Use of pharmaceutical compounds alone or in combination

Abstract

The present invention relates to the technical field of medicine, and relates to a use of compound A, compound B, compound C, compound D, or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, alone or in any combination, in treatment of a new disease or condition, and a treatment method.

Description

Use of drug compounds, alone or in combination. Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to the use and treatment methods of free benzamide compound A or its pharmaceutically acceptable salts, esters, solvates, and hydrates, free sulfonamide compound B or its pharmaceutically acceptable salts, esters, solvates, and hydrates, and / or compounds C and / or D or their pharmaceutically acceptable salts, esters, solvates, and hydrates, in the treatment of new diseases or conditions. Background Technology

[0002] Acute lymphoblastic leukemia (ALL) is a malignant neoplastic disease caused by the abnormal proliferation of B-cell or T-cell lymphocytes in the bone marrow. T-cell acute lymphoblastic leukemia (T-ALL) is a subtype of ALL originating from the T-cell lineage, accounting for 10-15% of ALL patients in children and 20-25% of ALL patients in adults. T-ALL often presents with more aggressive clinical manifestations than other types of ALL and is prone to complications such as central nervous system leukemia (CNSL). Current treatment options for T-ALL mainly include combination chemotherapy, hematopoietic stem cell transplantation, and CAR-T therapy. Limited treatment options and a poor prognosis still make it difficult to provide satisfactory treatment outcomes.

[0003] In addition, existing BCR-ABL tyrosine kinase inhibitors (TKIs) can only be used to treat acute B-cell lymphoblastic leukemia or Philadelphia positive lymphoblastic leukemia.

[0004] In T cell activation, activation of lymphocyte-specific protein tyrosine kinase (LCK kinase) is a necessary step; therefore, selective inhibition of LCK kinase can produce immunosuppressive effects. Simultaneously, ectopic expression of LCK kinase in other cells can induce cell carcinogenesis, thus inhibiting LCK can also play an anti-cancer role. However, because LCK is very similar to other kinases in the Src family, such as Hck and Fyn, in exon composition and protein structure, exhibiting high homology, selective inhibition of LCK is difficult to achieve.

[0005] Therefore, there is an urgent need in the field for means to selectively inhibit LCK kinases or to effectively prevent and / or treat cancer, autoimmune diseases, inflammatory diseases and organ transplant rejection. Summary of the Invention

[0006] Through long-term research, the inventors unexpectedly discovered that a single compound A or a combination of the following compounds can selectively inhibit LCK kinase, particularly inhibiting phosphorylation at the Tyr394 site of LCK kinase. This effectively inhibits the proliferation of Philadelphia negative T-cell lymphoblastic leukemia cells. Furthermore, in the case of the compound combinations, there is a synergistic effect among the compounds: combinations of compound A and compound B, combinations of compound A and compound C / compound D, combinations of compound B and compound C / compound D, and combinations of compound A and compound B + compound C / compound D. This invention is thus completed, wherein compounds A, B, C, and D each have the following structural formulas:

[0007] In this paper, the expression "compound C / compound D" means including compound C alone, compound D alone, and both compound C and compound D. When both compound C and compound D are present, there is no particular restriction on their ratio.

[0008] Therefore, a first aspect of the present invention relates to the use of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof for the preparation of a medicament for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases.

[0009] A second aspect of the invention relates to a method for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases using compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, comprising administering to a patient in need of such a preventive and / or therapeutically effective amount of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof.

[0010] A third aspect of the invention relates to compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases.

[0011] A fourth aspect of the invention relates to a pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt, ester, solvate, hydrate, and a pharmaceutically acceptable carrier thereof.

[0012] The fifth aspect of the invention relates to a medicine box comprising: (i) a compound A or a pharmaceutically acceptable salt, ester, solvate, hydrate thereof, and a pharmaceutically acceptable carrier, and (ii) optional instructions.

[0013] The sixth aspect of the invention relates to a method for inhibiting the phosphorylation of LCK kinase Tyr394, comprising contacting LCK kinase with compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof.

[0014] The seventh aspect of the invention relates to the use of a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof in the preparation of a medicament for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases.

[0015] The eighth aspect of the invention relates to a method for preventing and / or treating diseases associated with selective inhibition of LCK kinases, comprising administering to a patient in need a preventive and / or therapeutically effective amount of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof.

[0016] The ninth aspect of the present invention relates to a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases.

[0017] The tenth aspect of the present invention relates to a pharmaceutical composition comprising a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier.

[0018] The eleventh aspect of the present invention relates to a medicine box comprising: (i) a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier and (ii) optional instructions.

[0019] The twelfth aspect of the present invention relates to a method for inhibiting the phosphorylation of LCK kinase Tyr394, comprising contacting LCK kinase with compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound B or a pharmaceutically acceptable combination of salt, ester, solvate, or hydrate thereof.

[0020] The thirteenth aspect of the present invention relates to the use of a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, in the preparation of a medicament for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases.

[0021] The fourteenth aspect of the present invention relates to a method for preventing and / or treating diseases associated with selective inhibition of LCK kinases, comprising administering to a patient in need of such prevention and / or treatment a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, hydrate, compound B or a pharmaceutically acceptable salt, ester, solvate, hydrate, and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, hydrate, or compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, hydrate, or compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, hydrate, or compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, hydrate, or compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, hydrate, or compound C / compound D.

[0022] The fifteenth aspect of the present invention relates to a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases.

[0023] The sixteenth aspect of the present invention relates to a pharmaceutical composition comprising a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier.

[0024] The seventeenth aspect of the present invention relates to a medicine box comprising: (i) a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier and (ii) optional instructions.

[0025] The eighteenth aspect of the present invention relates to a method for inhibiting the phosphorylation of LCK kinase Tyr394, comprising contacting LCK kinase with compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, with compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and with a combination of compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof.

[0026] The nineteenth aspect of the present invention relates to the use of a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof in the preparation of a medicament for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases.

[0027] The twentieth aspect of the invention relates to a method for preventing and / or treating diseases associated with selective inhibition of LCK kinases, comprising administering to a patient in need a preventive and / or therapeutically effective amount of compound A or a pharmaceutically acceptable salt, ester, solvate, hydrate of the same or compound C / compound D or the same or compound D.

[0028] The twenty-first aspect of the present invention relates to a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases.

[0029] The twenty-second aspect of the present invention relates to a pharmaceutical composition comprising a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier.

[0030] The twenty-third aspect of the present invention relates to a medicine box comprising: (i) a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier and (ii) optional instructions.

[0031] The twenty-fourth aspect of the present invention relates to a method for inhibiting Tyr394 phosphorylation of LCK kinase, comprising contacting LCK kinase with compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound C / compound D or a pharmaceutically acceptable combination of salt, ester, solvate, or hydrate thereof.

[0032] The twenty-fifth aspect of the present invention relates to the use of a combination of compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof in the preparation of a medicament for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases.

[0033] The twenty-sixth aspect of the present invention relates to a method for preventing and / or treating diseases associated with selective inhibition of LCK kinases, comprising administering to a patient in need a preventive and / or therapeutically effective amount of compound A or a pharmaceutically acceptable salt, ester, solvate, hydrate of compound A or a pharmaceutically acceptable salt, ester, solvate, hydrate of compound C or compound D or a pharmaceutically acceptable salt, ester, solvate, hydrate of compound C or compound D or a pharmaceutically acceptable salt, ester, solvate, hydrate of compound A ...

[0034] The twenty-seventh aspect of the present invention relates to a combination of compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases.

[0035] The twenty-eighth aspect of the present invention relates to a pharmaceutical composition comprising a combination of compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier.

[0036] The twenty-ninth aspect of the invention relates to a medicine box comprising: (i) a combination of compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier and (ii) optional instructions.

[0037] The thirtieth aspect of the invention relates to a method for inhibiting Tyr394 phosphorylation of LCK kinase, comprising contacting LCK kinase with compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound C / compound D or a pharmaceutically acceptable combination of a salt, ester, solvate, or hydrate thereof.

[0038] In some implementations, diseases associated with selective inhibition of LCK kinases include T-cell-mediated diseases such as cancer, autoimmune diseases, inflammatory diseases, and organ transplant rejection, such as heart allogeneic transplant rejection.

[0039] In some implementations, cancers include lymphoma, blastoma, medulloblastoma, retinoblastoma, sarcoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumors, carcinoid tumors, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, melanoma, glioblastoma, adenocarcinoma, squamous cell carcinoma, epithelial squamous cell carcinoma, skin cancer, brain cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, squamous cell lung cancer, peritoneal cancer, hepatocellular carcinoma, gastric cancer, intestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, metastatic breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, Merkel cell carcinoma, esophageal cancer, bone cancer, biliary tract tumors, central nervous system tumors, head and neck cancers, and hematologic malignancies.

[0040] In some implementation schemes, hematologic malignancies include T-lymphoblastic leukemia such as acute T-lymphoblastic leukemia and chronic T-lymphoblastic leukemia, B-lymphoblastic leukemia such as acute B-lymphoblastic leukemia and chronic B-lymphoblastic leukemia, plasma cell tumors, multiple myeloma, macroglobulinemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, essential thrombocythemia, and polycythemia vera.

[0041] In some implementation schemes, autoimmune diseases are selected from multiple sclerosis, myasthenia gravis, Graves' disease, chronic lymphocytic thyroiditis, Addison's disease, vitiligo, scleroderma, nephritis-pulmonary hemorrhage syndrome, Becet's disease, segmental ileitis, ankylosing spondylitis, uveitis, thrombocytopenic purpura, pemphigus vulgaris, diabetes, autoimmune anemia, cryoglobulinemia, adrenoleukodystrophy (ALD), and systemic lupus erythematosus (SLE).

[0042] In some implementations, the inflammatory disease is selected from rheumatoid arthritis, osteoarthritis, asthma, allergic dermatitis, atopic dermatitis, multiple sclerosis, psoriasis, human endothelial cell disease, eczematous dermatitis, psoriatic arthritis, traumatic arthritis, urticaria arthritis, gouty arthritis, inflammatory bowel disease, and osteoporosis.

[0043] In some implementations, T-lymphocytic leukemia is Philadelphia-negative T-cell lymphocytic leukemia.

[0044] In some implementations, compound A or its pharmaceutically acceptable salt, ester, solvate, or hydrate inhibits LCK kinase by inhibiting the phosphorylation of Tyr394.

[0045] In some embodiments, a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof inhibits LCK kinase by inhibiting the phosphorylation of Tyr394.

[0046] In some embodiments, a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof inhibits LCK kinase by inhibiting the phosphorylation of Tyr394.

[0047] In some embodiments, a combination of compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof inhibits LCK kinase by inhibiting the phosphorylation of Tyr394.

[0048] In some embodiments, a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof inhibits LCK kinase by inhibiting the phosphorylation of Tyr394.

[0049] In some implementations, the inhibition of LCK kinase by compound A or its pharmaceutically acceptable salts, esters, solvates, or hydrates is performed in vitro or in vivo.

[0050] In some embodiments, the inhibition of LCK kinase by compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, in combination with compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, is carried out in vitro or in vivo.

[0051] In some embodiments, the inhibition of LCK kinase by compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, in combination with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, is carried out in vitro or in vivo.

[0052] In some embodiments, the inhibition of LCK kinase by compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, in combination with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, is carried out in vitro or in vivo.

[0053] In some embodiments, the inhibition of LCK kinase by compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, combined with compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, is carried out in vitro or in vivo.

[0054] In some implementations, the inhibition of LCK kinase by compound A or its pharmaceutically acceptable salts, esters, solvates, or hydrates is performed in patients with Philadelphia negative T-cell lymphoblastic leukemia.

[0055] In some implementations, the inhibition of LCK kinase by compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, in combination with compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, is performed in patients with Philadelphia negative T-cell lymphoblastic leukemia.

[0056] In some implementations, the inhibition of LCK kinase by compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, in combination with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, is performed in patients with Philadelphia negative T-cell lymphoblastic leukemia.

[0057] In some implementations, the inhibition of LCK kinase by compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, in combination with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, is performed in patients with Philadelphia negative T-cell lymphoblastic leukemia.

[0058] In some implementations, the inhibition of LCK kinase by combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof is performed in patients with Philadelphia negative T-cell lymphoblastic leukemia.

[0059] In some implementations, a preventive and / or therapeutically effective amount of compound A or its pharmaceutically acceptable salt, ester, solvate, or hydrate is administered orally to patients in need.

[0060] In some implementations, a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate of compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate of compound A or compound B or compound B or compound B or compound B is administered orally to patients in need for prevention and / or treatment.

