Use of pyrrolopyridine-containing compound in treatment of tumors

Abstract

The present application belongs to the pharmaceutical field, relates to the use of a pyrrolopyridine-containing compound in the treatment of tumors, and specifically relates to the use of a compound of formula (I-1) or a pharmaceutically acceptable salt thereof in the treatment of hematological tumors, wherein the hematological tumors are selected from recurrent and / or refractory hematological tumors.

Description

Use of pyrrolopyridine-containing compounds in treating tumors

[0001] Reference to Related Applications

[0002] This application claims priority to and the benefit of Chinese Patent Application No. 202411298044.7, filed September 14, 2024, and Chinese Patent Application No. 202510617008.0, filed May 13, 2025, in the State Intellectual Property Office of the People’s Republic of China, the entire contents of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0003] The present application belongs to the field of medicine, and relates to the use of pyrrolopyridine-containing compounds in treating tumors, in particular to the use of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof in treating hematological tumors. BACKGROUND

[0004] BCL-2 proteins are divided into three families: the BCL-2 family (whose family members include BCL-2, BCL-XL, etc.), the BAX family, and the BH3-only family, wherein the BCL-2 family plays an anti-apoptotic role, and the members of the latter two families play a pro-apoptotic role.

[0005] Anti-apoptotic BCL-2 family proteins are associated with many diseases and are being studied as potential therapeutic drug targets. These targets for intervention therapy include, for example, BCL-2 family proteins BCL-2 and BCL-XL, etc. Inhibitors of BCL-2 family proteins are inhibitors that bind to the target protein, and the binding affinity of the compound is only one of many parameters to be considered, and a goal is to produce a compound that preferentially binds to one protein over another, i.e., is selective for it. To show this selectivity, it is known that a compound shows a high binding affinity to a particular protein, and a lower binding affinity to another member.

[0006] Compounds that selectively inhibit BCL-2 proteins can be used to treat hyperproliferative diseases, such as tumors. For example, WO2019185025, WO2020088442, WO2020238785 disclose compounds or pharmaceutically acceptable salts thereof as BCL-2 inhibitors. SUMMARY

[0007] In one aspect, the present application provides a method of treating hematological tumors, comprising administering to a subject a therapeutically effective amount of a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0008] On the other hand, this application provides the use of a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating hematologic malignancies. This application also provides a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating hematologic malignancies. This application further provides the use of the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating hematologic malignancies.

[0009] In another aspect, this application also provides a pharmaceutical composition for treating hematologic malignancies, the pharmaceutical composition comprising a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

[0010] In some embodiments, this application also provides a kit for treating hematologic malignancies, comprising: a pharmaceutical composition containing a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof; optionally, further comprising instructions for use of the pharmaceutical composition containing the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the instructions for use refer to instructing a subject to administer the pharmaceutical composition containing the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the BCL-2 inhibitor described in this application or a pharmaceutically acceptable salt thereof is selected from compounds of formula I-1 or pharmaceutically acceptable salts thereof.

[0012] R 1 Selected from hydrogen, halogen or C 1-6 alkyl;

[0013] Ring A is selected from 5-6 membered heterocyclic alkyl groups.

[0014] R 2 Each is independently selected from 4-6 membered heterocyclic alkyl groups, C 3-6 cycloalkyl, -COR a -SO2R b C, or C that is optionally replaced by halogens 1-6 alkyl;

[0015] R a or R b Each is independently selected from H, 4-6 membered heterocyclic alkyl groups, and C. 3-6 cycloalkyl or C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally halogenated, -CN, or -N(C) 1-6 Alkyl)2、-NHC 1-6 Alkyl or -OC 1-6 Alkyl substitution;

[0016] m is selected from 0, 1, 2 or 3.

[0017] In some implementations, structural fragments Selected from

[0018] In some implementation schemes, R 1 Selected from hydrogen, halogen or C 1-3 Alkyl group. In some embodiments, R 1 Selected from hydrogen, fluorine, chlorine, or methyl. In some embodiments, R 1 Selected from hydrogen, chlorine, or methyl.

[0019] In some embodiments, ring A is selected from a 6-membered heterocyclic alkyl group. In some embodiments, ring A is selected from a 6-membered heterocyclic alkyl group containing one or more O atoms, such as a 6-membered heterocyclic alkyl group containing one or two O atoms. In some embodiments, ring A is selected from dioxane or pyran ring.

[0020] In some implementation schemes, R 2 Each is independently selected from 4-6 membered heterocyclic alkyl groups, C 4-6 cycloalkyl, -COR a -SO2R b C, or C that is optionally replaced by halogens 1-4 alkyl.

[0021] In some implementation schemes, R a or R b Each is independently selected from H, 4-6 membered heterocyclic alkyl groups, and C. 3-6 cycloalkyl or C 1-4 Alkyl, the C 1-4 Alkyl groups are optionally halogenated, -CN, or -N(C) 1-4 Alkyl)2、-NHC 1-4 Alkyl or -OC 1-4 Alkyl substitution.

[0022] In some implementation schemes, R 2 Each of the following is independently selected from -C(O)H, -COC(CH3)3, -COCF3, -COCH2CN, -COCH2N(CH3)2, -SO2CH2CH3, -SO2CF3, -SO2C2F5, -CF3, -C2F5, tetrahydropyran, monooxetane, -SO2-cyclopropane, -CO-cyclopropane, -CO-monoxetane, -SO2-monoxetane, or -SO2-cyclobutane.

[0023] In some implementations, m is selected from 0 or 1.

[0024] In some embodiments, the BCL-2 inhibitor described in this application or a pharmaceutically acceptable salt thereof is selected from compounds of formula I, II, III, or IV or pharmaceutically acceptable salts thereof.

[0025] In some embodiments, the BCL-2 inhibitor or pharmaceutically acceptable salt thereof is selected from a compound of Formula I or a pharmaceutically acceptable salt thereof; or is selected from a compound of Formula II or a pharmaceutically acceptable salt thereof; or, is selected from a compound of Formula III or a pharmaceutically acceptable salt thereof; or is selected from a compound of Formula IV or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof is selected from a compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof is selected from a compound of Formula II or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof is selected from a compound of Formula III or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof is selected from a compound of Formula IV or a pharmaceutically acceptable salt thereof.

[0027] hematological tumor

[0028] In some embodiments, the hematological tumor is selected from a relapsed and / or refractory hematological tumor. In some embodiments, the hematological tumor is selected from a relapsed and / or refractory advanced hematological tumor.

[0029] In some embodiments, the hematological tumor is selected from a histologically or cytologically confirmed hematological tumor. In some embodiments, the above diagnosis is in accordance with the 2016 WHO diagnostic criteria.

[0030] In some embodiments, the hematological tumor is selected from a lymphoid tumor or a leukemia.

[0031] In some embodiments, the hematological tumor is selected from a lymphoid tumor or a myeloid leukemia. In some embodiments, the lymphoid tumor is selected from a non-Hodgkin lymphoma. In some embodiments, the myeloid leukemia is acute myeloid leukemia.

[0032] In some embodiments, the hematological tumor is selected from a non-Hodgkin lymphoma or an acute myeloid leukemia. In some embodiments, the non-Hodgkin lymphoma is selected from a mantle cell lymphoma, a diffuse large B-cell lymphoma, a chronic lymphocytic leukemia, and / or a small lymphocytic lymphoma.

[0033] In some embodiments, the hematological tumor is selected from a mantle cell lymphoma, a diffuse large B-cell lymphoma, a chronic lymphocytic leukemia, and / or a small lymphocytic lymphoma, or an acute myeloid leukemia.

[0034] In some embodiments, the hematological tumor is selected from a leukemia.

[0035] In some embodiments, the hematological tumor is selected from a myeloid leukemia.

[0036] In some embodiments, the hematological tumor or leukemia is selected from acute myeloid leukemia.

[0037] In some embodiments, the hematological tumor is selected from lymphoid tumors.

[0038] In some embodiments, the hematological tumor is selected from non-Hodgkin lymphoma.

[0039] In some embodiments, the hematological tumor or non-Hodgkin lymphoma is selected from mantle cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and / or small lymphocytic lymphoma.

[0040] In some embodiments, the subject with a hematological tumor is a subject who has not received treatment with one prior treatment regimen. In some embodiments, the subject with a hematological tumor has received treatment with one or more than one prior treatment regimen. In some embodiments, the subject with a hematological tumor has received treatment with one, two, three, four, or five prior treatment regimens. In some embodiments, the subject with a hematological tumor is a subject who is ineligible for one or more treatment regimens.

[0041] In some embodiments, the subject with a hematological tumor has received treatment with one or more than one prior treatment regimen and is ineligible for another one or more treatment regimens.

[0042] In some embodiments, the subject with a hematological tumor is selected from a subject who is relapsed or refractory. In some embodiments, the subject with a hematological tumor is selected from a subject who has disease that is refractory to initial induction or re-induction therapy. In some embodiments, the subject with a hematological tumor is selected from a subject who has relapsed or failed treatment following prior treatment. In some embodiments, the subject with a hematological tumor is selected from a subject who has relapsed or failed treatment following prior standard treatment. In some embodiments, the subject with a hematological tumor is selected from a subject who has failed prior treatment. In some embodiments, the subject with a hematological tumor is selected from a subject who has failed standard treatment. In some embodiments, the subject with a hematological tumor is selected from a subject who is intolerant to a prior treatment regimen. In some embodiments, the subject with a hematological tumor is selected from a subject who is intolerant to a standard treatment regimen. In some embodiments, the subject with a hematological tumor is selected from a subject who is intolerant to a prior treatment regimen and has no other better treatment options. In some embodiments, the subject with a hematological tumor is selected from a subject who is intolerant to a standard treatment regimen and has no other better treatment options. In some embodiments, the subject with a hematological tumor is selected from a subject who is intolerant to a prior treatment regimen or who has not achieved a remission (e.g., achieved a PR or better remission) or has disease progression following adequate treatment.

[0043] In some embodiments, the subject with a hematological tumor is selected from a subject who has received at least one systemic treatment regimen in the past, who has disease progression during or after the most recent treatment, or who has not achieved a remission (e.g., PR or better) with adequate treatment.

[0044] In some embodiments, the treatment regimen received in the past includes a first line treatment regimen, a second line treatment regimen, and / or a third line treatment regimen.

[0045] In some embodiments, the subject with a hematological tumor has at least one lesion / measurable disease that can be assessed for efficacy.

[0046] In some embodiments, the subject with acute myeloid leukemia has bone marrow blasts. In some embodiments, the subject with acute myeloid leukemia has bone marrow blasts > 5%.

[0047] In some embodiments, the subject with non-Hodgkin’s lymphoma has at least one imaging measurable tumor lesion (e.g., intranodal lesion long diameter > 15 mm, extranodal lesion long diameter > 10 mm) in 2 perpendicular directions assessed by CT or MRI.

[0048] In some embodiments, the subject with a hematological tumor has not received a BCL-2 inhibitor treatment in the past. In some embodiments, the BCL-2 inhibitor includes, but is not limited to, venetoclax or pelcitoclax.

[0049] In some embodiments, the subject with a hematological tumor optionally has the following comorbidities:

[0050] For the tumor patients who have had other malignancies within 3 years prior to the first dose or who have concurrent malignancies, the tumor patients can be other malignancies that have been treated by single surgery, tumor patients who have achieved disease free survival (DFS) for 5 consecutive years;

[0051] Alternatively, the tumor or advanced malignancy patients can be patients with cured cervical carcinoma in situ, non-melanoma skin cancer, and superficial bladder tumors (including, but not limited to, Ta (non-invasive tumor), Tis (carcinoma in situ), and T1 (tumor infiltrating basement membrane)).

[0052] In some embodiments, the subject with a hematological tumor does not have any one or more of the following:

[0053] 1) Patients diagnosed with Burkitt lymphoma, lymphoblastic lymphoma / leukemia; and / or,

[0054] 2) Central nervous system (CNS) involvement; and / or,

[0055] 3) Previously received allogeneic hematopoietic stem cell transplantation; and / or,

[0056] 4) Unresolved toxicity reactions of ≥ CTC AE Grade 1 due to any prior treatment, excluding alopecia; and / or,

[0057] 5) Presence of active or uncontrolled primary autoimmune cytopenia, including autoimmune hemolytic anemia (AIHA), idiopathic thrombocytopenic purpura (ITP), etc.; and / or,

[0058] 6) Occurred venous / thrombotic events within 6 months before first drug use; and / or,

[0059] 7) Presence of any severe and / or uncontrolled disease in patients; and / or,

[0060] 8) Received chemotherapy, radiotherapy within 4 weeks before first drug use or immune checkpoint inhibitors, CAR-T treatment within 12 weeks before first drug use, other antitumor treatment received before first drug use (calculated from the end time of the last treatment, with an elution period) within 5 half-lives; and / or,

[0061] 9) Previously received BCL-2 inhibitors.

[0062] In some embodiments, the venous / thrombotic events within 6 months before first drug use in 6) above optionally refers to cerebrovascular accidents (including but not limited to transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism, etc.

[0063] In some embodiments, the patients with any severe and / or uncontrolled disease in 7) above include: 1. Suffered from ≥ Grade 2 myocardial ischemia or myocardial infarction, arrhythmia (male QTc > 450 ms, female QTc > 470 ms), and ≥ Grade 2 congestive heart failure (New York Heart Association (NYHA) classification) within 6 months before first drug use; 2. Presence of active severe infection (≥ CTC AE Grade 2 infection), cardiac ultrasound evaluation of left ventricular ejection fraction (LVEF) < 50%; 3. Active hepatitis; 4. History of immunodeficiency, including HIV positive or suffering from other acquired, congenital immunodeficiency diseases, or history of organ transplantation; 5. Suffered from epilepsy and needed treatment.

