Crystalline forms

Abstract

The present invention relates to crystalline Forms of (III). The compound may be useful for the treatment of a disease, syndrome, condition, or disorder, particularly a MALT1-related disease, syndrome, condition, or disorder, including but not limited to, cancer and immunological diseases.

Description

[0001] CRYSTALLINE FORMS

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to crystalline Forms of

[0004] The compound may be useful for the treatment of a disease, syndrome, condition, or disorder, particularly a MALTl-related disease, syndrome, condition, or disorder, including but not limited to, cancer and immunological diseases.

[0005] BACKGROUND OF THE INVENTION

[0006] 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 T cell receptor (TCR). MALT1 is the active subunit of the CBM complex which is formed upon receptor activation. The CBM complex consists of multiple subunits of three proteins: CARD 11 (caspase recruitment domain family member 11), BCL10 (B-cell CLL / Lymphoma 10) and MALT1. MALT1 affects NFKB signaling by two mechanisms: firstly, MALT1 functions as a scaffolding protein and recruits NFKB signaling proteins such as TRAF6, TAB-TAK1 or NEMO-IKKa / P; and secondly, MALT1, as a cysteine protease, cleaves and thereby deactivates negative regulators of NFKB signaling, such as RelB, A20 or CYLD. The ultimate endpoint of MALT1 activity is the nuclear translocation of the NFKB transcription factor complex and activation of NFKB signaling.

[0007] Constitutive activation of NFKB signaling is the hallmark of ABC-DLBCL (Diffuse Large B cell Lymphoma of the Activated B Cell-like subtype), the 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 comprises approximately 40% of DLBCL. NFKB pathway activation is driven by mutations of signaling components, such as CD79A / B, CARD11, MYD88 or A20, in ABC-DLBCL patients.

[0008] The use of BTK inhibitors, for example Ibrutinib, provides clinical proof-of-concept that inhibiting NFKB signaling in ABC-DLBCL is efficacious. MALT1 is downstream of BTK in the NFKB signaling pathway and a MALT1 inhibitor could provide a therapeutic option for ABC-DLBCL patients not responding to Ibrutinib, patients with CARD 11 mutations, and patients that have acquired resistance to Ibrutinib.

[0009] Small molecule tool compound inhibitors of MALT1 protease have demonstrated efficacy in preclinical models of ABC-DLBCL.

[0010] The chromosomal translocation creating the API2-MALT1 fusion oncoprotein is the most common mutation identified in MALT (mucosa-associated lymphoid tissue) lymphoma. API2-MALT1 is a potent activator of the NFKB pathway. API2-MALT1 mimics ligand-bound TNF receptor, promotes TRAF2-dependent ubiquitination of RIP 1 which acts as a scaffold for activating canonical NFKB signaling. Furthermore, API2-MALT1 has been shown to cleave and generate a stable, constitutively active fragment of NFKB-inducing kinase (NIK) thereby activating the non-canonical NFKB pathway.

[0011] In addition to lymphomas, MALT1 has been shown to play a critical role in innate and adaptive immunity. MALT1 protease inhibitor can attenuate disease onset and progression of mouse experimental allergic encephalomyelitis, a mouse model of multiple sclerosis. Mice expressing catalytically inactive MALT1 mutant showed loss of marginal zone B cells and Bl B cells and general immune deficiency characterized as decreased T and B cell activation and proliferation. However, those mice also developed spontaneous multi-organ autoimmune inflammation at the age of 9 to 10 weeks. It is still poorly understood why MALT1 protease dead knock-in mice show a break of tolerance while conventional MALT1 KO mice do not. One hypothesis suggests the unbalanced immune homeostasis in MALT1 protease dead knock- in mice may be caused by incomplete deficiency in T and B cell but severe deficiency of immunoregulatory cells. Similarly, MALT deficiency in humans has been associated with combined immunodeficiency disorder. Given the difference between genetic mutation and pharmacological inhibition, a phenotype of MALT1 protease dead knock-in mice might not resemble that of patients treated with MALT1 protease inhibitors. A reduction of immunosuppressive T cells by MALT1 protease inhibition may be beneficial to cancer patients by potentially increasing antitumor immunity.

[0012] Thus, MALT1 inhibitors of the present invention may provide a therapeutic benefit to patients suffering from cancer and / or immunological diseases.

[0013] BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The summary, as well as the following detailed description, is further understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there are shown in the drawings exemplary embodiments of the invention; however, the invention is not limited to the specific disclosure of the drawings.

[0015] In the drawings:

[0016] Figure la is an X-ray powder diffraction (XRPD) pattern of a crystalline Form III Figure lb is a differential scanning calorimetry (DSC) thermogram of crystalline Form III Figure 1c is a thermogravimetric analysis (TGA) curve of crystalline Form III

[0017] Figure 2a is an X-ray powder diffraction (XRPD) patern of a crystalline Form IV

[0018] Figure 2b is a differential scanning calorimetry (DSC) thermogram of crystalline Form IV

[0019] Figure 3a is an X-ray powder diffraction (XRPD) patern of a crystalline Form V

[0020] Figure 3b is a differential scanning calorimetry (DSC) thermogram of crystalline Form V

[0021] Figure 3c is a thermogravimetric analysis (TGA) curve of crystalline Form V

[0022] Figure 4a is an X-ray powder diffraction (XRPD) patern of a crystalline Form VI

[0023] Figure 4b is a differential scanning calorimetry (DSC) thermogram of crystalline Form IV

[0024] Figure 5a is an X-ray powder diffraction (XRPD) patern of a crystalline Form VII

[0025] Figure 5b is a differential scanning calorimetry (DSC) thermogram of crystalline Form VII

[0026] Figure 6a is an X-ray powder diffraction (XRPD) patern of a crystalline Form VIII

[0027] Figure 6b is a differential scanning calorimetry (DSC) thermogram of crystalline Form VIII

[0028] Figure 6c is a thermogravimetric analysis (TGA) curve of crystalline Form VIII

[0029] SUMMARY OF THE INVENTION

[0030] The present invention is directed to the crystalline Form III of as a solvate. In particular the solvate is a solvate with an organic solvent such as for example selected from 1 -butanol, 1 -pentanol, 1 -propanol, 2-butanol, 2-butanon, 2- propanol, 4-methyl-2-pentanone, acetone, anisole, butyl acetate, 1,4-di oxane, ethanol, ethyl acetate, isopropyl acetate, isobutyl acetate, n-propyl acetate, tetrahydrofuran, 2- methyl tetrahydrofuran, toluene, p-xylene, formic acid, acetic acid, methyl acetate, tertbutylmethyl ether, dimethylsulfoxide, diethyl ether, dichloromethane, propylene glycol, polyethylene glycol, cyclopentyl methyl ether and mixtures thereof. In particular the solvate is a solvate with an organic solvent such as for example 1 -butanol, 1 -pentanol, 1 -propanol, 2-butanol, 2-butanon, 2 -propanol, 4-methyl-2-pentanone, acetone, anisole, butyl acetate, 1,4-di oxane, ethanol, ethyl acetate, isopropyl acetate, isobutyl acetate, n- propyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, toluene, p-xylene, formic acid, acetic acid, methyl acetate, tert-butylmethyl ether, dimethylsulfoxide, diethyl ether, dichloromethane, propylene glycol, polyethylene glycol, or cyclopentyl methyl ether.

[0031] The present invention is directed to the anhydrous crystalline Form IV of

[0032]

[0033] The present invention is directed to the crystalline Form V of as a solvate, in particular a hydrate.

[0034] The present invention is directed to the anhydrous crystalline Form VI of The present invention is directed to the crystalline Form VII of as a solvate, in particular a hydrate.