[0061] In some implementations, a combination of compound A or its pharmaceutically acceptable salt, ester, solvate, or hydrate with compound C / compound D or its pharmaceutically acceptable salt, ester, solvate, or hydrate is administered orally to patients in need for prevention and / or treatment.

[0062] In some implementations, a combination of compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate of compound B or compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate of compound B or compound D or compound D or compound D or compound C / D ...

[0063] In some implementations, a preventive and / or therapeutically effective amount of compound A or its pharmaceutically acceptable salt, ester, solvate, or hydrate, together with compound B or its pharmaceutically acceptable salt, ester, solvate, or hydrate, and compound C / compound D or its pharmaceutically acceptable salt, ester, solvate, or hydrate, are administered orally to patients in need.

[0064] In some implementations, compound A or its pharmaceutically acceptable salts, esters, solvates, or hydrates are administered twice daily, once daily, or every other day in amounts of about 1 mg, about 2 mg, about 2.5 mg, about 4 mg, about 5 mg, about 8 mg, about 10 mg, about 12.5 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg.

[0065] In some implementations, compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, in combination with compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, is administered twice daily, once daily, or every other day in amounts of about 1 mg, about 2 mg, about 2.5 mg, about 4 mg, about 5 mg, about 8 mg, about 10 mg, about 12.5 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg.

[0066] In some implementations, compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, in combination with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, is administered twice daily, once daily, or every other day in amounts of about 1 mg, about 2 mg, about 2.5 mg, about 4 mg, about 5 mg, about 8 mg, about 10 mg, about 12.5 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg.

[0067] In some implementations, compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, in combination with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, is administered twice daily, once daily, or every other day in amounts of about 1 mg, about 2 mg, about 2.5 mg, about 4 mg, about 5 mg, about 8 mg, about 10 mg, about 12.5 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, or about 1200 mg.

[0068] In some implementations, compound A or its pharmaceutically acceptable salts, esters, solvates, or hydrates, together with compound B or its pharmaceutically acceptable salts, esters, solvates, or hydrates, and compound C / compound D or its pharmaceutically acceptable salts, esters, solvates, or hydrates, are administered twice daily, once daily, or every other day in amounts of about 1 mg, about 2 mg, about 2.5 mg, about 4 mg, about 5 mg, about 5 mg, about 8 mg, about 10 mg, about 12.5 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg.

[0069] In a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, the ratio of free compound A to compound B by weight is preferably in the range of 1:50 to 50:1, although not limited thereto. In some embodiments, the ratio of compound A to compound B by weight is 1:100 to 100:1, preferably 1:50 to 50:1, or 1:25 to 25:1, or 1:10 to 10:1, or 1:10 to 5:1, or 1:10 to 2:1, or 1:10 to 1:1, etc. For example, the ratio can be about 1:5, about 1:10, about 1:30, about 1:60, or about 1:100.

[0070] In combinations of compound A or its pharmaceutically acceptable salts, esters, solvates, or hydrates with compound C / compound D or its pharmaceutically acceptable salts, esters, solvates, or hydrates, the ratio of free compound A to compound B by weight is preferably in the range of 1:50 to 50:1, although not limited thereto. In some embodiments, the ratio of compound A to compound B by weight is 1:100 to 100:1, preferably 1:50 to 50:1, or 1:25 to 25:1, or 1:10 to 10:1, or 1:10 to 5:1, or 1:10 to 2:1, or 1:10 to 1:1, etc. For example, the ratio can be about 1:5, about 1:10, about 1:30, about 1:60, or about 1:100.

[0071] In combinations of compound B or its pharmaceutically acceptable salts, esters, solvates, and hydrates with compound C / compound D or their pharmaceutically acceptable salts, esters, solvates, and hydrates, the ratio of free compound A to compound B by weight is preferably in the range of 1:50 to 50:1, although not limited thereto. In some embodiments, the ratio of compound A to compound B by weight is 1:100 to 100:1, preferably 1:50 to 50:1, or 1:25 to 25:1, or 1:10 to 10:1, or 1:10 to 5:1, or 1:10 to 2:1, or 1:10 to 1:1, etc. For example, the ratio can be about 1:5, about 1:10, about 1:30, about 1:60, or about 1:100.

[0072] In the combination of compound A or its pharmaceutically acceptable salt, ester, solvate, hydrate, and compound B or its pharmaceutically acceptable salt, ester, solvate, hydrate, and compound C / compound D or its pharmaceutically acceptable salt, ester, solvate, hydrate, the ratio between them, based on the weight of free compound A, compound B, and compound C / compound D, is preferably in the range of (1-100):(1-100):(1-100), although not limited thereto. In some embodiments, the ratio of compound A, compound B, and (compound C / compound D) in the combination, based on the weight of free compound A, compound B, and (compound C / compound D), is (1-100):(1-100):(1-100), preferably (1-50):(1-50):(1-50), (1-25):(1-25):(1-25), (1-10):(1-10):(1-10), (1-5):(1-5):(1-5), (1-2):(1-2):(1-2), etc.

[0073] This invention, through comparison with existing BCR-ABL tyrosine kinase inhibitors, found that compounds A, B, or combinations of compound A or its pharmaceutically acceptable salts, esters, solvates, hydrates with compound B or its pharmaceutically acceptable salts, esters, solvates, hydrates; or combinations of compound A or its pharmaceutically acceptable salts, esters, solvates, hydrates with compound C / compound D or its pharmaceutically acceptable salts, esters, solvates, hydrates; or combinations of compound B or its pharmaceutically acceptable salts, esters, solvates, hydrates with compound C / compound D or its pharmaceutically acceptable salts, esters, solvates, hydrates; or combinations of compound A or its pharmaceutically acceptable salts, esters, solvates, hydrates with compound B or its pharmaceutically acceptable salts, esters, solvates, hydrates with compound C / compound D or its pharmaceutically acceptable salts, esters, solvates, hydrates; and combinations of compound A or its pharmaceutically acceptable salts, esters, solvates, hydrates with compound B or its pharmaceutically acceptable salts, esters, solvates, hydrates with compound C / compound D or its pharmaceutically acceptable salts, esters, solvates, hydrates, all effectively inhibit the phosphorylation of Tyr394 by LCK kinase. Furthermore, these inhibitors were found in Philadelphia-negative MOLT-4 cells and Jurkat, Clone In E6-1 cells, the inhibitors showed superior efficacy compared to known BCR-ABL tyrosine kinase inhibitors, with IC50-90% efficacy. 50 The indicated antiproliferative activity (in μM) is at least an order of magnitude lower. Furthermore, combinations of compound A or its pharmaceutically acceptable salts, esters, solvates, and hydrates with compound B or its pharmaceutically acceptable salts, esters, solvates, and hydrates; combinations of compound A or its pharmaceutically acceptable salts, esters, solvates, and hydrates with compound C / compound D or its pharmaceutically acceptable salts, esters, solvates, and hydrates; combinations of compound B or its pharmaceutically acceptable salts, esters, solvates, and hydrates with compound C / compound D or its pharmaceutically acceptable salts, esters, solvates, and hydrates; and combinations of compound A or its pharmaceutically acceptable salts, esters, solvates, and hydrates with compound B or its pharmaceutically acceptable salts, esters, solvates, and hydrates with compound C / compound D or its pharmaceutically acceptable salts, esters, solvates, and hydrates all exhibit synergistic effects. Attached Figure Description

[0074] Figure 1 shows the results of the first batch of MOLT-4 cells in the in vitro cell anti-proliferation experiment of Example 1.

[0075] Figure 2 shows the results of the second batch of MOLT-4 cells in the in vitro cell anti-proliferation experiment of Example 1.

[0076] Figure 3 shows the results of the first batch of Jurkat,Clone E6-1 cells in the in vitro cell anti-proliferation experiment of Example 1.

[0077] Figure 4 shows the results of the second batch of Jurkat,Clone E6-1 cells in the in vitro cell anti-proliferation experiment of Example 1.

[0078] Figure 5 shows the results of the third batch of Jurkat,Clone E6-1 cells in the in vitro cell anti-proliferation experiment of Example 1.

[0079] Figure 6 shows the results of the immunoblotting experiment of MOLT-4 cells in Example 2.

[0080] Figure 7 shows the results of the immunoblotting experiment of Jurkat,Clone E6-1 cells in Example 2.

[0081] Figure 8 illustrates the effects of compound A and compound B alone, as well as compound A in combination with compound B, on MOLT-4 cell proliferation in Example 3.

[0082] Figure 9 illustrates the effects of compound A and compound B alone, as well as compound A in combination with compound B, on the proliferation of Jurkat E6-1 cells in Example 3.

[0083] Figure 10 illustrates the effects of compound A, compound B, compound C, compound B combined with compound C, and the combination of the three on MOLT-4 cell proliferation in Example 3.

[0084] Figure 11 illustrates the effects of compound A, compound B, compound C, compound B combined with compound C, and the combination of all three on Jurkat E6-1 cell proliferation in Example 3.

[0085] Figure 12 shows the effects of compound A and compound B alone, as well as compound A in combination with compound B, on apoptosis of MOLT-4 cells in Example 4; wherein, each bar on the horizontal axis of the bar chart from left to right corresponds to each meaning listed in the legend on the right side of the bar chart from top to bottom; that is, each bar from left to right means the result obtained using the following substances: (1) DMSO, (2) 0.1 μM compound A, (3) 3 μM compound B, (4) 6 μM compound B, (5) combination of 0.1 μM compound A and 3 μM compound B, (6) combination of 0.1 μM compound A and 6 μM compound B.

[0086] Figure 13 shows the effects of compound A and compound B alone, as well as compound A in combination with compound B, on apoptosis of Jurkat E6-1 cells in Example 4; wherein, each bar on the horizontal axis of the bar chart from left to right corresponds to each meaning listed in the legend on the right side of the bar chart from top to bottom; that is, each bar from left to right means the result obtained using the following substances: (1) DMSO, (2) 0.1 μM compound A, (3) 3 μM compound B, (4) 6 μM compound B, (5) combination of 0.1 μM compound A and 3 μM compound B, (6) combination of 0.1 μM compound A and 6 μM compound B.

[0087] Figure 14 shows the effects of compound A, compound B, compound C alone, two combinations of compounds (A+B, B+C, and A+C), and the combination of the three on MOLT-4 cell apoptosis in Example 4; wherein, each bar on the horizontal axis of the bar chart from left to right corresponds to each meaning listed in the legend on the right side of the bar chart from top to bottom; that is, each bar from left to right means the result obtained using the following substances: (1) DMSO, (2) 0.1 μM compound A, (3) 3 μM compound B, (4) 0.01 μM compound C, (5) combination of 0.1 μM compound A and 3 μM compound B, (6) combination of 0.1 μM compound A and 0.01 μM compound C, (7) combination of 3 μM compound B and 0.01 μM compound C, (8) combination of 0.1 μM compound A, 3 μM compound B, and 0.01 μM compound C.

[0088] Figure 15 shows the effects of compound A, compound B, compound C alone, two combinations of compounds (A+B, B+C, and A+C), and the combination of the three on apoptosis of Jurkat E6-1 cells in Example 4; wherein, each bar on the horizontal axis of the bar chart from left to right corresponds to each meaning listed in the legend on the right side of the bar chart from top to bottom; that is, each bar from left to right means the result obtained using the following substances: (1) DMSO, (2) 0.1 μM compound A, (3) 3 μM compound B, (4) 0.1 μM compound C, (5) combination of 0.1 μM compound A and 3 μM compound B, (6) combination of 0.1 μM compound A and 0.1 μM compound C, (7) combination of 3 μM compound B and 0.1 μM compound C, (8) combination of 0.1 μM compound A, 3 μM compound B, and 0.1 μM compound C.

[0089] Figure 16 illustrates the effects of compound A and compound B alone, as well as compound A in combination with compound B, on MOLT-4 cell apoptosis-related proteins in Example 5.

[0090] Figure 17 illustrates the effects of compound A and compound B alone, as well as compound A in combination with compound B, on apoptosis-related proteins in Jurkat E6-1 cells in Example 5.

[0091] Figure 18 illustrates the effects of compound A, compound B, compound C alone, two compound combinations (A+B, B+C, and A+C), and the combination of the three on MOLT-4 cell apoptosis-related proteins in Example 5.

[0092] Figure 19 illustrates the effects of compound A, compound B, compound C alone, two-compound combinations (A+B, B+C, and A+C), and the combination of all three on apoptosis-related proteins in Jurkat E6-1 cells in Example 5.

[0093] Figure 20 illustrates the effects of compound A and compound B alone, as well as compound A in combination with compound B, on proteins related to the MOLT-4 cell signaling pathway in Example 5.

