N-(phenylsulfonyl) benzamides and related compounds as BCL-2 inhibitors

Abstract

The invention relates to N-(phenylsulfonyl) benzamides and related compounds as BCL-2 inhibitors. Described herein are methods of treating a hematological malignancy in a patient in need thereof, comprising administering a Bcl-2 inhibitor to the patient in a stepwise dosing regimen.

Description

[0001] This application is a divisional application of an invention patent application with an application date of December 3, 2020, application number 202011411048.3, and invention name “N-(phenylsulfonyl)benzamide and related compounds as BCL-2 inhibitors”. Background Art

[0002] Apoptosis is a process of programmed cell death and an important biological process for tissue homeostasis. In mammals, it has been shown to regulate early embryonic development. Later in life, cell death is a default mechanism by which potentially dangerous cells, such as those carrying cancerous defects, are eliminated. Several apoptotic pathways are known. One of the most important apoptotic pathways involves the Bcl-2 family of proteins, which are key regulators of the mitochondrial (also called "intrinsic or intrinsic") pathway of apoptosis. The homeodomains BH1, BH2, BH3, and BH4 are characteristic of the Bcl-2 protein family. The Bcl-2 protein family can be further divided into three subfamilies, depending on how many homeodomains each protein contains and its biological activity, that is, whether it has pro-apoptotic or anti-apoptotic functions.

[0003] Down-regulated apoptosis, more specifically the Bcl-2 family of proteins, may be associated with the development of cancerous malignancies. The anti-apoptotic proteins Bcl-2 and Bcl-xL are overexpressed in many cancer cell types. As a result of this dysregulation, diseased cells survive that would otherwise undergo apoptosis under normal conditions. The repetition of these defects associated with uncontrolled proliferation is considered the starting point for carcinogenesis. In addition, BH3-only proteins can act as tumor suppressors when expressed in diseased animals.

[0004] The natural expression level of anti-apoptotic Bcl-2 protein family members is different in different cell types. For example, in newly born platelets, Bcl-xL protein is highly expressed and plays an important role in regulating cell death (lifespan) of platelets. Moreover, in specific cancer cell types, the survival of cancer cells is attributed to the disorder of apoptotic pathways caused by overexpression of one or more anti-apoptotic Bcl-2 protein family members. In view of the important role of the Bcl-2 protein family in regulating apoptosis of cancer cells and normal cells (i.e., non-cancerous cells), and the recognized variability of cell-to-cell type of expression of the Bcl-2 protein family, for small molecule inhibitors with selective targeting and preferably binding to an anti-apoptotic Bcl-2 protein or its subtype, for example, binding to anti-apoptotic Bcl-2 family members overexpressed in specific cancer types. Such selective compounds can also confer certain advantages in the clinic, by providing, for example, flexibility in selecting dosing regimens, reduced on-target toxicity in normal cells, etc., especially in Bcl-2-deficient mice. Lymphocytopenia is observed.

[0005] There is a growing need for compounds that selectively inhibit one Bcl-2 protein or its isoforms for the treatment of hyperproliferative diseases such as cancer, including hematological malignancies. Summary of the invention

[0006] The present invention provides, for example, methods of treating a hematological malignancy in a patient in need thereof, comprising administering to the patient a Bcl-2 inhibitor in a step-wise dosing regimen.

[0007] For example, described herein, in part, is a method for treating a hematological malignancy in a patient in need thereof, the method comprising: administering the compound N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide or a pharmaceutically acceptable salt thereof in a daily step-wise dosing regimen; wherein the administration of the daily step-wise dosing regimen comprises: administering a first dose of 20 mg of the compound to the patient for one day; administering a second dose of 50 mg of the compound to the patient the day after the first dose for one day; and administering a third dose of 100 mg of the compound to the patient the day after the second dose for one day.

[0008] In another embodiment, described herein is a method of treating a hematological malignancy in a patient in need thereof, the method comprising: administering the compound N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide or a pharmaceutically acceptable salt thereof on a daily step-wise dosing schedule; wherein administering the daily step-wise dosing schedule comprises administering to the patient a first dose of 20 mg to 100 mg of the compound for one day; and administering to the patient a second dose of 50 mg to 200 mg of the compound on the second day after the first dose for one day.

[0009] In another embodiment, described herein is a method of treating a hematological malignancy in a patient in need thereof, wherein the patient is also administered a CYP2C8 inhibitor, another CYP inhibitor (e.g., a CYP3A4 inhibitor), or a specific food, such as grapefruit juice, comprising administering an effective amount of the compound N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt to the patient, wherein the patient takes about 60% or less, about 50% or less, about 40% or less, or about 20% or less of the effective amount for a patient not administered the CYP2C8 inhibitor.

[0010] This application also involves the following projects:

[0011] 1. A method for treating a hematological malignancy in a patient in need thereof, comprising:

[0012] administering the compound N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide or a pharmaceutically acceptable salt thereof in a daily stepwise dosing regimen;

[0013] The daily stepwise dosing regimen includes: administering a first dose of 20 mg of the compound to the patient for one day; administering a second dose of 50 mg of the compound to the patient on the second day after the first dose, for one day; administering a third dose of 100 mg of the compound to the patient on the second day after the second dose, for one day.

[0014] 2. The method according to item 1 further comprises administering a fourth dose of 200 mg of the compound to the patient daily for 1-5 days or longer.

[0015] 3. The method according to claim 2, characterized in that the fourth dose is administered to the patient for one day.

[0016] 4. The method according to item 2 or 3, characterized in that the daily stepwise dosing regimen also includes administering a fifth dose of 400 mg to the patient after administering the fourth dose.

[0017] 5. The method according to any one of items 1-4, characterized in that it also includes administering to the patient a dose of 400 mg to 800 mg of the compound per day after the third or fourth dose.

[0018] 6. The method according to any one of items 1-5, characterized in that it also includes administering to the patient a daily dose of 400 mg, 600 mg, 800 mg or 1000 mg of the compound 1 week or more, or 1 month or more after the daily step-wise dosing regimen.

[0019] 7. The method according to any one of items 1-6, characterized in that it also includes administering to the patient a daily dose of 400 mg, 600 mg, or 800 mg of the compound 1 week or more, or 1 month or more after the daily step-wise dosing regimen.

[0020] 8. A method for treating a hematological malignancy in a patient in need thereof, comprising:

[0021] administering the compound N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide or a pharmaceutically acceptable salt thereof in a daily stepwise dosing regimen;

[0022] Characterized in that the implementation of the daily stepwise dosing regimen comprises: administering a first dose of 20 mg to 100 mg of the compound to the patient on the first day; and administering a second dose of 50 mg to 200 mg of the compound to the patient on the second day after the first dose.

[0023] 9. The method according to item 8, characterized in that the daily stepwise dosing regimen further comprises administering to the patient a third dose of 100 to 400 mg of the compound on the second day after the second dose.

[0024] 10. The method according to item 9, characterized in that the daily stepwise dosing regimen further comprises administering to the patient a fourth dose of 200 mg to 800 mg of the compound one to seven days after the third dose.

[0025] 11. The method of any one of items 8-10, further comprising administering to the patient about 400 mg to 1000 mg of the compound daily for 1 week or longer following the daily stepwise dosing regimen.

[0026] 12. The method of any one of items 8-11, further comprising administering to the patient about 400 mg to 800 mg of the compound per day for 1 week or longer following the daily stepwise dosing regimen.

[0027] 13. The method of any one of items 1-12, characterized in that the patient has a reduced risk of developing tumor lysis syndrome during or after administration of the daily stepwise dosing regimen.

[0028] 14. The method of any one of items 1-13, characterized in that the patient has a susceptibility risk of developing tumor lysis syndrome before or during administration of the compound.

[0029] 15. The method according to any one of items 1 to 14, characterized in that the hematological malignancy is selected from chronic lymphocytic leukemia, acute myeloid leukemia, multiple myeloma, lymphoplasmacytic lymphoma, non-Hodgkin's lymphoma, small lymphocytic leukemia and primary light-chain amyloidosis.

[0030] 16. The method according to any one of items 1 to 15, characterized in that the hematological malignancy is selected from chronic lymphocytic leukemia, acute myeloid leukemia, multiple myeloma, lymphoplasmacytic lymphoma and non-Hodgkin's lymphoma.

