Crystalline forms of compounds that are MALT1 inhibitors

Abstract

The present invention relates to a crystalline form of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]-1H-pyrazole-4-carboxamide (Compound A) monohydrate and a preparation method thereof. The crystalline form and a composition thereof can be used to treat MALT-1 related diseases.

Description

Technical Field

[0001] The present invention relates to a crystalline form of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]-1H-pyrazole-4-carboxamide (Compound A) monohydrate. The crystalline form can be used to treat diseases, syndromes, conditions or disorders, in particular MALT1-related diseases, syndromes, conditions or disorders, including but not limited to cancer and immune diseases. The present invention also relates to a pharmaceutical composition comprising such a crystalline form, a method for preparing such a crystalline form, and the use of such a crystalline form or a pharmaceutical composition for treating cancer and autoimmune diseases, syndromes, disorders or conditions associated with MALT1 inhibitors. Background Art

[0002] MALT1 (Mucosa-associated lymphoid tissue lymphoma translocation 1) is a key mediator of the classical NFKB signaling pathway. MALT1 is the only human paracaspase and transduces signals from the B cell receptor (BCR) and the T cell receptor (TCR). MALT1 is the active subunit of the CBM complex formed after receptor activation. The CBM complex consists of multiple subunits of three proteins: CARD11 (caspase recruitment domain family member 11), BCL10 (B cell CLL / lymphoma 10) and MALT1. MALT1 affects NFKB signaling through two mechanisms: first, MALT1 acts as a scaffold protein and recruits NFKB signaling proteins, such as TRAF6, TAB-TAK1 or NEMO-ΙKKα / β; second, MALT1, as a cysteine ​​protease, cuts and thereby inactivates negative regulators of NFKB signaling, such as RelB, A20 or CYLD. The ultimate endpoint of MALT1 activity is nuclear translocation of the FKB transcription factor complex and activation of FKB signaling (Jaworski et al., Cell Mol Life Science 2016. 73, 459-473).

[0003] The constitutive activation of FKB signaling is a hallmark of ABC-DLBCL (diffuse large B-cell lymphoma of activated B-cell-like subtype, which is a more aggressive form of DLBCL). DLBCL is the most common form of non-Hodgkin's lymphoma (NHL), accounting for approximately 25% of lymphoma cases, while ABC-DLBCL accounts for approximately 40% of DLBCL. In ABC-DLBCL patients, NFKB pathway activation is driven by mutations in signaling components (e.g., CD79A / B, CARD11, MYD88 or A20) (Staudt, Cold Spring Harb Perspect Biol [Cold Spring Harb Biology Outlook] 2010, 2; Lim et al., Immunol Rev [Immunology Review] 2012, 246, 359-378).

[0004] The use of BTK inhibitors (e.g., ibrutinib) provides clinical proof of concept that inhibition of NFKB signaling is effective in ABC-DLBCL. MALT1 is downstream of BTK in the NFKB signaling pathway, and MALT1 inhibitors can target ABC-DLBCL patients who do not respond to ibrutinib (primarily those with CARD11 mutations), as well as treat patients who have acquired resistance to ibrutinib.

[0005] Small molecule tool compound inhibitors of the MALT1 protease have shown efficacy in preclinical models of ABC-DLBCL (Fontan et al., Cancer Cell 2012, 22, 812-824; Nagel et al., Cancer Cell 2012, 22, 825-837). Interestingly, covalent catalytic sites and allosteric inhibitors of MALT1 protease function have been described, suggesting that inhibitors of this protease may be useful as pharmaceutical agents (Demeyer et al., Trends Mol Med 2016, 22, 135-150).

[0006] Chromosomal translocations that produce API2-MALT1 fusion oncoproteins are the most common mutations identified in MALT (mucosa-associated lymphoid tissue) lymphomas. API2-MALT1 is an effective activator of the NFKB pathway (Rosebeck et al., World J Biol Chem [World Journal of Biochemistry] 2016, 7, 128-137). API2-MALT1 mimics ligand-bound TNF receptors, promoting TRAF2-dependent ubiquitination of RIP1 (which serves as a scaffold for activating classical NFKB signaling). In addition, it has been shown that API2-MALT1 cuts and generates stable constitutively active fragments of NFKB-induced kinases (NIK), thereby activating non-classical FKB pathways (Rosebeck et al., Science [Science], 2011, 331, 468-472).

[0007] In addition to lymphoma, MALT1 has been shown to play a key role in innate and adaptive immunity (Jaworski M et al., Cell Mol Life Sci. 2016). MALT1 protease inhibitors can reduce disease onset and progression in experimental allergic encephalomyelitis in mice, a mouse model of multiple sclerosis (Mc Guire et al., J. Neuroinflammation 2014, 11, 124). Mice expressing catalytically inactive MALT1 mutants show loss of marginal zone B cells and B1 B cells, as well as general immune defects characterized by reduced T and B cell activation and proliferation. However, those mice also develop spontaneous multi-organ autoimmune inflammation at 9 to 10 weeks of age. It is still poorly understood why the knock-in mice with disabled MALT1 protease show a breakdown of tolerance, while the conventional MALT1 KO mice do not. One hypothesis suggests that the imbalance in immune homeostasis in MALT1 protease knock-in mice may be caused by an incomplete lack of T cells and B cells but a severe lack of immunoregulatory cells (Jaworski et al., EMBO J. [Journal of the European Molecular Biology Association] 2014; Gewies et al., Cell Reports [Cell Reports] 2014; Bornancin et al., J. Immunology [Journal of Immunology] 2015; Yu et al., PLOS One [Public Library of Science Journal] 2015). Similarly, human MALT deficiency is associated with combined immunodeficiency disorder (McKinnon et al., J. Allergy Clin. Immunol. 2014, 133, 1458-1462; Jabara et al., J. Allergy Clin. Immunol. 2013, 132, 151-158; Punwani et al., J. Clin. Immunol. 2015, 35, 135-146). Given the differences between genetic mutations and pharmacological inhibition, the phenotype of knock-in mice with ineffective MALT1 protease may not be similar to the phenotype of patients treated with MALT1 protease inhibitors. Reducing immunosuppressive T cells by MALT1 protease inhibition may benefit cancer patients by potentially improving anti-tumor immunity.

[0008] Therefore, MALT1 inhibitors may provide therapeutic benefit to patients suffering from cancer and / or immune diseases.

[0009] WO 2018 / 119036 (which is incorporated herein by reference) discloses compounds that inhibit MALT1, including 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]-1H-pyrazole-4-carboxamide (referenced in WO 2018 / 119036 as Compound 158).

[0010] There is a need to provide alternative forms of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]-1H-pyrazole-4-carboxamide. Summary of the invention

[0011] The present invention relates to crystalline form III of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide (Compound A) monohydrate:

[0012]

[0013] One of ordinary skill in the art will recognize that other tautomeric arrangements of Compound A are possible. For example, it should be understood that

[0014]

[0015] Can exist in another tautomeric arrangement.

[0016]

[0017] In the context of the present invention, in the crystalline form of compound A, compound A may be in one of the above tautomeric arrangements or may be a mixture thereof, the exact tautomeric arrangement being unknown. For simplicity, only one possible tautomeric arrangement of the groups of compound A is used to describe these compounds, but it should be clear to a person skilled in the art that in the crystalline form of compound A (e.g., crystalline form III of compound A monohydrate), compound A may be in one of the above tautomeric arrangements or may be a mixture thereof.

[0018] One embodiment of the present invention relates to a pharmaceutical composition comprising crystalline Form III of Compound A monohydrate.

[0019] The present invention also provides a pharmaceutical composition comprising, consisting of and / or essentially consisting of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and / or a pharmaceutically acceptable diluent, and crystalline form III of compound A monohydrate.

