Use of pyrido[1,2-a]pyrimidinone compounds for the treatment of peripheral t-cell lymphoma

Abstract

Pyrido[1,2-a]pyrimidinone compounds or pharmaceutical compositions thereof for treating peripheral T-cell lymphoma, and methods or uses of pyrido[1,2-a]pyrimidinone compounds for treating peripheral T-cell lymphoma.

Description

[0001] Cross-references to related applications

[0002] This application claims priority and benefit to Chinese Patent Application No. 202010967168.5, filed with the China National Intellectual Property Administration on September 15, 2020, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] This application belongs to the field of medicinal chemistry and relates to the use of pyrido[1,2-a]pyrimidinone compounds for the treatment of peripheral T-cell lymphoma. Background Technology

[0004] The PI3K pathway is the most common site of mutation in human cancer cells, which can lead to cell proliferation, activation, and signal amplification.

[0005] PI3K kinase (phosphatidylinositol-3-kinase, PI3Ks) belongs to the lipid kinase family and phosphorylates the 3'-OH terminus of the inositol ring of phosphatidylinositol. It is a lipid kinase composed of a regulatory subunit p85 or p101 and a catalytic subunit p110. It activates downstream Akt and other kinases by catalyzing the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3), thus playing a crucial role in cell proliferation, survival, and metabolism. Therefore, inhibiting phosphatidylinositol-3-kinase can affect the PI3K pathway, thereby inhibiting the proliferation and activation of cancer cells.

[0006] The tumor suppressor gene PTEN (phosphatase and tension homolog deleted onchromosome ten) dephosphorylates PIP3 to generate PIP2, thereby negatively regulating the PI3K / Akt signaling pathway, inhibiting cell proliferation and promoting apoptosis. The frequent occurrence of PI3K gene mutations and amplifications in cancer, as well as the absence of PTEN in cancer, all suggest a close relationship between PI3K and tumorigenesis.

[0007] WO2015192760 discloses a series of compounds that are PI3K inhibitors, and specifically discloses compounds of formula I with the following structures:

[0008] Summary of the Invention

[0009] This application provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for the treatment of patients with peripheral T-cell lymphoma:

[0010]

[0011] On the other hand, this application provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating peripheral T-cell lymphoma in patients.

[0012] On the other hand, this application provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the treatment of patients with peripheral T-cell lymphoma.

[0013] On the other hand, this application provides a method for treating a patient with peripheral T-cell lymphoma, the method comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments of this application, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is used as a single active agent.

[0015] In some embodiments of this application, the compound of Formula I, or a pharmaceutically acceptable salt thereof, may be a pharmaceutical composition comprising a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is a single-dose pharmaceutical composition.

[0016] On the other hand, this application provides a pharmaceutical composition for treating peripheral T-cell lymphoma, said pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof.

[0017] On the other hand, this application provides a method for treating a patient with peripheral T-cell lymphoma, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0018] On the other hand, this application provides a kit for treating peripheral T-cell lymphoma, the kit comprising a compound of formula I described in this application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, preferably in a single-dose form; and instructions for use. Invention Details

[0020] Peripheral T-cell lymphoma

[0021] In some embodiments of this application, the peripheral T-cell lymphoma is selected from relapsed or refractory peripheral T-cell lymphoma.

[0022] In some embodiments of this application, the patient with the peripheral T-cell lymphoma has previously received one or more prior treatment regimens. In some embodiments of this application, the patient with the peripheral T-cell lymphoma has previously received one, two, three, four, or five prior treatment regimens.

[0023] In some embodiments of this application, the patient with peripheral T-cell lymphoma is a patient with peripheral T-cell lymphoma who has received first-line, second-line, or third-line or higher prior treatment regimens.

[0024] In some embodiments of this application, the patient with peripheral T-cell lymphoma experienced disease relapse after achieving objective remission with a prior treatment regimen, or the patient with peripheral T-cell lymphoma received prior treatment but did not achieve objective remission. In some embodiments of this application, "no objective remission" refers to disease stability or disease progression during treatment.

[0025] In some embodiments of this application, the patient with peripheral T-cell lymphoma is a patient with peripheral T-cell lymphoma who has previously received ≥1 line of systemic therapy and whose most recently received treatment regimen has shown no objective response (disease stability or disease progression during treatment) or whose disease has progressed after treatment.

[0026] In some embodiments of this application, the patient with peripheral T-cell lymphoma is a patient with relapsed or refractory peripheral T-cell lymphoma who has previously received prior treatment.

