0258] A drug combination can also be a packaged product, similar to Pfizer's COVID-19 drug Paxlovid, that can be sold together or separately. In this case, the active ingredients are formulated separately, but the two or more separately formulated drugs can be administered simultaneously or at intervals, depending on the properties of their respective formulations.

[0259] As a specific embodiment of the present invention, when formulated separately, one of the drugs contains the active ingredients AST-3424, AST-3423, AST-2870 or their salts, esters, solvates, isotopomers, and pharmaceutically acceptable excipients, and the other drug contains the active ingredients celecoxib, naproxen, or ibuprofen, and pharmaceutically acceptable excipients. The drug combination consisting of the above two drugs can be administered simultaneously or separately at intervals depending on the properties of the respective formulations.

[0260] As a specific embodiment of the present application, in order to relieve the patient's pain, AST-3424 and celecoxib or ibuprofen can be administered simultaneously without affecting or significantly affecting the anti-tumor efficacy of AST-3424.

[0261] As a specific embodiment of the present application, in order to relieve the patient's pain, AST-3424 and naproxen are administered separately without affecting or significantly affecting the anti-tumor efficacy of AST-3424. AST-3424 can be administered first and then naproxen, or naproxen can be administered first and then AST-3424 can be administered after naproxen is metabolized.

[0262] The present invention also provides a pharmaceutical preparation, which is prepared from the active ingredients of the above-mentioned drug combination and pharmaceutically acceptable excipients.

[0263] As a specific embodiment of the present invention, the dosage form of the above-mentioned pharmaceutical preparation is selected from granules, tablets, pills, capsules, injections or lyophilized powder injections.

[0264] The present invention also provides use of the above-mentioned drug combination and / or the above-mentioned drug preparation in the preparation of anti-tumor drugs.

[0265] Optionally, the above-mentioned cancer or tumor is selected from ovarian cancer, breast cancer, pancreatic cancer, fallopian tube cancer, primary peritoneal cancer, gastric cancer, prostate cancer, liver cancer, colon cancer, rectal cancer, lung cancer, and bladder cancer.

[0266] Preferably, the lung cancer is selected from non-small cell lung cancer and small cell lung cancer.

[0267] The present invention provides a method for treating cancer patients with pain by combining an AKR1C3-activating prodrug compound with an analgesic drug, pharmaceutical uses, drug combinations, and pharmaceutical preparations thereof, providing a reasonable option for clinical cancer treatment. In particular, the combination of AST-3424 and a non-steroidal analgesic drug can achieve the effects of simultaneously treating cancer and relieving pain. BRIEF DESCRIPTION OF THE DRAWINGS

[0268] Figure 1 shows the in vitro proliferation inhibition dose-effect curve of AST-3424 in combination with TH-3021, Celecoxib, Naproxen, and Ibuprofen on the H460 cell line, where Figure a shows TH-3021, Figure b shows Celecoxib, Figure c shows Naproxen, and Figure d shows Ibuprofen.

[0269] Figure 2 shows the in vitro proliferation inhibition dose-effect curves of AST-3424 and Naproxen on the H460 cell line under different combination modes and different dosage conditions. Among them, Figure a shows the combination group in which Naproxen or TH-3021 was pretreated for 2 hours, the above two compounds were washed away, and then AST-3424 was added for 2 hours respectively; Figure b shows the combination group in which Naproxen or TH-3021 and AST-3424 were co-treated for 2 hours respectively; Figure c shows the combination group in which AST-3424 was pretreated for 2 hours, the compounds were washed away, and then Naproxen or TH-3021 was added for 2 hours respectively; Figure d shows the combination group in which Naproxen or TH-3021 was pretreated for 2 hours, the above two compounds were not washed away, and AST-3424 was added for a continuous co-treatment for 2 hours.

[0270] Figure 3 is a curve showing the changes in tumor volume of mice in each group over treatment time in the human lung cancer NCI-H460 model.

[0271] Figure 4 is a curve showing changes in body weight of mice in each group over treatment time in the human lung cancer NCI-H460 model.

[0272] Figure 5 shows the pharmacokinetic curves of OBI-3424 (A) and OBI-2660 (B) during cycle 1 (combined days 1 and 8) (excerpted from the Phase I clinical trial poster of OBI-3424 released at ASCO2022) ※ Figure 3 in the figure). Example

[0273] 1. In vitro cell experiments

[0274] 1.1 In vitro cell proliferation inhibition experiment using drug combination

[0275] The CTG assay was used to evaluate the in vitro proliferation inhibitory effects of AST-3424 alone and in combination with Celecoxib, Naproxen, Ibuprofen, and TH-3021 on the H460 cell line.

[0276] The product was synthesized by referring to the corresponding patent.

[0277] Celecoxib, Naproxen, and Ibuprofen were all purchased from a reagent company.

[0278] According to research literature, TH-3021 is a specific inhibitor of AKR1C3 and can effectively inhibit the activation process of AKR1C3-catalyzed activation of AST-3424 and other similar AKR1C3-activated anticancer prodrug compounds, greatly reducing the ability of such compounds to inhibit tumor cell proliferation.

[0279] 1.1.1 Cell culture

[0280] a) H460 cells (human non-small lung cancer cells, high expression of AKR1C3 enzyme) were cultured in RPMI-1640 medium supplemented with 10% FBS and 1% double antibody at 37°C and 5% CO2.

[0281] 1.1.2 Cell plating

[0282] a) Cells are routinely cultured until the cell saturation reaches 80%-90%. When the cell number reaches the required level, the cells are harvested.