[0035] The present invention is directed to the crystalline Form VIII of as a solvate, in particular a methyl cyclohexane solvate.

[0036] Crystalline Form IV is thermodynamically more stable, in particular at elevated temperatures.

[0037] Crystalline Form VI is thermodynamically more stable, in particular under ambient conditions.

[0038] Where stereochemistry is specified by bonds which are shown as solid wedged or hashed wedged bonds, hashed or bold bonds, then that stereoisomer is so specified and defined.

[0039] It will be clear for a skilled person that a hashed bond and a bold bond on a 1,3- disubstituted cyclobutyl moiety as shown below: , whereby X and X represent substituents, indicate that the substituents on the cyclobutyl moiety have trans-configuration.

[0040] The stereodescriptor label “R” or “(7? / ’ at a stereocenter designates that the stereocenter is purely of the ^-configuration as defined in the art; likewise, the stereodescriptor label “S” or “ S / ’ means that the stereocenter is purely of the / / -configuration.

[0041] DETAILED DESCRIPTION OF THE INVENTION

[0042] The disclosure may be more fully appreciated by reference to the following description, including the following glossary of terms and the concluding examples.

[0043] Some of the quantitative expressions given herein are not qualified with the term "about. " It is understood that whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and / or measurement conditions for such given value.

[0044] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, for example "comprising" and "comprises", mean "including but not limited to", and are not intended to (and do not) exclude other components.

[0045] For the purposes of this disclosure, the terms "crystalline form" and "polymorph" are synonymous. Characterizing information for crystalline forms is provided herein. It should be understood that the determination of a particular form can be achieved using any portion of the characterizing information that one skilled in the art would recognize as sufficient for establishing the presence of a particular form. For example, even a single distinguishing peak can be sufficient for one skilled in the art to appreciate that a particular form is present.

[0046] The term "isolated form" refers to a compound present in a form which is separate from any mixture with another compound(s), solvent system or biological environment. In an embodiment of the present invention, the crystalline form is present in an isolated form.

[0047] The term “room temperature” (RT) refers to a temperature of from about 15 °C to about 30 °C, in particular from about 20 °C to about 30 °C. Preferably, room temperature is a temperature of about 25 °C.

[0048] When a crystalline form is identified using one or more XRPD peaks given as angles 20 (two theta), each of the 20 values is understood to mean the given value ± 0.2 degrees two theta, unless otherwise expressed.

[0049] The term “seeding” refers to the addition of crystalline material to a solution or mixture to initiate crystallisation or recrystallisation.

[0050] The crystalline Form III may be provided in a substantially pure form, wherein the mole percent 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, most preferably, less than about 0.1 mole percent. In an embodiment of the present invention, the crystalline Form III is present as a substantially pure form.

[0051] The crystalline Form IV may be provided in a substantially pure form, wherein the mole percent 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, most preferably, less than about 0.1 mole percent. In an embodiment of the present invention, the crystalline Form IV is present as a substantially pure form.

[0052] The crystalline Form V may be provided in a substantially pure form, wherein the mole percent 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, most preferably, less than about 0.1 mole percent. In an embodiment of the present invention, the crystalline Form V is present as a substantially pure form.

[0053] The crystalline Form VI may be provided in a substantially pure form, wherein the mole percent 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, most preferably, less than about 0. 1 mole percent. In an embodiment of the present invention, the crystalline Form VI is present as a substantially pure form.

[0054] The crystalline Form VII may be provided in a substantially pure form, wherein the mole percent 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, most preferably, less than about 0.1 mole percent. In an embodiment of the present invention, the crystalline Form VII is present as a substantially pure form.

[0055] The crystalline Form VIII may be provided in a substantially pure form, wherein the mole percent 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, most preferably, less than about 0.1 mole percent. In an embodiment of the present invention, the crystalline Form VIII is present as a substantially pure form.

[0056] In an embodiment, crystalline Form III may contain one or more additional forms of the compound, including other crystalline forms or solvates thereof. At least a particular weight percentage may be the crystalline Form III. Particular weight percentages include 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5% and 99.9%.

[0057] In an embodiment, crystalline Form IV may contain one or more additional forms of the compound, including other crystalline forms or solvates thereof. At least a particular weight percentage may be the crystalline Form IV. Particular weight percentages include 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5% and 99.9%.

[0058] In an embodiment, crystalline Form V may contain one or more additional forms of the compound, including other crystalline forms or solvates thereof. At least a particular weight percentage may be the crystalline Form V. Particular weight percentages include 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5% and 99.9%.

[0059] In an embodiment, crystalline Form VI may contain one or more additional forms of the compound, including other crystalline forms or solvates thereof. At least a particular weight percentage may be the crystalline Form VI. Particular weight percentages include 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5% and 99.9%.

[0060] In an embodiment, crystalline Form VII may contain one or more additional forms of the compound, including other crystalline forms or solvates thereof. At least a particular weight percentage may be the crystalline Form VII. Particular weight percentages include 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5% and 99.9%.

[0061] In an embodiment, crystalline Form VIII may contain one or more additional forms of the compound, including other crystalline forms or solvates thereof. At least a particular weight percentage may be the crystalline Form VIII. Particular weight percentages include 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5% and 99.9%. The term solvate comprises the solvent addition forms. Examples of such solvent addition forms are e.g. hydrates, alcoholates and the like. A “solvate” may be a solvate with water (i.e., a hydrate) or with a common organic solvent.

[0062] It has been found that the crystalline forms described in this application inhibit MALT1 activity.

[0063] In some embodiments, the inhibition of MALT1 by a provided crystalline form may be useful in treating or preventing, in particular treating, the non-limiting list of cancers described herein.

[0064] The invention relates to crystalline forms described in this application for use as a medicament.

[0065] The invention relates to crystalline forms described in this application for use in the inhibition of MALT 1 activity.

[0066] The invention relates to crystalline forms described in this application for use in the treatment of diseases mentioned herein.

[0067] The invention relates to crystalline forms described in this application for the treatment or prevention, in particular for the treatment, of said diseases.

[0068] The invention relates to crystalline forms described in this application for the treatment or prevention, in particular in the treatment, of MALT1 mediated diseases or conditions.

[0069] The invention relates to crystalline forms described in this application for the manufacture of a medicament.

[0070] The invention relates to crystalline forms described in this application for the manufacture of a medicament for the inhibition of MALT 1.

[0071] The invention relates to crystalline forms described in this application for the manufacture of a medicament for the treatment or prevention, in particular for the treatment, of any one of the disease conditions mentioned herein.

[0072] The invention relates to crystalline forms described in this application for the manufacture of a medicament for the treatment of any one of the disease conditions mentioned herein.

[0073] The invention relates to crystalline forms described in this application can be administered to mammals, preferably humans, for the treatment or prevention of any one of the diseases mentioned herein.

[0074] The crystalline forms described herein can be used for (use in) treating a disease, syndrome, condition, or disorder mediated by MALT1. In particular said disease, syndrome, condition, or disorder mediated by MALT1 is selected from the group consisting of lymphomas, leukemias, carcinomas, and sarcomas, e.g. non-Hodgkin’s lymphoma (NHL (including 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 macroglobulinemia, lymphoblastic T cell leukemia, chronic myelogenous leukemia (CML), hairy-cell leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erytholeukemia, brain (gliomas), glioblastomas, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver 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, vulval cancer, esophageal cancer, salivary gland cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, and GIST (gastrointestinal stromal tumor), comprising, consisting of, and / or consisting essentially of, administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described in the present invention.

[0075] In another embodiment, the disease, syndrome, condition, or disorder mediated by MALT1 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.