[0027] In some embodiments of this application, the patient with peripheral T-cell lymphoma is a patient who has previously received one or more prior treatment regimens containing pegaspargase or L-asparaginase.

[0028] In some embodiments of this application, the prior treatment regimen includes drug therapy, radiotherapy, or hematopoietic stem cell transplantation.

[0029] In some embodiments of this application, the prior treatment regimen includes interferon therapy, chemotherapy, or targeted drug therapy.

[0030] In some embodiments of this application, the chemotherapy drugs used in the prior treatment regimen include pegaspargase, asparaginase (e.g., L-asparaginase), cyclophosphamide, ifosfamide, vincristine, vindesine, prednisone, prednisolone, doxorubicin, doxorubicin, dexamethasone, methotrexate, cytarabine, carboplatin, cisplatin, bendamustine, fludarabine, mitoxantrone, etoposide, procarbazine, gemcitabine, methylprednisolone, methylprednisolone sodium succinate, mesna, oxaliplatin, 5-fluorouracil, or azacitidine.

[0031] In some embodiments of this application, the targeted drug therapy of the prior treatment regimen includes antitumor folic acid analogue therapy, histone deacetylase inhibitor therapy, proteasome inhibitor therapy, immunomodulatory inhibitor therapy, or immune checkpoint inhibitor therapy.

[0032] In some embodiments of this application, the antitumor folic acid analogue includes pralatrexate.

[0033] In some embodiments of this application, the histone deacetylase inhibitor includes romidesin, belistat, or chidamide.

[0034] In some embodiments of this application, the proteasome inhibitor includes bortezomib.

[0035] In some embodiments of this application, the immunomodulatory inhibitor includes lenalidomide or thalidomide.

[0036] In some embodiments of this application, the immune checkpoint inhibitor includes programmed death receptor-1 (PD-1) inhibitors and their ligand-1 (PD-L1) inhibitors. In some embodiments of this application, the immune checkpoint inhibitor includes Genolimzumab, Cemiplimab, Pembrolizumab, Nivolumab, Sintilimab, Tislelizumab, Avelumab, or Atezolizumab.

[0037] In some embodiments of this application, the targeted drugs of the prior treatment regimen include pralatrexate, romidesin, belistat, chidamide, bortezomib, lenalidomide, thalidomide, genolimzumab, cemiplimab, pembrolizumab, nivolumab, sintilimab, tislelizumab, avelumab, or atezolizumab.

[0038] In some embodiments of this application, the drugs used in the prior treatment regimen include pegaspargase, asparaginase (e.g., L-asparaginase), cyclophosphamide, ifosfamide, vincristine, vindesine, prednisone, prednisolone, doxorubicin, doxorubicin, epirubicin, dexamethasone, methotrexate, cytarabine, carboplatin, cisplatin, bendamustine, fludarabine, mitoxantrone, etoposide, procarbazine, gemcitabine, methylprednisolone, and methylprednisolone amber. Sodium benzoate, mesna, oxaliplatin, 5-fluorouracil, azacitidine, pralatrexate, romidesin, belipista, chidamide, bortezomib, lenalidomide, thalidomide, leucovorin, rituximab, genolimab, cemiplimab, pembrolizumab, nivolumab, sintilimab, tislelizumab, avelumab, atezolizumab mab, G-CSF, or a combination of one or more of the above drugs; preferably, the drugs used in the prior treatment regimen include pegaspargase, L-asparaginase, cyclophosphamide, ifosfamide, vincristine, vindesine, prednisone, prednisolone, doxorubicin, doxorubicin, dexamethasone, methotrexate, cytarabine, carboplatin, cisplatin, bendamustine, fludarabine, mitoxantrone, etoposide, procarbazine, gemcitabine, methylprednisolone sodium succinate, mesna, oxaliplatin, 5-fluorouracil, pralatrexate, romidesin, belipista, chidamide, bortezomib, lenalidomide, genolizumab, cemiplimab, pembrolizumab, nivolumab, sintilimab, tislelizumab, avelumab, atezolizumab, G-CSF, or a combination of one or more of the above drugs.

