PI3K inhibitors for use in the treatment of B-cell lymphoma

Abstract

The present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof. This compound, or a pharmaceutically acceptable salt thereof, is useful as a PI3K inhibitor and is therefore useful in therapy. In particular, this compound, or a pharmaceutically acceptable salt thereof, is useful in the treatment of B-cell lymphoma. JPEG2022537925000014.jpg4988

Description

Technical Field

[0001] The present invention relates to the use of 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt thereof for treating or preventing B-cell lymphoma. This compound has the following chemical structure.

Chemical Formula

Background Art

[0002] Phosphoinositide 3-kinase (PI3K) constitutes a family of lipid kinases involved in the regulation of a network of signaling pathways that control a series of cellular processes. PI3K is classified into three different subfamilies, class I, II, and III, based on their substrate specificities. Class IA PI3K has a p110α, p110β, or p110δ catalytic subunit complexed with any one of three regulatory subunits, p85α, p85β, or p55δ. Class IA PI3K is activated by receptor tyrosine kinases, antigen receptors, G protein-coupled receptors (GPCRs), and cytokine receptors. Class IA PI3K mainly phosphorylates phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P 3Generate [[ID=]], which is a second messenger that activates downstream target AKT. The consequences of the biological activation of AKT include tumor cell progression, proliferation, survival, and growth, and there is significant evidence suggesting that the PI3K / AKT pathway is dysregulated in many human cancers. Additionally, PI3K activity has been associated with endocrinology, cardiovascular disease, immune disorders, and inflammation. PI3K-p110δ has been established to play an important role in the recruitment and activation of immune and inflammatory cells. PI3K-p110δ is also upregulated in many human tumors and plays an important role in tumor cell proliferation and survival. Compounds that can regulate p110δ activity have important therapeutic uses in cancer.

[0003] Despite advances in treatment, for some blood cancers, particularly B-cell lymphoma, the currently available treatments remain inadequate. Most patients respond to the first-line treatment, but many patients cannot achieve remission of the disease, and some patients experience recurrence of the disease. As a result, there is a significant need for the design and development of new drugs to reduce these disorders, particularly agents that modulate molecular targets associated with the development and progression of blood cancers. The compounds of the present invention are characterized and described in the international patent application published as WO2015 / 121657.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

Means for Solving the Problems

[0005] Reference to the compound (4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]tridec-1(13),2(7),3,5,9,11-hexaene) or a pharmaceutically acceptable salt thereof may be included.

Mode for Carrying Out the Invention

[0006] When the chemical structure is shown, the accuracy of the structure takes precedence over the compound name.

[0007] The present invention is based on a compound or a pharmaceutically acceptable salt thereof for use in the treatment of B-cell lymphoma, and the compound has the following structure.

Chemical Formula

[0008] B-cell lymphoma can be one or more of diffuse large B-cell lymphoma, follicular non-Hodgkin lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, primary central nervous system lymphoma, primary intraocular lymphoma, or Waldenström macroglobulinemia. In one embodiment, this compound is for use in the treatment of diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, or Waldenström macroglobulinemia.

[0009] As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid or nitric acid, and organic acids such as citric acid, fumaric acid, maleic acid, malic acid, ascorbic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, salicylic acid, stearic acid, benzenesulfonic acid or p-toluenesulfonic acid. The compound is preferably provided as its succinate salt.

[0010] The compound for use is preferably administered once or twice a day.

[0011] Preferably, 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt is preferably administered orally with water, preferably after the patient has consumed food. In a preferred embodiment, 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt is administered with about 240 mL of water within 1 hour after the patient has ingested food. For this purpose, 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt can be administered in capsule form.

[0012] In the case of oral administration, the compound can be administered as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. Preferred pharmaceutical compositions of the present invention are tablets and capsules.

[0013] The compounds of the present invention can also be formulated with agents that reduce the degradation of substances by processes other than the normal metabolism of the patient, such as antibacterial agents, or inhibitors of protease enzymes that may be present in symbiotic or parasitic organisms living on or within the patient and that can degrade the compound.

[0014] Liquid dispersions for oral administration can be syrups, emulsions and suspensions.

[0015] Suspensions and emulsions can contain, as a carrier, for example, natural gums, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.

[0016] The compound for use is preferably administered at a dose of at least 50 mg per day, more preferably 100 mg per day, even more preferably 150 mg per day, and most preferably 200 mg per day.

[0017] The compound for use can be administered at a dose of up to 600 mg per day, more preferably up to 500 mg per day, even more preferably up to 400 mg per day, even more preferably up to 300 mg per day, and most preferably up to 200 mg per day.

[0018] The compound for use can be administered at a dose of 50 - 400 mg per day, preferably 200 - 400 mg per day, and more preferably 200 mg per day.

[0019] The compound for use can be administered in capsule form.

