WO2024217552A1 - 含有三氟甲基的化合物在治疗血液肿瘤中的应用 - Google Patents

含有三氟甲基的化合物在治疗血液肿瘤中的应用 Download PDF

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Publication number
WO2024217552A1
WO2024217552A1 PCT/CN2024/088858 CN2024088858W WO2024217552A1 WO 2024217552 A1 WO2024217552 A1 WO 2024217552A1 CN 2024088858 W CN2024088858 W CN 2024088858W WO 2024217552 A1 WO2024217552 A1 WO 2024217552A1
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pharmaceutically acceptable
acceptable salt
dose
pharmaceutical composition
formula
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English (en)
French (fr)
Inventor
赵倩
张喜全
赵伟
王训强
于鼎
张倩倩
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Priority to EP24792136.4A priority Critical patent/EP4714448A1/en
Priority to CN202480026269.9A priority patent/CN121001725A/zh
Priority to TW113140360A priority patent/TW202541803A/zh
Publication of WO2024217552A1 publication Critical patent/WO2024217552A1/zh
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present application belongs to the field of medicine and relates to the use of a trifluoromethyl-containing compound in the treatment of blood tumors, and specifically relates to the use of a compound of formula I-1 or a pharmaceutically acceptable salt thereof in the treatment of blood tumors.
  • BCL-2 proteins are divided into three families: BCL-2 family (whose family members include BCL-2, BCL-XL, etc.), BAX family and BH3-only family. Among them, the BCL-2 family plays an anti-apoptotic role, while the members of the latter two families play a pro-apoptotic role.
  • Anti-apoptotic BCL-2 family proteins are associated with many diseases and are being studied as potential therapeutic drug targets. These targets for interventional therapy include, for example, BCL-2 family proteins BCL-2 and BCL-XL, etc.
  • Inhibitors of BCL-2 family proteins are inhibitors of target protein binding, and compound binding affinity is only one of many parameters to be considered.
  • One goal is to produce compounds that preferentially bind to one protein relative to another protein, i.e., selectivity for it. To show this selectivity, it is known that the compound shows high binding affinity for a specific protein, and lower binding affinity for another member.
  • BCL-2 proteins can be used to treat hyperproliferative diseases, such as tumors.
  • WO2019185025, WO2020088442, and WO2020238785 disclose compounds or pharmaceutically acceptable salts thereof as BCL-2 inhibitors.
  • the present application provides a method for treating a hematological tumor, 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.
  • the present 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 a blood tumor.
  • the present application also provides a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating a blood tumor.
  • the present application also provides the use of the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating a blood tumor.
  • the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof described herein is selected from a compound of formula I-1 or a pharmaceutically acceptable salt thereof,
  • R 2 is independently selected from 4-6 membered heterocycloalkyl, C 3-6 cycloalkyl, -COR a , -SO 2 R b , or C 1-6 alkyl optionally substituted by halogen;
  • Ra or Rb are each independently selected from H, 4-6 membered heterocycloalkyl, C3-6 cycloalkyl, or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with halogen, -CN, -N( C1-6 alkyl) 2 , -NHC1-6 alkyl, or -OC1-6 alkyl;
  • R 1 is selected from hydrogen, halogen, or C 1-3 alkyl. In some embodiments, R 1 is selected from hydrogen, fluorine, chlorine, or methyl. In some embodiments, R 1 is selected from hydrogen, chlorine, or methyl.
  • ring A is selected from 6-membered heterocycloalkyl. In some embodiments, ring A is selected from 6-membered heterocycloalkyl containing one or more O atoms, such as 6-membered heterocycloalkyl containing 1 or 2 O atoms. In some embodiments, ring A is selected from dioxane or pyran ring.
  • R 2 is each independently selected from 4-6 membered heterocycloalkyl, C 4-6 cycloalkyl, -COR a , -SO 2 R b , or C 1-4 alkyl optionally substituted with halogen.
  • Ra or Rb are each independently selected from H, 4-6 membered heterocycloalkyl, C3-6 cycloalkyl, or C1-4 alkyl, said C1-4 alkyl optionally substituted with halogen, -CN, -N( C1-4 alkyl) 2 , -NHC1-4 alkyl, or -OC1-4 alkyl.
  • R 2 is each independently selected from -C(O)H, -COC(CH 3 ) 3 , -COCF 3 , -COCH 2 CN, -COCH 2 N(CH 3 ) 2 , -SO 2 CH 2 CH 3 , -SO 2 CF 3 , -SO 2 C 2 F 5 , -CF 3 , -C 2 F 5 , tetrahydropyran, monooxetane, -SO 2 -cyclopropane, -CO-cyclopropane, -CO-monooxetane, -SO 2 -monooxetane, or -SO 2 -cyclobutane.
  • m is selected from 0 or 1.
  • the BCL-2 inhibitor described herein or a pharmaceutically acceptable salt thereof is selected from a compound of Formula I, Formula II, Formula III, or Formula IV or a pharmaceutically acceptable salt thereof,
  • the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof is selected from a compound of formula I or a pharmaceutically acceptable salt thereof; or a compound of formula II or a pharmaceutically acceptable salt thereof; or a compound of formula III or a pharmaceutically acceptable salt thereof; or a compound of formula IV or a pharmaceutically acceptable salt thereof.
  • 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.
  • the blood tumor is selected from an advanced blood tumor. In some embodiments, the blood tumor is selected from a relapsed and/or refractory blood tumor. In some embodiments, the blood tumor is selected from a relapsed and/or refractory advanced blood tumor.
  • the blood tumor is selected from blood tumors clearly diagnosed by histology or cytology.In some embodiments, the above diagnosis meets the 2016 diagnostic criteria of WHO.
  • the hematological tumor is selected from a lymphoid tumor or a leukemia.
  • the blood tumor is selected from lymphoid tumors or myeloid leukemia.
  • the lymphoid tumor is selected from non-Hodgkin's lymphoma.
  • the myeloid leukemia is acute myeloid leukemia.
  • the hematological tumor is selected from non-Hodgkin's lymphoma or acute myeloid leukemia.
  • the non-Hodgkin's lymphoma is selected from mantle cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia and/or small lymphocytic lymphoma.
  • the hematological neoplasm is selected from mantle cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia and/or small lymphocytic lymphoma, or acute myeloid leukemia.
  • the hematological tumor is selected from leukemia.
  • the hematological tumor is selected from a myeloid leukemia.
  • the blood tumor or leukemia is selected from acute myeloid leukemia.
  • the hematological tumor is selected from lymphoid tumors.
  • the hematological tumor is selected from non-Hodgkin's lymphoma.
  • the hematological neoplasm or non-Hodgkin's lymphoma is selected from mantle cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and/or small lymphocytic lymphoma.
  • the subject with a blood tumor may be a subject who has not been treated with a previous treatment regimen. In some embodiments, the subject with a blood tumor has been treated with one or more previous treatment regimens. In some embodiments, the subject with a blood tumor has been treated with one, two, three, four, or five previous treatment regimens.
  • the subject of the blood tumor is selected from a relapsed or refractory subject. In some embodiments, the subject of the blood tumor is selected from a subject with an initial induction or re-induction treatment-refractory disease. In some embodiments, the subject of the blood tumor is selected from a subject who has relapsed or failed treatment after previous treatment. In some embodiments, the subject of the blood tumor is selected from a subject who has relapsed or failed treatment after previous standard treatment. In some embodiments, the subject of the blood tumor is selected from a subject who has failed previous treatment. In some embodiments, the subject of the blood tumor is selected from a subject who has failed after standard treatment.
  • the subject of the blood tumor is selected from a subject who is intolerant to previous treatment regimens. In some embodiments, the subject of the blood tumor is selected from a subject who is intolerant to standard treatment regimens. In some embodiments, the subject of the blood tumor is selected from a subject who is intolerant to previous treatment regimens and has no other better treatment options. In some embodiments, the subject of the blood tumor is selected from a subject who is intolerant to standard treatment regimens and has no other better treatment options.
  • the subject with a blood tumor is selected from a subject who has previously received at least one systemic treatment regimen, has disease progression or intolerance during or after the last treatment, or has not been relieved after adequate treatment. In some embodiments, the subject with a blood tumor is selected from a subject who has previously received at least one or two systemic treatment regimens, has disease progression or intolerance during or after the last treatment, or has not been relieved after adequate treatment.
  • the previously received treatment regimen includes a first-line treatment regimen, a second-line treatment regimen, and/or a third-line treatment regimen.
  • the subject with a hematological neoplasm has at least 1 lesion/measurable disease that is evaluable for efficacy.
  • the subject with acute myeloid leukemia has bone marrow blasts. In some embodiments, the subject with acute myeloid leukemia has bone marrow blasts ⁇ 5%.
  • the non-Hodgkin's lymphoma subject has at least one radiologically measurable tumor lesion in two perpendicular directions (eg, the long diameter of the intranodal lesion is >15 mm, and the long diameter of the extranodal lesion is >10 mm) as assessed by CT or MRI.
  • the subject with the hematological tumor has not been previously treated with a BCL-2 inhibitor.
  • the BCL-2 inhibitor includes but is not limited to venetoclax or pelcitoclax.
  • the subject with hematological tumor has the following comorbidities:
  • the tumor patients can be tumor patients with other malignant tumors who have been treated with a single surgery and achieved 5 consecutive years of disease-free survival (DFS);
  • DFS disease-free survival
  • the patient with the tumor or advanced malignancy may be a cured patient of carcinoma in situ of the cervix, non-melanoma skin cancer, and superficial bladder tumors including but not limited to Ta (non-invasive tumor), Tis (carcinoma in situ), and T1 (tumor invading basement membrane).
  • the subject with the hematological tumor does not have any one or more of the following conditions:
  • AIHA autoimmune hemolytic anemia
  • ITP idiopathic thrombocytopenic purpura
  • the arterial/venous thrombotic event occurring within 6 months before the first medication in 6) above may optionally refer to cerebrovascular accident (including but not limited to transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis and pulmonary embolism, etc.
  • patients with any severe and/or uncontrolled diseases mentioned in 7) above include: 1. Patients with ⁇ grade 2 myocardial ischemia or myocardial infarction, arrhythmia (QTc>450ms for males, QTc>470ms for females) and ⁇ grade 2 congestive heart failure (New York Heart Association (NYHA) classification) within 6 months prior to the first medication; 2. Patients with active serious infection ( ⁇ CTC AE grade 2 infection), left ventricular ejection fraction (LVEF) assessed by cardiac ultrasound ⁇ 50%; 3. Active hepatitis; 4. Patients with a history of immunodeficiency, including HIV positivity or other acquired or congenital immunodeficiency diseases, or a history of organ transplantation; 5. Patients with epilepsy and requiring treatment.
  • AML Acute Myeloid Leukemia
  • the acute myeloid leukemia is selected from relapsed and/or refractory acute myeloid leukemia.
  • the acute myeloid leukemia is selected from acute myeloid leukemia that is intolerant to standard treatment regimens and has no other better treatment options.
  • the acute myeloid leukemia patient/subject meets one or more of the following conditions:
  • the acute myeloid leukemia patient relapses within 12 months after CR/CRi and consolidation therapy.
  • the acute myeloid leukemia patient relapses 12 months after CR/CRi but does not achieve CR/CRi after re-induction therapy.
  • the acute myeloid leukemia patient has 2 or more relapses.
  • the acute myeloid leukemia patient did not achieve CR/CRi after first-line induction therapy.
  • the relapse in a) above refers to peripheral blood leukemic blasts or bone marrow blasts ⁇ 5%, or new extramedullary lesions.
  • the failure of first-line induction therapy to achieve CR/CRi in d) above means:
  • first-line standard induction therapy should contain anthracyclines and/or standard-dose cytarabine for at least 2 cycles;
  • first-line induction therapy should contain demethylating drugs and last for at least 4 cycles.
  • the acute myeloid leukemia excludes non-acute promyelocytic leukemia.
  • MCL Mantle Cell Lymphoma
  • the lymphoid neoplasm or non-Hodgkin lymphoma is selected from mantle cell lymphoma.
  • the mantle cell lymphoma is selected from relapsed and/or refractory mantle cell lymphoma.
  • the subject with mantle cell lymphoma has been treated with one or more 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.
  • the subject with mantle cell lymphoma has previously received at least one systemic treatment regimen, and has disease progression or intolerance during or after completion of the most recent treatment, or has not responded after adequate treatment.
  • Diffuse large B-cell lymphoma Diffuse large B-cell lymphoma
  • the lymphoid neoplasm or non-Hodgkin's lymphoma is selected from diffuse large B-cell lymphoma.
  • the diffuse large B-cell lymphoma is selected from relapsed and/or refractory diffuse large B-cell lymphoma.
  • the subject with diffuse large B-cell lymphoma has been treated with one or more prior treatment regimens. In some embodiments, the subject with diffuse large B-cell lymphoma has been treated with one, two, three, four, or five prior treatment regimens.
  • the subject with diffuse large B-cell lymphoma has previously received at least one or two systemic treatment regimens, and has disease progression or intolerance during or after completion of the most recent treatment, or has not responded after adequate treatment.
  • CLL/SLL Chronic lymphocytic leukemia/small lymphocytic lymphoma
  • the lymphoid neoplasm or non-Hodgkin's lymphoma is selected from chronic lymphocytic leukemia or small lymphocytic lymphoma.
  • the chronic lymphocytic leukemia or small lymphocytic lymphoma is selected from relapsed and/or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.
  • the subject with chronic lymphocytic leukemia or small lymphocytic lymphoma has been treated with one or more prior treatment regimens. In some embodiments, the subject with chronic lymphocytic leukemia or small lymphocytic lymphoma has been treated with one, two, three, four, or five prior treatment regimens.
  • the subject with chronic lymphocytic leukemia or small lymphocytic lymphoma has previously received at least one systemic treatment regimen, and has disease progression or intolerance during or after completion of the most recent treatment, or has not experienced remission after adequate treatment.
  • the subject with chronic lymphocytic leukemia has a peripheral blood monoclonal B lymphocyte count>5 ⁇ 10 9 /L, or has imaging measurable lesions.
  • the subject with chronic lymphocytic leukemia has at least one imaging measurable tumor lesion in two perpendicular directions as assessed by CT or MRI.