[0039] In some of the regimens described in this application, the prior treatment regimens include the AOEP regimen, AOEP+G-CSF regimen, AspaMetDex regimen, B regimen, BAC regimen, CHOP regimen, miniCHOP regimen, CHOEP regimen, CHOEP combined with chidamide regimen, CIFOX regimen, COP regimen, COEP-L regimen, DHAP regimen, DDGP regimen, EPOCH regimen, DA-EPOCH regimen, ESHAP regimen, GDP regimen, GDPE regimen, GEMOX regimen, FC regimen, FM regimen, HyperCVAD regimen, ICE regimen, LOP regimen, MA regimen, and P-GEMOX regimen. The prior treatment regimen includes the SMILE regimen, V-CAP regimen, or the above regimens in combination with rituximab (hereinafter also referred to as "R"); preferably, the prior treatment regimen includes the AOEP regimen, AOEP+G-CSF regimen, AspaMetDex regimen, R-HyperCVAD regimen, BR regimen, CHOP regimen, R-CHOP regimen, R-miniCHOP regimen, CHOEP regimen, COP regimen, COEP-L regimen, DHAP regimen, R-DHAP regimen, DA-EPOCH regimen, DA-EPOCH-R regimen, DDGP regimen, ESHAP regimen, FCR regimen, FMR regimen, GDP regimen, and R. 2 The regimens include R-GDP, R-GDPE, GEMOX, HyperCVAD, ICE, R-ICE, LOP, VR-CAP, R-GEMOX, P-GEMOX, or R-high-dose cytarabine.

[0040] In some embodiments of this application, the prior treatment regimen includes radiotherapy selected from total lymphatic irradiation (TLI) and subtotal lymphatic irradiation (STLI). In some embodiments of this application, the radiotherapy includes involved field irradiation (IFRT), involved lymph node irradiation (INRT), or involved site irradiation (ISRT).

[0041] In some embodiments of this application, the hematopoietic stem cell transplantation of the prior treatment regimen includes autologous hematopoietic stem cell transplantation or allogeneic hematopoietic stem cell transplantation.

[0042] In some embodiments of this application, the peripheral T-cell lymphoma is selected from peripheral T-cell lymphoma (not otherwise specified, PTCL-NOS); angioimmunoblastic T-cell lymphoma (AITL); anaplastic large cell lymphoma (ALCL); or extranodal NK / T-cell lymphoma, nasal type (NK / T cell lymphoma, NKTCL).

[0043] In some embodiments of this application, the peripheral T-cell lymphoma is selected from nonspecific peripheral T-cell lymphoma (PTCL-NOS).

[0044] In some embodiments of this application, the nonspecific peripheral T-cell lymphoma is selected from GATA3 overexpression type, TBX21 overexpression type, or cytotoxic genotype overexpression type.

[0045] In some embodiments of this application, the peripheral T-cell lymphoma is selected from relapsed or refractory peripheral T-cell lymphoma; optionally, the patient with the peripheral T-cell lymphoma has previously received one or more prior treatment regimens; optionally, the patient with the peripheral T-cell lymphoma experienced disease recurrence after achieving objective remission with a prior treatment regimen, or the patient with the peripheral T-cell lymphoma received a prior treatment regimen but did not achieve objective remission; optionally, the prior treatment regimen includes drug therapy, radiotherapy, or hematopoietic stem cell transplantation.

[0046] Dosing regimen

[0047] In some embodiments of this application, the treatment cycle for peripheral T-cell lymphoma is 2-6 weeks. In some embodiments of this application, the treatment cycle for peripheral T-cell lymphoma is 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or any range of the above values. In some embodiments of this application, the treatment cycle for peripheral T-cell lymphoma is 3 weeks.

[0048] In some embodiments of this application, the daily dose of the treatment for peripheral T-cell lymphoma in patients is selected from 1-100 mg. In some embodiments of this application, the daily dose of the treatment for peripheral T-cell lymphoma in patients is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, and 49 mg. 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg, or any range of the above values. In some embodiments of this application, the daily dose of the treatment for peripheral T-cell lymphoma in patients is selected from 1-50 mg, 5-50 mg, 10-50 mg, 10-40 mg, or 20-40 mg.

[0049] In some embodiments of this application, the number of daily doses for treating peripheral T-cell lymphoma in the patient is once, twice, or three times.

[0050] In some embodiments of this application, the administration of the treatment for peripheral T-cell lymphoma in the patient may be once every two days.

[0051] In some embodiments of this application, the dosing regimen for treating patients with peripheral T-cell lymphoma includes: a dosing cycle of 2-6 weeks, a daily dose of 1-40 mg, and a daily dosing frequency of 1-3 times.

[0052] The compounds of Formula I of this application, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, may be administered via a variety of routes, including but not limited to: oral, parenteral, intraperitoneal, intravenous, intra-arterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, local, subcutaneous, intra-fat, intra-articular, or intrathecal administration. In certain regimens, oral administration is permitted.

[0053] The method of administration can be determined based on factors such as the drug's activity, toxicity, and patient tolerability. In some embodiments, the compound of formula I of this application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered at intervals.

