Use of sulfoximine compound for treating lymphoma

Abstract

The present application pertains to the field of medicinal chemistry and provides use of a sulfoximine compound for treating lymphoma. Specifically, the present application relates to use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating lymphoma.

Description

Use of imino sulfone compounds for treating lymphoma

[0001] Cross-reference to Related Applications

[0002] This application claims priority to and the benefit of Chinese Patent Application No. 202410685908.4, filed May 30, 2024, in the China National Intellectual Property Office, the contents of which are incorporated herein in their entirety. TECHNICAL FIELD

[0003] The present application belongs to the field of medicinal chemistry, and relates to the use of imino sulfone compounds for treating lymphoma. Specifically, the present application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating lymphoma. BACKGROUND

[0004] Epigenetic regulation of transcriptional genes plays an important role in the development of diseases such as tumors. Histone acetylation is usually most relevant to the activation of gene transcription, and the recognition of histone lysine acetylation is a key step for histone acetylation to participate in epigenetic regulation. Bromodomain (BRD) is a conserved region that can specifically recognize acetylated lysine (KAc) in histone and form a protein complex that drives active transcription.

[0005] BET (Bromodomain and Extra Terminal) proteins include two interrelated bromodomain centers and an extra terminal domain, and are divided into Brd2, Brd3, Brd4 and BrdT according to the difference in amino acid sequence. BET is a kind of transcriptional regulatory protein, which plays a very important role in the regulation of gene expression through interaction with chromatin. In the disease state, BET proteins can promote the abnormal expression of oncogenes such as c-Myc, NF-κB, Aurora B and BCL-2. Therefore, the development of BET inhibitors provides a new idea for the treatment of various diseases.

[0006] WO2020020288A1 discloses the use of an imino sulfone compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating diseases mediated by BET proteins, SUMMARY

[0007] In one aspect, the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for treating T-cell lymphoma,

[0008] This application provides for the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the treatment of T-cell lymphoma.

[0009] This application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of T-cell lymphoma.

[0010] This application provides a method for treating T-cell lymphoma, comprising administering to a subject in need of the treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0011] On the other hand, this application provides a kit comprising: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; and b) instructions for use for treating T-cell lymphoma. In some embodiments, the instructions for use are instructions to a subject to administer the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0012] In some embodiments, the T-cell lymphoma is selected from peripheral T-cell lymphoma, T-lymphoblastic lymphoma, nasal extranodal NK / T-cell lymphoma, and cutaneous T-cell lymphoma. In some embodiments, the T-cell lymphoma is selected from peripheral T-cell lymphoma.

[0013] In some embodiments, the pharmaceutical composition is a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0014] Furthermore, this application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for the treatment of B-cell lymphoma.

[0015] This application provides for the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the treatment of B-cell lymphoma.

[0016] This application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of B-cell lymphoma.

[0017] This application provides a method for treating B-cell lymphoma, comprising administering to a subject in need of the treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0018] In another aspect, this application provides a kit comprising: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; and b) instructions for use for treating B-cell lymphoma. In some embodiments, the instructions for use instruct a subject to administer the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0019] In some embodiments, the B-cell lymphoma is selected from diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma.

[0020] In some embodiments, the pharmaceutical composition is a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0021] On the other hand, this application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for the treatment of Hodgkin's lymphoma.

[0022] This application provides for the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the treatment of Hodgkin's lymphoma.

[0023] This application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of Hodgkin's lymphoma.

[0024] This application provides a method for treating Hodgkin's lymphoma, comprising administering to a subject in need of the treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0025] In another aspect, this application provides a kit comprising: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; and b) instructions for use for treating Hodgkin's lymphoma. In some embodiments, the instructions for use instruct a subject to administer the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0026] In some implementations, the Hodgkin lymphoma is selected from classical Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma.

[0027] In some embodiments, the pharmaceutical composition is a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0028] T-cell lymphoma

[0029] In some embodiments, the T-cell lymphoma is selected from peripheral T-cell lymphoma (PTCL), T-lymphoblastic lymphoma, nasal extranodal NK / T-cell lymphoma, and cutaneous T-cell lymphoma.

[0030] In some embodiments, the T-cell lymphoma is selected from limited-stage or advanced-stage T-cell lymphomas.

[0031] In some embodiments, the T-cell lymphoma is selected from T-cell lymphomas of Lugano stage I, II, III, or IV.

[0032] In some embodiments, the patient with the T-cell lymphoma has at least one measurable lesion other than a brain lesion. In some embodiments, the measurable lesion is selected from lymph node lesions with a long diameter >15 mm or extranodal lesions with a long diameter >10 mm.

[0033] In some implementations, the T-cell lymphoma is selected from newly diagnosed T-cell lymphoma or relapsed / refractory T-cell lymphoma.

[0034] In some implementations, the T-cell lymphoma is selected from T-cell lymphomas for which there is no standard treatment or which have progressed or are intolerable after prior standard treatment.

[0035] In some implementations, patients with the T-cell lymphoma have no standard treatment options or whose disease has progressed or is intolerable after receiving standard treatment.

[0036] In some implementations, patients with the T-cell lymphoma have not received standard treatment.

[0037] In some implementations, patients with the T-cell lymphoma have received one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) standard treatments.

[0038] In some implementations, patients with the T-cell lymphoma have received one, two, or three standard treatments.

[0039] In some embodiments, the peripheral T-cell lymphoma is selected from peripheral T-cell lymphoma nonspecific type (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma, and peripheral T-cell lymphoma with follicular helper T-cell (TFH) phenotype.

[0040] In some embodiments, the peripheral T-cell lymphoma is selected from limited-stage or advanced-stage peripheral T-cell lymphoma.

[0041] In some embodiments, the peripheral T-cell lymphoma is selected from peripheral T-cell lymphomas of Lugano stage I, II, III, or IV.

[0042] In some embodiments, the patient with the peripheral T-cell lymphoma has at least one measurable lesion other than a brain lesion. In some embodiments, the measurable lesion is selected from lymph node lesions with a long diameter >15 mm or extranodal lesions with a long diameter >10 mm.

