Use of bruton's tyrosine kinase inhibitor

Abstract

The present invention belongs to the technical field of medicine, and specifically relates to the use of a compound as represented by the following formula (I) or a pharmaceutically acceptable salt, isomer, or crystal form thereof in the preparation of a drug for preventing or treating malignant B cell tumors.

Description

Uses of Bruton's tyrosine kinase inhibitors Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to the use of Bruton's tyrosine kinase inhibitors. Background Technology

[0002] B-cell malignancies account for nearly 90% of all non-Hodgkin lymphomas (NHL), characterized by abnormal growth and clonal proliferation of B lymphocytes. Among the various subtypes of B-NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), and Waldenström macroglobulinemia are prominent. Macroglobulinemia (WM) is the most common.

[0003] The B cell receptor (BCR) signaling pathway plays a crucial role in the regulation of cell proliferation, cell survival, and adaptive immunity. LYN (Lck / Yes novel tyrosine kinase) and SYK (Spleen Tyrosine Kinase) recruit and activate PI3-kinase (PI3K), generating the second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and recruiting BTK (Bruton's Tyrosine Kinase) to the plasma membrane. BTK phosphorylation mediated by LYN and SYK leads to the activation of the key downstream signaling effector phospholipase Cγ2 (PLCG2). PLCG2 mediates the production of the second messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), which further induce the activation of several key signaling effectors: nuclear factor of activated T cells (NFAT), mitogen-activated protein kinase (MAPK) / extracellular signal-regulated kinase (ERK), protein kinase C (PKC), and nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), thereby leading to cell proliferation and survival. Therefore, BCR signaling can promote disease development in the occurrence and progression of malignant B cells, ultimately manifesting as B-cell malignancies. Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase known to be an important component of BCR signaling. Therefore, inhibiting BTK is an attractive strategy for treating B-cell malignancies.

[0004] Ibrutinib, the first small-molecule BTK inhibitor approved by the FDA (Food and Drug Administration), is approved for the treatment of various relapsed / refractory (R / R) B-cell malignancies. It primarily inhibits BTK activity by irreversibly, covalently binding to the active site Cys-481. However, its dose-limiting toxicity (DLT) and hematologic toxicity limit its application. To reduce the off-target effects of ibrutinib, pharmaceutical companies have developed second-generation BTK inhibitors such as acalabrutinib, zanubrutinib, and orelabrutinib. These inhibitors share the same irreversible covalent mechanism as ibrutinib but offer higher selectivity and potency. However, they are prone to resistance mutations after treatment, leading to unsatisfactory treatment outcomes and difficulty in achieving complete remission in patients with B-cell malignancies.

[0005] Therefore, there remains a huge unmet need for the treatment of B-cell malignancies, especially for relapsed, refractory, and / or intolerant B-cell malignancies. Summary of the Invention

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] Use of the compound of formula (I) or its pharmaceutically acceptable salts, isomers (such as stereoisomers or tautomers) or crystal forms in the preparation of medicaments for the prevention or treatment of B-cell malignancies; or

[0008] A method for preventing or treating B-cell malignancies includes administering to a patient in need a preventative or therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt, isomer (such as a stereoisomer or tautomer) or crystal form thereof; or

[0009] A pharmaceutical composition for the prevention or treatment of B-cell malignancies, comprising a preventive or therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt, isomer (such as a stereoisomer or tautomer) or crystal form thereof; or

[0010] A compound of formula (I) or a pharmaceutically acceptable salt, isomer (such as a stereoisomer or tautomer) or crystal form thereof for the prevention or treatment of B-cell malignancies:

[0011] In some embodiments, the B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma, mantle cell lymphoma, Waldenström macroglobulinemia, follicular lymphoma, marginal zone lymphoma, or transformed lymphoma.

[0012] In some implementations, the B-cell malignancy is a small lymphocytic lymphoma, mantle cell lymphoma, Waldenström macroglobulinemia, marginal zone lymphoma, or transformed lymphoma.

[0013] In some implementations, the B-cell malignancy is mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenström macroglobulinemia, or marginal zone lymphoma.

[0014] In some embodiments, the B-cell malignancy is relapsed, refractory, and / or intolerant mantle cell lymphoma, relapsed, refractory, and / or intolerant chronic lymphocytic leukemia, relapsed, refractory, and / or intolerant small lymphocytic lymphoma, relapsed, refractory, and / or intolerant Waldenström macroglobulinemia, or relapsed, refractory, and / or intolerant marginal zone lymphoma.