[0054] Pharmaceutical Composition

[0055] The pharmaceutical compositions of this application may be prepared by combining a compound of Formula I of this application, or a pharmaceutically acceptable salt thereof, with a suitable pharmaceutically acceptable excipient / carrier, for example, by formulating it into a solid, semi-solid, liquid or gaseous formulation.

[0056] In some embodiments of this application, the pharmaceutical composition is a formulation suitable for oral administration, including tablets, capsules, powders, granules, pellets, pastes, powders, etc., with tablets and capsules being preferred. The oral formulation can be prepared using pharmaceutically acceptable carriers known in the art through conventional methods. Pharmaceutically acceptable carriers include diluents, binders, wetting agents, disintegrants, lubricants, etc.

[0057] In some embodiments of this application, the pharmaceutical composition is a single-dose pharmaceutical composition. In some embodiments, the pharmaceutical composition contains 1 mg to 50 mg of a compound of formula I of this application, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 1 mg, 2 mg, 5 mg, 8 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg, 22 mg, 25 mg, 28 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 42 mg, 45 mg, 48 mg, or 50 mg, or any of the aforementioned values ​​as endpoints within a range or any value thereof, such as 2 mg to 50 mg, 10 mg to 40 mg, 5 mg to 30 mg, 5 mg to 20 mg, etc.

[0058] Technical effect

[0059] The compound of Formula I of this application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, exhibits good efficacy in reducing the growth of peripheral T-cell lymphoma or even eliminating tumors, providing treated patients with a good disease control rate (DCR) and resulting in longer survival (e.g., median survival, progression-free survival, or overall survival) and a longer duration of disease remission (DOR). Furthermore, the compound of Formula I of this application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, demonstrates good safety while reducing the growth of peripheral T-cell lymphoma.

[0060] Definitions and Explanations

[0061] Unless otherwise stated, the terms used in this application 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 in this application, it is intended to refer to the corresponding product or its active ingredient.

[0062] 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.

[0063] For purposes of description and disclosure, all patents, patent applications and other identified publications are expressly incorporated herein by reference. Any reference to these publications herein does not constitute an endorsement that such publication is part of the general knowledge in the art.

[0064] 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.

[0065] The term "pharmaceutically acceptable salt" includes salts formed by base ions and free acids or salts formed by acid ions and free bases.

[0066] As used in this application, the amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, such as dosage, amount, or content in a pharmaceutical composition, is calculated in its free base form.

[0067] As used in this application, compounds in the pharmaceutical composition of this application, if having, for example, at least one basic center, can form acid addition salts. If desired, corresponding acid addition salts having additionally present basic centers can also be formed. Compounds having at least one acidic group (e.g., COOH) can also form salts with a base. If the compound, for example, contains both a carboxyl group and an amino group, it can also form corresponding internal salts.

[0068] The term "patient" refers to a mammal. In some implementations, the patient is a human.

[0069] The term "pharmaceutical composition" refers to one or more compounds of Formula I of this application, or pharmaceutically acceptable salts thereof, or combinations thereof, and a mixture thereof with pharmaceutically acceptable excipients / carriers. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application or combinations thereof to a patient.

[0070] The term "single dose" refers to the smallest packaged unit containing a certain amount of medicine. For example, each tablet is a single dose; if a box of medicine contains seven capsules, then each capsule is a single dose; or each vial of injection is a single dose.

[0071] 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.

[0072] The term "therapeutic effective amount" means (i) the amount of the compound of this application used to treat a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to delay the onset of one or more symptoms of a particular 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 the present disclosure.

[0073] In the context of cancer, the term "refractory" refers to a particular cancer that is resistant to or unresponsive to a particular treatment agent. Cancers that are difficult to treat with a particular treatment agent may begin when treatment with that particular treatment agent is initiated (i.e., there is no response upon initial exposure to the agent), or may result from the development of resistance to the agent during the initial treatment period or during subsequent treatments with that agent.

[0074] In the context of cancer, the term "relapse" refers to the recurrence of the disease after a period of objective remission following treatment with a particular regimen. "Objective remission" includes both complete and partial remission.

[0075] In the context of cancer, the term "first-line therapy" refers to the first treatment administered to a disease. It is typically part of a set of standard treatments, such as chemotherapy and radiation therapy following surgery. First-line therapy, when used alone, is generally considered the best treatment option. If it fails to cure the disease or causes serious side effects, other treatments may be added or used.