[0020] The compounds for use are advantageously administered to patients who have already received treatment with a regimen comprising one or more of conventional first-line treatments, such as conventional cytotoxic agents such as cyclophosphamide, doxorubicin, vincristine, prednisone or chlorambucil, CD20 antibodies with or without drug conjugates such as rituximab, obinutuzumab or ibritumomab, BCL2 inhibitors such as venetoclax, BTK inhibitors such as ibrutinib, immunomodulatory imide drugs such as lenalidomide, proteasome inhibitors such as bortezomib, radiation therapy, agents that modulate antitumor immunity including agents that modulate immune checkpoints (e.g., PD(L)1 targeting agents such as pembrolizumab or nivolumab, CTLA-4 targeting agents such as ipilimumab, agents that target OX40, LAG3, TIM3 or other immune regulatory molecules), bispecific T cell engager therapies, or cell therapies (e.g., adoptive T cell therapy, CAR-T therapy). The compounds for use can be advantageously administered to patients who have already received a BTK inhibitor such as ibrutinib and / or a BCL2 inhibitor such as venetoclax.

[0021] In one embodiment, the treatment comprises administering an effective amount of 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt thereof in a 28- to 35-day cycle, wherein 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene is administered daily or twice a day for 3 or 4 weeks, and 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene is not administered for 1 week.

[0022] The present invention also provides a pharmaceutical composition for use in the treatment of B-cell lymphoma, comprising an embodiment of 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene as defined above and a pharmaceutically acceptable excipient.

[0023] Preferably, the compound is enantiomerically pure at least 60%, more preferably 70%, even more preferably 80%, even more preferably 90%, even more preferably 95%, even more preferably 99%.

[0024] The pharmaceutical excipient may include one or more of lactose monohydrate, microcrystalline cellulose, crospovidone, hydroxypropyl cellulose, magnesium stearate, and sodium lauryl sulfate. In one embodiment, the pharmaceutical formulation consists of lactose monohydrate, microcrystalline cellulose, crospovidone, hydroxypropyl cellulose, magnesium stearate, and sodium lauryl sulfate, and 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene as succinate.

[0025] In one embodiment, the pharmaceutical composition is for use in the treatment of one or more of diffuse large B-cell lymphoma, follicular non-Hodgkin lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, primary central nervous system lymphoma, primary intraocular lymphoma, or Waldenström macroglobulinemia. Advantageously, the pharmaceutical composition is for use in the treatment of B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, or Waldenström macroglobulinemia.

[0026] The pharmaceutical composition may include at least one second agent selected from the group consisting of conventional cytotoxic agents such as cyclophosphamide, doxorubicin, vincristine, prednisone or chlorambucil, CD20 antibodies with or without drug conjugates such as rituximab, obinutuzumab or ibritumomab, BCL2 inhibitors such as venetoclax, BTK inhibitors such as ibrutinib, MEK inhibitors such as trametinib, immunomodulatory imide drugs such as lenalidomide, proteasome inhibitors such as bortezomib, radiotherapy, agents that regulate anti-tumor immunity including agents that regulate immune checkpoints (e.g., PD(L)1 targeting agents such as pembrolizumab or nivolumab, CTLA-4 targeting agents such as ipilimumab, agents that target OX40, LAG3, TIM3 or other immune regulatory molecules), bispecific T cell engager therapies, or cell therapies (e.g., adoptive T cell therapy, CAR-T therapy), as a combined preparation for simultaneous, sequential or separate use in therapy. Preferably, the second agent is selected from p70S6K inhibitors, BTK and TEC family inhibitors, and MEK1 inhibitors.

[0027] The present invention also provides a kit comprising at least one agent selected from the group consisting of 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]tridec-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt thereof, preferably a succinate salt, and a conventional cytotoxic agent such as cyclophosphamide, doxorubicin, vincristine, prednisone or chlorambucil, a drug conjugate such as rituximab, obinutuzumab or ibritumomab, a CD20 antibody with or without the foregoing, a BCL2 inhibitor such as venetoclax, a BTK inhibitor such as ibrutinib, an MEK inhibitor such as trametinib, an immunomodulatory imide drug such as lenalidomide, a proteasome inhibitor such as bortezomib, a drug that modulates anti-tumor immunity including a drug that modulates an immune checkpoint (e.g., a PD(L)1 targeting agent such as pembrolizumab or nivolumab, a CTLA-4 targeting agent such as ipilimumab, a drug that targets OX40, LAG3, TIM3 or other immune regulatory molecules), a bispecific T cell engager therapy, or a cell therapy (e.g., adoptive T cell therapy, CAR-T therapy), as a combined preparation for simultaneous, sequential or separate use in therapy.

[0028] The present invention also provides a method for treating or preventing B cell lymphoma in a patient, comprising administering to the patient a therapeutically effective amount of at least one compound defined above or a pharmaceutical composition defined above, or using a kit defined above.

[0029] This method may be for treating or preventing diffuse large B-cell lymphoma, follicular non-Hodgkin lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, primary central nervous system lymphoma, primary intraocular lymphoma, or Waldenström macroglobulinemia. Advantageously, this method is for treating or preventing B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, or Waldenström macroglobulinemia.

[0030] This method may provide that the compound is administered at a dose of at least 50 mg per day, more preferably 100 mg per day, even more preferably 150 mg per day, and most preferably 200 mg per day.

[0031] This method may provide that the compound is administered at a dose of up to 600 mg per day, more preferably up to 500 mg per day, even more preferably up to 400 mg per day, even more preferably up to 300 mg per day, and most preferably 200 mg per day.

[0032] This method may provide that the compound is administered at a dose of 50 - 400 mg per day, preferably 200 - 400 mg per day, and more preferably 200 mg per day.

[0033] The compound to be used may be administered once a day, twice a day, three times a day, or four times a day. Preferably, the compound is administered once or twice a day, and more preferably, the compound is administered once a day.