[0031] 17. The method of any one of items 1 to 15, characterized in that the hematological malignancy is selected from chronic lymphocytic leukemia and small lymphocytic leukemia.

[0032] 18. The method according to any one of items 1 to 14, characterized in that the hematological malignancy is Waldenstrom's macroglobulinemia.

[0033] 19. The method according to any one of items 1 to 18, characterized in that the patient suffers from primary refractory acute myeloid leukemia.

[0034] 20. The method according to any one of items 1-19, characterized in that the patient suffers from refractory small lymphocytic leukemia or refractory chronic lymphocytic leukemia.

[0035] 21. The method according to any one of items 1 to 20, characterized in that the patient has relapsed after receiving previous therapy for a hematological malignancy.

[0036] 22. The method according to item 21, characterized in that the previous therapy for hematological malignancies is therapy for small lymphocytic leukemia.

[0037] 23. The method of claim 21, wherein the previous therapy for hematological malignancy is therapy for chronic lymphocytic leukemia.

[0038] 24. The method according to item 21, characterized in that the previous therapy for hematological malignancies is therapy for acute myeloid leukemia.

[0039] 25. A method according to any one of items 1 to 24, wherein the patient has received at least one prior treatment for a hematological malignancy.

[0040] 26. The method according to any one of items 1 to 25, characterized in that it further comprises administering rituximab to the patient before, during or after the daily stepwise dosing regimen.

[0041] 27. The method of any one of items 1-26, further comprising administering rituximab to the patient following a daily stepwise dosing regimen.

[0042] 28. The method according to item 26 or 27, characterized in that rituximab is administered to the patient for about 1 week or more following a daily stepwise dosing regimen.

[0043] 29. The method of any one of items 1-28, further comprising administering azacitidine, decitabine or low-dose cytarabine to the patient before, during or after the daily stepwise dosing regimen.

[0044] 30. Any of the methods of items 1-29, characterized in that it also includes administering ibrutinib, topotecan, an MDM2 inhibitor, a CD20 inhibitor, a CDK9i inhibitor or a homoharringtonine (HTT) inhibitor to the patient before, during or after the daily step-dosing regimen.

[0045] 31. The method according to any one of items 1 to 30, further comprising administering ibrutinib, topotecan, an MDM2 inhibitor, a CD20 inhibitor, a CDK9i inhibitor or a homoharringtonine (HTT) inhibitor to the patient after the daily stepwise dosing regimen.

[0046] 32. The method according to any one of items 1-31, further comprising administering a BTK inhibitor to the patient before, during or after the daily stepwise dosing regimen.

[0047] 33. The method of any one of items 1-32, further comprising administering a BTK inhibitor to the patient following a daily stepwise dosing regimen.

[0048] 34. The method according to item 32 or 33, characterized in that the BTK inhibitor is administered to the patient for about 1 week or more following a daily stepwise dosing regimen.

[0049] 35. The method according to any one of items 32-34, characterized in that the BTK inhibitor is ibrutinib.

[0050] 36. The method of any one of items 1-35, further comprising administering azacitidine to the patient before, during, or after the daily stepwise dosing regimen.

[0051] 37. The method according to any one of items 1-36, characterized in that it further comprises administering cytarabine to the patient following a daily stepwise dosing regimen.

[0052] 38. The method of any one of items 1-37, further comprising administering homoharringtonine to the patient before, during, or after the daily stepwise dosing regimen.

[0053] 39. The method of any one of items 1-38, further comprising administering homoharringtonine to the patient following the daily stepwise dosing regimen.

[0054] 40. The method according to any one of items 8 to 39, characterized in that the daily stepwise dosing regimen comprises administering to the patient a first dose of 100 mg of the compound for one day.

[0055] 41. The method of any one of items 1-40, characterized in that the compound is (R)-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide.

[0056] 42. The method of any one of items 1-40, characterized in that the compound is (S)-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide.

[0057] 43. A method for treating multiple myeloma and / or primary light chain amyloidosis in a patient in need thereof, comprising: administering to the patient 200 mg or more of the compound N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide.

[0058] 44. The method of claim 43, further comprising administering pomalidomide and dexamethasone to the patient.

[0059] 45. The method according to item 43 or item 44, characterized in that it comprises further administering lenalidomide and dexamethasone to the patient.

[0060] 46. ​​The method according to any one of items 43-45, characterized in that it further comprises administering daratumumab, lenalidomide and dexamethasone to the patient.

[0061] 47. The method according to any one of items 43-46, characterized in that it comprises administering 200 mg, 400 mg, 600 mg or 800 mg of the compound to the patient.

[0062] 48. The method according to any one of items 43-47, characterized in that the patient suffers from refractory multiple myeloma.

[0063] 49. The method according to any one of items 43-48, wherein the patient has relapsed after receiving previous treatment for multiple myeloma.

[0064] 50. The method of any one of items 43-49, characterized in that the compound is (R)-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide.

[0065] 51. The method of any one of items 43-49, characterized in that the compound is (S)-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide. BRIEF DESCRIPTION OF THE DRAWINGS

[0066] Figure 1 Shown are exemplary plasma concentration-time profiles following single oral administration of 50 mg, 100 mg, 200 mg, and 400 mg of Compound 1 in human patients.

[0067] Figure 2 Shown are exemplary plasma concentration-time profiles following single oral administration of 50 mg, 100 mg, 200 mg, 300 mg and 400 mg of Compound Z in human patients.

[0068] Figure 3 Exemplary dosing regimen for a Phase Ib / II study showing the safety, tolerability, and efficacy of Compound 1 alone or in combination with other therapeutic agents in patients with Waldenstrom's macroglobulinemia.

[0069] Figure 4 Shown are exemplary dosing regimens for a Phase Ib / II study of Compound 1 as a single agent or in combination with other therapeutic agents in patients with relapsed and / or refractory chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL).

[0070] Figure 5 shows the study design of an exemplary Phase Ib / II study of Compound 1 as a single agent or in combination with ibrutinib or rituximab for patients with relapsed and / or refractory chronic lymphocytic leukemia (CLL) or relapsed and / or refractory small lymphocytic lymphoma (SLL). The study includes (a) a dose expansion study using Compound 1 as a single agent to evaluate the safety and antitumor activity and pharmacokinetic characteristics of Compound 1 monotherapy in patients with relapsed or refractory CLL / SLL (Figure 5a) and (b) a study of Compound 1 in combination with ibrutinib or rituximab to explore the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), Phase II recommended dose (RP2D) and safety of Compound 1 in the studied combination therapy regimen, as well as pharmacokinetic studies and efficacy evaluations (Figure 5b).

[0071] Figure 6 The study design of an exemplary Phase Ib / II clinical study showing the combination of Compound 1 with Pd or DRd for the treatment of patients with relapsed and / or refractory multiple myeloma (RRMM) is shown. The study comprises one treatment group for a dose escalation and dose expansion study of Compound 1 in combination with Pd, and another treatment group for a dose escalation and dose expansion study of Compound 1 in combination with DRd.

[0072] Figure 7The study design of an exemplary Phase Ib / II clinical study showing Compound 1 monotherapy or in combination with Rd for the treatment of patients with relapsed and / or refractory multiple myeloma. The study includes one treatment group for dose escalation and dose expansion studies of Compound 1 monotherapy; and another treatment group for dose escalation and dose expansion studies of Compound 1 in combination with Rd. DETAILED DESCRIPTION

[0073] As described herein, the compound N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide has the following structure:

[0074]

[0075] As described herein, "Compound 1" refers to (S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide, having the following structure:

[0076]

[0077] As described herein, the compound (R)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide has the following structure:

[0078]

[0079] "Compound Z" refers to a compound having the following structure:

[0080]

[0081] Compound Z is also known as Venetoclax.

[0082] Compounds useful in the methods described herein, such as N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide, (R)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide [2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide and (S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide. Based on the anti-proliferative, anti-tumor and apoptosis-inducing activities exhibited by Compound 1 in patients, it is expected to have better efficacy than other known Bcl-2 inhibitors such as Venetoclax (Compound Z). In addition, the pharmacokinetic properties of compound 1 are superior to those of compound Z, such as a shorter half-life and higher Cmax systemic exposure with a half-life and higher Cmax similar to that in tumor tissues. This preferred pharmacokinetic property can lead to lower toxicity without affecting the therapeutic efficacy of the compound.

