Drug combination containing PD-l1 small molecule inhibitor and use thereof

Abstract

A drug combination containing a PD-L1 small molecule inhibitor and the use thereof. The drug combination comprises a PD-L1 small molecule inhibitor and a chemotherapeutic drug molecule, or a PD-L1 small molecule inhibitor and a COX-2 inhibitor. The drug combination can be used for treating tumors.

Description

Drug combinations containing PD-L1 small molecule inhibitors and their applications

[0001] This application claims priority to Chinese Patent Application No. 202310785638X filed on June 29, 2023, and Chinese Patent Application No. 2023117625926 filed on December 20, 2023. The entire contents of the aforementioned Chinese patent applications are incorporated herein by reference. Technical Field

[0002] The present invention relates to a drug combination containing a PD-L1 small molecule inhibitor and application thereof. Background Art

[0003] Malignant tumors are serious diseases that endanger human life and health. With the rapid development of tumor biology and related disciplines in recent years, specific anti-tumor drugs and immunotherapy drugs targeting abnormal signaling systems within tumor cells have become the focus of new drug research and development. Furthermore, the combination of multiple anti-tumor drugs for the treatment of tumor diseases is also a hot topic in scientific research.

[0004] Programmed cell death-1 (PD-1), also known as CD279, is a cell surface receptor expressed on activated T cells, natural killer T cells, B cells, and macrophages. It functions as an intrinsic negative feedback system, preventing T cell activation, which in turn reduces autoimmunity and promotes self-tolerance. PD-1 is also known to play an important role in suppressing antigen-specific T cell responses in diseases such as cancer and viral infections.

[0005] The structure of PD-1 consists of an extracellular immunoglobulin variable region-like domain, followed by a transmembrane region and an intracellular domain. The intracellular domain contains two phosphorylation sites located within an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif, suggesting that PD-1 negatively regulates T cell receptor-mediated signaling. PD-1 has two ligands, PD-L1 and PD-L2, which differ in their expression patterns. PD-L1 protein is upregulated on macrophages and dendritic cells in response to lipopolysaccharide and GM-CSF treatment, and on T cells and B cells following T cell receptor and B cell receptor signaling. PD-L1 is also highly expressed on nearly all tumor cells, and its expression is further increased after IFN-γ treatment. Numerous studies have demonstrated that PD-L1 is elevated on the surface of tumor cells in the tumor microenvironment and binds to PD-1 on activated T cells, transmitting negative regulatory signals that lead to apoptosis or anergy of tumor antigen-specific T cells, thereby suppressing the immune response and promoting tumor cell escape.

[0006] Although no PD-L1 small molecule inhibitors are currently on the market, some are already in the clinical research stage. WO2019128918A1 discloses the structure and preparation method of a PD-L1 small molecule inhibitor. In vitro and pharmacokinetic studies have shown that it has good tumor inhibitory activity. Its specific structure is shown in Formula I.

[0007] Summary of the Invention

[0008] The technical problem to be solved by the present invention is to overcome the limited variety of anti-tumor drugs in the prior art by providing a drug combination containing a small molecule PD-L1 inhibitor and its application. Compared with the use of a small molecule PD-L1 inhibitor or other small molecule drugs (such as targeted small molecule inhibitors or chemotherapy drugs) alone, the drug combination of the present invention has a synergistic effect and further has better effects in treating cancer and prolonging survival.

[0009] The present invention provides a drug combination A, which includes a PD-L1 small molecule inhibitor and a chemotherapy drug molecule.

[0010] In some embodiments, the drug combination A has a synergistic effect.

[0011] In the drug combination A, the PD-L1 small molecule inhibitor is preferably a compound as shown in Formula I or a pharmaceutically acceptable salt thereof;

[0012] In the drug combination A, the chemotherapy drug molecule is preferably one or more of capecitabine, paclitaxel, oxaliplatin and temozolomide, preferably capecitabine or paclitaxel.

[0013] In some embodiments, the chemotherapy drug molecule is temozolomide.

[0014] In the drug combination A, the mass ratio of the PD-L1 small molecule inhibitor to the chemotherapy drug molecule can be (0.04-50):1, preferably (0.2-16):1, more preferably (0.2-2):1 or (6-16):1, for example 0.45:1, 0.58:1, 1.2:1, 10:1 or 11:1.

[0015] In some embodiments, the mass ratio of the PD-L1 small molecule inhibitor to the chemotherapy drug molecule is 6:1, 9.5:1 or 16:1.

[0016] In some embodiments, the pharmaceutical combination A comprises the compound of formula I as described above and capecitabine. The mass ratio of the compound of formula I to capecitabine is preferably (0.2-2):1, for example 0.45:1, 0.58:1 or 1.2:1.

[0017] In some embodiments, the pharmaceutical combination A comprises the compound of formula I described above and paclitaxel. The mass ratio of the compound of formula I to paclitaxel is preferably (6-16):1, for example 10:1 or 11:1.

[0018] In some embodiments, the pharmaceutical combination A comprises the compound of formula I and temozolomide. The mass ratio of the compound of formula I to temozolomide is preferably (6-16):1, for example 6:1, 9.5:1 or 16:1.

[0019] The active ingredients of the drug combination A are preferably the PD-L1 small molecule inhibitors and the chemotherapy drug molecules as described above.

[0020] In some embodiments, the active ingredients of the pharmaceutical combination A are the compound represented by Formula I as described above and capecitabine.

[0021] In some embodiments, the active ingredients of the pharmaceutical combination A are the compound represented by Formula I as described above and paclitaxel.

[0022] In some embodiments, the active ingredients of the pharmaceutical combination A are the compound represented by Formula I as described above and temozolomide.

[0023] In the drug combination A, the PD-L1 small molecule inhibitor is preferably administered via the gastrointestinal tract (e.g., oral, sublingual, or rectal administration), injection (e.g., subcutaneous, intradermal, intravenous, intraperitoneal, or intramuscular), respiratory tract, or topical administration (e.g., mucosa or skin), more preferably via the gastrointestinal tract, such as oral administration.

[0024] In the drug combination A, the chemotherapy drug molecules are preferably administered via the gastrointestinal tract (e.g., oral, sublingual or rectal administration), injection (e.g., subcutaneous, intradermal, intravenous, intraperitoneal or intramuscular), respiratory tract or local administration (e.g., mucosa or skin), preferably via the gastrointestinal tract or injection, such as oral administration or intravenous injection.

[0025] In the drug combination A, the PD-L1 small molecule inhibitor is preferably administered orally; and the chemotherapy drug is preferably administered orally.

[0026] In the drug combination A, the PD-L1 small molecule inhibitor is preferably administered orally; and the chemotherapy drug molecule is preferably administered via intravenous injection.

[0027] The present invention provides a pharmaceutical composition B, which includes a PD-L1 small molecule inhibitor, a chemotherapy drug molecule and a pharmaceutical excipient.

[0028] In some embodiments, the pharmaceutical composition B has a synergistic effect.

[0029] In the pharmaceutical composition B, the types of the PD-L1 small molecule inhibitor and the chemotherapy drug molecule are preferably as described above.

[0030] In the pharmaceutical composition B, the content of the PD-L1 small molecule inhibitor is preferably 30-500 mg, more preferably 40-400 mg, such as 50 mg, 150 mg or 300 mg.

[0031] In the pharmaceutical composition B, the content of the chemotherapy drug molecule is preferably 10-650 mg, more preferably 30-550 mg, such as 30 mg, 60 mg, 100 mg, 150 mg or 500 mg.

[0032] In some embodiments, the amount of the chemotherapy drug molecule is 20 mg.

[0033] In the pharmaceutical composition B, the mass ratio of the PD-L1 small molecule inhibitor to the chemotherapy drug molecule may be (0.04-50):1, preferably (0.2-16):1, more preferably (0.2-2):1 or (6-16):1, for example 0.45:1, 0.58:1, 1.2:1, 10:1 or 11:1.

[0034] In some embodiments, the mass ratio of the PD-L1 small molecule inhibitor to the chemotherapy drug molecule is 6:1, 9.5:1 or 16:1.

[0035] In some embodiments, the active ingredients of the pharmaceutical composition B are the PD-L1 small molecule inhibitor described above and the chemotherapy drug molecules described above, preferably the compound as shown in Formula I and capecitabine, or the compound as shown in Formula I and paclitaxel.

[0036] In some embodiments, the active ingredients of the pharmaceutical composition B are the compound of formula I and temozolomide.

[0037] In some embodiments, when the pharmaceutical composition B comprises the compound of formula I, capecitabine and pharmaceutical excipients, the mass ratio of the compound of formula I to the capecitabine is preferably (0.2-2):1, for example, 0.45:1, 0.58:1 or 1.2:1.

[0038] In some embodiments, when the pharmaceutical composition B comprises the compound of formula I, paclitaxel, and pharmaceutical excipients, the mass ratio of the compound of formula I to paclitaxel is preferably (6-16):1, for example, 10:1 or 11:1.

[0039] In some embodiments, when the pharmaceutical composition B comprises the compound of formula I, temozolomide and pharmaceutical excipients, the mass ratio of the compound of formula I to the temozolomide is preferably (6-16):1, for example, 6:1, 9.5:1 or 16:1.