[0034] This method can be provided for administration to a patient who has already received treatment with a regimen comprising one or more of conventional first-line treatments, such as conventional cytotoxic agents such as cyclophosphamide, doxorubicin, vincristine, prednisone or chlorambucil, CD20 antibodies with or without drug conjugates such as rituximab, obinutuzumab or ibritumomab, BCL2 inhibitors such as venetoclax, BTK inhibitors such as ibrutinib, immunomodulatory imide drugs such as lenalidomide, proteasome inhibitors such as bortezomib, radiation therapy, drugs that modulate antitumor immunity including drugs that modulate immune checkpoints (e.g., PD(L)1 targeting agents such as pembrolizumab or nivolumab, CTLA-4 targeting agents such as ipilimumab, drugs that target OX40, LAG3, TIM3 or other immune regulatory molecules), bispecific T cell engager therapies, or cell therapies (e.g., adoptive T cell therapy, CAR-T therapy). The compound for use can be advantageously administered to patients who have already received a BTK inhibitor such as ibrutinib and / or a BCL2 inhibitor such as venetoclax therapy.

[0035] The present invention also provides a method for treating B cell lymphoma, which comprises administering, to a patient in need thereof, an effective amount of 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt thereof, such as a succinate salt.

[0036] The present invention also provides a method of doing so in a patient in need of treating a progressive or metastatic B-cell lymphoma, comprising administering an effective amount of 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt thereof, wherein the patient has progressive B-cell lymphoma following a previous administration of another therapy.

[0037] This method may provide that the previous administration of another therapy is a therapy for progressive or metastatic B-cell lymphoma.

[0038] In this method, optionally, the previous administration of another therapy is, for example, a conventional cytotoxic agent such as cyclophosphamide, doxorubicin, vincristine, prednisone or chlorambucil, a CD20 antibody with or without a drug conjugate such as rituximab, obinutuzumab or ibritumomab, a BCL2 inhibitor such as venetoclax, a BTK inhibitor such as ibrutinib, an immunomodulatory imide drug such as lenalidomide, a proteasome inhibitor such as bortezomib, an agent that modulates anti-tumor immunity including an agent that modulates immune checkpoint (e.g., a PD(L)1 targeting agent such as pembrolizumab or nivolumab, a CTLA-4 targeting agent such as ipilimumab, an agent that targets OX40, LAG3, TIM3 or other immune regulatory molecules), a bispecific T-cell engager therapy, or an administration of another chemotherapeutic agent such as a regimen comprising one or more of cell therapy (e.g., adoptive T-cell therapy, CAR-T therapy). The compound for use may be advantageously administered to patients who have already received a BTK inhibitor such as ibrutinib and / or a BCL2 inhibitor such as venetoclax therapy.

[0039] In this method, administering an effective amount of 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]tridec-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt thereof may include orally administering from about 200 mg to about 400 mg, preferably 200 mg, of 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]tridec-1(13),2(7),3,5,9,11-hexaene per total daily dose.

[0040] In this method, administering an effective amount of 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]tridec-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt thereof may include orally administering from about 200 mg to about 400 mg, preferably 200 mg, of 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]tridec-1(13),2(7),3,5,9,11-hexaene once or twice a day.

[0041] Preferably, the patient has a histological or cytological diagnosis of B-cell lymphoma. Administering an effective amount of 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]tridec-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt thereof may include administration in a 28- to 35-day cycle, and 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]tridec-1(13),2(7),3,5,9,11-hexaene is administered to the patient daily or twice a day for 3 weeks or 4 weeks, and 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]tridec-1(13),2(7),3,5,9,11-hexaene is not administered for 1 week.

[0042] This method may further include administering to the patient at least one second agent selected from the group consisting of a therapeutically effective amount of a conventional cytotoxic agent such as cyclophosphamide, doxorubicin, vincristine, prednisone or chlorambucil, a CD20 antibody with or without a drug conjugate such as rituximab, obinutuzumab or ibritumomab, a BCL2 inhibitor such as venetoclax, a BTK inhibitor such as ibrutinib, an MEK inhibitor such as trametinib, an immunomodulatory imide drug such as lenalidomide, a proteasome inhibitor such as bortezomib, radiation therapy, an agent that modulates anti-tumor immunity including an agent that modulates an immune checkpoint (e.g., a PD(L)1 targeting agent such as pembrolizumab or nivolumab, a CTLA-4 targeting agent such as ipilimumab, an agent that targets OX40, LAG3, TIM3 or other immune regulatory molecules), bispecific T cell engager therapy, or cell therapy (e.g., adoptive T cell therapy, CAR-T therapy).

[0043] The administration of the compound and at least one second agent can be separate, sequential or simultaneous.

[0044] The present invention also provides a compound or a pharmaceutically acceptable salt thereof for use in the treatment of B cell lymphoma, the compound having the following formula,

Chemical formula

Examples

[0045] On the clinical cut-off date, 21 patients with relapsed or refractory B cell lymphoma were treated in this study. 6 patients were enrolled and treated at 50 mg per day, 3 patients were treated at 100 mg per day, 7 patients were treated at 200 mg per day, and 5 patients were treated at 400 mg per day.