[0076] An embodiment of the present invention is directed to crystalline forms described in this application for (use in) the treatment of immunological diseases that are affected by the inhibition of MALT1, including but not limited to, autoimmune and inflammatory disorders, e.g. arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatits, Crohn’s disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplact rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet’s diseases, uveitis, myasthenia gravis, Grave’s disease, Hashimoto thyroiditis, Sjorgen’s syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune- complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, and polymyositis.

[0077] In another embodiment, the present invention is directed to crystalline forms described in this application for (use in) the treatment of a disease, syndrome, condition, or disorder affected by inhibition of MALT1, selected from the group consisting of rheumatoid arthritis (RA), psoritic arthritis (PsA), psorisis (Pso), ulcerative colitis (UC), Crohn’s disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD).

[0078] In an alternate embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is selected from non-Hodgkin’s lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma, mantle cell lymphoma (MCL), follicular lymphoma (FL), transformed follicular lymphoma, chronic lymphocytic leukemia, and Waldenstrom macroglobulinemia.

[0079] In yet another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is lymphoma.

[0080] In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is the activated B cell like (ABC) subtype of diffuse large B- cell lymphoma (DLBCL).

[0081] In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is germinal center B cell like (GCB) subtype of diffuse large B-cell lymphoma (DLBCL).

[0082] In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is non-germinal center B cell like (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL).

[0083] In an additional embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is chronic lymphocytic leukemia (CLL). In another embodiment, the disorder or condition small lymphocytic lymphoma (SLL).

[0084] In another embodiment of the invention, the lymphoma is MALT lymphoma.

[0085] In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is Waldenstrom macroglobulinemia (WM).

[0086] In yet another embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 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.

[0087] In an alternate embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is non-Hodgkin’s lymphoma (NHL). In a further embodiment, the nonHodgkin’s lymphoma (NHL) is B-cell NHL.

[0088] Crystalline forms described in this application may be used for the treatment of immunological diseases including, but not limited to, autoimmune and inflammatory disorders, e.g. sepsis-related acute lung injury (ALI), acute respiratory distress syndrome (ARDS), arthritis, rheumatoid arthritis (RA), psoriatic arthritis (PsA), 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 allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet’s diseases, uveitis, myasthenia gravis, Grave’s disease, Hashimoto thyroiditis, Sjorgen’s syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, and polymyositis.

[0089] In particular, the crystalline forms described in this application may be useful for treating or ameliorating 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.

[0090] More particularly, the crystalline forms described in this application may be useful for treating or ameliorating diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) as herein defined.

[0091] Further, the crystalline forms described in this application may be useful for treating or ameliorating an immunological disease, syndrome, disorder, or condition selected from the group consisting of rheumatoid arthritis (RA), psoritic arthritis (PsA), psorisis (Pso), ulcerative colitis (UC), Crohn’s disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD).

[0092] In an embodiment, the crystalline forms described in this application may be useful for treating diffuse large B-cell lymphoma (DLBCL). In some embodiments, the DLBCL is relapsed or refractory DLBCL.

[0093] In an embodiment, the crystalline forms described in this application may be useful for treating mantle cell lymphoma (MCL). In some embodiments, the MCL is relapsed or refractory MCL. In an embodiment, the crystalline forms described in this application may be useful for treating follicular lymphoma (FL). In some embodiments, the FL is relapsed or refractory FL. In an embodiment, the crystalline forms described in this application may be useful for treating transformed follicular lymphoma (tFL). In some embodiments, the tFL is relapsed or refractory tFL.

[0094] In an embodiment, the crystalline forms described in this application may be useful for treating marginal zone lymphoma (MZL). In some embodiments, the MZL is relapsed or refractory MZL.

[0095] In an embodiment, the crystalline forms described in this application may be useful for treating chronic lymphocytic leukemia (CLL). In some embodiments, the CLL is relapsed or refractory CLL.

[0096] In an embodiment, the crystalline forms described in this application may be useful for treating small lymphocytic lymphoma (SLL). In some embodiments, the SLL is relapsed or refractory SLL.

[0097] In an embodiment, the crystalline forms described in this application may be useful for treating Waldenstrom macroglobulinemia (WM). In some embodiments, the WM is relapsed or refractory WM.

[0098] In an embodiment, the crystalline forms described in this application may be useful for treating MALT lymphoma. In some embodiments, the MALT lymphoma is relapsed or refractory MALT lymphoma.

[0099] In an embodiment, the crystalline forms described in this application may be useful for treating relapsed / refractory GCB-DLBCL. In an embodiment, the crystalline forms described in this application may be useful for treating relapsed / refractory non-GCB-DLBCL. In an embodiment, the crystalline forms described in this application may be useful for treating relapsed / refractory ABC-DLBCL.

[0100] It will be appreciated that variations to the foregoing embodiments of the invention can be made while still falling within the scope of the invention. Each feature disclosed in this specification, unless stated otherwise, may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

[0101] All possible combinations of the above-indicated embodiments are considered to be embraced within the scope of this invention.

[0102] In another embodiment, the present invention is directed to crystalline forms described in this application for (use in) the treatment of said disease, syndrome, condition, or disorder affected by the inhibition of MALT1.

[0103] A pharmaceutical composition comprising a crystalline form as described herein, in particular any of forms III, IV, V, VI, VII or VIII, and at least one additional ingredient selected from pharmaceutically acceptable carriers, diluents and excipients.

[0104] A pharmaceutical composition prepared starting from a crystalline form as described herein, in particular any of forms III, IV, V, VI, VII or VIII, and at least one additional ingredient selected from pharmaceutically acceptable carriers, diluents and excipients.

[0105] A process comprising preparing any of the crystalline forms described herein, in particular any of forms III, IV, V, VI, VII or VIII.

[0106] The use of a crystalline form as described herein, in particular any of forms III, IV, V, VI, VII or VIII, in the manufacture of a medicament for the treatment or prevention of a disease, syndrome, condition, or disorder affected by inhibition of MALT 1.

[0107] The process comprising formulating a crystalline form as described herein, in particular any of forms III, IV, V, VI, VII or VIII, wherein the crystalline form is formulated into an oral dosage form. A tablet, pill or capsule obtainable by said process.

[0108] In another embodiment, the present invention is directed to a composition comprising a crystalline form described in this application for (use in) the treatment of said disease, syndrome, condition, or disorder affected by inhibition of MALT 1.

[0109] In another embodiment, the present invention is directed to methods of treating said disease, syndrome, condition, or disorder mediated by MALT1. In another embodiment, the present invention is directed to methods of treating said disease, syndrome, condition, or disorder mediated by MALT1 comprising administering to a subject in need thereof, a therapeutically effective amount of a crystalline form as disclosed herein.

[0110] Another embodiment of the present invention is directed to a pharmaceutical composition comprising a crystalline form described in this application and uses thereof as described in any of the other embodiments.

[0111] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0112] The term "subject" refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0113] The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medicinal doctor or other clinician, which includes alleviation or reversal of the symptoms of the disease or disorder being treated.

[0114] The term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

[0115] As used herein, unless otherwise noted, the term "affect" or "affected" (when referring to a disease, syndrome, condition or disorder that is affected by the inhibition of menin / MLL protein / protein interaction inhibitor) includes a reduction in the frequency and / or severity of one or more symptoms or manifestations of said disease, syndrome, condition or disorder; and / or includes the prevention of the development of one or more symptoms or manifestations of said disease, syndrome, condition or disorder or the development of the disease, condition, syndrome or disorder.

[0116] The terms “treatment” and “treating,” as used herein, are intended to refer to all processes wherein there may be a slowing, interrupting, arresting or stopping of the progression of a disorder, or amelioration of one or more symptoms thereof, but does not necessarily indicate a total elimination of all symptoms.