[0083] The methods described herein can reduce the risk of tumor lysis syndrome (TLS) in patients during treatment of hematological malignancies. TLS is a common but dangerous side effect that patients experience while taking Bcl-2 inhibitors. In order to reduce the risk of TLS, a weekly increasing dose regimen should be used to reach the recommended therapeutic dose in patients given the Bcl-2 inhibitor Venetoclax. However, this weekly increasing dose regimen may result in low drug exposure and negatively affect the efficacy of Bcl-2 inhibitors. The methods described herein include a more therapeutically effective daily increasing dose regimen that allows shortening the time required to reach the standard therapeutic dose of the administered compound while reducing the risk of TLS.

[0084] How to use

[0085] In one embodiment, described herein is a method of treating a hematological malignancy in a patient in need thereof, comprising: administering the compound N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide or a pharmaceutically acceptable salt thereof in a daily stepwise dosing regimen; wherein the administration of the daily stepwise dosing regimen comprises: administering a first dose of 20 mg of the compound to the patient for one day; administering a second dose of 50 mg of the compound to the patient the day after the first dose for one day; administering a third dose of 100 mg of the compound to the patient the day after the second dose for one day. In some embodiments, the method further comprises administering a fourth dose of 200 mg of the compound to the patient daily for 1-5 days or more. In some embodiments, the fourth dose is administered to the patient for one day. In some embodiments, the daily step-wise dosing regimen further includes administering a fifth dose of 400 mg to the patient after administering the fourth dose. In some embodiments, the method further includes administering a 400 mg to 800 mg dose of the compound to the patient every day after the third or fourth dose. In some embodiments, the method further includes administering a daily dose of 400 mg, 600 mg or 800 mg of the compound to the patient after the daily step-wise dosing regimen for 1 week or more, 1 month or more. In some embodiments, the method further includes administering a daily dose of 400 mg, 600 mg, 800 mg or 1000 mg of the compound to the patient after the daily step-wise dosing regimen for 1 week or more, or 1 month or more. In some embodiments, the compound is (R)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide. In some embodiments, the compound is (S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide.

[0086] Also contemplated herein are methods of treating a hematological malignancy in a patient in need thereof, the method comprising: administering the compound N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide or a pharmaceutically acceptable salt thereof daily in a daily step-wise dosing regimen; wherein the daily step-wise dosing regimen comprises administering to the patient a first dose of 20 mg to 100 mg of the compound for one day. The second day after the first dose, administering to the patient a second dose of 50 mg to 200 mg of the compound for one day. In some embodiments, the daily step-wise dosing regimen comprises administering to the patient a first dose of 100 mg of the compound for one day. In some embodiments, the daily step-wise dosing regimen further comprises administering to the patient a third dose of 100 to 400 mg of the compound on the second day after the second dose. In some embodiments, the daily stepwise dosing regimen further includes administering to the patient a fourth dose of 200 mg to 800 mg of the compound one to seven days after the third dose. In some embodiments, the method further includes administering to the patient about 400 mg to 800 mg of the compound daily for 1 week or longer after the daily stepwise dosing regimen. In some embodiments, the method further includes administering to the patient about 400 mg to 1000 mg of the compound daily for 1 week or longer after the daily stepwise dosing regimen. In some embodiments, the patient has a reduced risk of tumor lysis syndrome during or after administration of the daily stepwise dosing regimen. In some embodiments, the hematological malignancy is selected from the group consisting of chronic lymphocytic leukemia, acute myeloid leukemia, multiple myeloma, lymphoplasmacytic lymphoma, non-Hodgkin's lymphoma and small lymphocytic leukemia. In some embodiments, the hematological malignancy is selected from the group consisting of chronic lymphocytic leukemia, acute myeloid leukemia, multiple myeloma, lymphoplasmacytic lymphoma, non-Hodgkin's lymphoma and primary light chain amyloidosis. In some embodiments, the hematological malignancy is selected from chronic lymphocytic leukemia and small lymphocytic leukemia. In some embodiments, the hematological malignancy is Waldenstrom's macroglobulinemia. In some embodiments, the patient suffers from primary refractory acute myeloid leukemia. In some embodiments, the patient suffers from refractory small lymphocytic leukemia or refractory chronic lymphocytic leukemia. In some embodiments, the patient has relapsed after a previous hematological malignancy treatment. In some embodiments, the previous hematological malignancy therapy is a therapy for chronic lymphocytic leukemia. In some embodiments, the previous hematological malignancy therapy is a therapy for small lymphocytic leukemia. In some embodiments, the previous hematological malignancy therapy is a therapy for acute myeloid leukemia.In some embodiments, the patient has received at least one previous treatment for a hematological malignancy, for example, the patient has previously received ibrutinib, obinutuzumab, bendamustine, prednisone, fludarabine, cyclophosphamide, pentostatin, or a combination of two or more thereof; and / or the patient has previously received radiation therapy or surgery. In some embodiments, the method further includes administering rituximab to the patient before, during, or after the daily step-wise dosing regimen. In some embodiments, the method further includes administering rituximab to the patient after the daily step-wise dosing regimen. In some embodiments, rituximab is administered to the patient about 1 week or more after the daily step-wise dosing regimen. In some embodiments, the method further includes administering azacitidine, decitabine, or low-dose cytarabine to the patient before, during, or after the daily step-wise dosing regimen. In some embodiments, the method further includes administering ibrutinib, topotecan, an MDM2 inhibitor, a CD20 inhibitor, a CDK9i inhibitor, or a homoharringtonine inhibitor to the patient before, during, or after the daily step-wise dosing regimen. In some embodiments, the method further comprises administering ibrutinib, topotecan, an MDM2 inhibitor, a CD20 inhibitor, a CDK9i inhibitor, or a homoharringtonine inhibitor to the patient after a daily stepwise dosing regimen. In some embodiments, the method further comprises administering a BTK inhibitor to the patient before, during, or after a daily stepwise dosing regimen. In some embodiments, the method further comprises administering a BTK inhibitor to the patient after a daily stepwise dosing regimen. In some embodiments, the BTK inhibitor is administered to the patient about 1 week or more after the daily stepwise dosing regimen. In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the method further comprises administering azacitidine to the patient before, during, or after a daily stepwise dosing regimen. In some embodiments, the method further comprises administering azacitidine to the patient after a daily stepwise dosing regimen. In some embodiments, the method further comprises administering homoharringtonine to the patient before, during, or after a daily stepwise dosing regimen. In some embodiments, the method further comprises administering homoharringtonine to the patient after a daily stepwise dosing regimen. In some embodiments, the compound is (R)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide.In some embodiments, the compound is (S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide.

[0087] In another embodiment, provided herein is a method of treating multiple myeloma and / or primary light chain amyloidosis in a patient in need thereof, the method comprising administering to the patient 200 mg or more of the compound N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises administering pomalidomide and dexamethasone to the patient. In some embodiments, the method further comprises administering lenalidomide and dexamethasone to the patient. In some embodiments, the method further comprises administering daratumumab, lenalidomide, and dexamethasone to the patient. In some embodiments, the method includes administering 200 mg, 400 mg, 600 mg or 800 mg of the compound to the patient. In some embodiments, the patient suffers from refractory multiple myeloma. In some embodiments, the patient has relapsed after a previous multiple myeloma treatment. In some embodiments, the compound is (R)-N-((4-(((1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-ene-7-yl)methyl)piperazine-1-yl)benzamide. In some embodiments, the compound is (S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide.