[0094] Figure 21 illustrates the effects of compound A and compound B alone, as well as compound A in combination with compound B, on Jurkat E6-1 cell signaling pathway-related proteins in Example 5.

[0095] Figure 22 illustrates the effects of compounds A, B, and C alone, combinations of two compounds (A+B, B+C, and A+C), and combinations of the three on proteins related to the MOLT-4 cell signaling pathway in Example 5.

[0096] Figure 23 illustrates the effects of compounds A, B, and C alone, combinations of two compounds (A+B, B+C, and A+C), and combinations of all three on proteins related to the Jurkat E6-1 cell signaling pathway in Example 5.

[0097] Figure 24 illustrates the effects of compounds A and B alone, and the combination of compounds A and B, on tumor size in MOLT-4 subcutaneous model mice in Example 6; the line perpendicular to the horizontal axis from top to bottom at a scale of 22 will sequentially pass through broken lines with the following meanings:

[0098] (1) Compound A, 10 mg / kg, PO, QOD×21D; n=8,

[0099] (2) Solvent control; n = 8,

[0100] (3) Compound B 100mg / kg, PO, QD×21D; n=8,

[0101] (4) Compound A 20 mg / kg, PO, QOD×21D; n=8,

[0102] (5) Compound A 20 mg / kg + Compound B 100 mg / kg, n = 8,

[0103] (6) Compound A 10mg / kg + Compound B 100mg / kg, n=8.

[0104] Figure 25 illustrates the effects of compounds A and B alone, and the combination of compounds A and B, on the body weight of MOLT-4 subcutaneous model mice in Example 6; the line perpendicular to the horizontal axis from top to bottom at a scale of 22 will sequentially pass through broken lines with the following meanings:

[0105] (1) Compound B 100 mg / kg, PO, QD×21D; n=8,

[0106] (2) Compound A, 10 mg / kg, PO, QOD×21D; n=8,

[0107] (3) Compound A 20 mg / kg, PO, QOD×21D; n=8,

[0108] (4) Compound A 10 mg / kg + Compound B 100 mg / kg, n = 8,

[0109] (5) Solvent control; n = 8,

[0110] (6) Compound A 20mg / kg + Compound B 100mg / kg, n=8.

[0111] Figure 26 illustrates the effects of compound A, compound B, compound C, compound B combined with compound C, and the combination of the three on PEER cell proliferation in Example 3.

[0112] Figure 27 illustrates the effects of compound A, compound B, compound C, compound B combined with compound C, and the combination of the three on LOUCY cell proliferation in Example 3.

[0113] Figure 28 shows the effects of compound A, compound B, compound C alone, two combinations of compounds (A+B, B+C, and A+C), and the combination of the three on PEER cell apoptosis in Example 4; wherein, each bar on the horizontal axis of the bar chart from left to right corresponds to each meaning listed in the legend on the right side of the bar chart from top to bottom; that is, each bar from left to right means the result obtained using the following substances: (1) DMSO, (2) 0.01 μM compound A, (3) 3 μM compound B, (4) 0.01 μM compound C, (5) combination of 0.01 μM compound A and 3 μM compound B, (6) combination of 0.01 μM compound A and 0.01 μM compound C, (7) combination of 3 μM compound B and 0.01 μM compound C, (8) combination of 0.1 μM compound A, 3 μM compound B, and 0.1 μM compound C.

[0114] Figure 29 shows the effects of compound A, compound B, compound C alone, two combinations of compounds (A+B, B+C, and A+C), and the combination of the three on LOUCY cell apoptosis in Example 4; wherein, each bar on the horizontal axis of the bar chart from left to right corresponds to each meaning listed in the legend on the right side of the bar chart from top to bottom; that is, each bar from left to right means the result obtained using the following substances: (1) DMSO, (2) 0.5 μM compound A, (3) 0.02 μM compound B, (4) 0.002 μM compound C, (5) combination of 0.5 μM compound A and 0.02 μM compound B, (6) combination of 0.5 μM compound A and 0.002 μM compound C, (7) combination of 0.02 μM compound B and 0.002 μM compound C, (8) combination of 0.1 μM compound A, 3 μM compound B, and 0.1 μM compound C.

[0115] Figure 30 illustrates the effects of compound A, compound B, compound C alone, two-compound combinations (A+B, B+C, and A+C), and the combination of the three on PEER cell apoptosis-related proteins in Example 5.

[0116] Figure 31 illustrates the effects of compound A, compound B, compound C alone, two compound combinations (A+B, B+C, and A+C), and the combination of the three on LOUCY cell apoptosis-related proteins in Example 5.

[0117] Figure 32 illustrates the effects of compound A, compound B, compound C alone, two compound combinations (A+B, B+C, and A+C), and the combination of the three on PEER cell apoptosis-related proteins in Example 5.

[0118] Figure 33 illustrates the effects of compound A, compound B, compound C alone, two compound combinations (A+B, B+C, and A+C), and the combination of the three on LOUCY cell apoptosis-related proteins in Example 5. Detailed Implementation

[0119] All publicly available documents cited in this article are incorporated herein by reference in their entirety.

[0120] Any one or more aspects and features defined in any one or more embodiments herein may be freely combined, unless there is a conflict between them, to form another one or more aspects or embodiments of the invention.

[0121] Unless otherwise defined separately, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which they pertain.

[0122] Compound A can be prepared, for example, according to the method described in US8846671B2.

[0123] Compound B can be prepared, for example, according to the method described in WO2018 / 027097A1.

[0124] Compounds C and D can be prepared, for example, according to the method described in WO2014 / 113413A1, and are also Bcl-2 / Bcl-xL inhibitors. The chemical name of compound C is (R)-1-(3-(4-(N-(4-(4-(3-(2-(4-chlorophenyl)-1-isopropyl-5-methyl-4-(methylsulfonyl)-1H-pyrrolo-3-yl)-5-fluorophenyl)piperazin-1-yl)phenyl)-aminosulfonyl)-2-(trifluoromethylsulfonyl)phenylamino)-4-(phenylthio)butyl)piperidine-4-carboxylic acid. Compound D is chemically named (R)-2-(1-(3-(4-(N-(4-(4-(3-(2-(4-chlorophenyl)-1-isopropyl-5-methyl-4-(methylsulfonyl)-1H-pyrrolo-3-yl)-5-fluorophenyl)piperazin-1-yl)phenyl)aminosulfonyl)-2-(trifluoromethylsulfonyl)phenylamino)-4-(phenylthio)butyl)piperidine-4-carbonyloxy)ethylphosphonic acid).

[0125] Compound D selectively binds to Bcl-2, Bcl-xL, and Bcl-w proteins with high affinity, with IC50 values ​​of 1.6 nM, 4.4 nM, and 9.3 nM, respectively. Compound D also binds weakly to Mcl-1. Through chemical structural modification, compound D effectively reduces the platelet toxicity defects of first-generation BCL-2 inhibitors in the bloodstream, while still achieving specific enzyme activation in tissues to effectively kill tumor cells. Its platelet toxicity is reduced by 10-30 times, but its activity is approximately 10 times that of first-generation BCL-2 inhibitors. Compound C is the active metabolite of compound D.

[0126] As used herein, the term “approximately” is used to indicate a roughly or approximate range. When the term “approximately” is used in conjunction with a single numerical value or range of values, it modifies that range by extending the upper and lower boundaries of the given numerical value. Typically, the term “approximately” in this document includes a difference of 10% above and below the stated value.

[0127] As used herein, the term "treatment" means reversing, alleviating, or delaying the onset of a disease or condition, or inhibiting its progression or one or more symptoms, including but not limited to providing therapeutic benefits. In some embodiments, treatment is administered after one or more symptoms have occurred. In some embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a subject before the onset of symptoms (e.g., based on the subject's medical history and / or based on genetic or other susceptibility factors). In some cases, treatment may continue even after symptoms have subsided, for example, to prevent or delay their recurrence. The therapeutic benefits obtained by using compound A or its pharmaceutically acceptable salts, esters, solvates, or hydrates, or a combination of compound A or its pharmaceutically acceptable salts, esters, solvates, or hydrates with compound B or its pharmaceutically acceptable salts, esters, solvates, or hydrates, or a combination of compound A or its pharmaceutically acceptable salts, esters, solvates, or hydrates with compound C / compound D or its pharmaceutically acceptable salts, esters, solvates, or hydrates, or a combination of compound B or its pharmaceutically acceptable salts, esters, solvates, or hydrates with compound C / compound D or its pharmaceutically acceptable salts, esters, solvates, or hydrates, or a combination of compound A or its pharmaceutically acceptable salts, esters, solvates, or hydrates with compound B or its pharmaceutically acceptable salts, esters, solvates, or hydrates with compound C / compound D or its pharmaceutically acceptable salts, esters, solvates, or hydrates, include eradication and / or improvement of an underlying disease being treated, such as cancer, autoimmune diseases, inflammatory diseases, and organ transplant rejection; eradication and / or improvement of one or more symptoms associated with the underlying disease.

[0128] As used in this article, the term "prevention" refers to reducing the risk of developing a disease or condition. Prevention does not require that the subject's disease or condition never occur or recur.

[0129] As used herein, the term "administration" refers to the administration of compound A alone, or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, or a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, or a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, or a combination of compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, or a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, including delivery to a subject using any suitable formulation, such as those defined in the art or herein, via any suitable route of administration. Compound A, or its pharmaceutically acceptable salt, ester, solvate, or hydrate, may be administered alone or in combination, or in combination with compound B, or its pharmaceutically acceptable salt, ester, solvate, or hydrate; or in combination with compound C / compound D, or its pharmaceutically acceptable salt, ester, solvate, or hydrate; or in combination with compound B / compound D, or its pharmaceutically acceptable salt, ester, solvate, or hydrate; or in combination with compound A, or its pharmaceutically acceptable salt, ester, solvate, or hydrate, or with compound B / compound D, or its pharmaceutically acceptable salt, ester, solvate, or hydrate; or in combination with compound C / compound D, or its pharmaceutically acceptable salt, ester, solvate, or hydrate; or in combination with compound B / compound D, or its pharmaceutically acceptable salt, ester, solvate, or hydrate.Furthermore, a combination of compound A alone or its pharmaceutically acceptable salt, ester, solvate, or hydrate; or compound A or its pharmaceutically acceptable salt, ester, solvate, or hydrate with compound B or its pharmaceutically acceptable salt, ester, solvate, or hydrate; or compound A or its pharmaceutically acceptable salt, ester, solvate, or hydrate with compound C / compound D or its pharmaceutically acceptable salt, ester, solvate, or hydrate; or compound B or its pharmaceutically acceptable salt, ester, solvate, or hydrate with compound C / compound D or its pharmaceutically acceptable salt, ester, solvate, or hydrate. The combination of compound A or its pharmaceutically acceptable salts, esters, solvates, hydrates, and compound B or its pharmaceutically acceptable salts, esters, solvates, hydrates, and compound C / compound D or its pharmaceutically acceptable salts, esters, solvates, hydrates, may be administered to the patient requiring treatment via the enteral, non-enteric, or local routes. Enteral routes typically include oral administration, such as oral solutions, tablets, capsules, granules, and suspensions; non-enteric routes include subcutaneous, intramuscular, intraperitoneal, and intravenous infusions, and non-enteric forms include injections and lyophilized preparations; local forms include patches, pastes, and ointments.

[0130] As used herein, the term "therapeutic effective amount" or "effective amount" refers to an amount that effectively elicits the desired biological or medical response, including an amount of compound sufficient to achieve treatment of a condition when administered to a subject. Effective amounts will vary depending on the condition and its severity, and the age, weight, etc., of the subject being treated. An effective amount may be one or more doses (e.g., a single or multiple doses may be required to achieve the desired therapeutic endpoint). An effective amount may be considered as being administered at an effective amount if it can achieve the desired or beneficial result when combined with one or more other agents. The appropriate dose of co-administered compounds may optionally be reduced due to the combined, additive, or synergistic effects of the compounds.

[0131] As used herein, the terms “subject” or “patient” include, but are not limited to, humans (i.e., men or women of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young, middle-aged or elderly) and / or non-human animals, preferably mammals, more preferably other primates (e.g., cynomolgus monkeys, rhesus monkeys).

[0132] As used herein, the terms “pharmaceuticalally acceptable” or “physiologically acceptable” are used to modify compounds, salts, compositions, dosage forms and their carriers that can be used to prepare pharmaceutical compositions suitable for veterinary or human use.