[0043] In some implementations, the peripheral T-cell lymphoma is selected from newly diagnosed peripheral T-cell lymphoma or relapsed / refractory peripheral T-cell lymphoma.

[0044] In some implementations, the peripheral T-cell lymphoma is selected from peripheral T-cell lymphomas for which there is no standard treatment or which have progressed or are intolerable to previous standard treatment.

[0045] In some implementations, patients with the peripheral T-cell lymphoma have no standard treatment options or whose disease has progressed or is intolerable after receiving standard treatment.

[0046] In some implementations, patients with the peripheral T-cell lymphoma have not received standard treatment.

[0047] In some implementations, patients with the peripheral T-cell lymphoma have received one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) standard treatments.

[0048] In some implementations, patients with the peripheral T-cell lymphoma have received one, two, or three standard treatments.

[0049] In some implementations, the standard treatment includes, but is not limited to, one or more of radiotherapy, chemotherapy, targeted therapy, and transplantation.

[0050] In some implementations, the radiotherapy is selected from affected part radiotherapy (ISRT).

[0051] In some embodiments, the chemotherapy drugs include, but are not limited to, platinum complexes (e.g., oxaliplatin, cisplatin, carboplatin), pyrimidine derivatives (e.g., gemcitabine), vincristine alkaloids (e.g., vincristine, vindesine), anthracyclines (e.g., doxorubicin, epirubicin, mitoxantrone), cytarabine, etoposide, ifosfamide, cyclophosphamide, methotrexate, bendamustine, prednisone, mesna, dexamethasone, pralatrexate, methylprednisolone, lenalidomide, or one or more of bortezomib.

[0052] In some embodiments, the chemotherapy drugs include, but are not limited to, one or more of cyclophosphamide, doxorubicin, epirubicin, prednisone, vincristine, vindesine, etoposide, mesna, dexamethasone, methotrexate, cytarabine, pralatrexate, bendamustine, gemcitabine, cisplatin, methylprednisolone, oxaliplatin, ifosfamide, carboplatin, mitoxantrone hydrochloride liposomes, lenalidomide, or bortezomib.

[0053] In some embodiments, the targeted therapy includes, but is not limited to, one or more of the following: anti-CD52 antibodies, CD30-targeting ADCs (e.g., brentuximab vedotinib), HDAC inhibitors (e.g., chidamide), ALK inhibitors (e.g., crizotinib, alectinib), JAK inhibitors (e.g., golixitinib, ruxolitinib), or PI3Kδ inhibitors (e.g., limpruciate, duveliate).

[0054] In some implementations, the transplantation therapy is selected from autologous hematopoietic stem cell transplantation (ASCT) or allogeneic hematopoietic stem cell transplantation (allo-SCT).

[0055] In some implementations, the standard treatment includes, but is not limited to, brentuximab vedotin + cyclophosphamide + doxorubicin + prednisone, cyclophosphamide + doxorubicin + vincristine + etoposide + prednisone ± ISRT, vincristine + doxorubicin + cyclophosphamide + etoposide + dexamethasone, cyclophosphamide + doxorubicin + vincristine + prednisone ± ISRT, etoposide + vincristine + doxorubicin + cyclophosphamide + prednisone, cyclophosphamide + mesna + vincristine + doxorubicin + dexamethasone, methotrexate + cytarabine, chidamide, brentuximab vedotinib, crizotinib, and pralatrexate. Bendamustine, gemcitabine, dexamethasone + cytarabine + cisplatin, etoposide + methylprednisolone + cisplatin + cytarabine, gemcitabine + dexamethasone, gemcitabine + cisplatin + dexamethasone, gemcitabine + oxaliplatin, ifosfamide + carboplatin + etoposide, mitoxantrone hydrochloride liposome, golixitinib, limprixetine, brentuximab vemetiximab + bendamustine, ASCT, allo-SCT, lenalidomide, bortezomib, duveritine, ruxolitinib, alectinib, anti-CD52 antibody, or one or more of cyclophosphamide + epirubicin + vincristine + etoposide.

[0056] In some implementations, the standard treatment includes, but is not limited to, one or more of the following: chidamide, gemcitabine + chidamide + dexamethasone, cyclophosphamide + liposomal doxorubicin + vincristine + prednisone + chidamide, vindesine + liposomal doxorubicin + cyclophosphamide + etoposide + dexamethasone + chidamide, cyclophosphamide + doxorubicin + vincristine + prednisone, gemcitabine + oxaliplatin + chidamide, mitoxantrone hydrochloride liposomal, anti-CD52 antibody, and cyclophosphamide + epirubicin + vincristine + etoposide.

[0057] Hodgkin's lymphoma

[0058] In some implementations, the Hodgkin lymphoma is selected from limited-stage or advanced-stage Hodgkin lymphoma.

[0059] In some implementations, the Hodgkin lymphoma is selected from classical Hodgkin lymphoma (cHL) and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL).

[0060] In some implementations, the classical Hodgkin lymphoma is selected from nodular sclerosis or mixed cellular classical Hodgkin lymphoma.

[0061] In some implementations, the Hodgkin lymphoma is selected from newly diagnosed classical Hodgkin lymphoma or relapsed / refractory Hodgkin lymphoma.

[0062] In some implementations, the Hodgkin lymphoma is selected from Hodgkin lymphomas of Lugano stage I, II, III, or IV.

[0063] In some implementations, the classical Hodgkin lymphoma is selected from newly diagnosed classical Hodgkin lymphoma or relapsed / refractory classical Hodgkin lymphoma.

[0064] In some implementations, the classical Hodgkin lymphoma is selected from classical Hodgkin lymphomas of Lugano stage I, II, III, or IV.

[0065] In some embodiments, the patient with the Hodgkin's lymphoma has at least one measurable lesion other than a brain lesion. In some embodiments, the measurable lesion is selected from lymph node lesions with a long diameter >15 mm or extranodal lesions with a long diameter >10 mm.