[0064] In some embodiments, the hematological tumor is selected from a subject with lugano I, II, III, or IV. In some embodiments, the hematological tumor is selected from a subject with lugano I, II, III, or IV. In some embodiments, the hematological tumor is selected from a subject with lugano III or IV. In some embodiments, the hematological tumor is selected from a subject with lugano II-III.

[0065] acute myeloid leukemia (AML)

[0066] In some embodiments, the acute myeloid leukemia is selected from relapsed and / or refractory acute myeloid leukemia.

[0067] In some embodiments, the acute myeloid leukemia is selected from acute myeloid leukemia that is not tolerable to standard treatment regimen, and has no other better treatment options.

[0068] In some embodiments, the acute myeloid leukemia patient / subject meets one or more of the following conditions:

[0069] a) CR / CRi and relapse within 12 months after consolidation treatment; and / or

[0070] b) relapse after 12 months after CR / CRi but failed to achieve CR / CRi after reinduction treatment; and / or

[0071] c) 2 or more relapses; and / or

[0072] d) failed to achieve CR / CRi after first-line induction treatment; and / or

[0073] e) a newly diagnosed subject who cannot receive standard treatment due to age, comorbidities, performance status, and / or adverse risk factors, etc.

[0074] In some embodiments, the acute myeloid leukemia patient relapses within 12 months after CR / CRi and consolidation treatment.

[0075] In some embodiments, the acute myeloid leukemia patient relapses after 12 months after CR / CRi but failed to achieve CR / CRi after reinduction treatment.

[0076] In some embodiments, the acute myeloid leukemia patient has 2 or more relapses.

[0077] In some embodiments, the acute myeloid leukemia patient failed to achieve CR / CRi after first-line induction treatment.

[0078] In some embodiments, the relapse in a) above refers to peripheral blood leukemia blast cells or bone marrow blast cells ≥ 5%, or new extramedullary lesions.

[0079] In some embodiments, the failure to achieve CR / CRi with the first line induction therapy described in d) above means:

[0080] For those eligible for intensive chemotherapy, the first line standard induction therapy should contain an anthracycline and / or standard dose cytarabine for at least 2 cycles.

[0081] For those not eligible for intensive chemotherapy, the first line induction therapy should contain a demethylating agent for at least 4 cycles.

[0082] In some embodiments, the acute myeloid leukemia does not include non-acute promyelocytic leukemia.

[0083] Mantle cell lymphoma (MCL)

[0084] In some embodiments, the lymphoid neoplasm or non-Hodgkin lymphoma (NHL) is selected from mantle cell lymphoma.

[0085] In some embodiments, the mantle cell lymphoma is selected from relapsed and / or refractory mantle cell lymphoma.

[0086] In some embodiments, the subject with mantle cell lymphoma has been treated with one or more than two prior treatment regimens. In some embodiments, the subject with mantle cell lymphoma has been treated with one, two, three, four, or five prior treatment regimens. In some embodiments, the subject with mantle cell lymphoma is a subject who is ineligible for one or more treatment regimens. In some embodiments, the subject with mantle cell lymphoma is a subject who is ineligible for one or more treatment regimens (e.g., immunotherapy). In some embodiments, the subject with mantle cell lymphoma is a subject who is ineligible to receive immunotherapy.

[0087] In some embodiments, the subject with mantle cell lymphoma has been treated with one, two, three, four, or five prior treatment regimens and is ineligible for another one or more treatment regimens.

[0088] In some embodiments, the MCL is selected from MCLs identified based on the 2016 World Health Organization classification criteria for hematopoietic and lymphoid tumors. In some embodiments, the MCL comprises Cyclin D1 positive and / or MCL with t(11;14) translocation. In some embodiments, the MCL is selected from MCLs identified based on the 2016 World Health Organization classification criteria for hematopoietic and lymphoid tumors with pathology and independent pathology review (stage 2), and comprises immunohistochemistry Cyclin D1 positive and / or molecular testing t(11;14) translocation. In some embodiments, the MCL is selected from MCLs with measurable lesions shown by CT / MRI. Optionally, measurable lesions refer to: >1 lymph node with the longest diameter >1.5 cm or >1 extranodal lesion with the longest diameter >1.0 cm, measurable by >2 perpendicular dimensions.

[0089] In some embodiments, the MCL is selected from MCLs that failed to achieve a PR or better response or had disease progression during or after prior adequate therapy, or required termination of last line therapy due to toxicity / tolerability despite dose adjustments and best supportive care. In some embodiments, the adequate therapy is not applicable to subjects who are intolerant to the therapy.

[0090] In some embodiments, the MCL is selected from MCLs that failed to achieve a PR or better response or had disease progression during or after prior adequate therapy, or required termination of last line therapy due to toxicity / tolerability despite dose adjustments and best supportive care. In some embodiments, the adequate therapy is not applicable to subjects who are intolerant to the therapy.

[0091] In some embodiments, the subject with MCL is selected from subjects who have received one or more treatment regimens of immunotherapy, immunochemotherapy, or BTK inhibitor therapy. In some embodiments, the subject with MCL is selected from subjects who have relapsed and / or are refractory to one or more treatment regimens of immunotherapy, immunochemotherapy, or BTK inhibitor therapy. In some embodiments, the subject with MCL is selected from subjects who are intolerant to prior treatment regimens. In some embodiments, the subject with MCL is selected from subjects who are intolerant to one or more treatment regimens of immunotherapy, immunochemotherapy, or BTK inhibitor therapy that the subject has received.

[0092] In some embodiments, the subject with MCL is selected from a subject who has previously received a CD20 mAb treatment or a BTK inhibitor treatment. In some embodiments, the subject with MCL is selected from a subject who has previously been treated with a CD20 mAb treatment or a BTK inhibitor treatment. In some embodiments, the subject with MCL is a relapsed or refractory subject who has progressed after a CD20 mAb treatment or a BTK inhibitor treatment. In some embodiments, the subject with MCL is a drug resistant subject. In some embodiments, the subject with MCL is selected from a subject who is intolerant to a CD20 mAb treatment or a BTK inhibitor treatment previously received.

[0093] In some embodiments, the subject with MCL is selected from a subject who has previously received a CD20 mAb treatment. In some embodiments, the subject with MCL is selected from a subject who has previously been treated with a CD20 mAb treatment. In some embodiments, the subject with MCL is selected from a subject who has previously been treated with a CD20 mAb treatment as a first line treatment. In some embodiments, the subject with MCL is selected from a subject who has previously been fully treated. In some embodiments, the MCL is selected from a relapsed or refractory MCL that has progressed after a CD20 mAb treatment. In some embodiments, the subject with MCL is selected from a subject who has previously received at least a CD20 mAb treatment. In some embodiments, the subject with MCL is selected from a subject who has previously received one or more of a CD20 mAb-containing immunotherapy, a CD20 mAb-containing immunochemotherapy, a CD20 mAb-containing immunotherapy in combination with a BTK inhibitor, or a CD20 mAb-containing immunochemotherapy in combination with a BTK inhibitor. In some embodiments, the subject with MCL is selected from a subject who has previously been treated with a CD20 mAb-containing immunotherapy, a CD20 mAb-containing immunochemotherapy, a CD20 mAb-containing immunotherapy in combination with a BTK inhibitor, or a CD20 mAb-containing immunochemotherapy in combination with a BTK inhibitor.

[0094] In some embodiments, the subject with MCL is selected from a subject who has previously received a BTK inhibitor treatment. In some embodiments, the subject with MCL is selected from a subject who has previously been treated with a BTK inhibitor. In some embodiments, the subject with MCL is selected from a subject who has previously been fully treated with a BTK inhibitor. In some embodiments, the MCL is selected from a relapsed or refractory MCL that has progressed after a BTK inhibitor treatment. In some embodiments, the subject with MCL is selected from a subject who is intolerant to a BTK inhibitor treatment previously received. In some embodiments, the BTK inhibitor treatment is a monotherapy or in combination with other anti-neoplastic agents. In some embodiments, the BTK inhibitor is in a monotherapy form for treatment or in combination with other anti-neoplastic agents.

[0095] In some embodiments, the subject with MCL is selected from subjects in which an anti-CD20 mAb is used in combination with a BTK inhibitor; optionally, the subject with MCL must have failed to achieve PR or better after adequate therapy, or progressed during therapy or within 6 months of discontinuation.

[0096] In some embodiments, the anti-CD20 mAb is selected from rituximab, ofatumumab, golimumab, aselizumab, or ocrelizumab.

[0097] In some embodiments, the BTK inhibitor is selected from acalabrutinib, zanubrutinib, ibrutinib, ontulrutinib, Tirabrutinib, SHR1459, BT-1053, LP168, pirtobrutinib, limertinib, evobrutinib, fenebrutinib, nemtabrutinib, remibrutinib, rilzabrutinib, tolebrutinib, ABBV-599, BIIB091, BMS-986142, CT-1530, LP-168, MH048, TAS5315, erdalbrutinib, elsubrutinib, cenabrutinib, IG-100, CX1440, HBW-3220, HZ-A-018, XNW1011, IMG-004, JDB175, YZJ-3058, ZXBT-1158, HBW-3210, SYHA1811, FCN-647, or HMPL-760.

[0098] In some embodiments, the BTK inhibitor is selected from acalabrutinib, zanubrutinib, ibrutinib, ontulrutinib, Tirabrutinib, SHR1459, BT-1053, LP168, FCN-647, or HMPL-760.

[0099] In some embodiments, the BTK inhibitor is selected from acalabrutinib, zanubrutinib, ibrutinib, or ontulrutinib.

[0100] In some embodiments, the CD20 mAb therapy comprises rituximab, bendamustine + rituximab, bendamustine + rituximab + cytarabine, lenalidomide + rituximab, bortezomib + rituximab, a BTK inhibitor + rituximab, a BTK inhibitor + lenalidomide + rituximab, R-DHA regimen, R-DHAP regimen, R-CHOP regimen, NORDIC regimen, VR-CAP regimen, or R-HyperCVAD regimen.

[0101] In some embodiments, the BTK inhibitor treatment can include a BTK inhibitor, a BTK inhibitor + rituximab, or a BTK inhibitor + lenalidomide + rituximab.

[0102] In some embodiments, the mantle cell lymphoma subject has received at least one systemic treatment regimen in the past and has disease progression or intolerance during or after the most recent treatment, or failed to achieve remission after adequate treatment.

[0103] In some embodiments, treatment intolerance is defined as unacceptable toxicity and despite the administration of dose adjustments and best supportive care. In some embodiments, the mantle cell lymphoma is selected from a subject in lugano stage I, II, III, or IV. In some embodiments, the mantle cell lymphoma is selected from a subject in lugano stage II-III.

[0104] Diffuse large B-cell lymphoma (DLBCL)

[0105] In some embodiments, the lymphoid neoplasm or non-Hodgkin lymphoma is selected from a diffuse large B-cell lymphoma.

[0106] In some embodiments, the diffuse large B-cell lymphoma is selected from a relapsed and / or refractory diffuse large B-cell lymphoma.

[0107] In some embodiments, the diffuse large B-cell lymphoma subject has received treatment with one or more than two prior treatment regimens. In some embodiments, the diffuse large B-cell lymphoma subject has received treatment with one, two, three, four, or five prior treatment regimens.

[0108] In some embodiments, the diffuse large B-cell lymphoma subject has received at least one or two systemic treatment regimens in the past and has disease progression or intolerance during or after the most recent treatment, or failed to achieve remission after adequate treatment.

[0109] Chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL)

[0110] In some embodiments, the lymphoid neoplasm or non-Hodgkin lymphoma is selected from a CLL / SLL.

[0111] In some embodiments, the CLL / SLL is selected from a relapsed and / or refractory CLL / SLL.

[0112] In some embodiments, the subject with CLL / SLL has received treatment with one or more than two prior treatment regimens. In some embodiments, the subject with CLL / SLL has received treatment with one, two, three, four, or five prior treatment regimens. In some embodiments, the subject with CLL / SLL has received treatment with one or two prior treatment regimens. In some embodiments, the subject with CLL / SLL is a subject who is ineligible for one or more treatment regimens (e.g., immunochemotherapy). In some embodiments, the subject with CLL / SLL is a subject who is ineligible to receive immunochemotherapy.

[0113] In some embodiments, the subject with CLL / SLL is refractory to prior treatment. In some embodiments, the CLL / SLL has relapsed during / upon completion of the most recent treatment or is confirmed refractory after adequate treatment. In some embodiments, the CLL / SLL is selected from CLL / SLL that has relapsed during / upon completion of the most recent treatment or is confirmed refractory after adequate treatment, who has received at least one prior treatment regimen with chemotherapy, immunotherapy, immunochemotherapy, or a BTK inhibitor.

[0114] In some embodiments, the CLL / SLL is selected from CLL / SLL that has received one or more treatment regimens with chemotherapy, immunotherapy, immunochemotherapy, or a BTK inhibitor. In some embodiments, the CLL / SLL is selected from relapsed and / or refractory CLL / SLL that has received one or more treatment regimens with chemotherapy, immunotherapy, immunochemotherapy, or a BTK inhibitor. In some embodiments, the CLL / SLL is selected from relapsed / refractory CLL / SLL that has received a treatment regimen with immunochemotherapy and / or a BTK inhibitor. In some embodiments, the CLL / SLL is selected from CLL / SLL that has received a treatment regimen with immunochemotherapy and a BTK inhibitor. In some embodiments, the CLL / SLL is selected from relapsed and / or refractory CLL / SLL that has received a treatment regimen with immunochemotherapy and a BTK inhibitor. In some embodiments, the CLL / SLL is selected from CLL / SLL that has received a treatment regimen with a CD20 mAb or a BTK inhibitor. In some embodiments, the CLL / SLL is selected from CLL / SLL that has received a treatment regimen with immunochemotherapy with a CD20 mAb and / or a BTK inhibitor. In some embodiments, the CLL / SLL is selected from relapsed or refractory CLL / SLL that has received a treatment regimen with immunochemotherapy with a CD20 mAb and / or a BTK inhibitor. In some embodiments, the CLL / SLL is selected from relapsed and / or refractory CLL / SLL that has received a treatment regimen with a CD20 mAb or a BTK inhibitor.