[0133] As used herein, the term "pharmaceutically acceptable salt" means that salts suitable for contact with human or animal tissues without excessive toxicity, irritation, allergic reactions, etc., within the bounds of reasonable medical judgment and in proportion to a reasonable benefit / risk ratio. In this document, pharmaceutically acceptable salts include those derived from suitable inorganic and / or organic acids and / or bases. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, and perchloric acid. Examples of organic acids include acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts formed using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucohepanoate, glyceryl phosphate, glucuronate, hemisulfate, heptaate, hexanoate, hydroiodate, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, dodecyl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, neopentyl ester, propionate, stearate, succinate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

[0134] As used herein, the term "pharmaceuticalally acceptable carrier" refers to a substance compatible with the recipient host (preferably mammals, more preferably humans) and suitable for delivering the active formulation to the target site without terminating the activity of the formulation. The carrier-related toxicities or adverse reactions (if any) should preferably be proportionate to the reasonable risk / benefit of the intended use of the active pharmaceutical ingredient.

[0135] As used herein, the term "oral" means administration of a composition intended to be ingested. Examples of oral forms include, but are not limited to, tablets, pills, capsules, powders, granules, solutions or suspensions, and drops.

[0136] In the context of numerical values ​​listed herein, it should be understood that any listed numerical value may be an upper or lower limit of a numerical range; therefore, it should be further understood that the present invention covers a numerical range consisting of a combination of an upper and a lower numerical limit, wherein the value of each of the upper and lower numerical limits may be any numerical value mentioned herein or used in the embodiments.

[0137] Implementation Plan

[0138] Implementation Scheme 1. Use of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof for the preparation of a medicament for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases, wherein compound A has the following structure:

[0139] Implementation Scheme 2. Use of Implementation Scheme 1, wherein diseases associated with selective inhibition of LCK kinases include T-cell mediated diseases.

[0140] Implementation scheme 3. The use of implementation scheme 1 or 2, wherein diseases associated with selective inhibition of LCK kinases include cancer, autoimmune diseases, inflammatory diseases and organ transplant rejection.

[0141] Implementation scheme 4. Use of any one of implementation schemes 1-3, wherein diseases associated with selective inhibition of LCK kinase include cardiac allogeneic transplant rejection.

[0142] Implementation Plan 5. Use of any one of Implementation Plans 1-3, wherein diseases associated with selective inhibition of LCK kinase include lymphoma, blastoma, medulloblastoma, retinoblastoma, sarcoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumors, carcinoid tumors, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, melanoma, glioblastoma, adenocarcinoma, squamous cell carcinoma, epithelial squamous cell carcinoma, skin cancer, brain cancer, and lung cancer. Cancer, small cell lung cancer, non-small cell lung cancer, squamous cell lung cancer, peritoneal cancer, hepatocellular carcinoma, stomach cancer, intestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, metastatic breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, Merkel cell carcinoma, esophageal cancer, bone cancer, biliary tract tumors, central nervous system tumors, head and neck cancers, and hematologic malignancies.

[0143] Implementation Plan 6. The uses of Implementation Plan 5, wherein hematologic malignancies include T-lymphoblastic leukemia such as acute T-lymphoblastic leukemia and chronic T-lymphoblastic leukemia, B-lymphoblastic leukemia such as acute B-lymphoblastic leukemia and chronic B-lymphoblastic leukemia, plasma cell tumors, multiple myeloma, macroglobulinemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, essential thrombocytosis, and polycythemia vera.

[0144] Implementation Scheme 7. Use of any one of Implementation Schemes 1-3, wherein the autoimmune disease is selected from multiple sclerosis, myasthenia gravis, Graves' disease, chronic lymphocytic thyroiditis, Addison's disease, vitiligo, scleroderma, nephritis-pulmonary hemorrhage syndrome, Becet's disease, segmental ileitis, ankylosing spondylitis, uveitis, thrombocytopenic purpura, pemphigus vulgaris, diabetes, autoimmune anemia, cryoglobulinemia, adrenoleukodystrophy (ALD), and systemic lupus erythematosus (SLE).

[0145] Implementation Plan 8. Use of any one of Implementation Plans 1-3, wherein the inflammatory disease is selected from rheumatoid arthritis, osteoarthritis, asthma, allergic dermatitis, atopic dermatitis, multiple sclerosis, psoriasis, human endothelial cell disease, eczematous dermatitis, psoriatic arthritis, traumatic arthritis, urticaria arthritis, gouty arthritis, inflammatory bowel disease, and osteoporosis.

[0146] Implementation Plan 9. The purpose of Implementation Plan 6, wherein T-lymphocytic leukemia is Philadelphia negative T-cell lymphocytic leukemia.

[0147] Implementation Scheme 10. Use of any one of Implementation Schemes 1-9, wherein compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof inhibits LCK kinase by inhibiting phosphorylation of Tyr394.

[0148] Implementation Scheme 11. Use of any one of Implementation Schemes 1-10, wherein the inhibition of LCK kinase by compound A or its pharmaceutically acceptable salt, ester, solvate, or hydrate is carried out in vitro or in vivo.

[0149] Implementation Scheme 12. Use of any one of Implementation Schemes 1-11, wherein the inhibition of LCK kinase by compound A or its pharmaceutically acceptable salts, esters, solvates, or hydrates is performed in patients with Philadelphia negative T-cell lymphoblastic leukemia.

[0150] Implementation Scheme 13. A method for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases using compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, comprising administering to a patient in need of this method a preventive and / or therapeutically effective amount of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, wherein compound A has the following structure:

[0151] Implementation Scheme 14. The method of Implementation Scheme 13, wherein a preventive and / or therapeutically effective amount of compound A or its pharmaceutically acceptable salt, ester, solvate, or hydrate is administered orally to a patient in need.

[0152] Implementation Scheme 15. The method of Implementation Scheme 13, wherein Compound A or its pharmaceutically acceptable salts, esters, solvates, or hydrates are administered twice daily, once daily, or every other day in amounts of about 1 mg, about 2 mg, about 4 mg, about 5 mg, about 8 mg, about 10 mg, about 12.5 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg.

[0153] Implementation Scheme 16. Compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases, wherein compound A has the following structure:

[0154] Implementation Scheme 17. Compound A of Implementation Scheme 16 or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, wherein the diseases associated with selective inhibition of LCK kinases include T-cell-mediated diseases.

[0155] Implementation Scheme 18. Compound A of Implementation Scheme 16 or 17 or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, wherein diseases associated with selective inhibition of LCK kinase include cancer, autoimmune diseases, inflammatory diseases, and organ transplant rejection.

[0156] Implementation Scheme 19. Compound A of any one of Implementation Schemes 16-18 or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, wherein the disease associated with selective inhibition of LCK kinase includes cardiac allogeneic transplant rejection.

[0157] Implementation Scheme 20. Compound A of any one of Implementation Schemes 16-18, or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, wherein the diseases associated with selective inhibition of LCK kinase include lymphoma, blastoma, medulloblastoma, retinoblastoma, sarcoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumors, carcinoid tumors, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, melanoma, glioblastoma, adenocarcinoma, squamous cell carcinoma, epithelial squamous cell carcinoma, etc. Squamous cell carcinoma, skin cancer, brain cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, squamous cell lung cancer, peritoneal cancer, hepatocellular carcinoma, stomach cancer, intestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, metastatic breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, Merkel cell carcinoma, esophageal cancer, bone cancer, biliary tract tumors, central nervous system tumors, head and neck cancers, and hematologic malignancies.

[0158] Implementation Scheme 21. Compound A of Implementation Scheme 20 or its pharmaceutically acceptable salts, esters, solvates, and hydrates, wherein hematologic malignancies include T-lymphoblastic leukemia such as acute T-lymphoblastic leukemia and chronic T-lymphoblastic leukemia, B-lymphoblastic leukemia such as acute B-lymphoblastic leukemia and chronic B-lymphoblastic leukemia, plasma cell tumors, multiple myeloma, macroglobulinemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, essential thrombocytosis, and polycythemia vera.

[0159] Implementation Scheme 22. Compound A of any one of Implementation Schemes 16-18 or its pharmaceutically acceptable salt, ester, solvate, or hydrate, wherein the autoimmune disease is selected from multiple sclerosis, myasthenia gravis, Graves' disease, chronic lymphocytic thyroiditis, Addison's disease, vitiligo, scleroderma, nephritis-pulmonary hemorrhage syndrome, Becet's disease, segmental ileitis, ankylosing spondylitis, uveitis, thrombocytopenic purpura, pemphigus vulgaris, diabetes, autoimmune anemia, cryoglobulinemia, adrenoleukodystrophy (ALD), and systemic lupus erythematosus (SLE).

[0160] Implementation Scheme 23. Compound A of any one of Implementation Schemes 16-18 or its pharmaceutically acceptable salt, ester, solvate, or hydrate, wherein the inflammatory disease is selected from rheumatoid arthritis, osteoarthritis, asthma, allergic dermatitis, atopic dermatitis, multiple sclerosis, psoriasis, human endothelial cell disease, eczematous dermatitis, psoriatic arthritis, traumatic arthritis, urticaria arthritis, gouty arthritis, inflammatory bowel disease, and osteoporosis.

[0161] Implementation Scheme 24. Compound A of Implementation Scheme 21 or its pharmaceutically acceptable salt, ester, solvate, or hydrate, wherein the T-lymphocytic leukemia is Philadelphia negative T-cell lymphocytic leukemia.

[0162] Implementation Scheme 25. Compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof from any of Implementation Schemes 16-24, wherein Compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof inhibits LCK kinase by inhibiting phosphorylation of Tyr394.

[0163] Implementation Scheme 26. Compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof from any one of Implementation Schemes 16-25, wherein the inhibition of LCK kinase by Compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof is carried out in vitro or in vivo.

[0164] Implementation Scheme 27. Compound A of any one of Implementation Schemes 16-26 or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, wherein the inhibition of LCK kinase by Compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof is performed in a patient with Philadelphia negative T-cell lymphoblastic leukemia.

[0165] Implementation Scheme 28. A pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt, ester, solvate, hydrate thereof, and a pharmaceutically acceptable carrier, wherein compound A has the following structure:

[0166] Implementation Scheme 29. A medicine box comprising: (i) a compound A or a pharmaceutically acceptable salt, ester, solvate, hydrate, and a pharmaceutically acceptable carrier thereof, and (ii) optional instructions; wherein compound A has the following structure:

[0167] Implementation Scheme 30. A method for inhibiting Tyr394 phosphorylation of LCK kinase, comprising contacting LCK kinase with compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, wherein compound A has the following structure:

[0168] Implementation Scheme 31. The use of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, in combination with compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, for the preparation of a medicament for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases, wherein compound A and compound B each have the following structures:

[0169] Implementation scheme 32. Use of implementation scheme 31, wherein diseases associated with selective inhibition of LCK kinases include T-cell mediated diseases.

[0170] Implementation scheme 33. The use of implementation scheme 31 or 32, wherein diseases associated with selective inhibition of LCK kinases include cancer, autoimmune diseases, inflammatory diseases and organ transplant rejection.

[0171] Implementation scheme 34. Use of any one of implementation schemes 31-33, wherein diseases associated with selective inhibition of LCK kinase include cardiac allogeneic transplant rejection.

[0172] Implementation Scheme 35. Use of any one of Implementation Schemes 31-33, wherein diseases associated with selective inhibition of LCK kinase include lymphoma, blastoma, medulloblastoma, retinoblastoma, sarcoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumors, carcinoid tumors, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, melanoma, glioblastoma, adenocarcinoma, squamous cell carcinoma, epithelial squamous cell carcinoma, skin cancer, and brain cancer. Lung cancer, small cell lung cancer, non-small cell lung cancer, squamous cell lung cancer, peritoneal cancer, hepatocellular carcinoma, stomach cancer, intestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, metastatic breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, Merkel cell carcinoma, esophageal cancer, bone cancer, biliary tract tumors, central nervous system tumors, head and neck cancers, and hematologic malignancies.

[0173] Implementation Plan 36. The uses of Implementation Plan 35, wherein hematologic malignancies include T-lymphoblastic leukemia such as acute T-lymphoblastic leukemia and chronic T-lymphoblastic leukemia, B-lymphoblastic leukemia such as acute B-lymphoblastic leukemia and chronic B-lymphoblastic leukemia, plasma cell tumors, multiple myeloma, macroglobulinemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, essential thrombocytosis, and polycythemia vera.

[0174] Implementation Scheme 37. Use of any one of Implementation Schemes 31-33, wherein the autoimmune disease is selected from multiple sclerosis, myasthenia gravis, Graves' disease, chronic lymphocytic thyroiditis, Addison's disease, vitiligo, scleroderma, nephritis-pulmonary hemorrhage syndrome, Becet's disease, segmental ileitis, ankylosing spondylitis, uveitis, thrombocytopenic purpura, pemphigus vulgaris, diabetes, autoimmune anemia, cryoglobulinemia, adrenoleukodystrophy (ALD), and systemic lupus erythematosus (SLE).