[0117] EXPERIMENTAL PART

[0118] Methods for preparing the intermediates and Compounds of this invention are illustrated in the following examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification, or alternatively can be synthesized by a skilled person by using well-known methods.

[0119] Table 1: Abbreviations

[0120] Preparation of intermediates

[0121] For intermediates that were used in a next reaction step as a crude or as a partially purified intermediate, in some cases no mol amounts are mentioned for such intermediate in the next reaction step or alternatively estimated mol amounts or theoretical mol amounts for such intermediate in the next reaction step are indicated in the reaction protocols described below. Intermediate 1

[0122] Into a 10 L 3-necked flask was placed ethyl 2-(benzylamino)acetate (550 g, 2.85 mol, 1.00 equiv), CHCk (5.5 L), TEA (576 g, 5.70 mmol, 2.00 equiv). Propanoyl chloride (290 g, 3.13 mol, 1.10 equiv) in CHCk (300 mL) was added dropwise at 0 °C. The mixture was stirred for 1 h at 25 °C. The mixture was poured into H2O (6 L). The resulting solution was extracted with DCM (2x 2 L). The organic layers were combined, dried over anhydrous MgSCk, and concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: EtOAc / PE 1:2) to give Intermediate 1 (561 g, 79% yield) as a light-yellow oil.

[0123] Intermediate 2

[0124] Intermediate 1 (561 g, 2.25 mol, 1.00 equiv) in THF (2 L) was added dropwise at 75 °C to a mixture of NaH (108 g, 2.70 mol, 1.20 equiv, 60%) and THF (10 L). After 12 h at 75 °C, the reaction was cooled to 20 °C, water (100 mL) was added, and the mixture was concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: MeOH / DCM 1:30) to give Intermediate 2 (231 g, 50% yield) as an off-white solid.

[0125] Intermediate 3

[0126] NaH (45.5 g, 1.14 mol, 1.00 equiv, 60%) was added portionwise at 0 °C to Intermediate 2 (231 g, 1.14 mol, 1.00 equiv) in DMF (4.6 L). The mixture was stirred for 0.5 h at 25 °C. 5- (Trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate (457 g, 1.14 mol, 1.00 equiv) was added to the mixture at -55 °C. The mixture was gradually warmed up to 25 °C and stirred for 1 h. The mixture was poured into a mixture of ice / water (10 L) and extracted with EtOAc (2x 5 L). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: EtOAc / PE 1:4) to give Intermediate 3 (275 g, 89% yield) as a light-yellow oil.

[0127] Intermediate 4

[0128] LAH (154 g, 4.10 mol, 4.00 equiv) was added at 0 °C to a mixture of Intermediate 3 (275 g, 1.01 mol, 1.00 equiv) in THF (5.5 L). The mixture was warmed up to 80 °C and stirred at this temperature for 15 h. The mixture was cooled to 0 °C, and were added 154 g of water, 154 g of aqueous of NaOH solution (10%), and 154 g of H2O. The mixture was stirred for 30 min at 25 °C and the precipitate was filtered off. The filtrate was concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: MeOH / DCM 1:50) to give Intermediate 4 (204 g, 78% yield) as a colorless oil.

[0129] Intermediate 5

[0130] HC1 (787 mL, 1 M) and Pd / C (8.37 g, 78.7 mmol, 0.10 equiv) were added to a solution of Intermediate 4 (204 g, 787 mmol, 1.00 equiv) in EtOH (2 L). The mixture was degassed and flushed with hydrogen. The mixture was stirred for 18 h at 25 °C under an atmosphere of hydrogen (balloon). Then was added HC1 (787 mL, 1 M) and the mixture was stirred for 30 min at 25 °C. The solid was filtered out and the filtrate was concentrated under vacuum to give Intermediate 5 (106 g, 66% yield; as a HC1 salt, number of equivalents not determined) as a yellow solid which was used without further purifications.

[0131] Intermediate 6 di-' / c / V-butyl dicarbonate (169 g, 773 mmol, 1.50 equiv) was added to a mixture of Intermediate 5 (106 g, 515 mmol, 1.00 equiv), THF (2 L), and TEA (2089 g, 2.06 mol, 4.00 equiv). The flask was stirred for 2 h at 25 °C. The mixture was concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: EtOAc / PE 1:4) to give Intermediate 6 (134 g, 96% yield) as a white solid.

[0132] Intermediate 7

[0133] A mixture of Intermediate 6 (134 g, 0.496 mol, 1.00 equiv), DCM (2.6 L), PCC (534 g, 2.48 mol, 5.00 equiv) and silica gel (268 g, 4.46 mol, 9.00 equiv) was stirred for 12 h at 40 °C. The mixture was concentrated under vacuum and the resulting residue was purified by flash column chromatography over silica gel (eluent: EtOAc / PE 1 : 10) to give Intermediate 7 (79 g, 60% yield) as a white solid.

[0134] Intermediate 8

[0135] Intermediate 7 (79 g, 296 mmol, 1.00 equiv) and DMF-DMA (790 mL) were stirred for 1 h at 35 °C. The mixture was concentrated to give Intermediate 8 (100 g, crude) as a light-yellow oil which was used without any further purification.

[0136] Intermediate 9

[0137] A mixture of Intermediate 8 (100 g, 310 mmol, 1.00 equiv), 5-chloro-27 / -pyrazol-3-amine [CAS: 916211-79-5] (36.5 g, 310 mmol, 1.00 equiv), toluene (1 L) and AcOH (100 mL) was stirred for 15 h at 95 °C. The reaction was cooled to 25 °C and concentrated under vacuum. NaHCOs (1000 mL) was added to the mixture, and the resulting solution was extracted with EtOAc (2x 1 L). The organic layers were combined, dried over anhydrous MgSO4, and concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: EtOAc / PE 15:85) to give Intermediate 9 (39.7 g, 34% yield) as a yellow oil.

[0138] Intermediate 10

[0139] A mixture of Intermediate 9 (39.7 g, 105 mmol, 1.00 equiv), DCM (400 mL) and TFA(80 mL) was stirred for 1 h at 25 °C. The mixture was concentrated under vacuum and NaHCCh (500 mL) was added. The resulting mixture was extracted with DCM (3x300 mL). The organic layers were combined, dried over anhydrous MgSO-i. and concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: EtOAc:PE (1: 1). This resulted in 2-chloro-8-methyl-8-(trifluoromethyl)-7.8-dihydro-67 / -pyrazolo| 1.5- al pyrrolo| 2.3-e| pyrimidine (Intermediate 10, [CAS: 2661482-67-1], 15.2 g, 51% yield) as a yellow solid.

[0140] Intermediate 11 and 12

[0141] Intermediate 11 Intermediate 12

[0142] Intermediate 10 (5.0 g) was separated in enantiomers via chiral SFC, using as stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 zPrNEb to provide two fractions as follows:

[0143] Fraction 1: Intermediate 11 (2.35 g, 47% yield)

[0144] Fraction 2: Intermediate 12 (2.35 g, 47% yield) To a cooled (0 °C) suspension of NaH (60% in mineral oil, 2.59 g, 64.85 mmol) in THF (100 mL) was added triethylphosphonopropionate (13.9 mL, 64.85 mmol) dropwise. The reaction was stirred for 30 minutes, then a solution of 4-bromobenzaldehyde [1122-91-4] (10.0 g, 54.0 mmol) in THF (20 mL) was added dropwise, keeping the internal temperature between 0 °C and 5 °C. The mixture was allowed to warm to RT and stirred for 16 h. The reaction was quenched with a saturated aqueous solution of NH4CI (60 mL), and the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous MgSO-i. filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography over silica gel (eluent: heptane / EtOAc up to 90 / 10). The fractions containing compound were combined and concentrated in vacuo to give Intermediate 13 (12.3 g, 84% yield) as a colorless oil.