[0066] In some implementations, the Hodgkin lymphoma is selected from Hodgkin lymphomas for which there is no standard treatment or for which the disease has progressed or is intolerable after prior standard treatment.

[0067] In some implementations, patients with the Hodgkin lymphoma have no standard treatment options or whose disease has progressed or is intolerable after receiving standard treatment.

[0068] In some implementations, patients with the aforementioned Hodgkin lymphoma have not received standard treatment.

[0069] In some implementations, patients with the Hodgkin lymphoma have received one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) standard treatments.

[0070] In some implementations, patients with the Hodgkin lymphoma have received two, three, four, five, six, or seven standard treatments.

[0071] In some implementations, the standard treatment includes, but is not limited to, one or more of radiotherapy (RT), chemotherapy, targeted therapy, or transplantation.

[0072] In some embodiments, the chemotherapeutic agents include, but are not limited to, one or more of the following: platinum complexes (e.g., cisplatin, carboplatin), pyrimidine derivatives (e.g., gemcitabine, decitabine), vinblastine alkaloids (e.g., vinorelbine, vincristine, vinblastine), anthracyclines (e.g., doxorubicin), cytarabine, dacarbazine, etoposide, ifosfamide, cyclophosphamide, bendamustine, bleomycin, procarbazine, prednisone, dexamethasone, lenalidomide, or everolimus.

[0073] In some implementations, the chemotherapy drugs include, but are not limited to, one or more of doxorubicin, bleomycin, vincristine, dacarbazine, etoposide, cyclophosphamide, procarbazine, prednisone, decitabine, gemcitabine, vinorelbine, ifosfamide, carboplatin, dexamethasone, cytarabine, cisplatin, oxaliplatin, bendamustine, lenalidomide, or everolimus.

[0074] In some implementations, the targeted therapy includes, but is not limited to, one or more of the following: CD30 antibody-drug conjugates (e.g., brentuximab vedotin), PD-1 monoclonal antibodies (e.g., sintilimab, tislelizumab, camrelizumab, nivolumab, pembrolizumab, cepallimab, penprimab), or anti-CD20 monoclonal antibodies (e.g., rituximab).

[0075] In some implementations, the transplantation therapy is selected from autologous hematopoietic stem cell transplantation (ASCT) or allogeneic hematopoietic stem cell transplantation (allo-SCT).

[0076] In some implementations, the standard treatment includes, but is not limited to, doxorubicin + bleomycin + vincristine + dacarbazine ± RT, bleomycin + etoposide + doxorubicin + cyclophosphamide + vincristine + procarbazine + prednisone ± RT, doxorubicin + vincristine + dacarbazine, brentuximab vedotin + doxorubicin + vincristine + dacarbazine ± RT, ASCT, allo-SCT, brentuximab vedotin, sintilimab, tislelizumab, camrelizumab, nivolumab, pembrolizumab, serpalimumab, and penicillin. One or more of the following: prilimab, camrelizumab + decitabine, brentuximab + nivolumab, gemcitabine + vinorelbine + doxorubicin, gemcitabine + oxaliplatin, ifosfamide + carboplatin + etoposide, ifosfamide + doxorubicin + bleomycin + vincristine + dacarbazine, cyclophosphamide + doxorubicin + vincristine + prednisone, bendamustine, lenalidomide, everolimus, rituximab ± RT, cyclophosphamide + doxorubicin + vincristine + prednisone, cyclophosphamide + vincristine + prednisone, cyclophosphamide + doxorubicin + prednisone, and rituximab.

[0077] In some implementations, the standard treatment includes, but is not limited to, doxorubicin + bleomycin + vincristine + dacarbazine, local radiotherapy, brentuximab vedotin + ifosfamide + carboplatin + etoposide, ifosfamide + doxorubicin + bleomycin + vincristine + dacarbazine, cyclophosphamide + doxorubicin + vincristine + prednisone, tislelizumab, camrelizumab, nivolumab, pembrolizumab, and cyproheptadine. Palimab, Pembrolizumab, Brentuximab + Cyclophosphamide + Doxorubicin + Prednisone, Sintilimab + Doxorubicin + Vincristine + Dacarbazine, Doxorubicin + Vincristine + Dacarbazine, Sintilimab, Rituximab, Gemcitabine + Oxaliplatin, Bleomycin + Etoposide + Doxorubicin + Cyclophosphamide + Vincristine + Procarbazine + Prednisone, and one or more of the following: autologous hematopoietic stem cell transplantation.

[0078] B-cell lymphoma

[0079] In some embodiments, the B-cell lymphoma is selected from limited-stage or advanced-stage B-cell lymphoma.

[0080] In some embodiments, the B-cell lymphoma is selected from diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and mantle cell lymphoma.

[0081] In some implementations, the B-cell lymphoma is selected from newly diagnosed B-cell lymphoma or relapsed / refractory B-cell lymphoma.

[0082] In some embodiments, the B-cell lymphoma is selected from B-cell lymphomas of Lugano stage I, II, III, or IV.

[0083] In some embodiments, the patient with the B-cell lymphoma has at least one measurable lesion other than a brain lesion. In some embodiments, the measurable lesion is selected from lymph node lesions with a long diameter >15 mm or extranodal lesions with a long diameter >10 mm.

[0084] In some implementations, the B-cell lymphoma is selected from B-cell lymphomas for which there is no standard treatment or for which the disease has progressed or is intolerable after prior standard treatment.

[0085] In some implementations, patients with the aforementioned B-cell lymphoma have no standard treatment options or whose disease has progressed or is intolerable after receiving standard treatment.

[0086] In some implementations, patients with the aforementioned B-cell lymphoma have not received standard treatment.

[0087] In some implementations, patients with the B-cell lymphoma have received one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) standard treatments.

[0088] In some implementations, patients with the aforementioned B-cell lymphoma have received two, three, four, five, six, or seven standard treatments.

[0089] In some implementations, the standard treatment includes, but is not limited to, one or more of radiotherapy (RT), chemotherapy, targeted therapy, or transplantation.

[0090] In some implementations, the radiotherapy is selected from radiotherapy of the affected part / affected lymph nodes.