[0175] Implementation Scheme 38. Use of any one of Implementation Schemes 31-33, wherein the inflammatory disease is selected from rheumatoid arthritis, osteoarthritis, asthma, allergic dermatitis, atopic dermatitis, multiple sclerosis, psoriasis, human endothelial cell disease, eczematous dermatitis, psoriatic arthritis, traumatic arthritis, urticaria arthritis, gouty arthritis, inflammatory bowel disease, and osteoporosis.

[0176] Implementation Plan 39. The purpose of Implementation Plan 36, wherein T-lymphocytic leukemia is Philadelphia negative T-cell lymphocytic leukemia.

[0177] Implementation Scheme 40. Use of any one of Implementation Schemes 31-39, wherein a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof inhibits LCK kinase by inhibiting phosphorylation of Tyr394.

[0178] Implementation Scheme 41. Use of any one of Implementation Schemes 31-40, wherein the inhibition of LCK kinase by compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof is carried out in vitro or in vivo.

[0179] Implementation Scheme 42. Use of any one of Implementation Schemes 31-41, wherein the inhibition of LCK kinase by compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof is performed in a patient with Philadelphia negative T-cell lymphoblastic leukemia.

[0180] Implementation Scheme 43. A method for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases, comprising administering to a patient in need of such prevention and / or treatment a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate of compound A or compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate of compound A or compound B, wherein compound A and compound B each have the following structures:

[0181] Implementation Scheme 44. The method of Implementation Scheme 43, wherein a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate of compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate of compound A or compound B or compound B or compound B or compound B or compound B, is administered orally to a patient in need of the method for prevention and / or treatment.

[0182] Implementation Scheme 45. The method of Implementation Scheme 43, wherein compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, in combination with compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, is administered twice daily, once daily, or every other day in amounts of about 1 mg, about 2 mg, about 2.5 mg, about 4 mg, about 5 mg, about 8 mg, about 10 mg, about 12.5 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg.

[0183] Implementation Scheme 46. A combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases, wherein compound A and compound B each have the following structures:

[0184] Implementation scheme 47. A combination of implementation scheme 46, wherein diseases associated with selective inhibition of LCK kinases include T-cell mediated diseases.

[0185] Implementation scheme 48. A combination of implementation schemes 46 or 47, wherein diseases associated with selective inhibition of LCK kinases include cancer, autoimmune diseases, inflammatory diseases, and organ transplant rejection.

[0186] Implementation scheme 49. A combination of any one of implementation schemes 46-48, wherein the disease associated with selective inhibition of LCK kinases includes cardiac allogeneic transplant rejection.

[0187] Implementation Scheme 50. A combination of any one of Implementation Schemes 46-48, wherein the diseases associated with selective inhibition of LCK kinase include lymphoma, blastoma, medulloblastoma, retinoblastoma, sarcoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumors, carcinoid tumors, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, melanoma, glioblastoma, adenocarcinoma, squamous cell carcinoma, epithelial squamous cell carcinoma, skin cancer, and brain cancer. Lung cancer, small cell lung cancer, non-small cell lung cancer, squamous cell lung cancer, peritoneal cancer, hepatocellular carcinoma, stomach cancer, intestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, metastatic breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, Merkel cell carcinoma, esophageal cancer, bone cancer, biliary tract tumors, central nervous system tumors, head and neck cancers, and hematologic malignancies.

[0188] Implementation Scheme 51. A combination of Implementation Scheme 50, wherein hematologic malignancies include T-lymphoblastic leukemia such as acute T-lymphoblastic leukemia and chronic T-lymphoblastic leukemia, B-lymphoblastic leukemia such as acute B-lymphoblastic leukemia and chronic B-lymphoblastic leukemia, plasma cell tumors, multiple myeloma, macroglobulinemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, essential thrombocytosis, and polycythemia vera.

[0189] Implementation Scheme 52. A combination of any one of Implementation Schemes 46-48, wherein the autoimmune disease is selected from multiple sclerosis, myasthenia gravis, Graves' disease, chronic lymphocytic thyroiditis, Addison's disease, vitiligo, scleroderma, nephritis-pulmonary hemorrhage syndrome, Becet's disease, segmental ileitis, ankylosing spondylitis, uveitis, thrombocytopenic purpura, pemphigus vulgaris, diabetes, autoimmune anemia, cryoglobulinemia, adrenoleukodystrophy (ALD), and systemic lupus erythematosus (SLE).

[0190] Implementation Scheme 53. A combination of any one of Implementation Schemes 46-48, wherein the inflammatory disease is selected from rheumatoid arthritis, osteoarthritis, asthma, allergic dermatitis, atopic dermatitis, multiple sclerosis, psoriasis, human endothelial cell disease, eczematous dermatitis, psoriatic arthritis, traumatic arthritis, urticaria arthritis, gouty arthritis, inflammatory bowel disease, and osteoporosis.

[0191] Implementation scheme 54. A combination of implementation scheme 51, wherein the T-lymphocytic leukemia is Philadelphia negative T-cell lymphocytic leukemia.

[0192] Implementation Scheme 55. A combination of any one of Implementation Schemes 46-54, wherein a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof inhibits LCK kinase by inhibiting phosphorylation of Tyr394.

[0193] Implementation Scheme 56. A combination of any one of Implementation Schemes 46-55, wherein the inhibition of LCK kinase by compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof is carried out in vitro or in vivo.

[0194] Implementation Scheme 57. A combination of any one of Implementation Schemes 46-56, wherein the inhibition of LCK kinase by compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof is performed in a patient with Philadelphia negative T-cell lymphoblastic leukemia.

[0195] Implementation Scheme 58. A pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier, wherein compound A and compound B each have the following structures:

[0196] Implementation Scheme 59. A medicine box comprising: (i) a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier, and (ii) optional instructions; wherein compound A and compound B each have the following structures:

[0197] Implementation Scheme 60. A method for inhibiting Tyr394 phosphorylation of LCK kinase, comprising contacting LCK kinase with compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound B or a pharmaceutically acceptable combination of salt, ester, solvate, or hydrate thereof, wherein compound A and compound B each have the following structures:

[0198] Implementation Scheme 61. The use of a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, for the preparation of a medicament for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases, wherein compounds A and B, and compounds C and D, respectively, have the following structures:

[0199] Implementation Scheme 62. Use of Implementation Scheme 61, wherein diseases associated with selective inhibition of LCK kinases include T-cell mediated diseases.

[0200] Implementation scheme 63. The use of implementation scheme 61 or 62, wherein diseases associated with selective inhibition of LCK kinases include cancer, autoimmune diseases, inflammatory diseases and organ transplant rejection.

[0201] Implementation scheme 64. Use of any one of implementation schemes 61-63, wherein diseases associated with selective inhibition of LCK kinase include cardiac allogeneic transplant rejection.

[0202] Implementation Scheme 65. Use of any one of Implementation Schemes 61-63, wherein diseases associated with selective inhibition of LCK kinase include lymphoma, blastoma, medulloblastoma, retinoblastoma, sarcoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumors, carcinoid tumors, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, melanoma, glioblastoma, adenocarcinoma, squamous cell carcinoma, epithelial squamous cell carcinoma, skin cancer, and brain cancer. Lung cancer, small cell lung cancer, non-small cell lung cancer, squamous cell lung cancer, peritoneal cancer, hepatocellular carcinoma, stomach cancer, intestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, metastatic breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, Merkel cell carcinoma, esophageal cancer, bone cancer, biliary tract tumors, central nervous system tumors, head and neck cancers, and hematologic malignancies.

[0203] Implementation Plan 66. The uses of Implementation Plan 65, wherein hematologic malignancies include T-lymphoblastic leukemia such as acute T-lymphoblastic leukemia and chronic T-lymphoblastic leukemia, B-lymphoblastic leukemia such as acute B-lymphoblastic leukemia and chronic B-lymphoblastic leukemia, plasma cell tumors, multiple myeloma, macroglobulinemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, essential thrombocytosis, and polycythemia vera.

[0204] Implementation Scheme 67. Use of any one of Implementation Schemes 61-63, wherein the autoimmune disease is selected from multiple sclerosis, myasthenia gravis, Graves' disease, chronic lymphocytic thyroiditis, Addison's disease, vitiligo, scleroderma, nephritis-pulmonary hemorrhage syndrome, Becet's disease, segmental ileitis, ankylosing spondylitis, uveitis, thrombocytopenic purpura, pemphigus vulgaris, diabetes, autoimmune anemia, cryoglobulinemia, adrenoleukodystrophy (ALD), and systemic lupus erythematosus (SLE).

[0205] Implementation Scheme 68. Use of any one of Implementation Schemes 61-63, wherein the inflammatory disease is selected from rheumatoid arthritis, osteoarthritis, asthma, allergic dermatitis, atopic dermatitis, multiple sclerosis, psoriasis, human endothelial cell disease, eczematous dermatitis, psoriatic arthritis, traumatic arthritis, urticaria arthritis, gouty arthritis, inflammatory bowel disease, and osteoporosis.

[0206] Implementation Scheme 69. The purpose of Implementation Scheme 66, wherein T-lymphocytic leukemia is Philadelphia negative T-cell lymphocytic leukemia.

[0207] Implementation Scheme 70. Use of any one of Implementation Schemes 61-69, wherein a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof inhibits LCK kinase by inhibiting the phosphorylation of Tyr394.

[0208] Implementation Scheme 71. Use of any one of Implementation Schemes 61-70, wherein the inhibition of LCK kinase by a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof is carried out in vitro or in vivo.

[0209] Implementation Scheme 72. Use of any one of Implementation Schemes 61-71, wherein the inhibition of LCK kinase by a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof is performed in a patient with Philadelphia negative T-cell lymphoblastic leukemia.

[0210] Implementation Scheme 73. A method for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases, comprising administering to a patient in need of such prevention and / or treatment a prophylactic and / or therapeutically effective amount of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, wherein compound A and compound B, compound C, and compound D have the following structures respectively:

[0211] Implementation Scheme 74. The method of Implementation Scheme 73, wherein a preventive and / or therapeutically effective amount of compound A or its pharmaceutically acceptable salt, ester, solvate, hydrate, and compound B or its pharmaceutically acceptable salt, ester, solvate, hydrate, and combination of compound C / compound D or its pharmaceutically acceptable salt, ester, solvate, hydrate is administered orally to a patient in need.

[0212] Implementation Scheme 75. The method of Implementation Scheme 73, wherein compound A or its pharmaceutically acceptable salt, ester, solvate, hydrate, and compound B or its pharmaceutically acceptable salt, ester, solvate, hydrate, and combination of compound C / compound D or its pharmaceutically acceptable salt, ester, solvate, hydrate, or combination thereof are administered twice daily, once daily, or every other day in amounts of about 1 mg, about 2 mg, about 2.5 mg, about 4 mg, about 5 mg, about 8 mg, about 10 mg, about 12.5 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg.

[0213] Implementation Scheme 76. A combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases, wherein compound A and compound B, compound C, and compound D have the following structures:

[0214] Implementation scheme 77. A combination of implementation scheme 76, wherein diseases associated with selective inhibition of LCK kinases include T-cell mediated diseases.

[0215] Implementation scheme 78. A combination of implementation scheme 76 or 77, wherein diseases associated with selective inhibition of LCK kinases include cancer, autoimmune diseases, inflammatory diseases, and organ transplant rejection.

[0216] Implementation scheme 79. A combination of any one of implementation schemes 76-78, wherein the disease associated with selective inhibition of LCK kinases includes cardiac allogeneic transplant rejection.

[0217] Implementation Scheme 80. A combination of any one of Implementation Schemes 76-78, wherein the diseases associated with selective inhibition of LCK kinase include lymphoma, blastoma, medulloblastoma, retinoblastoma, sarcoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumors, carcinoid tumors, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, melanoma, glioblastoma, adenocarcinoma, squamous cell carcinoma, epithelial squamous cell carcinoma, skin cancer, and brain cancer. Lung cancer, small cell lung cancer, non-small cell lung cancer, squamous cell lung cancer, peritoneal cancer, hepatocellular carcinoma, stomach cancer, intestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, metastatic breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, Merkel cell carcinoma, esophageal cancer, bone cancer, biliary tract tumors, central nervous system tumors, head and neck cancers, and hematologic malignancies.