[0015] In some implementations, the B-cell malignancy is a relapsed, refractory, and / or intolerable B-cell malignancy.

[0016] In some implementations, the B-cell malignancy is relapsed, refractory, and / or intolerable chronic lymphocytic leukemia.

[0017] In some implementations, the B-cell malignancy is a relapsed, refractory, and / or intolerable small lymphocytic lymphoma.

[0018] In some embodiments, the B-cell malignancy is a relapsed, refractory, and / or intolerable diffuse large B-cell lymphoma.

[0019] In some implementations, the B-cell malignancy is a relapsed, refractory, and / or intolerable mantle cell lymphoma.

[0020] In some implementations, the B-cell malignancy is relapsed, refractory, and / or intolerable Waldenström macroglobulinemia.

[0021] In some implementations, the B-cell malignancy is a relapsed, refractory, and / or intolerable follicular lymphoma.

[0022] In some implementations, the B-cell malignancy is a relapsed, refractory, and / or intolerable marginal zone lymphoma.

[0023] In some implementations, the B-cell malignancy is a relapsed, refractory, and / or intolerable transformed lymphoma.

[0024] In some implementations, the B-cell malignancy is defined as having previously received two or more standard treatment regimens.

[0025] In some implementations, the B-cell malignancy is a result of prior treatment with at least two lines of therapy.

[0026] In some implementations, the B-cell malignancy has been previously treated with at least one BTK inhibitor.

[0027] In some implementations, the B-cell malignancy is one that has not previously received BTK inhibitor treatment.

[0028] In some implementations, the BTK inhibitors include acutinib, zanubrutinib, orelabrutinib, ibrutinib, and teirabrutinib.

[0029] In some implementations, the B-cell malignancy is chronic lymphocytic leukemia, small lymphocytic lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, Waldenström macroglobulinemia, follicular lymphoma, marginal zone lymphoma, or transformed lymphoma that has previously received two or more standard treatment regimens.

[0030] In some implementations, the B-cell malignancy is chronic lymphocytic leukemia, small lymphocytic lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, Waldenström macroglobulinemia, follicular lymphoma, marginal zone lymphoma, or transformed lymphoma that has previously received at least two lines of treatment.

[0031] In some implementations, the B-cell malignancy is chronic lymphocytic leukemia, small lymphocytic lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, Waldenström macroglobulinemia, follicular lymphoma, marginal zone lymphoma, or transformed lymphoma that has previously received at least one BTK inhibitor therapy.

[0032] In some implementations, the B-cell malignancy is previously untreated.

[0033] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, isomer or crystal form thereof is formulated with one or more pharmaceutically acceptable drug carriers into a pharmaceutically acceptable drug formulation for therapeutically effective administration to a patient or subject with B-cell malignancies.

[0034] In some implementations, the pharmaceutical formulation may contain one or more pharmaceutically acceptable carriers and may be administered to patients or subjects requiring treatment via oral, parenteral, rectal, or pulmonary routes.

[0035] In some embodiments, the pharmaceutical formulation can be formulated as conventional solid dosage forms, such as tablets, capsules, pills, granules, etc.; or as oral liquid dosage forms, such as oral solutions, oral suspensions, syrups, etc. When formulating oral dosage forms, suitable fillers, binders, disintegrants, lubricants, etc., can be added. For parenteral administration, the entity can be formulated as an injectable, including injection solutions, sterile powders for injection, and concentrated solutions for injection. When formulating injectables, conventional methods in the existing pharmaceutical field can be used. When preparing injectables, excipients may not be added, or suitable excipients may be added depending on the properties of the drug (e.g., physiologically compatible buffers such as Hanks' solution, Ringer's solution, or saline buffer). For rectal administration, the entity can be formulated as suppositories, etc. (e.g., containing conventional suppository base materials such as cocoa butter or other glycerides). When intended for transpulmonary administration, the entity may be formulated as an inhalant or spray, etc. (e.g., delivered as an aerosol jet from a pressurized pack or nebulizer, by means of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas).

[0036] In some embodiments, the "preventive / therapeutic effective amount" of the compound of formula (I) of the present invention or its pharmaceutically acceptable salt, isomer or crystal form is 50 mg / day to 400 mg / day, and may be 50 mg / day, 100 mg / day, 150 mg / day, 200 mg, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, based on the weight of the compound of formula (I) of the present invention; the dosing frequency is once daily, twice daily, three times daily, once every 2 days, or once every 3 days.