[0091] In some embodiments, the chemotherapy drugs include, but are not limited to, one or more of the following: platinum complexes (e.g., cisplatin, carboplatin, oxaliplatin), pyrimidine derivatives (e.g., gemcitabine, decitabine), vinblastine alkaloids (e.g., vinorelbine, vincristine, vinblastine), anthracyclines (e.g., doxorubicin, epirubicin, mitoxantrone), cytarabine, etoposide, ifosfamide, cyclophosphamide, bendamustine, prednisone, methylprednisolone, dexamethasone, lenalidomide, or mesna.

[0092] In some embodiments, the chemotherapy drugs include, but are not limited to, one or more of doxorubicin, epirubicin, vincristine, etoposide, cyclophosphamide, prednisone, methylprednisolone, gemcitabine, ifosfamide, carboplatin, dexamethasone, cytarabine, cisplatin, oxaliplatin, bendamustine, lenalidomide, mesna, or mitoxantrone.

[0093] In some implementations, the targeted therapy includes, but is not limited to, one or more of the following: anti-CD19 antibodies (e.g., tancituzumab, Loncastuximab), CD79b antibody-drug conjugates (e.g., velpostuzumab), anti-CD20 antibodies (e.g., rituximab, glucentumab), XPO1 inhibitors (e.g., celiniso), and BTK inhibitors (e.g., ibrutinib, zanubrutinib).

[0094] In some implementations, the transplantation therapy is selected from autologous hematopoietic stem cell transplantation (ASCT) or allogeneic hematopoietic stem cell transplantation (allo-SCT).

[0095] In some implementations, the standard treatment includes, but is not limited to, rituximab + cyclophosphamide + doxorubicin / epirarubicin + vincristine + prednisone, rituximab + veportozumab + cyclophosphamide + doxorubicin + prednisone, rituximab + cyclophosphamide + doxorubicin / epirarubicin + vincristine + etoposide + prednisone, dexamethasone + cytarabine + cisplatin ± rituximab, ifosfamide + carboplatin + etoposide ± rituximab, gemcitabine + cisplatin + dexamethasone ± rituximab, etoposide + methylprednisolone + cisplatin + cytarabine ± rituximab, etoposide + Prednisone + vincristine + cyclophosphamide + doxorubicin ± rituximab, gemcitabine + oxaliplatin ± rituximab, mesna + ifosfamide + mitoxantrone + etoposide ± rituximab, veportozumab + bendamustine + rituximab, rituximab + lenalidomide ± ibrutinib / zanubrutinib, bendamustine + rituximab, celiac, glimetuzumab, tancituzumab, Loncastuximab, radiation therapy to the affected part / affected lymph nodes, autologous hematopoietic stem cell transplantation, allogeneic hematopoietic stem cell transplantation, or one or more of CAR-T therapy.

[0096] Compound of formula (I) or a pharmaceutically acceptable salt thereof

[0097] The compound of formula (I) of this application can be administered in its free base form or in the form of its pharmaceutically acceptable salt. For example, a pharmaceutically acceptable salt of the compound of formula (I) can be produced by various organic and inorganic acids according to methods known in the art, such as inorganic acids selected from hydrochloric acid, sulfuric acid, or phosphoric acid, and organic acids selected from methanesulfonic acid.

[0098] In some implementations, the compound of formula (I) is administered in the form of its pharmaceutically acceptable salt.

[0099] In some implementations, the compound of formula (I) is administered in its free base form.

[0100] Pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof

[0101] The "compound of formula (I) or a pharmaceutically acceptable salt thereof" described in this application may be in the form of a "pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof".

[0102] In some embodiments, the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof further comprises a pharmaceutically acceptable excipient.

[0103] In some embodiments, the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof may be suitable for oral administration.

[0104] In some embodiments, the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition. In some embodiments, the solid pharmaceutical composition is a capsule.

[0105] In some embodiments, the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof is a single-dose pharmaceutical composition.

[0106] In some embodiments, the single dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is 0.01-10 mg, preferably 0.01-1.0 mg, more preferably 0.01-0.5 mg, and most preferably 0.05-0.5 mg. In some embodiments, a single dose of the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, ... 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4.0mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6.0mg, 6.5mg, 7.0mg, 7.5mg, 8.0mg, 8.5mg, 9.0mg, 9.5mg, 10.0mg, or any range of the above values. In some embodiments, a single dose of the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, or 0.3 mg. In some embodiments, a single dose of the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 0.05 mg, 0.1 mg, or 0.5 mg.

[0107] In some embodiments, the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof is a multi-dose pharmaceutical composition.

[0108] In some embodiments, the multi-dose pharmaceutical composition may consist of a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, in a single dose of 0.01-10 mg, preferably 0.01-1.0 mg, more preferably 0.01-0.5 mg, and most preferably 0.05-0.5 mg.

[0109] In some embodiments, the multi-dose pharmaceutical composition may consist of a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, in a single dose of 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, or 0.3 mg.

[0110] In some embodiments, the multi-dose pharmaceutical composition may consist of a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, in a single dose of 0.05 mg, 0.1 mg, or 0.5 mg.

[0111] Dosing regimen

[0112] The method of administration can be determined comprehensively based on the activity, toxicity, and patient tolerability of the drug. Those skilled in the art can determine the appropriate amount, dose, or dosage of each drug used in combination according to the present invention for administration to a patient. Those skilled in the art can adjust the dosage and administration regimen according to methods well known in the therapeutic field. For example, the maximum tolerated dose can be easily determined, as can the effective amount to provide a detectable therapeutic benefit to the patient, and the time required for administering each drug to provide a detectable therapeutic benefit to the patient. Therefore, while the present invention illustrates certain dosages and administration regimens, these examples are by no means limited to the dosages and administration regimens that can be provided to patients in the practice of the present invention.

[0113] In this application, the dosage or mass of pharmaceutically acceptable salts of formula (I) is based on the formula (I) compound.

[0114] In some embodiments, the compound of formula (I) of this application or a pharmaceutically acceptable salt thereof is used as a single active agent.