[0218] Implementation Plan 81. A combination of Implementation Plan 80, wherein hematologic malignancies include T-lymphoblastic leukemia such as acute T-lymphoblastic leukemia and chronic T-lymphoblastic leukemia, B-lymphoblastic leukemia such as acute B-lymphoblastic leukemia and chronic B-lymphoblastic leukemia, plasma cell tumors, multiple myeloma, macroglobulinemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, essential thrombocytosis, and polycythemia vera.

[0219] Implementation Scheme 82. A combination of any one of Implementation Schemes 76-78, wherein the autoimmune disease is selected from multiple sclerosis, myasthenia gravis, Graves' disease, chronic lymphocytic thyroiditis, Addison's disease, vitiligo, scleroderma, nephritis-pulmonary hemorrhage syndrome, Becet's disease, segmental ileitis, ankylosing spondylitis, uveitis, thrombocytopenic purpura, pemphigus vulgaris, diabetes, autoimmune anemia, cryoglobulinemia, adrenoleukodystrophy (ALD), and systemic lupus erythematosus (SLE).

[0220] Implementation Scheme 83. A combination of any one of Implementation Schemes 76-78, wherein the inflammatory disease is selected from rheumatoid arthritis, osteoarthritis, asthma, allergic dermatitis, atopic dermatitis, multiple sclerosis, psoriasis, human endothelial cell disease, eczematous dermatitis, psoriatic arthritis, traumatic arthritis, urticaria arthritis, gouty arthritis, inflammatory bowel disease, and osteoporosis.

[0221] Implementation scheme 84. A combination of implementation scheme 81, wherein the T-lymphocytic leukemia is Philadelphia negative T-cell lymphocytic leukemia.

[0222] Implementation scheme 85. A combination of any one of implementation schemes 76-84, wherein the combination inhibits LCK kinase by inhibiting phosphorylation of Tyr394.

[0223] Implementation Scheme 86. A combination of any one of Implementation Schemes 76-85, wherein the inhibition of LCK kinase by the combination is performed in vitro or in vivo.

[0224] Implementation scheme 87. A combination of any one of implementation schemes 76-86, wherein the inhibition of LCK kinase by the combination is performed in a patient with Philadelphia negative T-cell lymphoblastic leukemia.

[0225] Implementation Scheme 88. A pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier, wherein compounds A and B, and compounds C and D respectively have the following structures:

[0226] Implementation Scheme 89. A medicine box comprising: (i) a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier and (ii) optional instructions; wherein compound A and compound B, compound C, and compound D each have the following structures:

[0227] Implementation Scheme 90. A method for inhibiting Tyr394 phosphorylation of LCK kinase, comprising contacting LCK kinase with compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, with compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, wherein compound A and compound B, and compound C, respectively have the following structures:

[0228] Implementation Scheme 91. The use of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, or compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, in combination with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, for the preparation of a medicament for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases, wherein compound A, compound B, compound C, and compound D each have the following structures:

[0229] Implementation scheme 92. Use of implementation scheme 91, wherein diseases associated with selective inhibition of LCK kinases include T-cell mediated diseases.

[0230] Implementation scheme 93. The use of implementation scheme 91 or 92, wherein diseases associated with selective inhibition of LCK kinases include cancer, autoimmune diseases, inflammatory diseases and organ transplant rejection.

[0231] Implementation scheme 94. Use of any one of implementation schemes 91-93, wherein diseases associated with selective inhibition of LCK kinase include cardiac allogeneic transplant rejection.

[0232] Implementation Scheme 95. Use of any one of Implementation Schemes 91-93, wherein diseases associated with selective inhibition of LCK kinase include lymphoma, blastoma, medulloblastoma, retinoblastoma, sarcoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumors, carcinoid tumors, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, melanoma, glioblastoma, adenocarcinoma, squamous cell carcinoma, epithelial squamous cell carcinoma, skin cancer, and brain cancer. Lung cancer, small cell lung cancer, non-small cell lung cancer, squamous cell lung cancer, peritoneal cancer, hepatocellular carcinoma, stomach cancer, intestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, metastatic breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, Merkel cell carcinoma, esophageal cancer, bone cancer, biliary tract tumors, central nervous system tumors, head and neck cancers, and hematologic malignancies.

[0233] Implementation Plan 96. The uses of Implementation Plan 95, wherein hematologic malignancies include T-lymphoblastic leukemia such as acute T-lymphoblastic leukemia and chronic T-lymphoblastic leukemia, B-lymphoblastic leukemia such as acute B-lymphoblastic leukemia and chronic B-lymphoblastic leukemia, plasma cell tumors, multiple myeloma, macroglobulinemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, essential thrombocytosis, and polycythemia vera.

[0234] Implementation Scheme 97. Use of any one of Implementation Schemes 91-93, wherein the autoimmune disease is selected from multiple sclerosis, myasthenia gravis, Graves' disease, chronic lymphocytic thyroiditis, Addison's disease, vitiligo, scleroderma, nephritis-pulmonary hemorrhage syndrome, Becet's disease, segmental ileitis, ankylosing spondylitis, uveitis, thrombocytopenic purpura, pemphigus vulgaris, diabetes, autoimmune anemia, cryoglobulinemia, adrenoleukodystrophy (ALD), and systemic lupus erythematosus (SLE).

[0235] Implementation Scheme 98. Use of any one of Implementation Schemes 91-93, wherein the inflammatory disease is selected from rheumatoid arthritis, osteoarthritis, asthma, allergic dermatitis, atopic dermatitis, multiple sclerosis, psoriasis, human endothelial cell disease, eczematous dermatitis, psoriatic arthritis, traumatic arthritis, urticaria arthritis, gouty arthritis, inflammatory bowel disease, and osteoporosis.

[0236] Implementation Plan 99. The purpose of Implementation Plan 96, wherein T-lymphocytic leukemia is Philadelphia negative T-cell lymphocytic leukemia.

[0237] Implementation Scheme 100. Use of any one of Implementation Schemes 91-99, wherein a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, or compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, inhibits LCK kinase by inhibiting the phosphorylation of Tyr394.

[0238] Implementation Scheme 101. Use of any one of Implementation Schemes 91-100, wherein the inhibition of LCK kinase by compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, or compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, in combination with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, is carried out in vitro or in vivo.

[0239] Implementation Scheme 102. Use of any one of Implementation Schemes 91-101, wherein the inhibition of LCK kinase by compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof or compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, in combination with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, is carried out in a patient with Philadelphia negative T-cell lymphoblastic leukemia.

[0240] Implementation Scheme 103. A method for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases, comprising administering to a patient in need of such prevention and / or treatment a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, hydrate, or compound B or a pharmaceutically acceptable salt, ester, solvate, hydrate, or compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, hydrate, or compound D, wherein compound A, compound B, compound C, and compound D each have the following structures:

[0241] Implementation Scheme 104. The method of Implementation Scheme 103, wherein a preventive and / or therapeutically effective amount of compound A or its pharmaceutically acceptable salt, ester, solvate, hydrate or compound B or its pharmaceutically acceptable salt, ester, solvate, hydrate and compound C / compound D or its pharmaceutically acceptable salt, ester, solvate, hydrate is administered orally to a patient in need.

[0242] Implementation Scheme 105. The method of Implementation Scheme 103, wherein compound A or its pharmaceutically acceptable salt, ester, solvate, hydrate, or compound B or its pharmaceutically acceptable salt, ester, solvate, hydrate, and combination of compound C / compound D or its pharmaceutically acceptable salt, ester, solvate, hydrate, or hydrate are administered twice daily, once daily, or every other day, in amounts of about 1 mg, about 2 mg, about 2.5 mg, about 4 mg, about 5 mg, about 8 mg, about 10 mg, about 12.5 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg.

[0243] Implementation Scheme 106. A combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, or compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases, wherein compound A, compound B, compound C, and compound D each have the following structures:

[0244] Implementation scheme 107. A combination of implementation scheme 106, wherein diseases associated with selective inhibition of LCK kinases include T-cell mediated diseases.

[0245] Implementation scheme 108. A combination of implementation schemes 106 or 107, wherein diseases associated with selective inhibition of LCK kinases include cancer, autoimmune diseases, inflammatory diseases, and organ transplant rejection.

[0246] Implementation scheme 109. A combination of any one of implementation schemes 106-108, wherein the disease associated with selective inhibition of LCK kinase includes cardiac allogeneic transplant rejection.

[0247] Implementation Scheme 110. A combination of any one of Implementation Schemes 106-108, wherein the diseases associated with selective inhibition of LCK kinase include lymphoma, blastoma, medulloblastoma, retinoblastoma, sarcoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumors, carcinoid tumors, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, melanoma, glioblastoma, adenocarcinoma, squamous cell carcinoma, epithelial squamous cell carcinoma, skin cancer, and brain cancer. Cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, squamous cell lung cancer, peritoneal cancer, hepatocellular carcinoma, stomach cancer, intestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, metastatic breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, Merkel cell carcinoma, esophageal cancer, bone cancer, biliary tract tumors, central nervous system tumors, head and neck cancers, and hematologic malignancies.

[0248] Implementation Plan 111. A combination of Implementation Plan 100, wherein hematologic malignancies include T-lymphoblastic leukemia such as acute T-lymphoblastic leukemia and chronic T-lymphoblastic leukemia, B-lymphoblastic leukemia such as acute B-lymphoblastic leukemia and chronic B-lymphoblastic leukemia, plasma cell tumors, multiple myeloma, macroglobulinemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, essential thrombocytosis, and polycythemia vera.

[0249] Implementation Scheme 112. A combination of any one of Implementation Schemes 106-108, wherein the autoimmune disease is selected from multiple sclerosis, myasthenia gravis, Graves' disease, chronic lymphocytic thyroiditis, Addison's disease, vitiligo, scleroderma, nephritis-pulmonary hemorrhage syndrome, Becet's disease, segmental ileitis, ankylosing spondylitis, uveitis, thrombocytopenic purpura, pemphigus vulgaris, diabetes, autoimmune anemia, cryoglobulinemia, adrenoleukodystrophy (ALD), and systemic lupus erythematosus (SLE).

[0250] Implementation Scheme 113. A combination of any one of Implementation Schemes 106-108, wherein the inflammatory disease is selected from rheumatoid arthritis, osteoarthritis, asthma, allergic dermatitis, atopic dermatitis, multiple sclerosis, psoriasis, human endothelial cell disease, eczematous dermatitis, psoriatic arthritis, traumatic arthritis, urticaria arthritis, gouty arthritis, inflammatory bowel disease, and osteoporosis.

[0251] Implementation scheme 114. A combination of implementation scheme 101, wherein the T-lymphocytic leukemia is Philadelphia negative T-cell lymphocytic leukemia.

[0252] Implementation Scheme 115. A combination of any one of Implementation Schemes 96-104, wherein a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof or compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof inhibits LCK kinase by inhibiting the phosphorylation of Tyr394.

[0253] Implementation scheme 116. A combination of any one of implementation schemes 96-105, wherein the inhibition of LCK kinase by the combination is performed in vitro or in vivo.

[0254] Implementation scheme 117. A combination of any one of implementation schemes 96-106, wherein the inhibition of LCK kinase by the combination is performed in a patient with Philadelphia negative T-cell lymphoblastic leukemia.

[0255] Implementation Scheme 118. A pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, or compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and a combination of compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier, wherein compound A, compound B, compound C, and compound D each have the following structures:

[0256] Implementation Scheme 119. A medicine box comprising: (i) a pharmaceutically acceptable salt, ester, solvate, or hydrate of compound A or thereof, or a pharmaceutically acceptable salt, ester, solvate, or hydrate of compound B or thereof, and a combination of compound C / compound D or thereof, or a pharmaceutically acceptable salt, ester, solvate, or hydrate, and a pharmaceutically acceptable carrier and (ii) optional instructions; wherein compound A, compound B, compound C, and compound D each have the following structures:

[0257] Implementation Scheme 120. A method for inhibiting Tyr394 phosphorylation of LCK kinase, comprising contacting LCK kinase with compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, or compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, wherein compound A, compound B, compound C, and compound D each have the following structures:

[0258] Example

[0259] Experimental materials

[0260] 1. Cell lines

[0261] MOLT-4, PEER, and LOUCY were purchased from Nanjing Cobioer Biotechnology Co., Ltd.

[0262] Jurkat, Clone E6-1, was obtained from Professor Shaomeng Wang of the University of Michigan.

[0263] All of the above cells were Philadelphia negative T-cell lymphoblastic leukemia cells.

[0264] MOLT-4, PEER, and LOUCY cells were cultured in RPMI 1640 (#C11875500BT, GIBCO) medium supplemented with 1% penicillin / streptomycin (P / S) (#15140-122, GIBCO) and 10% fetal bovine serum (FBS) (#1943609-65-1, Sigma-Aldrich).