[0088] In another embodiment, described herein is a method of treating a hematological malignancy in a patient in need thereof, wherein the patient is also administered a CYP2C8 inhibitor (and / or another drug that may cause a drug / drug interaction, such as a CYP3A4 inhibitor or a food (e.g., grapefruit juice), comprising administering an effective amount of the compound N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl) In some embodiments, the effective amount for a patient taking a CYP2C8 inhibitor is about 20 mg to about 100 mg of the compound per day. In some embodiments, the effective amount for a patient taking a CYP2C8 inhibitor is about 10 mg, 20 mg, or about 50 mg per day. 30mg, 40mg, 50mg, 100mg or 200mg. In some embodiments, the method comprises administering an effective amount to a patient taking a CYP2C8 inhibitor after administering the compound via an initial daily or weekly stepwise dosing regimen. In some embodiments, the CYP2C8 inhibitor is a strong CYP2C8 inhibitor. In some embodiments, the CYP2C8 inhibitor is selected from gemfibrozil, trimethoprim, thiazolidinedione, montelukast and quercetin. In some embodiments, the compound is (R)-N-((4-(((1,4-dioxane-2-yl)methyl)amino)-3-nitro In some embodiments, the compound is (S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide.

[0089] definition

[0090] An "effective amount" includes the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. The compounds described herein, such as Compound 1, are administered in an effective amount to treat a condition, such as a hematological malignancy. Alternatively, an effective amount of a compound is the amount necessary to achieve the desired therapeutic and / or preventive effect, such as an amount that results in the prevention or alleviation of symptoms associated with the condition.

[0091] "Individual", "patient" or "subject" are used interchangeably herein and include any animal, including mammals, including mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates and humans. The compounds described herein can be administered to mammals, such as humans, but can also be administered to other mammals, such as animals in need of veterinary treatment, such as livestock (e.g., dogs, cats, etc.), farm animals (e.g., cattle, sheep, pigs, horses, etc.) and experimental animals (e.g., rats, mice, guinea pigs, etc.). The mammal treated with the methods described herein is ideally a mammal in need of treatment for a condition described herein, such as a human.

[0092] The term "pharmaceutically acceptable salt" as used herein refers to salts of acidic or basic groups of the compounds used in the compositions. The compounds included in the compositions of the present invention are basic in nature and are capable of forming a variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, including but not limited to malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, phosphoric acid, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, sucrose, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and palmitate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)) salts.

[0093] As used herein, "treating" includes any action resulting in improvement of a condition, disease, disorder, etc., such as alleviating, reducing, regulating, or eliminating.

[0094] The compounds described herein, such as Compound 1 or a pharmaceutically acceptable salt thereof, can be formulated as pharmaceutical compositions using a pharmaceutically acceptable carrier and administered by a variety of routes. In some embodiments, such compositions are for oral administration. In some embodiments, such compositions are for parenteral (by injection) administration. In some embodiments, such compositions are for transdermal administration. In some embodiments, such compositions are for intravenous (IV) administration. In some embodiments, such compositions are for intramuscular (IM) administration. Such pharmaceutical compositions and methods for their preparation are well known in the art. See, for example, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al., eds., 19 th ed., Mack Publishing Co., 1995).

[0095] Example

[0096] The compounds described herein can be prepared in a variety of ways based on the teachings contained herein and synthetic methods known in the art. It should be understood that, unless otherwise stated, all suggested reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and post-processing procedures can be selected as the condition standard for the reaction. It should be understood by those skilled in the art of organic synthesis that the functional groups present on the various parts of the molecule should be compatible with the proposed reagents and proposed reactions. Substituents incompatible with the reaction conditions will be obvious to those skilled in the art, so alternative methods are indicated. The starting materials of the embodiments are commercially available or can be easily prepared from known materials by standard methods.

[0097] N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide, (R)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide and compound 1 can be used according to WO 99 / 02668. Synthesized according to the synthetic method described in 2018 / 027097, which is incorporated herein by reference.

[0098] Abbreviations: PK: pharmacokinetics; MTD: maximum tolerated dose; DLT: dose-limiting toxicity; RP2D: recommended phase 2 dose; BTKi: BTK inhibitor.

[0099] Example 1. Clinical studies of hematological malignancies in human patients.

[0100] Compound 1 is being evaluated in the dose escalation phase of a Phase 1 study in patients with hematological malignancies. In this study, 3+3 dose escalation cohorts are administered on an ascending schedule consisting of daily increasing doses of Compound 1 or placebo until the recommended daily dose is reached. Dosing will start at 20 mg. Subsequent dose increments per day will be 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, and 800 mg (based on the recommended daily dose for this cohort).

[0101] Starting from this dosing regimen, the dose is escalated until the maximum tolerated dose (MTD) is determined. In a dose expansion cohort of up to 20 patients, the MTD is the recommended daily dose, where the daily escalation schedule as described above is applied until the MTD is reached.

[0102] Example 2. Clinical pharmacological effects of Compound 1 and Compound Z in patients.

[0103] The pharmacokinetics of Compound 1 and Compound Z were evaluated in patients. For example, Figure 1 and Figure 2 The plasma concentration-time curves of Compound 1 and Compound Z after a single oral administration of 50 mg, 100 mg, 200 mg, 300 mg (Compound Z only) and 400 mg to patients are shown in FIG.

[0104] In addition, Table 1 shows a comparison of the pharmacokinetic parameters of Compound 1 and Compound Z at steady state after multiple oral administration of 400 mg once daily.

[0105] Table 1. Comparison of steady-state pharmacokinetics of Compound 1 and Compound Z following multiple oral dosing of 400 mg once daily.

[0106]

[0107] Example 3. Comparative metabolism studies of Compound 1 and Compound Z.

[0108] Metabolism studies of Compound 1 and Compound Z were evaluated in both mouse and dog liver microsome assays. From these studies, Compound 1 was found to be primarily metabolized by CYP3A4 and CYP2C8. Compound 1 was not found to inhibit or induce any of the major CYP enzymes in the assays. In the mouse liver microsome assay, the major metabolite (>10%) in mouse plasma was the amide bond hydrolyzing M2, along with a minor oxidative metabolite. Minor oxidative metabolites were found in dog plasma evaluated in dog liver microsomes.

[0109] In contrast, compound Z was found to be metabolized primarily by CYP3A4 and CYP3A5. For compound Z, the major metabolite (>10%) in human plasma was the oxidative metabolite M27. Other minor oxidative metabolites were found in both mouse and dog plasma evaluated.

[0110] Example 4. Study of the safety, tolerability and efficacy of Compound 1 alone or in combination with other therapeutic agents in patients with Waldenstrom's macroglobulinemia.

[0111] A clinical study evaluating the safety, tolerability, efficacy and PK of compound 1 as a single agent or in combination with other therapeutic agents such as ibrutinib or rituximab was conducted. The study included dose escalation and dose expansion phases. The clinical trial has multiple groups, with the ability to subsequently add more treatment groups based on the clinical activity of compound 1 in Waldenstrom's macroglobulinemia (WM). Initially, the study contained 3 groups as described below, all of which were independent.

[0112] Group A: Compound 1 is administered as a single agent to determine the MTD / RP2D in WM patients who have relapsed / resistant or intolerant to ibrutinib or other BTK inhibitors. After the MTD / RP2D is determined, up to 12 additional patients will be recruited in the dose expansion phase at the RP2D level to further evaluate the safety and efficacy of Compound 1.

[0113] Arm B: Compound 1 is administered in combination with ibrutinib in previously untreated WM patients. The MTD / RP2D for Compound 1 in combination with ibrutinib will be established in Cycle 1 of Arm B. After the MTD / RP2D is determined, up to 15 patients will be enrolled at this dose level in the dose expansion phase.

[0114] Cohort C: Compound 1 was administered in combination with rituximab in WM patients with relapsed / resistant disease who had not been previously treated with ibrutinib or other BTKi. The MTD / RP2D of Compound 1 in combination with rituximab was established in Cohort C Cycle 1. After the MTD / RP2D was determined, 15 additional patients were enrolled at this dose level in the dose expansion phase. Each cycle was 4 weeks (28 days long).

[0115] The dose-escalation phase of compound 1 as monotherapy or in combination with ibrutinib or rituximab will follow the mTPI-2 dose-escalation design:

[0116] Compound 1 is administered orally once daily for 28 consecutive days in a 28-day cycle until disease progression or unacceptable toxicity occurs. The initial target dose (with escalating doses if necessary) is 400 mg (dose level 1; DL1), and is increased accordingly to 600 mg (DL2) and 800 mg (DL3). Based on discussions between the investigator and the sponsor, the dose may be increased to a higher level based on safety and PK results. Starting on Day 1 of Cycle 1, ibrutinib is administered orally at 420 mg daily and continuously thereafter. Each cycle is 4 weeks (28 days). Rituximab is administered intravenously at 375 mg / m2 per pack weekly for four consecutive weeks, followed by a second four-week course of rituximab after a three-month interval (Day 1 of Weeks 1-4 and Day 1 of Weeks 17-20, for a total of 8 injections of rituximab). Infusion of rituximab begins on Day 1 of Cycle 1. Figure 3 Dosing regimens for representative studies are provided in .