[0115] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0116] In some embodiments, the average daily dose of the compound of formula (I) of this application or its pharmaceutically acceptable salt, or its pharmaceutical composition thereof, is selected from 0.01-10 mg, preferably 0.01-1.0 mg, more preferably 0.01-0.5 mg, and most preferably 0.03-0.3 mg. In some embodiments, the average daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is selected from 0.01 mg, 0.02 mg, 0.03 mg, 0.031 mg, 0.032 mg, 0.033 mg, 0.034 mg, 0.035 mg, 0.036 mg, 0.037 mg, 0.038 mg, 0.039 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.061 mg, 0.062 mg, 0.063 mg, 0.064 mg, 0.065 mg, 0.066 mg, 0.067 mg, 0.068 mg, 0. 069mg, 0.07mg, 0.08mg, 0.09mg, 0.1mg, 0.11mg, 0.111mg, 0.112mg, 0.113mg, 0.114mg, 0.115mg, 0.116mg, 0.117mg, 0.118mg, 0.119mg, 0.12mg, 0.13mg, 0.131mg, 0.132mg, 0.133mg, 0.134mg, 0.135mg, 0.136mg, 0.137mg, 0.138mg, 0.139mg, 0.14mg, 0.15mg, 0.16mg, 0.161 mg, 0.162mg, 0.163mg, 0.164mg, 0.165mg, 0.166mg, 0.167mg, 0.168mg, 0.169mg, 0.17mg, 0.18mg, 0.181mg, 0.182mg, 0.183mg, 0.184mg , 0.185mg, 0.186mg, 0.187mg, 0.188mg, 0.189mg, 0.19mg, 0.2mg, 0.21mg, 0.22mg, 0.221mg, 0.222mg, 0.223mg, 0.224mg, 0.225mg, 0.22 6mg, 0.227mg, 0.228mg, 0.229mg, 0.23mg, 0.24mg, 0.25mg, 0.26mg, 0.27mg, 0.28mg, 0.29mg, 0.3mg, 0.35mg, 0.4mg, 0.45mg, 0.5mg, 0.6 mg, 0.7mg, 0.8mg, 0.9mg, 1.0mg, 1.1mg, 1.2mg, 1.3mg, 1.4mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2.0mg, 2.1mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4.0mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6.0mg, 6.5mg, 7.0mg, 7.5mg, 8.0mg, 8.5mg, 9.0mg, 9.5mg, 10.0mg, or any range of the above values. In some embodiments, the average daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is selected from 0.05-0.3 mg or 0.05-0.15 mg. In some embodiments, the average daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is selected from 0.033-0.2 mg or 0.067-0.2 mg. In some embodiments, the average daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is selected from 0.037-0.225 mg. In some embodiments, the average daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is selected from 0.037-0.1 mg. In some embodiments, the average daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is selected from 0.067-0.1 mg.

[0117] In some embodiments, the dosage of the compound of formula (I) of this application or its pharmaceutically acceptable salt, or its pharmaceutical composition, for each or daily administration is 0.01-10 mg, preferably 0.01-1.0 mg, more preferably 0.01-0.5 mg, and most preferably 0.05-0.5 mg. In some embodiments, the dosage of the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, for each or daily administration, is selected from 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, etc. mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4.0mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6.0mg, 6.5mg, 7.0mg, 7.5mg, 8.0mg, 8.5mg, 9.0mg, 9.5mg, 10.0mg, or any range of the above values. In some embodiments, the dosage of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, for each or daily administration, is selected from 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, or 0.3 mg.

[0118] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, or its pharmaceutical composition, may be administered three times daily, twice daily, once daily, once every two days, once every three days, once every four days, once every five days, once every six days, three times per week, twice per week, once per week, once every two weeks, or once every three weeks. In some embodiments, the compound of formula I or its pharmaceutically acceptable salt, or its pharmaceutical composition, may be administered three times daily, twice daily, or once daily. In some embodiments, the compound of formula I or its pharmaceutically acceptable salt, or its pharmaceutical composition, may be administered once daily.

[0119] In some implementations, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered continuously or intermittently.

[0120] In some embodiments, a single dosing cycle of the administerable compound (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is 2-6 weeks. In some embodiments, a single dosing cycle of the administerable compound (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or any range of the foregoing values. In some embodiments, a single dosing cycle of the administerable compound (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is 3 or 4 weeks.

[0121] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, is administered to the subject once daily in the following manner: 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, or 0.3 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, is administered to the subject once daily for a period of 4 weeks. The administration dose is 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, or 0.3 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0123] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, is administered to the subject once daily for 4 weeks as a dosing cycle, with each dose being 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, or 0.3 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, for 3 consecutive weeks followed by a 1-week break.

[0124] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, is administered to the subject once daily for 3 weeks as a dosing cycle, with each dose being 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, or 0.3 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, for 2 weeks onwards and 1 week off.

[0125] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, is administered as follows: in a 3-week dosing cycle; in cycles 1 and 2, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily to the subject at a dose of 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, or 0.3 mg once daily; starting from cycle 3, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily to the subject at a dose of 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, or 0.3 mg once daily for 2 weeks followed by a 1-week break.

[0126] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered on an empty stomach.

[0127] In some embodiments, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, or its pharmaceutical composition, is a repeated single dosing cycle until the subject no longer benefits, the disease progresses, or intolerable toxicity occurs. In some embodiments, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, or its pharmaceutical composition, may be for 2-40 dosing cycles, for example 3-15 or 8-20 dosing cycles, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 dosing cycles, or even 2-40 or more dosing cycles as needed.

[0128] Technical effect

[0129] The compound of formula (I) of this application, or its pharmaceutically acceptable salt, or pharmaceutical composition thereof, has good safety and antitumor effects.