[0145] Intermediate 14

[0146] To a cooled (0 °C) solution of Intermediate 13 (12.3 g, 45.7 mmol) in dry THF (230 mL) under nitrogen, was added DIBAL-H (IM in THF, 115 mL, 115 mmol) dropwise. The mixture was then allowed to slowly warm up to RT and stirred for 1 h. The reaction was cooled down to 0 °C, diluted with EtOAc (100 mL) and quenched with a saturated aqueous solution of Rochelle's salt (250 mL). After stirring for 1 h, the reaction was allowed to warm up to RT, the organic layer was separated, and the aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give Intermediate 14 (9.8 g, 94% yield) as a white solid.

[0147] Intermediate 15

[0148] To a solution of Intermediate 14 (8.70 g, 38.3 mmol) and imidazole (3.13 g, 46.0 mmol) in DCM (100 mL) pre-cooled to 0 °C, was added triisopropylsilyl chloride (9.0 mL, 42.1 mmol) dropwise. The mixture was allowed to warm up to RT and stirred for 16 h. The mixture was diluted with water (100 mL) and DCM (100 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous MgSCL, filtered, and concentrated in vacuo. The crude was purified by flash column chromatography over silica gel (eluent: heptane / DCM up to 90 / 10) to obtain Intermediate 15 (14 g, 95% yield) as a colorless oil. Intermediate 16

[0149] In a 20 mL pressure tube charged with Intermediate 15 (1.15 g, 3.0 mmol) and tetrabutylammonium bromide (48.3 mg, 0.15 mmol), were added toluene (6 mL) and (bromodifluoromethyl)trimethylsilane (1.4 mL, 9 mmol). The reaction was stirred at 110 °C for 6 h. Six identical reactions were run in parallel and combined before work-up and purification. The reactions were cooled down to RT, each diluted with water (10-15 mL), EtOAc (20-25 mL), and combined. The organic layer was separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was dissolved in anhydrous THF (50 mL), cooled to 0 °C and TBAF (IM in THF, 27 mL, 27 mmol) was added. The reaction was allowed to warm up to RT and stirred for 1 h. Volatiles were removed under reduced pressure and the residue was diluted with water (50 mL) and EtOAc (100 mL). The aqueous layer was separated, and the organic layer was washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography over silica gel (eluent: heptane / EtOAc 70 / 30) to obtain Intermediate 16 (4.6 g, 92% yield) as a yellowish oil.

[0150] Intermediate 17

[0151] To a solution of Intermediate 16 (3.81 g, 13.75 mmol) in water / MeCN (87 mL / 87 mL), were added TEMPO (1.07 g, 6.87 mmol), (Diacetoxyiodo)benzene (13.29 g, 41.25 mmol) and NaHCOs (2.89 g, 34.37 mmol). The mixture was stirred for 6 h at RT, the mixture was diluted with water, and aq HC1 (1 M) was added until the pH reached approximately 2. EtOAc was added and the organic layer was separated.The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over anhydrous MgSO4, filtered, and evaporated. The product was stirred in diisopropyl ether and filtered. The filtrate was evaporated and stirred in heptane to obtain a precipitate that was filtered and dried over anhydrous MgSO4 to give Intermediate 17 (3.46 g, 86% yield) as white solid. Intermediate 21

[0152] To a mixture of Intermediate 17 (200.0 mg, 0.687 mmol) and A-[(Dimethylamino)-17 / -l,2,3- triazolo-[4,5-b]pyridin-l-ylmethylene]-A-methylmethanaminium hexafluorophosphate N- oxide (522.5 mg, 1.37 mmol) and AA-Diethylethanamine (0.38 mL, 2.75 mmol) in MeCN (5.2 mL) was added 3-(methylsulfonyl)cyclobutan-l-amine hydrochloride [2639792-63-3] (205.0 mg, 1.37 mmol). The reaction was stirred at RT for 1 h. The reaction was diluted with EtOAc and water. The water layer was separated, and the acqueouse phase was extracted with EtOAc. The combined organic layers were then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography over silica gel (eluent: MeOH / DCM 0 to 7%) to give Intermediate 21 (264 mg, 91% yield) as a white solid.

[0153] Intermediate 22

[0154] Intermediate 22 was prepared by an analogous reaction protocol as Intermediate 21, starting from trans-3-methylsulfonylcyclobutylamine hydrochloride [1408075-97-7] (1.25 g, 6.73 mmol) instead of 3-(methylsulfonyl)cyclobutan-l -amine hydrochloride [2639792-63-3] to give Intermediate 22 (1.16 g, 73% yield) as a light-yellow solid.

[0155] A pressure tube was charged with Intermediate 22 (175 mg, 0.41 mmol), Intermediate 11 (126.11 mg, 0.46 mmol), BrettPhos Pd G3 (37.57 mg, 0.041 mmol), BrettPhos (22.24 mg, 0.041 mmol), CS2CO3 (202.53 mg, 0.62 mmol), and 1,4-di oxane (4.05 mL). The mixture was degassed, then stirred at 60 °C for 8 h. The reaction was cooled down to RT and filtered through celite. The filtrate was concentrated under reduced pressure and the crude was purified by Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-lOpm, 30x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to obtain Compound 1 as a yellow solid (147 mg, 58% yield).

[0156] 'H NMR (CHLOROFORM-d, 400 MHz) 6 ppm: 8.29 - 8.25 (m, 1H), 7.26 - 7.23 (m, 1H), 7.18 - 7.06 (m, 2H), 6.70 (s, 1H), 6.08 (d, J=6.2 Hz, 1H), 4.55 (sxt, J=7.6 Hz, 1H), 4.25 (d, J=12.3 Hz, 1H), 4.06 (d, J=11.7 Hz, 1H), 3.80 (tt, J=4.6, 9.5 Hz, 1H), 3.62 (d, J=15.6 Hz, 1H), 3.04 - 2.90 (m, 2H), 2.87 (s, 3H), 2.70 - 2.60 (m, 2H), 2.00 (s, 3H), 1.25 (s, 3H).

[0157] Compound 2 and Compound 3

[0158] Compound 2 Compound 3

[0159] Compound 1 (147 mg) was separated via chiral SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 zPrNH2). The fractions containing compound were combined and the solvent was concentrated in vacuo to provide two fractions as follows:

[0160] Fraction 1: Compound 2 (61 mg, 24% yield starting from intermediate 22)

[0161] 'H NMR (CHLOROFORM-d, 400 MHz) 6 ppm: 8.26 (d, J=1.3 Hz, IH), 7.26 - 7.22 (m, IH), 7.15 (d, J=11.9 Hz, IH), 7.08 (d, J=8.3 Hz, IH), 6.71 (s, IH), 6.08 (br d, J=6.4 Hz, IH), 4.55 (sxt, J=7.6 Hz, IH), 4.26 (d, J=10.5 Hz, IH), 4.06 (d, J=11.4 Hz, IH), 3.79 (tt, J=4.7, 9.5 Hz, IH), 3.64 - 3.59 (m, IH), 3.00 - 2.92 (m, 2H), 2.87 (s, 3H), 2.70 - 2.61 (m, 2H), 2.00 (s, 3H), 1.25 (s, 3H).

[0162] Fraction 2: Compound 3 (63 mg, 25% yield starting from intermediate 22)

[0163] 'H NMR (CHLOROFORM-d, 400 MHz) 6 ppm: 8.26 (d, J=1.3 Hz, IH), 7.25 - 7.05 (m, 3H), 6.70 (s, IH), 6.06 (d, J=6.2Hz. IH), 4.59 - 4.50 (m, IH), 4.24 (d, J=10.5 Hz, IH), 4.06 (d, .7=11.5 Hz, IH), 3.83 - 3.75 (m, IH), 3.61 (d,J=16.0Hz, IH), 2.99 - 2.92 (m, 2H), 2.86 (s, 3H), 2.69 - 2.60 (m, 2H), 1.99 (s, 3H), 1.24 (s, 3H).