  • the tumor lesion is selected from intranodal lesions with a long diameter>15mm and extranodal lesions with a long diameter>10mm.
  • the method of administration can be comprehensively determined according to the activity, toxicity and tolerance of the subject/patient of the drug.
  • Those skilled in the art can determine the appropriate amount, dosage or dosage of each drug used in combination of the present invention to be applied to the subject/patient.
  • Those skilled in the art can adjust the dosage and dosage regimen according to methods well known in the therapeutic field. For example, the maximum tolerated dose can be easily determined, and the effective amount that can be detected for the subject/patient can also be determined, and the time requirement for applying each drug to provide a detectable therapeutic benefit to the subject/patient can also be determined. Therefore, although the application illustrates certain dosages and dosage regimens, these examples are by no means limited to the dosages and dosage regimens that can be provided to the subject/patient when practicing the present invention.
  • the present application provides a method for treating hematological tumors, which comprises administering to a subject a dose (daily or each time) selected from 20-2000 mg, 20-1200 mg, 100-1200 mg, 100-800 mg, 200-800 mg or 200-600 mg of a compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • 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 preparation of a drug for treating a blood tumor, wherein the drug comprises 20-2000 mg, 20-1200 mg, 100-1200 mg, 100-800 mg, 200-800 mg or 200-600 mg of a compound of formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • 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 preparation of a drug for treating a blood tumor, wherein the drug 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.
  • 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 preparation of a medicament for treating hematological tumors, wherein the administration dosage (daily or each 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).
  • the present application also provides a compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating hematological tumors, wherein the administration dosage (daily or each 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).
  • the present application also provides the use of the compound of formula I-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition for treating blood tumors, wherein the administration dosage (daily or each time) of the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 20-2000 mg, 20-1200 mg, 100-1200 mg, 100-800 mg, 200-800 mg or 200-600 mg (for example, 300 mg, 400 mg, 500 mg or 600 mg).
  • the present application also provides a kit for treating tumors, comprising: a pharmaceutical composition containing a compound of formula I-1 or a pharmaceutically acceptable salt thereof; optionally, further comprising instructions for use of the pharmaceutical composition of the compound of formula I-1 or a pharmaceutically acceptable salt thereof, wherein the instructions for use
  • the dosage (daily or each time) of the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition 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).
  • the instructions for use refer to guiding the subject to administer a pharmaceutical composition containing a compound of formula I-1 or its pharmaceutically acceptable salt.
  • the daily or each dose of the compound of formula I-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition 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.
  • the daily or each dose of the compound of formula I-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition 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 the range formed by any of the above values.
  • the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 100mg-1200mg, 100-800mg, 200-800mg or 200-600mg. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 200-1000mg or 200-800mg. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 10-800mg, 20-800mg or 100-800mg.
  • the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 10-300mg, 20-400mg, 20-200mg or 20-100mg. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 10mg, 20mg, 50mg, 100mg, 200mg, 300mg or 400mg. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, 1000mg or 1200mg.
  • the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 100-800mg. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 400-600mg. In some embodiments, the daily or each dose of the compound of formula I-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 200 mg, 300 mg, 400 mg, 500 mg or 600 mg.
  • the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 50mg-800mg. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 100mg-800mg. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 100mg-600mg. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 50mg-400mg (such as 50mg, 100mg, 200mg, 300mg or 400mg).
  • the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 100mg-400mg (such as 100mg, 200mg or 400mg). In some embodiments, the daily or per dose of the compound of formula I-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 100 mg to 200 mg. In some embodiments, the daily or per dose of the compound of formula I-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 200 mg, 300 mg, 400 mg, 600 mg or 800 mg.
  • the present application provides a method for treating hematological tumors, comprising administering to a subject a dose (daily or each time) selected from 20-2000 mg, 20-1200 mg or 100-1200 mg of a compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • 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 preparation of a drug for treating a blood tumor, wherein the drug contains 20-2000 mg, 20-1200 mg or 100-1200 mg of a compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • 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 preparation of a drug for treating a blood tumor, wherein the dosage (daily or each 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.
  • the present application also provides a compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating blood tumors, wherein the administration dosage (daily or each 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.
  • the present application also provides the use of the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition for treating blood tumors, wherein the administration dosage (daily or each time) of the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 20-2000 mg, 20-1200 mg or 100-1200 mg.
  • the present application also provides a kit for treating tumors, comprising: a pharmaceutical composition containing a compound of formula I-1 or a pharmaceutically acceptable salt thereof; optionally, instructions for use of the pharmaceutical composition of the compound of formula I-1 or a pharmaceutically acceptable salt thereof, wherein the instructions for use relate to an administration dose (daily 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.
  • the instructions for use refer to guiding the subject to administer a pharmaceutical composition of a compound of formula I-1 or a pharmaceutically acceptable salt thereof.
  • the daily or each dose of the compound of formula I-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition 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.
  • the daily or each dose of the compound of formula I-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition 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 the range formed by any of the above values.
  • the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 100-1200mg. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 200-1000mg. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 10-800mg or 20mg-800mg. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 10-300mg, 20-400mg, 20-200mg or 20-100mg.
  • the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 10mg, 20mg, 50mg, 100mg, 200mg, 300mg or 400mg. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, 1000mg or 1200mg. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 100-800mg.
  • the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 400-600mg. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 200mg, 300mg, 400mg, 500mg or 600mg.
  • the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition 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 its pharmaceutically acceptable salt, or its pharmaceutical composition is administered at 0.0001 to 20 mg/kg weight per administration.
  • the frequency of administration of the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition may be 3 times a day, 2 times a day, 1 time a day, 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 a week, 2 times a week, 1 time a week, 1 time every two weeks, or 1 time every three weeks.
  • the frequency of administration of the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition may be 1 time or 2 times a day.
  • the frequency of administration of the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition may be 1 time a day.
  • administering an effective amount of the compound of formula I-1 of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a subject is continuous daily administration.
  • 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.
  • the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered orally.
  • the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition can be orally administered within 30 minutes after starting a meal.
  • the compound of Formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition is administered orally on an empty stomach.
  • 8-32 days are used as a dosing cycle, for example, 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 are used as a dosing cycle.
  • 28 days or 32 days are used as a dosing cycle.
  • 28 days (4 weeks) are used as a dosing cycle.
  • the application repeats one or more dosing cycles.
  • the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition is administered as follows: 20 mg-1200 mg, 100 mg-1200 mg, 100 mg-800 mg, 200-800 mg or 400 mg-600 mg each time, administered continuously daily (e.g., once a day) for one or more dosing cycles; optionally, 8-32 days (e.g., every 28 days) is one dosing cycle.
  • the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition is administered as follows: 20 mg-1200 mg, 100 mg-1200 mg, 100 mg-800 mg, 200-800 mg or 400 mg-600 mg each time, administered continuously daily (e.g., once a day) for one or more dosing cycles; optionally, one dosing cycle is every 28 days.
  • the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition is administered as follows: 100 mg-1200 mg, 100 mg-800 mg or 200-800 mg each time, once a day, orally for one or more administration cycles; optionally, one administration cycle is every 28 days.
  • the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition is administered as follows: 20-1200 mg, 100-1200 mg, 100-800 mg, 300-600 mg or 400-600 mg each time, administered continuously daily (e.g., once a day) for one or more dosing cycles; optionally, every 8-32 days (e.g., every 28 days) is a dosing cycle.
  • the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition is administered as follows: 20-1200 mg, 100-1200 mg, 100-800 mg, 300-600 mg or 400-600 mg each time, administered once a day continuously; optionally, one administration cycle is 28 days.
  • the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition is administered in a dosage of 100-1200 mg or 100-800 mg once a day for one or more oral administration cycles; optionally, one administration cycle is 28 days.
  • the administration of the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition may be 2-40 administration cycles, for example 4-10 or 8-20 administration 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 administration cycles, and even 2-40 or more administration cycles as needed.
  • the administration of the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition is repeated until the subject can no longer benefit, the disease progresses, or an intolerable toxic reaction occurs.
  • the treatment cycle of the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition is 2-40 dosing cycles, such as 4-10 or 8-20 dosing cycles, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 dosing cycles.
  • the treatment cycle of the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition is when the above-mentioned dosing cycle is repeated until the subject can no longer benefit, the disease progresses, or an intolerable toxic reaction occurs.
  • the daily or each dose of the compound of Formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition is a treatment dose.
  • the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition is administered as a single agent; optionally, it can be used in combination with other agents.
  • a pre-dosing incremental cycle (also referred to as an introduction period) is also included.
  • the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition is administered with at least one gradient incremental dose (hereinafter also referred to as "gradient dose"), wherein the first gradient dose in the at least one gradient dose is lower than the dose in the dosing cycle.
  • the at least one gradient dose may include a first gradient dose and another gradient dose.
  • the last gradient dose is less than or equal to the dose used in the dosing cycle.
  • the gradient dose is administered with the same administration method and frequency of administration as the dose in the dosing cycle.
  • the introduction period is not included in the dosing cycle, i.e., the treatment cycle (the administration within the treatment cycle is the therapeutic dose).
  • the difference between each gradient dose can be the same or different.
  • 1-14 gradient doses may be included, for example 1,2,3,4,5,6,7,8,9,10,11,12,13 or 14 gradient doses.
  • the first increasing dose can be selected from: 10 mg, 20 mg, 50 mg or 100 mg.
  • each increasing dose can be administered for 1-10 days, for example, for 1, or continuously administered for 2-10 days.
  • the subject before the subject receives administration or treatment according to the application, the subject is applied in advance to the subject with a daily or weekly gradient increasing dose of the present application of the formula I-1 compound or its pharmaceutically acceptable salt or its pharmaceutical composition.
  • a specific dose e.g., 100mg, 200mg, 400mg, 600mg, 800mg or 1200mg
  • the subsequent administration cycle is performed, such as daily administration of a therapeutic dose (e.g., 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 700mg, 800mg or 1200mg) of the formula I-1 compound or its pharmaceutically acceptable salt or its pharmaceutical composition.
  • the subject has leukemia, such as acute myeloid leukemia.
  • the administration of a therapeutic dose refers to the administration of the present application of the formula I-1 compound or its pharmaceutically acceptable salt or its pharmaceutical composition in the administration cycle in the manner of a therapeutic dose with the dosage defined above.
  • the subject before the subject receives administration or treatment according to the application, the subject is applied in advance to the subject daily or weekly gradient increasing dose of the present application of formula I-1 compound or its pharmaceutically acceptable salt or its pharmaceutical composition.
  • a specific dose e.g., 50mg, 100mg, 200mg, 400mg, 600mg, 800mg or 1200mg
  • the dosing cycle is followed up, such as daily administration of a therapeutic dose (e.g., 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or 1200mg) of formula I-1 compound or its pharmaceutically acceptable salt or its pharmaceutical composition.
  • the subject has lymphoid tumors, including non-Hodgkin's lymphoma.
  • the duration of the administration of daily gradient increasing doses is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days or the duration of the range formed by any of the above values. In some embodiments, the duration of the administration of daily gradient increasing doses is 2-10 or 3-4 or 5-7 days.
  • the subject is administered a gradient increasing dose of the compound of formula I-1 of the present application or a pharmaceutically acceptable salt thereof before receiving the dose (e.g., therapeutic dose) of the administration cycle.
  • the gradient increasing dose includes changing a dose every 1 day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days or every week (7 days) for a gradient increasing dose.
  • the gradient increasing dose includes changing a dose every 1 day for a gradient increasing dose.
  • the gradient increasing dose includes at least one of the following: 20mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg or 800mg. In some embodiments, the gradient increasing dose includes at least one of the following: 20mg, 50mg, 100mg, 200mg, 400mg, 600mg or 800mg. In some embodiments, the gradient increasing dose includes 20mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg or 800mg. In some embodiments, the gradient increasing dose includes 20mg, 50mg, 100mg, 200mg, 400mg, 600mg or 800mg.
  • the first gradient dose of the gradient increasing dose is selected from 10mg, 20mg, 50mg or 100mg.
  • the second gradient dose of the gradient increasing dose is selected from 20mg, 50mg, 100mg or 200mg.
  • the gradient increasing dose also includes a third gradient dose.
  • the third gradient dose of the gradient increasing dose is selected from 50mg, 100mg, 200mg or 400mg.
  • the gradient increasing dose also includes a fourth gradient dose.
  • the gradient increasing dose also includes a fourth gradient dose, which is selected from 100mg, 200mg, 400mg or 600mg.
  • the gradient increasing dose also includes a fifth gradient dose.
  • the gradient increasing dose also includes a fifth gradient dose, which is selected from 200mg, 400mg, 600mg or 800mg.
  • the dosage of the dosing cycle or the therapeutic dose comprises 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1200 mg.
  • the first gradient dose of the gradient increasing dose is selected from 20 mg.
  • the second gradient dose of the gradient increasing dose is selected from 50 mg.
  • the gradient increasing dose also includes a third gradient dose.
  • the third gradient dose of the gradient increasing dose is selected from 100 mg.
  • the gradient increasing dose also includes a fourth gradient dose.
  • the gradient increasing dose also includes a fourth gradient dose, which is selected from 200 mg.
  • the gradient increasing dose also includes a fifth gradient dose.
  • the gradient increasing dose also includes a fifth gradient dose, which is selected from 400 mg.
  • the gradient increasing dose also includes a sixth gradient dose.
  • the gradient increasing dose also includes a sixth gradient dose, which is selected from 600 mg. In some embodiments, optionally, the gradient increasing dose also includes a seventh gradient dose. In some embodiments, optionally, the gradient increasing dose also includes a seventh gradient dose, which is selected from 800 mg. In some embodiments, administration or treatment includes or does not include a lead-in period, for example, when it does not include a lead-in period, the treatment period dose is 100 mg.
  • the first gradient dose of the gradient increasing dose is selected from 100 mg.
  • the second gradient dose of the gradient increasing dose is selected from 200 mg.
  • the gradient increasing dose also includes a third gradient dose.
  • the third gradient dose of the gradient increasing dose is selected from 400 mg.
  • the dose of the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition used in the dosing cycle is subsequently administered in a fixed dose mode (i.e., therapeutic dose) every day for treatment.