[0040] The pharmaceutical composition B is preferably composed of the PD-L1 small molecule inhibitor, the chemotherapy drug molecule and pharmaceutical excipients.

[0041] The pharmaceutical composition B may be a separate pharmaceutical composition.

[0042] The pharmaceutical composition B can be prepared into various suitable dosage forms according to different administration methods, including gastrointestinal dosage forms (such as oral dosage forms) and parenteral dosage forms (such as injection dosage forms, respiratory tract dosage forms, mucosal dosage forms or cavity dosage forms), preferably capsules, tablets, pills, granules, powders or oral liquids.

[0043] The pharmaceutical composition B is preferably presented in the form of an oral dosage form or an injection dosage form.

[0044] The present invention provides a pharmaceutical composition C comprising:

[0045] A first pharmaceutical composition C-1, comprising a PD-L1 small molecule inhibitor and a pharmaceutically acceptable excipient; and

[0046] The second pharmaceutical composition C-2 comprises a chemotherapy drug molecule and a pharmaceutically acceptable excipient.

[0047] In some embodiments, the pharmaceutical composition C has a synergistic effect.

[0048] The first pharmaceutical composition C-1 can be a separate pharmaceutical composition; the second pharmaceutical composition C-2 can be a separate pharmaceutical composition.

[0049] In the pharmaceutical composition C, the PD-L1 small molecule inhibitor and the chemotherapy drug molecule are as described above.

[0050] In the pharmaceutical composition C, the content of the PD-L1 small molecule inhibitor is preferably 30-500 mg, more preferably 40-400 mg, such as 50 mg, 150 mg or 300 mg.

[0051] In the pharmaceutical composition C, the content of the chemotherapy drug molecule is preferably 10-650 mg, more preferably 30-550 mg, such as 30 mg, 60 mg, 100 mg, 150 mg or 500 mg.

[0052] In some embodiments, the content of the chemotherapy drug molecule in the pharmaceutical composition C is 20 mg.

[0053] In the pharmaceutical composition C, the mass ratio of the PD-L1 small molecule inhibitor to the chemotherapy drug molecule is (0.04-50):1, preferably (0.2-16):1, more preferably (0.2-2):1 or (6-16):1, for example, 0.45:1, 0.58:1, 1.2:1, 10:1 or 11:1.

[0054] In some embodiments, in the pharmaceutical composition C, the mass ratio of the PD-L1 small molecule inhibitor to the chemotherapy drug molecule is 6:1, 9.5:1 or 16:1.

[0055] In some embodiments, the pharmaceutical composition C consists of a first pharmaceutical composition C-1 and a second pharmaceutical composition C-2; the first pharmaceutical composition C-1 consists of the PD-L1 small molecule inhibitor as described above and a pharmaceutical excipient, preferably consisting of the compound shown in Formula I as described above and a pharmaceutical excipient; the second pharmaceutical composition C-2 consists of the chemotherapy drug molecules as described above and a pharmaceutical excipient, preferably consisting of capecitabine or paclitaxel, and a pharmaceutical excipient.

[0056] In some embodiments, the pharmaceutical composition C consists of a first pharmaceutical composition C-1 and a second pharmaceutical composition C-2; the first pharmaceutical composition C-1 consists of the compound shown in Formula I as described above and pharmaceutical excipients; the second pharmaceutical composition C-2 consists of temozolomide and pharmaceutical excipients.

[0057] In some embodiments, when the first pharmaceutical composition C-1 includes the compound as shown in Formula I and a pharmaceutical excipient as described above, and the second pharmaceutical composition C-2 includes capecitabine and a pharmaceutical excipient, the mass ratio of the compound as shown in Formula I to the capecitabine is preferably (0.2-2):1, for example 0.45:1, 0.58:1 or 1.2:1.

[0058] In some embodiments, when the first pharmaceutical composition C-1 comprises the compound of Formula I and a pharmaceutical excipient as described above, and the second pharmaceutical composition C-2 comprises paclitaxel and a pharmaceutical excipient, the mass ratio of the compound of Formula I to the paclitaxel is preferably (6-16):1, for example, 10:1 or 11:1.

[0059] In some embodiments, when the first pharmaceutical composition C-1 includes the compound as shown in Formula I and pharmaceutical excipients as described above, and the second pharmaceutical composition C-2 includes temozolomide and pharmaceutical excipients, the mass ratio of the compound as shown in Formula I to the temozolomide is preferably (6-16):1, for example 6:1, 9.5:1 or 16:1.

[0060] The first pharmaceutical composition C-1 is preferably presented in the form of an oral dosage form.

[0061] The second pharmaceutical composition C-2 is preferably presented in the form of an oral dosage form or an injection dosage form.

[0062] The present invention provides a combination medicine kit D, which comprises:

[0063] A first container comprising the first pharmaceutical composition C-1 as described above; and

[0064] A second container comprises the second pharmaceutical composition C-2 as described above.

[0065] The present invention also provides the use of the above-mentioned pharmaceutical combination A, pharmaceutical composition B or pharmaceutical composition C in the preparation of a drug for treating tumors.

[0066] The present invention also provides an application of the PD-L1 small molecule inhibitor in combination with the chemotherapy drug molecule in the preparation of a drug for treating tumors.

[0067] The present invention also provides a use of the PD-L1 small molecule inhibitor in the preparation of a drug for treating tumors, wherein the PD-L1 small molecule is used in combination with the chemotherapy drug molecule.

[0068] The present invention also provides a use of the chemotherapy drug molecule in the preparation of a drug for treating tumors, wherein the chemotherapy drug molecule is used in combination with the PD-L1 small molecule inhibitor.

[0069] The present invention also provides a method for treating tumors, comprising administering a therapeutically effective amount of the pharmaceutical combination A, pharmaceutical composition B or pharmaceutical composition C described above to a subject (eg, a human) in need thereof.

[0070] In the above-mentioned pharmaceutical combination A, pharmaceutical composition B, pharmaceutical composition C, their uses and their methods of treatment:

[0071] In some embodiments, the tumor is one or more of gastric cancer, nasopharyngeal cancer, lung cancer, colorectal cancer, breast cancer, colon cancer, bladder cancer, cervical cancer, endometrial cancer, pancreatic cancer, prostate cancer, hepatocellular carcinoma, melanoma, head and neck cancer, esophageal cancer, ovarian cancer, bone cancer, central nervous system tumor, adrenal adenoma, renal cell carcinoma and neuroblastoma, preferably breast cancer, gastric cancer or nasopharyngeal cancer.

[0072] In some embodiments, the tumor is one or more of gastric cancer, nasopharyngeal cancer, lung cancer, colorectal cancer, breast cancer, colon cancer, bladder cancer, cervical cancer, endometrial cancer, pancreatic cancer, prostate cancer, hepatocellular carcinoma, melanoma, head and neck cancer, esophageal cancer, ovarian cancer, bone cancer, central nervous system tumor, adrenal adenoma, renal cell carcinoma, neuroblastoma and glioma, preferably glioma.

[0073] In some embodiments, the PD-L1 small molecule inhibitor and the chemotherapeutic drug molecule can be administered simultaneously or separately.

[0074] The “simultaneous administration” means that the PD-L1 small molecule inhibitor and the chemotherapeutic drug molecule are contained in a separate pharmaceutical composition and administered simultaneously; or, alternatively, a “separate pharmaceutical composition comprising the PD-L1 small molecule inhibitor” and a “separate pharmaceutical composition comprising the chemotherapeutic drug molecule” are administered simultaneously.

[0075] The term "separate administration" means that the "separate pharmaceutical composition comprising the PD-L1 small molecule inhibitor" and the "separate pharmaceutical composition comprising the chemotherapeutic drug molecule" are administered separately at different times, for example, one of the "separate pharmaceutical composition comprising the PD-L1 small molecule inhibitor" and the "separate pharmaceutical composition comprising the chemotherapeutic drug molecule" is administered first, and the other is administered subsequently. The separate administration may be close in time or remote in time.

[0076] Whether administered simultaneously or separately, the administration regimens (including administration route, administration dosage, administration interval, etc.) of the PD-L1 small molecule inhibitor and the chemotherapeutic drug molecule may be the same or different, and may be adjusted by those skilled in the art as needed to provide the optimal therapeutic effect.

[0077] In some embodiments, the total daily dosage of the PD-L1 small molecule inhibitor is in the range of 30-2400 mg; preferably 500-2000 mg; for example, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg or 1900 mg.

[0078] In some embodiments, the PD-L1 small molecule inhibitor is administered twice a day, once a day, or once every two days, preferably twice a day.

[0079] In some embodiments, the total daily dose of the PD-L1 small molecule inhibitor is 500-2000 mg, for example, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg or 1900 mg; the frequency of administration is twice a day, once a day or once every two days, preferably twice a day (BID).

[0080] In some embodiments, the total daily dose of the PD-L1 small molecule inhibitor is 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg or 1900 mg; the administration frequency is twice a day.

[0081] In some embodiments, the PD-L1 small molecule inhibitor is administered orally according to the above-mentioned total dosage and frequency.