[0037] Invention Details

[0038] The “transformed lymphoma” described in this invention is broadly defined as the histological transformation process in which a low-grade malignant lymphoma develops into a high-grade malignant lymphoma. Lymphomas that undergo histological transformation are called transformed lymphomas (TL).

[0039] In this invention, "subject" and "patient" refer to mammals, preferably humans (male or female).

[0040] In this invention, "relapse" refers to disease progression that occurs 6 months or more after a subject or patient has achieved complete remission (CR) or partial remission (PR).

[0041] The term "refractory" as used in this invention refers to any of the following conditions: 1. Treatment failure; 2. Disease progression within 6 months after the last treatment; 3. Disease progression or pathological transformation after treatment within 6 months after achieving complete remission.

[0042] The term "treatment intolerance" or "intolerance" as used in this invention refers to the inability to continue treatment due to drug toxicity or other reasons.

[0043] The "pharmaceutically acceptable salts" described in this invention refer to pharmaceutically acceptable addition salts and solvates of acids and bases. Such pharmaceutically acceptable salts include salts of acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, and alkanonic acids (such as acetic acid, HOOC-(CH2)n-COOH (where n = an integer from 0 to 4)). Such pharmaceutically acceptable salts also include salts of bases such as sodium, potassium, calcium, and ammonium. Those skilled in the art are familiar with a variety of non-toxic pharmaceutically acceptable addition salts.

[0044] The “crystal form” described in this invention can be prepared from the compound of formula (I) by conventional methods used in the art for preparing crystal forms.

[0045] The "isomers" of the compounds of formula (I) described in this invention include stereoisomers and tautomers.

[0046] The "stereoisomers" described in this invention refer to isomers produced by the different spatial arrangements of atoms in a molecule. When a compound contains asymmetric carbon atoms, enantiomers will be produced; when a compound contains carbon-carbon double bonds or cyclic structures, cis-trans isomers will be produced.

[0047] The "tautomers" described in this invention are isomers of different functional groups in a dynamic equilibrium that can rapidly interconvert, representing a special type of functional group isomerism. For example, the presence of ketones or oximes will produce tautomers, with representative examples including ketone-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, and imine-enamine tautomers.

[0048] All enantiomers, diastereomers, racemic isomers, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof are included within the scope of this invention.

[0049] The "compound of formula (I)" described in this invention is prepared according to the method described in the published patent WO2020063012A1.

[0050] The "pharmaceutically acceptable carrier" as described in this invention refers to a carrier (or excipient) that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the applied compound. Any commonly used pharmaceutically acceptable carrier can be used, and its selection depends on factors such as the specific administration method, the carrier's effect on solubility and stability, and the nature of the dosage form, and is within the ordinary skill of those skilled in the art. Examples of pharmaceutically acceptable carriers include, but are not limited to: fillers (e.g., lactose, sucrose, mannitol or sorbitol, cellulose derivatives and / or calcium phosphate); binders (e.g., corn, wheat or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone); disintegrants (e.g., starch, carboxymethyl starch, cross-linked polyvinylpyrrolidone, alginate or its salts); lubricants (e.g., silica, talc, stearic acid or its salts, and / or polyethylene glycol or its derivatives); diluents, wetting agents, colorants (dyes or pigments such as titanium dioxide, lacquer solutions), fragrances, absorption enhancers, surfactants, adsorbents, etc., such as gelatin, gum tragali, gum arabic, carbapenem gel, glycerin, sorbitol, liquid paraffin, liquid polyethylene glycol, fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes.

[0051] The "standard treatment" described in this invention refers to a treatment method that is widely recognized and recommended for a specific disease or clinical condition based on scientific evidence and evidence-based medicine. This treatment approach typically undergoes clinical trials to verify its safety and effectiveness and is widely accepted and used by medical experts and practitioners. It is also known as best practice, standard medical care, or standard therapy. "Standard treatment" encompasses all standardized treatment protocols, including first-line, second-line, and third-line treatments.

[0052] The "first-line treatment plan" described in this invention refers to the preferred or best treatment plan after a patient is diagnosed. It is usually the most effective and safest plan and has the highest recommendation level in the treatment guidelines.

[0053] The "second-line treatment regimen" described in this invention refers to a treatment regimen that must be changed when first-line treatment is ineffective, drug resistance occurs, or adverse reactions are intolerable. The subsequent treatment regimen is called "second-line treatment".