[0117] All patients were assessed for a specific risk of tumor lysis syndrome (TLS) and received prophylaxis (including hydration, antihyperuricemic agents, close laboratory monitoring, and hospitalization, if any) starting at least 72 hours prior to the first dose of Compound 1. For patients at high risk for TLS, a dose escalation regimen could be implemented regardless of the dose level assigned prior to reaching the final dose level, and for patients at low / intermediate risk for TLS, they could start at the final assigned dose. A fixed daily 3-day escalation schedule is listed in Table 2 below.

[0118] Table 2. Daily escalation schedule for compound 1

[0119]

[0120] *Cycle 1, Day 1 (C1D1) is Day 1 of the assigned 400 mg dose.

[0121] **Cycle 1, Day 1 (C1D1) is Day 1 of the assigned 600 mg dose.

[0122] ***Cycle 1, Day 1 (C1D1) is Day 1 of the assigned 800 mg dose.

[0123] To be considered evaluable for a DLT, subjects must have received at least 70% of the planned dose of Compound 1 or its combination during the DLT evaluation period (Cycle 1). If a patient receives less than 70% of the planned dose total during the evaluation period for reasons other than DLT, they are not evaluable for DLT. If a subject experiences a DLT (during the DLT evaluation period), treatment with Compound 1 alone or in combination must be interrupted, and depending on the severity of the DLT, the patient may be discontinued from the study. However, after the DLT is resolved to Grade 1 or baseline value, the investigator may continue the patient's study treatment at a reduced dose level at the discretion of the investigator.

[0124] Example 5. Clinical study of Compound 1 as a single agent or in combination with other therapeutic drugs in patients with relapsed and / or refractory chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL).

[0125] An open-label study evaluating the safety, tolerability, efficacy, and PK of Compound 1 as a single agent or in combination therapy was conducted. The study consisted of a daily ramp-up period, dose escalation, and dose expansion portions. Each patient will undergo a daily ramp-up period prior to entering a treatment cycle. The duration of the daily ramp-up period will depend on the assigned dose level. Daily ramp-ups consist of treatment with Compound 1 administered once daily, starting with 20 mg on Day 1, 50 mg on Day 2, 100 mg on Day 3, 200 mg on Day 4, 400 mg on Day 5, 600 mg on Day 6, 800 mg on Day 7, and 1000 mg on Day 8. The scheduled maximum cohort dose for evaluation begins at 400 mg Compound 1 to a maximum of 1000 mg Compound 1. For example, a patient scheduled to receive a dose of 400 mg will have a 4-day ramp-up period, a patient scheduled to receive a dose of 600 mg will have a 5-day ramp-up period, and so on, see Figure 1 Part 1 evaluated compound 1 monotherapy at four dose levels (400 mg, 600 mg, 800 mg, and 1,000 mg); Part 2 was a combination of compound 1 and rituximab, with dose escalation and expansion at any safe dose level (including 400 mg, 600 mg, and 800 mg of compound 1) (see Figure 4 In this study, the maximum tolerated dose (MTD) was defined as the dose that did not cause unacceptable toxicity in the six patients treated in the first 28-day cycle, as demonstrated by zero or one patient experiencing dose-limiting toxicity (DLT), with the next higher dose demonstrating unacceptable toxicity (≥2 / 3 or ≥2 / 6 DLT).

[0126] Part 1: Compound 1 is administered orally once daily (QD) as a single agent to determine the MTD / RP2D in patients with relapsed or refractory CLL. Patients will be treated in 28-day cycles. First, they will undergo a daily escalation phase from Days 1 to 4 (Day 1, 20 mg; Day 2, 50 mg; Day 3, 100 mg; Day 4, 200 mg); then on Day 1 of Cycle 1, Compound 1 will be used in parallel at 400 mg, 600 mg, 800 mg, and 1000 mg. PK analysis is required for the first 3 patients in each dose cohort. After the first 3 patients, each dose cohort is deemed to have no safety issues and up to 15 additional patients may be treated to further characterize safety and efficacy. The optimal dose of Compound 1 in CLL monotherapy depends on the overall safety, PK, and preliminary efficacy data after discussion between the investigator and the sponsor.

[0127] Part 2: Compound 1 is administered in combination with rituximab. Patients are treated in 28-day cycles. Compound 1 doses are increased starting from Day 1 to Day 4 (Day 1, 20 mg; Day 2, 50 mg; Day 3, 100 mg and Day 4, 200 mg), followed by Compound 1 at three dose levels: 400 mg, 600 mg, and 800 mg on Day 1 of Cycle 1. As described above, the escalation period increases accordingly for each higher dose. Compound 1 is taken until disease progression, unacceptable toxicity, initiation of alternative therapy, or withdrawal of consent. The combination begins on Day 8 of Cycle 1 as follows: Rituximab is administered at 375 mg / m2 IV infusion on Day 8 of Cycle 1 and 500 mg / m2 IV infusion on Day 1 of Cycles 2-6.

[0128] All patients will be assessed for specific risk of tumor lysis syndrome (TLS), and all patients will receive prophylaxis (including hydration, antihyperuricemic agents, close laboratory monitoring, and hospitalization if necessary) prior to the first Compound 1 dose. The daily escalation schedule for Compound 1 is detailed in Table 3.

[0129] Table 3. Dose escalation schedule for compound 1

[0130]

[0131] Dose Cohorts: a 400 mg, cycle 1, day 1; b 600 mg, cycle 1, day 1; c 800 mg, cycle 1, day 1; d 1000 mg, cycle 1, day 1.

[0132] Example 6. Clinical study of Compound 1 as a single agent or in combination with chemotherapy for the treatment of patients with relapsed and / or refractory acute myeloid leukemia (r / r AML).

[0133] This is a single dose escalation study of compound 1 to evaluate the DLT, MTD or RP2D of compound 1 monotherapy and to evaluate the in vivo pharmacokinetics and anti-AML efficacy of compound 1. The dose of compound 1 was increased according to the standard 3+3 regimen. The initial dose cohort of compound 1 received 200 mg. The dose was then increased at dose levels of 400 mg, 600 mg, and 800 mg in three dose escalation cohorts. Compound 1 was administered once a day (QD), with a dosing cycle of every 28 days.

[0134] The study followed an ascending daily dose regimen that included the following. The daily dose for the 200 mg dose group was as follows: 100 mg to 200 mg. The 400 mg dose group should be dosed at the following daily dose: 100 mg to 200 mg to 400 mg. The 600 mg dose group should be dosed at the following daily dose: 100 mg to 200 mg to 400 mg to 600 mg. The 800 mg dose group should be dosed at the following daily dose: 100 mg to 200 mg to 400 mg to 600 mg to 800 mg.

[0135] Example 7. Phase Ib / II study of the safety, PK, PD and efficacy of compound 1 as a single agent or in combination with rituximab or ibrutinib in patients with relapsed and / or refractory chronic lymphocytic leukemia (CLL) or relapsed and / or refractory small lymphocytic lymphoma (SLL)

[0136] This is an open-label, multicenter Phase Ib / II study investigating the safety, PK, PD, and efficacy of compound 1 as a single agent or in combination with rituximab or ibrutinib in patients with relapsed and / or refractory CLL and / or SLL. Subjects cannot receive other anti-malignant tumor investigational drugs, commercially available drugs, or treatments other than compound 1 and rituximab, or ibrutinib. Symptomatic supportive care is acceptable, including control of symptoms caused by the tumor. A schematic diagram of the study is shown in Figure 5.

[0137] This study consists of two parts. The first part of this study is a compound 1 monotherapy expansion cohort study, the purpose of which is to evaluate the safety, anti-tumor activity and pharmacokinetic characteristics of compound 1 monotherapy in patients with relapsed or refractory CLL and / or SLL. The cohort expansion is carried out at three dose levels, namely 400mg, 600mg and 800mg, and 12-15 patients are planned to be included in each dose level.