[0076] As used in this application, the medications used in the prior treatment regimens may refer to the following, or to treatment guidelines or textbooks related to medicine and pharmacy:

[0077] AOEP regimen: cytarabine, vincristine, etoposide, and dexamethasone;

[0078] AspaMetDex regimen: asparaginase, methotrexate, and dexamethasone;

[0079] Option B: Bendamustine;

[0080] BAC regimen: Bendamustine and Cytarabine;

[0081] BR regimen: Bendamustine and Rituximab;

[0082] CHOP regimen: cyclophosphamide, doxorubicin / epirubicin, vincristine, and prednisone; the CHOP regimen includes, but is not limited to, the CHOP-21 day regimen or the CHOP-14 day regimen;

[0083] miniCHOP regimen: Reduced dose CHOP (dose reduced to 1 / 2 to 1 / 3 of the standard dose);

[0084] CHOEP regimen: cyclophosphamide, doxorubicin / epirubicin, vincristine, etoposide, and prednisone (CHOP regimen combined with etoposide);

[0085] CIFOX regimen: 5-fluorouracil and oxaliplatin;

[0086] COEP-L regimen: cyclophosphamide, vincristine (or vindesine), etoposide, prednisone (or dexamethasone), and pegaspargase;

[0087] COP regimen: cyclophosphamide, vincristine, and prednisone;

[0088] EPOCH regimen: etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin;

[0089] DA-EPOCH regimen (Dose-adjustment EPOCH): etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin;

[0090] DA-EPOCH-R regimen (Dose-adjustment EPOCH-R): etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab;

[0091] DDGP regimen: dexamethasone, cisplatin, gemcitabine, and pegaspargase;

[0092] DHAP regimen: dexamethasone, high-dose cytarabine, and cisplatin;

[0093] ESHAP regimen: etoposide, methylprednisolone, high-dose cytarabine and cisplatin;

[0094] FC regimen: Fludarabine and cyclophosphamide;

[0095] FCR regimen: fludarabine, cyclophosphamide, and rituximab;

[0096] FM regimen: Fludarabine and Mitoxantrone;

[0097] FMR regimen: fludarabine, mitoxantrone, and rituximab;

[0098] G-CSF (Granulocyte-Colony Stimulating Factor): Granulocyte colony-stimulating factor;

[0099] GDP-based approach: gemcitabine, dexamethasone, and cisplatin;

[0100] GDPE regimen: gemcitabine, dexamethasone, cisplatin, and etoposide;

[0101] GEMOX regimen: gemcitabine and oxaliplatin;

[0102] HyperCVAD regimens: Regimen A: Cyclophosphamide, Mesna, Vincristine, Doxorubicin, and Dexamethasone; Regimen B: Methotrexate and Cytarabine;

[0103] ICE regimen: ifosfamide, carboplatin, and etoposide;

[0104] LOP regimen: Pegaspargase, vincristine, and prednisone;

[0105] MA regimen: methotrexate and cytarabine;

[0106] P-GEMOX regimen: pegaspargase, gemcitabine, and oxaliplatin;

[0107] R regimen: Rituximab;

[0108] R 2 Treatment regimen: Rituximab + Lenalidomide;

[0109] R-: Refers to the combination of rituximab with a treatment regimen. This includes, but is not limited to, the following:

[0110] R-CHOP regimen: rituximab, cyclophosphamide, doxorubicin / epiroxorubicin, vincristine, and prednisone;

[0111] R-miniCHOP regimen: Rituximab, reduced dose CHOP (dose reduced to 1 / 2 to 1 / 3 of the standard dose);

[0112] R-DHAP regimen: rituximab, dexamethasone, cytarabine, and cisplatin;

[0113] R-GDP regimen: rituximab, gemcitabine, dexamethasone, and cisplatin;

[0114] R-GDPE regimen: rituximab, gemcitabine, dexamethasone, cisplatin, and etoposide;

[0115] R-GEMOX regimen: rituximab, gemcitabine, and oxaliplatin;

[0116] R-HyperCVAD regimens: Regimen A: Rituximab, cyclophosphamide, mesna, vincristine, doxorubicin, and dexamethasone; Regimen B: Rituximab, methotrexate, and cytarabine;

[0117] R-ICE regimen: rituximab, ifosfamide, carboplatin, and etoposide.

[0118] SMILE regimen: Dexamethasone, methotrexate, leucovorin calcium, mesna, ifosfamide, L-asparaginase and etoposide (depending on actual clinical use, the SMILE regimen may also include: dexamethasone, methotrexate, ifosfamide, pegaspargase and etoposide).

[0119] V-CAP regimen: bortezomib, cyclophosphamide, doxorubicin, and prednisone.

[0120] VR-CAP regimen: bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone.