[0115] In some embodiments, the CLL / SLL is selected from CLL / SLL that relapsed or is refractory after prior treatment with an immunotherapy containing a CD20 antibody or a BTK inhibitor. In some embodiments, the CLL / SLL is selected from CLL / SLL that relapsed or is refractory after prior treatment with an immunotherapy containing a CD20 antibody and a BTK inhibitor.

[0116] In some embodiments, the CLL / SLL is selected from CLL / SLL that is refractory, relapsed, or intolerant to prior treatment with a BTK inhibitor and an immunotherapy containing a CD20 antibody. Alternatively, in some embodiments, the CLL / SLL is selected from CLL / SLL that failed first line treatment with a BTK inhibitor and is not suitable for immunotherapy.

[0117] In some embodiments, the CLL / SLL is selected from CLL / SLL that is refractory, relapsed, or intolerant to prior treatment with a BTK inhibitor and an immunotherapy containing a CD20 antibody. Alternatively, in some embodiments, the CLL / SLL is selected from CLL / SLL that failed first line treatment with a BTK inhibitor and is not suitable for immunotherapy.

[0118] In some embodiments, the subject with CLL / SLL experiences treatment intolerance during or after immunotherapy and / or BTK inhibitor treatment, or fails to achieve a PR or better response or experiences disease progression after adequate treatment. In some embodiments, the subject with CLL / SLL experiences treatment intolerance during or after immunotherapy and BTK inhibitor treatment, or fails to achieve a PR or better response or experiences disease progression after adequate treatment.

[0119] In some embodiments, the CLL / SLL is selected from CLL / SLL that experiences treatment intolerance during or after immunotherapy containing a CD20 antibody and BTK inhibitor treatment, or fails to achieve a PR or better response or experiences disease progression after adequate treatment.

[0120] In some embodiments, the CLL / SLL is selected from CLL / SLL that is not suitable for immunotherapy and experiences treatment intolerance during BTK inhibitor treatment, or fails to achieve a PR or better response or experiences disease progression after adequate treatment (best overall response during last treatment was either disease remission or stable disease followed by disease progression).

[0121] In some embodiments, the SLL is selected from patients with measurable disease by CT / MRI, defined as >1 lymph node with the longest diameter >1.5 cm or >1 extranodal lesion with the longest diameter >1.0 cm, measurable by >2 perpendicular dimensions.

[0122] In some embodiments, the immunotherapy is selected from an immunotherapy containing an anti-CD20 antibody.

[0123] In some embodiments, the anti-CD20 mAb is selected from rituximab, ofatumumab, golimumab, aselizumab, or ocrelizumab.

[0124] In some embodiments, the BTK inhibitor is selected from acalabrutinib, zanubrutinib, ibrutinib, onartamab, Tirabrutinib, SHR1459, BT-1053, LP168, pirtobrutinib, limertinib, evobrutinib, XS004, evobrutinib, fenebrutinib, nemtabrutinib, remibrutinib, rilzabrutinib, tolebrutinib, ABBV-599, BIIB091, BMS-986142, CT-1530, LP-168, MH048, TAS5315, erdalbrutinib, elsubrutinib, crizotinib, IG-100, CX1440, HBW-3220, HZ-A-018, XNW1011, IMG-004, JDB175, YZJ-3058, ZXBT-1158, HBW-3210, SYHA1811, FCN-647, or HMPL-760.

[0125] In some embodiments, the BTK inhibitor is selected from acalabrutinib, zanubrutinib, ibrutinib, onartamab, Tirabrutinib, SHR1459, BT-1053, LP168, FCN-647, or HMPL-760.

[0126] In some embodiments, the BTK inhibitor is selected from acalabrutinib, zanubrutinib, ibrutinib, or onartamab.

[0127] In some embodiments, the chemotherapy, immunotherapy, immunochemotherapy, or BTK inhibitor treatment regimen is selected from a BTK inhibitor (acalabrutinib, ibrutinib, zanubrutinib, or onartamab, etc.), chlormethine, lenalidomide, rituximab, bendamustine + CD20 mAb, bendamustine + rituximab, methylprednisolone + rituximab, fludarabine + cyclophosphamide + rituximab, fludarabine + rituximab, ibritumomab + rituximab, lenalidomide + rituximab, bendamustine + rituximab + ibritumomab.

[0128] In some embodiments, the CLL / SLL subject has received at least one systemic treatment regimen previously and has disease progression or intolerance during or after the most recent treatment, or has not achieved remission (e.g., PR or better remission) after adequate treatment. In some embodiments, the systemic treatment regimen is selected from a chemotherapy, an immunotherapy, an immunochemotherapy, or a BTK inhibitor treatment regimen.

[0129] In some embodiments, the CLL / SLL subject is selected from a CLL / SLL subject who has received at least one systemic treatment comprising a BTK inhibitor previously. In some embodiments, the CLL / SLL subject is selected from an adult CLL / SLL subject who has received at least one systemic treatment comprising a BTK inhibitor previously.

[0130] In some embodiments, the CLL / SLL is selected from a CLL / SLL diagnosed according to the revised 2018 iwCLL diagnostic criteria.

[0131] In some embodiments, the CLL / SLL subject has a peripheral blood monoclonal B-lymphocyte count >5 x 10 9 / L, or has an imaging measurable lesion. In some embodiments, the CLL / SLL subject has at least one imaging measurable tumor lesion in 2 perpendicular directions as assessed by CT or MRI. Alternatively, the tumor lesion is selected from (≥1) intranodal lesion with longest diameter >15 mm and (≥1) extranodal lesion with longest diameter >10 mm.

[0132] In some embodiments, the CLL / SLL is selected from a subject in lugano stage I, II, III, or IV. In some embodiments, the CLL / SLL is selected from a subject in lugano stage I, II, III, or IV. In some embodiments, the CLL / SLL is selected from a subject in lugano stage II-III.

[0133] In some embodiments, the CLL / SLL subject is in Rai stage I, II, III, or IV. In some embodiments, the CLL / SLL subject is in Rai stage III or IV. In some embodiments, the CLL / SLL subject is in Binet stage B or C. In some embodiments, the CLL / SLL subject is in Binet stage C.

[0134] In some embodiments, the CLL / SLL subject is in intermediate, high, or very high risk disease according to CLL-International Prognostic Index (IPI).

[0135] In some embodiments, the subject with CLL / SLL has CLL / SLL with an adverse prognostic feature.

[0136] In some embodiments, the adverse prognostic feature comprises one or more of: IGHV unmutated, or with Del(17p) / TP53 mutation (i.e., 17p deletion and / or TP53 mutation).

[0137] In some embodiments, the subject with CLL / SLL has the following feature: IGHV unmutated. In some embodiments, the subject with CLL / SLL has the following feature: with Del(17p). In some embodiments, the subject with CLL / SLL has the following feature: with TP53 mutation.

[0138] In some embodiments, the subject with CLL / SLL refractory to immunotherapy (e.g., CD20-containing immunotherapy) is selected from: disease progression during treatment; or best response status after adequate treatment did not achieve partial response; or achieved remission after treatment, but disease progression occurred within 6 months after treatment ended.

[0139] In some embodiments, the subject with CLL / SLL relapsed after immunotherapy (e.g., CD20-containing immunotherapy) is selected from: achieved partial response or complete response after treatment, but disease progression occurred after 6 months after treatment ended, except for those with disease progression during treatment, which is not required to have at least 4 cycles of immunotherapy (e.g., CD20-containing immunotherapy).

[0140] In some embodiments, the subject refractory to BTK inhibitor is selected from: disease progression during treatment; or progression within 6 months of remission; or stable disease for the best response after 6 months of treatment with standard dose of BTK inhibitor.

[0141] In some embodiments, the subject relapsed after BTK inhibitor is selected from: achieved PR or above remission previously and ≥6 months, but progression occurred. For subjects with disease progression during treatment, the BTK inhibitor treatment is required to be no less than 8 weeks; for subjects with remission after treatment, the treatment is required to continue until disease progression or the treatment is continued for no less than 6 months after remission.

[0142] In some embodiments, the subject who is not suitable for immunochemotherapy is selected from a patient who is assessed as not suitable for immunochemotherapy or who would have very limited benefit from anticipated immunochemotherapy. In some embodiments, the CLL / SLL subject who is not suitable for immunochemotherapy is selected from a subject who has one or more of the following characteristics: Del(17p) / TP53 mutation, IGHV unmutated, complex karyotype, CLL IPI very high risk, or elderly patient (> 65 years old). In some embodiments, the subject who is not suitable for immunochemotherapy is selected from a patient who has one or more of the following characteristics: Del(17p) / TP53 mutation, IGHV unmutated, complex karyotype, CLL IPI very high risk, or elderly patient (> 65 years old), who is assessed as not suitable for immunochemotherapy or who would have very limited benefit from anticipated immunochemotherapy.

[0143] In some embodiments, the present application provides use of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for monotherapy of CLL / SLL that relapsed or is refractory after prior immunochemotherapy and / or BTK inhibitor treatment. In some embodiments, the present application provides use of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for monotherapy of CLL / SLL that relapsed or is refractory after prior immunochemotherapy and BTK inhibitor treatment.

[0144] In some embodiments, the present application provides a method of monotherapy of CLL / SLL that relapsed or is refractory after prior immunochemotherapy and / or BTK inhibitor treatment, comprising administering to the subject a therapeutically effective amount of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0145] In some embodiments, the present application provides a method of monotherapy of CLL / SLL that relapsed or is refractory after prior immunochemotherapy and BTK inhibitor treatment, comprising administering to the subject a therapeutically effective amount of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0146] In some embodiments, the present application provides a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for monotherapy of CLL / SLL that relapsed or is refractory after prior immunochemotherapy and / or BTK inhibitor treatment. In some embodiments, the present application provides a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for monotherapy of CLL / SLL that relapsed or is refractory after prior immunochemotherapy and BTK inhibitor treatment.

[0147] In some embodiments, the present application provides use of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for monotherapy of CLL / SLL that relapsed or is refractory after prior immunochemotherapy and / or BTK inhibitor treatment. In some embodiments, the present application provides use of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for monotherapy of CLL / SLL that relapsed or is refractory after prior immunochemotherapy and / or BTK inhibitor treatment. In some embodiments, the present application provides use of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for monotherapy of CLL / SLL that relapsed or is refractory after prior immunochemotherapy and BTK inhibitor treatment.

[0148] In some embodiments, the present application provides the use of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a monotherapy for treating CLL / SLL that relapsed or is refractory after prior treatment with an immunochemotherapy and a BTK inhibitor.

[0149] In some embodiments, the present application provides the use of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating CLL / SLL that relapsed or is refractory after prior treatment with an immunochemotherapy and / or a BTK inhibitor as a monotherapy. In some embodiments, the present application provides the use of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating CLL / SLL that relapsed or is refractory after prior treatment with an immunochemotherapy and a BTK inhibitor as a monotherapy.

[0150] In some embodiments, the present application provides a method of treating CLL / SLL that relapsed or is refractory after prior treatment with an immunochemotherapy and / or a BTK inhibitor as a monotherapy, comprising administering to a subject a therapeutically effective amount of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0151] In some embodiments, the present application provides a method of treating CLL / SLL that relapsed or is refractory after prior treatment with an immunochemotherapy and a BTK inhibitor as a monotherapy, comprising administering to a subject a therapeutically effective amount of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0152] In some embodiments, the present application provides a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a monotherapy for use in treating CLL / SLL that relapsed or is refractory after prior treatment with an immunochemotherapy and / or a BTK inhibitor.

[0153] In some embodiments, the present application provides a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a monotherapy for use in treating CLL / SLL that relapsed or is refractory after prior treatment with an immunochemotherapy and a BTK inhibitor.

[0154] In some embodiments, the present application provides the use of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a monotherapy for treating CLL / SLL that relapsed or is refractory after prior treatment with an immunochemotherapy and / or a BTK inhibitor.

[0155] In some embodiments, the present application provides the use of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a monotherapy for treating CLL / SLL that relapsed or is refractory after prior treatment with an immunochemotherapy and a BTK inhibitor.

[0156] In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof is the sole active ingredient of the pharmaceutical composition.

[0157] Dosing regimen

[0158] The method of administration can be determined in view of the activity, toxicity of the drugs, and tolerability of the subject / patient, etc. One skilled in the art can determine the appropriate amount, dose or usage of each drug used in the present application to be administered to the subject / patient. One skilled in the art can adjust the dose and dosing regimen according to methods well known in the art of treatment. For example, the maximum tolerated dose can be readily determined, as can the effective amount to provide a detectable therapeutic benefit to the subject / patient, as can the time requirement for administration of each drug to provide a detectable therapeutic benefit to the subject / patient. Thus, while the present application illustrates certain doses and dosing regimens, these examples in no way limit the doses and dosing regimens that can be provided to the subject / patient in practicing the present application. The treatment regimen described in the present application for immunochemotherapy or immunotherapy includes CD20 mAb. The immunotherapeutic agent in the immunochemotherapy or immunotherapy described in the present application is selected from CD20 mAb.

[0159] In some embodiments, the present application provides a method of treating a hematological tumor comprising administering to a subject a dose (per day or per administration) of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof selected from 20-2000 mg, 20-1200 mg, 100-1200 mg, 100-800 mg, 200-800 mg, or 200-600 mg.

[0160] In some embodiments, the present application provides use of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating a hematological tumor, wherein the medicament comprises 20-2000 mg, 20-1200 mg, 100-1200 mg, 100-800 mg, 200-800 mg, or 200-600 mg of the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the present application provides use of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating a hematological tumor, wherein the medicament comprises a single dose or multiple doses of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the present application provides use of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating a hematological tumor, wherein the administration dose (per day or per time) of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is selected from 20-2000 mg, 20-1200 mg, 100-1200 mg, 100-800 mg, 200-800 mg, or 200-600 mg (e.g., 300 mg, 400 mg, 500 mg, or 600 mg).