[0046] The first patient enrolled started treatment with 50 mg of 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene. The progression of each patient in each cohort up to the clinical cut-off date is summarized in Tables 1 and 2.

Table 1

Table 2

[0047] Table 3 shows a summary of the efficacy results in previous studies. Complete responses were observed in subjects 01004, 01013, 01018, and 01020, partial responses in subjects 01010, 01011, and 01017, and stable disease in subjects 01006, 01007, 01009, and 01019. Among subjects who initiated treatment at a dose of 200 mg or more per day for which response data were reported, the ORR was 50% (6 / 12). Patients who achieved at least a partial response included those with indolent NHL, MCL, and DLBCL. Thus, there is evidence that this agent is effective as monotherapy for lymphoma that has relapsed after prior treatment.

[0048] [Table 3]

[0049] An independent review of imaging from the study was performed by ABX-CRO. This independent review was substantially consistent with the evaluations at the study sites (MD Anderson Cancer Center; MDACC). In the independent review, a single subject was classified differently (subject 01018, classified as a complete response by MDACC and a partial response by ABX-CRO; Table 4).

[0050] [Table 4]

[0051] Synthesis of the Compounds of the Invention [Chemical Formula] Reagents and Conditions: 1) K 2 CO 3 , ethyl glycolate, DMF, 115 °C, 2) (i) chlorosulfonyl isocyanate, CH 2 Cl 2、 0 - 10 °C, then room temperature (ii) water, 75 °C (iii) NaOH, maximum temperature 40 °C, 3) POCl 3, N,N-dimethylaniline, 107 °C, 4) morpholine, MeOH, room temperature, 5) N,N-dimethylacrylamide, PdCl 2 (PPh 3 ) 2 , NaOAc, DMF, 110 °C, 6) NaIO 4 , OsO 4 , THF, water, room temperature, 7) indole-4-boronic acid pinacol ester, PdCl 2 (PPh 3 ) 2 , sodium carbonate, dioxane, water, 102 °C.

[0052] i. Ethyl 3-amino-5-bromofuro[2,3-b]pyridine-2-carboxylate N 2 (g) To a 10 L flask under N 2 (g), 5-bromo-2-chloropyridine-3-carbonitrile (435 g, 2.0 mol, 1 equivalent), DMF (2790 mL) and potassium carbonate (553 g, 4.0 mol, 2 equivalents) were added. Subsequently, ethyl glycolate (208.2 mL, 2.2 mol, 1.1 equivalents) was added. The reaction mixture was heated at 115 °C overnight. When complete, the reaction mixture was cooled to room temperature and water (13.1 L) was added, whereby a precipitate formed. The mixture was stirred for 20 minutes and then filtered. The resulting brown solid was dried at 50 °C and slurried in Et 2 O:heptane (9:1, 2.8 L), filtered to obtain 405.6 g. Further purification by Soxhlet extraction using TBME (4.5 L) gave the product as a yellow solid (186 g, 34%). This procedure was repeated twice.

[0053] 1 H NMR (400 MHz, CDCl 3 ) δ H : 8.53 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 5.00 (br.s., 2H), 4.44 (q, J = 7.0 Hz, 2H), 1.44 (t, J = 7.0 Hz, 3H).

[0054] MS (ES +)309(100%, [M+Na] + )、307(100%, [M+Na] + )。

[0055] ii. 12-Bromo-8-oxa-3,5,10-triazatricyclo[7.4.0.0 2,7 trideca-1(9),2(7),10,12-tetraene-4,6-dione CH 2 Cl 2 (5.5 L) of ethyl-3-amino-5-bromofuro[2,3-b]pyridine-2-carboxylate (239.0 g, 0.84 mol, 1 equivalent) dissolved in was added dropwise with chlorosulfonyl isocyanate (87.6 mL, 1.0 mol, 1.2 equivalents) at 0 - 10 °C. The resulting reaction mixture was stirred for 30 minutes, stripped to dryness, and the obtained solid was pulverized into fine powder. Water (5.5 L) was added to the solid, and the suspension was heated at 75 °C for 1 hour. After cooling to room temperature, solid NaOH (335 g, 8.4 mol, 10 equivalents) was added, and the reaction mixture was exothermic (maximum temperature 40 °C). The reaction mixture was cooled to 0 - 10 °C, and the pH was adjusted to 5 - 6 using 5M HCl (about 1 L). The reaction mixture was stirred for 30 minutes and then filtered. The solid was washed with water (2.3 L) and pulled to dry. It was further dried in a vacuum oven at 40 °C to obtain the product as a brown solid (193 g, 76%). This procedure was repeated twice.

[0056] 1 H NMR(400MHz, DMSO-d 6 ) δ H : 12.01(br.s., 1H), 11.58(br.s, 1H), 8.72(d, J = 2.0Hz, 1H), 8.59(d, J = 2.0Hz, 1H).