[0082] In some embodiments, the PD-L1 small molecule inhibitor is administered orally at a total daily dose of 1000-1900 mg twice a day.

[0083] In some embodiments, the chemotherapeutic drug molecule is administered at a dosage based on the subject's body surface area.

[0084] In some embodiments, when the chemotherapy drug molecule is capecitabine, the total daily dose range is 1000-3000 mg / m 2 , preferably 1000 mg / m 2 , 1250mg / m 2 , 1500mg / m 2 , 1750mg / m 2 , 2000mg / m 2 , 2250mg / m 2 , 2500mg / m 2 , 2750mg / m 2 or 3000 mg / m 2 , for example 2000mg / m 2 or 2500 mg / m 2 ; The frequency of administration is once a day or twice a day, preferably twice a day.

[0085] In some embodiments, when the chemotherapy drug molecule is capecitabine, capecitabine is administered orally at a total daily dose of 1000-3000 mg / m 2 , applied twice daily.

[0086] In some embodiments, when the chemotherapy drug molecule is paclitaxel, the total daily dose range is 50-200 mg / m 2 , preferably 50 mg / m 2 , 75mg / m 2 , 80mg / m 2 , 100mg / m 2 , 125mg / m 2 , 135mg / m 2 , 145mg / m 2 , 155mg / m 2 , 165mg / m 2 , 175mg / m 2 , 185mg / m 2 , 195mg / m 2 or 200 mg / m 2 , for example 80 mg / m 2 , 135mg / m 2 or 175 mg / m 2 ; The frequency of administration is once every two weeks, once every three weeks or once every four weeks; preferably once every three weeks.

[0087] In some embodiments, when the chemotherapy drug molecule is paclitaxel, paclitaxel is administered intravenously at a total daily dose of 50-200 mg / m 2 , applied once every three weeks.

[0088] In some embodiments, when the chemotherapy drug molecule is temozolomide, the total daily dose range is 100-250 mg / m 2 , preferably 100 mg / m 2 , 125mg / m 2 , 150mg / m 2 , 175mg / m 2 , 200mg / m 2 , 225mg / m 2 or 250 mg / m 2 , for example 150 mg / m 2 or 200 mg / m 2 ; The frequency of administration is once a day for 5 days, followed by a 23-day break before entering the next cycle.

[0089] In some embodiments, when the chemotherapy drug molecule is temozolomide, temozolomide is orally administered at a total daily dose of 100-250 mg / m 2 The dosage frequency is once a day for 5 days, and then the next cycle begins after 23 days of discontinuation.

[0090] In some embodiments, the PD-L1 small molecule inhibitor is administered orally twice daily at a total dose of 1000-1900 mg per day, and the chemotherapy drug molecule is administered at a dose of 1000-3000 mg / m 2 The total dose is administered orally twice daily.

[0091] In some embodiments, the PD-L1 small molecule inhibitor is administered orally twice daily at a total daily dose of 1000-1900 mg, and the chemotherapy drug molecule is administered at a daily dose of 50-200 mg / m 2 The total dose is administered once every three weeks via intravenous injection.

[0092] In some embodiments, the PD-L1 small molecule inhibitor is administered orally twice daily at a total daily dose of 1000-1900 mg, and the chemotherapy drug molecule is administered at a daily dose of 100-250 mg / m 2 The total dosage is once a day for 5 days, followed by a 23-day break before entering the next cycle.

[0093] The present invention provides a drug combination E, which includes a PD-L1 small molecule inhibitor and a COX-2 inhibitor.

[0094] In some embodiments, the pharmaceutical combination E has a synergistic effect.

[0095] In the drug combination E, the PD-L1 small molecule inhibitor is preferably a compound as shown in Formula I or a pharmaceutically acceptable salt thereof;

[0096] In the drug combination E, the COX-2 inhibitor is preferably nimesulide, meloxicam, celecoxib or rofecoxib, more preferably celecoxib.

[0097] In the drug combination E, the mass ratio of the PD-L1 small molecule inhibitor to the COX-2 inhibitor is preferably (0.1-10):1, more preferably (2-10):1, for example 6:1 or 7.5:1.

[0098] In some embodiments, the active ingredients of the pharmaceutical combination E are the PD-L1 small molecule inhibitor and the COX-2 inhibitor as described above, preferably the compound represented by Formula I and celecoxib as described above.

[0099] In the pharmaceutical combination E, the PD-L1 small molecule inhibitor is preferably administered via the gastrointestinal tract (e.g., oral, sublingual, or rectal administration), injection (e.g., subcutaneous, intradermal, intravenous, intraperitoneal, or intramuscular), respiratory tract, or topical administration (e.g., mucosa or skin), more preferably via the gastrointestinal tract, such as oral administration.

[0100] In the pharmaceutical combination E, the COX-2 inhibitor is preferably administered via the gastrointestinal tract (e.g., orally, sublingually, or rectally), injected (e.g., subcutaneously, intradermally, intravenously, intraperitoneally, or intramuscularly), respiratory tract, or topically (e.g., mucosa or skin), more preferably via the gastrointestinal tract, such as orally.

[0101] In the pharmaceutical combination E, the PD-L1 small molecule inhibitor is preferably administered orally; and the COX-2 inhibitor is preferably administered orally.

[0102] The present invention provides a pharmaceutical composition F, which includes a PD-L1 small molecule inhibitor, a COX-2 inhibitor and pharmaceutical excipients.

[0103] In some embodiments, the pharmaceutical composition F has a synergistic effect.

[0104] In the pharmaceutical composition F, the PD-L1 small molecule inhibitor and COX-2 inhibitor can be as described above.

[0105] In the pharmaceutical composition F, the content of the PD-L1 small molecule inhibitor is preferably 30-500 mg, more preferably 40-400 mg, such as 50 mg, 150 mg or 300 mg.

[0106] In the pharmaceutical composition F, the content of the COX-2 inhibitor is preferably 50-250 mg, more preferably 100-200 mg, such as 100 mg or 200 mg.

[0107] In the pharmaceutical composition F, the mass ratio of the PD-L1 small molecule inhibitor to the COX-2 inhibitor is preferably (0.1-10):1, more preferably (2-10):1, for example 6:1 or 7.5:1.

[0108] In some embodiments, the active ingredients of the pharmaceutical composition F are the PD-L1 small molecule inhibitor and the COX-2 inhibitor as described above, preferably the compound represented by Formula I and celecoxib as described above.

[0109] In some embodiments, the pharmaceutical composition F consists of the PD-L1 small molecule inhibitor described above, the COX-2 inhibitor described above, and pharmaceutical excipients.

[0110] The pharmaceutical composition F can be a separate pharmaceutical composition.

[0111] The pharmaceutical composition F can be prepared into various suitable dosage forms according to different administration methods, including gastrointestinal dosage forms (such as oral dosage forms) and parenteral dosage forms (such as injection dosage forms, respiratory tract dosage forms, mucosal dosage forms or cavity dosage forms), preferably capsules, tablets, pills, granules, powders or oral liquids.

[0112] The present invention also provides a pharmaceutical composition G, comprising:

[0113] A first pharmaceutical composition G-1, which includes a PD-L1 small molecule inhibitor and a pharmaceutical excipient; and,

[0114] The second pharmaceutical composition G-2 includes a COX-2 inhibitor and pharmaceutically acceptable excipients.

[0115] In some embodiments, the pharmaceutical composition G has a synergistic effect.

[0116] In the pharmaceutical composition G, the PD-L1 small molecule inhibitor and COX-2 inhibitor can be as described above.

[0117] In some embodiments, the pharmaceutical composition G consists of a first pharmaceutical composition G-1 and a second pharmaceutical composition G-2; the first pharmaceutical composition G-1 consists of the PD-L1 small molecule inhibitor as described above and a pharmaceutical excipient, preferably consists of the compound shown in Formula I as described above and a pharmaceutical excipient; the second pharmaceutical composition G-2 consists of the COX-2 inhibitor as described above and a pharmaceutical excipient, preferably consists of celecoxib and a pharmaceutical excipient.

[0118] The first pharmaceutical composition G-1 is a separate pharmaceutical composition; the second pharmaceutical composition G-2 is a separate pharmaceutical composition.

[0119] In the pharmaceutical composition G, the content of the PD-L1 small molecule inhibitor is preferably 30-500 mg, more preferably 40-400 mg, for example 50 mg, 150 mg or 300 mg.

[0120] In the pharmaceutical composition G, the content of the COX-2 inhibitor is preferably 50-250 mg, more preferably 100-200 mg, such as 100 mg or 200 mg.

[0121] In the pharmaceutical composition G, the mass ratio of the PD-L1 small molecule inhibitor to the COX-2 inhibitor is preferably (0.1-10):1, more preferably (2-10):1, for example 6:1 or 7.5:1.

[0122] In the pharmaceutical composition G, the first pharmaceutical composition G-1 is preferably presented in the form of an oral dosage form.

[0123] In the pharmaceutical composition G, the second pharmaceutical composition G-2 is preferably presented in the form of an oral dosage form.