[0020] Also provided are methods for preparing pharmaceutical compositions comprising mixing, consisting of and / or consisting essentially of crystalline Form III of Compound A monohydrate, and a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and / or a pharmaceutically acceptable diluent.

[0021] The present invention further provides a method of using crystalline Form III of Compound A monohydrate to treat or ameliorate a disease, syndrome, condition or disorder in a subject (including a mammal and / or a human), wherein the disease, syndrome, condition or disorder (including but not limited to cancer and / or immune disease) is affected by the inhibition of MALT1.

[0022] The present invention also relates to the use of crystalline form III of Compound A monohydrate in the preparation of a medicament for the treatment of a disease, syndrome, disorder or condition affected by inhibition of MALT1, such as cancer and / or immune diseases.

[0023] Exemplified herein are methods of treating a disease, syndrome, condition or disorder mediated by MALT1 selected from the group consisting of lymphoma, leukemia, carcinoma and sarcoma, such as non-Hodgkin's lymphoma (NHL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small cell lymphoma (SCL), or both. Lymphocytic lymphoma (SLL), Waldenstrom's macroglobulinemia, lymphoblastic T-cell leukemia, chronic myeloid leukemia (CML), hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, brain cancer (glioma), malignant glioma, breast cancer, colorectal cancer / colon cancer, prostate cancer, lung cancer (including non-small cell lung cancer), gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer (kidney cancer), squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, cheek cancer, oral cancer, and GIST (gastrointestinal stromal tumor), the methods comprising administering to a subject in need thereof a therapeutically effective amount of crystalline Form III of Compound A monohydrate, consisting of and / or consisting essentially of the same.

[0024] In another embodiment, the present invention is directed to crystalline Form III of Compound A monohydrate for use as a medicament.

[0025] In another embodiment, the present invention is directed to crystalline Form III of Compound A monohydrate for use in the treatment of a disease, syndrome, condition or disorder affected by inhibition of MALT1 selected from the group consisting of lymphoma, leukemia, carcinoma and sarcoma, such as non-Hodgkin's lymphoma (NHL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, Chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom's macroglobulinemia, lymphoblastic T-cell leukemia, chronic myeloid leukemia (CML), hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, brain cancer (glioma), malignant glioma, breast cancer, colorectal cancer / colon cancer, prostate cancer, lung cancer (including non-small cell lung cancer), gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer (kidney cancer), squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial carcinoma, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, cheek cancer, oral cancer, and GIST (gastrointestinal stromal tumor).

[0026] In another embodiment, the present invention is directed to a composition comprising crystalline Form III of Compound A monohydrate for use in treating a disease, syndrome, condition or disorder affected by inhibition of MALT1, the disease, syndrome, condition or disorder selected from the group consisting of lymphoma, leukemia, carcinoma and sarcoma, such as non-Hodgkin's lymphoma (NHL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma tumors, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom's macroglobulinemia, lymphoblastic T-cell leukemia, chronic myeloid leukemia (CML), hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, brain cancer (glioma), malignant glioma, breast cancer, colorectal cancer / colon cancer, prostate cancer, lung cancer (including non-small cell lung cancer), gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer (kidney cancer), squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, cheek cancer, oral cancer, and GIST (gastrointestinal stromal tumor).

[0027] In another embodiment, the present invention is directed to a composition comprising crystalline Form III of Compound A monohydrate for use in treating a disease, syndrome, condition or disorder affected by inhibition of MALT1 selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma.

[0028] One embodiment of the present invention relates to a composition comprising crystalline Form III of Compound A monohydrate for use in treating immune diseases affected by inhibition of MALT1, including but not limited to autoimmune disorders and inflammatory disorders, such as arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplant rejection, chronic allogeneic transplant rejection, acute or chronic graft-versus-host disease, dermatitis (including atopic dermatitis, dermatomyositis, psoriasis), Behcet's disease ( diseases), uveitis, myasthenia gravis, Graves' disease, Hashimoto's thyroiditis, Sjögren's syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune complex vasculitis, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, lung disease (including edema, embolism), fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, and polymyositis.

[0029] In another embodiment, the present invention is directed to a composition comprising crystalline Form III of Compound A monohydrate for use in treating a disease, syndrome, condition or disorder affected by inhibition of MALT1 selected from the group consisting of rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (Pso), ulcerative colitis (UC), Crohn's disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD).

[0030] The present invention also relates to the preparation of crystalline form III of compound A monohydrate. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] When read in conjunction with the accompanying drawings, the content of the present invention and the following detailed description will be further understood. For the purpose of illustrating the present invention, exemplary embodiments of the present invention are shown in the accompanying drawings; however, the present invention is not limited to the specific disclosure of these drawings. In these drawings:

[0032] Figure 1 is the X-ray powder diffraction (XRPD) pattern of Compound A monohydrate crystalline Form III.

[0033] Figure 2 is a differential scanning calorimetry (DSC) thermogram of Compound A monohydrate crystalline Form III.

[0034] Figure 3 is the thermogravimetric analysis (TGA) curve of Compound A monohydrate crystalline form III.

[0035] Figure 4 is a dynamic vapor sorption (DVS) isotherm plot of Compound A monohydrate crystalline Form III.

[0036] Figure 5 It is the DVS mass change diagram of Compound A monohydrate crystalline form III.

[0037] Figure 6 is the infrared (IR) spectrum of Compound A monohydrate crystalline Form III.

[0038] Figure 7 is the XRPD pattern of Compound A Hydrate Crystalline Form I.

[0039] Figure 8 is the DSC thermogram of Compound A Hydrate Crystalline Form I.

[0040] Fig. 9 is the TGA curve of Compound A Hydrate Crystalline Form I.

[0041] Fig.10 : is the DVS isotherm diagram of Compound A hydrate crystalline form I.

[0042] Fig.11 It is the DVS mass change diagram of Compound A Hydrate Crystalline Form I.

[0043] Fig.12 is the IR spectrum of Compound A Hydrate Crystalline Form I. DETAILED DESCRIPTION

[0044] This disclosure can be more fully understood by reference to the following description, including the following glossary of terms and summary examples. It should be understood that, for clarity, certain features of the disclosed crystalline forms, compositions and methods described herein in the context of separate aspects may also be provided in combination in a single aspect. Conversely, for brevity, the different features of the disclosed crystalline forms, compositions and methods described in the context of a single aspect may also be provided individually or in any subcombination.

[0045] Some quantitative expressions given herein are not qualified with the term "about". It should be understood that, whether or not the term "about" is explicitly used, each amount given herein is intended to refer to the actual value given, and also to approximate values ​​based on reasonable inferences of such given values ​​by one of ordinary skill in the art, including approximate values ​​due to experimental and / or measurement conditions for such given values.

[0046] Throughout the specification and claims of this application, the words “comprise” and “contain”, and variations of these words such as “comprising and comprises” mean “including but not limited to” and are not intended to (and do not) exclude other components.

[0047] For purposes of this disclosure, the terms "crystalline form" and "polymorph" are synonymous. Characterization information for crystalline forms is provided herein. It should be understood that determination of a specific form can be accomplished using any portion of the characterization information that one skilled in the art would recognize as sufficient to establish the presence of a specific form. For example, even a single distinguishing peak is sufficient for one skilled in the art to understand that a specific form is present.

[0048] The term "isolated form" refers to a compound that exists in a form separated from any mixture, solvent system or biological environment of one or more other compounds. In one embodiment of the present invention, the crystalline form exists in an isolated form.

[0049] The term "room temperature (RT)" refers to a temperature from about 15°C to about 30°C, specifically from about 20°C to about 30°C. Preferably, room temperature is a temperature of about 25°C.