[0161] The present application also provides a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a hematological tumor, wherein the administration dose (per day or per time) of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is selected from 20-2000 mg, 20-1200 mg, 100-1200 mg, 100-800 mg, 200-800 mg, or 200-600 mg (e.g., 300 mg, 400 mg, 500 mg, or 600 mg).

[0162] The present application also provides use of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application, for treating a hematological tumor, wherein the administration dose (per day or per time) of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is selected from 20-2000 mg, 20-1200 mg, 100-1200 mg, 100-800 mg, 200-800 mg, or 200-600 mg (e.g., 300 mg, 400 mg, 500 mg, or 600 mg).

[0163] In some embodiments, the present application also provides a kit for treating a tumor, comprising: a pharmaceutical composition comprising a compound of Formula I-1 or a pharmaceutically acceptable salt thereof; optionally, further comprising instructions for use of the pharmaceutical composition comprising a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, the instructions relating to the administration dose (per day or per time) of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, selected from 20-2000 mg, 20-1200 mg, 100-1200 mg, 100-800 mg, 200-800 mg, or 200-600 mg (e.g., 300 mg, 400 mg, 500 mg, or 600 mg). In some embodiments, the instructions are for administering the pharmaceutical composition comprising a compound of Formula I-1 or a pharmaceutically acceptable salt thereof to a subject.

[0164] In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 10-5000 mg, 20-5000 mg, or 20-4000 mg, or 20-3000 mg, or 20-2000 mg, or 50-1500 mg, or 100-1200 mg, or 200-1000 mg, or 100-1000 mg, or 100-800 mg, or 200-800 mg, or 200-600 mg, or 200-400 mg. In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, or 2000 mg, or any value in a range formed by any of the foregoing. In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 100 mg-1200 mg, 100-800 mg, 200-800 mg, or 200-600 mg. In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 200-1000 mg or 200-800 mg. In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 10-800 mg, 20-800 mg, or 100-800 mg. In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 10-300 mg, 20-400 mg, 20-200 mg, or 20-100 mg. In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 300 mg, or 400 mg. In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, or 1200 mg.In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 100-800 mg. In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 400-600 mg. In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg. In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 300 mg, 400 mg, 500 mg, or 600 mg. In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 400 mg.

[0165] In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 50 mg-800 mg. In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 100 mg-800 mg. In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 100 mg-600 mg. In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 50 mg-400 mg (such as 50 mg, 100 mg, 200 mg, 300 mg, or 400 mg). In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 100 mg-400 mg (such as 100 mg, 200 mg, or 400 mg). In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 100 mg-200 mg. In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg.

[0166] In some embodiments, the present application provides a method of treating a hematological tumor, comprising administering to a subject a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in a dose (daily or per dose) selected from 20-2000 mg, 20-1200 mg, or 100-1200 mg.

[0167] In some embodiments, the present application provides use of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating a hematological tumor, wherein the medicament comprises 20-2000 mg, 20-1200 mg, or 100-1200 mg of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the present application provides use of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating a hematological tumor, wherein the administration dose (per day or per time) of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is selected from 20-2000 mg, 20-1200 mg, or 100-1200 mg.

[0168] The present application also provides a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a hematological tumor, wherein the administration dose (per day or per time) of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is selected from 20-2000 mg, 20-1200 mg, or 100-1200 mg.

[0169] The present application also provides use of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application, for treating a hematological tumor, wherein the administration dose (per day or per time) of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is selected from 20-2000 mg, 20-1200 mg, or 100-1200 mg.

[0170] In some embodiments, the present application also provides a kit for use in treating a tumor, comprising: a pharmaceutical composition comprising a compound of Formula I-1 or a pharmaceutically acceptable salt thereof; and optionally, instructions for use of the pharmaceutical composition comprising a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, the instructions for use relating to an administration dose (per day or per time) of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, selected from 20-2000 mg, 20-1200 mg, or 100-1200 mg. In some embodiments, the instructions for use are for administering the pharmaceutical composition comprising a compound of Formula I-1 or a pharmaceutically acceptable salt thereof to a subject.

[0171] In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 10-5000 mg, 20-5000 mg, or 20-4000 mg, or 20-3000 mg, or 20-2000 mg, or 50-1500 mg, or 100-1200 mg, or 200-1000 mg, or 200-800 mg, or 200-600 mg, or 200-400 mg. In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, or 2000 mg, or any value in a range formed by any of the foregoing. In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 100-1200 mg. In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 200-1000 mg. In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 10-800 mg or 20 mg-800 mg. In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 10-300 mg, 20-400 mg, 20-200 mg, or 20-100 mg. In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 300 mg, or 400 mg. In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, or 1200 mg. In some embodiments, the daily or per dose of a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 100-800 mg.In some embodiments, the daily or per dose of the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application is selected from 400-600 mg. In some embodiments, the daily or per dose of the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application is selected from 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg.

[0172] In some embodiments of the present application, the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered at 0.0001 to 20 mg / kg weight per administration. In some embodiments of the present application, the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered at 0.0001 to 20 mg / kg body weight per administration.

[0173] In some embodiments, the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered at a frequency of 3 times daily, 2 times daily, 1 time daily, 1 time every two days, 1 time every three days, 1 time every four days, 1 time every five days, 1 time every six days, 3 times per week, 2 times per week, 1 time per week, 1 time every two weeks, or 1 time every three weeks. In some embodiments, the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered at a frequency of 1 or 2 times daily. In some embodiments, the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered at a frequency of 1 time daily.

[0174] In some embodiments, the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application is administered to a subject as a continuous daily administration.

[0175] In some embodiments, the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered in a single dose or multiple doses.

[0176] In some embodiments, the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered by oral administration.

[0177] In some embodiments, the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered orally within 30 minutes after the start of a meal.

[0178] In some embodiments, the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered by oral administration on an empty stomach.

[0179] In some embodiments, the 8-32 days is one dosing cycle, e.g., 8-28 days, 8-21 days, 8-15 days, 15-28 days, 15-21 days, 21-28 days, 21-32 days, 28-32 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, or 32 days is one dosing cycle. In some embodiments, 28 days or 32 days is one dosing cycle. In some embodiments, 28 days (4 weeks) is one dosing cycle. In some embodiments, the present application repeats one or more dosing cycles.

[0180] In some embodiments, the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered at a dosage of 20 mg-1200 mg, 100 mg-1200 mg, 100 mg-800 mg, 200-800 mg, or 400 mg-600 mg per administration, once daily (e.g., once daily) for one or more dosing cycles; optionally, 8-32 days (e.g., every 28 days) is one dosing cycle.

[0181] In some embodiments, the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered at a dosage of 20 mg-1200 mg, 100 mg-1200 mg, 100 mg-800 mg, 200-800 mg, or 400 mg-600 mg per administration, once daily (e.g., once daily) for one or more dosing cycles; optionally, 8-32 days (e.g., every 28 days) is one dosing cycle.

[0182] In some embodiments, the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered at a dosage of 100 mg-1200 mg, 100 mg-800 mg, or 200-800 mg per administration, once daily, orally for one or more dosing cycles; optionally, every 28 days is one dosing cycle.

[0183] In some embodiments, the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered at a dosage of 20-1200 mg, 100-1200 mg, 100-800 mg, 300-600 mg, or 400-600 mg per administration, once daily (e.g., once daily) for one or more dosing cycles; optionally, 8-32 days (e.g., every 28 days) is one dosing cycle.

[0184] In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered in a manner of 20-1200 mg, 100-1200 mg, 100-800 mg, 300-600 mg, or 400-600 mg per administration, once daily for continuous administration; optionally, for one administration cycle every 28 days.

[0185] In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered in a manner of 100-1200 mg or 100-800 mg per administration, once daily, for one or more administration cycles; optionally, for one administration cycle every 28 days.

[0186] In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered in a manner of 400 mg per administration, once daily.

[0187] In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered for 2-40 cycles, such as 4-10 or 8-20 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, or 30 cycles, or even 2-40 or more cycles as needed. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered for as long as the above-mentioned cycles are repeated until the subject is unable to continue to benefit, the disease progresses, or an intolerable toxic reaction occurs.

[0188] In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered for 2-40 cycles, such as 4-10 or 8-20 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, or 30 cycles. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered for as long as the above-mentioned cycles are repeated until the subject is unable to continue to benefit, the disease progresses, or an intolerable toxic reaction occurs.

[0189] In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered for 2-40 cycles, such as 4-10 or 8-20 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, or 30 cycles. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered for as long as the above-mentioned cycles are repeated until the subject is unable to continue to benefit, the disease progresses, or an intolerable toxic reaction occurs.

[0190] In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered as a single agent (i.e., monotherapy); optionally, in combination with other agents.

[0191] In some embodiments, in the treatment methods described herein, the dosing cycle is preceded by a pre-dosing escalation period (also referred to as a run-in period). In the pre-dosing escalation period, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered at at least one escalating dose (also referred to as "escalating doses" hereinafter), wherein the first escalating dose of the at least one escalating dose is lower than the dose in the dosing cycle. In some embodiments, the at least one escalating dose can comprise a first escalating dose and a further escalating dose. In particular, for the case where the pre-dosing escalation period comprises multiple escalating doses, the last escalating dose is less than or equal to the dose used in the dosing cycle. In preferred embodiments, the escalating doses are administered in the same mode of administration and frequency of administration as the dose in the dosing cycle. The run-in period is not counted as part of the dosing cycle, i.e., the treatment cycle (dosing in the treatment cycle is at therapeutic dose).

[0192] In some embodiments, for the case where the pre-dosing escalation period comprises multiple escalating doses, the difference between each escalating dose can be the same or different. In some embodiments, for the case where the pre-dosing escalation period comprises multiple escalating doses, it can comprise 1-14 escalating doses, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 escalating doses.

[0193] In some embodiments, the first escalating dose can be selected from 10 mg, 20 mg, 50 mg, or 100 mg. In preferred embodiments, each escalating dose can be administered for 1-10 days, such as 1, or for 2-10 consecutive days.

[0194] In some embodiments, prior to a subject receiving a dosing or treatment according to the present application, the subject is pre-administered a daily or weekly escalating dose of a compound of Formula I-I of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Optionally, after escalating to a particular dose (e.g., 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, or 1200 mg), the dosing cycle is followed by administering a therapeutic dose (e.g., 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1200 mg) of a compound of Formula I-I of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, daily. In some embodiments, the subject has a lymphoid neoplasm, including non-Hodgkin lymphoma.

[0195] In some embodiments, prior to a subject receiving a dosing or treatment according to the present application, the subject is pre-administered a daily or weekly escalating dose of a compound of Formula I-I of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Optionally, after escalating to a particular dose (e.g., 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, or 1200 mg), the dosing cycle is followed by administering a therapeutic dose (e.g., 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1200 mg) of a compound of Formula I-I of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, daily. In some embodiments, the subject has a lymphoid neoplasm, including non-Hodgkin lymphoma.

[0196] In some embodiments, the duration of the administration of the daily escalating dose is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, or a range formed by any of the above values. In some embodiments, the duration of the administration of the daily escalating dose is 2-10 or 3-4 or 5-7 days.

[0197] In some embodiments, the subject is optionally administered an escalating dose of a compound of Formula I-I of the present application, or a pharmaceutically acceptable salt thereof, prior to receiving a dose (e.g., a therapeutic dose) of the dosing cycle. The escalating dose includes escalating the dose every 1 day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, or every week (7 days). The escalating dose includes escalating the dose every 1 day.

[0198] In some embodiments, the escalating gradient dose comprises at least one of: 20 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 800 mg. In some embodiments, the escalating gradient dose comprises at least one of: 20 mg, 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, or 800 mg. In some embodiments, the escalating gradient dose comprises 20 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 800 mg. In some embodiments, the escalating gradient dose comprises 20 mg, 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, or 800 mg.

[0199] In some embodiments, the first gradient dose of the escalating gradient dose is selected from 10 mg, 20 mg, 50 mg, or 100 mg. In some embodiments, the second gradient dose of the escalating gradient dose is selected from 20 mg, 50 mg, 100 mg, or 200 mg. Optionally, the escalating gradient dose further comprises a third gradient dose. In some embodiments, the third gradient dose of the escalating gradient dose is selected from 50 mg, 100 mg, 200 mg, or 400 mg. In some embodiments, optionally, the escalating gradient dose further comprises a fourth gradient dose. In some embodiments, optionally, the escalating gradient dose further comprises a fourth gradient dose selected from 100 mg, 200 mg, 400 mg, or 600 mg. In some embodiments, optionally, the escalating gradient dose further comprises a fifth gradient dose. In some embodiments, optionally, the escalating gradient dose further comprises a fifth gradient dose selected from 200 mg, 400 mg, 600 mg, or 800 mg.

[0200] In some embodiments, the dose or therapeutic dose of the dosing cycle comprises 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1200 mg.

[0201] In some embodiments, the first escalation dose of the escalating dose regimen is selected from 20 mg. In some embodiments, the second escalation dose of the escalating dose regimen is selected from 50 mg. Optionally, the escalating dose regimen further comprises a third escalation dose. In some embodiments, the third escalation dose of the escalating dose regimen is selected from 100 mg. In some embodiments, optionally, the escalating dose regimen further comprises a fourth escalation dose. In some embodiments, optionally, the escalating dose regimen further comprises a fourth escalation dose selected from 200 mg. In some embodiments, optionally, the escalating dose regimen further comprises a fifth escalation dose. In some embodiments, optionally, the escalating dose regimen further comprises a fifth escalation dose selected from 400 mg. In some embodiments, optionally, the escalating dose regimen further comprises a sixth escalation dose. In some embodiments, optionally, the escalating dose regimen further comprises a sixth escalation dose selected from 600 mg. In some embodiments, optionally, the escalating dose regimen further comprises a seventh escalation dose. In some embodiments, optionally, the escalating dose regimen further comprises a seventh escalation dose selected from 800 mg. In some embodiments, the administration or treatment comprises or does not comprise a run-in period, for example, when the run-in period is not included, the treatment period dose is 100 mg.