[0124] In the pharmaceutical composition G, preferably, the first pharmaceutical composition G-1 is presented in the form of an oral dosage form; and the second pharmaceutical composition G-2 is presented in the form of an oral dosage form.

[0125] The present invention provides a combination medicine kit H, which comprises:

[0126] A first container comprising the first pharmaceutical composition G-1 as described above; and

[0127] A second container comprises the second pharmaceutical composition G-2 as described above.

[0128] The present invention also provides the use of the above-mentioned pharmaceutical combination E, pharmaceutical composition F or pharmaceutical composition G in the preparation of drugs for treating tumors.

[0129] The present invention provides an application of the PD-L1 small molecule inhibitor in combination with the COX-2 inhibitor in the preparation of a drug for treating tumors.

[0130] The present invention provides a use of the PD-L1 small molecule inhibitor in the preparation of a drug for treating tumors, wherein the PD-L1 small molecule inhibitor is used in combination with the COX-2 inhibitor.

[0131] The present invention provides a use of the COX-2 inhibitor in the preparation of a drug for treating tumors, wherein the COX-2 inhibitor is used in combination with the PD-L1 small molecule inhibitor.

[0132] The present invention provides a method for treating tumors, comprising administering a therapeutically effective amount of the above-described pharmaceutical composition E, pharmaceutical composition F, or pharmaceutical composition G to a subject (eg, a human) in need thereof.

[0133] In the above-mentioned pharmaceutical combination E, pharmaceutical composition F, pharmaceutical composition G, their uses and their methods of treatment:

[0134] In some embodiments, the tumor is one or more of gastric cancer, nasopharyngeal cancer, lung cancer, colorectal cancer, breast cancer, colon cancer, bladder cancer, cervical cancer, endometrial cancer, pancreatic cancer, prostate cancer, hepatocellular carcinoma, melanoma, head and neck cancer, esophageal cancer, ovarian cancer, bone cancer, central nervous system tumor, adrenal adenoma, renal cell carcinoma and neuroblastoma, preferably breast cancer, gastric cancer or nasopharyngeal cancer.

[0135] In some embodiments, the tumor is one or more of gastric cancer, nasopharyngeal cancer, lung cancer, colorectal cancer, breast cancer, colon cancer, bladder cancer, cervical cancer, endometrial cancer, pancreatic cancer, prostate cancer, hepatocellular carcinoma, melanoma, head and neck cancer, esophageal cancer, ovarian cancer, bone cancer, central nervous system tumor, adrenal adenoma, renal cell carcinoma, neuroblastoma and glioma, preferably glioma.

[0136] In some embodiments, the PD-L1 small molecule inhibitor and the COX-2 inhibitor can be administered simultaneously or separately.

[0137] The “simultaneous administration” means that the PD-L1 small molecule inhibitor and the COX-2 inhibitor are contained in separate pharmaceutical compositions and administered simultaneously; alternatively, “a separate pharmaceutical composition of the PD-L1 small molecule inhibitor” and “a separate pharmaceutical composition of the COX-2 inhibitor” are administered simultaneously.

[0138] The term "separate administration" means that the "single pharmaceutical composition of the PD-L1 small molecule inhibitor" and the "single pharmaceutical composition of the COX-2 inhibitor" are administered separately at different times, for example, one of the "single pharmaceutical composition of the PD-L1 small molecule inhibitor" and the "single pharmaceutical composition of the COX-2 inhibitor" is administered first, and the other is administered subsequently. The separate administration may be close in time or remote in time.

[0139] Whether administered simultaneously or separately, the administration regimens (including administration route, administration dosage, administration interval, etc.) of the "single pharmaceutical composition of the PD-L1 small molecule inhibitor" and the "single pharmaceutical composition of the COX-2 inhibitor" may be the same or different, and may be adjusted as needed by those skilled in the art to provide the optimal therapeutic effect.

[0140] In some embodiments, the PD-L1 small molecule inhibitor can be administered via the gastrointestinal tract (e.g., oral, sublingual, or rectal administration), injection (e.g., subcutaneous, intradermal, intravenous, intraperitoneal, or intramuscular), respiratory tract, or topical administration (e.g., mucosa or skin), preferably via the gastrointestinal tract, such as oral administration.

[0141] In some embodiments, the COX-2 inhibitor can be administered gastrointestinal tract (e.g., orally, sublingually, or rectally), injected (e.g., subcutaneously, intradermally, intravenously, intraperitoneally, or intramuscularly), respiratory tract, or topically (e.g., mucosa or skin), preferably gastrointestinal tract, such as orally.

[0142] In some embodiments, the PD-L1 small molecule inhibitor is administered orally; and, the COX-2 inhibitor is administered orally.

[0143] In some embodiments, the total daily dosage of the PD-L1 small molecule inhibitor can range from 30-2400 mg; more preferably 500-2000 mg; for example, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg or 1900 mg.

[0144] In some embodiments, the PD-L1 small molecule inhibitor is administered twice a day, once a day, or once every two days, preferably twice a day.

[0145] In some embodiments, the total daily dose of the PD-L1 small molecule inhibitor is 500-2000 mg, for example, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg or 1900 mg; the frequency of administration is twice a day, once a day or once every two days, preferably twice a day (BID).

[0146] In some embodiments, the total daily dose of the PD-L1 small molecule inhibitor is 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg or 1900 mg, and the administration frequency is twice a day.

[0147] In some embodiments, the PD-L1 small molecule inhibitor is administered orally according to the above-mentioned total dosage and frequency.

[0148] In some embodiments, the PD-L1 small molecule inhibitor is administered orally at a total daily dose of 1000-1900 mg twice a day.

[0149] In some embodiments, the total daily dose of the COX-2 inhibitor is in the range of 50-250 mg, preferably 100-200 mg, such as 100 mg or 200 mg.

[0150] In some embodiments, the COX-2 inhibitor is administered once daily or twice daily.

[0151] In some embodiments, the total daily dose of the COX-2 inhibitor is 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, or 200 mg, and the administration frequency is once a day or twice a day.

[0152] In some embodiments, the COX-2 inhibitor is administered orally at the total dosage and frequency described above.

[0153] In some embodiments, the PD-L1 small molecule inhibitor is orally administered twice daily at a total daily dose of 1000-1900 mg, and the COX-2 inhibitor is orally administered once daily or twice daily at a total daily dose of 100-200 mg.

[0154] The term "pharmaceutically acceptable salt" refers to salts prepared from compounds of the present invention with relatively nontoxic, pharmaceutically acceptable acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent.

[0155] The term "pharmaceutical excipients" refers to excipients and additives used in the production of pharmaceuticals and in the preparation of prescriptions. They are all substances, other than the active ingredient, contained in a pharmaceutical preparation. For a complete list, see Part IV of the Pharmacopoeia of the People's Republic of China (2015 edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition).

[0156] The term "treat" refers to any of the following: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that leads to a disease; or (3) slowing the progression of one or more biological manifestations of a disease.

[0157] The term "therapeutically effective amount" refers to the amount of a compound administered to a subject that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the compound, the type of disease, the severity of the disease, the age of the subject, etc., but can be adjusted by those skilled in the art as appropriate.

[0158] The term "subject" refers to any animal that has been or is about to be treated, preferably a mammal, most preferably a human. Mammals include but are not limited to cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0159] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0160] The reagents and raw materials used in the present invention are commercially available.

[0161] The positive progress of the present invention is that in the treatment of tumor diseases, the combination of PD-L1 small molecule inhibitors and different small molecule drugs (such as COX-2 inhibitors, chemotherapy drug molecules, etc.) has a synergistic effect, showing better anti-tumor activity or longer survival than using small molecule drugs alone. BRIEF DESCRIPTION OF THE DRAWINGS

[0162] FIG1 is a graph showing the growth curves of tumor volumes in each group of mice in Example 1.

[0163] FIG2 is a curve diagram of the tumor inhibition rate of each group of mice in Example 1.

[0164] FIG3 is a graph showing changes in body weight of mice in each group in Example 1.

[0165] FIG4 is a curve diagram of the relative change rate of body weight of mice in each group in Example 1.

[0166] FIG5 is a graph showing the growth curves of tumor volumes in each group of mice in Example 2.

[0167] FIG6 is a curve diagram of the tumor inhibition rate of each group of mice in Example 2.

[0168] FIG7 is a graph showing changes in body weight of mice in each group in Example 2.

[0169] FIG8 is a curve diagram of the relative change rate of body weight of mice in each group in Example 2.

[0170] FIG9 is a survival curve diagram of each group of mice in Example 3.

[0171] FIG10 is a graph showing changes in body weight of mice in each group in Example 3.

[0172] FIG11 is a curve diagram of the relative change rate of body weight of mice in each group in Example 3.

[0173] FIG12 is a graph showing changes in body weight of mice in each group in Example 4.

[0174] FIG13 is a curve diagram of the relative change rate of body weight of mice in each group in Example 4.

[0175] FIG14 is a graph showing the fluorescence signal intensity of each group of mice in Example 4.

[0176] FIG15 is a curve diagram of the tumor inhibition rate of each group of mice in Example 4.