[0057] MS(ES - ) 282(100%, [M+H] + )。

[0058] iii. 12-Bromo-4,6-dichloro-8-oxa-3,5,10-triazatricyclo[7.4.0.0 2,7Trideca-1(9),2(7),3,5,10,12-hexaene 12-Bromo-8-oxa-3,5,10-triazatricyclo[7.4.0.0 2,7 Trideca-1(9),2(7),10,12-tetraene-4,6-dione (387 g, 1.27 mol, 1 eq) was added to POCl 3 (6070 mL) and N,N-dimethylaniline (348 mL, 2.8 mol, 2.2 eq). The mixture was heated at 107 °C for 10 h. Once cooled to room temperature, the solvent was removed by vacuum azeotropic distillation using toluene (3 x 3.9 L). The resulting residue was partitioned between CH 2 Cl 2 (12.76 L) and water (3.9 L), and the phases were separated. The organic phase was washed with water (2 x 3.9 L). The combined aqueous solutions were back-extracted with CH 2 Cl 2 (7.7 L), and the combined organics were dried over MgSO 4 and filtered and stripped to give the product as a brown solid (429 g, approximate yield).

[0059] 1 1H NMR (400 MHz, CDCl 3 ) δ H : 8.78 (d, J = 2.5 Hz, 1H), 8.72 (d, J = 2.5 Hz, 1H).

[0060] iv. 12-Bromo-4-chloro-6-(morpholin-4-yl)-8-oxa-3,5,10-triazatricyclo[7.4.0.0 2,7 Trideca-1(9),2(7),3,5,10,12-hexaene 12-Bromo-4,6-dichloro-8-oxa-3,5,10-triazatricyclo[7.4.0.0 in MeOH (8588 mL) 2,7Trideca-1(9),2(7),3,5,10,12-hexaene (419.3 g, 1.32 mol, 1 equivalent) was added with morpholine (259 mL, 2.90 mol, 2.2 equivalents) at room temperature. After stirring for 2 hours, water (0.8 L) was added. Then, it was cooled to 0 - 5 °C and stirred for an additional 30 minutes. The obtained solid was filtered, washed with water (5.2 L), and pulled to dry. CH 2 Cl 2 Further purification by silica gel column chromatography using CH 2 Cl / EtOAc (1:0 - 9:1) gave the desired product (419 g, 84%).

[0061] 1 H NMR (400 MHz, CDCl 3 ) δ H : 8.66 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 2.0 Hz, 1H), 4.07 - 4.21 (m, 4H), 3.85 - 3.91 (m, 4H).

[0062] MS (ES + ) 393 (100%, [M + Na] + )、391 (80%, [M + Na] + ).

[0063] v. (2E)-3-[4-chloro-6-(morpholin-4-yl)-8-oxa-3,5,10-triazatricyclo[7.4.0.0 2,7 trideca-1(9),2(7),3,5,10,12-hexaen-12-yl]-N,N-dimethylprop-2-enamide 12-Bromo-4-chloro-6-(morpholin-4-yl)-8-oxa-3,5,10-triazatricyclo[7.4.0.0 2,7 trideca-1(9),2(7),3,5,10,12-hexaene (60 g, 0.15 mol, 1 equivalent) was added with N,N-dimethylacrylamide (16.7 mL, 0.15 mol, 1 equivalent), PdCl 2 (PPh 3 ) 2(3.4 g, 4.5 mmol, 0.03 eq) and NaOAc (40 g, 0.45 mol, 3 eq) in DMF (1.2 L) were added. The reaction mixture was heated at 110 °C for 7 h. This process was repeated three times and the batches were combined. Once cooled to room temperature, the solvent was removed in vacuo and the resulting residue was partitioned between CH 2 Cl 2 (6.5 L) and water (5.5 L). The phases were separated and the aqueous phase was extracted with CH 2 Cl 2 (2 x 4 L). The combined organics were washed with brine (2 x 4 L), dried over MgSO 4 , filtered and stripped. The resulting solid was slurried in EtOAc / heptane (1:1, 0.8 L) for 30 min, filtered, washed and washed with EtOAc / heptane (1:1, 2 x 450 mL). Further drying in a vacuum oven at 40 °C gave the desired product as an orange solid (203.0 g, 86%).

[0064] 1 1H NMR (400 MHz, CDCl 3 ) δ H : 8.70 (s, 2H), 7.82 (d, J = 15.6 Hz, 1H), 7.07 (d, J = 15.6 Hz, 1H), 4.11 - 4.19 (m, 4H), 3.85 - 3.93 (m, 4H), 3.22 (s, 3H), 3.11 (s, 3H). MS (ES + ) 388 (100%, [M + H] + ).

[0065] vi. 4-Chloro-6-(morpholin-4-yl)-8-oxa-3,5,10-triazatricyclo[7.4.0.0 2,7 trideca-1(9),2(7),3,5,10,12-hexaen-12-carbaldehyde (2E)-3-[4-Chloro-6-(morpholin-4-yl)-8-oxa-3,5,10-triazatricyclo[7.4.0.0 2,7[[Trideca-1(9),2(7),3,5,10,12-hexaen-12-yl]-N,N-dimethylprop-2-enamide (124.0 g, 0.39 mol, 1 equiv) was dissolved in THF (12.4 L) at 65 °C. Once cooled to 35 °C, water (4.1 L), NaIO 4 (205.4 g, 1.17 mol, 3 equiv) and OsO 4 ( t 2.5 wt% in BuOH, 80.3 mL, 2%) were added. The mixture was stirred at room temperature for 60 h. The reaction was cooled to 0 - 5 °C, stirred for 30 min, and then filtered. The solid was washed with water (545 mL) and pulled dry. The crude product was combined with two additional batches (2 × 118.3 g scale) and slurried in water (6.3 L) at room temperature for 30 min. The solids were filtered, washed with water (1.6 L), and pulled dry. Further drying in a vacuum oven gave the desired product as a pink solid (260 g, 88%).