[0202] In some embodiments, the first escalation dose of the escalating dose regimen is selected from 100 mg. In some embodiments, the second escalation dose of the escalating dose regimen is selected from 200 mg. Optionally, the escalating dose regimen further comprises a third escalation dose. In some embodiments, the third escalation dose of the escalating dose regimen is selected from 400 mg.

[0203] In some embodiments, after the pre-administration escalation period or run-in period (i.e., after escalation through a gradient dose to a particular dose), the dose of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof used in the administration period is administered in a fixed dose pattern (i.e., a treatment dose) on each subsequent day. In some embodiments, the dose used in the administration period is as defined above, for example, the treatment dose can be selected from 100 mg to 400 mg or 100 mg to 800 mg. A second escalation dose of, for example, 50 mg completes the pre-administration escalation period, and 100 mg is administered in a fixed dose pattern in the administration period; a third escalation dose of, for example, 100 mg completes the pre-administration escalation period, and 200 mg is administered in a fixed dose pattern in the administration period; a fourth escalation dose of, for example, 200 mg completes the pre-administration escalation period, and 400 mg is administered in a fixed dose pattern in the administration period.

[0204] In some embodiments, the therapeutic dose of the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, in a dosing cycle is selected from 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, or 1200 mg; in some embodiments, from 100 mg, 200 mg, 400 mg, 600 mg, or 800 mg.

[0205] In some embodiments, the subject is administered a daily or weekly escalating dose of the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, of the present application prior to receiving a dosing cycle (e.g., a fixed dose regimen). Optionally, after escalating to a particular dose (e.g., 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, or 1200 mg), a subsequent dosing cycle is performed, e.g., daily administration of a therapeutic dose (e.g., 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, or 1200 mg) of the compound of Formula I-1, or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments, the subject is administered a daily or weekly escalating dose of the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, of the present application prior to receiving a dosing cycle (e.g., a fixed dose regimen). Optionally, after escalating to a particular dose (e.g., 50 mg, 100 mg, or 200 mg), a subsequent dosing cycle is performed, e.g., corresponding daily administration of a therapeutic dose of 100 mg, 200 mg, and 400 mg, respectively, of the compound of Formula I-1, or a pharmaceutically acceptable salt thereof. In some embodiments, the daily escalating dose comprises: 20 mg on the first day, 50 mg on the second day, and 100 mg on the third day. In some embodiments, the daily escalating dose comprises: 20 mg on the first day, 50 mg on the second day, 100 mg on the third day, and 200 mg on the fourth day. In some embodiments, the daily escalating dose comprises: 20 mg on the first day, 50 mg on the second day, 100 mg on the third day, 200 mg on the fourth day, and 400 mg on the fifth day. In some embodiments, the daily escalating dose comprises: 20 mg on the first day, 50 mg on the second day, 100 mg on the third day, 200 mg on the fourth day, 400 mg on the fifth day, and 600 mg on the sixth day.

[0207] In some embodiments, the daily escalating gradient dose comprises: 20 mg on the first day, 50 mg on the second day, 100 mg on the third day, 200 mg on the fourth day, 400 mg on the fifth day, 600 mg on the sixth day, and 800 mg on the seventh day. In some embodiments, the daily escalating gradient dose comprises: 20 mg on the first day, 50 mg on the second day, 100 mg on the third day, 200 mg on the fourth day, 400 mg on the fifth day, 600 mg on the sixth day, 800 mg on the seventh day, and 1200 mg on the eighth day. In some embodiments, the daily escalating gradient dose comprises: 100 mg on the first day. In some embodiments, the daily escalating gradient dose comprises: 100 mg on the first day and 200 mg on the second day. In some embodiments, the daily escalating gradient dose comprises: 100 mg on the first day, 200 mg on the second day, and 400 mg on the third day. In some embodiments, the daily escalating gradient dose comprises: 100 mg on the first day, 200 mg on the second day, 400 mg on the third day, and 600 mg on the fourth day. In some embodiments, the daily escalating gradient dose comprises: 100 mg on the first day, 200 mg on the second day, 400 mg on the third day, 800 mg on the fourth day.

[0208] In some embodiments, the daily escalating gradient dose comprises: 10 mg on the first day, 20 mg on the second day, 50 mg on the third day, and 100 mg on the fourth day. In some embodiments, the daily escalating gradient dose comprises: 10 mg on the first day, 20 mg on the second day, 50 mg on the third day, 100 mg on the fourth day, and 200 mg on the fifth day. In some embodiments, the daily escalating gradient dose comprises: 10 mg on the first day, 20 mg on the second day, 50 mg on the third day, 100 mg on the fourth day, 200 mg on the fifth day, and 300 mg on the sixth day.

[0209] In some embodiments, the treatment in subsequent dosing cycles uses a therapeutic dose of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof.

[0210] In some embodiments, the daily escalating gradient dose comprises: 100 mg on the first day; optionally, the treatment in subsequent dosing cycles administers 100 mg or 200 mg per day.

[0211] In some embodiments, the daily escalating gradient dose comprises: 100 mg on the first day and 200 mg on the second day. Optionally, the treatment in subsequent dosing cycles administers 400 mg per day.

[0212] In some embodiments, the daily escalating dose comprises: 100 mg on the first day, 200 mg on the second day, and 400 mg on the third day. Optionally, the treatment of the subsequent dosing cycle comprises 600 mg or 800 mg per day.

[0213] In some embodiments, the daily escalating dose comprises: 100 mg on the first day, 200 mg on the second day, 400 mg on the third day, and 600 mg on the fourth day. In some embodiments, the daily escalating dose comprises: 100 mg on the first day, 200 mg on the second day, 400 mg on the third day, and 800 mg on the fourth day.

[0214] In some embodiments, the daily escalating dose comprises: 50 mg on the first day. In some embodiments, the daily escalating dose comprises: 50 mg on the first day, and 100 mg on the second day. In some embodiments, the daily escalating dose comprises: 50 mg on the first day, 100 mg on the second day, and 200 mg on the third day. In some embodiments, the daily escalating dose comprises: 50 mg on the first day, 100 mg on the second day, 200 mg on the third day, optionally 300 mg or 400 mg on the fourth day, and optionally 400 mg on the fifth day.

[0215] In some embodiments, the duration of the administration of the weekly escalating dose is 1, 2, 3, 4, 5, 6, or 7 weeks, or a range formed by any of the above values. In some embodiments, the duration of the administration of the weekly escalating dose is 2-5 or 2-3 or 3-4 weeks. In some embodiments, the duration of the administration of the weekly escalating dose is 4 weeks.

[0216] In some embodiments, the weekly escalating dose comprises: 20 mg per day in the first week, 50 mg per day in the second week, 100 mg per day in the third week, and 200 mg per day in the fourth week. Optionally, the treatment of the dosing cycle is initiated in the fifth week and beyond, for example, a therapeutic dose of 400-600 mg (e.g., 400 mg, 500 mg, or 600 mg) per day. In some embodiments, the weekly escalating dose comprises: 10 mg per day in the first week, 20 mg per day in the second week, 50 mg per day in the third week, 100 mg per day in the fourth week, and 200 mg per day in the fifth week. Optionally, the treatment of the dosing cycle is initiated in the sixth week and beyond, for example, a therapeutic dose of 200-600 mg (e.g., 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg) per day.

[0217] In some embodiments, the daily or weekly escalated dose of the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is a run-in dose.

[0218] In some embodiments, the run-in period is selected from: 20 mg→ 50 mg→ 100 mg→ 200 mg→ 400 mg escalated daily; or, 100 mg→ 200 mg→ 400 mg escalated daily; or 20 mg (for 1 week)→ 50 mg (for 3 days)→ 100 mg (1 day)→ 200 mg (1 day)→ 400 mg. In some embodiments, for a subject dosed at 400 mg, the run-in period is selected from: 20 mg→ 50 mg→ 100 mg→ 200 mg→ 400 mg escalated daily; or, 100 mg→ 200 mg→ 400 mg escalated daily; or 20 mg (for 1 week)→ 50 mg (for 3 days)→ 100 mg (1 day)→ 200 mg (1 day)→ 400 mg.

[0219] In some embodiments, the run-in period for the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is selected from the following: 20 mg (for 1 week)→ 50 mg (for 3 days)→ 100 mg (1 day)→ 200 mg (1 day)→ 400 mg.

[0220] Alternatively, in some embodiments, the hematological tumor treatment further comprises: adjusting the administered dose (daily or per occasion) of the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, when used in combination or concomitantly with a CYP inhibitor or inducer.

[0221] In some embodiments, the hematological tumor treatment further comprises: reducing or not changing the administered dose (daily or per occasion) of the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, when used in combination or concomitantly with a CYP inhibitor.

[0222] In some embodiments, the administered dose (daily or per occasion) of the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is reduced to 50-80%, or 50-70%, or 50-60% of the original, when used in combination or concomitantly with a potent CYP inhibitor (e.g. itraconazole, etc.).

[0223] In some embodiments, the administered dose (daily or per occasion) of the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is not changed, when used in combination or concomitantly with a moderate or weak CYP inhibitor (e.g. verapamil, etc.).

[0224] In some embodiments, the blood tumor treatment further comprises: increasing or not changing the administered dose (daily or each time) of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, when used in combination or concomitantly with a CYP inducer.

[0225] In some embodiments, the administered dose (daily or each time) of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is increased by 10-50%, or 20-40%, or 25-35% when used in combination or concomitantly with a potent CYP inducer.

[0226] In some embodiments, the administered dose (daily or each time) of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is not changed or increased by 10-30%, or 15-25% when used in combination or concomitantly with a moderate CYP inducer.

[0227] In some embodiments, the administered dose (daily or each time) of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is not changed when used in combination or concomitantly with a weak CYP inducer.

[0228] In some embodiments, the CYP comprises CYP3A4 or CYP2C8.

[0229] In some embodiments, the CYP inhibitor is selected from a weak inhibitor, a moderate inhibitor, or a potent inhibitor.

[0230] In some embodiments, the CYP inducer is selected from a weak inducer, a moderate inducer, or a potent inducer.

[0231] In some embodiments, the CYP inducer is selected from rifampicin or efavirenz.

[0232] In some embodiments, the moderate CYP inducer is selected from efavirenz.

[0233] In some embodiments, the potent CYP inducer is selected from rifampicin.

[0234] In some embodiments, the potent CYP3A4 inhibitor is selected from atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, posaconazole, nefazadone, nelfinavir, ritonavir, saquinavir, or telithromycin. In some embodiments, the potent CYP3A4 inhibitor is selected from itraconazole, ketoconazole, or posaconazole. In some embodiments, the potent CYP3A4 inhibitor is selected from itraconazole.

[0235] In some embodiments, the moderate potency CYP3A4 inhibitor is selected from the group consisting of amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit, or verapamil. In some embodiments, the moderate potency CYP3A4 inhibitor is selected from the group consisting of verapamil.

[0236] In some embodiments, the weak potency CYP3A4 inhibitor is selected from the group consisting of fluvoxamine.

[0237] In some embodiments, the dose of rifampin administered is selected from the group consisting of 600 mg. The method of administration of rifampin is selected from the group consisting of once daily oral administration.

[0238] In some embodiments, the dose of itraconazole administered is selected from the group consisting of 200 mg. The method of administration of itraconazole is selected from the group consisting of once daily oral administration.

[0239] In some embodiments, the dose of efavirenz administered is selected from the group consisting of 600 mg. The method of administration of efavirenz is selected from the group consisting of once daily oral administration.

[0240] In some embodiments, the dose of verapamil administered is selected from the group consisting of 120 mg. The method of administration of verapamil is selected from the group consisting of oral administration every 8 hours.

[0241] In some embodiments, the dose of fluvoxamine administered is selected from the group consisting of 50 mg. The method of administration of fluvoxamine is selected from the group consisting of once daily oral administration.

[0242] In some embodiments, the potent CYP2C8 inhibitor is selected from the group consisting of gemfibrozil or its glucuronide conjugate.

[0243] In some embodiments, the moderate potency CYP2C8 inhibitor is selected from the group consisting of clopidogrel or its glucuronide conjugate.

[0244] In some embodiments, the hematological tumor treatment further comprises a reduction in the dose (daily or per administration) of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, by at least 20%, 30%, 40%, 50%, 60%, or 70%, or any range formed by any of the aforementioned values, when used in combination or concomitantly with a potent CYP3A4 inhibitor. In some embodiments, the hematological tumor treatment further comprises a reduction in the dose (daily or per administration) of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, by 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg, or any range formed by any of the aforementioned values, when used in combination or concomitantly with a potent CYP3A4 inhibitor. In some embodiments, the hematological tumor treatment further comprises a dose (daily or per administration) of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg, or any range formed by any of the aforementioned values, when used in combination or concomitantly with a potent CYP3A4 inhibitor.

[0245] In some embodiments, the hematological tumor treatment further comprises a reduction in the dose (daily or per administration) of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, by at least 20%, 30%, 40%, 50%, 60%, or 70%, or any range formed by any of the aforementioned values, when used in combination or concomitantly with a moderate CYP3A4 inhibitor. In some embodiments, the hematological tumor treatment further comprises a reduction in the dose (daily or per administration) of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, by 50 mg, 100 mg, 150 mg, or 200 mg, or any range formed by any of the aforementioned values, when used in combination or concomitantly with a moderate CYP3A4 inhibitor. In some embodiments, the hematological tumor treatment further comprises a dose (daily or per administration) of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg, or any range formed by any of the aforementioned values, when used in combination or concomitantly with a potent CYP3A4 inhibitor.

[0246] In some embodiments, the hematological tumor treatment further comprises no change in the dose (daily or per administration) of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, when used in combination or concomitantly with a weak CYP3A4 inhibitor.