  • the dose used in the dosing cycle is as defined above, for example, the therapeutic dose can be selected from 100 mg-400 mg or 100 mg-800 mg.
  • the second gradient dose for example, 50 mg, completes the pre-dosing increment cycle, and then 100 mg is administered in the dosing cycle in a fixed dose mode;
  • the third gradient dose for example, 100 mg, completes the pre-dosing increment cycle, and then the fixed dose mode is used in the dosing cycle.
  • 200 mg is administered during the medication cycle;
  • the fourth gradient dose such as 200 mg, completes the pre-dosing escalation cycle, and subsequently 400 mg is administered during the medication cycle in a fixed dose mode.
  • the therapeutic dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof during the administration cycle is selected from 100 mg, 200 mg, 400 mg, 600 mg, 800 mg or 1200 mg; in some embodiments, selected from 100 mg, 200 mg, 400 mg, 600 mg or 800 mg.
  • the subject is treated with a daily or weekly gradient increasing dose of the formula I-1 compound of the present application or a pharmaceutically acceptable salt thereof before receiving a dosing cycle (e.g., a fixed dose pattern).
  • a dosing cycle is performed, such as a daily administration of a therapeutic dose (e.g., 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, or 1200 mg) of a formula I-1 compound or a pharmaceutically acceptable salt thereof.
  • the subject is administered a daily or weekly gradient increasing dose of the present application's formula I-1 compound or its pharmaceutically acceptable salt to the subject before receiving the treatment of the administration cycle (e.g., fixed dose mode).
  • a specific dose e.g., 50mg, 100mg, or 200mg
  • the subsequent administration cycle is performed, for example, the corresponding daily administration treatment dose is 100mg, 200mg, and 400mg of the formula I-1 compound or its pharmaceutically acceptable salt.
  • the daily gradient increasing dose includes: 20mg is applied on the first day, 50mg is applied on the second day, and 100mg is applied on the third day.
  • the daily gradient increasing dose includes: 20mg is applied on the first day, 50mg is applied on the second day, 100mg is applied on the third day, and 200mg is applied on the fourth day. In some embodiments, the daily gradient increasing dose includes: 20mg is applied on the first day, 50mg is applied on the second day, 100mg is applied on the third day, and 200mg is applied on the fourth day. In some embodiments, the daily gradient increasing dose includes: 20mg is applied on the first day, 50mg is applied on the second day, 100mg is applied on the third day, 200mg is applied on the fourth day, and 400mg is applied 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.
  • the daily gradient increasing dose includes: 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 gradient increasing dose includes: 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 gradient increasing dose includes: 100 mg on the first day. In some embodiments, the daily gradient increasing dose includes: 100 mg on the first day, 200 mg on the second day.
  • the daily gradient increasing dose includes: 100 mg on the first day, 200 mg on the second day, and 400 mg on the third day. In some embodiments, the daily gradient increasing dose includes: 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 gradient increasing dose includes: 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.
  • the daily gradient increasing dose includes: 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 gradient increasing dose includes: 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 gradient increasing dose includes: 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.
  • treatment in subsequent dosing cycles uses a therapeutic dose of a compound of Formula 1-1 or a pharmaceutically acceptable salt thereof.
  • the daily escalating dose comprises: 100 mg on the first day; optionally, 100 mg or 200 mg is administered daily in subsequent dosing cycles.
  • the daily escalating dose comprises: 100 mg on the first day, 200 mg on the second day.
  • 400 mg is administered daily in subsequent dosing cycles.
  • the daily escalating dose includes: 100 mg on the first day, 200 mg on the second day, and 400 mg on the third day.
  • the subsequent dosing cycle of treatment is 600 mg or 800 mg per day.
  • the daily gradient increasing dose includes: 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 gradient increasing dose includes: 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.
  • the daily gradient increasing dose includes: 50 mg on the first day. In some embodiments, the daily gradient increasing dose includes: 50 mg on the first day, 100 mg on the second day. In some embodiments, the daily gradient increasing dose includes: 50 mg on the first day, 100 mg on the second day, and 200 mg on the third day. In some embodiments, the daily gradient increasing dose includes: 50 mg on the first day, 100 mg on the second day, and 200 mg on the third day. Increased doses include: 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.
  • the duration of the application of the weekly gradient increasing dose is 1, 2, 3, 4, 5, 6 or 7 weeks or the duration of the range formed by any of the above values. In some embodiments, the duration of the application of the weekly gradient increasing dose is 2-5 or 2-3 or 3-4 weeks. In some embodiments, the duration of the application of the weekly gradient increasing dose is 4 weeks.
  • the weekly gradient increasing dose includes: 20 mg is applied every day in the first week, 50 mg is applied every day in the second week, 100 mg is applied every day in the third week, and 200 mg is applied every day in the fourth week.
  • the administration cycle is started in the fifth week and thereafter, for example, a therapeutic dose of 400-600 mg (such as 400 mg, 500 mg or 600 mg) is applied every day.
  • the weekly gradient increasing dose includes: 10 mg is applied every day in the first week, 20 mg is applied every day in the second week, 50 mg is applied every day in the third week, 100 mg is applied every day in the fourth week, and 200 mg is applied every day in the fifth week.
  • the administration cycle is carried out in the sixth week and thereafter, for example, a therapeutic dose of 200 mg-600 mg (such as 200 mg, 300 mg, 400 mg, 500 mg or 600 mg) is applied every day.
  • the daily or weekly escalating dose of the compound of Formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition is a lead-in dose.
  • the method for treating hematological tumors provided herein comprises:
  • the method for treating hematological tumors provided herein comprises:
  • the treatment includes inhibiting, reducing the severity, reducing the risk, or inhibiting the metastasis of a hematological tumor in the patient.
  • 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.
  • 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 its pharmaceutically acceptable salt, hydrate and prodrug, wherein the prodrug can be converted into the free base form of the compound of formula I-1 in vivo.
  • composition of the compound of formula I-1 or a pharmaceutically acceptable salt thereof of the present application comprises the compound of formula I-1 or a pharmaceutically acceptable salt thereof, and further contains a pharmaceutically acceptable excipient.
  • the compound of formula I-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition 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 its pharmaceutically acceptable salt, or its pharmaceutical composition.
  • the compound of formula I-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg, 1600mg, 1700mg, 1800mg, 1900mg or 2000mg, or any value of the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition in the range formed by any of the above values.
  • the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 100-1200mg of the formula I-1 compound or its pharmaceutically acceptable salt, or its pharmaceutical composition. In some embodiments, the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 200-1000mg of the formula I-1 compound or its pharmaceutically acceptable salt, or its pharmaceutical composition. In some embodiments, the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 10-800mg or 20mg-800mg of the formula I-1 compound or its pharmaceutically acceptable salt, or its pharmaceutical composition.
  • the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 10-300mg, 20-400mg, 20-200mg or 20-100mg of the formula I-1 compound or its pharmaceutically acceptable salt, or its pharmaceutical composition.
  • the compound of formula I-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition 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 its pharmaceutically acceptable salt. Salt, or its pharmaceutical composition.
  • the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, 1000mg or 1200mg of the formula I-1 compound or its pharmaceutically acceptable salt, or its pharmaceutical composition.
  • the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 100-800mg of the formula I-1 compound or its pharmaceutically acceptable salt, or its pharmaceutical composition.
  • the formula I-1 compound of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 300-600mg or 400-600mg of the formula I-1 compound or its pharmaceutically acceptable salt, or its pharmaceutical composition.
  • the compound of formula I-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 200 mg, 300 mg, 400 mg, 500 mg or 600 mg of the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition.
  • the compound of formula I-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 50mg-800mg of the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition. In some embodiments, the compound of formula I-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 100mg-800mg of the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition. In some embodiments, the compound of formula I-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 100mg-600mg of the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition.
  • the compound of formula I-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 50mg-400mg (such as 50mg, 100mg, 200mg, 300mg or 400mg) of the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition.
  • the compound of formula I-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 100mg-400mg (such as 100mg, 200mg or 400mg) of formula I-1 compound or its pharmaceutically acceptable salt, or its pharmaceutical composition.
  • the compound of formula I-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 100mg-200mg of formula I-1 compound or its pharmaceutically acceptable salt, or its pharmaceutical composition. In some embodiments, the compound of formula I-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 200mg, 400mg, 600mg or 800mg of formula I-1 compound or its pharmaceutically acceptable salt, or its pharmaceutical composition.
  • the pharmaceutical composition of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof is selected from solid pharmaceutical compositions, including but not limited to tablets or capsules.
  • the pharmaceutical composition of the compound of formula I-1 or its pharmaceutically acceptable salt is a pharmaceutical composition with a single dose of 5mg-500mg, preferably 10mg-200mg, and most preferably 10mg-100mg.
  • a pharmaceutical composition selected from a single dose of 5mg, 10mg, 15mg, 20mg, 50mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, or 500mg or any value in the range formed by any of the above values.
  • the single dose of the pharmaceutical composition containing the compound of formula I-1 or its pharmaceutically acceptable salt is selected from 10mg, 50mg or 100mg.
  • the pharmaceutical composition containing the compound of formula I-1 or a pharmaceutically acceptable salt thereof is a multi-dose pharmaceutical composition, and the multi-dose may be composed of multiple single-dose pharmaceutical compositions containing the compound of formula I-1 or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition containing the compound of formula I-1 or a pharmaceutically acceptable salt thereof is a multi-dose pharmaceutical composition, and the multi-dose may be composed of a single dose of 10 mg, 50 mg or 100 mg of a pharmaceutical composition containing the compound of formula I-1 or a pharmaceutically acceptable salt thereof.
  • 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.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • an ethyl group is "optionally" substituted with a halogen, which means that the ethyl group may be unsubstituted ( -CH2CH3 ) , monosubstituted (such as -CH2CH2F ), polysubstituted (such as -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, no substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will be introduced.
  • C mn means that the moiety has an integer number of carbon atoms in a given range.
  • C 1-6 means that the group may have 1 carbon atom. , 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • alkyl refers to a hydrocarbon group of the general formula CnH2n +1 .
  • the alkyl group may be straight-chain or branched.
  • C1-6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • C1-4 alkyl refers to an alkyl group containing 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.).
  • cycloalkyl refers to a fully saturated carbocyclic ring that 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 include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, etc.
  • heterocycloalkyl refers to 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 ring containing 1 to 3 (preferably 1 or 2) heteroatoms independently selected from sulfur, oxygen and/or nitrogen, such as a 4 to 6 ring or a 5 to 6 ring.
  • the dosages and ranges provided herein for compounds of formula I-1, such as compounds of formula I, or pharmaceutically acceptable salts thereof, are calculated based on the molecular weight of the free base of the compound of formula I-1, such as compounds of formula I.
  • administering means 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 skilled in the art.
  • administering or “giving” or “administration” are used interchangeably herein.
  • treat generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be therapeutic in terms of partial or complete stabilization or cure of a disease and/or side effects resulting from a disease.
  • "treat” encompasses any treatment of a patient's disease that: (a) inhibits the symptoms of a disease, i.e., arrests its development; or (b) alleviates the symptoms of a disease, i.e., causes regression of the disease or symptoms.
  • an effective amount means an amount of the compound of the present application that (i) treats or prevents a specific disease, condition or disorder, (ii) alleviates, ameliorates or eliminates one or more symptoms of a specific disease, condition or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition or disorder described herein.
  • the amount of the compound of the present application that constitutes a “therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.
  • subject refers to an animal, preferably a mammal, preferably a primate, including humans and non-human primates (such as apes, monkeys, orangutans and chimpanzees, such as cynomolgus monkeys, spider monkeys and macaques, such as rhesus monkeys), that has been the subject of treatment, observation or experiment, and most preferably humans.
  • the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.
  • the compound of formula I-1 can be administered by any suitable route and method, such as by oral or parenteral (eg, intravenous) administration.
  • composition refers to a mixture of one or more compounds of the present application or their drug combination or salts and pharmaceutically acceptable excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application or their drug combination to a subject.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid preparations such as tablets, pills, capsules, etc.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which 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 problems or complications, commensurate with a reasonable benefit/risk ratio.
  • Solid oral pharmaceutical compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then The mixture is processed into granules to obtain the core of tablets, capsules or sugar-coated tablets.
  • Suitable auxiliary materials include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • pharmaceutically acceptable salt or “pharmaceutically usable salt” refers to salts of the compounds of the present application within the definition of “pharmaceutically acceptable”.
  • single dose refers to the smallest packaging unit containing a certain amount of medicine, for example, if a box of medicine contains seven capsules, each capsule is a single dose; or each bottle of injection is a single dose.
  • multiple dose consists of multiple single doses.
  • the pharmaceutical combination of the present application can be formulated into a pharmaceutical composition suitable for single or multiple administrations.
  • the pharmaceutical combination of the present application can be a single-dose or multi-dose pharmaceutical composition.
  • first-line therapy refers to the first treatment given to a disease. It is usually part of a group of standard treatments, such as surgery followed by chemotherapy and radiation therapy. When used alone, first-line therapy is generally considered the best treatment. If it does not cure the disease or causes serious side effects, other treatments may be added or used.
  • second-line therapy refers to treatment given when the initial treatment (first-line treatment) is ineffective or stops working. The same can be said for third-line or more-line treatments.
  • day When referring to a dosing regimen, the terms "day,” “daily,” and the like refer to the times within a calendar day, beginning at midnight and ending at the following midnight.
  • refractory refers to a subject or mammal that does not respond to, or has an inadequate response to, an anti-cancer treatment.
  • AE adverse event
  • NCI-CTC AE v5.0 Common Toxicity Criteria of the National Cancer Institute of the United States
  • OS refers to the overall survival time of tumor patients.
  • DFS refers to the disease-free survival of cancer patients.
  • SAE refers to serious adverse event.
  • TEAEs treatment-emergent adverse events.
  • the treatment scheme of the present application has good efficacy in treating hematological tumors.
  • the formula I-1 compound described in the present application such as a formula I compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, has excellent effects in at least one of the objective response rate (ORR), complete remission (CR) rate, median duration of remission (DOR), median progression-free survival (PFS), EFS (median event-free survival), and median overall survival (OS), such as ORR, CR, CRi, partial remission (PR), and partial remission (PR-L) with increased lymphocytes.