[0066] 1 H NMR (400 MHz, CDCl 3 :MeOD, 9:1) δ H : 10.13 (s, 1H), 9.04 (d, J = 2.0 Hz, 1H), 8.91 (d, J = 2.0 Hz, 1H), 3.99 - 4.13 (m, 4H), 3.73 - 3.84 (m, 4H).

[0067] MS (ES + ) 351 (100%, [M + MeOH + H] + ).

[0068] vii. 4-(1H-Indol-4-yl)-6-(morpholin-4-yl)-8-oxa-3,5,10-triazatricyclo[7.4.0.0 2,7 trideca-1(9),2,4,6,10,12-hexaene-12-carbaldehyde 4-Chloro-6-(morpholin-4-yl)-8-oxa-3,5,10-triazatricyclohe[7.4.0.0 2,7Trideca-1(9),2(7),3,5,10,12-hexaen-12-carbaldehyde (164.4 g, 0.52 mol, 1 equiv) was added with indole-4-boronic acid pinacol ester (376.0 g, 1.55 mol, 3 equiv), PdCl 2 (PPh 3 ) 2 (72.0 g, 0.10 mol, 2 equiv) and sodium carbonate (110.2 g, 1.04 mol, 2 equiv) in dioxane (16.4 L) / water (5.8 L). The reaction mixture was refluxed for 1 hour. Then, the reaction mixture was cooled to 60 - 70 °C. Water (9.8 L), brine (4.9 L) and EtOAc (9.5 L) were added. The phases were separated and the aqueous phase was extracted with EtOAc (3 x 9.5 L) at 60 - 65 °C. The combined organics were dried over MgSO 4 , filtered and stripped. The resulting solid was slurried in CH 2 Cl 2 (4.75 L) for 30 minutes, filtered and washed with CH 2 Cl 2 (3 x 238 mL) and pulled dry. It was further dried in a vacuum oven at 40 °C to obtain Intermediate X as a yellow solid (135.7 g, 66%).

[0069] 1 H NMR (300 MHz, CDCl 3 ) δ H : 11.27 (br.s, 1H), 10.26 (s, 1H), 9.16 (d, J = 2.3 Hz, 1H), 9.11 (d, J = 2.3 Hz, 1H), 8.18 (d, J = 7.5 Hz, 1H), 7.58 - 7.67 (m, 2H), 7.49 (t, J = 2.8 Hz, 1H), 7.23 (t, J = 7.7 Hz, 1H), 4.08 - 4.16 (m, 4H), 3.83 - 3.90 (m, 4H).

[0070] MS (ES + ) 432.0 (100%, [M + MeOH + H] + ).

[0071] 4-(1H-Indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.0 2,7 trideca-1(13),2(7),3,5,9,11-hexaene (A) [Chemical formula]

[0072] Anhydrous CH 2 Cl 2 (150 mL) of a suspension of intermediate X (7.00 g, 17.53 mmol, 1 equivalent), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (7.13 g, 52.58 mmol, 3 equivalents) and NaOAc (4.31 g, 52.58 mmol, 3 equivalents) was added to NaBH(OAc) 3 (7.43 g, 35.06 mmol, 2 equivalents). The reaction mixture was stirred overnight at room temperature. Then, the reaction mixture was separated with 1N NaOH (100 mL), and extracted with CH 2 Cl 2 (3 x 200 mL). The combined organic extracts were washed with brine (50 mL), then dried over MgSO 4 , and the solvent was removed in vacuo. Purification by silica gel column chromatography using EtOAc / MeOH (1:0 - 7:1) gave the product A (the compound of the present invention) as a white solid (6.02 g, 71%).

[0073] 1 H NMR (300 MHz, CDCl 3 ) δ H: 8.65 (d, J = 2.1 Hz, 1H), 8.58 (d, J = 2.1 Hz, 1H), 8.37 (br.s., 1H), 8.24 (dd, J = 7.5, 0.9 Hz, 1H), 7.62 (td, J = 2.6, 0.8 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.37 - 7.41 (m, 1H), 7.31 - 7.37 (m, 1H), 4.47 (s, 1H), 4.22 - 4.30 (m, 4H), 4.18 (d, J = 8.1 Hz, 1H), 3.98 (d, J = 2.3 Hz, 2H), 3.91 - 3.97 (m, 4H), 3.70 (dd, J = 7.9, 1.7 Hz, 1H), 3.53 (s, 1H), 2.94 (dd, J = 10.0, 1.5 Hz, 1H), 2.64 (d, J = 10.2 Hz, 1H), 1.97 (dd, J = 9.8, 1.9 Hz, 1H), 1.80 (dt, J = 9.8, 1.1 Hz, 1H).

[0074] MS(ES + ) 483.1 (100%, [M + H] + ).

[0075] 4-(1H-Indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.0 2,7 trideca-1(13),2(7),3,5,9,11-hexaene; succinic acid (AS)

Chem.

[0076] 1. Ethanol (5 volumes) was added and distilled at atmospheric pressure (Tend = 49 °C). Precipitation started during concentration.

[0077] 2. Ethanol (5 volumes) was added and distilled at atmospheric pressure (Tend = 73 °C).

[0078] 3. Additional solvent was removed (Tend = 75 °C).