[0164] 'H NMR spectra were recorded on Bruker Avance III 400MHz and Avance NEO 400MHz spectrometers. CHLOROFORM-d was used as solvent, unless otherwise mentioned. The chemical shifts are expressed in ppm relative to tetramethylsilane. Crystalline Form I of Compound 3

[0165] 100 mg crystalline Form II of Compound 3 was dried in the vacuum oven at 35°C and 200 mbar pressure for 4 hours. This process yielded Form I of Compound 3 with a yield of 97%.

[0166] Crystalline Form II (Ila and lib) of Compound 3

[0167] 60 mg of crystalline Form I of Compound 3 was dissolved in 0.3 mL acetonitrile at 80°C, the resulting solution was cooled down to room temperature, while spontaneous crystallization occurred. This process yielded Form Ila of Compound 3 with a yield of 90%.

[0168] 60 mg of crystalline Form I of Compound 3 was dissolved in 0.7 mL acetonitrile: water 9:1 V / V mixture at 75°C, the resulting solution was cooled down to room temperature, while spontaneous crystallization occurred. This process yielded Form Ila of Compound 3 with a yield of 84%.

[0169] 60 mg of crystalline Form I of Compound 3 was dissolved in 8 mL methanol at 62°C, the resulting solution was cooled down to room temperature, while spontaneous crystallization occurred. This process yielded Form lib of Compound 3 with a yield of 77%.

[0170] Any form of Compound 3 can be used as the starting material in the synthesis of crystalline Form II, including amorphous Compound 3 described hereinbefore.

[0171] Crystalline Form III of Compound 3:

[0172] 60 mg of crystalline Form I of Compound 3 was dissolved in 1.0 mL acetone at 55°C, the resulting solution was cooled down to room temperature, while spontaneous crystallization occurred. This process yielded Form III of Compound 3 with a yield of 73%.

[0173] 60 mg of crystalline Form I of Compound 3 was dissolved in 0.3 mL methyl ethyl ketone at 78°C, the resulting solution was cooled down to room temperature, while spontaneous crystallization occurred. This process yielded Form III of Compound 3 with a yield of 80%.

[0174] 60 mg of crystalline Form I of Compound 3 was dissolved in 2.5 mL ethanokwater 3:1 V / V mixture at 80°C, the resulting solution was cooled down to room temperature, while spontaneous crystallization occurred. This process yielded Form III of Compound 3 with a yield of 93%. Crystalline Form III of Compound 3 was obtained as an isostructural solvate and was obtained via slurrying or via crystallization from organic solvents as 1 -butanol, 1 -pentanol, 1- propanol, 2 -butanol, 2-butanon, 2 -propanol, 4-methyl-2-pentanone, acetone, anisole, butyl acetate, 1,4-di oxane, ethanol, ethyl acetate, isopropyl acetate, isobutyl acetate, n-propyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, toluene, p-xylene, 1 -propanol: water 95:5 (V:V), 1 -propanol: water 98:2 (V:V), 2-propanol:water 9:1 (V:V), 2-propanol: water 95:5 (V:V), 2-propanol: water 98:2 (V:V), 2-propanol: water 1:1 (V:V), acetone:water 1:1 (V:V), acetone:water 95:5 (V:V), acetone:water 98:2 (V:V), dioxane:water 1: 1 (V:V), ethanohwater 3:1 (V:V), ethanohwater 9:1 (V:V), ethanohwater 95:5 (V:V), tetrahydrofuran:water 95:5 (V:V), dichloromethane, formic acid / water (100 / 0 to 50 / 50 V / V), acetic acid / water (100 / 0 to 50 / 50 V / V), methyl acetate, tert-butylmethyl ether, dimethylsulfoxide, diethyl ether, propylene glycol, polyethylene glycol, and cyclopentyl methyl ether.

[0175] Form III forms instantaneously upon exposure in organic solvents. Form III can be obtained via exposing the amorphous or crystalline compound to vapors of these solvents.

[0176] Crystalline Form IV of Compound 3:

[0177] 50 mg of neat amorphous Compound 3 was suspended in Fasted State Simulated Intestinal Fluid (FaSSIF) at 37°C. After one day of stirring, the resulting solids were isolated and the process yielded crystalline Form IV of Compound 3 with a yield of 95%.

[0178] 300 mg of crystalline Form III of Compound 3 was heated to 180°C. The resulting solids yielded crystalline Form IV of Compound 3 with a yield of 95%.

[0179] 3 mg of crystalline Form VI of Compound 3 was heated to 180°C. The resulting solids yielded crystalline Form IV of Compound 3 with a yield of 99%.

[0180] Crystalline Form V of Compound 3:

[0181] 50 mg of neat amorphous Compound 3 was suspended in water / FaSSGF (Fasted State Simulated Gastric Fluid) at 37°C. After one day of stirring, the resulting solids were isolated and the process yielded crystalline Form V of Compound 3 with a yield of 95%.

[0182] Crystalline Form VI of Compound 3:

[0183] 50 mg of neat amorphous Compound 3 was suspended in n-heptane / methyl cyclohexane / FaSSIF at 25°C. After two months of stirring, the resulting solids were isolated and the process yielded crystalline Form VI of Compound 3 with a yield of 95%. 50 mg of neat amorphous Compound 3 was suspended in n-heptane / methyl cyclohexane / FaSSGF at 50°C. After two months of stirring, the resulting solids were isolated and the process yielded crystalline Form VI of Compound 3 with a yield of 95%.

[0184] Crystalline Form VII of Compound 3:

[0185] 12.5 mg of crystalline Form I of Compound 3 was dissolved in 0.5 mL DMSO at 25°C. The solution was slowly dispensed into 10 mL of Fed State Simulated Intestinal Fluid (FeSSIF) media, while spontaneous crystallization occurred. The resulting solids were isolated and the process yielded crystalline Form VII of Compound 3 with a yield of 90%.

[0186] Crystalline Form VIII of Compound 3:

[0187] The form was obtained by suspending 2.1g of the neat amorphous Compound 3 in 21 mL of methyl cyclohexane at 25°C and agitating it for 3 days and the suspending the same amount of neat amorphous API in methyl cyclohexane at 60°C and stirring it for 3 days. Both 25°C and 60°C experiments resulted in Form VIII as a methyl cyclohexane solvate.

[0188] Table: LCMS results. Rt means retention time, in minutes (min.); [M+H]+means the protonated mass of the compound; method refers to the method used for LCMS analysis of compounds; No. means number. Rt means retention time (in minutes).

[0189] Analytical Analysis

[0190] The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below).

[0191] Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g., scanning range, dwell time... ) to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software.

[0192] Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]+(protonated molecule) and / or [M-H]' (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. [M+NH4]+, [M+HCOO]', etc... ). For molecules with multiple isotopic patterns (Br, Cl), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used.

[0193] Hereinafter, “SQD” means Single Quadrupole Detector, “MSD” Mass Selective Detector, “RT” room temperature, “BEH” bridged ethylsiloxane / silica hybrid, “DAD” Diode Array Detector, ”HSS” High Strength silica.

[0194] LCMS Method Codes (Flow expressed in mL / min, column temperature (T) in °C, Run time in minutes, ‘ACN1means acetonitrile)

[0195] LC-MS methods:

[0196] Pharmacological Analysis

[0197] Biological Examples

[0198] In vitro assays include assays that determine cell morphology, protein expression, and / or the cytotoxicity, enzyme inhibitory activity, and / or the subsequent functional consequences of treatment of cells with compounds of the invention. Alternate or additional in vitro assays may be used to quantitate the ability of the inhibitor to bind to protein or nucleic acid molecules within the cell.