[0050] When one or more XRPD peaks given in angles of two theta (2θ) are used to identify a crystalline form, each 2θ value is understood to mean ± 0.2° of the given value unless otherwise stated.

[0051] When one or more temperatures (eg, onset of endothermic transition, melting, etc.) from a differential scanning calorimetry thermogram (DSC) curve are used to identify a crystalline form, unless otherwise indicated, each temperature value should be understood to mean the given value ± 2°C.

[0052] The term "seeding" refers to the addition of a crystallization material to a solution or mixture to initiate crystallization or recrystallization.

[0053] Compound A may exist as a solvate. The "solvate" may be a solvate with water (ie, hydrate) or with a common organic solvent.

[0054] The crystalline form III of compound A monohydrate can be provided in a substantially pure form, wherein the mole percentage of impurities in the isolated crystalline form is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably less than about 0.5 mole percent, and most preferably less than about 0.1 mole percent. In one embodiment of the present invention, the crystalline form III of compound A monohydrate is present in a substantially pure form.

[0055] Compound A is also provided herein as a mixture of a crystalline form III of a monohydrate of compound A and one or more other forms of compound A or its solvate. At least a specific weight percentage of compound A can be a crystalline form III of a monohydrate of compound A. Specific weight percentages include 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5% and 99.9%. When a specific weight percentage of the compound is a monohydrate crystalline form III, the remainder of the compound can be an amorphous form of compound A, a hydrate crystalline form I of compound A, one or more other crystalline forms of compound A, or a mixture thereof.

[0056] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or corresponding agency in countries outside the United States or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0057] The term "subject" refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0058] The term "therapeutically effective amount" refers to an amount of active compound or agent (including crystalline forms of the invention) that elicits the biological or medical response in a tissue system, animal or human that is being sought by a researcher, veterinarian, physician or other clinician, including reduction or inhibition of enzyme or protein activity, or improvement of symptoms, alleviation of symptoms, slowing or delaying disease progression, or prevention of disease.

[0059] In one embodiment, the term "therapeutically effective amount" refers to an amount of the crystalline form of the present invention that, when administered to a subject, is able to: (1) at least partially alleviate, inhibit, prevent and / or reduce (i) a disorder or disease mediated by MALT1; or (ii) associated with MALT1 activity; or (iii) characterized by (normal or abnormal) activity of MALT1; or (2) reduce or inhibit the activity of MALT1; or (3) reduce or inhibit the expression of MALT1; or (4) modify the protein level of MALT1.

[0060] The term "composition" refers to a product comprising the specified ingredients in therapeutically effective amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0061] The term "MALT1-mediated" refers to any disease, syndrome, condition or disorder that may occur in the absence of MALT1 but may occur in the presence of MALT1. Suitable examples of diseases, syndromes, conditions or disorders mediated by MALT1 include, but are not limited to, lymphomas, leukemias, carcinomas and sarcomas, such as non-Hodgkin's lymphoma (NHL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) , Waldenstrom's macroglobulinemia, lymphoblastic T-cell leukemia, chronic myeloid leukemia (CML), hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, brain cancer (glioma), malignant glioma, breast cancer, colorectal cancer / colon cancer, prostate cancer, lung cancer (including non-small cell lung cancer), gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer (kidney cancer), squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial carcinoma, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, cheek cancer, oral cancer, and GIST (gastrointestinal stromal tumor).

[0062] As used herein, the term "MALT1 inhibitor" refers to an agent that inhibits or reduces at least one condition, symptom, disorder and / or disease of MALT1.

[0063] As used herein, unless otherwise indicated, the terms "affect" or "affected" (when referring to a disease, syndrome, condition or disorder affected by inhibition of MALT1) include a reduction in the frequency and / or severity of one or more symptoms or manifestations of the disease, syndrome, condition or disorder; and / or include preventing the development of one or more symptoms or manifestations of the disease, syndrome, condition or disorder or the development of the disease, condition, syndrome or disorder.

[0064] As used herein, in one embodiment, the term "treat, treating or treatment" of any disease, disorder, syndrome or disorder refers to improving the disease, disorder, syndrome or disorder (i.e., slowing down or preventing or reducing the development of the disease or at least one clinical symptom thereof). In another embodiment, "treat, treating or treatment" refers to alleviating or improving at least one physical parameter, including those that cannot be discerned by the patient. In other embodiments, "treat, treating or treatment" refers to regulating the disease, disorder, syndrome or disorder in terms of body (e.g., stabilization of discernible symptoms), physiology (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treat, treating or treatment" refers to preventing or delaying the onset or development or progression of the disease, disorder, syndrome or disorder.

[0065] Crystalline Form I of Compound A Hydrate

[0066] 1-(1-Oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]-1H-pyrazole-4-carboxamide has the following structure and is identified herein as "Compound A".

[0067]

[0068] Compound A can be prepared, for example, by a procedure similar to that described in Example 158 of WO 2018 / 119036 (which is incorporated herein by reference). The procedure of Example 158 has been determined to provide a crystalline Form I of a hydrate of Compound A. Crystalline Form I exhibits hygroscopic behavior.

[0069] Crystalline Form I can be characterized by an X-ray powder diffraction pattern. The X-ray powder diffraction pattern can be obtained using copper K-alpha X-rays having a wavelength of 1.5406.

[0070] The X-ray powder diffraction pattern comprises peaks at 8.4, 12.7, 13.3 and 16.7 ° 2θ ± 0.2 ° 2θ. The X-ray powder diffraction pattern may further comprise at least one peak selected from 6.7, 10.0, 10.7, 12.0, 12.3, 13.5, 14.1, 14.6, 15.4, 15.6, 16.0, 18.1, 18.4, 19.2, 20.0, 20.3, 21.1, 22.0 and 24.9 ° 2θ ± 0.2 ° 2θ.

[0071] Crystalline Form I can be further characterized by an X-ray powder diffraction pattern having four, five, six, seven, eight, nine or more peaks selected from those identified in Table 1.

[0072] Crystalline Form I can be further characterized by an X-ray powder diffraction pattern comprising peaks identified in Table 1, wherein the relative intensity of these peaks is greater than about 2%, preferably greater than about 5%, more preferably greater than about 10%, more preferably greater than about 15%.

[0073] Crystalline Form I can be further treated by essentially Figure 7 The X-ray powder diffraction pattern is shown.

[0074] Crystalline Form I may also be characterized by a differential scanning calorimetry thermogram (DSC) comprising an endotherm with an onset temperature of 66° C. and a peak temperature of 99° C. The DSC may comprise a second endotherm with an onset temperature of 145° C. and a peak temperature of 157° C. Crystalline Form I may be characterized by substantially Figure 8 The DSC shown is used for characterization.

[0075] Crystalline Form I may be further characterized by thermogravimetric analysis (TGA). Crystalline Form I may exhibit substantially Fig. 9 TGA curve shown.

[0076] Crystalline Form I may be further characterized by dynamic vapor sorption (DVS). Crystalline Form I may exhibit substantially Fig.10 DVS isotherm diagram shown.

[0077] Crystalline Form III of Compound A Monohydrate

[0078] Crystalline form III exhibits non-hygroscopic behavior (water absorption is less than 0.2% at 80% relative humidity). Unlike hydrate crystalline form I, crystalline form III avoids the loss of water at low relative humidity (e.g., relative humidity is 20% or less). These are desirable properties in active pharmaceutical ingredients (particularly those intended for solid dosage forms). When variations in water content are avoided, accurate amounts of compound A can be dispensed, and weighing errors can be avoided (e.g., when preparing formulations or dosage forms).

[0079] Crystalline Form III can be characterized by an X-ray powder diffraction pattern. The X-ray powder diffraction pattern can be obtained using copper K-alpha X-rays having a wavelength of 1.5406.