[0283] b) Resuspend the cells in the appropriate culture medium, count the cells, and prepare a cell suspension of appropriate density.

[0284] c) Add the cell suspension to a 96-well plate, 100 μL per well, with a cell density of 2000 cells / well.

[0285] d) The cells were cultured in a 37°C, 5% CO2 incubator overnight.

[0286] 1.1.3 Compound treatment of cells (72 hours)

[0287] AST-3424 alone: ​​24 hours after cell plating, the compound was applied alone. 99 μL of growth medium was added to each well, and then 1 μL of the prepared AST-3424 solution was added to form different AST-3424 concentrations. The wells were gently shaken to ensure uniform mixing, and then placed in a 37°C, 5% CO2 incubator.

[0288] Place the cell plate in the incubator for 72 hours.

[0289] 1.1.4 Compound treatment of cells (2 hours)

[0290] a) Single drug administration: 24 hours after cell plating, the compound was treated alone. 99 μL of growth medium was added to each well. 1 μL of the prepared AST-3424 solution was added to each well to form different AST-3424 concentrations. Gently shake to ensure uniform mixing. After 2 hours in the incubator, the supernatant was discarded, the cells were washed twice with growth medium, and 200 μL of fresh medium was added.

[0291] b) Combination therapy: 24 hours after plating the cells, TH-3021, Celecoxib, Naproxen, and Ibuprofen were combined with AST-3424. 98 μL of growth medium was added to each well, and 1 μL of the prepared TH-3021, Celecoxib, Naproxen, or Ibuprofen combination compound was added to each well to form different concentrations of each compound. Gently shaken to ensure uniform mixing, and placed in an incubator for 2 hours. 1 μL of the prepared AST-3424 solution was added to form different AST-3424 concentrations. Gently shaken to ensure uniform mixing, and then placed in a 37°C, 5% CO2 incubator for another 2 hours. The supernatant was discarded, the cells were washed twice with growth medium, and 200 μL of fresh medium was added.

[0292] Place the cell plate in the incubator for 72 hours.

[0293] 1.1.5 Final concentration of test compound

[0294] Single drug concentration:

[0295] AST-3424 concentrations: 100, 33.3, 11.1, 3.7, 1.23, 0.41, 0.14, 0.046, 0.015 [nM].

[0296] Combined drug concentration:

[0297] AST-3424 concentrations: 100, 33.3, 11.1, 3.7, 1.23, 0.41, 0.14, 0.046, 0.015 [nM]

[0298] Celecoxib compound (2#) 1 μM, 3 μM, 6 μM;

[0299] Naproxen compound (3#) 200 μM, 300 μM, 400 μM;

[0300] Ibuprofen compound (4#) 100 μM, 150 μM, 200 μM;

[0301] TH-3021 compound (5#) 3 μM.

[0302] Check the pharmacokinetic parameters of celecoxib (200 mg) in healthy subjects in the Pfizer H20140107 / H20140106 drug package insert or the Jiangsu Zhengda Qingjiang Pharmaceutical Co., Ltd. drug package insert with the national medicine standard H20193414. max The concentration of PEG-1 was 705 ng / ml, which was converted to a molar concentration of 1.85 μmol / L. The concentration added in the experiment was designed accordingly.

[0303] According to the drug package insert of ATNAHS PHARMA US with the FDA application number NDA017581 in the United States, the C max The concentration of PEG-1 was 97.4 μg / ml, which was converted to a molar concentration of 423 μmol / L. The concentration added in the experiment was designed accordingly.

[0304] The main pharmacokinetic parameters of ibuprofen after a single dose of fasting were investigated (Li Xiaobin, Yu Ming, Wang Nan et al., Pharmacokinetics and bioequivalence study of ibuprofen tablets in healthy Chinese subjects [J]. Chinese Journal of Clinical Pharmacology, 2020, 36(22): 3600-3604. DOI: 10.13699 / j.cnki.1001-6821.2020.22.007). max 1.94×10 4 ng / ml, which is converted to a molar concentration of 94.05 μmol / L, and the concentration added in the experiment was designed accordingly.

[0305] 1.1.6 CTG method detection

[0306] a) The cell plate to be tested was placed at room temperature for equilibration for 30 minutes, and 100 μL of culture medium was discarded from each well.

[0307] b) Add 25 μL of CTG reagent (CelltiterGlo kit) to each well, shake on a high-speed shaker for 2 minutes, and store at room temperature in the dark for 30 minutes.

[0308] c) Read the chemiluminescent signal using a multifunctional microplate reader with a reading time of 1000 ms.

[0309] 1.1.7 Data Analysis

[0310] IC was calculated using GraphPad Prism 5 software. 50 , the IC of the compound is obtained using the following nonlinear fitting formula 50 (50% inhibitory concentration): Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope))

[0311] X: log value of compound concentration, Y: inhibition rate (%inhibition)

[0312] Inhibition rate (% inhibition) = 100-((Compound well reading - low reading control reading) / (High reading control reading - low reading control reading)*100)

[0313] The dose-effect curve was obtained, as shown in Figure 1, and the half-maximal killing concentration (IC 50 ), as shown in Table 1 below.

[0314] Table 1: In vitro proliferation inhibition data of H460 cell lines using AST-3424 alone and in combination with Celecoxib, Naproxen, Ibuprofen, and TH-3021

[0315] Experimental Conclusion

[0316] By comparison, it can be found that the combination of AST-3424 with celecoxib and ibuprofen has almost no effect on the cell proliferation inhibitory activity of AST-3424 (AKR1C3-activating anticancer prodrug compound), while the combination of AST-3424 with naproxen will significantly affect the cell proliferation inhibitory activity of AST-3424, but the effect is far lower than that of the AKR1C3-specific inhibitor TH-3021 reported in the literature.