[0130] The treatment regimen described in this application has shown good efficacy in patients with T-cell lymphoma, Hodgkin's lymphoma, and / or B-cell lymphoma. Efficacy can be assessed according to the 2014 Lugano Conference revised evaluation criteria, wherein the compound of formula (I) or its pharmaceutically acceptable salt, or its pharmaceutical composition, demonstrates excellent efficacy in at least one of the following aspects: survival efficacy evaluation (e.g., overall survival (OS), 12-month OS rate, 24-month OS rate, median survival); tumor response efficacy evaluation (e.g., disease-free survival (DFS), median DFS, progression-free survival (PFS), 6-month PFS rate, 12-month PFS rate, time to disease progression (TTP), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), intracranial response rate (CNS-ORR), duration of intracranial response (CNS-DOR), time to intracranial disease progression (CNS-TTP); and tolerability or safety evaluation (e.g., incidence of adverse events, incidence of serious adverse events, severity of adverse events).

[0131] In some embodiments of this application, efficacy is assessed according to the 2014 Lugano Conference revised evaluation criteria, and the efficacy of the treatment regimens in this application can achieve stable disease (SD), partial remission (PR), or complete remission (CR).

[0132] definition

[0133] Unless otherwise stated, the following terms as used in this application shall have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0134] In this document, unless otherwise stated, the terms “comprise,” “comprises,” and “comprising” or their equivalents are open-ended expressions, meaning that they may cover other unspecified elements, components, and steps in addition to those listed.

[0135] In this application, unless otherwise specified, the Lugano grading is based on the 2014 Lugano grading standard.

[0136] In this application, "+" in chemotherapy or standard treatment indicates combination therapy, " / " indicates "or", and "±" indicates "combination or no combination therapy". For example, "doxorubicin + bleomycin + vinblastine / vincristine + dacarbazine ± RT" indicates the following drug regimens: doxorubicin, bleomycin, vinblastine, and dacarbazine in combination; doxorubicin, bleomycin, vinblastine, dacarbazine, and RT in combination; and doxorubicin, bleomycin, vinblastine, dacarbazine, and RT in combination.

[0137] As used herein, “combination” or “concurrent use” means the simultaneous, parallel, or sequential administration of two or more treatments to an individual. The treatments include, but are not limited to, the administration of an active substance, which may be a single entity or dosage form or administered separately in its respective entity or dosage form.

[0138] The terms “application” or “administration” mean introducing a composition containing a therapeutic agent into a host body using any of a variety of methods and delivery systems known to those skilled in the art.

[0139] As used in this application, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, may be administered by any suitable route, including but not limited to oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, local administration, subcutaneous, intra-fat, intra-articular, intraperitoneal, and intrathecal administration, preferably orally.

[0140] When referring to dosing regimens, terms such as "day" or "daily" refer to the time within a calendar day, beginning at midnight and ending at the next midnight.

[0141] The term "treatment" generally refers to achieving the desired pharmacological and / or physiological effect. This effect can be therapeutic, depending on whether it partially or completely stabilizes or cures the disease and / or causes side effects due to the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., preventing its progression; or (b) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress.

[0142] The term "therapeutic effective amount" means the amount of the compound of this application used to treat a specific disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a specific disease, condition, or disorder; or (iii) to delay the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and this disclosure.

[0143] In this application, the terms "subject," "patient," or "individual" are used interchangeably. In some embodiments, the subject or patient is a mammal. In some embodiments, the subject or patient is a mouse. In some embodiments, the subject or patient is a human.

[0144] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this application or a combination thereof, or a salt thereof, with a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application or the combination thereof to a subject.

[0145] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0146] As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids may be mentioned.

[0147] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0148] The pharmaceutical compositions of this application may be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients, for example, by formulating them into solid dosage forms (e.g., granules, tablets, pills, capsules, etc.) or into liquid dosage forms (e.g., injections).

[0149] The pharmaceutical composition of this application can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0150] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a capsule, tablet, or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0151] The term "single-dose pharmaceutical composition" refers to the smallest packaging unit containing a certain amount of pharmaceutical product. For example, if a box of medicine contains seven capsules, then each capsule is a single-dose pharmaceutical composition; or each vial of injection is a single-dose pharmaceutical composition. In this application, the terms "single-dose pharmaceutical composition" and "unit-dose pharmaceutical composition" have the same meaning and can be used interchangeably.

[0152] The term "multi-dose pharmaceutical composition" refers to a combination of multiple single-dose pharmaceutical compositions.

[0153] The term "single dose" refers to the content of the active ingredient in a single-dose pharmaceutical composition. In this application, the terms "single dose" and "unit dose" have the same meaning and are used interchangeably. For example, a pharmaceutical composition of formula (I) compound or its pharmaceutically acceptable salt with a single dose of 0.01 mg to 10 mg refers to a single-dose pharmaceutical composition containing 0.01 mg to 10 mg of formula (I) compound or its pharmaceutically acceptable salt as the active ingredient.

[0154] The term "daily dose" refers to the dose administered to a patient over one day.

[0155] In this application, "average daily dose" refers to the ratio of the total dose to the number of days within a cycle. For example, if a dosing cycle is 3 weeks, and the compound of formula (I) or its pharmaceutically acceptable salt is administered once daily at a dose of 0.1 mg, for 2 weeks on and 1 week off, then the average daily dose is the ratio of (0.1 mg × 7 × 2) / (7 × 3) days.

[0156] The dosage of the compound of formula (I) of this application or a pharmaceutically acceptable salt thereof may be determined based on the severity of the disease, the response to the disease, any treatment-related toxicities, the patient’s age and health status.

[0157] The administration regimen of the compound of formula (I) of this application or its pharmaceutically acceptable salt, or the pharmaceutical composition thereof, can be determined comprehensively based on drug activity, side effects and patient tolerability, and can be administered continuously or intermittently. For example, an individual may receive a daily dose of the compound of formula (I) or its pharmaceutically acceptable salt for a period of several days, and then, for a period of several or more days, the patient may not receive a daily dose of the compound of formula (I) or its pharmaceutically acceptable salt.

[0158] Unless otherwise stated, the validity assessment in this application may be evaluated in accordance with the 2014 Lugano Conference revised evaluation criteria. Detailed Implementation

[0159] For clarity, the invention is further illustrated by examples, but these examples are not intended to limit the scope of this application. Example 1: Safety and efficacy study of compound (I) or its pharmaceutically acceptable salt, or pharmaceutical composition thereof, against lymphoma.