  • ORR objective response rate
  • CR complete remission
  • DOR median duration of remission
  • PFS median progression-free survival
  • OS median overall survival
  • ORR ORR
  • CR complete remission
  • PR partial remission
  • PR-L partial remission
  • CR CR
  • CR and minimal residual disease negative CR MRD-
  • CRi CR with incomplete blood cell count recovery
  • MLFS morphological leukemia-free state
  • CRh CR with incomplete blood recovery
  • CRp CR with incomplete platelet recovery
  • PR PR
  • the compounds of formula I-1 described in the present application such as compounds of formula I or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, have good drug tolerance in patients, low therapeutic doses, and a short required introduction period; have small side effects, including small effects on cardiovascular function, respiratory system, and central nervous system, for example, related adverse events (TRAEs) are mainly hematological adverse events and abnormal laboratory test values, mostly grade 1-2; and can effectively reduce the risk of tumor lysis syndrome (TLS).
  • TLS tumor lysis syndrome
  • the compound of formula I-1 e.g., compound of formula I
  • a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application has good pharmaceutical value, and can benefit patients who have received (including first-line, second-line, third-line or fourth-line) or have not received treatment in the past.
  • AML acute myeloid leukemia
  • ENN European Leukemia Network
  • CLL Chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • NCL non-Hodgkin lymphomas
  • Objective response rate is calculated using the following method:
  • SLL, MCL and DLBCL the proportion of objective response cases (CR+PR) to the total number of cases
  • CLL the proportion of objective response cases (CR+CRi+PR+PR-L) to the total number of cases
  • AML the proportion of objective response cases (CR+CRi+MLFS+PR) to the total number of cases.
  • SLL, MCL and DLBCL the proportion of complete remission (CR) cases to the total number of cases
  • CLL the proportion of complete remission cases (CR+CRi) to the total number of cases
  • AML the proportion of complete remission cases (CR+CRi) or (CR+CRh) to the total number of cases.
  • PFS Median progression-free survival
  • EFS median event-free survival
  • OS median overall survival
  • the compound of formula I-1 for example, the compound of formula I, can be prepared by referring to the method disclosed in WO2020088442A1.
  • Compound of formula I specifications: 10 mg, 100 mg, tablets.
  • At least 1 lesion/measurable disease that can be evaluated for efficacy.
  • the compound of formula I tablets are taken orally with warm water within 30 minutes after starting a meal, 20 mg to 1200 mg each time, once a day, and 28 days as a dosing cycle.
  • the length of the lead-in period will depend on the treatment dose level.
  • the day when the treatment dose level is reached is considered C1D1 of the treatment period.
  • the NHL patient lead-in period is as follows. The following are all given orally once a day in a daily increasing manner, and the last dose is the therapeutic dose:
  • 200 mg dose group 20 mg ⁇ 50 mg ⁇ 100 mg ⁇ 200 mg
  • 400 mg dose group 20 mg ⁇ 50 mg ⁇ 100 mg ⁇ 200 mg ⁇ 400 mg
  • 600 mg dose group 20 mg ⁇ 50 mg ⁇ 100 mg ⁇ 200 mg ⁇ 400 mg ⁇ 600 mg
  • 1200mg dosage group 20mg ⁇ 50mg ⁇ 100mg ⁇ 200mg ⁇ 400mg ⁇ 600mg ⁇ 800mg ⁇ 1200mg.
  • the lead-in period for AML patients was as follows. All of the following were given orally once a day in a daily increasing manner, with the last dose being the treatment dose:
  • 200 mg dose group 100 mg ⁇ 200 mg
  • 400 mg dose group 100 mg ⁇ 200 mg ⁇ 400 mg
  • 600 mg dose group 100 mg ⁇ 200 mg ⁇ 400 mg ⁇ 600 mg
  • 800mg dosage group 100mg ⁇ 200mg ⁇ 400mg ⁇ 800mg.
  • Effectiveness indicators include CR rate, ORR, DOR, PFS, OS, etc.
  • Adverse events The occurrence of all adverse events (AEs), serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs), including, for example, the grade of adverse reactions, the overall incidence of adverse events, etc.
  • SAEs serious adverse events
  • TEAEs treatment-emergent adverse events
  • the adverse events (TRAEs) associated with the compound of formula I were mainly hematological adverse events and abnormal laboratory test values, most of which were grade 1-2.
  • the ORR was 25% to 65%, and the CR rate was 25% to 55%.
  • the ORR was 56% to 70%, and the CR rate was 44% to 60%.
  • the ORR was 45% to 68%, and the CR rate was 15% to 50%.
  • the ORR was 45% to 68%, and the CR rate was 14% to 50%.
  • the ORR was 89% to 95%, and the CR rate was 45% to 55%.
  • the ORR was 89% to 95%, and the CR rate was 44% to 55%.
  • the ORR was 40% to 60%, and the CR rate was 40% to 50%.
  • the ORR was 40% to 60%, and the CR rate was 40% to 50%.
  • the number of complete remission cases/(number of objective remission cases + number of complete remission cases) reached 27%; among the evaluated CLL/SLL patients, the number of complete remission cases/(number of objective remission cases + number of complete remission cases) reached 50%; among the evaluated AML patients, the number of complete remission cases/(number of objective remission cases + number of complete remission cases) reached 71%.
  • Patients who have received previous treatment can all show benefits (for example, they can show benefits for a longer period of time, have good efficacy and low side effects).

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Abstract

本申请属于医药领域，涉及含有三氟甲基的化合物在治疗血液肿瘤中的应用，具体的涉及式I-1化合物或其药学上可接受的盐在治疗血液肿瘤中的用途。

Description

含有三氟甲基的化合物在治疗血液肿瘤中的应用
相关申请的引用
本申请要求于2023年4月20日向中华人民共和国国家知识产权局提交的第202310429276.0号中国专利申请的优先权和权益以及于2023年4月20日向中华人民共和国国家知识产权局提交的第202310426190.2号中国专利申请的优先权和权益，在此将其全部内容以援引的方式整体并入文本中。
技术领域
本申请属于医药领域，涉及含有三氟甲基的化合物在治疗血液肿瘤中的应用，具体的涉及式I-1化合物或其可药用盐在治疗血液肿瘤中的用途。
背景技术
BCL-2蛋白分为三个家族：BCL-2家族(其家族成员包括BCL-2、BCL-XL等)、BAX家族和BH3-only家族，其中BCL-2家族起着抗细胞凋亡的作用，后两个家族的成员起着促细胞凋亡的作用。
抗细胞凋亡BCL-2族蛋白与许多疾病有关并且正研究作为潜在的治疗药物目标。用于介入疗法的这些目标包括，例如，BCL-2族蛋白BCL-2和BCL-XL等。BCL-2族蛋白的抑制剂是对靶蛋白结合的抑制剂，化合物结合亲合力仅仅是许多待考虑的参数之一，一个目标是产生这样的化合物：其相对于另一种蛋白，优先地结合到一种蛋白，即对其的选择性。为显示这种选择性，周知的是化合物显示对特定的蛋白的高结合亲合力，以及对另一成员的较低的结合亲合力。
选择性抑制BCL-2蛋白的化合物可以用于治疗过度增生性疾病，例如肿瘤。例如WO2019185025、WO2020088442、WO2020238785公开了作为BCL-2抑制剂的化合物或其可药用盐。
发明内容
一方面，本申请提供治疗血液肿瘤的方法，包括向受试者施用治疗有效量的BCL-2抑制剂或其可药用盐、或其药物组合物。
另一方面，本申请提供BCL-2抑制剂或其可药用盐、或其药物组合物在制备用于治疗血液肿瘤的药物中的用途。本申请还提供用于治疗血液肿瘤的BCL-2抑制剂或其可药用盐、或其药物组合物。本申请还提供本申请的BCL-2抑制剂或其可药用盐、或其药物组合物用于治疗血液肿瘤的用途。
再一方面，本申请还提供用于治疗血液肿瘤的药物组合物，所述药物组合物包含BCL-2抑制剂或其可药用盐作为活性成分。
在一些实施方案中，本申请还提供用于治疗血液肿瘤的试剂盒，其中包含：含有BCL-2抑制剂或其可药用盐的药物组合物；任选地，还包含所述BCL-2抑制剂或其可药用盐的药物组合物的使用说明。在一些实施方案中，所述使用说明是指导向受试者施用所述包含BCL-2抑制剂或其可药用盐的药物组合物。
在一些实施方案中，本申请所述的BCL-2抑制剂或其可药用盐选自式I-1化合物或其可药用盐，
R1选自氢、卤素或C1-6烷基；
环A选自5-6元杂环烷基，
R2分别独立地选自4-6元杂环烷基、C3-6环烷基、-CORa、-SO2Rb、或任选地被卤素取代的C1-6烷基；
Ra或Rb分别独立地选自H、4-6元杂环烷基、C3-6环烷基、或C1-6烷基，所述C1-6烷基任选地被卤素、-CN、-N(C1-6烷基)2、-NHC1-6烷基、或-OC1-6烷基取代；
m选自0、1、2或3。
在一些实施方案中，结构片段选自
在一些实施方案中，R1选自氢、卤素或C1-3烷基。在一些实施方案中，R1选自氢、氟、氯或甲基。在一些实施方案中，R1选自氢、氯或甲基。
在一些实施方案中，环A选自6元杂环烷基。在一些实施方案中，环A选自含一个或多个O原子的6元杂环烷基，例如含1或2个O原子的6元杂环烷基。在一些实施方案中，环A选自二氧六环或吡喃环。
在一些实施方案中，R2分别独立地选自4-6元杂环烷基、C4-6环烷基、-CORa、-SO2Rb、或任选地被卤素取代的C1-4烷基。