[0317] 1.2 Experimental study on cell proliferation inhibition by combining naproxen and AST-3424 in different dosing orders

[0318] In order to further study the inhibitory mechanism of naproxen, a non-steroidal analgesic drug that significantly affects the cell proliferation inhibitory activity of AKR1C3-activated anticancer prodrug compounds such as AST-3424, experiments with different dosing sequences were conducted to explore the inhibitory mechanism.

[0319] Similar operations to those in 1.1.1, 1.1.2, 1.1.6, and 1.1.7 will not be described again, and the process of compound treatment of cells will be directly described.

[0320] Compound-treated cells

[0321] a) Combination medication:

[0322] 24 hours after cell plating, Naproxen and TH-3021 were combined with AST-3424, respectively. The following are different treatment methods.

[0323] 1) TH-3021-3μM-2h-pretreatment-AST-3424-2h or Naproxen-400μM-2h-pretreatment-AST-3424-2h, i.e., after pretreatment with Naproxen or TH-3021 for 2 hours, the above two compounds were washed away and then AST-3424 was added for 2 hours:

[0324] 24 hours after cell plating, Naproxen or TH-3021 were combined with AST-3424.

[0325] Add 99 μL of growth medium to each well, add 1 μL of Naproxen or TH-3021 solution to each well, shake gently to ensure uniform mixing, place in the incubator for 2 hours, wash off the compound, add 99 μL of fresh complete medium, and then add 1 μL of prepared AST-3424 solution to form different AST-3424 concentrations, shake gently to ensure uniform mixing, then place in the incubator for 2 hours, wash off the compound, and continue to culture in a 37°C, 5% CO2 incubator for 72 hours.

[0326] 2) TH-3021-3μM + AST-3424-2h-simutaniously or Naproxen-400μM + AST-3424-2h-simutaniously, i.e., Naproxen or TH-3021 and AST-3424 co-treated for 2 hours:

[0327] 24 hours after cell plating, Naproxen or TH-3021 were combined with AST-3424.

[0328] Fill each well with 98 μL of growth medium, add 1 μL of prepared Naproxen or TH-3021 solution to each well, shake gently to ensure uniform mixing, then add 1 μL of prepared AST-3424 solution respectively, shake gently to ensure uniform mixing, then place in the incubator for 2 hours, wash off the compound, and continue to culture in a 37°C, 5% CO2 incubator for 72 hours.

[0329] 3) AST-3424-2h-pretreatment-TH-3021-3μM-2h or AST-3424-2h-pretreatment-Naproxen-400μM-2h, i.e., after AST-3424 pretreatment for 2 hours, the compound was washed away, and then Naproxen or TH-3021 was added for treatment for 2 hours:

[0330] 24 hours after cell plating, AST-3424 was combined with Naproxen or TH-3021.

[0331] Add 99 μL of growth medium to each well, add 1 μL of prepared AST-3424 solution to each well, shake gently to ensure even mixing, place in the incubator for 2 hours, wash away the compound, add 99 μL of fresh complete medium, and then add 1 μL of prepared Naproxen or TH-3021 solution, shake gently to ensure even mixing, then place in the incubator for 2 hours, wash away the compound, and continue to culture in a 37°C, 5% CO2 incubator for 72 hours.

[0332] 4) TH-3021-3μM-2h-pretreatment-AST-3424-2h-cotreatment or Naproxen-400μM-2h-pretreatment-AST-3424-2h-cotreatment, i.e., pretreatment with Naproxen or TH-3021 for 2 hours, without washing away the above two compounds, and then adding AST-3424 to continue co-treatment for 2 hours.

[0333] 24 hours after cell plating, Naproxen or TH-3021 were combined with AST-3424.

[0334] Add 98 μL of growth medium to each well, add 1 μL of the prepared compound Naproxen or TH-3021 to each well, shake gently to ensure uniform mixing, place in the incubator for 2 hours, then add 1 μL of the prepared AST-3424 solution respectively, shake gently to ensure uniform mixing, then place in the incubator for 2 hours, wash off the compound, and continue to culture in a 37°C, 5% CO2 incubator for 72 hours.

[0335] b) Single drug use: 24 hours after cell plating, the compound was applied alone. 99 μL of growth medium was added to each well, followed by 1 μL of the prepared AST-3424 solution. Gently shaken to ensure uniform mixing, the cells were placed in a 37°C, 5% CO2 incubator for 2 hours, the compound was washed off, and fresh medium was added. The cells were then incubated in a 37°C, 5% CO2 incubator for another 72 hours.

[0336] c) Final concentration of test compound:

[0337] Single drug concentration:

[0338] AST-3424 concentration:

[0339] i.100, 33.33, 11.11, 3.70, 1.23, 0.41, 0.14, 0.046, 0.015, 0[nM].

[0340] ii.10, 3.33, 1.11, 0.37, 0.123, 0.041, 0.014, 0.0046, 0.0015, 0[nM]

[0341] Combined drug concentration:

[0342] AST-3424 concentration:

[0343] i.50000, 16666.67, 5555.56, 1851.85, 617.28, 205.76, 68.59.22.86, 7.62[nM];

[0344] ii.10000, 2000, 400, 80, 16, 3.2, 0.64, 0.13, 0.03[nM];

[0345] iii.100, 33.33, 11.11, 3.70, 1.23, 0.41, 0.14, 0.05, 0.02 [nM].

[0346] Naproxen concentration: 400 [μM];

[0347] TH-3021 concentration: 3 [μM].