[0177] FIG16 is a survival curve diagram of each group of mice in Example 4. DETAILED DESCRIPTION

[0178] po: “orally” or “by mouth”; ip: intraperitoneally; iv: intravenously; BID: twice daily; QD: once daily; Q2D: every other day; BIW: twice a week; QW: once a week.

[0179] Example 1 Pharmacodynamic Study of Test Drugs on Mouse Breast Cancer 4T1 hPD-L1 Model

[0180] 1. Experimental Materials

[0181] Experimental animals: 100 female BALB / c mice, 6-8 weeks old, weighing 18-21 g, were purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd. (SCXK (Shanghai) 2020-0009; certificate number: 20220009001922).

[0182] Drug: Compound of formula I Production unit: Kanglong Chemical (Tianjin) Pharmaceutical Preparation Technology Co., Ltd., batch number: TJ-MAX-10181-A-2; Capecitabine, production unit: Shanghai Yuanye Biotechnology Co., Ltd., batch number: J10J12L137020.

[0183] 2. Experimental steps and methods

[0184] 2.1 Cell culture

[0185] Murine 4T1 hPD-L1 cells adhered to the culture medium in vitro using RPMI-1640 medium supplemented with 10% heat-inactivated fetal bovine serum and 4 μg / mL Blasticidin (Biyuntian / ST018-1mL) at 37°C and 5% CO2. Cells were passaged 2-3 times weekly. When cells reached the exponential growth phase, they were harvested, counted, and inoculated subcutaneously on the right dorsal flank of BALB / c mice.

[0186] 2.2 Tumor cell inoculation and group administration

[0187] 100 μL 1×10 6 BALB / c mice were inoculated subcutaneously with a 4T1 hPD-L1 cell suspension on the right dorsal flank. Six days after inoculation, appropriate animals were selected based on tumor volume and body weight and divided into four groups of 10 mice using a stratified randomization method. Dosing began on the same day of grouping.

[0188] Table 1 Animal experimental groups and dosing regimens

[0189] 2.3 Preparation of test drugs

[0190] Table 2 Preparation method of the test drugs

[0191] 2.4 Experimental indicators

[0192] The experimental indicators examine whether tumor growth can be inhibited, delayed or cured. Tumors are measured three times a week with a digital vernier caliper. The tumor volume is calculated as: V = 0.5a × b 2 , a and b represent the long diameter and short diameter of the tumor, respectively. The anti-tumor efficacy of the compound is expressed as TGI, TGI (%) = [1-(TV i -TV0) / (TV Vi -TV V0 )]×100% (TV0 is the average volume of the treatment group on day 0, TV V0 is the average volume of the control group on day 0; TV i is the mean volume of the treatment group on day i, TV Vi is the average volume of the control group on day i).

[0193] 2.5 End of the experiment

[0194] If the animal's health condition continues to deteriorate, or the tumor volume exceeds 2,000 mm 3 If the animal is seriously ill or in pain, it must be euthanized. If the animal has any of the following conditions, notify the veterinarian and euthanize it:

[0195] (1) Obvious emaciation, weight loss greater than 20%;

[0196] (2) Unable to freely access food and water;

[0197] (3) The average tumor volume of the control group reached 2000 mm 3 , the experiment terminated.

[0198] 2.6 Data Analysis

[0199] GraphPad Prism 8.0 software was used for graphing. Two-way ANOVA was used to analyze the changes in mouse tumor volume. The tumor volume of the mice was compared with that of the vehicle control group according to the Dunnett method. P < 0.05 was considered to be a significant difference.

[0200] 3. Experimental results

[0201] 3.1 Tumor volume

[0202] The tumor volumes, tumor inhibition effects, and statistical analysis results of each treatment group in the pharmacodynamic experiment of the test drugs in the mouse breast cancer 4T1 hPD-L1 model are shown in Table 3, Figures 1, and 2.

[0203] Table 3 Tumor volume (mm 3 )(Mean)

[0204] The average tumor volume of the compound of formula I (Group 2) on day 21 after po administration was 1103.30 mm 3 , compared with the control group (Group 1, tumor volume on day 21 was 1807.62 mm 3 ) showed significant difference (TGI% = 41.88%).

[0205] The mean tumor volume of Capecitabine (Group 3) was 862.73 mm on day 21 after po administration. 3 , compared with the control group (Group 1, tumor volume on day 21 was 1807.62 mm 3 ) showed significant difference (TGI%=56.16%).

[0206] The average tumor volume of the group treated with the compound of formula I and Capecitabine (Group 4) was 484.07 mm on day 21 after administration. 3 , compared with the control group (Group 1, tumor volume on day 21 was 1807.62 mm 3 Compared with the group treated with compound I alone (Group 2) and the group treated with Capecitabine alone (Group 3), the combination group showed a significantly improved tumor inhibition effect, showing a synergistic effect.

[0207] 3.2 Mouse weight

[0208] Table 4 Body weight changes of treated mice (Mean)

[0209] The results of the body weight and relative body weight changes of mice in each treatment group are shown in Table 4, Figures 3, and 4. During the experiment, no mice in any treatment group showed significant weight loss or other abnormal symptoms, indicating that the mice tolerated all treatments well.

[0210] Example 2 Pharmacodynamic Study of Test Drugs in Mouse Breast Cancer 4T1 hPD-L1 Model

[0211] 1. Experimental Materials

[0212] Experimental animals: 100 BALB / c female mice, 6-8 weeks old, weighing 18-21 g, purchased from

[0213] Shanghai Jihui Experimental Animal Breeding Co., Ltd. (SCXK(Shanghai)2020-0009; Certificate No.: 20220009001922).

[0214] Drug: Compound of formula I, produced by Kanglong Chemical (Tianjin) Pharmaceutical Preparation Technology Co., Ltd., batch number: TJ-MAX-10181-A-2; Celecoxib, produced by Shanghai Yuanye Biotechnology Co., Ltd., batch number: D11A6S2152.

[0215] 2. Experimental steps and methods

[0216] 2.1 Cell culture

[0217] Murine 4T1 hPD-L1 cells adhered to the culture medium in vitro using RPMI-1640 medium supplemented with 10% heat-inactivated fetal bovine serum and 4 μg / mL Blasticidin (Biyuntian / ST018-1mL) at 37°C and 5% CO2. Cells were passaged 2-3 times weekly. When cells reached the exponential growth phase, they were harvested, counted, and inoculated subcutaneously on the right dorsal flank of BALB / c mice.

[0218] 2.2 Tumor cell inoculation and group administration

[0219] 100 μL 1×10 6 BALB / c mice were subcutaneously inoculated with a 4T1 hPD-L1 cell suspension on the right dorsal flank. Seven days after inoculation, mice were randomly divided into four groups of 10 based on tumor volume and body weight. Dosing began on the same day.

[0220] Table 5 Animal experimental groups and dosing regimens

[0221] 2.3 Preparation of test drugs

[0222] Table 6 Preparation method of test drugs

[0223] 2.4 Experimental indicators

[0224] The experimental indicators examine whether tumor growth can be inhibited, delayed or cured. Tumors are measured three times a week with a digital vernier caliper. The tumor volume is calculated as: V = 0.5a × b 2 , a and b represent the long diameter and short diameter of the tumor, respectively. The anti-tumor efficacy of the compound is expressed as TGI, TGI (%) = [1-(TV i -TV0) / (TV Vi -TV V0 )]×100% (TV0 is the average volume of the treatment group on day 0, TV V0 is the average volume of the control group on day 0; TV i is the mean volume of the treatment group on day i, TV Viis the average volume of the control group on day i).

[0225] 2.5 End of the experiment

[0226] If the animal's health condition continues to deteriorate, or the tumor volume exceeds 2,000 mm 3 If the animal is seriously ill or in pain, it must be euthanized. If the animal has any of the following conditions, notify the veterinarian and euthanize it:

[0227] (1) Obvious emaciation, weight loss greater than 20%;

[0228] (2) Unable to freely access food and water;

[0229] (3) The average tumor volume of the control group reached 2000 mm 3 , the experiment terminated.

[0230] 2.6 Data Analysis

[0231] GraphPad Prism 8.0 software was used for graphing. Two-way ANOVA was used to analyze the changes in mouse tumor volume. The tumor volume of the mice was compared with that of the vehicle control group according to the Dunnett method. P < 0.05 was considered to be a significant difference.

[0232] 3. Experimental results

[0233] 3.1 Tumor volume

[0234] The tumor volume, tumor inhibition effect and statistical analysis results of each treatment group in the pharmacodynamic experiment of the test drugs in the mouse breast cancer 4T1 hPD-L1 model are shown in Table 7, Figures 5 and 6.

[0235] Table 7 Tumor volume (mm 3 )(Mean)

[0236] The average tumor volume of the compound of formula I (Group 2) on day 21 after po administration was 921.91 mm 3 , compared with the control group (Group 1, tumor volume on day 21 was 1290.12 mm 3 ) showed significant difference (TGI%=32.78%).

[0237] The mean tumor volume of Celecoxib (Group 3) was 341.70 mm on day 21 after po administration. 3 , compared with the control group (Group 1, tumor volume on day 21 was 1290.12 mm 3 ) showed significant difference (TGI%=83.90%).