在一些实施方案中，Ra或Rb分别独立地选自H、4-6元杂环烷基、C3-6环烷基、或C1-4烷基，所述C1-4烷基任选地被卤素、-CN、-N(C1-4烷基)2、-NHC1-4烷基、或-OC1-4烷基取代。
在一些实施方案中，R2分别独立地选自-C(O)H、-COC(CH3)3、-COCF3、-COCH2CN、-COCH2N(CH3)2、-SO2CH2CH3、-SO2CF3、-SO2C2F5、-CF3、-C2F5、四氢吡喃、单氧杂环丁烷、-SO2-环丙烷、-CO-环丙烷、-CO-单氧杂环丁烷、-SO2-单氧杂环丁烷、或-SO2-环丁烷。
在一些实施方案中，m选自0或1。
在一些实施方案中，本申请所述的BCL-2抑制剂或其可药用盐选自式I、式II、式III、或式IV化合物或其可药用盐，
在一些实施方案中，所述BCL-2抑制剂或其可药用盐选自式I化合物或其可药用盐；或者选自式II化合物或其可药用盐；或者，选自式III化合物或其可药用盐；或者选自式IV化合物或其可药用盐。
在一些实施方案中，所述式I-1化合物或其可药用盐选自式I化合物或其可药用盐。在一些实施方案中，所述式I-1化合物或其可药用盐选自式II化合物或其可药用盐。在一些实施方案中，所述式I-1化合物或其可药用盐选自式III化合物或其可药用盐。在一些实施方案中，所述式I-1化合物或其可药用盐选自式IV化合物或其可药用盐。
血液肿瘤
在一些实施方案中，所述血液肿瘤选自晚期血液肿瘤。在一些实施方案中，所述血液肿瘤选自复发和/或难治的血液肿瘤。在一些实施方案中，所述血液肿瘤选自复发和/或难治的晚期血液肿瘤。
在一些实施方案中，所述血液肿瘤选自经组织学或细胞学明确诊断的血液肿瘤。在一些实施方案中，上述诊断符合WHO的2016诊断标准。
在一些实施方案中，所述血液肿瘤选自淋巴类肿瘤或白血病。
在一些实施方案中，所述血液肿瘤选自淋巴类肿瘤或髓系白血病。在一些实施方案中，所述淋巴类肿瘤选自非霍奇金淋巴瘤。在一些实施方案中，所述髓系白血病为急性髓系白血病。
在一些实施方案中，所述血液肿瘤选自非霍奇金淋巴瘤或急性髓系白血病。在一些实施方案中，所述非霍奇金淋巴瘤选自套细胞淋巴瘤、弥漫大B细胞淋巴瘤、慢性淋巴细胞白血病和/或小淋巴细胞性淋巴瘤。
在一些实施方案中，所述血液肿瘤选自套细胞淋巴瘤、弥漫大B细胞淋巴瘤、慢性淋巴细胞白血病和/或小淋巴细胞性淋巴瘤、或急性髓系白血病。
在一些实施方案中，所述血液肿瘤选自白血病。
在一些实施方案中，所述血液肿瘤选自髓系白血病。
在一些实施方案中，所述血液肿瘤或白血病选自急性髓系白血病。
在一些实施方案中，所述血液肿瘤选自淋巴类肿瘤。
在一些实施方案中，所述血液肿瘤选自非霍奇金淋巴瘤。
在一些实施方案中，所述血液肿瘤或非霍奇金淋巴瘤选自套细胞淋巴瘤、弥漫大B细胞淋巴瘤、慢性淋巴细胞白血病和/或小淋巴细胞性淋巴瘤。
在一些实施方案中，所述血液肿瘤的受试者可为未接受过在先治疗方案的治疗的受试者。在一些实施方案中，所述血液肿瘤的受试者已接受过一种或两种以上在先治疗方案的治疗。在一些实施方案中，所述血液肿瘤的受试者已接受过一种、两种、三种、四种、或五种在先治疗方案的治疗。
在一些实施方案中，所述血液肿瘤的受试者选自复发或难治的受试者。在一些实施方案中，所述血液肿瘤的受试者选自具有初始诱导或再诱导治疗难治性疾病的受试者。在一些实施方案中，所述血液肿瘤的受试者选自既往接受治疗后复发或治疗失败的受试者。在一些实施方案中，所述血液肿瘤的受试者选自既往接受标准治疗后复发或治疗失败的受试者。在一些实施方案中，所述血液肿瘤的受试者选自既往治疗失败的受试者。在一些实施方案中，所述血液肿瘤的受试者选自采用标准治疗后失败的受试者。在一些实施方案中，所述血液肿瘤的受试者选自对既往治疗方案不耐受的受试者。在一些实施方案中，所述血液肿瘤的受试者选自对标准治疗方案不耐受的受试者。在一些实施方案中，所述血液肿瘤的受试者选自对既往治疗方案不耐受，且没有其他更好治疗选择的受试者。在一些实施方案中，所述血液肿瘤的受试者选自对标准治疗方案不耐受，且没有其他更好治疗选择的受试者。
在一些实施方案中，所述血液肿瘤的受试者选自既往至少接受过1种全身系统性治疗方案，最近一次治疗期间或完成后存在疾病进展或不耐受，或经充分治疗后没有出现缓解的受试者。在一些实施方案中，所述血液肿瘤的受试者选自既往至少接受过1种或2种全身系统性治疗方案，最近一次治疗期间或完成后存在疾病进展或不耐受，或经充分治疗后没有出现缓解的受试者。
在一些实施方案中，所述既往接受过的治疗方案包括一线治疗方案、二线治疗方案、和/或三线治疗方案。
在一些实施方案中，所述血液肿瘤的受试者具有至少1个可进行疗效评估的病灶/可测量疾病。
在一些实施方案中，急性髓系白血病受试者存在骨髓原始细胞。在一些实施方案中，急性髓系白血病受试者的骨髓原始细胞≥5％。
在一些实施方案中，所述非霍奇金淋巴瘤受试者具有经CT或MRI评估，在2个垂直方向至少存在一个影像学可测量的肿瘤病灶(例如结内病灶长径＞15mm，结外病灶长径＞10mm)。
在一些实施方案中，所述血液肿瘤的受试者既往未接受过BCL-2抑制剂治疗。在一些实施方案中，所述BCL-2抑制剂包括但不限于维奈托克或pelcitoclax。
在一些实施方案中，可选地，所述血液肿瘤的受试者存在如下合并疾病：
对于首次用药前3年内出现过或当前同时患有其它恶性肿瘤，所述肿瘤患者可以是经单一手术治疗的其他恶性肿瘤，达到连续5年的无疾病生存(DFS)的肿瘤患者；
或者，所述肿瘤或晚期恶性肿瘤的患者可以是治愈的子宫颈原位癌、非黑色素瘤的皮肤癌和表浅的膀胱肿瘤(包括但不限于Ta(非浸润性肿瘤)、Tis(原位癌)和T1(肿瘤浸润基膜))的患者。
在一些实施方案中，所述血液肿瘤的受试者不存在以下任一种或多种情况：
1)经诊断为Burkitt淋巴瘤、淋巴母细胞淋巴瘤/白血病的患者；和/或，
2)中枢神经系统(CNS)侵犯；和/或，
3)既往接受过异基因造血干细胞移植；和/或，
4)由于任何既往治疗引起的≥CTC AE 1级的未缓解的毒性反应，不包括脱发；和/或，
5)存在活跃或未控制的原发性自身免疫性血细胞减少症，包括自身免疫性溶血性贫血(AIHA)、特发性血小板减少性紫癜(ITP)等；和/或，
6)首次用药前6个月内发生过动/静脉血栓事件；和/或，
7)存在任何重度和/或未能控制的疾病的患者；和/或，
8)首次用药前4周内曾接受过化疗、放疗或首次用药前12周接受过免疫检查点抑制剂、CAR-T治疗，首次用药前接受的其它抗肿瘤治疗(从末次治疗结束时间开始计算洗脱期)在5个半衰期内；和/或，
9)既往接受过BCL-2抑制剂。
在一些实施方案中，上述6)中所述首次用药前6个月内发生过动/静脉血栓事件可选地是指脑血管意外(包括但不限于暂时性缺血性发作、脑出血、脑梗塞)、深静脉血栓及肺栓塞等。
在一些实施方案中，上述7)中存在任何重度和/或未能控制的疾病的患者包括：1.首次用药前6个月内患有≥2级心肌缺血或心肌梗塞、心律失常(男性QTc>450ms，女性QTc>470ms)及≥2级充血性心功能衰竭(纽约心脏病协会(NYHA)分级)；2.存在活动性的严重感染(≥CTC AE 2级感染)，心脏彩超评估左室射血分数(LVEF)<50％；3.活动性肝炎；4.有免疫缺陷病史，包括HIV阳性或患有其它获得性、先天性免疫缺陷疾病，或有器官移植史者；5.患有癫痫并需要治疗者。
急性髓系白血病(AML)
在一些实施方案中，所述急性髓系白血病选自复发和/或难治性急性髓系白血病。
在一些实施方案中，所述急性髓系白血病选自对标准治疗方案不耐受，且没有其他更好治疗选择的急性髓系白血病。
在一些实施方案中，所述急性髓系白血病患者/受试者满足以下一种或多种条件：
a)CR/CRi且巩固治疗后12个月内复发；和/或
b)CR/CRi后12个月后复发但再诱导治疗未获CR/CRi；和/或
c)2次及2次以上复发；和/或
d)一线诱导治疗未获CR/CRi；和/或
e)由于年龄、合并症、体能状态和/或不良风险因素等原因不能接受标准治疗的初治的受试者。
在一些实施方案中，所述急性髓系白血病患者在CR/CRi且巩固治疗后12个月内复发。
在一些实施方案中，所述急性髓系白血病患者在CR/CRi后12个月后复发但再诱导治疗未获CR/CRi。
在一些实施方案中，所述急性髓系白血病患者具有2次及2次以上复发。
在一些实施方案中，所述急性髓系白血病患者经一线诱导治疗未获CR/CRi。
在一些实施方案中，上述a)中的复发是指外周血白血病原始细胞或骨髓原始细胞≥5％、或有新发髓外病灶。
在一些实施方案中，上述d)中的一线诱导治疗未获CR/CRi表示：
针对适合强化疗者，一线标准诱导治疗应含蒽环类药物和/或标准剂量阿糖胞苷，且至少2个周期；
不适合强化疗者，一线诱导治疗应含去甲基化药物且至少4个周期。
在一些实施方案中，所述急性髓系白血病不包括非急性早幼粒细胞白血病。
套细胞淋巴瘤(MCL)
在一些实施方案中，所述淋巴类肿瘤或非霍奇金淋巴瘤(NHL)选自套细胞淋巴瘤。
在一些实施方案中，所述套细胞淋巴瘤选自复发和/或难治性套细胞淋巴瘤。
在一些实施方案中，所述套细胞淋巴瘤的受试者已接受过一种或两种以上在先治疗方案的治疗。在一些实施方案中，所述套细胞淋巴瘤的受试者已接受过一种、两种、三种、四种、或五种在先治疗方案的治疗。
在一些实施方案中，所述套细胞淋巴瘤的受试者既往至少接受过1种系统性治疗方案，且最近一次治疗期间或完成后存在疾病进展或不耐受，或经充分治疗后没有出现缓解。
弥漫大B细胞淋巴瘤(DLBCL)
在一些实施方案中，所述淋巴类肿瘤或非霍奇金淋巴瘤选自弥漫大B细胞淋巴瘤。
在一些实施方案中，所述弥漫大B细胞淋巴瘤选自复发和/或难治性弥漫大B细胞淋巴瘤。
在一些实施方案中，所述弥漫大B细胞淋巴瘤的受试者已接受过一种或两种以上在先治疗方案的治疗。在一些实施方案中，所述弥漫大B细胞淋巴瘤的受试者已接受过一种、两种、三种、四种、或五种在先治疗方案的治疗。
在一些实施方案中，所述弥漫大B细胞淋巴瘤的受试者既往至少接受过1种或2种全身系统性治疗方案，且最近一次治疗期间或完成后存在疾病进展或不耐受，或经充分治疗后没有出现缓解。
慢性淋巴细胞白血病/小淋巴细胞性淋巴瘤(CLL/SLL)
在一些实施方案中，所述淋巴类肿瘤或非霍奇金淋巴瘤选自慢性淋巴细胞白血病或小淋巴细胞性淋巴瘤。
在一些实施方案中，所述慢性淋巴细胞白血病或小淋巴细胞性淋巴瘤选自复发和/或难治性慢性淋巴细胞白血病或小淋巴细胞性淋巴瘤。
在一些实施方案中，所述慢性淋巴细胞白血病或小淋巴细胞性淋巴瘤的受试者已接受过一种或两种以上在先治疗方案的治疗。在一些实施方案中，所述慢性淋巴细胞白血病或小淋巴细胞性淋巴瘤的受试者已接受过一种、两种、三种、四种、或五种在先治疗方案的治疗。
在一些实施方案中，所述慢性淋巴细胞白血病或小淋巴细胞性淋巴瘤的受试者既往至少接受过1种全身系统性治疗方案，且最近一次治疗期间或完成后存在疾病进展或不耐受，或经充分治疗后没有出现缓解。
在一些实施方案中，所述慢性淋巴细胞白血病的受试者具有外周血单克隆B淋巴细胞计数>5×109/L，或者存在影像学可测量病灶。在一些实施方案中，所述慢性淋巴细胞白血病的受试者具有经CT或MRI评估，在2个垂直方向至少存在一个影像学可测量的肿瘤病灶。可选地，所述肿瘤病灶选自结内病灶长径＞15mm和结外病灶长径>10mm。
给药方案
给药的方法可根据药物的活性、毒性以及受试者/患者的耐受性等来综合确定。本领域技术人员能确定本发明联合使用的每种药物的适当量、剂量或用量以施用于受试者/患者。本领域技术人员可以根据治疗领域中熟知的方法调整剂量和给药方案。例如，可以容易地确定最大耐受剂量，还可以确定为受试者/患者提供可检测治疗益处的有效量，也可以确定施用每种药物以向受试者/患者提供可检测治疗益处的时间要求。因此，虽然本申请举例说明了某些剂量和给药方案，但这些实例决不限制在实践本发明时可以提供给受试者/患者的剂量和给药方案。
在一些实施方案中，本申请提供治疗血液肿瘤的方法，其包括向受试者施用剂量(每日或每次)选自20-2000mg、20-1200mg、100-1200mg、100-800mg、200-800mg或200-600mg的式I-1化合物或其可药用盐、或其药物组合物。
在一些实施方案中，本申请提供了式I-1化合物或其可药用盐、或其药物组合物在制备用于治疗血液肿瘤的药物中的用途，其中，所述药物包含20-2000mg、20-1200mg、100-1200mg、100-800mg、200-800mg或200-600mg的式I-1化合物、或其可药用盐或其药物组合物。在一些实施方案中，本申请提供了式I-1化合物或其可药用盐、或其药物组合物在制备用于治疗血液肿瘤的药物中的用途，其中，所述药物包含单剂量或多剂量的所述式I-1化合物或其可药用盐、或其药物组合物。在一些实施方案中，本申请提供了式I-1化合物或其可药用盐、或其药物组合物在制备用于治疗血液肿瘤的药物中的用途，其中，所述式I-1化合物或其可药用盐、或其药物组合物的施用剂量(每日或每次)选自20-2000mg、20-1200mg、100-1200mg、100-800mg、200-800mg或200-600mg(例如300mg、400mg、500mg或600mg)。
本申请还提供用于治疗血液肿瘤的式I-1化合物或其可药用盐、或其药物组合物，所述式I-1化合物或其可药用盐、或其药物组合物的施用剂量(每日或每次)选自20-2000mg、20-1200mg、100-1200mg、100-800mg、200-800mg或200-600mg(例如300mg、400mg、500mg或600mg)。
本申请还提供本申请的式I-1化合物或其可药用盐、或其药物组合物用于治疗血液肿瘤的用途，所述式I-1化合物或其可药用盐、或其药物组合物的施用剂量(每日或每次)选自20-2000mg、20-1200mg、100-1200mg、100-800mg、200-800mg或200-600mg(例如300mg、400mg、500mg或600mg)。
在一些实施方案中，本申请还提供了用于治疗肿瘤的试剂盒，其中包含：含有式I-1化合物或其可药用盐的药物组合物；任选地，还包含式I-1化合物或其可药用盐的药物组合物的使用说明，所述使用说明 涉及式I-1化合物或其可药用盐、或其药物组合物的施用剂量(每日或每次)选自20-2000mg、20-1200mg、100-1200mg、100-800mg、200-800mg或200-600mg(例如300mg、400mg、500mg或600mg)。在一些实施方案中，所述使用说明是指导向受试者施用含有式I-1化合物或其可药用盐的药物组合物。
在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自10-5000mg、20-5000mg、或者20-4000mg、或者20-3000mg、或者20-2000mg、或者50-1500mg、或者100-1200mg、或者200-1000mg、或者100-1000mg、或者100-800mg、或者200-800mg、或者200-600mg、或者200-400mg。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg、950mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、1600mg、1700mg、1800mg、1900mg或2000mg、或上述任意值形成的范围中的任意值。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自100mg-1200mg、100-800mg、200-800mg或200-600mg。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自200-1000mg或200-800mg。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自10-800mg、20-800mg或100-800mg。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自10-300mg、20-400mg、20-200mg或20-100mg。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自10mg、20mg、50mg、100mg、200mg、300mg或400mg。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自200mg、300mg、400mg、500mg、600mg、800mg、1000mg或1200mg。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自100-800mg。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自400-600mg。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自200mg、300mg、400mg、500mg或600mg。