[0348] Finally, after data processing, the dose-effect curve was obtained, as shown in Figure 2, and the half-maximal killing concentration (IC) of AST-3424 on cells under different combinations was calculated. 50 ), as shown in Table 2 below.

[0349] Table 2: The median lethal concentration (IC) of AST-3424 on cells in combination experiments with different drugs and different dosing orders 50 )

[0350] Experimental Conclusion

[0351] Analysis of the effect of TH-3021 on intracellular AKR1C3 enzyme activation AST-3424 showed that:

[0352] First, Groups 1, 2, and 4 all demonstrated the compound's effect on the activation process of AST-3424. This is because TH-3021 was added to the cells 2 hours in advance. This process ensured that TH-3021 entered the cells and bound to the AKR1C3 enzyme, preventing AST-3424 from activating the AKR1C3 enzyme and inhibiting cell proliferation. This was because the AKR1C3 enzyme had already bound to TH-3021 and was unable to activate AST-3424.

[0353] Second, the effects of groups 2 and 4 were stronger, and IC 50 The numerical difference is 200-fold, with Group 1 being relatively weak at only 6-fold. Comparing the cell treatment process of Group 1 with that of Groups 2 and 4, it can be seen that after adding TH-3021 to the cell solution and culturing for 2 hours, this group immediately washed away the compound and re-added the culture medium and AST-3424 drug, resulting in the elution of TH-3021, which in turn affected the inhibitory effect of TH-3021 on the enzyme activation process of AST-3424. Therefore, the final effect was relatively small.

[0354] Third, because AST-3424 had already been in contact with the cells and cultured for 2 hours in Group 3, the drug had already entered the cells and was fully activated by the AKR1C3 enzyme in the cells, releasing AST-2660 that could inhibit cell proliferation. In this case, adding TH-3021 was no longer effective.

[0355] Analysis of the effect of Naproxen on intracellular AKR1C3 enzyme activation AST-3424 showed that:

[0356] First, both Groups 2 and 4 demonstrated the compound's effect on the activation process. This is because in Group 2, naproxen and AST-3424 were added to the cell system simultaneously and incubated for 2 hours, while in Group 4, naproxen was added to the cell system and incubated for 2 hours before AST-3424 was added. In other words, both groups completed the binding inhibition of the AKR1C3 enzyme in the cells within a 2-hour incubation period after contact with the cells, thereby affecting the process of enzyme activation and metabolism of AST-3424 to AST-2660.

[0357] Second, in Group 3, similar to TH-3021, AST-3424 had already been in contact with the cells and cultured for 2 hours, causing the drug to enter the cells and be fully activated by the AKR1C3 enzyme within the cells, releasing AST-2660, which can inhibit cell proliferation. In this case, the addition of naproxen was ineffective.

[0358] Third, due to the different chemical structures of naproxen and TH-3021, its ability to enter cells, bind to the AKR1C3 enzyme in cells, and ultimately affect the enzyme activation of AST-3424 to metabolize AST-2660 are far less than TH-3021. Therefore, naproxen can basically not achieve the pre-inhibition of the AKR1C3 enzyme in cells after culturing with cells for 2 hours, and the subsequent washing away of the compound directly leads to the disappearance of its influence, and therefore cannot reflect the effect on the enzyme activation of AST-3424 to metabolize AST-2660.

[0359] In summary, we can find that:

[0360] TH-3021 has a much greater inhibitory effect on the process of AKR1C3 enzyme activating AST-3424 to metabolize AST-2660 than Naproxen;

[0361] If AST-3424 is added first and then cultured with cells, AKR1C3 will quickly activate AST-3424 to metabolize AST-2660. After a period of time (e.g., 2 hours in the experimental conditions), the conversion to AST-2660 is complete and retained in the cells. Adding naproxen or TH-3021 thereafter will not affect the final cell proliferation.

[0362] If an AKR1C3 enzyme inhibitor (Naproxen or TH-3021) is added first and incubated with cells for a period of time (e.g., 2 hours in the experimental conditions), binding of the inhibitor to the enzyme will occur. However, this binding is likely to be largely reversible. After the inhibitor is washed away, whether the process of AKR1C3 enzyme activating AST-3424 to metabolize AST-2660 is significantly affected depends on the inhibitor's inhibitory effect: strong inhibitors such as TH-3021 can still show a significant inhibitory effect on the enzyme activation process, while weak inhibitors such as Naproxen cannot exert an inhibitory effect on the enzyme activation process due to the short incubation time with cells.

[0363] If AST-3424 and AKR1C3 enzyme inhibitors (Naproxen or TH-3021) are added at the same time, the process of AKR1C3 enzyme activating AST-3424 to metabolize AST-2660 will be significantly affected.

[0364] Therefore, it can be clearly stated that for compounds that have the effect of inhibiting the process of AKR1C3 enzyme activating AST-3424 to metabolize AST-2660 (such as some non-steroidal analgesics), if the patient has already taken non-steroidal analgesics, then the drug containing the AKR1C3-activating anticancer prodrug compound or its salt, ester, solvate, isotope isomer should be administered after the non-steroidal analgesics are eliminated. This prevents these drugs from inhibiting the process of AKR1C3 enzyme activating AST-3424 to metabolize AST-2660;

[0365] When the patient has been administered a drug containing an AKR1C3-activating anticancer prodrug compound or its salt, ester, solvate, or isotope isomer, the nonsteroidal analgesic drug should be administered only after the AKR1C3-activating anticancer prodrug compound is completely or substantially partially activated by enzymes to metabolize AST2660.