[0054] Examples of "first-line treatment regimens" described in this invention (different types of B-cell malignancies may have similar or different regimens, which are not distinguished here): RCHOP regimen (rituximab + cyclophosphamide + doxorubicin / epirubicin + vincristine + prednisone), RCHOEP regimen (rituximab + cyclophosphamide + doxorubicin / epirubicin + vincristine + etoposide + prednisone), R-miniCHOP regimen (rituximab + reduced dose CHOP), DA-EPOCH-R regimen (rituximab + etoposide + prednisone + vincristine + cyclophosphamide + doxorubicin), Pola-R-CHP regimen (rituximab + velpoxetine + cyclophosphamide + doxorubicin + prednisone), CR-CHOP regimen (chidamide + rituximab + cyclophosphamide + doxorubicin / epirubicin + vincristine + prednisone), Hi- CHOP regimen (Zebutumab + Cyclophosphamide + Doxorubicin / Epirubicin + Vincristine + Prednisone), RCVP regimen (Rituximab + Cyclophosphamide + Vincristine + Prednisone), Rituximab + Bendamustine regimen, Rituximab + Lenalidomide regimen, Rituximab + Chlorambucil regimen, Oxtobitumab + Chlorambucil regimen, Oxtobitumab regimen, RDHAP regimen (Rituximab + Dexamethasone) +cisplatin + cytarabine), VR-CAP regimen (bortezomib + rituximab + cyclophosphamide + doxorubicin + prednisone), zanubrutinib regimen, orelabrutinib regimen, ibrutinib regimen, acomitinib regimen, veneclax + oxotuzumab regimen, ibrutinib + oxotuzumab regimen, acomitinib + oxotuzumab regimen, acomitinib + veneclax ± oxotuzumab regimen, fludarabine + cyclophosphamide + rituximab regimen

[0055] Examples of "second-line treatment regimens" described in this invention (different types of B-cell malignancies may have similar or different regimens, which are not distinguished here. Additionally, some second-line regimens overlap with first-line regimens): RDHAP regimen (rituximab + dexamethasone + cisplatin + cytarabine), RICE regimen (rituximab + ifosfamide + carboplatin + etoposide), RGDP regimen (rituximab + gemcitabine + cisplatin + dexamethasone), R-ESHAP regimen (rituximab + etoposide + methylprednisolone + cisplatin + cytarabine). The following regimens are mentioned: DA-EPOCH-R (rituximab + etoposide + prednisone + vincristine + cyclophosphamide + doxorubicin), R-GemOx (rituximab + gemcitabine + oxaliplatin), R-MINE (rituximab + mesna + ifosfamide + mitoxantrone + etoposide), R2 (rituximab + lenalidomide), IR2 (ibrutinib + lenalidomide + rituximab), ZR2 (zanubrutinib + lenalidomide + rituximab), and Pola-BR. Rituximab + Verpottuzumab + Bendamustine, BR regimen (Rituximab + Bendamustine), Glofit + Gemox regimen (Gastrometuzumab + Gemcitabine + Oxaliplatin), Tafa-Len regimen (Taximetuzumab + Lenalidomide), Rituximab + CHOP regimen (Rituximab + Cyclophosphamide + Doxorubicin / Epirubicin + Vincristine + Prednisone), Oxtobitumab + CHOP regimen (Oxtobitumab + Cyclophosphamide + Doxorubicin / Epirubicin + Vincristine + Prednisone) ), Rituximab + CVP regimen (rituximab + cyclophosphamide + vincristine + prednisone), Oxtobitumab + CVP regimen (Oxtobitumab + cyclophosphamide + vincristine + prednisone), Copanrise regimen, Limprilix, Duveritine regimen, Regi-Olensine regimen, Tazesta regimen, Zanubrutinib regimen, Obrutinib regimen, Ibrutinib regimen, Acomitinib regimen, Ibrutinib + Rituximab regimen, Bortezomib ± Rituximab regimen, Ibrutinib + Venecla regimen, Venecla + Rituximab regimen.

[0056] The “treatment” described in this invention may include neoadjuvant therapy and adjuvant therapy.