[0121] R-high-dose cytarabine regimen: rituximab and high-dose cytarabine.

[0122] As used in this application, the prednisolone may also be prednisolone, and the two may be used interchangeably.

[0123] As used in this application, doxorubicin is also known as doxorubicin, and the two can be used interchangeably.

[0124] As used in this application, the chemotherapy regimens described are prior art in the art. Those skilled in the art can readily refer to existing treatment guidelines or relevant medical and pharmaceutical textbooks (e.g., the Chinese Society of Clinical Oncology (CSCO) Lymphoma Diagnosis and Treatment Guidelines 2019) to obtain the specific details of the chemotherapy regimens (including but not limited to the drugs used, dosages, or treatment cycles). The examples of drugs used in the chemotherapy regimens described above are exemplary, and the specific details of the chemotherapy regimens (including but not limited to the drugs used, dosages, or treatment cycles) shall be based on treatment guidelines or relevant medical and pharmaceutical textbooks. Detailed Implementation

[0125] The invention will be described in more detail through specific embodiments. The following embodiments are provided for illustrative purposes and should not be construed as limiting the invention in any way.

[0126] Example 1: Tablets of Formula I

[0127] Table 1 shows the formulation composition of tablets containing compound I.

[0128]

[0129] Preparation method:

[0130] 1) The compound of formula I, microcrystalline cellulose, mannitol, and cross-linked sodium carboxymethyl cellulose are sequentially passed through a pulverizer and granulator, sieved and collected, and then premixed to obtain a premixed material.

[0131] 2) Hydroxypropyl methylcellulose was prepared as an aqueous solution as a binder.

[0132] 3) Transfer the premixed material from step 1) to a wet granulation pot and add the binder obtained in step 2) to start granulation.

[0133] 4) The prepared soft wet material is granulated, dried, and then mixed with magnesium stearate.

[0134] 5) Tableting.

[0135] Optionally, the resulting tablets may be coated.

[0136] Compound I was prepared according to the method disclosed in WO2015192760.

[0137] Example 2: Clinical trial of peripheral T-cell lymphoma

[0138] 2.1 Dosing regimen

[0139] Administration: Oral administration, once daily, 15 mg or 20 mg each time, for 21 consecutive days as one cycle.

[0140] Drug: Tablets of Formula I compound, in 5 mg or 20 mg strength.

[0141] 2.2 Inclusion criteria

[0142] 1) Histopathologically confirmed relapsed / refractory peripheral T-cell lymphoma (PTCL) includes the following four subtypes: nonspecific peripheral T-cell lymphoma (PTCL-NOS); angioimmunoblastic T-cell lymphoma (AITL); anaplastic large cell lymphoma (ALCL); and extranodal NK / T-cell lymphoma, nasal type (NKTCL).

[0143] 2) Has previously received at least one first-line systemic therapy, and experienced disease progression during or after the most recent treatment or has not achieved objective remission after adequate treatment;

[0144] 3) At least one measurable target lesion (assessed according to the 2014 Lugano evaluation criteria);

[0145] 4) Age ≥ 18 years; ECOG (PS) score: 0–2; expected survival ≥ 3 months;

[0146] 5) During the screening period, the functions of major organs meet the following criteria:

[0147] Complete blood count (CBC) criteria (no growth factor use or blood transfusion within 14 days):

[0148] Absolute neutrophil count (ANC) ≥ 1.0 × 10⁻⁶ 9 / L;

[0149] Lymphocyte count (LYM) ≥ 0.5 × 10 9 / L;

[0150] CD4+ T lymphocyte count ≥0.2×10 9 / L;

[0151] Platelet count (PLT) ≥ 75 × 10 9 / L (patients with lymphoma bone marrow infiltration ≥50×10 9 / L allows inclusion);

[0152] Hemoglobin (Hb) ≥ 80 g / L;

[0153] Blood biochemistry test standards:

[0154] Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN (≤5×ULN for lymphoma involving the liver or biliary obstruction);

[0155] Serum total bilirubin (TBIL) ≤ 1.5 × ULN;

[0156] Coagulation function: Activated partial thromboplastin time (APTT), international normalized ratio (INR), and prothrombin time (PT) ≤ 1.5 × ULN;

[0157] Serum creatinine (Cr) ≤ 1.5 × ULN, or creatinine clearance ≥ 50 mL / min;

[0158] 6) Women should agree to use contraception (such as an intrauterine device [IUD], birth control pills, or condoms) during the study and for 6 months after the study ends; have a negative serum or urine pregnancy test within 7 days prior to study enrollment; and must be a non-lactating patient. Men should agree to use contraception during the study and for 6 months after the study ends.