[0247] In some embodiments, when the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered at a dose (daily or per administration) of 600 mg, the dose (daily or per administration) of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof can be adjusted to 500 mg or 400 mg when co-administered with a potent CYP3A4 inhibitor; the dose (daily or per administration) can be adjusted to 300 mg when the subject is still intolerant at 400 mg; or, the dose (daily or per administration) can be adjusted to 400 mg when co-administered with a moderate CYP3A4 inhibitor; or, the dose (daily or per administration) need not be adjusted when co-administered with a weak inhibitor.

[0248] In some embodiments, when the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered at a dose (daily or per administration) of 500 mg, the dose (daily or per administration) of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof can be adjusted to 400 mg or 300 mg when co-administered with a potent CYP3A4 inhibitor; the dose (daily or per administration) can be adjusted to 200 mg when the subject is still intolerant at 300 mg; or, the dose (daily or per administration) can be adjusted to 300 mg when co-administered with a moderate CYP3A4 inhibitor; or, the dose (daily or per administration) need not be adjusted when co-administered with a weak inhibitor.

[0249] In some embodiments, when the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered at a dose (daily or per administration) of 400 mg, the dose (daily or per administration) of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof can be adjusted to 300 mg when co-administered with a potent CYP3A4 inhibitor; the dose (daily or per administration) can be adjusted to 200 mg when the subject is still intolerant at 300 mg; or, the dose (daily or per administration) can be adjusted to 300 mg when co-administered with a moderate CYP3A4 inhibitor; or, the dose (daily or per administration) need not be adjusted when co-administered with a weak inhibitor.

[0250] In some embodiments, when the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered at a dose (daily or per administration) of 300 mg, the dose (daily or per administration) of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is adjusted to 200 mg when co-administered with a potent CYP3A4 inhibitor; the dose (daily or per administration) is adjusted to 100 mg when the subject is still intolerant at a dose of 200 mg; or, when co-administered with a moderate CYP3A4 inhibitor, the dose (daily or per administration) is adjusted to 200 mg when the subject is intolerant; or, when co-administered with a weak inhibitor, no adjustment of the dose (daily or per administration) is needed.

[0251] In some embodiments, when co-administered with a potent CYP3A4 inhibitor, the daily dose of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is adjusted to 300 mg (from a pre-adjustment daily / per administration dose of 400 mg), and can be adjusted to 200 mg if intolerant.

[0252] In some embodiments, when co-administered with a moderate CYP3A4 inhibitor, the daily dose of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is adjusted to 300 mg (from a pre-adjustment daily / per administration dose of 400 mg).

[0253] In some embodiments, the hematological tumor treatment further comprises: when co-administered with a potent CYP2C8 inhibitor, the dose (daily or per administration) of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is reduced by at least 20%, 30%, 40%, 50%, 60%, or 70%, or any range formed by any of the aforementioned values. In some embodiments, the hematological tumor treatment further comprises: when co-administered with a potent CYP2C8 inhibitor, the dose (daily or per administration) of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is reduced by 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg, or any range formed by any of the aforementioned values. In some embodiments, the hematological tumor treatment further comprises: when co-administered with a potent CYP2C8 inhibitor, the dose (daily or per administration) of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg, or any range formed by any of the aforementioned values.

[0254] In some embodiments, the blood tumor treatment further comprises: a reduction of at least 20%, 30%, 40%, 50%, 60%, or 70%, or any range formed by any of the aforementioned values, in the dose (daily or per administration) of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, when used in combination or concomitantly with a moderate potency CYP2C8 inhibitor. In some embodiments, the blood tumor treatment further comprises: a reduction of 50 mg, 100 mg, 150 mg, or 200 mg, or any range formed by any of the aforementioned values, in the dose (daily or per administration) of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, when used in combination or concomitantly with a moderate potency CYP2C8 inhibitor. In some embodiments, the blood tumor treatment further comprises: a dose of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg, or any range formed by any of the aforementioned values, of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, when used in combination or concomitantly with a potent CYP2C8 inhibitor.

[0255] In some embodiments, the blood tumor treatment further comprises: no change in the dose (daily or per administration) of the compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, when used in combination or concomitantly with a weak potency CYP2C8 inhibitor.

[0256] In some embodiments, the methods of treating a blood tumor provided herein comprise:

[0257] 1) identifying a subject as having a blood tumor; and

[0258] 2) administering to the identified subject a therapeutically effective amount of a compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0259] In some embodiments, the methods of treating a blood tumor provided herein comprise:

[0260] 1) performing an assay on a sample obtained from a subject to determine whether the subject has a blood tumor; and

[0261] 2) administering to the subject having a blood tumor a therapeutically effective amount of a compound of Formula I-I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0262] In some embodiments, the treatment comprises inhibiting, reducing the severity of, reducing the risk of, or inhibiting metastasis of a blood tumor in the subject.

[0263] In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of Formula II or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of Formula III or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of Formula IV or a pharmaceutically acceptable salt thereof.

[0264] a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof

[0265] The compound of Formula I-1 of the present application can be administered in the form of its free base, or in the form of a pharmaceutically acceptable salt, a hydrate, and a prodrug which can be converted into the free base form of the compound of Formula I-1 in vivo. The compound of Formula I-1 of the present application or a pharmaceutically acceptable salt thereof exists in a crystalline form or an amorphous form.

[0266] The pharmaceutical composition of the compound of Formula I-1 of the present application or a pharmaceutically acceptable salt thereof comprises the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, and further comprises a pharmaceutically acceptable excipient.

[0267] In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application is selected from 10-5000 mg, 20-5000 mg, or 20-4000 mg, or 20-3000 mg, or 20-2000 mg, or 50-1500 mg, or 100-1200 mg, or 200-1000 mg, or 200-800 mg, or 200-600 mg, or 200-400 mg of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application is selected from 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, or 2000 mg, or any value in a range formed by any of the foregoing. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application is selected from 100-1200 mg of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application is selected from 200-1000 mg of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application is selected from 10-800 mg or 20 mg-800 mg of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application is selected from 10-300 mg, 20-400 mg, 20-200 mg, or 20-100 mg of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application is selected from 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 300 mg, or 400 mg of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application is selected from 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, or 1200 mg of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application is selected from 100-800 mg of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application is selected from 300-600 mg or 400-600 mg of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application is selected from 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0268] In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application is selected from 50 mg-800 mg of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application is selected from 100 mg-800 mg of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application is selected from 100 mg-600 mg of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application is selected from 50 mg-400 mg (such as 50 mg, 100 mg, 200 mg, 300 mg, or 400 mg) of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application is selected from 100 mg-400 mg (such as 100 mg, 200 mg, or 400 mg) of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application is selected from 100 mg-200 mg of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application is selected from 200 mg, 400 mg, 600 mg, or 800 mg of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0269] In some embodiments, the pharmaceutical composition of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof is selected from a solid pharmaceutical composition, including but not limited to a tablet or a capsule.

[0270] In some embodiments, the pharmaceutical composition comprising a compound of Formula I-I or a pharmaceutically acceptable salt thereof is a pharmaceutical composition having a single dose of 5 mg to 500 mg, preferably 10 mg to 200 mg, most preferably 10 mg to 100 mg. Specifically, the pharmaceutical composition has a single dose selected from the group consisting of 5 mg, 10 mg, 15 mg, 20 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg or any range formed by any of the foregoing values. In some embodiments, the single dose of the pharmaceutical composition comprising a compound of Formula I-I or a pharmaceutically acceptable salt thereof is selected from the group consisting of 10 mg, 50 mg, or 100 mg.

[0271] In some embodiments, the pharmaceutical composition comprising a compound of Formula I-I or a pharmaceutically acceptable salt thereof is a multiple dose pharmaceutical composition, which can be comprised of multiple single dose pharmaceutical compositions comprising a compound of Formula I-I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprising a compound of Formula I-I or a pharmaceutically acceptable salt thereof is a multiple dose pharmaceutical composition, which can be comprised of single dose pharmaceutical compositions comprising a compound of Formula I-I or a pharmaceutically acceptable salt thereof having a single dose of 10 mg, 50 mg, or 100 mg.

[0272] In some embodiments, the compound of Formula I-I or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I-I or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of Formula II or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I-I or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of Formula III or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I-I or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of Formula IV or a pharmaceutically acceptable salt thereof.

[0273] Definitions and Descriptions

[0274] Unless otherwise indicated herein, the following terms used in this application have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but should be construed in accordance with the ordinary meaning in the art.

[0275] The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, provided that the valence of the particular atom is not normally exceeded, and that the substituted compound is stable. When the substituent is oxo (i.e., =0), it is meant that two hydrogen atoms are replaced by the oxo group. Oxos are not present on aromatic groups.

[0276] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances where the event or circumstance occurs and instances where it does not. For example, an ethyl group "optionally" substituted with a halogen means that the ethyl group can be unsubstituted (-CH2CH3), mono-substituted (e.g., -CH2CH2F), poly-substituted (e.g., -CHFCH2F, -CH2CHF2, etc.), or fully substituted (-CF2CF3). It will be understood by those skilled in the art that, for any group containing one or more substituents, such group does not include any substitution or substitution pattern that is not

[0277] C in this document m-n is an integer number of carbon atoms in the moiety having the given range. For example, "C 1-6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0278] The term "halogen" means fluorine, chlorine, bromine, and iodine.

[0279] The term "alkyl" means a hydrocarbon group of formula C n H 2n+1 The alkyl group can be straight-chained or branched. For example, the term "C 1-6 alkyl" means an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). For another example, the term "C 1-4 alkyl" means an alkyl group containing 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, etc.).

[0280] The term "cycloalkyl" means a carbocyclic ring that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 10-membered ring, preferably a 4- to 6-membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, and the like.

[0281] The term "heterocycloalkyl" means a cyclic group that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 7-membered ring containing 1 to 3 (preferably 1 or 2) heteroatoms independently selected from sulfur, oxygen, and / or nitrogen, e.g., a 4- to 6-membered ring or a 5- to 6-membered ring.

[0282] Unless otherwise indicated, the dosages provided herein relating to a compound of Formula I-1, e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof, and ranges thereof, are calculated based on the molecular weight of the free base of the compound of Formula I-1, e.g., a compound of Formula I.

[0283] The terms "administering" or "administered" or "administration" mean physically introducing a therapeutic agent or a composition comprising a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those in the art. The terms "administering" or "administered" or "administration" are used interchangeably herein.

[0284] The term "treatment" generally refers to obtaining a desired pharmacologic and / or physiologic effect. The effect can be therapeutic in terms of partially or completely

[0285] The term "effective amount" or "therapeutically effective amount" means the amount of a compound of the application that will elicit the biological or medical response of a particular disease, condition, or disorder, (ii) reduce, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the application that will constitute a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by the skilled practitioner as an initial guess of an appropriate amount of compound to be administered, based on the knowledge in the art and the disclosure herein.

[0286] The terms "subject," "patient," or "host" are used interchangeably herein and refer to an animal, preferably a mammal, more preferably a primate, including humans and non-human primates (such as apes, monkeys, chimpanzees, and gorillas, such as cynomolgus monkeys, spider monkeys, and macaques, such as rhesus monkeys), and most preferably a human (e.g., an adult human). In some embodiments, the subject has experienced and / or is exhibiting at least one symptom of a disease or disorder to be treated and / or prevented.

[0287] As used herein, the compound of Formula I-1, e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof, can be administered by any suitable route and method, e.g., by oral or parenteral (e.g., intravenous) administration.

[0288] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the application or a pharmaceutical combination thereof or a salt thereof with a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the application or a pharmaceutical combination thereof to a subject.

[0289] The term "pharmaceutically acceptable excipient" means an excipient that is not biologically or otherwise undesirable, i.e., the excipient can be administered to an organism without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Suitable excipients are well known to those skilled in the art, e.g., carbohydrates, waxes, water soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0290] The pharmaceutical compositions of the present application can be prepared by combining a compound of the present application with a suitable pharmaceutically acceptable excipient, such as can be formulated into solid dosage forms, e.g., tablets, pills, capsules, etc.

[0291] The pharmaceutical compositions of the present application can be manufactured using the methods well-known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, freeze-drying, etc. processes.

[0292] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0293] Solid oral pharmaceutical compositions can be prepared by conventional mixing, compounding or tabletting processes. For example, the active compound can be mixed with a solid excipient, optionally ground, and if necessary, with other suitable excipients, and then the mixture is processed into a granule, a core of a tablet or a capsule. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavorants.

[0294] The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salts" refers to those salts of the compounds of the present application which are within the scope of the definition of "pharmaceutically acceptable."

[0295] The singular terms "a," "an," and "the" include plural referents unless context clearly indicates otherwise. The use of "or" means "and / or" unless context clearly indicates otherwise.

[0296] In this document, the terms "comprising," "including," and "containing" or any variation thereof, are intended to indicate that the products include the specified elements, but not excluding others. Thus, these terms specify the presence of the stated elements, but do not preclude the presence of additional elements.

[0297] The term "single dose" refers to the smallest packaging unit containing a certain amount of a drug product, for example, a box of medicine has seven capsules, each capsule is a single dose; or each bottle of injection is a single dose. The term "multiple dose" is composed of multiple single doses.

[0298] For purposes of description and disclosure, all patents, patent applications, and other publications identified herein are expressly incorporated herein by reference. Such publications are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the claimed application is not entitled to antedate such publication by virtue of prior application. Further, the dates of publication provided herein can be off by a few days. Also, any reference to a document herein is not intended to constitute an admission that such document is widely available to the public or constitutes prior art to the claimed application.

[0299] In one embodiment, the pharmaceutical combination of the present application can be formulated into a pharmaceutical composition suitable for single or multiple administration. In one embodiment, the pharmaceutical combination of the present application can be a single dose or multiple dose pharmaceutical composition.