[0138] In the first part of the study, in order to minimize the risk of tumor lysis syndrome (TLS) in subjects, all subjects received compound 1 on a daily escalation schedule prior to receiving treatment at the target dose level. Subjects in the 400 mg dose level cohort were administered 20 mg, 50 mg, 100 mg, 200 mg and 400 mg of compound 1 daily with a target dose of 400 mg. Subjects in the 600 mg dose level cohort were administered 20 mg, 50 mg, 100 mg, 200 mg, 400 mg and 600 mg of compound 1 daily with a target dose of 600 mg. Subjects in the 800 mg dose level cohort were administered 20 mg, 50 mg, 100 mg, 200 mg, 400 mg, 600 mg and 800 mg of compound 1 daily with a target dose of 800 mg.

[0139] Figure 5a provides a schematic diagram of the first part of the study. Samples from the first three subjects in each cohort will be collected for pharmacokinetic (PK) data analysis. After the first three patients are enrolled in the 400mg cohort, the safety of these three patients in the first cycle will be evaluated. If the evaluation results show that the drug is safe, 9-12 patients in the 400mg cohort and the first 3 patients in the 600mg cohort will be enrolled. If the first three patients taking 600mg complete the first cycle evaluation and indicate that the drug is safe, the subsequent 9-12 patients are included in the 600mg cohort, and the first three patients in the 800mg cohort are included at the same time. After the PK and safety evaluations of the three 800mg patients, the last 9-12 patients are included in the 800mg cohort. If the complete PK samples of 3 subjects cannot be obtained for any reason, they should be replaced by subsequent subjects in the cohort until the complete PK samples of 3 subjects are collected.

[0140] Compound 1 was taken orally once a day for 28 days as a cycle. A preliminary analysis of safety and efficacy was conducted when all subjects completed 6 courses of treatment or stopped treatment (whichever occurred first). The second part of the study was conducted after the recruitment of the first part group was completed.

[0141] The second part of the study contains two groups: compound 1 combined with rituximab (group A) and compound 1 combined with ibrutinib (group B) (Figure 5b). The purpose is to explore and evaluate the DLT, MTD, RP2D and safety, pharmacokinetic studies and efficacy of compound 1 in the combination therapy studied. Compound 1 has 4 dose levels: 200 mg, 400 mg, 600 mg and 800 mg. The two groups include two phases of dose escalation (phase I) and dose expansion (phase II). Both groups of subjects were treated in 28-day cycles. Compound 1 is provided in the form of oral tablets, each containing 10 mg or 50 mg of compound 1.

[0142] To minimize the risk of tumor lysis syndrome (TLS) in the second part of the study group, all subjects received compound 1 according to a daily escalation schedule prior to treatment at the target dose level. Subjects in the 200 mg dose level cohort took 200 mg as the target dose and took 20 mg, 50 mg, 100 mg and 200 mg of compound 1 continuously every day. Subjects in the 400 mg dose level cohort took 400 mg as the target dose and took 20 mg, 50 mg, 100 mg, 200 mg and 400 mg of compound 1 continuously every day. Subjects in the 600 mg dose level cohort took 600 mg as the target dose and took 20 mg, 50 mg, 100 mg, 200 mg, 400 mg and 600 mg of compound 1 continuously every day. Subjects in the 800 mg dose level cohort took 800 mg as the target dose and took 20 mg, 50 mg, 100 mg, 200 mg, 400 mg, 600 mg and 800 mg of compound 1 continuously every day.

[0143] The first phase of the second part is a dose-escalation study of compound 1 in combination with rituximab or ibrutinib. The dose escalation of compound 1 follows the standard 3+3 regimen, with an initial dose of 200 mg, followed by dose escalation, for a total of 4 dose levels (200 mg, 400 mg, 600 mg, and 800 mg). After reaching the target dose level following the daily escalation regimen, compound 1 was continuously orally administered once a day for a 28-day cycle (Figure 5b).

[0144] In the first cycle of the rituximab group (group A), the use of rituximab or ibrutinib started on day 8 of cycle 1. Rituximab was administered at 375 mg / m 2 Intravenous injection at a rate of 500 mg / m on day 1 of cycles 2-6 2 The drug was injected intravenously at a rate of 100 mg / kg for a total of 6 injections per subject.

[0145] In the ibrutinib group, ibrutinib was taken orally at a dose of 420 mg starting from day 8 of cycle 1 and continued thereafter. During the administration of the combination drug, rituximab was administered within 30-90 minutes after oral administration of compound 1 in each single treatment group, and compound 1 and ibrutinib were administered simultaneously.

[0146] The second phase of the second part of the study is the RP2D expansion phase. Once the RP2D values ​​for Group A and Group B are determined, each group enters the expansion cohort of the second phase of the study (Figure 5b). At each RP2D dose level, up to 15 subjects will receive compound 1 combined with rituximab or ibrutinib to further evaluate the safety and efficacy of the combination regimen at this dose level. Groups A and B allow subjects to escalate their own doses. Before the investigators and sponsors increase the intra-patient dose, the subjects need to complete at least 3 dosing cycles at the initially assigned dose level and determine the safety of the higher dose level. The intra-subject dose is escalated, with the current dose as the starting dose for the gradient increase, and the daily increase reaches the target dose, completing the step-by-step increase, and the day of reaching the target dose is the first day of the medication cycle. From the day before the administration of compound 1, the patient is hospitalized until at least 48 hours after reaching the target dose, and receives intravenous fluids every day, while closely monitoring and promptly treating any metabolic changes that indicate tumor lysis.

[0147] Example 8. Phase Ib / II clinical study of compound 1 in combination with Pd or DRd for the treatment of patients with relapsed and / or refractory multiple myeloma (RRMM).

[0148] This is a Phase Ib / II, open-label, multicenter study that investigated and evaluated the safety, tolerability, efficacy, and PK / PD of compound 1 in combination with PD (in combination with pomalidomide and dexamethasone) or DRd (in combination with daratumumab, lenalidomide, and dexamethasone) in patients with relapsed / refractory multiple myeloma (MM). The study was divided into two phases: dose escalation and dose expansion. The study started with the following two groups, which were independent. The study design was as follows Figure 6 shown and further described below.

[0149] In this protocol, study treatment in Group A was defined as pomalidomide (P), dexamethasone (d) and compound 1, and daratumumab (d), lenalidomide (R), dexamethasone (d) and compound 1 in Group B. The study drug was compound 1. Subjects who discontinued treatment with Pd or DRd could continue to take compound 1 during the study.

[0150] All patients received tumor lysis syndrome (TLS) prophylaxis (including hydration, anti-hyperuricemia, close laboratory monitoring, and hospitalization, if necessary) at least 72 hours before the first dose of compound 1. If any TLS occurs in the clinical or laboratory setting during the dose escalation phase of Group A or Group B, the protocol may be modified so that a daily escalating dose schedule of compound 1 is implemented in patients enrolled subsequently.

[0151] Arm A: Compound 1 is co-administered with Pd to determine the MTD / RP2D in subjects with RRMM. Patients receive compound 1 at the target dose level once daily, co-administered with pomalidomide (4 mg) on ​​days 1 to 21, and dexamethasone (40 mg, 20 mg for patients over 75 years old) on days 1, 8, 15, and 22, repeated for 28 days. Patients may continue treatment until disease progression, unacceptable toxicity, withdrawal of consent, or proceeding to stem cell transplant, whichever comes first. Dose adjustments may be made based on toxicity / age. This is an all-oral therapy.

[0152] The dose escalation phase of compound 1 with Pd uses a 3+3 dose escalation design. The starting target dose of compound 1 is 400 mg once daily (dose level 1, or DL1) and is increased accordingly to 600 mg once daily (dose level 2, or DL2) and 800 mg once daily (dose level 3, or DL3) in subsequent cohorts. If the dose of compound 1, 400 mg, cannot be tolerated, the dose can be reduced to 200 mg once daily (dose level -1, or DL-1). This rule-based design first studies a cohort of three patients in DL1. If none of the three patients enrolled in DL1 experience a DLT, an additional three patients will be treated in DL2, and so on. However, if one patient experiences a DLT, three patients will be treated at the same dose. The dose continues to increase until at least two of the three to six patients experience a DLT. The MTD is generally defined as the highest dose level at which ≤33% of patients experience a DLT. After comprehensive analysis of the safety data to determine whether the 800 mg dose is tolerable, higher dose levels above 800 mg are considered. The RP2D for Group A is determined based on the efficacy and safety of Compound 1.