[0057] Neoadjuvant therapy refers to systemic treatment administered to patients with newly diagnosed tumors before planned surgery or surgery plus radiotherapy. Depending on the tumor type, neoadjuvant therapy may involve chemotherapy, endocrine therapy, targeted therapy, immunotherapy, or radiotherapy. The goal of neoadjuvant therapy is to provide immediate systemic treatment, potentially eradicating micrometastases that would otherwise proliferate in a standard sequence following surgery followed by systemic therapy. Neoadjuvant therapy can also help shrink tumor size, allowing for complete resection of tumors that were initially unresectable, or partial resection with preservation of organs and their functions. Furthermore, neoadjuvant therapy allows for in vivo assessment of drug efficacy, which can guide the selection of subsequent treatments.

[0058] "Adjuvant therapy" refers to treatment given after radical surgery (in which no evidence of residual disease can be detected) to eliminate any remaining cancer cells in the body, thereby reducing the likelihood of tumor recurrence or spread to other sites. The treatment methods are largely the same as neoadjuvant therapy. The goal of adjuvant therapy is to prevent cancer recurrence and, consequently, reduce the chance of cancer-related death. Neoadjuvant therapy is explicitly excluded from this discussion.

[0059] The "preventive / therapeutic effective amount" as described in this invention refers to the amount of the aforementioned compound or its pharmaceutically acceptable salts, isomers, or crystalline forms that, when administered to a subject / patient, at least prevent / alleviate the symptoms of the subject / patient's condition. The actual amount comprising the "preventive / therapeutic effective amount" will vary depending on various factors, including but not limited to the specific condition being prevented / treated, the severity of the condition, the patient's physical and health status, and the route of administration. For example, it may be administered as a single bolus, several fractions over time, or the dose may be proportionally reduced or increased as indicated by the urgency of the treatment situation. It should be noted that the dose value may vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. For any given individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the composition or supervising the administration of the composition.

[0060] The objective response rate (ORR), particulate response (PR), and stable disease (SD) described in this invention are defined as the percentage of subjects achieving PR or CR after treatment; the disease control rate (DCR) is defined as the percentage of subjects achieving PR, CR, or SD after treatment; the duration of overall response (DOR), progression-free survival (PFS), and overall survival (OS) are evaluated according to different disease types of subjects. For CLL subjects, reference 1: 2018 IW CLL guidelines efficacy criteria; for all malignant lymphomas other than CLL and WM (including SLL), reference 2: Lugano 2014 lymphoma treatment efficacy evaluation criteria; for WM subjects, reference 3: Waldenström macroglobulinemia efficacy evaluation criteria (IWWM-7 consensus).

[0061] Reference 1: 2018 IWCLL Guidelines Efficacy Criteria

[0062] Hallek M, Cheson BD, Catovsky D, et al.iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL[J]. Blood, The Journal of the American Society of Hematology, 2018, 131(25):2745-2760.

[0063] Reference 2: Lugano 2014 Lymphoma Treatment Efficacy Evaluation Criteria

[0064] Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification [J]. Journal of clinical oncology, 2014, 32(27): 3059-3067.

[0065] Reference 3: Evaluation criteria for the treatment of Waldenström macroglobulinemia (IWWM-7 consensus)

[0066] Dimopoulos MA,Kastritis E,Owen RG,et al.Treatment recommendations for patients with macroglobulinemia(WM)and related disorders:IWWM-7consensus[J].Blood,The Journal of the American Society of Hematology,2014,124(9):1404-1411.

[0067] The efficacy assessment described in this invention includes: complete remission (CR), partial remission (PR), stable disease (SD), objective response rate (ORR), disease control rate (DCR), duration of overall response (DOR), progression-free survival (PFS), and overall survival (OS).

[0068] Beneficial effects of the present invention

[0069] Studies have shown that the compound of formula (I) provided by this invention, or its pharmaceutically acceptable salts, isomers or crystal forms, have good therapeutic effects on B-cell malignancies, especially for relapsed, refractory and / or intolerable B-cell malignancies. Detailed Implementation

[0070] The following detailed description of specific embodiments further illustrates the above-described content of the present invention, but it should not be construed as limiting the scope of the subject matter of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention.

[0071] The compounds of formula (I) used in the following examples were prepared according to the method described in published patent WO2020063012A1. “QD” means once daily and “BID” means twice daily.

[0072] Example 1 is a clinical trial used to evaluate the safety and preliminary efficacy of the compound described in formula (I) in treating B-cell malignancies.

[0073] This trial is a multicenter, open-label, dose-escalation phase I trial designed to evaluate the safety and preliminary efficacy of compound (I) in adult subjects with B-cell malignancies.