[0300] In the context of cancer, the term "first-line therapy" refers to the first treatment for a disease. It is usually part of a standard set of treatments, such as chemotherapy and radiation therapy after surgery. First-line therapy, when used alone, is the accepted best treatment. If it does not cure the disease or causes severe side effects, other treatments can be added or used.

[0301] In the context of cancer, the term "second-line therapy" refers to the treatment given when the initial treatment (first-line therapy) is not effective or stops working. The meaning of third-line therapy or multi-line therapy can be extrapolated in this way.

[0302] The terms "day", "every day" and the like, when referring to a dosing regimen, refer to the time within a calendar day, beginning at midnight and ending at the next midnight.

[0303] The term "refractory" refers to a subject or mammal who does not respond or does not respond adequately to an anti-cancer treatment.

[0304] The term "Adverse Event (AE)" refers to all adverse medical occurrences that the subject experiences after receiving the investigational product, which can be manifested as symptoms, signs, diseases, or abnormalities in laboratory tests, but not necessarily related to the investigational product. The evaluation criteria for the nature and severity of adverse events are in accordance with the Common Toxicity Criteria of the National Cancer Institute (NCI-CTC AE v5.0). Items that cannot be evaluated according to this standard can be evaluated according to the following criteria: mild: only slightly affects the patient's daily life. Moderate: significantly affects the patient's daily life. Severe: causes patient dysfunction or severely interferes with daily life.

[0305] The term "OS": refers to the overall survival time of the tumor patient.

[0306] The term "DFS": refers to the disease-free survival period of the tumor patient.

[0307] The term "SAE": refers to a serious adverse event.

[0308] The term "TEAEs": treatment-related adverse events.

[0309] Referring to refractory of immunotherapy (such as immunotherapy containing CD20 monoclonal antibody) refers to one or more of the following: disease progression occurs during treatment; or the best remission status after receiving adequate treatment does not reach partial remission; or remission is achieved after treatment, but disease progression occurs within 6 months after treatment ends.

[0310] Referring to relapse of immunotherapy (such as immunotherapy containing CD20 monoclonal antibody) refers to disease progression occurring after 6 months after treatment ends, which achieves partial remission or complete remission. Except for those who have disease progression during treatment, the number of treatment cycles is not required, and others should receive at least 4 cycles of immunotherapy (such as immunotherapy containing CD20 monoclonal antibody).

[0311] Referring to refractory of BTK inhibitor (BTKi) regimen refers to: disease progression occurs during treatment; or progression occurs within 6 months of remission. For those who can only achieve stable disease as the best efficacy after 6 months of standard-dose BTKi treatment, it can be considered that the BTKi is refractory.

[0312] Referring to relapse of BTKi regimen refers to: PR or above remission is obtained previously and ≥6 months, and progression occurs. For subjects who have disease progression during treatment, the BTKi treatment time is required to be no less than 8 weeks; for subjects who have remission after treatment, the treatment needs to be continued until disease progression or the treatment is continued for no less than 6 months after remission.

[0313] A subject who is not suitable for immunochemotherapy is a patient who typically has one or more of the following characteristics: Del(17p) / TP53 mutation, IGHV unmutated, complex karyotype, CLL IPI very high risk, or elderly patient (> 65 years), a patient who the investigator assesses as not suitable for immunochemotherapy or who is expected to benefit very little from immunochemotherapy.

[0314] “Previously received” means that the patient received the relevant treatment regimen (e.g. single agent regimen or combination regimen) in the previous treatment history, optionally, the relevant treatment regimen is still included in the current treatment regimen.

[0315] Technical effects

[0316] The treatment regimen of the present application has good efficacy in treating hematological tumors. The compound of formula I-1 (e.g. the compound of formula I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof described in the present application has excellent effects in at least one of the following aspects: objective response rate (ORR), complete remission (CR) rate, median duration of remission (DOR), 6-month DOR (duration of remission) rate, median progression-free survival (PFS), EFS (median event-free survival), median overall survival (OS), e.g. ORR, CR, CRi, partial remission (PR), partial remission with lymphocytosis (PR-L). For example, CR, CR and minimal residual disease negative (CR MRD- ), CR with incomplete blood count recovery (CRi), morphologic leukemia-free state (MLFS), CR with incomplete blood recovery (CRh), CR with incomplete platelet recovery (CRp), PR. Also, the compound of formula I-1 (e.g. the compound of formula I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof described in the present application has good drug tolerance in patients, low treatment dose, short required induction period; small side effects, including small effects on cardiovascular function, respiratory system, central nervous system, e.g. the related adverse events (TRAE) are mainly hematological adverse events and laboratory test value abnormalities, mostly grade 1-2; can effectively reduce the risk of tumor lysis syndrome (TLS).

[0317] It can be seen that the compound of formula I-1 (e.g. the compound of formula I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application has good pharmaceutical value. Also, the compound of formula I-1 (e.g. the compound of formula I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application can show benefits for patients who have previously received (including first-line, second-line, third-line or fourth-line) or have not received treatment.

[0318] CYP3A-mediated drug-drug interactions (DDIs) have a low degree of impact on the pharmacokinetics of compounds of formula I-1 (e.g., compounds of formula I), their pharmaceutically acceptable salts, or pharmaceutical compositions thereof, and in particular, no significant effect of intermediate or weak CYP3A inhibitors on exposure has been observed.

[0319] In a phase I DDI clinical trial in healthy subjects, when compound I was used in combination with the strong inducer rifampin, both the Cmax and AUC exposures of compound I were reduced, with Cmax decreasing by approximately 30-40%. When compound I was used in combination with the strong inhibitor itraconazole, both the Cmax and AUC exposures of compound I were increased, with Cmax increasing by approximately 1.4-1.5 times.

[0320] Based on the relevant data obtained from clinical trials, the PBPK model was used ( Simulations were performed using software (version 11.3, developed by www.open-systems-pharmacology.com). Results showed that when compound I was used in combination with the intermediate-acting CYP inducer efavirenz, both the Cmax and AUC exposures of compound I decreased, with Cmax decreasing by approximately 15-25%. When compound I was used in combination with the intermediate-acting CYP inhibitor verapamil, both the Cmax and AUC exposures of compound I increased, with Cmax increasing by approximately 1.1-1.3 times. When compound I was used in combination with the weak CYP inhibitor fluvoxamine, no significant changes in PK parameters were observed.

[0321] Regarding the efficacy evaluation criteria: For acute myeloid leukemia (AML), the 2017 European Leukemia Network (ELN) efficacy evaluation criteria can be referenced. For chronic lymphocytic leukemia (CLL), the IWCLL 2018 evaluation criteria can be referenced. For small lymphocytic lymphoma (SLL) and other non-Hodgkin lymphomas (NHL) such as MCL and DLBCL, the revised criteria from the 2014 Lugano Conference can be referenced.

[0322] Validity evaluation, for example

[0323] Objective response rate (ORR), optionally calculated using the following method:

[0324] SLL, MCL and DLBCL: The proportion of objective response cases (CR+PR) to their total number of cases;

[0325] CLL: The proportion of cases with objective remission (CR+CRi+PR+PR-L) to the total number of cases;

[0326] AML: The proportion of cases with objective remission (CR+CRi+MLFS+PR) to the total number of cases.

[0327] Complete remission (CR) rate:

[0328] SLL, MCL and DLBCL: the proportion of cases of complete remission (CR) in the total number of cases;

[0329] CLL: the proportion of cases of complete remission (CR+CRi) in the total number of cases;

[0330] AML: the proportion of cases of complete remission (CR+CRi) or (CR+CRh) in the total number of cases.

[0331] Median duration of remission (DOR): calculated using the Kaplan-Meier method.

[0332] Median progression-free survival PFS (for NHL), median event-free survival EFS (for AML) and median overall survival OS: estimated using the Kaplan-Meier method. DETAILED DESCRIPTION

[0333] For the sake of clarity, the present application is further illustrated by examples, but the examples are not intended to limit the scope of the present application. All reagents used in the present application are commercially available and can be used without further purification.

[0334] The compound of formula I-1, for example the compound of formula I, can be prepared according to the method disclosed in WO2020088442A1.

[0335] Example 1 clinical trial

[0336] 1. Test drug

[0337] Compound of formula I: 10 mg, 100 mg, tablet.

[0338] 2. Enrolled patients

[0339] Inclusion criteria:

[0340] 1) hematological malignancies diagnosed histologically or cytologically;

[0341] 2) patient population: non-Hodgkin's lymphoma (e.g. MCL, DLBCL, CLL / SLL), etc.; or, acute myeloid leukemia, etc.;

[0342] 3) at least 1 lesion that can be evaluated for efficacy / measurable disease;

[0343] 4) optionally, there is a history of prior treatment (including immunotherapy with CD20-containing monoclonal antibodies and / or treatment with BTK inhibitors).

[0344] 3. Dosing regimen

[0345] Compound of Formula I tablets, orally, within 30 minutes after the start of a meal with warm water, 20 mg to 1200 mg each time, once a day, 28 days for a dosing cycle.

[0346] If itraconazole or rifampin is involved, the optional dosing regimen is as follows:

[0347] For example, 100 mg of the compound of Formula I with 200 mg of itraconazole taken once a day;

[0348] 200 mg of the compound of Formula I with rifampin taken once a day;

[0349] 200 mg of the compound of Formula I with 600 mg of efavirenz taken once a day;

[0350] 100 mg of the compound of Formula I with 120 mg of verapamil taken every 8 hours; or

[0351] 100 mg of the compound of Formula I with 50 mg of fluvoxamine taken once a day.

[0352] The length of the induction period will depend on the therapeutic dose level. The day on which the therapeutic dose level is reached is designated as C1D1.

[0353] The induction period for NHL patients is carried out as follows, all of which are taken orally once a day in a daily escalation manner, and the last dose is the therapeutic dose:

[0354] 200 mg dose group: 20 mg→50 mg→100 mg→200 mg

[0355] 300 mg dose group: 20 mg→50 mg→100 mg→200 mg→300 mg

[0356] 400 mg dose group: 20 mg→50 mg→100 mg→200 mg→400 mg, daily escalation or 100 mg→200 mg→400 mg, or 20 mg (for 1 week)→50 mg (for 3 days)→100 mg (1 day)→200 mg (1 day)→400 mg.

[0357] 600 mg dose group: 20 mg→50 mg→100 mg→200 mg→400 mg→600 mg

[0358] 800 mg dose group: 20 mg→50 mg→100 mg→200 mg→400 mg→600 mg→800 mg

[0359] 1200 mg dose group: 20 mg→50 mg→100 mg→200 mg→400 mg→600 mg→800 mg→1200 mg.

[0360] The induction phase of AML patients is carried out as follows, all of which are carried out in a daily escalation manner, and the last dose is the therapeutic dose:

[0361] 200 mg dose group: 100 mg→200 mg

[0362] 400 mg dose group: 100 mg→200 mg→400 mg

[0363] 600 mg dose group: 100 mg→200 mg→400 mg→600 mg

[0364] 800 mg dose group: 100 mg→200 mg→400 mg→800 mg.

[0365] 4. Effectiveness and safety indicators

[0366] The effectiveness indicators include CR rate, ORR, DOR, PFS, OS, etc.

[0367] Adverse events: the occurrence of all adverse events (AEs), serious adverse events (SAEs), and treatment-related adverse events (TEAEs), including, for example, adverse reaction grades, overall incidence of adverse events, etc.

[0368] 5.1. Test results

[0369] The enrolled patients for the experimental results:

[0370] 1) blood system malignancies diagnosed by histology or cytology;

[0371] 2) patient population: non-Hodgkin's lymphoma (e.g., MCL, DLBCL, CLL / SLL), etc.; or, acute myeloid leukemia, etc.

[0372] 3) at least 1 lesion that can be evaluated for efficacy / measurable disease.

[0373] Safety: few adverse events, and adverse events related to the compound of formula I (TRAE) are mainly hematological adverse events and laboratory test value abnormalities, mostly grades 1-2.

[0374] In AML patients, the ORR is 25%-65%, and the CR rate is 25%-55%.

[0375] In MCL patients, the ORR is 45%-68%, and the CR rate is 15%-50%. In the 200-600 mg dose group, the ORR is 45%-68%, and the CR rate is 14%-50%.

[0376] In CLL / SLL patients, ORR was 89-95% and CR rate was 45-55%. In 200-600 mg dose groups, ORR was 89-95% and CR rate was 44-55%.

[0377] In DLBCL patients, ORR was 40-60% and CR rate was 40-50%. In 200-600 mg dose groups, ORR was 40-60% and CR rate was 40-50%.

[0378] In MCL, CLL / SLL, AML, DLBCL patients, the number of complete remission cases / (objective remission cases + complete remission cases) reached 25-100%.

[0379] Clinical phase I partial efficacy data:

[0380] For example, in the 400-600 mg dose group, 9 AML patients have been evaluated, 4 of which achieved CR / CRi, 1 achieved PR, ORR was 56%, and CR rate was 44%.

[0381] In the 100-600 mg dose group, 22 MCL patients have been evaluated, 3 of which achieved CR, 8 achieved PR, ORR was 50%, and CR rate was 14%.

[0382] In the 200-600 mg dose group, 27 CLL / SLL patients have been evaluated, 12 of which achieved CR / CRi, 12 achieved PR, ORR was 89%, and CR rate was 44%.

[0383] In the 100-600 mg dose group, 5 DLBCL patients have been evaluated, 2 of which achieved CR, ORR was 40%, and CR rate was 40%.

[0384] For example, in the evaluated MCL patients, the number of complete remission cases / (objective remission cases + complete remission cases) reached 27%; in the evaluated CLL / SLL patients, the number of complete remission cases / (objective remission cases + complete remission cases) reached 50%; in the evaluated AML patients, the number of complete remission cases / (objective remission cases + complete remission cases) reached 71%.

[0385] Patients who have received treatment (including first-line, second-line, third-line or fourth-line) or have not received treatment can all show benefits (for example, can show benefits for a longer period of time, have good efficacy, and have low side effects).