[0080] The X-ray powder diffraction pattern comprises peaks at 16.4, 23.7 and 25.7 ° 2θ ± 0.2 ° 2θ. The X-ray powder diffraction pattern may further comprise peaks at 13.6, 17.9, 22.6, 24.5, 25.2 and 27.1 ° 2θ ± 0.2 ° 2θ. The X-ray powder diffraction pattern may further comprise at least one peak selected from 8.3, 8.6, 11.5, 14.0, 15.4, 17.5, 19.7, 22.0, 22.2, 24.0 and 29.9 ° 2θ ± 0.2 ° 2θ.

[0081] The X-ray powder diffraction pattern may comprise peaks at 8.3, 8.6, 11.5, 13.6, 14.0, 15.4, 16.4, 17.5, 17.9, 19.7, 22.6, 23.7, 24.5, 25.2, 25.7 and 27.1 °2θ ± 0.2 °2θ.

[0082] The X-ray powder diffraction pattern may comprise peaks at 11.5, 16.4, 19.7, 23.7 and 25.7° 2θ ± 0.2° 2θ.

[0083] Crystalline Form III can be further characterized by an X-ray powder diffraction pattern having four, five, six, seven, eight, nine or more peaks selected from those identified in Table 2. Compound A monohydrate crystalline Form III can be further characterized by an X-ray powder diffraction pattern comprising those peaks identified in Table 2, wherein the relative intensity of these peaks is greater than about 2%, preferably greater than about 5%, more preferably greater than about 10%, more preferably greater than about 15%. However, the skilled person will recognize that the relative intensities of these peaks may vary between different samples and between different measurements of the same sample.

[0084] Crystalline Form III can be further prepared by essentially Figure 1 The X-ray powder diffraction pattern is shown.

[0085] Crystalline Form III can also be characterized by a differential scanning calorimetry thermogram (DSC) comprising an endotherm with an onset temperature of 142°C and a peak temperature of 158°C. Crystalline Form III can be characterized by substantially Figure 2 The differential scanning calorimetry thermogram is shown.

[0086] Crystalline Form III may be further characterized by thermogravimetric analysis (TGA). Crystalline Form III may exhibit substantially Figure 3 TGA curve shown.

[0087] Crystalline Form III may be further characterized by DVS. Crystalline Form III may exhibit substantially Figure 4 DVS isotherm diagram shown. Figure 4 The DVS isotherm plot of shows that crystalline Form III is non-hygroscopic.

[0088] Preparation of Crystalline Form III

[0089] Crystalline Form III of Compound A monohydrate can be prepared by recrystallizing Compound A or a hydrate or solvate thereof (eg, Compound A hydrate crystalline Form I) from a suitably selected solvent mixture.

[0090] The crystalline form III of compound A monohydrate can be prepared by the following method, which comprises the following steps: a) adding compound A or its hydrate or solvate to a mixture of ethyl acetate and ethanol and heating to a temperature ranging from about 30°C to the reflux temperature of the solvent; b) adding water to the mixture and filtering out any precipitate, maintaining the temperature; c) adding n-heptane to the mixture, seeding with crystalline form III, and maintaining the temperature; and d) cooling to room temperature to produce a precipitate of the crystalline form; wherein the amount of water is from about 0.1w / w% to about 3w / w% relative to the total weight of the solvent; specifically, wherein the amount of water is from about 1.0w / w% to about 3w / w% relative to the total weight of the solvent.

[0091] In one embodiment, the amount of water is at least 0.3w / w%, specifically 0.4w / w%, more specifically at least 0.8w / w%, even more specifically at least 1.0w / w%, relative to the total weight of the solvent. In one embodiment, the amount of water is at least 0.3w / w%, specifically 0.4w / w%, specifically at least 0.8w / w%, even more specifically at least 1.0w / w%, relative to the total mass of the reaction mixture. In one embodiment, the reaction mixture should contain an amount of water exceeding 0.038 times the amount of compound A.

[0092] In one embodiment, the amount of water is at most 3.0 w / w%, 2.5 w / w%, 2.0 w / w%, 1.5 w / w% or 1.0 w / w% relative to the total weight of the solvent.

[0093] In one embodiment, the amount of water is 1.0 w / w% relative to the total weight of the solvent. In one embodiment, the amount of water is from about 0.3 w / w% to about 1.5 w / w% relative to the total weight of the solvent. In one embodiment, the amount of water is from 0.3 w / w% to 1.5 w / w% relative to the total weight of the solvent.

[0094] Alternatively, the crystalline form III of compound A monohydrate can be prepared by the following method, which comprises the following steps: a) adding compound A or a hydrate or solvate thereof to a mixture of water and isopropanol and heating to a temperature ranging from about 30°C to the reflux temperature of the solvent; b) adding n-heptane to the mixture, seeding with crystalline form III, and maintaining the temperature; and c) cooling to room temperature to produce a precipitate of the crystalline form; wherein the amount of water is from about 1.0 w / w% to about 6.0 w / w% relative to the total weight of the solvent.

[0095] In one embodiment, the amount of water is at least 2.0 w / w%, specifically 2.5 w / w%, more specifically at least 2.8 w / w%, even more specifically at least 3.0 w / w%, relative to the total weight of the solvent. In one embodiment, the amount of water is at least 2.0 w / w%, specifically 2.5 w / w%, more specifically at least 2.8 w / w%, even more specifically at least 3.0 w / w%, relative to the total mass of the reaction mixture.

[0096] In one embodiment, the amount of water is at most 5.5 w / w%, 5.0 w / w%, 4.5 w / w%, 4.0 w / w% or 3.5 w / w% relative to the total weight of the solvent.

[0097] In one embodiment, the amount of water is 3.5 w / w% relative to the total weight of the solvent. In one embodiment, the amount of water is from about 2.0 w / w% to about 5.0 w / w% relative to the total weight of the solvent. In one embodiment, the amount of water is from 2.0 w / w% to 5.0 w / w% relative to the total weight of the solvent.

[0098] The skilled person will recognize that sufficient water must be present in the reaction mixture, and that the particular minimum amount of water depends on the amount of compound A. If the water content is too high, crystalline Form I of compound A may form instead of crystalline Form III of compound A, in which case the water content must be reduced.

[0099] The total weight of solvents mentioned in the above specification refers to the total weight of solvents in which Compound A or its hydrate (eg, monohydrate) or crystalline Form III of the solvate is soluble, excluding anti-solvents (water and n-heptane).

[0100] The skilled person will also understand that if Compound A used as a starting material in the preparation of crystalline Form III is a hydrate, then a certain amount of water will already be available in the system from the starting material. In contrast, if a non-hydrate solvate of Compound A is used as a starting material, then the skilled person will be aware that more water must be added to the mixture to obtain the desired w / w%.

[0101] Compound A or its hydrate or solvate may comprise hydrate crystalline form I. The temperature to which the mixture is heated in the methods described herein may be from about 40° C. to about 55° C. In step a), the mixture may be heated for at least 30 minutes or at least 1 hour. In the step in which n-heptane is added, crystalline form III seed material may be added to the mixture after the addition of n-heptane, and the temperature may be maintained for at least 4 hours. Additional portions of n-heptane may be slowly added over at least 5 hours, specifically over at least 8 hours, and more specifically over at least 10 hours. In the step in which the mixture is cooled to room temperature, the mixture may be stirred at room temperature for at least 12 hours.

[0102] The method described herein may further comprise the step of filtering out the precipitate and washing said precipitate with n-heptane.The method may further comprise the step of drying the precipitate under vacuum, optionally at a temperature of from about 45°C to about 55°C.