[0159] 7) Patients voluntarily joined this study, signed informed consent forms, and had good compliance.

[0160] 2.3 Evaluation Methods and Indicators

[0161] The efficacy was evaluated using the evaluation criteria revised at the 2014 Lugano Conference.

[0162] The primary efficacy endpoint was the objective response rate (ORR), which is the number of cases with complete remission (CR) and partial remission (PR) divided by the total number of cases, including cases with complete remission (CR) and partial remission (PR).

[0163] Secondary efficacy endpoints: progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and duration of response (DOR).

[0164] 2.4 Test Results

[0165] In one trial, to date, the efficacy of the compound has been evaluated in 6 enrolled patients with peripheral T-cell lymphoma. The objective response rate (ORR) was 50% (3 / 6), demonstrating that compound I has good therapeutic efficacy against peripheral T-cell lymphoma. Furthermore, compound I exhibits good safety profile during therapeutic use.

[0166] In another trial, to date, the efficacy of Formula I compounds in treating peripheral T-cell lymphoma has also been shown to be good, as detailed below:

[0167] Case 1

[0168] The patient, a 38-year-old male, presented with a 2×2cm mass in the right neck. Immunohistochemistry of the lymph node excision biopsy revealed the following: CK broad-spectrum (-), EMA (-), LCA (+), CD20 (+), CD79α (+), CD3 (+), CD43 (+), CD15 (+), CD5 (-), CD30 (+), CD38 (+), CD138 (-), CD21 (-), c-myc (+), ALK (-), Bcl2-2 (weakly +), Bcl6 (-), Mum-1 (+), PD-L1 (+), Pax-5 (-), Ki-67 (+, 60%). In situ hybridization showed EBER (+). The right cervical lymph nodes were consistent with ALK-negative anaplastic large cell lymphoma. A CT scan of the neck, chest, and abdomen revealed multiple enlarged lymph nodes in both neck areas, bilateral supraclavicular fossae, and axillae.

[0169] Following clinical diagnosis, the patient was given the CHOEP regimen (specifically: cyclophosphamide 1g, doxorubicin liposome 50mg, vincristine 2mg, etoposide 0.1g, prednisone 0.1g) for 4 cycles of chemotherapy. Due to incomplete tumor remission, the regimen was switched to CHOEP combined with chidamide, which proceeded smoothly. Approximately one month after the completion of the CHOEP combined with chidamide chemotherapy, the patient developed enlarged lymph nodes in the left preauricular and postauricular regions without any obvious cause, indicating disease progression.

[0170] After enrollment, patients began treatment with Formula I compound tablets, receiving 15 mg of Formula I compound daily for 21 days as one cycle. The baseline SPD (sum of the products of the maximum vertical diameters of multiple lesions) was 717 mm. After 2 cycles of treatment, the SPD was 495 mm, and after 4 cycles, the SPD was 409 mm. Baseline PET-CT showed a mediastinal SUVmax (maximum standard uptake value) of 1.9, a liver SUVmax of 2.6, and a left parotid gland SUVmax of 7.0 for the highest uptake lesion. After 4 cycles of treatment, PET-CT showed a mediastinal SUVmax of 1.5, a liver SUVmax of 2.5, and a left parotid gland SUVmax of 1.5 for the highest uptake lesion. The overall efficacy was complete remission (CR), with no new lesions appearing.

[0171] Case 2

[0172] The patient, a 33-year-old female, was diagnosed with extranodal NK / T-cell lymphoma (left nasal cavity), nasal type. Immunohistochemistry showed tumor cells: CK(-), CD20(+), CD2(+), CD3(+), CD4(-), CD8(-), CD43(+), CD56(+), GranzymeB(+), TIA-1(+), Ki-67 (30%+), EBER / ISH(+).

[0173] Following clinical diagnosis, the patient was initially treated with the COEP-L regimen (vinorelbine 4mg, cyclophosphamide 1.2g, pegaspargase 3750IU, etoposide 0.1g, dexamethasone 15mg); approximately four weeks later, the treatment was switched to the SMILE regimen (adjusted based on actual clinical medication use to dexamethasone 40mg, methotrexate 3g, ifosfamide 2.3g, pegaspargase 3750IU, etoposide 0.15g); approximately one month later, the treatment was switched to the P-GEMOX regimen (pegaspargase injection 3750IU + gemcitabine hydrochloride injection 1.9g + oxaliplatin injection 60mL). Treatment: After approximately five weeks, the patient switched to AOEP chemotherapy plus G-CSF regimen; after approximately six weeks, the patient switched to SMILE regimen (dexamethasone 40mg, methotrexate 3g, ifosfamide 2.3g, pegaspargase 3750IU, etoposide 0.15g), while simultaneously receiving intrathecal administration (methotrexate 10mg, dexamethasone 5mg, cytarabine 50mg); after approximately three weeks, the patient underwent autologous hematopoietic stem cell transplantation; approximately two months after the autologous hematopoietic stem cell transplantation, the patient began taking chidamide tablets continuously for approximately four months, twice a week, four tablets once a day. Pre-enrollment CT scans indicated disease progression.