[0238] The average tumor volume of the group treated with the compound of formula I and Celecoxib (Group 4) was 140.02 mm on day 21 after administration. 3 , compared with the control group (Group 1, tumor volume on day 21 was 1290.12 mm 3 Compared with the group treated with compound of formula I alone (Group 2) and the group treated with Celecoxib alone, the tumor inhibition effect of the combined drug group was significantly improved.

[0239] 3.2 Mouse weight

[0240] Table 8 Body weight changes of treated mice (Mean)

[0241] The results of the body weight and relative body weight changes of mice in each treatment group are shown in Table 8, Figures 7 and 8. During the experiment, no mice in any treatment group showed significant weight loss or other abnormal symptoms, indicating that the mice tolerated all treatments well.

[0242] Example 3 Study on the Growth and Metastasis of Orthotopic Transplanted Tumors and Prolonged Survival of Mice by Test Drugs in the BALB / c Mouse Breast Cancer Cell 4T1 Model

[0243] 1. Experimental Materials

[0244] Experimental animals: 50 female BALB / c mice, 6–8 weeks old, weighing 18–20 g. Zhejiang Weitonglihua Laboratory Animal Technology Co., Ltd., Tongxiang Branch (SCKX(Zhe)2021-0006); Certificate Number: 20220728Abzz0600000694.

[0245] Drug: Compound of Formula I, manufactured by Kanglong Chemical (Tianjin) Pharmaceutical Preparation Technology Co., Ltd., batch number: TJ-MAX-10181-A-2; Paclitaxel (paclitaxel) (6 mg / mL), manufactured by Corden Pharma Latina SPA, batch number: 2D07013.

[0246] 2. Experimental steps and methods

[0247] 2.1 Cell culture

[0248] Murine 4T1 cells were grown adherently in vitro in RPMI-1640 medium supplemented with 10% heat-inactivated fetal bovine serum at 37°C and 5% CO2. Cells were passaged 2-3 times weekly. When cells reached the exponential growth phase, they were harvested, counted, and inoculated into the fourth fat pad on the left side of the abdomen of BALB / c mice.

[0249] 2.2 Tumor cell inoculation and group administration

[0250] 50 μL 1×10 5 BALB / c mice were inoculated with a 4T1 cell suspension into the fourth fat pad on the left side of the abdomen. The day after inoculation, mice were randomly assigned to groups based on the order of tumor inoculation and body weight. Dosing began on the same day. Orthotopic tumors were surgically resected 13 days after inoculation (dosing was suspended on the day of surgery).

[0251] Table 9 Animal experimental groups and dosing regimens

[0252] 2.3 Preparation of test drugs

[0253] Table 10 Preparation method of test drugs

[0254] 2.4 Experimental indicators

[0255] The experimental indicators examine whether tumor growth can be inhibited, delayed or cured. Tumors are measured three times a week with a digital vernier caliper. The tumor volume is calculated as: V = 0.5a × b 2 , a and b represent the long diameter and short diameter of the tumor, respectively. The anti-tumor efficacy of the compound is expressed as TGI, TGI (%) = [1-(TV i -TV0) / (TV Vi -TV V0 )]×100% (TV0 is the average volume of the treatment group on day 0, TV V0 is the average volume of the control group on day 0; TV i is the mean volume of the treatment group on day i, TV Vi is the average volume of the control group on day i);

[0256] 2.5 End of the experiment

[0257] If the animal's health condition continues to deteriorate, or the tumor volume exceeds 2,000 mm 3 If the animal is seriously ill or in pain, it must be euthanized. If the animal has any of the following conditions, notify the veterinarian and euthanize it:

[0258] (1) Obvious emaciation, weight loss greater than 20%;

[0259] (2) Unable to freely access food and water;

[0260] (3) The average tumor volume of the control group reached 2000 mm 3 , the experiment terminated.

[0261] 2.6 Data Analysis

[0262] GraphPad Prism 8.0 software was used for graphing. Two-way ANOVA was used to analyze the changes in mouse tumor volume. The tumor volume of the mice was compared with that of the vehicle control group according to the Dunnett method. P < 0.05 was considered to be a significant difference.

[0263] 3. Experimental results

[0264] 3.1 Survival Curve

[0265] After each group of mice was inoculated with 4T1 cells and treated accordingly, the survival rate of mice in the combination treatment group (Group 4) was 50% on day 38 compared to the vehicle control group (Group 1), the group treated with the compound of Formula I alone (Group 3), and the group treated with paclitaxel alone (Group 2). The survival rate of mice in the combination treatment group was 0% on day 38, while the survival rate of mice in the group treated with the compound of Formula I alone (Group 3) was 0% on day 38. The survival rate of mice in the group treated with paclitaxel alone (Group 2) was 10% on day 38. The combination treatment group significantly improved the survival rate of mice. See Figure 9.

[0266] 3.2 Mouse weight

[0267] Twelve days after dosing, the weight of mice in each treatment group remained stable, with no significant adverse reactions. Following tumor resection, the weight of mice returned to normal within a short period of time. The weight changes and relative weight changes of tumor-bearing mice in each treatment group are shown in Figures 10 and 11.

[0268] Example 4 Pharmacodynamics and survival study of the test drug in the mouse glioma cell GL-261-luc orthotopic brain transplant tumor model

[0269] 1. Experimental Materials

[0270] Experimental animals: 57 C57 BL / 6 female mice, 6-8 weeks old, weighing 16-20 g, were purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd.

[0271] Drug: Compound of formula I Production unit: Kanglong Chemical (Tianjin) Pharmaceutical Preparation Technology Co., Ltd., batch number: TJ-MAX-10181-A-2; TMZ (temozolomide), production unit: Shanghai Aladdin Biochemical Technology Co., Ltd., batch number: J2227749.

[0272] 2. Experimental steps and methods

[0273] 2.1 Cell culture

[0274] Murine GL-261-luc cells were grown adherently in vitro in DMEM supplemented with 10% heat-inactivated fetal bovine serum and 0.6 mg / mL G418 (stock concentration: 100 mg / mL) at 37°C in 5% CO2. Cells were passaged 2-3 times weekly. When cells reached the exponential growth phase, they were harvested, counted, and inoculated into the right caudate nucleus of C57 BL / 6 mice.

[0275] 2.2 Tumor cell inoculation and group administration

[0276] GL-261-luc was collected when it was fully grown in the logarithmic growth phase, and the activity was guaranteed to be above 90%. Mice were anesthetized by intraperitoneal injection of 41.6 mg / kg of Zotalitol according to their body weight, and 1×10 5 The cells were inoculated in situ into the right caudate nucleus of each mouse at a concentration of 2 μL / mouse. The skin was sutured with 4 / 0 sutures, and the mice were returned to their cages after awakening. Four days after cell inoculation, the mice were imaged and grouped using an IVIS Lumina XR mouse animal imager. The fluorescence signal intensity was randomly divided into four groups of nine mice each using a stratified randomization method. Drug administration began on the day of grouping. The mice were weighed and their growth was observed daily, and the mice were imaged twice a week.

[0277] Table 11 Animal experimental groups and dosing regimens

[0278] 2.3 Preparation of test drugs

[0279] Table 12 Preparation method of test drugs

[0280] 2.4 Experimental indicators

[0281] The experimental indicators investigated whether tumor growth could be inhibited, delayed, or cured. According to the experimental design, mice were imaged using the small animal imaging instrument IVIS Lumina XR to monitor tumor growth. The anti-tumor efficacy of the compound was calculated using TGI, TGI (%) = [1-(TFtreatment-Dn-TFtreatment-D0) / (TFcontrol-Dn-TFcontrol-D0)] × 100% (TFtreatment-D0 is the fluorescence signal intensity of the treatment group on day 0, TFcontrol-D0 is the fluorescence signal intensity of the control group on day 0; TFtreatment-Dn is the fluorescence signal intensity of the treatment group on day n, TFcontrol-Dn is the fluorescence signal intensity of the control group on day n). The formula for calculating the extended lifespan (ILS) is: ILS = (MSTTreatment-MSTControl) / MSTControl x 100% (MSTTreatment is the median survival time in days of the treatment group, MSTControl is the median survival time in days of the control group).

[0282] 2.5 Data Analysis

[0283] Tumor size was analyzed based on fluorescence signal intensity using GraphPad Prism. Two-way ANOVA was used to compare the fluorescence signal intensity between the control group and each treatment group. A p value < 0.05 was considered a significant difference, and a p value < 0.01 was considered a highly significant difference.

[0284] 3. Experimental results

[0285] 3.1 Mouse weight

[0286] In the pharmacodynamics experiment of the test drug on the mouse glioma GL-261-luc orthotopic brain transplant tumor model, the results of the weight change and relative weight change of tumor-bearing mice in each group are shown in Table 13, Figure 12 and Figure 13.

[0287] Table 13 Body weight changes of treated mice (Mean)

[0288] The experimental results showed that by the 14th day of administration, in the vehicle control group (Group 1), two mice had a weight loss of more than 10%, of which one mouse had a weight loss of more than 15%; in the TMZ group (Temozolomide) (Group 2), two mice had a weight loss of more than 10%; in the Formula I compound group (Group 3), two mice had a weight loss of more than 10%; and in the Formula I compound and TMZ (Temozolomide) combination group (Group 4), there was no significant weight loss in the mice.