[0103] The crystalline form III of the monohydrate of compound A can be prepared by a method comprising the steps of: a) adding compound A or a hydrate or solvate thereof to ethyl acetate or isopropyl acetate; and b) stirring the resulting suspension at a temperature ranging from about 30° C. to the reflux temperature of the solvent to produce a precipitate of the crystalline monohydrate of crystalline form III of compound A. Compound A or a hydrate or solvate thereof may comprise hydrate crystalline form I.

[0104] The temperature to which the mixture is heated can be from about 40° C. to about the solvent reflux temperature or from about 50° C. to about the solvent reflux temperature. The temperature to which the mixture is heated can be about 60° C. The suspension can be stirred for at least 1 day, at least 2 days, at least 3 days, at least 4 days, or at least 5 days.

[0105] The method may further comprise the step c) of filtering out the precipitate. The method may further comprise the step d) of drying the precipitate under vacuum, optionally at a temperature of from about 45°C to about 55°C.

[0106] Alternatively, the crystalline form III of the monohydrate of compound A can be prepared by a process comprising the steps of: a) adding compound A or a hydrate or solvate thereof to a mixture of water and isopropanol; and b) stirring the resulting suspension at a temperature ranging from about 30° C. to the reflux temperature of the solvent to produce a precipitate of the crystalline monohydrate of crystalline form III of compound A. Compound A or a hydrate or solvate thereof may comprise hydrate crystalline form I.

[0107] The temperature to which the mixture is heated can be from about 40° C. to about the solvent reflux temperature or from about 50° C. to about the solvent reflux temperature. The temperature to which the mixture is heated can be about 60° C. The suspension can be stirred for at least 1 day, at least 2 days, at least 3 days, at least 4 days, or at least 5 days.

[0108] The method may further comprise the step c) of filtering out the precipitate. The method may further comprise the step d) of drying the precipitate under vacuum, optionally at a temperature of from about 45°C to about 55°C.

[0109] Composition

[0110] Even though the compounds of the embodiments of the present invention can be administered alone, they are usually administered in admixture with a selected pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and / or a pharmaceutically acceptable diluent, in terms of the intended route of administration and standard pharmaceutical or veterinary practice. Therefore, specific embodiments of the present invention relate to pharmaceutical compositions and veterinary compositions comprising crystalline form III of compound A monohydrate and at least one pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and / or a pharmaceutically acceptable diluent.

[0111] As an example, in the pharmaceutical composition of an embodiment of the present invention, the crystalline form III of compound A monohydrate can be mixed with any suitable one or more binders, one or more lubricants, one or more suspending agents, one or more coating agents, one or more solubilizing agents, and combinations thereof.

[0112] Where appropriate, solid oral dosage forms (eg tablets or capsules) containing the crystalline form of the invention may be administered in at least one dosage form at a time. It is also possible to administer the crystalline form in the form of a sustained release formulation.

[0113] Additional oral forms in which the crystalline form may be administered include elixirs, solutions, syrups, and suspensions; each optionally containing flavoring and coloring agents.

[0114] Alternatively, the crystalline form can be administered by (intratracheal or intranasal) inhalation or in the form of a suppository or vaginal suppository, or can be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. For example, it can be incorporated into a cream comprising, consisting of and / or substantially consisting of, an aqueous emulsion of polyethylene glycol or liquid paraffin. It can also be incorporated into an ointment comprising, consisting of and / or substantially consisting of, a wax or soft paraffin matrix and any stabilizer and preservative that may be needed with a concentration between about 1% and about 10% of the cream weight. Alternative modes of administration include transdermal administration using a skin or transdermal patch.

[0115] The pharmaceutical composition of the present invention (as well as the single monohydrate crystalline form III) can also be injected parenterally, for example, intracavernous, intravenous, intramuscular, subcutaneous, intradermal or intrathecal. In this case, these compositions will also include at least one of a suitable carrier, a suitable excipient, and a suitable diluent.

[0116] For parenteral administration, the pharmaceutical compositions of this invention are preferably used in the form of sterile aqueous solutions which may contain other substances, for example, sufficient salts and monosaccharides to render the solution isotonic with the blood.

[0117] For buccal or sublingual administration, the pharmaceutical compositions of this invention may be administered in the form of tablets or lozenges which can be formulated in conventional manner.

[0118] As another example, according to conventional pharmaceutical compounding techniques, a pharmaceutical composition containing the crystalline form as an active pharmaceutical ingredient can be prepared by mixing the crystalline form with a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, and / or a pharmaceutically acceptable excipient. Carriers, excipients, and diluents can take a variety of forms, depending on the desired route of administration (e.g., oral, parenteral, etc.). Therefore, for liquid oral preparations (e.g., suspensions, syrups, elixirs, and solutions), suitable carriers, excipients, and diluents include water, glycerol, oils, alcohols, flavoring agents, preservatives, stabilizers, colorants, etc.; for solid oral preparations (e.g., powders, capsules, and tablets), suitable carriers, excipients, and diluents include starch, sugar, diluents, granulating agents, lubricants, adhesives, disintegrants, etc. Solid oral preparations can also optionally be coated with substances such as sugars, or enteric coatings to regulate the main sites of absorption and disintegration. For parenteral administration, the carrier, excipient and diluent will usually include sterile water, and other ingredients may be added to increase the solubility and preservation of the composition. Injectable suspensions or solutions may also be prepared using an aqueous carrier and appropriate additives (such as solubilizers and preservatives).

[0119] For an average (70 kg) human, on a regimen of about 1 to about (4x) per day, a therapeutically effective amount of the crystalline Form III of Compound A monohydrate or a pharmaceutical composition thereof comprises an active pharmaceutical ingredient in a dosage range of from about 0.1 mg to about 3000 mg or any specific amount or range therein, particularly from about 1 mg to about 1000 mg or any specific amount or range therein, or more particularly from about 10 mg to about 500 mg or any specific amount or range therein; however, it will be clear to those skilled in the art that the therapeutically effective amount of the crystalline form will vary depending on the disease, syndrome, condition and disorder being treated.

[0120] For oral administration, the pharmaceutical composition is specifically provided in the form of a tablet containing about 1.0, about 10, about 50, about 100, about 150, about 200, about 250, and about 500 mg of crystalline Form III of Compound A monohydrate.

[0121] For oral administration, the pharmaceutical composition is specifically provided in the form of capsules containing about 1.0, about 10, about 50, about 100, about 150, about 200, about 250, and about 500 mg of crystalline Form III of Compound A monohydrate.

[0122] One embodiment of the present invention is directed to a pharmaceutical composition for oral administration comprising crystalline Form III of Compound A monohydrate in an amount from about 25 mg to about 500 mg.

[0123] Advantageously, crystalline Form III of Compound A monohydrate may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of twice, three times and 4x daily.

[0124] The optimal dose of the crystalline form to be administered can be easily determined and will vary with the specific compound used, the mode of administration, the strength of the preparation, and the progression of the disease, syndrome, condition or disorder. In addition, factors associated with the specific subject being treated, including subject sex, age, body weight, diet and administration time, will result in the need to adjust the dose to achieve the appropriate therapeutic level and desired therapeutic effect. Therefore, the above-mentioned doses are examples of average situations. Of course, there may be individual cases where a higher or lower dosage range should be used, and these are within the scope of the present invention.

[0125] Treatment

[0126] Crystalline Form III of Compound A monohydrate may be administered in any of the aforementioned compositions and dosage regimens or by those compositions and dosage regimens established in the art whenever use of the crystalline form is desired by a subject in need thereof.

[0127] Crystalline Form III can be used in methods for treating, ameliorating and / or preventing diseases, syndromes, conditions or disorders affected by inhibition of MALT1. Such methods comprise administering to a subject (including animals, mammals and humans) in need of such treatment, amelioration and / or prevention, a therapeutically effective amount of Crystalline Form III of Compound A monohydrate, consisting of and / or consisting essentially of it.