[0366] 2. Animal Model Efficacy and Safety Evaluation Experiment of Celecoxib Combined with AST-3424

[0367] To further investigate the in vivo efficacy and safety of the non-steroidal analgesic drug celecoxib, which does not significantly affect the cell proliferation inhibitory activity of AKR1C3-activating anticancer prodrug compounds such as AST-3424, an animal model experiment was conducted using celecoxib in combination with AST-3424.

[0368] Pharmacodynamics of the test substances AST-3424 and Celecoxib as monotherapy and in combination in the human lung cancer NCI-H460 subcutaneous xenograft BALB / c nude female mouse model.

[0369] BALB / c nude mice were subcutaneously inoculated with human lung cancer NCI-H460 cells to establish a subcutaneous human lung cancer tumor model. Seven groups, each containing five mice, were divided into the test drug Celecoxib 50 mg / kg and 100 mg / kg groups, the AST-3424 2.5 mg / kg group, and different combinations of Celecoxib 50 mg / kg or 100 mg / kg with AST-3424 2.5 mg / kg. A 0.5% sodium carboxymethylcellulose vehicle control group was also included. The 0.5% sodium carboxymethylcellulose vehicle control group and the Celecoxib 50 mg / kg and 100 mg / kg groups were administered via oral gavage once daily for 15 days, with observation for 13 days. The AST-3424 2.5 mg / kg group was administered via tail vein injection once weekly for three weeks, with observation for seven days. Celecoxib 50 mg / kg or 100 mg / kg and AST-3424 2.5 mg / kg were administered by oral gavage once a day for 15 days. AST-3424 2.5 mg / kg in the combination treatment group was administered by tail vein injection once a week for three weeks, and the patients were observed for 7 days.

[0370] After tumor inoculation, tumor growth was routinely monitored, and tumor volume and mouse body weight were measured. Efficacy was evaluated based on the relative tumor inhibition rate (TGI). Specific results are shown in Table 3 and Figure 3 below, with specific efficacy analysis data for 30 days after inoculation (end of dosing) shown in Table 4.

[0371] The body weights of the mice were measured after inoculation, and the results are shown in Table 5 and Figure 4.

[0372] Table 3: Changes in tumor volume of mice in each group over treatment time in the human lung cancer NCI-H460 model

[0373] Table 4: Efficacy analysis of each group in the human lung cancer NCI-H460 model 30 days after tumor cell inoculation

[0374] Table 5: Body weight changes in each group in the human lung cancer NCI-H460 model

[0375] Group 1, 0.5% sodium carboxymethylcellulose, 0mg / kg, QDx15, po

[0376] Group 2: Celecoxib, 50 mg / kg, QD x 15, po

[0377] Group 3, Celecoxib, 100 mg / kg, QD x 15, po

[0378] Group 4: Celecoxib 2 hours before, 50 mg / kg, QD x 15, po, AST-3424, 2.5 mg / kg, QW x 3, iv

[0379] Group 5: Celecoxib 2 hours before, 100 mg / kg, QD x 15, po, AST-3424, 2.5 mg / kg, QW x 3, iv

[0380] Group 6, AST-3424,2.5mg / kg,QWx3,iv,Celecoxib 2h after,50mg / kg,QDx15,po

[0381] Group 7, AST-3424, 2.5 mg / kg, QWx3, iv

[0382] Experimental Conclusion

[0383] Comparison revealed that the TGI of AST-3424 alone was 60.75%, while the TGI did not decrease when combined with celccoxib, regardless of whether the drug was administered first or later. Furthermore, the tumor inhibition rate of the combination group was not significantly different from that of the AST-3424 monotherapy group. This indicates that the combination of the two drugs did not affect the tumor growth inhibition effect of AST-3424. Both AST-3424 monotherapy and the combination were well tolerated by mice.

[0384] III. Pharmacokinetic Data Obtained from the Phase I Clinical Trial of AST-3424

[0385] A Phase I clinical trial poster for OBI-3424 was released at ASCO 2022. ※(Safety, pharmacokinetics, and clinical activity of OBI-3424, an AKR1C3-activated prodrug, in patients with advanced or metastatic solid tumors: A phase 1 dose-escalation study., Apostolia Maria Tsimberidou, Claire F. Verschraegen, Pei Hsu, and Tillman E. Pearce, Journal of Clinical Oncology, 2022 40:16_suppl, 3030-3030 (Safety, pharmacokinetics, and clinical activity of OBI-3424, an AKR1C3-activated prodrug, in patients with advanced or metastatic solid tumors: A phase 1 dose-escalation study., OBI Pharma Inc. website (download address: https: / / www.obipharma.com / zh-hant / news-zh-hant / poster-presentations-at-the-2022-asco-annual-meeting-for-adagloxad-simolenin-obi-999-and-obi-3424 / , download date: October 10, 2022) for the pharmacokinetic data of OBI-3424 in human clinical trials in the United States; or refer to the related research paper *Tsimberidou, AM, Verschraegen, CF, Wesolowski, R. et al. Phase 1 dose-escalation study evaluating the safety, pharmacokinetics, and clinical activity of OBI-3424 in patients with advanced or metastatic solid tumors. Br J published in May 2023. Cancer129,266–274(2023).https: / / doi.org / 10.1038 / s41416-023-02280-4:

[0386] OBI-3424 and OBI-2660 concentrations were analyzed in blood samples collected on day 1 of cycle 1 (pretreatment); 15 minutes after the start of infusion; at the end of infusion (EOI); and 15, 30, 60, and 90 minutes and 2, 4, 6, and 8 hours after treatment. The mean plasma concentration versus time curves of a single dose of OBI-3424 and OBI-2660 are shown in Figure 5, and the pharmacokinetic parameters of OBI-3424 and OBI-2660 are summarized in Table 6.