[0174] After enrollment, patients began treatment with Formula I compound tablets, receiving 15 mg of Formula I compound daily. Prior to treatment, enhanced MRI of the paranasal sinuses showed a measurable target lesion (anterior and lateral walls of the right nasal cavity) with a SPD of 280 mm, normal liver function, and a spleen vertical diameter of 12 cm. Following administration, enhanced MRI of the paranasal sinuses was performed periodically. After two cycles of treatment, the SPD decreased to 117 mm, achieving a partial response (PR) with a reduction rate of 58.2%. The liver function remained normal, the spleen vertical diameter was 11.5 cm, and no new lesions were observed.

Claims

1. Use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating peripheral T-cell lymphoma in patients: in, The peripheral T-cell lymphomas are selected from relapsed or refractory peripheral T-cell lymphomas.

2. The use as described in claim 1, wherein, The patient with peripheral T-cell lymphoma had previously achieved objective remission with a prior treatment regimen, but the disease recurred.

3. The use as described in claim 1, wherein, The patients with peripheral T-cell lymphoma had received prior treatment but had not achieved objective remission.

4. The use as described in claim 1, wherein, The peripheral T-cell lymphoma is selected from non-specific peripheral T-cell lymphoma; angioimmunoblastic T-cell lymphoma; anaplastic large cell lymphoma; or extranodal NK / T-cell lymphoma, nasal type.

5. The use as described in claim 4, wherein, The nonspecific peripheral T-cell lymphomas are selected from those overexpressing GATA3, overexpressing TBX21, or overexpressing cytotoxic genotypes.

6. The use as described in claim 1, wherein, The patients with peripheral T-cell lymphoma have previously received one or more prior treatment regimens.

7. The use as described in claim 6, wherein, The patients with peripheral T-cell lymphoma have previously received one, two, three, four, or five prior treatment regimens.

8. The use as described in claim 6, wherein, The patients with peripheral T-cell lymphoma are those who have previously received one or more prior treatment regimens containing pegaspargase or L-asparaginase.

9. The use as described in claim 6, wherein, The prior treatment options include drug therapy, radiotherapy, or hematopoietic stem cell transplantation.

10. The use as described in claim 9, wherein, The drug treatment includes interferon, chemotherapy, or targeted drug therapy; the radiotherapy is selected from whole lymphatic irradiation and subwhole lymphatic irradiation; the hematopoietic stem cell transplantation includes autologous hematopoietic stem cell transplantation or allogeneic hematopoietic stem cell transplantation.

11. The use as described in claim 9, wherein, The drugs used in the aforementioned treatment are selected from pegaspargase, asparaginase, cyclophosphamide, ifosfamide, vincristine, vindesine, prednisone, prednisolone, doxorubicin, doxorubicin, epirubicin, dexamethasone, methotrexate, cytarabine, carboplatin, cisplatin, bendamustine, fludarabine, mitoxantrone, etoposide, procarbazine, gemcitabine, methylprednisolone, methylprednisolone sodium succinate, mesna, oxaliplatin, 5-fluorouracil, azacitidine, and prazolam. Trixazone, Romidesin, Belistat, Chidamide, Bortezomib, Lenalidomide, Thalidomide, Leucovorin, Rituximab, Genolimzumab, Cemiplimab, Pembrolizumab, Nivolumab, Sintilimab, Tislelizumab, Avelumab, Atezolizumab, G-CSF, or a combination of one or more of the above drugs.

12. The use as described in any one of claims 1-11, wherein, The treatment cycle for peripheral T-cell lymphoma is 2-6 weeks.

13. The use as described in any one of claims 1-11, wherein, The daily dose for treating peripheral T-cell lymphoma is selected from 1-100 mg.

14. The use as described in any one of claims 1-11, wherein, The daily dosing frequency for treating peripheral T-cell lymphoma is once, twice, or three times.

15. Use of a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating peripheral T-cell lymphoma. in, The peripheral T-cell lymphomas are selected from relapsed or refractory peripheral T-cell lymphomas.

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