[0199] Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor / target molecule complex and determining the amount of radiolabel bound. Alternatively or additionally, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with purified proteins or nucleic acids bound to known radioligands. Detailed conditions of exemplary systems for assaying a compound of Formula (I) of the present invention as MALT1 inhibitors are set forth in the Biological Examples below.

[0200] Such assays are exemplary and not intended to limit the scope of the invention. The skilled practitioner can appreciate that modifications can be made to conventional assays to develop equivalent or other assays that can be employed to comparably assess activity or otherwise characterize compounds and / or compositions as described herein.

[0201] In Vitro Assays

[0202] Biological Example 1

[0203] MALT1 Biochemical Protease Assay

[0204] MALT1 protease activity was assessed in an in vitro assay using a tetrapeptide as substrate and full-length MALT1 protein (Strep-MALTl(l-824)-His) purified from baculovirus-infected insect cells. The tetrapeptide LRSR is coupled to AMC (7-amino-4-methylcoumarin) and provides a quenched, fluorescent substrate for the MALT1 protease (SM Biochemicals). Cleavage of AMC from the Arginine residue results in an increase in coumarin fluorescence measured at 460 nm (excitation 355 nm). The final assay buffer consisted of 10 nM FL MALT1 protein, 200 pM Ac-LRSR-AMC, 50 mM Tris pH 7.5, 0.6 M Citrate, 1 mM dithiothreitol (DTT), 1 mM ethylenediaminetetraacetic acid (EDTA), 0.05% bovine serum albumin (BSA) and 1.5% dimethyl sulfoxide (DMSO). Test compounds were spotted at 50 nL in 100% DMSO per well of a black 384-Proxiplate (Perkin Elmer). Test compound concentrations ranged from 30 pM to 0.5 nM using 11 dilution steps (1:3). Background signal was measured from control wells containing assay buffer without enzyme which functions as low control (LC). High control (HC) values were generated using the reaction with enzyme but no compound treatment. Compounds were pre-incubated with MALT1 enzyme for 50 minutes at RT. Substrate was added subsequently, and fluorescence was measured in Labsystems fluoroskan at excitation 355 nm and emission 460 nm to determine time 0. The reaction was subsequently incubated for 4 h at RT and fluorescence was measured. For ICso calculations, timepoint 0 was subtracted from the 4 h timepoint to correct for any potential autofluorescence of the compounds. The enzyme reaction was linear during the 4 h incubation period. Characterization of the substrate Ac-LRSR-AMC determined the Michaelis constant KM at 200 pM. ICso values were calculated using the following formula (Z prime should be >0.5):

[0205] LC = Median of the low control values

[0206] = Low control: Reaction without enzyme

[0207] HC = Median of the High control values

[0208] = High Control: Reaction with enzyme

[0209] %Effect = 100-[((sample-LC) / (HC-LC)) x 100]

[0210] %Control = (sample / HC) x 100

[0211] %Controlmin = ((sample-LC) / (HC-LC)) x 100

[0212] A best-fit curve was fitted by a minimum sum of squares method to the plot of %Controlmin vs. compound concentration. From this an ICso value (inhibitory concentration causing 50 % inhibition) can be obtained. An estimate of the slope of the plot in terms of the Hill coefficient was also obtained.

[0213] ICso Calculation:

[0214] With y = estimated response UB = upper bound LB = lower bound h = Hill slope of curve CONC = concentration

[0215] Used in “Lexis Dose Response Curve Fitting” Version 1.0. Resultant data are shown in Table 2 (‘Cpd No.’ means Compound Number, ‘n.d.’ means not determined, ‘Int’ means intermediate). Biological Example 2

[0216] GloSensor reporter MALT 1 -mediated cleavage In Jurkat Cells

[0217] MALT1 GloSensor™ is a split luciferase reporter, which utilizes a genetically modified form of firefly luciferase (CP UltraGio) split into 2 distinct domains by insertion of a RelB MALT1 cleavage site sequence PRLVSRGA. MALT1 -induced cleavage allows for a conformational change that reestablishes a functional luciferase protein resulting in luminescence, and hence luciferase activity would be a surrogate of endogenous MALT1 protease activity. Jurkat MALT1 GloSensor™ were generated by electroporation and selected and maintained in the presence of 0.5 mg / mL Geneticin. MALT1 protease is basally inactive in Jurkat cells and can be activated by treatment with PMA / Ionomycin. Small molecule MALT1 inhibitors added prior to PMA / Ionomycin addition prevent MALT1 protease activation and, therefore, the cleavage of the MALT1 GloSensor split luciferase reporter in a dose-dependent manner.

[0218] Jurkat MALT1 GloSensor™ cells were maintained in complete RPMI 1640 media containing 10% fetal bovine serum, lOmM 4-(2 -hydroxy ethyl)- 1 -piperazineethanesulfonic acid (HEPES), 100 units / mL of penicillin, 100 pg / mL of streptomycin and 0.5 mg / mL Geneticin. Prior to the assay, compounds were made 2.5-fold serial dilutions in DMSO. 100 nL of of test compounds were spotted per well of 384-well plates (Perkin Elmer, catalogue number 6007688). Jurkat cells were harvested by centrifuge at 1200 RPM for 5 min and suspended in fresh complete RPMI 1640 media with 2% GloSensor™ cAMP Reagent and preincubated for 45-60 minutes at 37 °C in a 5% CO2 incubator. A volume of 50 uL of preincubated Jurkat MALT1 GloSensor™ cells (1 x 105cells) were seeded in each well of 384-well plate. Next, a volume 2 pL of diluted PMA / lonomycin (2.5 pg / mL / 25 pM respectively, Sigma, catalogue number P1585 and 407953) in DMSO were added to each well. After incubation at 37 °C in 5% CO2 incubator for 4 h, luminescence was measured on the Envision (Perkin Elmer) at 37 °C.

[0219] IC50 values were calculated using SmartFit in GeneData Screener®:

[0220] . SmartFit uses the 4p curve fit equation seen below:

[0221] Where: x = concentration y = activity

[0222] So = activity at bottom plateau of curve

[0223] Sinf = activity at top plateau of curve

[0224] S50 = inflection point, halfway between SO and Sinf h = Hill slope of curve Resultant data are shown in Table 3 (‘Cpd No.’ means Compound Number, ‘Inf means intermediate).

[0225] Biological Example 3 Human IL-6 / IL-10 Mesoscale Assay

[0226] OCI-Ly3 cells were propagated in RPMI-1640 (Sigma Aldrich) supplemented with 10% fetal bovine serum (Hy Clone), 2 mM L-glutamine (Sigma Aldrich) and 1% PenStrep (Sigma Aldrich). Cell passage number should not exceed 30. Cells should be kept between 0.5 - 1.5 million cells per mL during culturing.

[0227] For the Mesoscale assay, 100,000 OCI-Ly3 cells were seeded per well into black-colored 96- well plates with clear bottom (Coming® #3904) and test compounds were added in 9 dilution steps (1:2) ranging from 15 pM to 58.6 nM (final DMSO concentration 0.3%). DMSO control wells were used to determine the maximum signal (High Control (HC)). Treatment with reference compounds at an appropriate dose served as positive control for MALT1 inhibition and was used to determine the maximum inhibition (Low Control (LC)). Compounds and cells were incubated for 24 h at 37 °C and 5% CO2 (assay volume is 150 pL). After 24 h of incubation 50 pL of the supernatant was transferred to an MSD plate (V-Plex Proinflammation Panel 1 (human) kit, Mesoscale (MSD)) and incubated for 2 h with vigorous shaking (600 rpm) at room temperature. Following incubation, plates were washed 3x with phosphate-buffered saline (PBS) + 0.05% Tween-20 and 25 pL detection antibody solution (IL-6 & IL-10 antibodies in diluent 3 (MSD)) was added per well followed by 2 h of incubation with vigorous shaking (600 rpm) at room temperature. After 3x washes with PBS + 0.05% Tween-20, plates were incubated with 150 pL 2x Read Buffer T and read on SECTOR imager. Resultant data are shown in Table 4 (‘Cpd No.’ means Compound Number, ‘Inf means intermediate, ‘n.d.’ means not determined).