[0387] Maximum serum concentrations (Cmax) of OBI-3424 generally occurred at the end of a 30-minute drug infusion; OBI-2660 had a slight delay in reaching maximum concentrations compared to OBI-3424, with Cmax achieved between 1.33 and 1.75 hours after the start of the drug infusion.

[0388] OBI-3424 has a shorter half-life (0.20 to 0.74 hours), while OBI-2660 has a longer half-life (1.87 to 3.48 hours).

[0389] The mean clearance of OBI-3424 was 4.8 to 8.8 L / h / m 2 , with a distribution volume of 2.4 to 4.3 L / m 2 .

[0390] For OBI-3424 and OBI-2660, no accumulation of exposure (Cmax and area under the concentration-time curve) was observed between the two doses (Cycle 1 Day 1 and Cycle 1 Day 8).

[0391] Table 6: Pharmacokinetic parameters of OBI-3424 and OBI-2660 (Excerpt from the Phase I clinical trial poster of OBI-3424 released at ASCO2022) ※ Table 3 in the or Table 1 in the relevant research paper* published in May 2023)

[0392] Data are expressed as mean (SD).

[0393] CL, clearance;

[0394] AUC 0-t , the area under the concentration-time curve from time 0 to the last measurable concentration;

[0395] Cmax, time to maximum concentration;

[0396] SD, standard deviation;

[0397] T 1 / 2 ,half life;

[0398] Tmax, time to maximum concentration;

[0399] Vdss, distribution volume at steady state.

[0400] According to published Phase I clinical data, OBI-2660 reaches its maximum concentration 1.33-1.75 hours after intravenous injection. At this time, the corresponding OBI-3424 is considered to be completely activated by the AKR1C3 enzyme and converted into OBI-2660. It is speculated that non-steroidal analgesics can be used at this time.

Claims

1. A method of treating cancer patients with pain using a drug containing an AKR1C3-activating anticancer prodrug compound or its salts, esters, solvates, or isotopomers in combination with a non-steroidal analgesic drug.

2. The method of claim 1, wherein the AKR1C3 activating anticancer prodrug compound is selected from the group consisting of structural formulas (1) to (11): in, R1, R2, R3, R4, R5, R8, R9, R 10 The definition is as set forth in the claims of patent application PCT / CN2020 / 089692, publication number WO2020228685A1 (corresponding to Chinese application number 2020800358890, publication number CN113853379A); Wherein, the definitions of A, E, G, X, and Y are as described in the claims of patent application PCT / NZ2019 / 050030, publication number WO2019190331A1 (corresponding to Chinese application number 2019800234236, publication number CN111918864A); Wherein, Rw is defined as described in the claims of patent application PCT / CN2020 / 120281, publication number WO2021068952A1 (corresponding to Chinese application number 202080071652.8, publication number CN114555574A); Among them, X, Y, Z, R, T, A and X 10 The definition of is as set forth in the claims of patent application PCT / US2016 / 021581, publication number WO2016145092A1 (corresponding to Chinese application number 2016800150788, publication number CN107530556A); in: A is a substituted or unsubstituted C6-C10 aryl, biaryl or substituted biaryl, 5-15 membered heteroaryl or -N=CR 1 R 2 , wherein the substituent when substituted is selected from the group consisting of: halogen, -CN, -NO2, -O-(CH2)-O-, -CO2H and its salts, -OR 100 、-CO2R 100 、-CONR 101 R 102 、-NR 101 R 102 、-NR 100 SO2R 100 、-SO2R 100 、-SO2NR 101 R 10 2 , C1-C6 alkyl, C3-C10 heterocyclic group; Among them, R 100 、R 101 and R 102 are independently hydrogen, C1-C8 alkyl, C6-C12 aryl; or R 101 and R 102 together with the nitrogen atom to which it is attached, form a 5-7 membered heterocyclic ring; wherein the alkyl group and the aryl group are each substituted with 1-3 halo groups or 1-3 C1-C6 alkyl groups; R 1 and R 2 each independently phenyl or methyl; X, Y and Z are each independently hydrogen or halo; R is hydrogen or C1-C6 alkyl or halogen-substituted alkyl; Among them, X, Y, Z, R, D, L 1 , A and X 10 The definition of is as set forth in the claims of patent application PCT / US2016 / 025665, publication number WO2016161342A3 (corresponding to Chinese application number 2016800200132, publication number CN108136214A); Wherein, the definitions of R1, R2, R3, R4, and T are as described in the claims of patent application PCT / CN2021 / 118597, publication number WO2022057838A1; Wherein, the definitions of R1, R2, R3, R4, G1, G2, G3, G4, E, T, Y, Z, m, n, s, t, v, w, and Ring A are as described in the claims of patent application CN202210585771.6, publication number CN115403579A; or a pharmaceutically acceptable salt thereof, Among them, R 1 、R 2a 、R 2b 、R 3 、R 4 、R 5 , n, and Z are defined as described in the claims of patent application PCT / IB2020 / 057285, publication number WO2021005586A1 (corresponding to Chinese application number CN202080053804.1, publication number CN114206870A); or a pharmaceutically acceptable salt thereof, Among them, R w ,X,R4,R 10 、R 13 、R 14 The definition of is as recorded in the claims of patent application PCT / CN2022 / 098082, publication number WO2022258043A1.