[0386] The following are representative cases:

[0387] Other efficacy data of clinical phase I:

[0388] In the two clinical phase I studies, the effectiveness of the compound of formula I as a single agent in relapsed / refractory CLL / SLL subjects was evaluated, with a median follow-up of 16.9 months, in which the 12-month PFS rate and the 18-month PFS rate were 76.67% and 70.62%, respectively, and the 12-month OS rate and the 18-month OS rate were 88.41 and 85.56%, respectively.

[0389] 5.2 Trial results (for patients with different prior treatment history)

[0390] The enrolled patients for which the trial results are directed:

[0391] 1) hematological malignancies confirmed by histology or cytology;

[0392] 2) patient population: MCL, CLL / SLL;

[0393] 3) at least 1 lesion that can be evaluated for efficacy / measurable disease;

[0394] 4) prior treatment history (including immunotherapy containing CD20 monoclonal antibody and / or BTK inhibitor treatment).

[0395] MCL efficacy evaluation indicators:

[0396] According to the Lugano standard, evaluate ORR (95% CI), DOR (95% CI), time to remission (TTR), PFS (95% CI), OS (95% CI);

[0397] Proportion of peripheral blood and / or bone marrow U-MRD (MRD4) (undetectable measurable residual disease, using peripheral blood and / or bone marrow by flow cytometry, detecting less than 1 MCL cell (less than 10 -4 ) in 10,000 white blood cells;

[0398] CR+PR data.

[0399] MCL efficacy data in clinical phase I:

[0400] 1. In the subject group who had previously received CD20 monoclonal antibody-containing treatment regimens and / or BTK inhibitor treatment regimens, the ORR was 35%-68% or 40%-68%.

[0401] Among them, in the 400-600 mg dose group, 15 patients had previously received BTK inhibitor (such as zanubratinib, ibritumomab, acalabrutinib, and obatinib) treatment, and 7 patients achieved CR or PR, with an ORR of 47%.

[0402] Among the 400-600 mg dose group, 18 patients had received prior treatment with a CD20 mAb, 9 of whom achieved CR or PR, with an ORR of 50%.

[0403] Among the patients with Lugano stage II-III at enrollment, all 3 patients enrolled achieved PR or CR.

[0404] CLL / SLL efficacy evaluation indicators:

[0405] According to the Lugano standard, evaluate ORR (95% CI), DOR (95% CI), 6-month DOR (duration of remission) rate, time to remission (TTR), PFS (95% CI), OS (95% CI), event-free survival (EFS), time to disease progression (TTP);

[0406] The depth of remission achieved in patients with relapsed or refractory CLL / SLL;

[0407] The proportion of peripheral blood and / or bone marrow U-MRD (undetectable measurable residual disease, MRD4).

[0408] Clinical phase I CLL / SLL efficacy data:

[0409] 1. In the subject group who had received prior treatment with a CD20 mAb (e.g., rituximab) containing regimen and / or a BTK inhibitor (e.g., zanubratinib, ibrtinib, acalabrutinib, olmutinib, etc.) regimen, the ORR was 85%-96% or 89%-96%, and the CR rate was 39%-68% or 39%-55%:

[0410] Among the 200-800 mg dose group, 35 CLL / SLL patients were evaluated, 16 of whom achieved CR / CRi, 16 achieved PR, the ORR was 91%, and the CR rate was 46%;

[0411] Among the 400 mg dose group, 22 CLL / SLL patients were evaluated, 14 of whom achieved CR / CRi, 7 achieved PR, the ORR was 95%, and the CR rate was 64%.

[0412] 2. In the subject group who had received prior treatment with a BTK inhibitor regimen, the ORR was 83%-96% or 89%-100%, and the CR rate was 39%-55% or 40%-70%;

[0413] Among the 200-800 mg dose group, 30 patients had received prior treatment with a BTK inhibitor, 14 of whom achieved CR / CRi, 14 achieved PR, the ORR was 93%, and the CR rate was 47%.

[0414] Of the 400 mg dose group, 18 patients had prior BTK inhibitor treatment, 12 achieved CR / CRi, 6 achieved PR, and the ORR was 100% and the CR rate was 67%. The estimated 12-month PFS rate and 12-month DOR rate were both > 85%.

[0415] 3. In the population of subjects who had prior treatment with a CD20- containing regimen, the ORR was 80-92% or 83-95% and the CR rate was 30-50% or 35-72%:

[0416] Of the 200-800 mg dose group, 18 patients had prior CD20 antibody treatment, 7 achieved CR / CRi, 8 achieved PR, the ORR was 83%, and the CR rate was 39%;

[0417] Of the 400 mg dose group, 10 patients had prior CD20 antibody treatment, 7 achieved CR / CRi, 2 achieved PR, the ORR was 90%, and the CR rate was 70%.

[0418] 4. In the population of subjects with any one or more of the features of IGHV unmutated, or with Del(17p) / TP53 mutation, the ORR was 83-92% or 83-100% and the CR rate was 33-45% or 35-45%:

[0419] Of the patients with IGHV unmutated, 10 CLL / SLL patients were evaluable, 4 achieved CR / CRi, 6 achieved PR, the ORR was 100%, and the CR rate was 40%;

[0420] Of the patients with Del(17p), 3 CLL / SLL patients were evaluable, 1 achieved CR / CRi, 2 achieved PR, the ORR was 100%, and the CR rate was 33%;

[0421] Of the patients with TP53 mutation, 6 CLL / SLL patients were evaluable, 2 achieved CR / CRi, 3 achieved PR, the ORR was 83%, and the CR rate was 33%.

[0422] 5. In the population of subjects in which the patients were in Binet stage B, the ORR was 85-100% and the CR rate was 30-50% or 40-70%:

[0423] Of the 200-800 mg dose group, 11 patients were in Binet stage B, 5 achieved CR / CRi, 5 achieved PR, the ORR was 91%, and the CR rate was 45%;

[0424] In the 400 mg dose group, 6 Binet stage B patients achieved CR / CRi, 2 achieved PR, and the ORR was 100% and the CR rate was 67%.

[0425] 6. In the subject group of patients in Binet stage C, the ORR was 85-95% and the CR rate was 43-60%:

[0426] In the 200-800 mg dose group, 20 Binet stage C patients achieved CR / CRi, 9 achieved PR, and the ORR was 90% and the CR rate was 45%.

[0427] In the 400 mg dose group, 14 Binet stage C patients achieved CR / CRi, 5 achieved PR, and the ORR was 93% and the CR rate was 57%.

[0428] CLL / SLL efficacy data from clinical phase II:

[0429] The subject group is: patients who experienced treatment intolerance or failed to achieve a PR or better response or who experienced disease progression after adequate treatment during or after treatment with immunotherapy (containing CD20 monoclonal antibody) and BTK inhibitor treatment; or who are not suitable for receiving immunotherapy (containing CD20 monoclonal antibody) and experienced treatment intolerance, failed to achieve a PR or better response or experienced disease progression after adequate treatment during BTK inhibitor treatment (the best response during the last treatment was disease remission or stable disease, and then experienced disease progression).

[0430] The ORR in the 400 mg dose group is ≥ 80%, for example 80-90%.

Claims

1. A BCL-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of hematologic malignancies, wherein the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof is selected from compounds of formula I, II, III, or IV, or pharmaceutically acceptable salts thereof. The hematological tumor is selected from CLL / SLL that has received one or more treatment regimen of chemotherapy, immunotherapy, immunochemotherapy or BTK inhibitor treatment, or MCL that has received one or more treatment regimen of immunotherapy, immunochemotherapy or BTK inhibitor treatment.

2. The BCL-2 inhibitor or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof for use according to claim 1, wherein, the BCL-2 inhibitor or pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of Formula I or a pharmaceutically acceptable salt thereof, 3. The BCL-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of claim 1 or 2, wherein, The hematological tumor is selected from advanced hematological tumor. Alternatively, the hematological tumor is selected from relapsed and / or refractory hematological tumor.

4. The BCL-2 inhibitor or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof for use according to any one of claims 1 to 3, wherein, The immunotherapeutic agent in the immunochemotherapy or immunotherapy is selected from CD20 mAb.

5. The BCL-2 inhibitor or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof for use according to any one of claims 1 to 4, wherein, The anti-CD20 mAb is selected from rituximab, ofatumumab, golimumab, aselizumab or ocrelizumab; Alternatively, the BTK inhibitor is selected from acalabrutinib, zanubrutinib, ibrutinib, osibrutinib, Tirabrutinib, SHR1459, BT-1053, LP168, pirtobrutinib, limertinib, evobrutinib, XS004, evobrutinib, fenebrutinib, nemtabrutinib, remibrutinib, rilzabrutinib, tolebrutinib, ABBV-599, BIIB091, BMS-986142, CT-1530, LP-168, MH048, TAS5315, erdalbrutinib, elsubrutinib, cenicriviroc, IG-100, CX1440, HBW-3220, HZ-A-018, XNW1011, IMG-004, JDB175, YZJ-3058, ZXBT-1158, HBW-3210, SYHA1811, FCN-647 or HMPL-760; Alternatively, the BTK inhibitor is selected from acalabrutinib, zanubrutinib, ibrutinib, osibrutinib, Tirabrutinib, SHR1459, BT-1053, LP168, FCN-647 or HMPL-760; Alternatively, the chemotherapy, immunotherapy, immunochemotherapy or BTK inhibitor treatment regimen is selected from BTK inhibitor, chiorambucil, lenalidomide, rituximab, bendamustine + CD20 mAb, bendamustine + rituximab, methylprednisolone + rituximab, fludarabine + cyclophosphamide + rituximab, fludarabine + rituximab, ibrutinib + rituximab, lenalidomide + rituximab, bendamustine + rituximab + ibrutinib.

6. The BCL-2 inhibitor or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof for use according to any one of claims 1 to 5, wherein, The subject of the hematological tumor has received treatment of one or two or more prior treatment regimen; Alternatively, the subject of the hematological tumor is selected from a subject who has received at least 1 systemic treatment regimen, has disease progression or intolerance during or after the most recent treatment, or has not achieved remission after adequate treatment; or the CLL / SLL subject has experienced treatment intolerance or failed to achieve a PR or better response or has disease progression during or after immunochemotherapy and BTK inhibitor treatment; or the CLL / SLL subject has experienced treatment intolerance or failed to achieve a PR or better response or has disease progression during or after immunochemotherapy and BTK inhibitor treatment; or the CLL / SLL subject is selected from those who are not suitable for immunochemotherapy and have experienced treatment intolerance or failed to achieve a PR or better response or have disease progression during BTK inhibitor treatment. or the CLL / SLL subject who is not suitable for immunochemotherapy is selected from those who have one or more of the following characteristics: Del(17p) / TP53 mutation, IGHV unmutated, complex karyotype, CLL IPI very high risk, or elderly patients (≥65 years old); or the CLL / SLL subject is in Binet stage B or C.

7. The BCL-2 inhibitor or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof for use according to any one of claims 1 to 6, wherein, the daily or per administration dose of the BCL-2 inhibitor or pharmaceutically acceptable salt thereof is selected from 20-2000 mg, 20-1200 mg, or 100-1200 mg; or the daily or per administration dose is selected from 10-5000 mg, or 20-5000 mg, or 20-4000 mg, or 20-3000 mg, or 20-2000 mg, or 50-1500 mg, or 100-1200 mg, or 200-1000 mg, or 200-800 mg, or 200-600 mg, or 200-400 mg; or the daily or per administration dose is selected from 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, or 2000 mg, or any value in a range formed by any of the foregoing; or the daily or per administration dose is 400 mg; or the administration dose of the compound of Formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is adjusted when used in combination or concomitantly with a CYP inhibitor or inducer.

8. The BCL-2 inhibitor or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof for use according to any one of claims 1 to 7, wherein, the frequency of administration of the BCL-2 inhibitor or pharmaceutically acceptable salt thereof is selected from 3 times daily, 2 times daily, 1 time daily, 1 time every two days, 1 time every three days, 1 time every four days, 1 time every five days, 1 time every six days, 3 times per week, 2 times per week, 1 time per week, 1 time every two weeks, or 1 time every three weeks; Alternatively, the BCL-2 inhibitor or pharmaceutically acceptable salt thereof is administered once daily.

9. The BCL-2 inhibitor or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof for use according to any one of claims 1 to 8, wherein, The administration of the BCL-2 inhibitor or pharmaceutically acceptable salt thereof is continuous daily administration; Alternatively, the BCL-2 inhibitor or pharmaceutically acceptable salt thereof is administered in a single dose or multiple doses; Alternatively, the BCL-2 inhibitor or pharmaceutically acceptable salt thereof is administered orally; Alternatively, the BCL-2 inhibitor or pharmaceutically acceptable salt thereof is administered orally within 30 minutes after a meal.

10. The BCL-2 inhibitor or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof for use according to any one of claims 1 to 9, wherein, Prior to the administration, the patient is administered at least one escalating dose of the BCL-2 inhibitor or pharmaceutically acceptable salt thereof, wherein the first escalating dose is lower than the daily or each administration dose of the BCL-2 inhibitor or pharmaceutically acceptable salt thereof for the treatment; Alternatively, the patient is administered escalating doses of the BCL-2 inhibitor or pharmaceutically acceptable salt thereof daily or weekly; Alternatively, the at least one escalating dose comprises a first escalating dose and a further escalating dose, wherein the last escalating dose is less than or equal to the daily or each administration dose of the BCL-2 inhibitor or pharmaceutically acceptable salt thereof for the treatment; Alternatively, the duration of the administration of the daily escalating dose is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, or a range formed by any of the aforementioned values.

11. A kit for treating hematological tumors, comprising the pharmaceutical composition of the BCL-2 inhibitor or pharmaceutically acceptable salt thereof of any one of claims 1-10; optionally, further comprising instructions for using the pharmaceutical composition of the BCL-2 inhibitor or pharmaceutically acceptable salt thereof for treating hematological tumors.

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