[0128] One embodiment of the present invention relates to a method of treating a MALT1-dependent or MALT1-mediated disease or condition in a subject in need thereof (including animals, mammals and humans in need of such treatment), the method comprising administering to the subject a therapeutically effective amount of crystalline Form III of Compound A monohydrate.

[0129] In another embodiment, the MALT1 -dependent or MALT1 -mediated disease or disorder is selected from cancers or solid tumors of hematopoietic origin, such as chronic myeloid leukemia, myeloid leukemia, non-Hodgkin's lymphoma, and other B-cell lymphomas.

[0130] Specifically, crystalline Form III of Compound A monohydrate can be used to treat or ameliorate diseases, syndromes, conditions or disorders, such as diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma.

[0131] More specifically, the crystalline form III of compound A monohydrate can be used to treat or improve diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma, and such treatment or improvement comprises administering a therapeutically effective amount of the crystalline form to a subject in need thereof.

[0132] In addition, the crystalline form III of compound A monohydrate can be used to treat or improve immune diseases, syndromes, disorders or conditions selected from the group consisting of rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (Pso), ulcerative colitis (UC), Crohn's disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD).

[0133] In one embodiment, cancers that may benefit from treatment with crystalline Form III of Compound A monohydrate (MALT1 inhibitor) include, but are not limited to, lymphomas, leukemias, carcinomas and sarcomas, such as non-Hodgkin's lymphoma (NHL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytes, and leukemia. lymphoblastic lymphoma (SLL), Waldenstrom's macroglobulinemia, lymphoblastic T-cell leukemia, chronic myeloid leukemia (CML), hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, brain cancer (glioma), malignant glioma, breast cancer, colorectal cancer / colon cancer, prostate cancer, lung cancer (including non-small cell lung cancer), gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer (kidney cancer), squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial carcinoma, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, cheek cancer, oral cancer, and GIST (gastrointestinal stromal tumor).

[0134] In another embodiment, the crystalline form III of compound A monohydrate can be used to treat immune diseases, including but not limited to autoimmune disorders and inflammatory disorders, such as arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplant rejection, chronic allogeneic transplant rejection, acute or chronic graft-versus-host disease, dermatitis (including atopic dermatitis, dermatomyositis, , psoriasis), Behcet's disease, uveitis, myasthenia gravis, Graves' disease, Hashimoto's thyroiditis, Sjögren's syndrome, blistering disorders, antibody-mediated vasculitis syndrome, immune complex vasculitis, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, lung disease (including edema, embolism), fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, and polymyositis.

[0135] One embodiment of the present invention relates to a method of treating a disease, syndrome, condition or disorder, wherein the disease, syndrome, condition or disorder is affected by inhibition of MALT1, the method comprising administering to a subject in need thereof a therapeutically effective amount of crystalline Form III of Compound A monohydrate.

[0136] In further embodiments, the disease, syndrome, condition or disorder is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma, rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (Pso), ulcerative colitis (UC), Crohn's disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD).

[0137] In further embodiments, the disease, syndrome, condition or disorder is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and Waldenstrom's macroglobulinemia.

[0138] In one embodiment, the present invention is directed to a method of treating a disease, syndrome, condition or disorder selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma, rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (Pso), ulcerative colitis (UC), Crohn's disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD), the method comprising administering to a subject in need thereof a therapeutically effective amount of crystalline Form III of Compound A monohydrate.

[0139] In another embodiment, the present invention relates to a method of treating a disease, syndrome, condition or disorder selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and Waldenstrom's macroglobulinemia, the method comprising administering to a subject in need thereof a therapeutically effective amount of crystalline Form III of Compound A monohydrate. In further embodiments, the disease, syndrome, condition or disorder is non-Hodgkin's lymphoma (NHL). In further embodiments, the non-Hodgkin's lymphoma (NHL) is B-cell NHL.

[0140] In another embodiment, the present invention relates to crystalline Form III of Compound A monohydrate for use in the preparation of a medicament for treating a disease, syndrome, disorder or condition in a subject in need thereof, the disease, syndrome, disorder or condition being selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma, rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (Pso), ulcerative colitis (UC), Crohn's disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD).

[0141] In another embodiment, the present invention relates to crystalline Form III of Compound A monohydrate for use in the preparation of a medicament for treating a disease, syndrome, condition or disorder in a subject in need thereof, the disease, syndrome, condition or disorder selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and Waldenstrom's macroglobulinemia. In further embodiments, the disease, syndrome, condition or disorder is non-Hodgkin's lymphoma (NHL). In further embodiments, the non-Hodgkin's lymphoma (NHL) is B-cell NHL.

[0142] In another embodiment, crystalline Form III of Compound A monohydrate is used for use in a method of treating a disorder in a subject in need thereof, the disorder being selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma, rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (Pso), ulcerative colitis (UC), Crohn's disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD).

[0143] In another embodiment, the crystalline Form III of Compound A monohydrate is used for use in a method of treating a disease, syndrome, condition or disorder in a subject in need thereof, the disease, syndrome, condition or disorder selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and Waldenstrom's macroglobulinemia. In further embodiments, in a subject in need thereof, the disease, syndrome, condition or disorder is non-Hodgkin's lymphoma (NHL). In further embodiments, the non-Hodgkin's lymphoma (NHL) is B-cell NHL.

[0144] In another embodiment, crystalline Form III of Compound A monohydrate is for use in treating a disorder in a subject in need thereof, the disorder being selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma, rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (Pso), ulcerative colitis (UC), Crohn's disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD).

[0145] In another embodiment, the crystalline Form III of Compound A monohydrate is for use in treating a disease, syndrome, condition or disorder in a subject in need thereof, the disease, syndrome, condition or disorder selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and Waldenstrom's macroglobulinemia. In further embodiments, in a subject in need thereof, the disease, syndrome, condition or disorder is non-Hodgkin's lymphoma (NHL). In further embodiments, the non-Hodgkin's lymphoma (NHL) is B-cell NHL.

[0146] In another embodiment, crystalline Form III of Compound A monohydrate is for use in treating a disease, syndrome, condition or disorder in a subject in need thereof, wherein the disease, syndrome, condition or disorder is affected by inhibition of MALT1.

[0147] In another embodiment of the present invention, the crystalline form III of compound A monohydrate can be used in combination with one or more other pharmaceutical agents, more particularly with other anticancer agents (e.g., chemotherapeutic agents, antiproliferative agents or immunomodulatory agents), or with adjuvants in cancer therapy (e.g., immunosuppressants or anti-inflammatory agents).

[0148] It will be appreciated that variations may be made to the foregoing embodiments of the invention while still falling within the scope of the invention. Unless otherwise stated, each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent or similar purpose. Therefore, unless otherwise stated, each feature disclosed is merely an example of a general series of equivalent or similar features.

[0149] All possible combinations of the above-indicated embodiments are considered to be encompassed within the scope of the invention.

[0150] The invention will now be illustrated in a non-limiting manner with reference to the following examples.

[0151] Examples

[0152] X-ray powder diffraction (XRPD) analysis was performed on a Bruker (D8 Advance) X-ray powder diffractometer. The compound was spread on a single crystal silicon plate and gently pressed into a flat and uniform shape for testing.