[0074] 1. Inclusion Criteria: Patients with histologically or cytologically confirmed B-cell malignancies who have received ≥2 standard / conventional treatment regimens (combined or sequential) or 1 BTK inhibitor-containing treatment regimen, and who meet the definition of relapsed / refractory / treatment intolerant and have treatment indications. Details are as follows:

[0075] Chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL);

[0076] Diffuse large B-cell lymphoma (DLBCL);

[0077] B-cell lymphomas other than CLL / SLL and DLBCL, such as mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), follicular lymphoma (FL), marginal zone lymphoma (MZL), and transformed lymphoma.

[0078] 2. This trial consists of two phases: dose escalation and dose expansion.

[0079] This trial employed a modified “3+3” dose escalation design to guide dose escalation and determine the dose extension recommended dose (DRDE). A starting dose of 50 mg was used, with the first dose group serving as the sentinel group and enrolling one subject. Subjects in the second and subsequent dose groups were then enrolled according to the standard “3+3” dose escalation design to determine the DRDE.

[0080] Once the DRDE is determined, the safety and preliminary efficacy of compound (I) observed in the dose escalation phase will be further validated in the dose extension phase.

[0081] The recommended dose for Phase II clinical trials (RP2D) will be determined based on the overall safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of the dose escalation and dose expansion phases, after consensus among investigators, medical monitors, and sponsors.

[0082] Dosage escalation:

[0083] Pre-set dosages of 50 mg QD, 100 mg QD, 150 mg QD, 200 mg QD, 100 mg BID, 150 mg BID, and 200 mg BID.

[0084] Dose expansion:

[0085] Once the maximum tolerated dose (MTD) or a dose extension recommended dose (DRDE) is determined, enrollment in the dose extension group will begin at that DRDE dose level.

[0086] Compound (I) is administered daily for 28-day cycles until confirmed disease progression, intolerable toxicity, death, or withdrawal of informed consent occurs.

[0087] 3. Evaluation criteria: The evaluation criteria are based on the different disease types of the subjects. For CLL subjects, reference 1: 2018 IW CLL guidelines efficacy criteria; for all malignant lymphomas other than CLL and WM (including SLL), reference 2: Lugano 2014 lymphoma treatment efficacy evaluation criteria; for WM subjects, reference 3: Waldenström macroglobulinemia efficacy evaluation criteria (IWWM-7 consensus).

[0088] 4. Study endpoint:

[0089] Primary endpoint:

[0090] Dose-limiting toxicities (DLTs) of compound (I), dose-extended recommended dose (DRDE) of compound (I), and maximum tolerated dose (MTD) for treatment with compound (I).

[0091] Secondary endpoint:

[0092] Safety: incidence and severity of adverse events (AEs), clinically significant abnormalities in laboratory test values ​​and vital signs, electrocardiogram (ECG), and changes in performance status of the Eastern Cooperative Oncology Group (ECOG).

[0093] Pharmacokinetic parameters: AUC 0-t C max T max t 1 / 2z MRT, V z / F CL z / F .

[0094] Preliminary efficacy: Disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and recommended dose for Phase II clinical trials (RP2D).

[0095] 5. Efficacy evaluation:

[0096] The compound described in formula (I) has shown good therapeutic effects against B-cell malignancies. In this preliminary clinical trial, among 14 evaluable subjects, 3 achieved complete remission (CR) and 5 achieved partial remission (PR). Among these 14 subjects, 5 were MCL subjects, with 3 achieving CR and 2 achieving PR; and 1 was WM subject, with 1 achieving PR.

[0097] According to the latest progress of clinical trials, in further clinical trials, among 16 MCL subjects, 7 achieved complete or partial remission; among 4 CLL / SLL subjects, 3 achieved complete or partial remission; among 2 WM subjects, 1 achieved complete or partial remission; and among 10 MZL subjects, 5 achieved complete or partial remission. The objective response rate (ORR) for each type of subject is assessed as follows:

[0098] This demonstrates that the compound described in formula (I) of the present invention has a good therapeutic effect on B-cell malignant tumors.