[0079] 4. Milli-Q water (100 mL, 1 volume) was added and distillation was continued until T = 76 °C.

[0080] The filtered solution of succinic acid was added dropwise to a suspension of compound A in ethanol under reflux. Subsequently, milli-Q water (50 mL, 0.5 volume) was added, and then additional milli-Q water was added (1 volume). The suspension was heated under reflux for 5 hours while slowly distilling the solvent. Then, the suspension was cooled to room temperature and stirred for ±10 hours. The product was filtered off and washed with EtOH (4 × 1 volume). The filter cake was dried on the filter in a vacuum oven at 50 °C for 21 hours to obtain the product AS (the succinate salt of the compound of the present invention) as a white to pale yellow solid. Yield: 119.05 grams = 198.2 mmol = 95.7%.

[0081] 1 H NMR (400 MHz, DMF-d7) δ H : 11.32 (br.s, 1H), 8.67 (s, 2H), 8.29 (d, J = 7.4 Hz, 1H), 7.70 (m, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.58 (m, 1H), 7.28 (t, J = 7.4 Hz, 1H), 4.39 (m, 1H), 4.22 (m, 4H), 4.04 (m, 3H), 3.94 (m, 4H), 3.61 (m, 2H), 2.87 (m, 1H), 2.57 (m, 5H), 1.69 (m, 1H), 1.51 (m, 1H).

[0082] MS (ES + ) 483.2 (100%, [M + H] + ). The present invention provides, for example, the following items. (Item 1) A compound or a pharmaceutically acceptable salt thereof for use in the treatment of B-cell lymphoma, having the following structure.

Chem.

Chem.

Claims

1. A composition comprising a compound for use in the treatment of B-cell lymphoma or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure. 【Chemical Formula 7】

2. The composition according to claim 1, wherein the B-cell lymphoma is one or more of diffuse large B-cell lymphoma, follicular non-Hodgkin lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, primary central nervous system lymphoma, primary intraocular lymphoma, or Waldenström macroglobulinemia.

3. The composition according to claim 1 or 2 for use in the treatment of diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, or Waldenström macroglobulinemia.

4. The composition according to any one of claims 1 to 3, wherein the compound is provided as its succinate salt.

5. The composition according to any one of claims 1 to 4, which is administered once or twice a day.

6. The composition according to any one of claims 1 to 5, wherein the compound is administered at a dose of at least 200 mg per day.

7. The composition according to any one of claims 1 to 6, wherein the compound is administered at a maximum dose of 400 mg per day.

8. The composition according to any one of claims 1 to 7, wherein the compound is administered at a dose of 50 to 400 mg per day.

9. The composition according to any one of claims 1 to 8, which is administered orally.

10. The composition according to any one of claims 1 to 9, which is administered in capsule form.

11. A composition according to any one of claims 1 to 10, which is administered to a patient who has already received a conventional first-line treatment, wherein the conventional first-line treatment comprises a regimen including one or more of a conventional cytotoxic agent, a CD20 antibody with or without a drug conjugate, a BCL2 inhibitor, a BTK inhibitor, an immunomodulatory imide drug, a proteasome inhibitor, radiotherapy, an agent for modulating anti-tumor immunity including an agent for modulating immune checkpoints, a bispecific T-cell engager therapy, or a cell therapy.

12. The composition according to any one of claims 1 to 11, which is administered to a patient who has already received a BTK inhibitor and / or a BCL2 inhibitor.

13. The treatment comprises administering an effective amount of 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt thereof in a cycle of 28 to 35 days, wherein 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene is administered to the patient daily or twice a day for 3 or 4 weeks, and 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene is not administered for 1 week. The composition according to any one of claims 1 to 12.

14. A pharmaceutical composition for use in the treatment of B-cell lymphoma, comprising the composition according to any one of claims 1 to 13 and a pharmaceutically acceptable excipient.

15. The pharmaceutical composition for use according to claim 14, wherein the B-cell lymphoma is diffuse large B-cell lymphoma, follicular non-Hodgkin lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, primary central nervous system lymphoma, primary intraocular lymphoma or Waldenström macroglobulinemia.

16. The pharmaceutical composition for use according to claim 14, wherein the B-cell lymphoma is B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma or Waldenström macroglobulinemia.

17. At least one second agent selected from the group consisting of a conventional cytotoxic agent, a CD20 antibody with or without a drug conjugate, a BCL2 inhibitor, a BTK inhibitor, an MEK inhibitor, an immunomodulatory imide drug, a proteasome inhibitor, radiation therapy, an agent that modulates an immune checkpoint, bispecific T cell engager therapy, or cell therapy, is included as a combined preparation for simultaneous, sequential, or separate use in therapy, the pharmaceutical composition according to any one of claims 14 to 16.

18. The pharmaceutical composition according to claim 17, wherein the second agent is selected from bortezomib, LY2584702, ibrutinib, and selumetinib.

19. The pharmaceutical composition according to claim 17, wherein the second agent is selected from a p70S6K inhibitor, a BTK and TEC family inhibitor, and a MEK1 inhibitor.