[0153] The samples were run on XRPD using the following method:

[0154] Tube: Cu:K-α

[0155] Generator: Voltage: 40kV; Current: 40mA

[0156] Detector:PSD:LynxEye

[0157] Divergence slit: 0.60mm; incident side Soller Slit: 2.5°

[0158] Detector slit: 10.50mm; Anti-scatter slit: 7.10mm

[0159] Diffraction side Soller slit: 2.5°

[0160] Scan Type: Locking Coupling

[0161] Scan mode: continuous scan

[0162] Scanning parameters: Scanning axis: 2-θ / θ

[0163] Scanning range: 3° to 50°; step length: 0.02°

[0164] Time / step: 0.12s

[0165] Sample speed: 60rpm

[0166] Scanning rate: 10° / min

[0167] Those skilled in the art will recognize that the diffraction pattern and peak positions

[0168] It is generally independent of the diffractometer used and

[0169] Whether a specific calibration method is used. Typically, the peak positions can differ by about ± 0.2 ° 2θ or less. The intensity (and relative intensity) of each specific diffraction peak can also vary according to various factors, including but not limited to particle size, orientation, sample purity, etc. However, the technician will be able to distinguish between Compound A Hydrate Form I and Compound A Monohydrate Form III.

[0170] Thermogravimetric analysis (TGA) was performed on a TA Instruments Q5000 IR Thermogravimetric Analyzer equipped with a Hiden quantitative gas analysis cell. The samples were placed in standard platinum sample pans from TA Instruments after the pans were tared. The samples were scanned from 25° to 300°C with a programmed heating rate of 20°C / min.

[0171] Moisture sorption analysis (DVS) was performed using a Surface Measurement Systems Advantage-1 dynamic vapor sorption apparatus. The moisture profile was evaluated by monitoring vapor sorption / desorption over a relative humidity range of 0% to 95% at 25°C. The moisture profile consisted of 2 cycles of vapor sorption / desorption.

[0172] Infrared (IR) spectroscopy was performed on a Nicolet 6700 FT-IR spectrometer with a micro-ATR accessory.

[0173] Example 1: Preparation of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]-1H-pyrazole-4-carboxamide (Compound A) Hydrate, Crystalline Form I

[0174] Compound A hydrate is prepared by a synthetic method similar to that described in Example 158 of WO 2018 / 119036. The compound prepared by this method is confirmed to be a hydrate crystalline form, crystalline form I.

[0175] X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), and IR spectroscopy ( Figures 7 to 12 ) to characterize crystalline Form I.

[0176] X-ray powder diffraction pattern of crystalline form I ( Figure 7 ) showed different diffraction peaks in the absence of halogen, indicating that it was a crystalline product.

[0177] Table 1 provides the XPRD of Compound A Hydrate Form I ( Figure 7 ) peak list and relative intensities.

[0178] Table 1:

[0179]

[0180]

[0181]

[0182]

[0183] DSC curve of crystalline form I ( Figure 8 ) shows a broad endothermic signal at 98.7°C (142 J / g) with an onset temperature of 66.3°C, which is due to the dehydration of the hydrate. A second endothermic signal is observed at 157.0°C (17 J / g) with an onset temperature of 145.2°C, corresponding to the melting of the dehydrated form.

[0184] TGA curve of crystalline form I ( Fig. 9) shows a weight loss of 4.7% from RT up to 82°C due to evaporation of the solvent (water) present. A weight loss of 0.4% was recorded between 82°C and 122°C and this weight loss corresponds to further evaporation of the solvent.

[0185] DVS mass change diagram of crystalline form I ( Fig.11 ) showed a weight loss of approximately 2.7% during the initial drying step. The compound rapidly adsorbs and desorbs water in the humidity range of 0-20% RH (relative humidity) ( Fig.10 and Fig.11 ). Depending on the atmospheric humidity, it can absorb up to 4.1%-4.2% of water (RH between 0%-20%) and completely dry during the desorption cycle. In the humidity range of 20%-95% RH, the compound slowly and reversibly adsorbs and desorbs with 1.8% of water adsorbed and desorbed. The XRPD pattern and IR spectrum of the fractions obtained after DVS testing were comparable to the starting material. No indication of a change in the solid state form was observed.

[0186] The data indicate that the water of hydration in crystalline Form I is loosely bound and is lost at RH of 20% and below.

[0187] Example 2: Preparation of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]-1H-pyrazole-4-carboxamide (Compound A) monohydrate, crystalline form III seed material

[0188] About 200 mg of Compound A, Hydrate Form I obtained from Example 1 was added to 400 μl-800 μl of ethyl acetate or isopropyl acetate, and the resulting suspension was stirred at 60° C. for 5 days. The precipitate was then filtered and dried under vacuum at 50° C. for 24 hours to yield a crystalline monohydrate of Compound A, Crystalline Form III.

[0189] Example 3: Preparation of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]-1H-pyrazole-4-carboxamide (Compound A) monohydrate, crystalline form III

[0190] 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]-1H-pyrazole-4-carboxamide (100 g) obtained by a procedure similar to the synthesis method described in Example 158 of WO 2018 / 119036 was charged into a flask (R1) together with ethanol (150 mL-170 mL) and ethyl acetate (80 mL-100 mL). The obtained mixture was heated to 40°-50°C and stirred for 0.5–2 hours. Water (4 mL–7 mL) was then added and the water content was measured by Karl Fischer titration. The contents of R1 were warmed to 40°-55°C and filtered into a second flask (R2) preheated at 40°-55°C. R1 was rinsed with ethyl acetate (80 mL-100 mL) at 40°-50°C, and the contents were filtered into R2. n-Heptane (340 mL-410 mL) was charged into R2 over about 20-40 min, maintaining 40°-55°C. The obtained solution was seeded with 1.9 g-2.1 g of Compound A monohydrate crystalline form III (obtained from Example 2), and the obtained mixture was stirred at 40°-55°C for 4-8 hours. n-Heptane (680 mL-750 mL) was added over 10-15 hours, maintaining 40°-55°C; the obtained mixture was stirred at 40°-55°C for another 2-5 hours, and then cooled to 20°-25°C for 7-13 hours. The suspension was stirred at 20°-25°C for 12h-18h, and then filtered and washed with n-heptane (180 mL-250 mL). After drying at 45°-55°C under vacuum for 15-22 hours, 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]-1H-pyrazole-4-carboxamide monohydrate (crystalline form III) was obtained with 80% yield.

[0191] Example 3b: Preparation of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]-1H-pyrazole-4-carboxamide (Compound A) monohydrate, crystalline form III

[0192] 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]-1H-pyrazole-4-carboxamide (25 g) obtained by a procedure similar to the synthesis method described in Example 158 of WO 2018 / 119036 was charged into a flask (R1) together with water (2.5 mL-4.5 mL) and isopropanol (IPA) (100 mL). The obtained mixture was heated to 50° C. and stirred for 0.5–2 hours. n-Heptane (125 mL) was charged into R1. The obtained solution was seeded with 500 mg of Compound A monohydrate crystalline form III (obtained from Example 2), and the obtained mixture was stirred at 50° C. for 72 hours. n-Heptane (275 mL) was added over 12 hours, maintaining 50°C; the obtained mixture was stirred at 50°C for another 58 hours, then cooled to 20°-25°C for 2 hours. The suspension was stirred at 20°-25°C for 94 hours, then filtered and washed with n-heptane (100 mL). After drying at 50°C under vacuum for 24 hours, 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]-1H-pyrazole-4-carboxamide monohydrate (crystalline form III) was obtained with a yield of 90%.

[0193] Using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), and IR spectroscopy – see Figures 1 to 6 To characterize crystalline Form III.

[0194] X-ray powder diffraction pattern of crystalline form III ( Figure 1 ) showed different diffraction peaks in the absence of halogen, indicating that the compound existed as a crystalline product.

[0195] Table 2 provides the XPRD of Compound A monohydrate crystalline Form III ( Figure 1 ) peak list and relative intensities.