[0265] Jurkat, Clone E6-1 cells were cultured in RPMI 1640 medium (#C11875500BT, GIBCO) supplemented with 4.5 g / L D-glucose (#G8769, Sigma-Aldrich), 10 mM HEPES (#B110JV, BasaMedia), 1.0 mM sodium pyruvate (#B410JV, BasaMedia), 1% penicillin / streptomycin (P / S) (#15140-122, GIBCO), and 10% fetal bovine serum (FBS) (#1943609-65-1, Sigma-Aldrich).

[0266] All cells were cultured at 37°C in a 5% CO2 incubator.

[0267] 2. Test substance

[0268] Compound A was provided by Jiangsu Ascentage Pharmaceutical Development Co., Ltd. (Taizhou, China). The remaining test compounds, imatinib, dasatinib, bosutinib, nilotinib, flumatinib, radotinib, ponatinib / panatinib, and ABL001, were purchased from Jiangsu Aikon Biopharmaceutical R&D Co., Ltd. (Nanjing, China). Compound B can be prepared, for example, according to the method described in WO2018 / 027097A1. The above compounds were dissolved in dimethyl sulfoxide (DMSO) (#D8418, Sigma-Aldrich) to a concentration of 10 mM as stock solutions. For testing, the stock solutions were then diluted to the specified concentration with the appropriate serum-free medium.

[0269] 3. Instruments

[0270] Biosafety cabinet (model: AC2-6S8-CN, ESCO); CO2 incubator (model: CLM-170B-8-CF, ESCO); inverted microscope (model: CKX53, Olympus); balance (model: XSR205DU, Mettler Toledo); low-speed centrifuge (model: L500, Hunan Xiangyi Centrifuge Instrument Co., Ltd.); refrigerated centrifuge (model: 5424R, Eppendorf); multi-functional microplate reader (model: SpectraMax plus 384, Max 190, Molecular). Devices, LLC., US); 10μl, 20μl, 100μl, 200μl, 1000μl single-channel pipettes (Eppendorf); multi-channel pipettes (Eppendorf); electric pipettes (model: INTEGRΛPIPETBOY, IBS); constant temperature water bath (model: DK-8AX, Shanghai Yiheng Scientific Instruments Co., Ltd.); dry thermostat (model: MK-10, Hangzhou Aosheng Instruments Co., Ltd.); vortex mixer (model: Kylin-Bell 5, Haimen Qilin Bell Instrument Manufacturing Co., Ltd.); transfer decolorization shaker (model: TS-8, Haimen Qilin Bell Instrument Manufacturing Co., Ltd.); sterilizer (model: LDZM-60KCS, Shanghai Shenan Medical Devices Co., Ltd.); electrophoresis apparatus (model: PowerPac HC, Bio-Rad Life Sciences (Shanghai) Co., Ltd.); iBlot TMGel transfer device (model: IB21001, ThermoFisher Scientific): Chemiluminescence imaging system (model: c300, Azure).

[0271] Example 1: In vitro cell anti-proliferation experiment

[0272] Antiproliferative activity was assessed using the CCK-8 (Cell Counting Kit-8) assay based on water-soluble tetrazolium (WST). Nine serial concentrations of the test substance were added to 96-well plates, and cells were incubated for 72 hours after seeding. Each test concentration was performed in triplicate. A dilution control and a blank control were included on the same plate. The plates were incubated at 37°C in a CO2 incubator. At the end of the culture, CCK-8 stock solution (#AC11L057, Shanghai Liji Pharmaceutical Technology Co., Ltd.) was added directly. The plates were then incubated at 37°C in a CO2 incubator for 2–4 hours. Optical density (OD) values ​​were measured using a microplate reader at A450nm. Cell viability % was calculated as: (OD test wells - OD blank control wells) / (OD dilution control wells - OD blank control wells) × 100. The IC50 was calculated using nonlinear regression analysis with GraphPad Prism 9.2.0 software (GraphPad Software Inc., San Diego, CA). 50 (μM).

[0273] Results: Multiple batches of each cell type were tested, and data were recorded (these data were plotted as cell viability relative to concentration, resulting in graphs as shown in Figures 1-5, where Figures 1 and 2 show the results of two batches of MOLT-4 cells, and Figures 3-5 show the results of three batches of Jurkat, Clone E6-1 cells). The average antiproliferative activity was then calculated based on the recorded data, and the results are shown in Table 1 below.

[0274] Table 1

[0275] Discussion: As can be seen from the measurement data listed in Table 1 above, compound A has a much lower antiproliferative activity IC50 compared to other known BCR-ABL inhibitors in the prior art, such as imatinib, dasatinib, besutinib, nilotinib, flumatinib, ladotinib, ponatinib / panatinib, and ABL001. 50 The values ​​indicate that compound A has a much higher in vitro inhibitory activity against T-ALL tumor cells than theirs.

[0276] Example 2: Western blotting experiment

[0277] Cells were collected 24 hours after treatment with the test substance and washed once with pre-cooled 1×PBS (#U10017B, Suzhou Keyoubo Biotechnology Co., Ltd.). Cell pellets were lysed using RIPA (Radio Immunoprecipitation Assay) lysis buffer (#P0013, Beyotime) containing 1% benzyl sulfonyl fluoride (PMSF) (#ST506, Beyotime Biotechnology Research Institute, hereinafter referred to as Beyotime), 1% phosphatase inhibitors (#20109-A, #20109-B, Shanghai Yisheng Biotechnology Co., Ltd., hereinafter referred to as Shanghai Yisheng)), and 1% protease inhibitors (#20104ES08, Shanghai Yisheng). Protein concentration was determined using a Bicinchoninic Acid Assay (BCA) protein assay kit (#P0010, Beyotime). Cell lysates (20-50 μg) were separated using 4-20% precast gel electrophoresis (ExpressPlus™ PAGE, #M42015C, Genscript Biotech Inc.). iBlot was used. TMThe gel transfer apparatus transferred the separated proteins to an NC (Nitrocellulose membrane) (#IB23001, Thermo). The NC membrane was blocked at room temperature for 30 minutes to 1 hour with 1-3% bovine serum albumin (BSA) buffer (#FA016, GEN-VIEW SCIENTIFIC INC). The primary antibody (P-LCK(Tyr505), #2751, Cell Signaling) diluted with 1×TBST (Triethanolamine buffered saline, TBS, #B548105, Sangon Biotech (Shanghai) Co., Ltd.; Tween-20, #ST825, Beyotime) containing 1-3% BSA was then used. Technology, Inc. (hereinafter referred to as CST); P-LCK (Y394), #MAB7500, R&D; LCK, #2984, CST; P-CD3ζ (Tyr142), #67748, CST; CD3ζ, #88083, CSTS; P-ZAP70 (Tyr493) / Syk (Tyr526), ​​#2704, CST; ZAP70, #2705, CST; P-LAT (Tyr191), #CSB-PA008847, Wuhan Huamei Biotechnology Co., Ltd.; P-LAT (Tyr171), #3581, CST; LAT, #45533, CST; P-PI3K p85 / p55 (Tyr458, Tyr199), #ab278545, Abcam; PI3K, #4292, CST; β-ACTIN, #4970, CST). Incubate overnight on a shaker at 4°C. Wash the NC membrane three times with 1×TBST. Incubate the membrane at room temperature for 1 hour with horseradish peroxidase-labeled secondary antibody (Goat Anti Rabbit, #GAR0072, Hangzhou Lianke Biotechnology Co., Ltd.). Wash the NC membrane three times with 1×TBST. Signal generation and detection are performed using an electrochemiluminescence (ECL) ultrasensitive colorimetric kit (#36208ES76, Shanghai Yisheng) and a chemiluminescence imaging system (Azure).

[0278] Results: The detection results are shown in Figures 6 and 7; Figure 6 shows the results for MOLT-4 cells, and Figure 7 shows the results for Jurkat, Clone E6-1 cells.

[0279] Discussion: The results showed that in T-ALL cells, compound A exhibited significantly superior activity compared to other TKIs (ICP-12). 50(The difference is at least 10-fold, i.e., at least one order of magnitude). Mechanistic studies showed that compound A potently and / or dose-dependently inhibited the activation of LCK and the phosphorylation activation of its downstream proteins CD3ζ, ZAP70, LAT, and PI3K. These results indicate that compound A can kill T-ALL tumor cells by inhibiting the LCK pathway.

[0280] Example 3: In vitro anti-cell proliferation assay (CTG detection)

[0281] Experimental methods:

[0282] Cells were cultured in their respective media (37°C, 5% CO2 incubator). Once they reached the exponential growth phase, cells were harvested and seeded into 96-well plates. Eight serially diluted test concentrations of the drug were then added, with three replicates for each concentration. A cell control without drug treatment and a cell-free blank control were also included on the same plate. After incubation for 72 hours, the prepared CellTiter-Glo assay solution (Promega, Madison, WI) was added directly, followed by incubation at room temperature on a shaker for 10 minutes. The luminescence value was then measured using a microplate reader. Cell viability % was calculated as: (Cell Titer-Glo luminescence value of test wells - Cell Titer-Glo luminescence value of blank control wells) / (Cell Titer-Glo luminescence value of cell control wells - Cell Titer-Glo luminescence value of blank control wells) × 100. The IC50 was calculated using nonlinear regression analysis with GraphPad Prism 9.2.0 software (GraphPad Software Inc., San Diego, CA). 50 The synergistic parameters (CI values) of the drugs were calculated using Calcusyn v2.11 software.

[0283] Experimental results:

[0284] The experiment was repeated for each cell type, and the results are shown in Figures 8 and 9. Compounds A and B each showed some inhibitory effect on cell growth, and the two drugs had a synergistic effect on each cell type when acted on simultaneously.

[0285] As shown in Figures 10, 11, 26, and 27: Further experiments revealed that compound C inhibited cell growth, and that compounds A or B had a synergistic effect with compound C. The combined effect of all three compounds was the strongest, exhibiting a strong synergistic effect.

[0286] Example 4: Apoptosis detection (flow cytometry)

[0287] Experimental methods:

[0288] After 20 hours of treatment with the test substance, cells were collected and washed once with pre-chilled 1×PBS (#U10017B, Koyobo Biotechnology Co., Ltd.). Following the instructions of the FITC Annexin V Apoptosis Detection Kit I (#556547, BD Pharmingen), cells were resuspended in 100 μL of 1× binding buffer, 5 μL of Annexin V-FITC was added, mixed, and 2 μL of Propidium Iodide (PI) was added. The mixture was incubated at room temperature in the dark for 20 minutes, then 400 μL of 1×PBS was added and mixed. The cells were then placed on ice. Flow cytometry (Attune NxT, Thermo) was used to record the fluorescence signals of Annexin V and PI to detect apoptosis. The apoptosis index or percentage was calculated by analyzing the number of cells in each of the four quadrants: (number of early apoptotic cells + number of late apoptotic cells) / total cell number. The data was processed using Flow Jo analysis software (version: Flow Jo 10.4.2, Treestar).

[0289] Experimental results:

[0290] The results are shown in Figures 12 and 13: Compound A alone at a concentration of 0.1 μM had virtually no effect on apoptosis, while Compound B at concentrations of 3 μM or 6 μM induced apoptosis to some extent. When both drugs were used simultaneously, they strongly induced apoptosis, significantly more so than when used alone.

[0291] As shown in Figures 14, 15, 28, and 29: Further experiments demonstrated that compound C, alone, induces apoptosis to a certain extent. Combinations of any two compounds (A and B, A and C, or B and C) strongly induce apoptosis, with effects significantly greater than those of a single drug. The simultaneous action of all three drugs produces the strongest apoptosis-inducing effect, significantly greater than any combination of any two drugs.