3. The method of claim 1, wherein the AKR1C3 activating anticancer prodrug compound is selected from the group consisting of the following structures:

4. The method of claim 1, wherein the drug containing the AKR1C3-activating anticancer prodrug compound or its salt, ester, solvate, or isotopomer is administered with a non-steroidal analgesic drug at intervals or simultaneously.

5. The method of claim 4, wherein when the patient has been taking nonsteroidal analgesics, the drug containing the AKR1C3-activating anticancer prodrug compound or its salt, ester, solvate, or isotope isomer should be administered only after the nonsteroidal analgesics have been eliminated; When the patient has been administered a drug containing an AKR1C3-activating anticancer prodrug compound or its salt, ester, solvate, or isotope isomer, the nonsteroidal analgesic drug should be administered only after the AKR1C3-activating anticancer prodrug compound or its salt, ester, solvate, or isotope isomer is activated.

6. The method of claim 5, wherein after the patient has been administered a drug containing an AKR1C3-activating anticancer prodrug compound or a salt, ester, solvate, or isotopomer thereof, a nonsteroidal analgesic drug should be administered 1.33-1.75 hours after the start of drug infusion.

7. The method of claim 4, wherein the drug containing AST-3424, AST-3423 or AST-2870 or its salts, esters, solvates or isotopomers is administered simultaneously with ibuprofen or celecoxib.

8. The method of claim 1 , wherein the nonsteroidal analgesic drug is selected from the group consisting of aspirin, sodium salicylate, paracetamol, indomethacin, naproxen, nabumetone, diclofenac, ibuprofen, rofecoxib, celecoxib, nimesulide, aceclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ketoprofen, ibuprofen, suprofen, tiaprofenic acid, ketorolac, zomepirac, mefenamic acid, flufenamic acid, and meclofenamic acid. Acid, Meloxicam, Oxaprozin, Piroxicam, Tenoxicam, Lornoxicam, Sasapyrine, Sulindac, Tolmetin, Phenacetin, Loxoprofen Sodium, Aminopyrine, Metamizole Sodium, Sudoxicam, Phenylbutazone, Oxyphenbutazone.

9. The method of claim 1, wherein the pain is mild pain.

10. Pharmaceutical use of an AKR1C3-activated anticancer prodrug compound or its salts, esters, solvates, or isotope isomers, for preparing a therapeutic drug for use in combination with a non-steroidal analgesic drug to treat cancer patients with pain.

11. The pharmaceutical use according to claim 9, wherein the AKR1C3 activating anticancer prodrug compound is selected from the group consisting of structural formulas (1) to (11): in, R1, R2, R3, R4, R5, R8, R9, R 10 The definition is as set forth in the claims of patent application PCT / CN2020 / 089692, publication number WO2020228685A1 (corresponding to Chinese application number 2020800358890, publication number CN113853379A); Wherein, the definitions of A, E, G, X, and Y are as described in the claims of patent application PCT / NZ2019 / 050030, publication number WO2019190331A1 (corresponding to Chinese application number 2019800234236, publication number CN111918864A); Wherein, Rw is defined as described in the claims of patent application PCT / CN2020 / 120281, publication number WO2021068952A1 (corresponding to Chinese application number 202080071652.8, publication number CN114555574A); Among them, X, Y, Z, R, T, A and X 10 The definition of is as set forth in the claims of patent application PCT / US2016 / 021581, publication number WO2016145092A1 (corresponding to Chinese application number 2016800150788, publication number CN107530556A); in: A is a substituted or unsubstituted C6-C10 aryl, biaryl or substituted biaryl, 5-15 membered heteroaryl or -N=CR 1 R 2 , wherein the substituent when substituted is selected from the group consisting of: halogen, -CN, -NO2, -O-(CH2)-O-, -CO2H and its salts, -OR 100 、-CO2R 100 、-CONR 101 R 102 、-NR 101 R 102 、-NR 100 SO2R 100 、-SO2R 100 、-SO2NR 101 R 10 2 , C1-C6 alkyl, C3-C10 heterocyclic group; Among them, R 100 、R 101 and R 102 are independently hydrogen, C1-C8 alkyl, C6-C12 aryl; or R 101 and R 102 together with the nitrogen atom to which it is attached, form a 5-7 membered heterocyclic ring; wherein the alkyl group and the aryl group are each substituted with 1-3 halo groups or 1-3 C1-C6 alkyl groups; R 1 and R 2 each independently phenyl or methyl; X, Y and Z are each independently hydrogen or halo; R is hydrogen or C1-C6 alkyl or halogen-substituted alkyl; Among them, X, Y, Z, R, D, L 1 , A and X 10 The definition of is as set forth in the claims of patent application PCT / US2016 / 025665, publication number WO2016161342A3 (corresponding to Chinese application number 2016800200132, publication number CN108136214A); Wherein, the definitions of R1, R2, R3, R4, and T are as described in the claims of patent application PCT / CN2021 / 118597, publication number WO2022057838A1; Wherein, the definitions of R1, R2, R3, R4, G1, G2, G3, G4, E, T, Y, Z, m, n, s, t, v, w, and Ring A are as described in the claims of patent application CN202210585771.6, publication number CN115403579A; or a pharmaceutically acceptable salt thereof, Among them, R 1 、R 2a 、R 2b 、R 3 、R 4 、R 5 , n, and Z are defined as described in the claims of patent application PCT / IB2020 / 057285, publication number WO2021005586A1 (corresponding to Chinese application number CN202080053804.1, publication number CN114206870A); or a pharmaceutically acceptable salt thereof, Among them, R w ,X,R4,R 10 、R 13 、R 14 The definition of is as recorded in the claims of patent application PCT / CN2022 / 098082, publication number WO2022258043A1.