[0153] After the MTD and RP2D of Group A were determined, 12 additional patients were added at RP2D (Group A) in the dose expansion phase to further evaluate the safety and efficacy of Compound 1 combined with Pd.

[0154] Arm B: Compound 1 is administered in combination with DRd to determine the MTD and RP2D for RRMM subjects in Arm B. Arm B studies should not be conducted until the safety of the 600 mg dose level in Arm A is established. Patients in both arms will then be recruited simultaneously at the discretion of the investigator.

[0155] Patients received compound 1 once daily at the target dose for 28 days, starting on day 1 of cycle 1. For backbone therapy, patients received lenalidomide orally (PO) once daily on days 1 to 21 of each 28-day cycle, and dexamethasone 40 mg (or 20 mg for patients 75 years and older) was administered weekly. Daratumumab 16 mg / kg IV (or 1800 mg SC where commercially available) was administered weekly in cycles 1 and 2, then every 2 weeks in cycles 3 to 6, and every 4 weeks thereafter. Patients could continue treatment until disease progression, unacceptable toxicity, withdrawal of consent, or proceeding to stem cell transplant, whichever came first. Dose adjustments may be made based on toxicity / age.

[0156] Compound 1 in combination with DRd follows a 3+3 dose-escalation design. The starting target dose is 400 mg once daily (dose level 1, or DL1) and is increased to 600 mg once daily (dose level 2, or DL2) and 800 mg once daily (dose level 3, or DL3) in subsequent cohorts. If compound 1 cannot tolerate a dose of 400 mg, the dose can be reduced to 200 mg (dose level -1, or DL-1). This rule-based design first studies a cohort of three patients in DL1. If none of the three patients enrolled in DL1 experience a DLT, the other three patients will be treated in DL2, and so on. However, if one of the three patients experiences a DLT, the other three patients will be treated at the same dose. The dose continues to increase until at least two of the three to six patients experience a DLT. The MTD is generally defined as the highest dose level at which ≤33% of patients experience a DLT. Higher dose levels beyond 800 mg will only be considered after a comprehensive analysis of the safety data to determine whether the 800 mg dose is tolerated. The RP2D of Group B was determined based on the efficacy and safety of Compound 1.

[0157] After the MTD and RP2D of Group B are determined, 12 additional patients will be enrolled in the Group B dose expansion phase RP2D to further evaluate the safety and efficacy of Compound 1 in combination with DRd.

[0158] Patients in Arm A or B who are not evaluable for DLTs during Cycle 1, and / or who withdraw for any reason other than DLTs during a defined DLT-evaluable treatment cycle, and / or who do not receive more than 70% of the planned doses (Compound 1 and / or co-study drug) in a cycle are considered unevaluable and should be replaced. Patients who are stable or responding may continue treatment once symptoms of DLTs resolve to less than or equal to Grade 1, based on discussion between the Investigator and the Ascentage Medical Monitor.

[0159] Phase Ib / II open-label study of compound 1 in combination with a novel therapeutic agent in patients with relapsed or refractory multiple myeloma and primary light-chain amyloidosis

[0160] Group C: Compound 1 will be administered in combination with Pd to determine the MTD and RP2D of Compound 1 in subjects with primary light-chain amyloidosis.

[0161] Patients will be administered Compound 1 once daily on Days 1 to 21 for 28 days, followed by pomalidomide (4 mg) and dexamethasone (40 mg for patients ≤75 years old and 20 mg for patients >75 years old) on Days 1, 8, 15, and 22 of each 28-day cycle. Patients may continue treatment until disease progression, unacceptable toxicity, withdrawal of consent, or proceeding to stem cell transplant, whichever comes first. Dose adjustments may be made based on toxicity / age, and this is an all-oral regimen.

[0162] Example 9. Phase Ib / II open-label study of Compound 1 monotherapy or in combination with lenalidomide / dexamethasone in subjects with relapsed and / or refractory multiple myeloma.

[0163] This is a Phase Ib / II, open-label, multicenter study to evaluate the safety, tolerability, efficacy, and pharmacokinetics / pharmacodynamics of Compound 1 as monotherapy or in combination with Rd (lenalidomide (R) and dexamethasone (d)) in patients with relapsed and / or refractory (R / R) multiple myeloma (MM). The primary objectives of this study are to evaluate the safety and tolerability of Compound 1 alone or in combination with Rd in Chinese R / RMM patients, and to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended dose (RP2D).

[0164] This study consists of two groups, including compound 1 alone (group A) and compound 1 combined with Rd (group B). Both groups include dose escalation and dose expansion phases. Group B was initiated after the dose escalation phase of group A was completed. The starting dose and maximum escalation dose of compound 1 in group B can be adjusted according to the MTD / RP2D of compound 1 in group A. All subjects received continuous treatment for 28 days. The study is summarized as follows and Figure 7 shown.

[0165] In Group A, Compound 1 was administered once daily for 28 days. In Group B, Compound 1 was administered once daily for 28 days. Patients took lenalidomide orally from day 1 to day 21 of each 28-day cycle at a dose of 25 mg (or 10 mg for patients with creatinine clearance (CrCl) of 30-60 ml / min). Dexamethasone was administered once a week (days 1, 8, 15, and 22) at a dose of 40 mg (20 mg for patients over 75 years old).

[0166] A 3+3 design dose escalation phase was used, including compound 1 monotherapy in group A and compound 1 in combination with Rd in group B. The starting target dose of compound 1 was 400 mg (dose level 1, or DL1), followed by escalation to 600 mg (dose level 2, or DL2) and 800 mg (dose level 3, or DL3) accordingly. This rule-based design starts with a cohort of three patients. If none of the three patients enrolled in DL1 experience a DLT, the other three patients will be treated in DL2, and so on. However, if one patient experiences a DLT, three patients will be treated with the same dose. The dose continues to increase until at least two of the three to six patients in the same cohort experience a DLT. The MTD is generally defined as the highest dose level at which ≤33% of patients experience a DLT. The RP2D is determined based on the overall efficacy and safety of compound 1 monotherapy or in combination with Rd. After the RP2D is determined, 6-9 patients in Group A and 12 patients in Group B will be enrolled in the dose expansion phase RP2D to further evaluate the safety and efficacy of Compound 1 monotherapy or in combination with Rd.

[0167] To minimize the risk of tumor lysis syndrome (TLS), all patients in the dose escalation phase were monitored (TLS chemistry and complete blood cell panel) for 3 days before and after the first dose of Compound 1. If no TLS (clinical or laboratory) was found during dose escalation, patients in dose expansion did not need to be monitored for TLS on Days 2 and 3 unless requested by the investigator.

[0168] All subjects continued to receive treatment until disease progression, unacceptable toxicity, or other discontinuation criteria specified in the protocol were met. All subjects completed survival follow-up after discontinuation of treatment until the end of the study, withdrawal of informed consent, loss of follow-up, or death.

[0169] Example 10. Phase Ib study of Compound 1 monotherapy and in combination with homoharringtonine (HHT) or azacitidine (AZA) in patients with relapsed and / or refractory acute myeloid leukemia (r / rAML).

[0170] This is a Phase Ib open-label, dose-escalation study of Compound 1 monotherapy and Compound 1 combined with HHT or AZA for the treatment of relapsed and refractory acute myeloid leukemia (AML). Subjects cannot receive other anti-malignant tumor investigational drugs, commercially available drugs, or treatments except Compound 1, HHT, and AZA. Patients can receive symptomatic supportive treatment, including control of symptoms caused by the subject's malignant tumor. This study can be divided into three phases.