在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自50mg-800mg。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自100mg-800mg。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自100mg-600mg。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自50mg-400mg(如50mg、100mg、200mg、300mg或400mg)。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自100mg-400mg(如100mg、200mg或400mg)。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自100mg-200mg。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自200mg、300mg、400mg、600mg或800mg。
在一些实施方案中，本申请提供治疗血液肿瘤的方法，其包括向受试者施用剂量(每日或每次)选自20-2000mg、20-1200mg或100-1200mg的式I-1化合物或其可药用盐、或其药物组合物。
在一些实施方案中，本申请提供了式I-1化合物或其可药用盐、或其药物组合物在制备用于治疗血液肿瘤的药物中的用途，其中，所述药物包含20-2000mg、20-1200mg或100-1200mg的式I-1化合物或其可药用盐或其药物组合物。在一些实施方案中，本申请提供了式I-1化合物或其可药用盐、或其药物组合物在制备用于治疗血液肿瘤的药物中的用途，其中，所述式I-1化合物或其可药用盐、或其药物组合物的施用剂量(每日或每次)选自20-2000mg、20-1200mg或100-1200mg。
本申请还提供用于治疗血液肿瘤的式I-1化合物或其可药用盐、或其药物组合物，所述式I-1化合物或其可药用盐、或其药物组合物的施用剂量(每日或每次)选自20-2000mg、20-1200mg或100-1200mg。
本申请还提供本申请的式I-1化合物或其可药用盐、或其药物组合物用于治疗血液肿瘤的用途，所述式I-1化合物或其可药用盐、或其药物组合物的施用剂量(每日或每次)选自20-2000mg、20-1200mg或100-1200mg。
在一些实施方案中，本申请还提供了用于治疗肿瘤的试剂盒，其中包含：含有式I-1化合物或其可药用盐的药物组合物；任选地，还包含式I-1化合物或其可药用盐的药物组合物的使用说明，所述使用说明涉及式I-1化合物或其可药用盐、或其药物组合物的施用剂量(每日或每次)选自20-2000mg、20-1200mg或100-1200mg。在一些实施方案中，所述使用说明是指导向受试者施用式I-1化合物或其可药用盐的药物组合物。
在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自10-5000mg、20-5000mg、或者20-4000mg、或者20-3000mg、或者20-2000mg、或者50-1500mg、或者100-1200mg、或者200-1000mg、或者200-800mg、或者200-600mg、或者200-400mg。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg、950mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、1600mg、1700mg、1800mg、1900mg或2000mg、或上述任意值形成的范围中的任意值。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自100-1200mg。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自200-1000mg。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自10-800mg或20mg-800mg。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自10-300mg、20-400mg、20-200mg或20-100mg。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自10mg、20mg、50mg、100mg、200mg、300mg或400mg。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自200mg、300mg、400mg、500mg、600mg、800mg、1000mg或1200mg。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自100-800mg。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自400-600mg。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量选自200mg、300mg、400mg、500mg或600mg。
在本申请的一些实施方案中，所述式I-1化合物或其可药用盐、或其药物组合物每次施用0.0001到20mg/kg重量。在本申请的一些实施方案中，所述式I-1化合物或其可药用盐、或其药物组合物每次施用0.0001到20mg/kg体重。
在一些实施方案中，所述式I-1化合物或其可药用盐、或其药物组合物的给药频率可以是每日3次、每日2次、每日1次、每两日1次、每三日1次、每四日1次、每五天1次、每六天1次、每一周3次、每一周2次、每一周1次、每两周1次、或每三周1次。在一些实施方案中，所述式I-1化合物或其可药用盐、或其药物组合物的给药频率可以是每日1次或2次。在一些实施方案中，所述式I-1化合物或其可药用盐、或其药物组合物的给药频率可以是每日1次。
在一些实施方案中，向受试者施用有效量的本申请的式I-1化合物或其可药用盐、或其药物组合物为连续每天施用。
在一些实施方案中，所述式I-1化合物或其可药用盐、或其药物组合物以单剂量或多剂量形式给药。
在一些实施方案中，所述式I-1化合物或其可药用盐、或其药物组合物的给药通过口服给药。
在一些实施方案中，所述式I-1化合物或其可药用盐、或其药物组合物的给药可在开始用餐后30分钟内口服。
在一些实施方案中，所述式I-1化合物或其可药用盐、或其药物组合物的给药通过空腹口服给药。
在一些实施方案中，以8-32天为1个给药周期，例如，以8-28天、8-21天、8-15天、15-28天、15-21天、21-28天、21-32天、28-32天、8天、9天、10天、11天、12天、13天、14天、15天、16天、17天、18天、19天、20天、21天、22天、23天、24天、25天、26天、27天、28天、29天、30天、31天、或32天为1个给药周期。在一些实施方案中，以28天或32天为1个给药周期。在一些实施方案中，以28天(4周)为1个给药周期。在一些实施方案中，本申请重复一个或多个给药周期。
在一些实施方案中，所述式I-1化合物或其可药用盐、或其药物组合物的给药方式为：每次服用20mg-1200mg、100mg-1200mg、100mg-800mg、200-800mg或400mg-600mg，每日(例如每日1次)连续给药一个或多个给药周期；任选地，以8-32天(例如每28天)为一个给药周期。
在一些实施方案中，所述式I-1化合物或其可药用盐、或其药物组合物的给药方式为：每次服用20mg-1200mg、100mg-1200mg、100mg-800mg、200-800mg或400mg-600mg，每日(例如每日1次)连续给药一个或多个给药周期；任选地，每28天为一个给药周期。
在一些实施方案中，所述式I-1化合物或其可药用盐、或其药物组合物的给药方式为：每次服用100mg-1200mg、100mg-800mg或200-800mg，每日1次，口服一个或多个给药周期；任选地，每28天为一个给药周期。
在一些实施方案中，所述式I-1化合物或其可药用盐、或其药物组合物的给药方式为：每次服用20-1200mg、100-1200mg、100-800mg、300-600mg或400-600mg，每日(例如每日1次)连续给药一个或多个给药周期；任选地，每8-32天(例如每28天)为一个给药周期。
在一些实施方案中，所述式I-1化合物或其可药用盐、或其药物组合物的给药方式为：每次服用20-1200mg、100-1200mg、100-800mg、300-600mg或400-600mg，每日1次连续给药；任选地，每28天为一个给药周期。
在一些实施方案中，所述式I-1化合物或其可药用盐、或其药物组合物的给药方式为：每次服用100-1200mg或100-800mg，每日1次，口服一个或多个给药周期；任选地，每28天为一个给药周期。
在一些实施方案中，所述式I-1化合物或其可药用盐、或其药物组合物的给药可为2-40个给药周期，例如4-10个或8-20个给药周期，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或30个给药周期，甚至可根据需要为2-40个或以上的给药周期。在一些实施方案中，所述式I-1化合物或其可药用盐、或其药物组合物的给药为当重复上述给药周期，直至受试者无法继续获益、疾病进展或出现无法耐受的毒性反应。
在一些实施方案中，所述式I-1化合物或其可药用盐、或其药物组合物的治疗周期为2-40个给药周期，例如4-10个或8-20个给药周期，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或30个给药周期。在一些实施方案中，所述式I-1化合物或其可药用盐、或其药物组合物的治疗周期为当重复上述给药周期，直至受试者无法继续获益、疾病进展或出现无法耐受的毒性反应。
在一些实施方案中，所述式I-1化合物或其可药用盐、或其药物组合物的每日或每次剂量为治疗期剂量。
在一些实施方案中，所述式I-1化合物或其可药用盐、或其药物组合物作为单一药剂施用；任选地，可以与其他药剂联用。
在一些实施方案中，在本申请所述的治疗方法中，在所述给药周期之前，还包括预给药递增周期(也可称为导入期)。在所述预给药递增周期中，以至少一个梯度递增剂量(下文也称为“梯度剂量”)给予所述式I-1化合物或其可药用盐、或其药物组合物，其中，所述至少一个梯度剂量中的第一梯度剂量低于给药周期中的剂量。在一些实施方案中，所述至少一个梯度剂量可包括第一梯度剂量和另外的梯度剂量。特别是，对于预给药递增周期中包含多个梯度剂量的情况，最后一个梯度剂量小于或等于给药周期中使用的剂量。在优选的实施方案中，所述梯度剂量与给药周期中的剂量以相同的给药方式和给药频率施用。所述导入期不计入给药周期，即治疗周期(治疗周期内的给药为治疗剂量)。
在一些的实施方案中，对于预给药递增周期中包含多个梯度剂量的情况，各梯度剂量之间的差异可以以相同或不同。在一些的实施方案中，对于预给药递增周期中包含多个梯度剂量的情况，可包括1-14个梯度剂量，例如1、2、3、4、5、6、7、8、9、10、11、12、13或14个梯度剂量。
在一些的实施方案中，所述第一递增剂量可选自：10mg、20mg、50mg或100mg。在优选的实施方案中，每个递增剂量可给予1-10天，例如，可给予1，或持续给予2-10天。
在一些实施方案中，在受试者接受根据本申请的给药或治疗前，预先向所述受试者施用每日或每周梯度递增剂量的本申请的式I-1化合物或其可药用盐、或其药物组合物。任选地，在递增到特定剂量后(例如100mg、200mg、400mg、600mg、800mg或1200mg)，后续进行所述给药周期，例如每日施用治疗剂量(例如100mg、200mg、300mg、400mg、500mg、600mg、700mg、800mg或1200mg)的式I-1化合物或其可药用盐、或其药物组合物。在一些实施方案中，例如，所述受试者具有白血病，例如急性髓系白血病。在本文中，施用治疗剂量指在给药周期中以上文所定义的剂量按照治疗剂量的方式施用本申请的式I-1化合物或其可药用盐、或其药物组合物。
在一些实施方案中，在受试者接受根据本申请的给药或治疗前，预先向所述受试者施用每日或每周梯度递增剂量的本申请的式I-1化合物或其可药用盐、或其药物组合物。任选地，在递增到特定剂量后(例如50mg、100mg、200mg、400mg、600mg、800mg或1200mg)，后续进行所述给药周期，例如每日施用治疗剂量(例如100mg、200mg、300mg、400mg、500mg、600mg、800mg或1200mg)的式I-1化合物或其可药用盐、或其药物组合物。在一些实施方案中，所述受试者具有淋巴类肿瘤，包括非霍奇金淋巴瘤。
在一些实施方案中，所述施用每日梯度递增剂量的持续时间为2、3、4、5、6、7、8、9、10、11、12、13、或14天、或上述任意值形成的范围的持续时间。在一些实施方案中，所述施用每日梯度递增剂量的持续时间为2-10或3-4或5-7天。
在一些实施方案中，可选地，所述受试者在接受给药周期的剂量(例如治疗剂量)前，向受试者施用梯度递增剂量的本申请的式I-1化合物或其可药用盐。梯度递增剂量包括每1天、每2天、每3天、每4天、每5天、每6天或每周(7天)换一个剂量进行梯度递增剂量。梯度递增剂量包括每1天换一个剂量进行梯度增剂量。
在一些实施方案中，所述梯度递增剂量包括以下中的至少一个：20mg、50mg、100mg、200mg、300mg、400mg、500mg、600mg或800mg。在一些实施方案中，所述梯度递增剂量包括以下中的至少一个：20mg、50mg、100mg、200mg、400mg、600mg或800mg。在一些实施方案中，所述梯度递增剂量包括20mg、50mg、100mg、200mg、300mg、400mg、500mg、600mg或800mg。在一些实施方案中，所述梯度递增剂量包括20mg、50mg、100mg、200mg、400mg、600mg或800mg。
在一些实施方案中，所述梯度递增剂量的第一梯度剂量选自10mg、20mg、50mg或100mg。在一些实施方案中，所述梯度递增剂量的第二梯度剂量选自20mg、50mg、100mg或200mg。可选地，所述梯度递增剂量还包含第三梯度剂量。在一些实施方案中，所述梯度递增剂量的第三梯度剂量选自50mg、100mg、200mg或400mg。在一些实施方案中，可选地，所述梯度递增剂量还包含第四梯度剂量。在一些实施方案中，可选地，所述梯度递增剂量还包含第四梯度剂量，其选自100mg、200mg、400mg或600mg。在一些实施方案中，可选地，所述梯度递增剂量还包含第五梯度剂量。在一些实施方案中，可选地，所述梯度递增剂量还包含第五梯度剂量，其选自200mg、400mg、600mg或800mg。
在一些实施方案中，所述给药周期的剂量或者治疗剂量包括100mg、200mg、300mg、400mg、500mg、600mg、800mg或1200mg。
在一些实施方案中，所述梯度递增剂量的第一梯度剂量选自20mg。在一些实施方案中，所述梯度递增剂量的第二梯度剂量选自50mg。可选地，所述梯度递增剂量还包含第三梯度剂量。在一些实施方案中，所述梯度递增剂量的第三梯度剂量选自100mg。在一些实施方案中，可选地，所述梯度递增剂量还包含第四梯度剂量。在一些实施方案中，可选地，所述梯度递增剂量还包含第四梯度剂量，其选自200mg。在一些实施方案中，可选地，所述梯度递增剂量还包含第五梯度剂量。在一些实施方案中，可选地，所述梯度递增剂量还包含第五梯度剂量，其选自400mg。在一些实施方案中，可选地，所述梯度递增剂量还包含第六梯度剂量。在一些实施方案中，可选地，所述梯度递增剂量还包含第六梯度剂量，其选自600mg。在一些实施方案中，可选地，所述梯度递增剂量还包含第七梯度剂量。在一些实施方案中，可选地，所述梯度递增剂量还包含第七梯度剂量，其选自800mg。在一些实施方案中，给药或治疗包含或不包含导入期，例如当不包含导入期时候，所述治疗期剂量为100mg。
在一些实施方案中，所述梯度递增剂量的第一梯度剂量选自100mg。在一些实施方案中，所述梯度递增剂量的第二梯度剂量选自200mg。可选地，所述梯度递增剂量还包含第三梯度剂量。在一些实施方案中，所述梯度递增剂量的第三梯度剂量选自400mg。