[0289] 3.2 Fluorescence signal intensity and tumor inhibition rate

[0290] In the pharmacodynamics experiment of the test drug on the mouse glioma GL-261-luc model, the changes in the fluorescence signal intensity of each group of tumor-bearing mice and the tumor inhibition rate of each group of tumor-bearing mice based on the fluorescence signal intensity are shown in Table 14, Figure 14 and Figure 15.

[0291] Table 14 Fluorescence signal intensity and tumor inhibition rate of mice in each group

[0292] The experimental results showed that by day 14 of administration, compared with the vehicle control group (Group 1), the tumor inhibition rate in the TMZ (temozolomide) group (Group 2) was 35.51%; the tumor inhibition rate in the Formula I compound group (Group 3) was 40.52%; and the tumor inhibition rate in the Formula I compound and TMZ (temozolomide) combination group (Group 4) was 63.61%. Compared with the TMZ (temozolomide) alone group (Group 2) and the Formula I compound alone group (Group 3), the combination group showed significantly improved tumor inhibition.

[0293] 3.3 Survival curve

[0294] After each group of mice was inoculated with GL-261-luc cells and received corresponding treatment, the experiment was terminated until all mice in each group died. The survival curves of each group of mice are shown in FIG16 .

[0295] The experimental results showed that by the end of the experiment, compared with the vehicle control group (Group 1), the TMZ group (temozolomide) (Group 2), the compound of Formula I group (Group 3), and the combination of the compound of Formula I and TMZ (temozolomide) group (Group 4) had an extended lifespan rate (ILS) of 25%, 20%, and 40%, respectively. The combination group significantly improved the median survival time and lifespan extension rate of mice.

Claims

1. A drug combination A, characterized in that: The drug combination A includes a PD-L1 small molecule inhibitor and a chemotherapy drug molecule.

2. The pharmaceutical combination A according to claim 1, characterized in that: The drug combination A satisfies one or more of the following conditions: (1) The drug combination A has a synergistic effect; (2) The PD-L1 small molecule inhibitor is a compound as shown in Formula I or a pharmaceutically acceptable salt thereof; (3) The chemotherapy drug molecule is one or more of capecitabine, paclitaxel, oxaliplatin and temozolomide, preferably capecitabine, paclitaxel or temozolomide; (4) The mass ratio of the PD-L1 small molecule inhibitor to the chemotherapeutic drug molecule is (0.04-50):1, preferably (0.2-16):1, more preferably (0.2-2):1 or (6-16):1, for example 0.45:1, 0.58:1, 1.2:1, 10:1 or 11:1; (5) The active ingredients of the drug combination A are the PD-L1 small molecule inhibitor and the chemotherapy drug molecule; (6) The PD-L1 small molecule inhibitor is administered via the gastrointestinal tract, injection, respiratory tract or local administration, such as oral administration; (7) The chemotherapeutic drug molecules are administered via the gastrointestinal tract, injection, respiratory tract or local administration, such as oral administration or intravenous injection.

3. The pharmaceutical combination A according to claim 2, characterized in that: The drug combination A comprises the compound as shown in formula I and capecitabine, and the mass ratio of the compound as shown in formula I to the capecitabine is preferably (0.2-2):1, such as 0.45:1, 0.58:1 or 1.2:1; Or, the drug combination A comprises the compound as shown in formula I and paclitaxel, and the mass ratio of the compound as shown in formula I to the paclitaxel is preferably (6-16):1, such as 10:1 or 11:1; Alternatively, the drug combination A comprises the compound as shown in formula I and temozolomide, and the mass ratio of the compound as shown in formula I to the temozolomide is preferably (6-16):1, for example 6:1, 9.5:1 or 16:

1.

4. A pharmaceutical composition B, characterized in that: The pharmaceutical composition B includes a PD-L1 small molecule inhibitor, a chemotherapy drug molecule and pharmaceutical excipients.

5. The pharmaceutical composition B according to claim 4, characterized in that The pharmaceutical composition B satisfies one or more of the following conditions: (1) The pharmaceutical composition B has a synergistic effect; (2) The PD-L1 small molecule inhibitor and the chemotherapy drug molecule are as described in claim 2; (3) The content of the PD-L1 small molecule inhibitor is 30-500 mg, preferably 40-400 mg, such as 50 mg, 150 mg or 300 mg; (4) The content of the chemotherapy drug molecule is 10-650 mg, preferably 30-550 mg, such as 20 mg, 30 mg, 60 mg, 100 mg, 150 mg or 500 mg; (5) The mass ratio of the PD-L1 small molecule inhibitor to the chemotherapeutic drug molecule is (0.04-50):1, preferably (0.2-16):1, more preferably (0.2-2):1 or (6-16):1, for example 0.45:1, 0.58:1, 1.2:1, 10:1 or 11:1; Preferably, when the pharmaceutical composition B comprises the compound of formula I as claimed in claim 2, capecitabine and pharmaceutical excipients, the mass ratio of the compound of formula I to the capecitabine is preferably (0.2-2):1, such as 0.45:1, 0.58:1 or 1.2:1; when the pharmaceutical composition B comprises the compound of formula I as claimed in claim 2, paclitaxel and pharmaceutical excipients, the mass ratio of the compound of formula I to the paclitaxel is preferably (6-16):1, such as 10:1 or 11:1; when the pharmaceutical composition B comprises the compound of formula I as claimed in claim 2, temozolomide and pharmaceutical excipients, the mass ratio of the compound of formula I to the temozolomide is preferably (6-16):1, such as 6:1, 9.5:1 or 16:1; (6) The active ingredients of the pharmaceutical composition B are the PD-L1 small molecule inhibitor and the chemotherapy drug molecule; (7) The dosage forms of the pharmaceutical composition B include gastrointestinal dosage forms and parenteral dosage forms, preferably capsules, tablets, pills, granules, powders or oral liquids.

6. A pharmaceutical composition C, characterized in that: The pharmaceutical composition C comprises: A first pharmaceutical composition C-1, which includes a PD-L1 small molecule inhibitor and a pharmaceutical excipient; and, The second pharmaceutical composition C-2 comprises a chemotherapeutic drug molecule and a pharmaceutical excipient.

7. The pharmaceutical composition C according to claim 6, characterized in that The pharmaceutical composition C satisfies one or more of the following conditions: (1) The pharmaceutical composition C has a synergistic effect; (2) The PD-L1 small molecule inhibitor and the chemotherapy drug molecule are as described in claim 2; (3) The content of the PD-L1 small molecule inhibitor is 30-500 mg, preferably 40-400 mg, such as 50 mg, 150 mg or 300 mg; (4) The content of the chemotherapy drug molecule is 10-650 mg, preferably 30-550 mg, such as 20 mg, 30 mg, 60 mg, 100 mg, 150 mg or 500 mg; (5) The mass ratio of the PD-L1 small molecule inhibitor to the chemotherapeutic drug molecule is (0.04-50):1, preferably (0.2-16):1, more preferably (0.2-2):1 or (6-16):1, for example 0.45:1, 0.58:1, 1.2:1, 10:1 or 11:1; Preferably, when the first pharmaceutical composition C-1 comprises the compound of formula I as claimed in claim 2 and a pharmaceutical excipient, and the second pharmaceutical composition C-2 comprises capecitabine and a pharmaceutical excipient, the mass ratio of the compound of formula I to the capecitabine is preferably (0.2-2):1, for example, 0.45:1, 0.58:1 or 1.2:1; when the first pharmaceutical composition C-1 comprises the compound of formula I as claimed in claim 2 and a pharmaceutical excipient, and the second pharmaceutical composition C-2 comprises paclitaxel and a pharmaceutical excipient, the mass ratio of the compound of formula I to the paclitaxel is preferably (6-16):1, for example, 10:1 or 11:1; when the first pharmaceutical composition C-1 comprises the compound of formula I as described above and a pharmaceutical excipient, and the second pharmaceutical composition C-2 comprises temozolomide and a pharmaceutical excipient, the mass ratio of the compound of formula I to the temozolomide is preferably (6-16):1, for example, 6:1, 9.5:1 or 16:1; (6) The pharmaceutical composition C consists of a first pharmaceutical composition C-1 and a second pharmaceutical composition C-2; the first pharmaceutical composition C-1 consists of the PD-L1 small molecule inhibitor and pharmaceutical excipients; the second pharmaceutical composition C-2 consists of the chemotherapeutic drug molecule and pharmaceutical excipients; (7) The first pharmaceutical composition C-1 is presented in an oral dosage form; (8) The second pharmaceutical composition C-2 is presented in the form of an oral dosage form or an injection dosage form.

8. A combination medicine box D, characterized in that: The combination kit D comprises: A first container comprising the first pharmaceutical composition C-1 according to claim 6 or 7; and, A second container comprising the second pharmaceutical composition C-2 according to claim 6 or 7.

9. A pharmaceutical combination E, characterized in that: The drug combination E includes a PD-L1 small molecule inhibitor and a COX-2 inhibitor.