[0160] 1. Investigational drug and dosing regimen

[0161] 1) Test drug: Capsules containing compound (I).

[0162] 2) Dosing regimen:

[0163] ◆Scheme 1: Each cycle is 28 days, and the drug is administered continuously for 28 days, once a day, with each dose being 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg or 0.3 mg of compound (I);

[0164] ◆Option 2: Each cycle is 21 days, with continuous administration for 14 days, once a day, with each dose of 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg or 0.3 mg of compound (I), followed by a 7-day break;

[0165] ◆Plan 3: Each cycle is 28 days. Subjects take the drug for 21 consecutive days, once a day, with each dose being 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg or 0.3 mg of compound (I), followed by a 7-day break.

[0166] ◆Option 4: Each cycle is 21 days (3 weeks). In cycles 1 and 2, the subjects will take the drug continuously for 21 days per cycle, once a day, with each dose being 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg or 0.3 mg of compound (I). Starting from cycle 3, the subjects will take the drug continuously for 14 days per cycle, once a day, with each dose being 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg or 0.3 mg of compound (I). The drug will be discontinued for 7 days.

[0167] 3. Main characteristics of enrolled patients

[0168] 1) Patients with T-cell lymphoma (including peripheral T-cell lymphoma, T-cell lymphoblastic lymphoma, nasal extranodal NK / T-cell lymphoma, and cutaneous T-cell lymphoma) confirmed by histopathology and / or cytology; among which, peripheral T-cell lymphoma includes peripheral T-cell lymphoma nonspecific type, angioimmunoblastic T-cell lymphoma, ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma, and lymph node peripheral T-cell lymphoma with follicular helper T-cell phenotype), patients with Hodgkin lymphoma (including classical Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma) or patients with B-cell lymphoma (including diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma); these patients include those with relapsed / refractory disease or those at different stages.

[0169] 2) Has at least one measurable lesion other than a brain lesion: Based on the long diameter of the lymph node lesion on CT cross-sectional images >

[0170] 15mm or extranodal lesions with a long diameter >10mm.

[0171] 3. Evaluation Criteria

[0172] 1) Effectiveness evaluation criteria: The evaluation criteria revised in 2014 by the Lugano Conference were used.

[0173] Efficacy indicators include: objective response rate (ORR), disease control rate (DCR), time to disease remission (DOR), progression-free survival (PFS), and overall survival (OS).

[0174] 2) Safety evaluation criteria: The adverse reactions of the drug are evaluated using the NCI-CTC AE5.0 standard.

[0175] 4. Test Results

[0176] 1) Validity evaluation

[0177] In all evaluable patients, 56% showed a reduction in the total vertical diameter of the target lesion relative to baseline, with an ORR ≥31%, a PR rate ≥21%, a CR rate ≥10%, a median DOR of 6.9 months, a median PFS of 4.8 months, and a median OS of 12.9 months. Specifically, the ORR in the 0.1 mg dose group (e.g., dosing regimens 1 and 4) was ≥35.7%. Specifically, in evaluable patients with Hodgkin lymphoma, the median DOR was 6.9 months and the median PFS was 4.8 months; in evaluable patients with T-cell lymphoma, the median PFS was 4.8 months and the median OS was 12.9 months; and in evaluable patients with B-cell lymphoma, the median PFS was 4.7 months.

[0178] In evaluable patients with Hodgkin's lymphoma, the ORR was ≥31%; in evaluable patients with T-cell lymphoma, the ORR was ≥31%; and in evaluable patients with B-cell lymphoma, the ORR was ≥29%. Specifically, in evaluable patients with PTCL, the ORR was ≥27%; and in evaluable patients with cHL, the ORR was ≥43%.

[0179] Table 1. Partial Patient Information and Best Treatment Results

[0180] 2) Safety evaluation

[0181] Among the enrolled patients, the most common treatment-related adverse reaction was thrombocytopenia (74% incidence, of which grade 3-4 adverse reactions occurred in 36%), followed by anemia (33% incidence).

[0182] Gastrointestinal adverse reactions (such as diarrhea, nausea, and vomiting) occurred in a low rate, all ≤10%.

Claims

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for the treatment of T-cell lymphoma, B-cell lymphoma, or Hodgkin's lymphoma.

2. The use as described in claim 1, wherein, The T-cell lymphoma is selected from peripheral T-cell lymphoma, T-lymphoblastic lymphoma, nasal extranodal NK / T-cell lymphoma, and cutaneous T-cell lymphoma; Alternatively, the peripheral T-cell lymphoma is selected from peripheral T-cell lymphoma nonspecific type, angioimmunoblastic T-cell lymphoma, ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma, and lymph node peripheral T-cell lymphoma with follicular helper T-cell phenotype. Alternatively, the B-cell lymphoma may be selected from diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma. Alternatively, the Hodgkin lymphoma is selected from classical Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma; Alternatively, the classical Hodgkin lymphoma may be selected from nodular sclerosis or mixed cellular classical Hodgkin lymphoma.

3. The use as described in claim 1 or 2, wherein, The T-cell lymphoma is selected from limited-stage or advanced-stage T-cell lymphoma; Alternatively, the T-cell lymphoma is selected from T-cell lymphomas of Lugano stage I, II, III, or IV. Alternatively, the T-cell lymphoma is selected from newly diagnosed T-cell lymphoma or relapsed / refractory T-cell lymphoma; Alternatively, the T-cell lymphoma is selected from T-cell lymphomas for which there is no standard treatment or which have progressed or are intolerable after prior standard treatment. Alternatively, a patient with the aforementioned T-cell lymphoma may have not received standard treatment or may have received one or more standard treatments.