20. A kit for use in the treatment of B cell lymphoma, comprising 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt thereof, and at least one agent selected from the group consisting of a conventional cytotoxic agent, a CD20 antibody with or without a drug conjugate, a BCL2 inhibitor, a BTK inhibitor, an MEK inhibitor, an immunomodulatory imide drug, a proteasome inhibitor, radiation therapy, an agent that modulates an immune checkpoint, bispecific T cell engager therapy, or cell therapy, included as a combined preparation for simultaneous, sequential, or separate use in therapy.

21. A composition as defined in any one of claims 1 to 13, or a pharmaceutical composition as defined in any one of claims 14 to 19, or a kit as defined in claim 20, for use in a method of treating or preventing B cell lymphoma in a patient.

22. The composition, pharmaceutical composition, or kit according to claim 21 for use in a method of treating or preventing diffuse large B-cell lymphoma, follicular non-Hodgkin lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, primary central nervous system lymphoma, primary intraocular lymphoma, or Waldenström macroglobulinemia.

23. The composition, pharmaceutical composition, or kit according to claim 21 for use in a method of treating or preventing B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, or Waldenström macroglobulinemia.

24. The composition, pharmaceutical composition, or kit according to any one of claims 21 to 23, wherein the compound is administered at a total daily dose of 50 to 400 mg.

25. The composition, pharmaceutical composition, or kit according to any one of claims 21 to 24, wherein the compound is administered once or twice daily.

26. The composition, pharmaceutical composition, or kit according to any one of claims 21 to 25, wherein the compound is administered to a patient who has already received a conventional first-line treatment, and the conventional first-line treatment includes one or more of a conventional cytotoxic agent, a CD20 antibody with or without a drug conjugate, a BCL2 inhibitor, a BTK inhibitor, an immunomodulatory imide drug, a proteasome inhibitor, radiation therapy, an agent that regulates anti-tumor immunity including an agent that regulates immune checkpoints, bispecific T-cell engager therapy, or cell therapy.

27. A composition for use in a method of treating a patient in need of treating B-cell lymphoma, comprising a compound or a pharmaceutically acceptable salt thereof, wherein the compound is 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene, and the method comprises administering an effective amount of 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt thereof.

28. A composition for use in a method of treating a patient in need of treating advanced or metastatic B-cell lymphoma, comprising a compound or a pharmaceutically acceptable salt thereof, wherein the compound is 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene, and the patient has B-cell lymphoma that has progressed after a previous administration of another therapy, and the method comprises administering an effective amount of 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt thereof.

29. The composition according to claim 28, wherein the previous administration of the another therapy is a therapy for advanced or metastatic B-cell lymphoma.

30. The composition according to claim 28 or 29, wherein the previous administration of the another therapy is an administration of another chemotherapeutic agent.

31. The composition according to claim 30, wherein the previous administration of the chemotherapeutic agent comprises an anti-tumor immunity modulating agent including a conventional cytotoxic agent, a CD20 antibody with or without a drug conjugate, a BCL2 inhibitor, a BTK inhibitor, an immunomodulatory imide drug, a proteasome inhibitor, radiotherapy, a drug that modulates an immune checkpoint, a bispecific T cell induction therapy, or a cell therapy.

32. Administering an effective amount of 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]tridec-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt thereof, which comprises orally administering 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]tridec-1(13),2(7),3,5,9,11-hexaene in a total daily dose of 200 mg to 400 mg, the composition according to any one of claims 27 to 31.

33. Administering an effective amount of 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]tridec-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt thereof, which comprises orally administering 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]tridec-1(13),2(7),3,5,9,11-hexaene once or twice a day in an amount of 200 mg to 400 mg, the composition according to any one of claims 27 to 32.

34. The composition according to any one of claims 27 to 33, wherein the patient has a histological or cytological diagnosis of B cell lymphoma.

35. Administering an effective amount of 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt thereof, which comprises a 28-35 day cycle, wherein 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene is administered to the patient daily or twice, over 3 weeks or 4 weeks, and 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene is not administered for 1 week, the composition according to any one of claims 27 to 34.

36. The method further comprises administering to the patient at least one second agent selected from the group consisting of a therapeutically effective amount of a conventional cytotoxic agent, a CD20 antibody with or without a drug conjugate, a BCL2 inhibitor, a BTK inhibitor, an MEK inhibitor, an immunomodulatory imide drug, a proteasome inhibitor, radiation therapy, an agent that modulates anti-tumor immunity including an agent that modulates an immune checkpoint, a bispecific T cell engager therapy, or a cell therapy, the composition, pharmaceutical composition, or kit according to any one of claims 21 to 25.

37. The pharmaceutical composition according to any one of claims 17 to 19, or the kit according to claim 36, wherein the compound and the at least one second agent are administered separately, sequentially, or simultaneously.

38. A composition for use in the treatment of B cell lymphoma, comprising a compound or a pharmaceutically acceptable salt thereof, wherein the compound has the following formula 【Chemical 8】 The composition, wherein the compound is administered at a total daily dose of 200 mg, the compound is administered to a patient who has already received a conventional first-line treatment, and the conventional first-line treatment comprises treatment with a regimen comprising one or more of a conventional cytotoxic agent, a CD20 antibody with or without a drug conjugate, a BCL2 inhibitor, a BTK inhibitor, an immunomodulatory imide drug, a proteasome inhibitor, radiotherapy, an agent that modulates antitumor immunity comprising an agent that modulates an immune checkpoint, a bispecific T cell engager therapy, or a cell therapy.

Images