10. The pharmaceutical combination E according to claim 9, characterized in that: The drug combination E satisfies one or more of the following conditions: (1) The drug combination E has a synergistic effect; (2) The PD-L1 small molecule inhibitor is a compound as shown in Formula I or a pharmaceutically acceptable salt thereof; (3) The COX-2 inhibitor is nimesulide, meloxicam, celecoxib or rofecoxib, preferably celecoxib; (4) The mass ratio of the PD-L1 small molecule inhibitor to the COX-2 inhibitor is (0.1-10):1, more preferably (2-10):1, for example 6:1 or 7.5:1; (5) The active ingredients of the drug combination E are the PD-L1 small molecule inhibitor and the COX-2 inhibitor; (6) The PD-L1 small molecule inhibitor is administered via the gastrointestinal tract, injection, respiratory tract or local administration, such as oral administration; (7) The COX-2 inhibitor is administered via the gastrointestinal tract, injection, respiratory tract or topical administration, for example, orally.

11. A pharmaceutical composition F, characterized in that: The pharmaceutical composition F comprises a PD-L1 small molecule inhibitor, a COX-2 inhibitor and pharmaceutical excipients.

12. The pharmaceutical composition F according to claim 11, characterized in that The pharmaceutical composition F satisfies one or more of the following conditions: (1) The pharmaceutical composition F has a synergistic effect; (2) The PD-L1 small molecule inhibitor and the COX-2 inhibitor are as described in claim 10; (3) The content of the PD-L1 small molecule inhibitor is 30-500 mg, preferably 40-400 mg, such as 50 mg, 150 mg or 300 mg; (4) the content of the COX-2 inhibitor is 50-250 mg, preferably 100-200 mg, for example 100 mg or 200 mg; (5) The mass ratio of the PD-L1 small molecule inhibitor to the COX-2 inhibitor is (0.1-10):1, preferably (2-10):1, For example, 6:1 or 7.5:1; (6) The active ingredients of the pharmaceutical composition F are the PD-L1 small molecule inhibitor and the COX-2 inhibitor; (7) The dosage forms of the pharmaceutical composition F include gastrointestinal dosage forms and parenteral dosage forms, preferably capsules, tablets, pills, granules, powders or oral liquids.

13. A pharmaceutical composition G, characterized in that: The pharmaceutical composition G comprises: A first pharmaceutical composition G-1, which includes a PD-L1 small molecule inhibitor and a pharmaceutical excipient; and, The second pharmaceutical composition G-2 comprises a COX-2 inhibitor and pharmaceutically acceptable excipients.

14. The pharmaceutical composition G according to claim 13, characterized in that The pharmaceutical composition G satisfies one or more of the following conditions: (1) The pharmaceutical composition G has a synergistic effect; (2) The PD-L1 small molecule inhibitor and COX-2 inhibitor are as described in claim 10; (3) The content of the PD-L1 small molecule inhibitor is 30-500 mg, preferably 40-400 mg, such as 50 mg, 150 mg or 300 mg; (4) the content of the COX-2 inhibitor is 50-250 mg, preferably 100-200 mg, for example 100 mg or 200 mg; (5) The mass ratio of the PD-L1 small molecule inhibitor to the COX-2 inhibitor is (0.1-10):1, preferably (2-10):1, for example 6:1 or 7.5:1; (6) The pharmaceutical composition G consists of a first pharmaceutical composition G-1 and a second pharmaceutical composition G-2; the first pharmaceutical composition G-1 consists of the PD-L1 small molecule inhibitor and pharmaceutical excipients, and the second pharmaceutical composition G-2 consists of the COX-2 inhibitor and pharmaceutical excipients; (7) The first pharmaceutical composition G-1 is presented in an oral dosage form; (8) The second pharmaceutical composition G-2 is presented in an oral dosage form.

15. A combination medicine box H, characterized in that: The combined medicine kit H comprises: A first container comprising the first pharmaceutical composition G-1 according to claim 13 or 14; and, A second container comprising the second pharmaceutical composition G-2 according to claim 13 or 14.

16. A use of the pharmaceutical combination A according to any one of claims 1 to 3, the pharmaceutical composition B according to claim 4 or 5, the pharmaceutical composition C according to claim 6 or 7, the pharmaceutical combination E according to claim 9 or 10, the pharmaceutical composition F according to claim 11 or 12, or the pharmaceutical composition G according to claim 13 or 14 in the preparation of a medicament for treating a tumor; the tumor is preferably one or more of gastric cancer, nasopharyngeal cancer, lung cancer, colorectal cancer, breast cancer, colon cancer, bladder cancer, cervical cancer, endometrial cancer, pancreatic cancer, prostate cancer, hepatocellular carcinoma, melanoma, head and neck cancer, esophageal cancer, ovarian cancer, bone cancer, central nervous system tumors, adrenal tumors, renal cell carcinoma, neuroblastoma and glioma, more preferably breast cancer, gastric cancer, nasopharyngeal cancer or glioma.

17. A method for treating a tumor, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical combination A according to any one of claims 1 to 3, the pharmaceutical composition B according to claim 4 or 5, the pharmaceutical composition C according to claim 6 or 7, the pharmaceutical combination E according to claim 9 or 10, the pharmaceutical composition F according to claim 11 or 12, or the pharmaceutical composition G according to claim 13 or 14.

18. The method for treating tumors according to claim 17, characterized in that: The method for treating tumors satisfies one or more of the following conditions: (1) The tumor is one or more of gastric cancer, nasopharyngeal cancer, lung cancer, colorectal cancer, breast cancer, colon cancer, bladder cancer, cervical cancer, endometrial cancer, pancreatic cancer, prostate cancer, hepatocellular carcinoma, melanoma, head and neck cancer, esophageal cancer, ovarian cancer, bone cancer, central nervous system tumor, adrenal tumor, renal cell carcinoma, neuroblastoma and brain glioma, preferably breast cancer, gastric cancer, nasopharyngeal cancer or brain glioma; (2) The total daily dosage of the PD-L1 small molecule inhibitor is in the range of 30-2400 mg; preferably 500-2000 mg; for example 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg or 1900 mg; (3) The administration frequency of the PD-L1 small molecule inhibitor is twice a day, once a day, or once every two days, preferably twice a day; (4) When a therapeutically effective amount of the pharmaceutical combination A according to any one of claims 1 to 3, the pharmaceutical composition B according to claim 4 or 5, or the pharmaceutical composition C according to claim 6 or 7 is administered to a subject in need thereof, when the chemotherapy drug molecule is capecitabine, the total daily dose range is 1000-3000 mg / m 2 , preferably 1000 mg / m 2 , 1250mg / m 2 , 1500mg / m 2 , 1750mg / m 2 , 2000mg / m 2 , 2250mg / m 2 , 2500mg / m 2 , 2750mg / m 2 or 3000 mg / m 2 , for example 2000mg / m 2 or 2500 mg / m 2 ; The frequency of administration is once a day or twice a day, preferably twice a day; (5) When a therapeutically effective amount of the drug combination A according to any one of claims 1 to 3, the drug composition B according to claim 4 or 5, or the drug composition C according to claim 6 or 7 is administered to a subject in need thereof, when the chemotherapy drug molecule is paclitaxel, the total daily dose range is 50-200 mg / m 2 , preferably 50 mg / m 2 , 75mg / m 2 , 80mg / m 2 , 100mg / m 2 , 125mg / m 2 , 135mg / m 2 , 145mg / m 2 , 155mg / m 2 , 165mg / m 2 , 175mg / m 2 , 185mg / m 2 , 195mg / m 2 or 200 mg / m 2 , for example 80 mg / m 2 , 135mg / m 2 or 175 mg / m 2 ; The frequency of administration is once every two weeks, once every three weeks or once every four weeks; preferably once every three weeks; (6) When a therapeutically effective amount of the pharmaceutical combination A according to any one of claims 1 to 3, the pharmaceutical composition B according to claim 4 or 5, or the pharmaceutical composition C according to claim 6 or 7 is administered to a subject in need thereof, when the chemotherapy drug molecule is temozolomide, the total daily dose range is 100-250 mg / m 2 , preferably 100 mg / m 2 , 125mg / m 2 , 150mg / m 2 , 175mg / m 2 , 200mg / m 2 , 225mg / m 2 or 250 mg / m 2 , for example 150 mg / m 2 or 200 mg / m 2 ; The frequency of administration is once a day for 5 days, and then the next cycle begins after 23 days of drug withdrawal; (7) When a therapeutically effective amount of the pharmaceutical combination E according to claim 9 or 10, the pharmaceutical composition F according to claim 11 or 12, or the pharmaceutical composition G according to claim 13 or 14 is administered to a subject in need thereof, the total daily dose of the COX-2 inhibitor is in the range of 50-250 mg, preferably 100-200 mg, for example 100 mg or 200 mg; (8) When a therapeutically effective amount of the pharmaceutical combination E according to claim 9 or 10, the pharmaceutical composition F according to claim 11 or 12, or the pharmaceutical composition G according to claim 13 or 14 is administered to a subject in need thereof, the COX-2 inhibitor is administered once a day or twice a day.

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