4. The use as described in claim 1 or 2, wherein, The B-cell lymphoma is selected from limited-stage or advanced-stage B-cell lymphoma; Alternatively, the B-cell lymphoma is selected from newly diagnosed B-cell lymphoma or relapsed / refractory B-cell lymphoma; Alternatively, the B-cell lymphoma is selected from B-cell lymphomas classified as Lugano stage I, II, III, or IV. Alternatively, the B-cell lymphoma is selected from B-cell lymphomas for which there is no standard treatment or which have progressed or are intolerable to previous standard treatments; Alternatively, a patient with the aforementioned B-cell lymphoma may not have received standard treatment or may have received one or more standard treatments.

5. The use as described in claim 1 or 2, wherein, The Hodgkin lymphoma is selected from localized or advanced Hodgkin lymphoma; Alternatively, the Hodgkin lymphoma is selected from newly diagnosed classical Hodgkin lymphoma or relapsed / refractory Hodgkin lymphoma; Alternatively, the Hodgkin lymphoma is selected from Hodgkin lymphomas that are stage I, II, III, or IV according to the Lugano staging. Alternatively, the Hodgkin lymphoma is selected from Hodgkin lymphomas for which there is no standard treatment or which have progressed or are intolerable after prior standard treatment. Alternatively, a patient with the aforementioned Hodgkin lymphoma may not have received standard treatment or may have received one or more standard treatments.

6. The use as described in claim 3, wherein, The standard treatment is selected from one or more of radiotherapy, chemotherapy, targeted therapy, and transplantation. Alternatively, the radiotherapy is selected from radiotherapy of the affected part; Alternatively, the chemotherapy drug is selected from one or more of platinum complexes, pyrimidine derivatives, vincristine alkaloids, anthracyclines, cytarabine, etoposide, ifosfamide, cyclophosphamide, methotrexate, bendamustine, prednisone, mesna, dexamethasone, prazolam, methylprednisolone, lenalidomide, or bortezomib. Alternatively, the targeted therapy drug is selected from one or more of the following: anti-CD52 antibody, CD30-targeting ADC drug, HDAC inhibitor, ALK inhibitor, JAK inhibitor, or PI3Kδ inhibitor. Alternatively, the transplantation treatment may be selected from autologous hematopoietic stem cell transplantation or allogeneic hematopoietic stem cell transplantation.

7. The use as described in claim 4, wherein, The standard treatment is selected from one or more of radiotherapy, chemotherapy, targeted therapy, and transplantation. Alternatively, the radiotherapy is selected from radiotherapy of the affected part / affected lymph nodes; Alternatively, the chemotherapy drug is selected from one or more of platinum complexes, pyrimidine derivatives, vincristine alkaloids, anthracyclines, cytarabine, etoposide, ifosfamide, cyclophosphamide, bendamustine, prednisone, methylprednisolone, dexamethasone, lenalidomide, or mesna. Alternatively, the targeted therapy drug is selected from one or more of the following: anti-CD19 antibody, CD79b antibody-drug conjugate, anti-CD20 antibody, XPO1 inhibitor, and BTK inhibitor; Alternatively, the transplantation treatment may be selected from autologous hematopoietic stem cell transplantation or allogeneic hematopoietic stem cell transplantation.

8. The use as described in claim 5, wherein, The standard treatment is selected from one or more of radiotherapy, chemotherapy, targeted therapy, or transplantation. Alternatively, the chemotherapy drug is selected from one or more of platinum complexes, pyrimidine derivatives, vincristine alkaloids, anthracyclines, cytarabine, dacarbazine, etoposide, ifosfamide, cyclophosphamide, bendamustine, bleomycin, procarbazine, prednisone, dexamethasone, lenalidomide, or everolimus. Alternatively, the targeted therapy drug may be selected from one or more of CD30 antibody-drug conjugates, PD-1 monoclonal antibodies, or anti-CD20 monoclonal antibodies; Alternatively, the transplantation treatment may be selected from autologous hematopoietic stem cell transplantation or allogeneic hematopoietic stem cell transplantation.

9. The use as described in any one of claims 1-8, wherein, The pharmaceutical composition is a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof; Alternatively, the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof may be suitable for oral administration; Alternatively, the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition, preferably a capsule; Alternatively, the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof is a single-dose pharmaceutical composition; Alternatively, the single dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is 0.01-10 mg, preferably 0.01-1.0 mg, more preferably 0.01-0.5 mg, and most preferably 0.05-0.5 mg; Alternatively, the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof is a multi-dose pharmaceutical composition.

10. The use as described in any one of claims 1-9, wherein, The average daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, or its pharmaceutical composition, is selected from 0.01-10 mg, preferably 0.01-1.0 mg, more preferably 0.01-0.5 mg, and most preferably 0.03-0.3 mg; Alternatively, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, or its pharmaceutical composition, for each or daily administration is 0.01-10 mg, preferably 0.01-1.0 mg, more preferably 0.01-0.5 mg, and most preferably 0.05-0.5 mg; Alternatively, the frequency of administration of the compound of formula (I) or its pharmaceutically acceptable salt, or its pharmaceutical composition, is three times a day, twice a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, three times a week, twice a week, once a week, once every two weeks, or once every three weeks, preferably three times a day, twice a day, or once a day, and most preferably once a day; Alternatively, the compound of formula (I) or its pharmaceutically acceptable salt, or its pharmaceutical composition, may be administered continuously or intermittently; Alternatively, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, may be administered to the subject once daily in the following manner: 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, or 0.3 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Alternatively, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, may be administered to the subject once daily for a period of 4 weeks. The administration dose may be 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, or 0.3 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Alternatively, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, may be administered as follows: once daily for 4 weeks as a dosing cycle, the subject is given 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, or 0.3 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each time, for 3 consecutive weeks and 1 week off; Alternatively, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, may be administered as follows: once daily for 3 weeks, in doses of 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, or 0.3 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, for 2 weeks on, followed by a 1-week break. Alternatively, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, may be administered as follows: in a 3-week dosing cycle; in cycles 1 and 2, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered once daily to the subject at a dose of 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, or 0.3 mg once daily; starting from cycle 3, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered once daily to the subject at a dose of 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, or 0.3 mg once daily for 2 weeks followed by a 1-week break.

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