[0196] Table 2:

[0197]

[0198]

[0199]

[0200] DSC curve of crystalline form III ( Figure 2 ) showed the collapse and liquefaction of the crystalline product as an endothermic signal with an onset temperature of 142 °C and a maximum temperature of 158 °C (145.9 J / g).

[0201] TGA curve of crystalline form III ( Figure 3 ) shows that the total weight loss from RT up to 180°C is 3.9% due to evaporation of the combined solvent.

[0202] The hygroscopic characteristics of crystalline Form III were evaluated by dynamic vapor sorption (DVS) analysis. Figure 4 and Figure 5 As can be seen from the DVS diagram in, crystalline form III is non-hygroscopic. Unlike crystalline form I, crystalline form III does not lose water under low RH (relative humidity) conditions. The XRPD diagram and IR spectrum of the fractions obtained after the DVS test are comparable to the starting material. No indication of a change in solid state form was observed.

[0203] Example 4: Physical stability study of Compound A monohydrate crystalline form III

[0204] The physical stability of Compound A monohydrate crystalline Form III was tested with respect to water loss or water absorption.

[0205] For initial studies, a 0.5 g sample of the monohydrate crystalline Form III was placed in a double layer antistatic colorless LDPE bag and sealed.

[0206] For long-term studies (stability after 1 month and 3 months), 1.5 g samples of the monohydrate crystalline form III were placed in double antistatic colorless LDPE bags and sealed. The samples were stored in cardboard drums at 30 ± 2 ° C / 75% ± 5% RH and 40 ± 2 ° C / 75% ± 5% RH.

[0207] For photostability studies, 1.5 g of crystalline Form III monohydrate was placed in a Petri dish and spread into a layer not more than 3 mm thick. The Petri dish was covered with a quartz cover slip and sealed with parafilm. Photostability testing was performed according to ICH Q1B Option 2 (ICH Harmonized Tripartite Guideline, Stability Testing: Photostability Testing of New Drugs and Products, Q1B, Step 4 Version, November 6, 1996). Photostability samples were stored under separate lamps emitting visible light and UV-A light so that the total exposure was not less than 1.2 million lux hours and 200 watt-hours / m, respectively. 2 .

[0208] According to the United States Pharmacopeia (USP <921> Method IC; recently appeared in Pharmacopoeia Forum: Volume 38(1); Page Information USP42 / NF37-7092) and European Pharmacopoeia 2.5.32 (Edition 10.0), uses the evaporative coulometric Karl Fischer method to determine the water content of each sample.

[0209] The results (Table 3) show that the monohydrate crystalline Form III is non-hygroscopic.

[0210] Table 3:

[0211]

[0212] Although preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Various modifications, changes, and substitutions are readily apparent to those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be used in practicing the present invention, and embodiments within the scope of these claims and their equivalents are thus covered.

Claims

1. A crystalline form of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]-1H-pyrazole-4-carboxamide (Compound A) monohydrate: wherein the crystalline form is crystalline Form III which produces an X-ray powder diffraction pattern comprising peaks at 11.5, 13.6, 16.4, 17.9, 22.6, 23.7, 24.5, 25.2, 25.7 and 27.1 °2θ±0.2 °2θ.

2. The crystalline form of claim 1, wherein the X-ray powder diffraction pattern further comprises at least one peak selected from 8.3, 8.6, 14.0, 15.4, 17.5, 19.7, 22.0, 22.2, 24.0 and 29.9° 2θ ± 0.2° 2θ.

3. The crystalline form of claim 1 or 2, wherein the X-ray powder diffraction pattern further comprises peaks at 8.3, 8.6, 14.0, 15.4, 17.5, 19.7, 22.0, 22.2, 24.0 and 29.9° 2θ ± 0.2° 2θ.

4. The crystalline form of claim 1 or 2, further characterized by a differential scanning calorimetry thermogram comprising an endotherm with an onset temperature of 142°C ± 2°C and / or a peak temperature of 158°C ± 2°C.

5. A pharmaceutical composition comprising the crystalline form according to any one of the preceding claims, and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient and a pharmaceutically acceptable diluent.

6. The pharmaceutical composition of claim 5, wherein the composition is a solid oral dosage form.

7. The pharmaceutical composition of claim 5, wherein the composition is a syrup, elixir or suspension.

8. Use of the crystalline form of any one of claims 1 to 4 for the preparation of a medicament for treating a disease, syndrome, disorder or condition affected by MALT1 inhibition in a subject in need thereof, wherein the disease, syndrome, condition or disorder is selected from cancer and immune diseases.

9. The use according to claim 8, wherein the cancer is selected from lymphoma, leukemia and sarcoma.

10. The method of claim 8, wherein the cancer is selected from the group consisting of non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom's macroglobulinemia, lymphoblastic T-cell leukemia, chronic myeloid leukemia (CML), hairy cell leukemia. , acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, brain cancer, malignant glioma, breast cancer, colorectal cancer / colon cancer, prostate cancer, lung cancer, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, osteosarcoma, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, urothelial cancer, vulvar cancer, esophageal cancer, and GIST (gastrointestinal stromal tumor).

11. The use of claim 8, wherein the cancer is B-cell NHL.

12. The use of claim 8, wherein the cancer is a sarcoma.

13. The use according to claim 8, wherein the cancer is thyroid cancer.

14. The use according to claim 8, wherein the cancer is salivary gland cancer.

15. The use according to claim 8, wherein the cancer is nasopharyngeal carcinoma.

16. The use according to claim 8, wherein the cancer is buccal cancer.

17. The use according to claim 8, wherein the cancer is oral cancer.

18. The use according to claim 8, wherein the immune disease is selected from the group consisting of autoimmune disorders and inflammatory disorders.

19. The method of claim 8, wherein the immune disease is selected from the group consisting of arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplant rejection, chronic allogeneic transplant rejection, acute or chronic graft-versus-host disease, dermatitis, Behcet's disease, uveitis, myasthenia gravis, Graves' disease, Hashimoto's thyroiditis, Sjögren's syndrome, blistering disorder, antibody-mediated vasculitis syndrome, immune complex vasculitis, allergic disorder, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, edema, embolism, fibrosis, sarcoidosis, hypertension, emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, and polymyositis.

20. The use of claim 8, wherein the disease, syndrome, condition or disorder is selected from diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (Pso), ulcerative colitis (UC), Crohn's disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD).

21. A method for preparing a crystalline form as claimed in any one of claims 1 to 4, comprising the step of recrystallizing compound A, wherein the recrystallization comprises the following steps: a) adding compound A or a hydrate or solvate thereof to a mixture of ethyl acetate and ethanol and heating to a temperature ranging from 30° C. to the reflux temperature of the solvent; b) adding water to the mixture and filtering off any precipitate, maintaining said temperature; c) adding n-heptane to the mixture, seeding with crystalline form III, and maintaining the temperature; and d) cooling to room temperature to produce a precipitate in the form of a crystal as claimed in any one of claims 1 to 4; The amount of water is from 0.1 w / w % to 3.0 w / w % relative to the total weight of the solvent.

22. The method of claim 21, wherein the temperature is from 40°C to 55°C.

23. A method for preparing a crystalline form as claimed in any one of claims 1 to 4, comprising the step of recrystallizing compound A, wherein the recrystallization comprises the following steps: a) adding compound A or a hydrate or solvate thereof to a mixture of water and isopropanol and heating to a temperature ranging from 30° C. to the reflux temperature of the solvent; b) adding n-heptane to the mixture, seeding with crystalline Form III, and maintaining said temperature; and c) cooling to room temperature to produce a precipitate in the form of crystals as claimed in any one of claims 1 to 4; The amount of water is from 1.0 w / w % to 6.0 w / w % relative to the total weight of the solvent.

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