在一些实施方案中，在预给药递增周期或导入期后(即通过梯度剂量递增到特定剂量后)，后续每天以固定剂量的模式(即治疗剂量)施用给药周期中所使用的剂量的式I-1化合物或其可药用盐、或其药物组合物进行治疗。在一些实施方案中，给药周期中所使用的剂量如上所定义，例如，所述治疗剂量可选自100mg-400mg或100mg-800mg。第二梯度剂量例如50mg完成了预给药递增周期，后续以固定剂量的模式在给药周期中给予100mg；第三梯度剂量例如100mg完成了预给药递增周期，后续以固定剂量的模式在给 药周期中给予200mg；例如第四梯度剂量例如200mg完成了预给药递增周期，后续以固定剂量的模式在给药周期中给予400mg。
在一些实施方案中，给药周期中所述式I-1化合物或其可药用盐的治疗剂量选自100mg、200mg、400mg、600mg、800mg或1200mg；在一些实施方案中，选自100mg、200mg、400mg、600mg或800mg。
在一些实施方案中，所述受试者在接受给药周期(例如固定剂量的模式)治疗前，向受试者施用每日或每周梯度递增剂量的本申请的式I-1化合物或其可药用盐。任选地，在递增到特定剂量(例如50mg、100mg、200mg、400mg、600mg、800mg或1200mg)后，后续进行给药周期，例如每日施用治疗剂量(例如100mg、200mg、400mg、600mg、800mg或1200mg)的式I-1化合物或其可药用盐。
在一些实施方案中，所述受试者在接受给药周期(例如固定剂量的模式)治疗前，向受试者施用每日或每周梯度递增剂量的本申请的式I-1化合物或其可药用盐。任选地，在递增到特定剂量(例如50mg、100mg、或200mg)后，后续进行给药周期，例如对应的每日施用治疗剂量分别为100mg、200mg及400mg的式I-1化合物或其可药用盐。在一些实施方案中，所述每日梯度递增剂量包括：第一天施用20mg，第二天施用50mg，第三天施用100mg。在一些实施方案中，所述每日梯度递增剂量包括：第一天施用20mg，第二天施用50mg，第三天施用100mg，第四天施用200mg。在一些实施方案中，所述每日梯度递增剂量包括：第一天施用20mg，第二天施用50mg，第三天施用100mg，第四天施用200mg，第五天施用400mg。在一些实施方案中，所述每日梯度递增剂量包括：第一天施用20mg，第二天施用50mg，第三天施用100mg，第四天施用200mg，第五天施用400mg，第六天施用600mg。
在一些实施方案中，所述每日梯度递增剂量包括：第一天施用20mg，第二天施用50mg，第三天施用100mg，第四天施用200mg，第五天施用400mg，第六天施用600mg，第七天施用800mg。在一些实施方案中，所述每日梯度递增剂量包括：第一天施用20mg，第二天施用50mg，第三天施用100mg，第四天施用200mg，第五天施用400mg，第六天施用600mg，第七天施用800mg，第八天施用1200mg。在一些实施方案中，所述每日梯度递增剂量包括：第一天施用100mg。在一些实施方案中，所述每日梯度递增剂量包括：第一天施用100mg，第二天施用200mg。在一些实施方案中，所述每日梯度递增剂量包括：第一天施用100mg，第二天施用200mg，第三天施用400mg。在一些实施方案中，所述每日梯度递增剂量包括：第一天施用100mg，第二天施用200mg，第三天施用400mg，第四天施用600mg。在一些实施方案中，所述每日梯度递增剂量包括：第一天施用100mg，第二天施用200mg，第三天施用400mg，第四天施用800mg。
在一些实施方案中，所述每日梯度递增剂量包括：第一天施用10mg，第二天施用20mg，第三天施用50mg，第四天施用100mg。在一些实施方案中，所述每日梯度递增剂量包括：第一天施用10mg，第二天施用20mg，第三天施用50mg，第四天施用100mg，第五天施用200mg。在一些实施方案中，所述每日梯度递增剂量包括：第一天施用10mg，第二天施用20mg，第三天施用50mg，第四天施用100mg，第五天施用200mg，第六天施用300mg。
在一些实施方案中，后续给药周期中的治疗使用治疗剂量的式I-1化合物或其可药用盐。
在一些实施方案中，所述每日梯度递增剂量包括：第一天施用100mg；可选地，后续给药周期的治疗每天施用100mg或200mg。
在一些实施方案中，所述每日梯度递增剂量包括：第一天施用100mg，第二天施用200mg。可选地，后续给药周期的治疗每天施用400mg。
在一些实施方案中，所述每日梯度递增剂量包括：第一天施用100mg，第二天施用200mg，第三天施用400mg。可选地，后续给药周期的治疗每天施用600mg或800mg。
在一些实施方案中，所述每日梯度递增剂量包括：第一天施用100mg，第二天施用200mg，第三天施用400mg，第四天施用600mg。在一些实施方案中，所述每日梯度递增剂量包括：第一天施用100mg，第二天施用200mg，第三天施用400mg，第四天施用800mg。
在一些实施方案中，所述每日梯度递增剂量包括：第一天施用50mg。在一些实施方案中，所述每日梯度递增剂量包括：第一天施用50mg，第二天施用100mg。在一些实施方案中，所述每日梯度递增剂量包括：第一天施用50mg，第二天施用100mg，第三天施用200mg。在一些实施方案中，所述每日梯度递 增剂量包括：第一天施用50mg，第二天施用100mg，第三天施用200mg，可选地，第四天施用300mg或400mg，可选地，第五天施用400mg。
在一些实施方案中，所述施用每周梯度递增剂量的持续时间为1、2、3、4、5、6、或7周、或上述任意值形成的范围的持续时间。在一些实施方案中，所述施用每周梯度递增剂量的持续时间为2-5或2-3或3-4周。在一些实施方案中，所述施用每周梯度递增剂量的持续时间为4周。
在一些实施方案中，所述每周梯度递增剂量包括：第一周每天施用20mg，第二周每天施用50mg，第三周每天施用100mg，第四周每天施用200mg。任选地，在第五周及之后开始给药周期，例如每天施用400-600mg(如400mg、500mg或600mg)的治疗剂量。在一些实施方案中，所述每周梯度递增剂量包括：第一周每天施用10mg，第二周每天施用20mg，第三周每天施用50mg，第四周每天施用100mg，第五周每天施用200mg。任选地，在第六周及之后进行给药周期，例如每天施用200mg-600mg(如200mg、300mg、400mg、500mg或600mg)的治疗剂量。
在一些实施方案中，所述式I-1化合物或其可药用盐、或其药物组合物的每日或每周梯度递增剂量为导入期剂量。
在一些实施方案中，本申请提供的治疗血液肿瘤的方法包括：
1)将受试者鉴定为血液肿瘤患者；以及；
2)给予所鉴定的患者治疗有效量的式I-1化合物或其可药用盐、或其药物组合物。
在一些实施方案中，本申请提供的治疗血液肿瘤的方法包括：
1)对从患者获得的样品进行测定，以确定患者是否具有血液肿瘤；以及
2)向具有血液肿瘤的患者施用治疗有效量的式I-1化合物或其可药用盐、或其药物组合物。
在一些方案中，所述治疗包括抑制患者的血液肿瘤、降低其严重性、降低其风险或抑制其转移。
在一些实施方案中，所述式I-1化合物或其可药用盐选自式I化合物或其可药用盐。在一些实施方案中，所述式I-1化合物或其可药用盐选自式II化合物或其可药用盐。在一些实施方案中，所述式I-1化合物或其可药用盐选自式III化合物或其可药用盐。在一些实施方案中，所述式I-1化合物或其可药用盐选自式IV化合物或其可药用盐。
式I-1化合物或其可药用盐、或其药物组合物
本申请式I-1化合物可以以其游离碱形式给药，也可以以其可药用盐、水合物和前药的形式给药，该前药可在体内转换成式I-1化合物的游离碱形式。
本申请的式I-1化合物或其可药用盐的药物组合物包含式I-1化合物或其可药用盐，还含有药学上可接受的辅料。
在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物选自10-5000mg、20-5000mg、或者20-4000mg、或者20-3000mg、或者20-2000mg、或者50-1500mg、或者100-1200mg、或者200-1000mg、或者200-800mg、或者200-600mg、或者200-400mg的式I-1化合物或其可药用盐、或其药物组合物。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物选自10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg、950mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、1600mg、1700mg、1800mg、1900mg或2000mg、或上述任意值形成的范围中的任意值的式I-1化合物或其可药用盐、或其药物组合物。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物选自100-1200mg的式I-1化合物或其可药用盐、或其药物组合物。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物选自200-1000mg的式I-1化合物或其可药用盐、或其药物组合物。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物选自10-800mg或20mg-800mg的式I-1化合物或其可药用盐、或其药物组合物。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物选自10-300mg、20-400mg、20-200mg或20-100mg的式I-1化合物或其可药用盐、或其药物组合物。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物选自10mg、20mg、50mg、100mg、200mg、300mg或400mg的式I-1化合物或其可药用 盐、或其药物组合物。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物选自200mg、300mg、400mg、500mg、600mg、800mg、1000mg或1200mg的式I-1化合物或其可药用盐、或其药物组合物。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物选自100-800mg的式I-1化合物或其可药用盐、或其药物组合物。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物选自300-600mg或400-600mg的式I-1化合物或其可药用盐、或其药物组合物。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物选自200mg、300mg、400mg、500mg或600mg的式I-1化合物或其可药用盐、或其药物组合物。
在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物选自50mg-800mg式I-1化合物或其可药用盐、或其药物组合物。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物选自100mg-800mg式I-1化合物或其可药用盐、或其药物组合物。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物选自100mg-600mg的式I-1化合物或其可药用盐、或其药物组合物。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物选自50mg-400mg(如50mg、100mg、200mg、300mg或400mg)的式I-1化合物或其可药用盐、或其药物组合物。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物选自100mg-400mg(如100mg、200mg或400mg)式I-1化合物或其可药用盐、或其药物组合物。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物选自100mg-200mg的式I-1化合物或其可药用盐、或其药物组合物。在一些实施方案中，本申请的式I-1化合物或其可药用盐、或其药物组合物选自200mg、400mg、600mg或800mg的式I-1化合物或其可药用盐、或其药物组合物。
在一些实施方案中，所述式I-1化合物或其可药用盐的药物组合物选自固体药物组合物，包括但不限于片剂或胶囊。
在一些实施方案中，所述式I-1化合物或其可药用盐的药物组合物为单剂量为5mg-500mg、优选10mg-200mg、最优选10mg-100mg的药物组合物。具体地，选自单剂量为5mg、10mg、15mg、20mg、50mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、或500mg或上述任意值形成的范围中的任意值的药物组合物。在一些实施方案中，所述含式I-1化合物或其可药用盐的药物组合物的单剂量选自10mg、50mg或100mg。
在一些实施方案中，所述含式I-1化合物或其可药用盐的药物组合物为多剂量药物组合物，所述多剂量可由多个含式I-1化合物或其可药用盐的单剂量药物组合物组成。在一些实施方案中，所述含式I-1化合物或其可药用盐的药物组合物为多剂量药物组合物，所述多剂量可由单剂量为10mg、50mg或100mg的含式I-1化合物或其可药用盐的药物组合物组成。
在一些实施方案中，所述式I-1化合物或其可药用盐选自式I化合物或其可药用盐。在一些实施方案中，所述式I-1化合物或其可药用盐选自式II化合物或其可药用盐。在一些实施方案中，所述式I-1化合物或其可药用盐选自式III化合物或其可药用盐。在一些实施方案中，所述式I-1化合物或其可药用盐选自式IV化合物或其可药用盐。
定义和说明
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(-CH2CH3)、单取代的(如-CH2CH2F)、多取代的(如-CHFCH2F、-CH2CHF2等)或完全被取代的(-CF2CF3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
本文中的Cm-n，是该部分具有给定范围中的整数个碳原子。例如“C1-6”是指该基团可具有1个碳原 子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。
术语“卤素”是指氟、氯、溴和碘。
术语“烷基”是指通式为CnH2n+1的烃基。该烷基可以是直链或支链的。例如，术语“C1-6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。再例如术语“C1-4烷基”指含有1至4个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基等)。
术语“环烷基”指完全饱和的并且可以以呈单环、桥环或螺环存在的碳环。除非另有指示，该碳环通常为3至10元环、优选4至6元环。环烷基的非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基等。
术语“杂环烷基”是指完全饱和的并且可以以单环、桥环或螺环存在的环状基团。除非另有指示，该杂环通常为含有1至3个(优选1或2个)独立地选自硫、氧和/或氮的杂原子的3至7元环，例如4至6元环或5至6元环。
除非另有说明，本申请提供的涉及式I-1化合物例如式I化合物或其可药用盐的剂量及其范围，均是基于式I-1化合物例如式I化合物游离碱的分子量计算的。
术语“施用”或“给予”或“给药”表示，使用本领域技术人员已知的多种方法和递送系统中的任一种，向主体物理引入治疗剂或包含治疗剂的组合物。术语“施用”或“给予”或“给药”在本文中可互换使用。
术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)抑制疾病的症状，即阻止其发展；或(b)缓解疾病的症状，即，导致疾病或症状退化。
术语“有效量”或“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“受试者”、“患者”或“主体”在本文中可互换使用，是指已成为治疗、观察或实验对象的动物，优选哺乳动物，优选灵长类动物，包括人和非人灵长类动物(如猿、猴、猩猩和黑猩猩，如食蟹猴、蜘蛛猴和猕猴，如恒河猴)，最优选人。在一些实施方案中，受试者已经历和/或表现出待治疗和/或预防的疾病或病症的至少一种症状。