[0099] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. Use of the compound of formula (I) or a pharmaceutically acceptable salt, isomer, or crystal form thereof in the preparation of a medicament for the prevention or treatment of B-cell malignancies:

2. A method for preventing or treating B-cell malignancies, comprising administering to a patient in need a preventative or therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt, isomer, or crystal form thereof:

3. A pharmaceutical composition for the prevention or treatment of B-cell malignancies, comprising a preventive or therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt, isomer, or crystal form thereof:

4. A compound of formula (I) or a pharmaceutically acceptable salt, isomer, or crystal form thereof for the prevention or treatment of B-cell malignancies:

5. The use according to claim 1, or the method according to claim 2, or the pharmaceutical composition according to claim 3, or the compound according to claim 4, or a pharmaceutically acceptable salt, isomer, or crystal form thereof, characterized in that, The B-cell malignancies mentioned are chronic lymphocytic leukemia, small lymphocytic lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, Waldenström macroglobulinemia, follicular lymphoma, marginal zone lymphoma, or transformed lymphoma. Preferably, the B-cell malignant tumor is mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenström macroglobulinemia, or marginal zone lymphoma; or the B-cell malignant tumor is small lymphocytic lymphoma, mantle cell lymphoma, Waldenström macroglobulinemia, marginal zone lymphoma, or transformed lymphoma. More preferably, the B-cell malignancy is mantle cell lymphoma or Waldenström macroglobulinemia.

6. The use according to claim 1, or the method according to claim 2, or the pharmaceutical composition according to claim 3, or the compound according to claim 4, or a pharmaceutically acceptable salt, isomer, or crystal form thereof, characterized in that, The B-cell malignancies mentioned are relapsed, refractory and / or intolerable chronic lymphocytic leukemia, relapsed, refractory and / or intolerable small lymphocytic lymphoma, relapsed, refractory and / or intolerable diffuse large B-cell lymphoma, relapsed, refractory and / or intolerable mantle cell lymphoma, relapsed, refractory and / or intolerable Waldenström macroglobulinemia, relapsed, refractory and / or intolerable follicular lymphoma, relapsed, refractory and / or intolerable marginal zone lymphoma, or relapsed, refractory and / or intolerable transformed lymphoma. Preferably, the B-cell malignancy is relapsed, refractory, and / or intolerable mantle cell lymphoma, relapsed, refractory, and / or intolerable chronic lymphocytic leukemia, relapsed, refractory, and / or intolerable small lymphocytic lymphoma, relapsed, refractory, and / or intolerable Waldenström macroglobulinemia, or relapsed, refractory, and / or intolerable marginal zone lymphoma; or the B-cell malignancy is relapsed, refractory, and / or intolerable small lymphocytic lymphoma, relapsed, refractory, and / or intolerable mantle cell lymphoma, relapsed, refractory, and / or intolerable Waldenström macroglobulinemia, relapsed, refractory, and / or intolerable follicular lymphoma, or relapsed, refractory, and / or intolerable transformed lymphoma. More preferably, the B-cell malignancy is relapsed, refractory, and / or intolerable mantle cell lymphoma, or relapsed, refractory, and / or intolerable Waldenström macroglobulinemia.

7. The use according to claim 1, 5, or 6, or the method according to claim 2, 5, or 6, or the pharmaceutical composition according to claim 3, 5, or 6, or the compound according to claim 4, 5, or 6, or a pharmaceutically acceptable salt, isomer, or crystal form thereof, characterized in that, The B-cell malignancy mentioned refers to a patient who has previously received two or more standard treatment regimens.

8. The use according to claim 1, 5, or 6, or the method according to claim 2, 5, or 6, or the pharmaceutical composition according to claim 3, 5, or 6, or the compound according to claim 4, 5, or 6, or a pharmaceutically acceptable salt, isomer, or crystal form thereof, characterized in that, The B-cell malignancy mentioned refers to a patient who has previously received at least two lines of treatment.

9. The use according to claim 1, 5, or 6, or the method according to claim 2, 5, or 6, or the pharmaceutical composition according to claim 3, 5, or 6, or the compound according to claim 4, 5, or 6, or a pharmaceutically acceptable salt, isomer, or crystal form thereof, characterized in that, The B-cell malignancy has been previously treated with at least one BTK inhibitor; or the B-cell malignancy has not been previously treated with a BTK inhibitor.

10. The use according to claim 1, 5, or 6, or the method according to claim 2, 5, or 6, or the pharmaceutical composition according to claim 3, 5, or 6, or the compound according to claim 4, 5, or 6, or a pharmaceutically acceptable salt, isomer, or crystal form thereof, characterized in that, The B-cell malignancy mentioned is one that has not been previously treated.

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