12. A drug combination, characterized in that: Contains the following substances as active ingredients: AKR1C3 activating prodrug compound or its salt, ester, solvate, isotope isomer, and nonsteroidal analgesics; The active ingredients are formulated together or separately for combined use, simultaneous use or separate use.

13. The pharmaceutical combination according to claim 12, which is used for treating cancer or tumor patients with pain.

14. The drug combination according to claim 12, wherein The AKR1C3 activating prodrug compound is selected from the structural formulas (1) to (11): Among them, R1, R2, R3, R4, R5, R8, R9, R 10 The definition is as set forth in the claims of patent application PCT / CN2020 / 089692, publication number WO2020228685A1 (corresponding to Chinese application number 2020800358890, publication number CN113853379A); Wherein, the definitions of A, E, G, X, and Y are as described in the claims of patent application PCT / NZ2019 / 050030, publication number WO2019190331A1 (corresponding to Chinese application number 2019800234236, publication number CN111918864A); Wherein, Rw is defined as described in the claims of patent application PCT / CN2020 / 120281, publication number WO2021068952A1 (corresponding to Chinese application number 202080071652.8, publication number CN114555574A); Among them, X, Y, Z, R, T, A and X 10 The definition is as described in the claims of patent application PCT / US2016 / 021581, publication number WO2016145092A1 (corresponding to Chinese application number 2016800150788, publication number CN107530556A). load; in: A is a substituted or unsubstituted C6-C10 aryl, biaryl or substituted biaryl, 5-15 membered heteroaryl or -N=CR 1 R 2 , wherein the substituent when substituted is selected from the group consisting of: halogen, -CN, -NO2, -O-(CH2)-O-, -CO2H and its salts, -OR 100 、-CO2R 100 、-CONR 101 R 102 、-NR 101 R 102 、-NR 100 SO2R 100 、-SO2R 100 、-SO2NR 101 R 10 2 , C1-C6 alkyl, C3-C10 heterocyclic group; Among them, R 100 、R 101 and R 102 are independently hydrogen, C1-C8 alkyl, C6-C12 aryl; or R 101 and R 102 together with the nitrogen atom to which it is attached, form a 5-7 membered heterocyclic ring; wherein the alkyl group and the aryl group are each substituted with 1-3 halo groups or 1-3 C1-C6 alkyl groups; R 1 and R 2 each independently phenyl or methyl; X, Y and Z are each independently hydrogen or halo; R is hydrogen or C1-C6 alkyl or halogen-substituted alkyl; Among them, X, Y, Z, R, D, L 1 , A and X 10 The definition of is as set forth in the claims of patent application PCT / US2016 / 025665, publication number WO2016161342A3 (corresponding to Chinese application number 2016800200132, publication number CN108136214A); Wherein, the definitions of R1, R2, R3, R4, and T are as described in the claims of patent application PCT / CN2021 / 118597, publication number WO2022057838A1; Wherein, the definitions of R1, R2, R3, R4, G1, G2, G3, G4, E, T, Y, Z, m, n, s, t, v, w, and Ring A are as described in the claims of patent application CN202210585771.6, publication number CN115403579A; or a pharmaceutically acceptable salt thereof, Among them, R 1 、R 2a 、R 2b 、R 3 、R 4 、R 5 , n, and Z are defined as described in the claims of patent application PCT / IB2020 / 057285, publication number WO2021005586A1 (corresponding to Chinese application number CN202080053804.1, publication number CN114206870A); or a pharmaceutically acceptable salt thereof, Among them, R w ,X,R4,R 10 、R 13 、R 14 The definition of is as recorded in the claims of patent application PCT / CN2022 / 098082, publication number WO2022258043A1.

15. The drug combination according to claim 12, wherein The AKR1C3 activation prodrug compound is selected from the following structural compounds:

16. The drug combination according to claim 12, wherein The nonsteroidal analgesic drug is selected from the group consisting of Aspirin, Sodium salicylate, Paracetamol, Indomethacin, Naproxen, Nabumetone, Diclofenac, Ibuprofen, Rofecoxib, Celecoxib, Nimesulide, Aceclofenac, Diflunisal, Etodolac, Fenoprofen, Flurbiprofen, Ketoprofen, Tiaprofenic Acid, Ketorolac, Zomepirac, Mefenamic acid, Flufenamic acid, and Meclofenamic acid. Acid, Meloxicam, Oxaprozin, Piroxicam, Tenoxicam, Lornoxicam, Sasapyrine, Sulindac, Tolmetin, Phenacetin, Loxoprofen Sodium, Aminopyrine, Metamizole Sodium, Sudoxicam, Phenylbutazone, Oxyphenbutazone.

17. A pharmaceutical preparation, characterized in that It is prepared from the active ingredients of the drug combination according to claim 12 and pharmaceutically acceptable excipients.

18. The pharmaceutical preparation according to claim 17, characterized in that The dosage form of the pharmaceutical preparation is selected from granules, tablets, pills, capsules, injections or freeze-dried powder injections.

19. Use of the drug combination according to claim 12 and / or the pharmaceutical preparation according to claim 17 in the preparation of an anti-tumor drug.

20. The pharmaceutical combination according to claim 13 and / or the use according to claim 19, wherein: The cancer or tumor is selected from ovarian cancer, breast cancer, pancreatic cancer, fallopian tube cancer, primary peritoneal cancer, gastric cancer, prostate cancer, liver cancer, colon cancer, rectal cancer, lung cancer, and bladder cancer, and the lung cancer is preferably non-small cell lung cancer or small cell lung cancer.

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