如本申请所用，所述式I-1化合物例如式I化合物或其可药用盐可以通过任何适用的途径和方法给药，例如通过口服或肠胃外(例如，静脉内)给药。
术语“药物组合物”是指一种或多种本申请的化合物或其药物组合或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对受试者给予本申请的化合物或其药物组合。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态制剂，如片剂、丸剂、胶囊剂等。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
术语“药学上可接受的”是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
可以通过常规的混合、填充或压片方法来制备固体口服药物组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将 该混合物加工成颗粒，得到了片剂或胶囊或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
术语“药学上可接受的盐”或“可药用盐”是指在“药学上可接受的”的定义范围内的本申请的化合物的盐。
除非另外特别说明，否则单数术语涵盖复数术语，并且复数术语涵盖单数术语。除非另外特别说明，否则词语“一个”或“一种”意指“至少一个”或“至少一种”。除非另外说明，否则“或”的使用意指“和/或”。
在本文中，除非另有说明，否则术语“包含、包括和含有”或等同物为开放式表述，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。
术语“单剂量”是指含有一定量药品的最小包装单元，例如一盒药有七粒胶囊，则每个胶囊为单剂量；或者每瓶注射液为单剂量。术语“多剂量”由多个单剂量组成。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本文中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
在一个实施方案中，本申请的药物组合可以配制成适合于单次或多次施用的药物组合物。在一个实施方案中，本申请的药物组合可为单剂量或多剂量的药物组合物。
在癌症背景下，术语“一线治疗”(first-line therapy)指针对疾病的第一次治疗。它通常是一组标准治疗方法的一部分，例如手术后进行化学治疗和放射治疗。一线疗法单独使用时，是公认的最佳疗法。如果它不能治愈疾病或引起严重的副作用，则可以添加或使用其他治疗方法。
在癌症背景下，术语“二线治疗”(second-line therapy)指当初始治疗(一线治疗)无效或停止发挥作用时所给予的治疗。三线治疗或多线治疗的意思可以此类推。
涉及给药方案时，术语“天(日)”、“每天(每日)”等指一个日历日内的时间，开始于午夜且终止于下一个午夜。
术语“难治”是指受试者或哺乳动物不对抗癌治疗响应或者对抗癌治疗响应不足。
术语“不良事件(Adverse Event,AE)”指受试者接受试验用药品后出现的所有不良医学事件，可以表现为症状体征、疾病或实验室检查异常，但不一定与试验用药品有因果关系。不良事件性质和严重程度的评价标准遵照美国国立癌症研究所的常见毒性反应标准(NCI-CTC AE v5.0)进行。无法根据此标准进行评估的项目，可按照以下标准评定：轻度：对病人日常生活只有轻微影响。中度：明显影响病人日常生活。重度：导致病人功能障碍或严重干扰日常生活。
术语“OS”：指肿瘤患者的总生存时间。
术语“DFS”：指肿瘤患者的无病生存期。
术语“SAE”：指严重不良事件。
术语“TEAEs”：治疗相关不良事件。
技术效果
本申请的治疗方案，在治疗血液肿瘤上具有较好的疗效。本申请所述的式I-1化合物例如式I化合物或其可药用盐、或其药物组合物至少客观缓解率(ORR)、完全缓解(CR)率、中位缓解持续时间(DOR)、中位无进展生存期(PFS)、EFS(中位无事件生存期)、中位总生存期(OS)中的至少一个方面具有优异的效果，例如ORR、CR、CRi、部分缓解(PR)、伴有淋巴细胞增高的部分缓解(PR-L)。例如CR、CR且微小残留病阴性(CRMRD-))、CR伴不完全血细胞计数恢复(CRi)、形态学无白血病状态(MLFS)、CR伴不完全血液恢复(CRh)、CR伴不完全血小板恢复(CRp)、PR。并且，本申请所述的式I-1化合物例如式I化合物或其可药用盐、或其药物组合物患者的药物耐受性好，治疗剂量低、所需的导入期短；副作用小，包括对于心血管功能、呼吸系统、中枢神经系统影响小，例如相关的不良事件(TRAE)主要为血液学不良事件和实验室检查值异常，多为1-2级；能有效降低肿瘤溶解综合征(TLS)的风险。
说明本申请的式I-1化合物(例如式I化合物)或其可药用盐、或其药物组合物具有良好的药用价值。并且对于既往接受过(包括一线、二线、三线或四线)或未接受过治疗的患者，均可表现出获益。
其中，关于有效性评价标准：急性髓系白血病(AML)可参考2017年欧洲白血病网(ELN)疗效评价标准。慢性淋巴细胞白血病(CLL)可参考IWCLL2018评价标准；小淋巴细胞性淋巴瘤(SLL)及其他非霍奇金淋巴瘤(NHL)例如MCL和DLBCL可参考2014年Lugano会议修订标准。
有效性评价例如
客观缓解率(ORR)，可选地，采用以下计算方法：
SLL、MCL和DLBCL：客观缓解例数(CR+PR)占其总病例数的比例；
CLL：客观缓解例数(CR+CRi+PR+PR-L)占其总病例数的比例；
AML：客观缓解例数(CR+CRi+MLFS+PR)占其总病例数的比例。
完全缓解(CR)率：
SLL、MCL和DLBCL：完全缓解例数(CR)占其总病例数的比例；
CLL：完全缓解例数(CR+CRi)占其总病例数的比例；
AML：完全缓解例数(CR+CRi)或(CR+CRh)占总病例数的比例。
中位缓解持续时间(DOR)：采用Kaplan-Meier法计算。
中位无进展生存期PFS(适用于NHL)、中位无事件生存期EFS(适用于AML)和中位总生存期OS：采用Kaplan-Meier法估计。
具体实施方式
为清楚起见，进一步用实施例来阐述本申请，但是实施例并非限制本申请的范围。本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。
式I-1化合物例如式I化合物可以参考WO2020088442A1中公开的方法制备获得。
实施例1临床试验
1.试验药物
式I化合物：规格10mg、100mg，片剂。
2.入组患者
入选标准：
1)经组织学或细胞学明确诊断的血液系统恶性肿瘤；
2)患者人群：非霍奇金淋巴瘤等；或者，急性髓系白血病等；
3)至少1个可进行疗效评估的病灶/可测量疾病。
3.给药方案
式I化合物片，口服，开始用餐后30分钟内用温水送服，每次服用20mg-1200mg，一天一次，28天为一个给药周期。
导入期时长将取决于治疗剂量水平。达当治疗剂量水平日作为治疗期的C1D1。
NHL患者导入期按照如下进行，以下均采用每日递增方式一天口服给予一次，最后一个剂量为治疗剂量：
200mg剂量组：20mg→50mg→100mg→200mg
400mg剂量组：20mg→50mg→100mg→200mg→400mg
600mg剂量组：20mg→50mg→100mg→200mg→400mg→600mg
800mg剂量组：20mg→50mg→100mg→200mg→400mg→600mg→800mg
1200mg剂量组：20mg→50mg→100mg→200mg→400mg→600mg→800mg→1200mg。
AML患者导入期按照如下进行，以下均采用每日递增方式一天口服给予一次，最后一个剂量为治疗 剂量：
200mg剂量组：100mg→200mg
400mg剂量组：100mg→200mg→400mg
600mg剂量组：100mg→200mg→400mg→600mg
800mg剂量组：100mg→200mg→400mg→800mg。
4.有效性及安全性指标
有效性指标包括CR率、ORR、DOR、PFS、OS等。
不良事件：所有不良事件(AE)、严重不良事件(SAE)和治疗相关不良事件(TEAEs)的发生情况，具体例如包括不良反应等级、不良事件总体发生率等。
5.试验结果
不良事件少，式I化合物相关的不良事件(TRAE)主要为血液学不良事件和实验室检查值异常，多为1-2级。
在AML患者中，ORR为25％～65％，CR率为25％～55％。400-600mg剂量组中，ORR为56～70％，CR率为44％～60％。
在MCL患者中，ORR为45％～68％，CR率为15％～50％。200-600mg剂量组中，ORR为45％～68％，CR率为14％～50％。
在CLL/SLL患者中，ORR为89％～95％，CR率为45％～55％。200-600mg剂量组中，ORR为89％～95％，CR率为44％～55％。
在DLBCL患者中，ORR为40％～60％，CR率为40％～50％。200-600mg剂量组中，ORR为40％～60％，CR率为40％～50％。
在MCL、CLL/SLL、AML、DLBCL患者中，完全缓解例数/(客观缓解例数+完全缓解例数)达到25％～100％。
部分疗效数据：
例如，400-600mg剂量组中，已评价AML患者9例，4例获得CR/CRi，1例获得PR，ORR为56％，CR率为44％。
100-600mg剂量组中，已评价MCL患者22例，3例获得CR，8例获得PR，ORR为50％，CR率为14％。
200-600mg剂量组中，已评价CLL/SLL患者27例，12例获得CR/CRi，12例获得PR，ORR为89％，CR率为44％。
100-600mg剂量组中，已评价DLBCL患者5例，2例获得CR，ORR为40％，CR率40％。
例如，在已评价MCL患者中，完全缓解例数/(客观缓解例数+完全缓解例数)达到27％；在已评价CLL/SLL患者中，完全缓解例数/(客观缓解例数+完全缓解例数)达到50％；在已评价AML患者中，完全缓解例数/(客观缓解例数+完全缓解例数)达到71％。
既往接受过(包括一线、二线、三线或四线)或未接受过治疗的患者，均可表现出获益(例如可以较长时间表现获益，疗效好，副作用低)。
以下是代表性病例：

Claims (11)

  1. 一种用于治疗血液肿瘤的BCL-2抑制剂或其可药用盐、或其药物组合物，所述BCL-2抑制剂或其可药用盐选自式I-1化合物或其可药用盐，
    其中，R1选自氢、卤素或C1-6烷基；
    环A选自5-6元杂环烷基，
    R2分别独立地选自4-6元杂环烷基、C3-6环烷基、-CORa、-SO2Rb、或任选地被卤素取代的C1-6烷基；
    Ra和Rb分别独立地选自H、4-6元杂环烷基、C3-6环烷基、或C1-6烷基，所述C1-6烷基任选地被卤素、CN、-N(C1-6烷基)2、-NHC1-6烷基、或-OC1-6烷基取代；
    m选自0、1、2或3，所述血液肿瘤选自淋巴类肿瘤或髓系白血病。
  2. 如权利要求1所述的BCL-2抑制剂或其可药用盐、或其药物组合物，其中，结构片段选自
    任选地，R1选自氢、卤素或C1-3烷基；
    或者，R1选自氢、氟、氯或甲基；
    或者，R1选自氢、氯或甲基；
    任选地，环A选自6元杂环烷基；
    或者，环A选自含一个或多个O原子的6元杂环烷基；
    或者，环A选自二氧六环或吡喃环；
    任选地，R2分别独立地选自4-6元杂环烷基、C4-6环烷基、-CORa、-SO2Rb、或任选地被卤素取代的C1-4烷基；
    任选地，Ra和Rb分别独立地选自H、4-6元杂环烷基、C3-6环烷基、或C1-4烷基，所述C1-4烷基任选地被卤素、CN、-N(C1-4烷基)2、-NHC1-4烷基、或-OC1-4烷基取代；
    任选地，R2分别独立地选自-C(O)H、-COC(CH3)3、-COCF3、-COCH2CN、-COCH2N(CH3)2、-SO2CH2CH3、-SO2CF3、-SO2C2F5、-CF3、-C2F5、四氢吡喃、单氧杂环丁烷、-SO2-环丙烷、-CO-环丙烷、-CO-单氧杂环丁烷、-SO2-单氧杂环丁烷、或-SO2-环丁烷；
    任选地，m选自0或1。
  3. 如权利要求1或2所述的BCL-2抑制剂或其可药用盐、或其药物组合物，其中，所述BCL-2抑制剂或其可药用盐选自式I、式II、式III、或式IV化合物或其可药用盐，
  4. 如权利要求1-3任一项所述的BCL-2抑制剂或其可药用盐、或其药物组合物，其中，
    所述血液肿瘤选自晚期血液肿瘤；
    任选地，所述血液肿瘤选自复发和/或难治的血液肿瘤；
    任选地，所述血液肿瘤选自复发和/或难治的晚期血液肿瘤；
    任选地，所述血液肿瘤选自经组织学或细胞学明确诊断的血液肿瘤。
  5. 如权利要求1-4任一项所述的BCL-2抑制剂或其可药用盐、或其药物组合物，其中，所述血液肿瘤选自非霍奇金淋巴瘤或急性髓系白血病；
    任选地，所述血液肿瘤选自套细胞淋巴瘤、弥漫大B细胞淋巴瘤、慢性淋巴细胞白血病和/或小淋巴细胞性淋巴瘤、或急性髓系白血病。
  6. 如权利要求1-5任一项所述的BCL-2抑制剂或其可药用盐、或其药物组合物，其中，所述血液肿瘤的患者为未接受过在先治疗方案的治疗的受试者；
    任选地，所述血液肿瘤的患者已接受过一种或两种以上在先治疗方案的治疗；
    任选地，所述血液肿瘤的患者选自既往至少接受过1种全身系统性治疗方案，最近一次治疗期间或完成后存在疾病进展或不耐受，或经充分治疗后没有出现缓解的受试者。
  7. 如权利要求1-6任一项所述的BCL-2抑制剂或其可药用盐、或其药物组合物，其中，所述BCL-2抑制剂或其可药用盐的每日或每次给药剂量选自20-2000mg、20-1200mg或100-1200mg；
    或者，每日或每次给药剂量选自10-5000mg、或者20-5000mg、或者20-4000mg、或者20-3000mg、或者20-2000mg、或者50-1500mg、或者100-1200mg、或者200-1000mg、或者200-800mg、或者200-600mg、或者200-400mg；
    或者，每日或每次给药剂量选自10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg、950mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、1600mg、1700mg、1800mg、1900mg或2000mg、或上述任意值形成的范围中的任意值。
  8. 如权利要求1-7任一项所述的BCL-2抑制剂或其可药用盐、或其药物组合物，其中，所述BCL-2抑制剂或其可药用盐的给药频率选自每日3次、每日2次、每日1次、每两日1次、每三日1次、每四日1次、每五天1次、每六天1次、每一周3次、每一周2次、每一周1次、每两周1次、或每三周1次。
  9. 如权利要求1-8任一项所述的BCL-2抑制剂或其可药用盐、或其药物组合物，其中，所述BCL-2抑制剂或其可药用盐的给药为连续每天施用；
    可选地，以单剂量或多剂量形式给药；
    任选地，所述BCL-2抑制剂或其可药用盐的给药通过口服；
    任选地，所述BCL-2抑制剂或其可药用盐的给药通过在开始用餐后30分钟内口服。
  10. 如权利要求1-9任一项所述的BCL-2抑制剂或其可药用盐、或其药物组合物，其中，在进行给药前，向患者施用至少一个梯度递增剂量的所述BCL-2抑制剂或其可药用盐，其中，第一梯度递增剂量低于用于治疗的所述BCL-2抑制剂或其可药用盐的每日或每次给药剂量；
    任选地，向患者施用每日或每周梯度递增剂量的所述BCL-2抑制剂或其可药用盐；
    任选地，所述至少一个梯度递增剂量包括第一梯度递增剂量和另外的梯度递增剂量，其中最后一个梯度递增剂量小于或等于用于治疗的所述BCL-2抑制剂或其可药用盐的每日或每次给药剂量；
    任选地，施用所述每日梯度递增剂量的持续时间为2、3、4、5、6、7、8、9、10、11、12、13、或14天、或上述任意值形成的范围的持续时间。
  11. 一种用于治疗血液肿瘤的试剂盒，其中包含：含有权利要求1-10中任一项所述的BCL-2抑制剂或其可药用盐的药物组合物；任选地，还包含BCL-2抑制剂或其可药用盐的药物组合物的使用说明。
PCT/CN2024/088858 2023-04-20 2024-04-19 含有三氟甲基的化合物在治疗血液肿瘤中的应用 Ceased WO2024217552A1 (zh)

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