[0171] Phase 1 - Compound 1 monotherapy dose escalation

[0172] The first phase is a dose-escalation study of compound 1 monotherapy, the purpose of which is to explore the DLT, MTD and / or RP2D of compound 1 monotherapy and to evaluate the pharmacokinetics and anti-AML efficacy of compound 1. According to the standard 3+3 design, the dose of compound 1 is increased in the dose level cohort. The initial dose is 200 mg, which is increased to 400 mg, 600 mg and 800 mg in sequence. Compound 1 is taken orally once a day (QD) at the target dose level of the study, and all subjects receive continuous treatment at the target dose level within a 28-day cycle.

[0173] To minimize the risk of clinical or laboratory tumor lysis syndrome (TLS) in Phase 1, all subjects received a daily escalation schedule, as shown below for each dose level. Subjects in the 200 mg dose level cohort took 100 mg and 200 mg of compound 1 continuously daily, with a target dose of 200 mg. Subjects in the 400 mg dose level cohort took 100 mg, 200 mg, and 400 mg of compound 1 continuously daily, with a target dose of 400 mg. Subjects in the 600 mg dose level cohort took 100 mg, 200 mg, 400 mg, and 600 mg of compound 1 continuously daily, with a target dose of 600 mg. Subjects in the 800 mg dose level cohort took 100 mg, 200 mg, 400 mg, 600 mg, and 800 mg of compound 1 continuously daily, with a target dose of 800 mg. See Table 4.

[0174] Table 4. Phase I dose escalation design.

[0175]

[0176] Phase II - Dose escalation of compound 1 in combination regimen

[0177] Phase II is a dose escalation study of compound 1 in combination with HHT or AZA. The purpose of Phase II is to determine the DLT, MTD or RP2D of compound 1 in combination with HHT or AZA, and to evaluate the pharmacokinetics and anti-AML efficacy of compound 1 in these combination regimens. In the combination study, the dose escalation of compound 1 follows a standard 3+3 design, with the dose levels studied being the MTD / RP2D-1 in Phase I (e.g., one dose level lower than the MTD / RP2D in Phase I) and the MTD / RP2D level in Phase I, with a total of two dose levels for the three combination regimens studied. Compound 1 is administered orally at each dose level, once a day (QD), for a 28-day cycle.

[0178] To minimize the risk of clinical or laboratory tumor lysis syndrome (TLS) in the second phase, all subjects first received a daily escalation regimen, with each dose level shown below. Subjects in the RP2D-1 dose level cohort received compound 1 starting at 100 mg, followed by continuous administration in increments of 100 mg per day until the target dose of RP2D-1 was reached. Subjects in the RP2D dose level cohort received compound 1 starting at 100 mg, followed by continuous administration in increments of 100 mg per day until the target dose of RP2D was reached. See Table 5.

[0179] Table 5. Phase II dose escalation design.

[0180]

[0181] *n=2-5

[0182] Subjects who received the initial dose on the first day were given daily escalating doses based on the specified dose level according to the above protocol if tolerated. The initial dose of daily escalation was fixed at 100 mg, reaching Day 1 of the medication cycle on the day the specified dose was reached. Subjects continued to receive treatment until disease progression, intolerable toxicity or transfer to other appropriate treatments, or when the investigator believed that they could not benefit, or met other criteria for termination of treatment specified in the protocol. Regardless of whether treatment was terminated, subjects will be followed up for survival (unless informed consent was withdrawn or follow-up was lost).

[0183] The initial dose and dose escalation regimen of compound 1 combination therapy will be discussed and decided by the sponsor and investigator based on the clinical results and PK data of single-drug dose exploration, and appropriate dose adjustments will be made.

[0184] The combination regimen of these two dose levels was studied in three cohorts. Group A at each dose level received compound 1 combined with low-dose HHT. HHT was administered as an intravenous drip of 1 mg per day for 14 consecutive days, for a total of 14 infusions. Group B at each dose level was treated with compound 1 combined with standard-dose HHT. In group B, HHT was administered at a dose of 2 mg / m2 once a day for 7 consecutive days, for a total of 7 infusions. HHT was administered as an intravenous infusion for 4 hours, with oral compound 1 administered within an interval of no more than 30 minutes after the first dose. Group C at each dose level received compound 1 in combination with AZA. AZA was injected subcutaneously at a dose of 75 mg / m2 once a day for 7 consecutive days. AZA was administered simultaneously with oral compound 1 within an interval of no more than 30 minutes from the first administration of AZA.

[0185] The sponsor determines the RP2D dose of compound 1 in each combination regimen based on clinical data. Once the RP2D of compound 1 in each combination regimen is determined, the study will enter Phase III, which is an expansion study of the combination regimen.

[0186] Phase III - Extended Research

[0187] The extension study includes 3 cohorts. From the second phase, up to 15 patients in each combination cohort with relapsed and refractory AML will receive HHT or AZA compound 1 at the RP2D dose level. Group A receives reduced-dose HHT with compound 1. 1 mg HHT is administered intravenously daily for 14 consecutive days, for a total of 14 infusions. Group B is treated with compound 1 in combination with standard-dose HHT. In group B, HHT is administered at a dose of 2 mg / m by intravenous infusion. 2 , once daily for 7 consecutive days, for a total of 7 infusions. HHT was administered as an intravenous infusion over 4 hours, and was co-administered with oral Compound 1 within an interval of no more than 30 minutes after the first dose of HHT. Group C received a combination of Compound 1 and AZA, once daily for 7 consecutive days at 75 mg / m 2 AZA was administered subcutaneously at a dose of 1.5 AZA. AZA was administered simultaneously with oral Compound 1 within an interval not exceeding 30 minutes from the first administration of AZA.

[0188] The third phase further evaluates the safety and efficacy of the combination regimen at this dose level for patients with relapsed and refractory AML. In order to minimize the risk of clinical or laboratory tumor lysis syndrome (TLS) in the third phase, all subjects first received a daily escalation regimen, and each dose level is shown below. Subjects in the RP2D (Phase II) dose level cohort received compound 1 starting at 100 mg, and then continued to be administered in increments of 100 mg per day until the target dose of RP2D was reached. See Table 6.

[0189] Table 6. Phase III dose escalation design.

[0190]

[0191] *n=2-5

[0192] Equivalent solution

[0193] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described specifically herein, and such equivalents are intended to be encompassed within the scope of the appended claims.

Claims

1. A method for treating a hematological malignancy in a patient in need thereof, characterized in that the method include: administering the compound N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide or a pharmaceutically acceptable salt thereof in a daily stepwise dosing regimen; The daily stepwise dosing regimen includes: administering a first dose of 20 mg of the compound to the patient for one day; administering a second dose of 50 mg of the compound to the patient on the second day after the first dose, for one day; administering a third dose of 100 mg of the compound to the patient on the second day after the second dose, for one day.

2. The method of claim 1, further comprising administering to the patient a fourth dose of 200 mg of the compound daily for 1-5 days or longer.

3. The method according to claim 2, characterized in that The fourth dose is administered to the patient for one day.

4. The method according to claim 2 or 3, characterized in that: The daily stepwise dosing regimen further includes administering to the patient a fifth dose of 400 mg after administering the fourth dose.

5. The method according to any one of claims 1 to 4, characterized in that Also included is administering to the patient a dose of 400 mg to 800 mg of the compound per day after the third or fourth dose.

6. The method according to any one of claims 1 to 5, characterized in that It also includes administering to the patient a daily dose of 400 mg, 600 mg, 800 mg or 1000 mg of the compound for 1 week or more, or 1 month or more after administering a daily step-wise dosing regimen.

7. The method according to any one of claims 1 to 6, characterized in that Also included is administering to the patient a daily dose of 400 mg, 600 mg, or 800 mg of the compound for 1 week or more, or 1 month or more, after a daily step-wise dosing regimen.

8. A method for treating a hematological malignancy in a patient in need thereof, characterized in that: include: administering the compound N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide or a pharmaceutically acceptable salt thereof in a daily stepwise dosing regimen; Characterized in that the implementation of the daily stepwise dosing regimen comprises: administering a first dose of 20 mg to 100 mg of the compound to the patient on the first day; and administering a second dose of 50 mg to 200 mg of the compound to the patient on the second day after the first dose.

9. A method for treating multiple myeloma and / or primary light chain amyloidosis in a patient in need thereof, comprising: Patients were given 200 mg or more of the compound N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide.

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