[0292] Example 5: Western blotting assay

[0293] Experimental methods:

[0294] Cells were collected 1 hour or 16 hours after treatment with the test substance and washed once with pre-cooled 1×PBS (#U10017B, Suzhou Koyobo Biotechnology Co., Ltd.). Cell pellets were lysed using RIPA (Radio Immunoprecipitation Assay) lysis buffer (#P0013, Beyotime) containing 1% benzyl sulfonyl fluoride (PMSF) (#ST506, Beyotime Biotechnology Research Institute, hereinafter referred to as Beyotime), 1% phosphatase inhibitor (#20109-A, #20109-B, Shanghai Yisheng Biotechnology Co., Ltd., hereinafter referred to as Shanghai Yisheng)), and 1% protease inhibitor (#20104ES08, Shanghai Yisheng). Protein concentration was determined using a Bicinchoninic Acid Assay (BCA) protein assay kit (#P0010, Beyotime). Cell lysates (20-50 μg) were separated using 4-20% precast gel electrophoresis (ExpressPlus™ PAGE, #M42015C, Genscript Biotech Inc.). iBlot was used. TMThe gel transfer device transfers the separated proteins to an NC (Nitrocellulose membrane) (#IB23001, Thermo). After blocking the NC membrane with 1-3% bovine serum albumin (BSA) (#FA016, GEN-VIEW SCIENTIFIC INC) buffer at room temperature for 30 minutes to 1 hour, the primary antibody (P-LCK(Tyr505), #2751, Cell Signaling Technology, Inc. (hereinafter referred to as CST); P-LCK(Tyr394), #70926, CST; P-SRC(Y416), #6943, CST; LCK, #2984, CST; PARP, #9532, CST; CASPASE-3, #14220, CST; CLEAVED) diluted with 1×TBST (triethanolamine buffered saline, TBS, #B548105, Sangon Biotech (Shanghai) Co., Ltd.; Tween-20, #ST825, Beyotime) containing 1-3% BSA was diluted with 1×TBST (triethanolamine buffered saline, TBS, #B548105, Sangon Biotech (Shanghai) Co., Ltd.; Tween-20, #ST825, Beyotime) solution containing 1-3% BSA) to CLEAVED solution. CASPASE-3, #9664, CST; BCL-2, #15071, CST; BCL-XL, #2764, CST; MCL-1, #94296, CST; GAPDH, #2118, CST; P-AKT(S473), #4060, CST; AKT, #4685, CST; NF-KB P65, #8242, CST; P-GSK3B(S9), #5558, CST; GSK3B, #12456, CST; C-MYC, #5605, CST). Incubate overnight on a shaker at 4°C. Wash the NC membrane three times with 1×TBST. Incubate the membrane at room temperature for 1 hour with horseradish peroxidase-labeled secondary antibody (Goat Anti Rabbit, #GAR0072, Hangzhou Lianke Biotechnology Co., Ltd.). Wash the NC membrane three times with 1×TBST. Signal generation and detection were performed using an electrochemiluminescence (ECL) ultrasensitive colorimetric kit (#36208ES76, Shanghai Yisheng) and a chemiluminescence imaging system (Azure).

[0295] Experimental results:

[0296] As shown in Figures 16, 17, 30, and 31, the simultaneous action of the two drugs induces the cleavage and activation of apoptosis-related proteins PARP and CASPASE-3, and downregulates the anti-apoptotic proteins BCL-XL and MCL-1. From a signaling pathway perspective, as shown in Figures 20, 21, 32, and 33, the simultaneous action of the two drugs inhibits the phosphorylation of LCK kinase, thereby inhibiting downstream NF-κB; additionally, the simultaneous action of the drugs inhibits the phosphorylation of AKT, thereby inhibiting the phosphorylation of GSK3B, leading to the degradation of C-MYC.

[0297] As shown in Figures 18, 19, 22, 23, 30, 31, 32, and 33: Further experiments showed that the three drugs produced the strongest combined effect when acting simultaneously on the aforementioned apoptosis-related proteins and signaling pathway-related proteins.

[0298] Example 6: In vivo drug efficacy in a mouse subcutaneous tumor model

[0299] Experimental method: MOLT-4 cells were subcutaneously injected into CB17-SCID mice. After the tumors grew to 150 mm, 3 When the tumor size was approximately equal to that of other tumors, the animals were randomly assigned to six groups of eight each, based on tumor volume and body weight. The groups were: solvent control group, compound A 10 mg / kg group, compound A 20 mg / kg group, compound B 100 mg / kg group, compound A 10 mg / kg combined with compound B 100 mg / kg group, and compound A 20 mg / kg combined with compound B 100 mg / kg group. Drug administration began on the day of randomization, with all drugs administered orally (PO) for 21 consecutive days. Compound A was administered every other day (QOD), and compound B was administered once daily (QD).

[0300] Experimental results:

[0301] As shown in Figure 24, when mice were treated with compound A or compound B alone, there was no significant change in the size of the tumors. However, when compound A at 10 mg / kg was combined with compound B at 100 mg / kg, the tumors in mice shrank significantly, indicating a synergistic effect between the two drugs (Table 2).

[0302] In addition, as shown in Figure 25, the monitoring results of weight change in mice showed that the group containing compound A at 20 mg / kg experienced a certain degree of weight loss, but the animals showed no other abnormalities.

[0303] Table 2. Synergistic effect of compound A combined with compound B in inhibiting tumor growth in mice

Claims

1. The following substances or combinations thereof are intended for use in the preparation of medicaments for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases: compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof; or a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof; or a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof; or a combination of compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof; or a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, wherein compounds A, B, C, and D have the following structures:

2. The use according to claim 1, wherein, Diseases associated with selective inhibition of LCK kinases include T-cell-mediated diseases, preferably cancer, autoimmune diseases, inflammatory diseases, and organ transplant rejection, more preferably cardiac allogeneic transplant rejection, lymphoma, blastoma, medulloblastoma, retinoblastoma, sarcoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumors, carcinoid tumors, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, melanoma, glioblastoma, adenocarcinoma, squamous cell carcinoma, epithelial squamous cell carcinoma, skin cancer, brain cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, squamous cell lung cancer, peritoneal cancer, hepatocellular carcinoma, gastric cancer, intestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, and bladder cancer. Liver cancer, breast cancer, metastatic breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, anal cancer, penile cancer, Merkel cell carcinoma, esophageal cancer, bone cancer, biliary tract tumors, central nervous system tumors, head and neck cancers, and hematologic malignancies, especially T-lymphoblastic leukemia such as acute T-lymphoblastic leukemia and chronic T-lymphoblastic leukemia, B-lymphoblastic leukemia such as acute B-lymphoblastic leukemia and chronic B-lymphoblastic leukemia, plasma cell tumors, multiple myeloma, macroglobulinemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, essential thrombocytosis, polycythemia vera; multiple sclerosis, myasthenia gravis, etc. Graves' disease, chronic lymphocytic thyroiditis, Addison's disease, vitiligo, scleroderma, nephritis-pulmonary hemorrhage syndrome, Becet's disease, segmental ileitis, ankylosing spondylitis, uveitis, thrombocytopenic purpura, pemphigus vulgaris, diabetes, autoimmune anemia, cryoglobulinemia, adrenoleukodystrophy (ALD), and systemic lupus erythematosus (SLE); rheumatoid arthritis, osteoarthritis, asthma, allergic dermatitis, atopic dermatitis, multiple sclerosis, psoriasis, human endothelial cell disease, eczematous dermatitis, psoriatic arthritis, traumatic arthritis, urticaria arthritis, gouty arthritis, inflammatory bowel disease, and osteoporosis; Philadelphia negative T-cell lymphoblastic leukemia.

3. The use according to claim 1, wherein, The compound A or its pharmaceutically acceptable salt, ester, solvate, hydrate, or combination thereof inhibits LCK kinase by inhibiting the phosphorylation of Tyr394. Preferably, the inhibition of LCK kinase by the compound A or its pharmaceutically acceptable salt, ester, solvate, hydrate, or combination thereof is performed in vitro or in vivo.

4. The use according to any one of claims 1-3, wherein, The inhibition of LCK kinase by compound A or its pharmaceutically acceptable salt, ester, solvate, hydrate, or combination thereof was performed in patients with T-cell lymphoblastic leukemia.

5. A method for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases, comprising administering to a patient in need of prevention and / or treatment an effective amount of the following substance or combination of substances: compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof; or a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof; or a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof; or a combination of compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof; or a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound C or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, wherein compound A, compound B, compound C, and compound D have the following structures: Preferably, a preventive and / or therapeutically effective amount of compound A or its pharmaceutically acceptable salt, ester, solvate, hydrate, or combination thereof is administered orally to a patient in need; More preferably, compound A or its pharmaceutically acceptable salts, esters, solvates, hydrates or combinations thereof may be administered twice daily, once daily, or every other day in amounts of about 1 mg, about 2 mg, about 4 mg, about 5 mg, about 8 mg, about 10 mg, about 12.5 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg.

6. Compound A or a pharmaceutically acceptable salt, ester, solvate, hydrate, or combination thereof: a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, hydrate, and compound B or a pharmaceutically acceptable salt, ester, solvate, hydrate; or a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, hydrate, and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, hydrate; or a combination of compound B or a pharmaceutically acceptable salt, ester, solvate, hydrate, and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, hydrate; or a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, hydrate, and compound B or a pharmaceutically acceptable salt, ester, solvate, hydrate, and compound C or a pharmaceutically acceptable salt, ester, solvate, hydrate, or compound D, for the prevention and / or treatment of diseases associated with selective inhibition of LCK kinases, wherein compound A, compound B, compound C, and compound D have the following structures:

7. Compound A according to claim 6, or a pharmaceutically acceptable salt, ester, solvate, hydrate, or combination thereof, wherein, Diseases associated with selective inhibition of LCK kinases include T-cell-mediated diseases, preferably cancer, autoimmune diseases, inflammatory diseases, and organ transplant rejection, more preferably cardiac allogeneic transplant rejection, lymphoma, blastoma, medulloblastoma, retinoblastoma, sarcoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumors, carcinoid tumors, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, melanoma, glioblastoma, adenocarcinoma, squamous cell carcinoma, epithelial squamous cell carcinoma, skin cancer, brain cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, squamous cell lung cancer, peritoneal cancer, hepatocellular carcinoma, gastric cancer, intestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, and bladder cancer. Liver cancer, breast cancer, metastatic breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, anal cancer, penile cancer, Merkel cell carcinoma, esophageal cancer, bone cancer, biliary tract tumors, central nervous system tumors, head and neck cancers, and hematologic malignancies, especially T-lymphoblastic leukemia such as acute T-lymphoblastic leukemia and chronic T-lymphoblastic leukemia, B-lymphoblastic leukemia such as acute B-lymphoblastic leukemia and chronic B-lymphoblastic leukemia, plasma cell tumors, multiple myeloma, macroglobulinemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, essential thrombocytosis, polycythemia vera; multiple sclerosis, myasthenia gravis, etc. Graves' disease, chronic lymphocytic thyroiditis, Addison's disease, vitiligo, scleroderma, nephritis-pulmonary hemorrhage syndrome, Becet's disease, segmental ileitis, ankylosing spondylitis, uveitis, thrombocytopenic purpura, pemphigus vulgaris, diabetes, autoimmune anemia, cryoglobulinemia, adrenoleukodystrophy (ALD), and systemic lupus erythematosus (SLE); rheumatoid arthritis, osteoarthritis, asthma, allergic dermatitis, atopic dermatitis, multiple sclerosis, psoriasis, human endothelial cell disease, eczematous dermatitis, psoriatic arthritis, traumatic arthritis, urticaria arthritis, gouty arthritis, inflammatory bowel disease, and osteoporosis; Philadelphia negative T-cell lymphoblastic leukemia.

8. Compound A according to claim 6 or 7, or a pharmaceutically acceptable salt, ester, solvate, hydrate, or combination thereof, wherein, Compound A or a pharmaceutically acceptable salt, ester, solvate, hydrate, or combination thereof inhibits LCK kinase by inhibiting the phosphorylation of Tyr394, preferably the inhibition is performed in vitro or in vivo, more preferably the inhibition is performed in a patient with T-cell lymphoblastic leukemia.

9. A pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, or a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, or a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, or a combination of compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, or a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof with compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier, wherein compound A, compound B, compound C, and compound D have the following structures:

10. A medicine box comprising: (i) a pharmaceutically acceptable salt, ester, solvate, hydrate, and a pharmaceutically acceptable carrier thereof, or a combination of a pharmaceutically acceptable salt, ester, solvate, hydrate, and compound B thereof, or a combination of a pharmaceutically acceptable salt, ester, solvate, hydrate, and compound C / compound D thereof, or a combination of a pharmaceutically acceptable salt, ester, solvate, hydrate, and compound B thereof, or a combination of a pharmaceutically acceptable salt, ester, solvate, hydrate, and compound C / compound D thereof, or a combination of a pharmaceutically acceptable salt, ester, solvate, hydrate, and compound A thereof, or a combination of a pharmaceutically acceptable salt, ester, solvate, hydrate, and compound B thereof, or a combination of a pharmaceutically acceptable salt, ester, solvate, hydrate, and compound C thereof; and (ii) an optional instruction manual; wherein compound A, compound B, compound C, and compound D have the following structures:

11. A method for inhibiting Tyr394 phosphorylation of LCK kinase, comprising contacting LCK kinase with compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, or with a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, or with a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, or with a combination of compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound C / compound D or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, or with a combination of compound A or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound B or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof and compound C or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof, wherein compounds A, B, C, and D have the following structures:

Images