[0228] Biological Example 4 Proliferation Assays

[0229] OCI-Ly3 cells were propagated in RPMI-1640 with Glutamax (ThermoFisher) supplemented with 10% heat inactivated fetal bovine serum (ThermoFisher). Cells should be kept between 0.2 - 1.5 million cells per mL and passed every 3-4 days during culturing. OCI- Ly7 cells were propagated in IMDM (ThermoFisher) supplemented with 10% fetal bovine serum (HyClone), 2 mM L-glutamine (Sigma Aldrich) and 50 pg / mL Gentamycin. Cells should be kept between 0.15 - 3 million cells per mL and passed every 3-4 days during culturing. Cell passage numbers should not exceed 20.

[0230] To assess anti-proliferative effects, 450 nL of test compounds were spotted per well of U-bottom 96-well plates (Coming®, #3975). 500 OCI-Ly3 or OCI-Ly7 cells were seeded in 150 pL media per well and incubated for 8 days at 37 °C and 5% CO2. Cell plating numbers were chosen based on growth curves to ensure linear cell growth. After 8 days of incubation, 100 pL of the plated cells were resuspended up and down by pipette and transferred to a flat bottom black plate (Coming®, #3904). 50 pL CellTiterGLO reagent (Promega) were added to each well and luminescence was measured on Envision (Perkin Elmer) after 10 minutes shaking at 300 rpm followed by 10 minutes of incubation at room temperature in the dark.

[0231] IC50 values were calculated using SmartFit in GeneData Screener®:

[0232] . SmartFit uses the 4p curve fit equation seen below:

[0233] Where: x = concentration y = activity

[0234] So = activity at bottom plateau of curve

[0235] Sinf = activity at top plateau of curve

[0236] S50 = inflection point, halfway between SO and Sinf h = Hill slope of curve

[0237] Resultant data are shown in Table 5 (‘Cpd No.’ means Compound Number, ‘n.d.’ means not determined, ‘Inf means intermediate)

[0238] Crystalline Form III

[0239] Crystalline Form III of Compound 3 may be characterised by an X-ray powder diffraction pattern. X-ray powder diffraction (XRPD) analyzes were carried out on a PANalytical Empyrean diffractometer.

[0240] The instrument is equipped with a Cu-Ka X-ray tube using iCore and dCore tunable optics for the incident and the diffracted beam, respectively. The compound was spread on the center of a zero-background holder assuring a flat surface.

[0241] INSTRUMENT PARAMETERS

[0242] Generator voltage: 45 kV

[0243] Generator amperage: 40 mA

[0244] Geometry: Bragg-Brentano

[0245] Stage: spinner stage

[0246] MEASUREMENT CONDITIONS

[0247] Scan mode: continuous

[0248] Scan range: 3-35° 20

[0249] Step size: 0.013 l° / step

[0250] Counting time: 250 sec / step

[0251] Spinner revolution time: 1 sec

[0252] Radiation type: Cu-Ka (1.541874 A)

[0253] Incident beam path (iCore)

[0254] Program, divergence slit: automatic

[0255] Irradiated length: 10 mm

[0256] Soller slit: 0.03 rad

[0257] Mask 1: 14 mm

[0258] Mask 2: 14 mm Width: 15.7 mm

[0259] Diffracted beam path (dCore)

[0260] Anti scatter slit: automatic

[0261] Irradiated length: 10 mm

[0262] Soller slit: 0.04 rad

[0263] Detector: PIXcel3D- Medipix3 1x1

[0264] One skilled in the art will recognize that diffraction patterns and peak positions are typically substantially independent of the diffractometer used and whether a specific calibration method is utilized. Typically, the peak positions may differ by about ± 0.2° two theta, or less. The intensities (and relative intensities) of each specific diffraction peak may also vary as a function of various factors, including, but not limited to particle size, orientation, sample purity, etc.

[0265] The X-ray powder diffraction pattern comprises peaks at 4.7, 9.4, 14.1, 14.3, 15.2, 17.7, 18.8 and 23.6 degrees two theta ± 0.2 degrees two theta. The X-ray powder diffraction pattern may further comprise at least one peak selected from 11.2, 11.8, 13.4, 16.4, 16.8, 20.6, 22.5, 26.5, 26.9, and 27.6 degrees two theta ± 0.2 degrees two theta.

[0266] Form III may further be characterized by an X-ray powder diffraction pattern having four, five, six, seven, eight, nine or more peaks selected from those peaks identified in Table 6.

[0267] Form III may further be characterized by an X-ray powder diffraction pattern comprising those peaks identified in Table 6, wherein the relative intensity of the peaks is greater than about 2%, preferably greater than about 5%, more preferably greater than about 10%, more preferably greater than about 15%. However, a skilled person will realize that the relative intensity of the peaks may vary between different samples and different measurements on the same sample.

[0268] Form III may further be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure la.

[0269] Table 6 provides peak listings and relative intensity for the XRPD of Crystalline form III (Figure la).

[0270] Table 6:

[0271] Pos. [°2Th,] Rel. Int. [%]

[0272] 4.732 100

[0273] 9.4046 64.48

[0274] 11.2022 5.02 11.7856 5.97

[0275] 13.4382 4.13

[0276] 14.1154 11.78

[0277] 14.2737 14.69

[0278] 15.1778 25.28

[0279] 16.441 11.37

[0280] 16.8056 13.04

[0281] 17.6523 15.25

[0282] 18.8301 62.08

[0283] 20.5558 13.05

[0284] 22.4726 6.98

[0285] 23.5844 23.01

[0286] 26.4995 6.3

[0287] 26.9426 6.02

[0288] 27.6116 2.97

[0289] Form III may also be characterized by a differential scanning calorimetry thermogram (DSC) substantially as depicted in Figure lb.

[0290] Form III may further be characterized by thermal gravimetric analysis (TGA). Form III may exhibit a TGA curve substantially as depicted in Figure 1c.

[0291] Crystalline Form IV

[0292] Crystalline Form IV of Compound 3 may be characterised by an X-ray powder diffraction pattern. X-ray powder diffraction (XRPD) analyzes were carried out on a PANalytical Empyrean diffractometer using the same parameters and conditions as described before for Form III.

[0293] The X-ray powder diffraction pattern comprises peaks at 9.4, 12.9, 15.5, 16.2, 18.7, 20.8, 22.0, 22.9, 28.2 and 31.3 degrees two theta± 0.2 degrees two theta. The X-ray powder diffraction pattern may further comprise at least one peak selected from 6.4, 9.0, 11.3, 13.2, 15.7, 17.1, 17.5, 17.9, 21.2, 25.6, 26.3, 31.8, 33.9 and 34.4 degrees two theta± 0.2 degrees two theta.

[0294] Form IV may further be characterized by an X-ray powder diffraction pattern having four, five, six, seven, eight, nine or more peaks selected from those peaks identified in Table 7.

[0295] Form IV may further be characterized by an X-ray powder diffraction pattern comprising those peaks identified in Table 7, wherein the relative intensity of the peaks is greater than about 2%, preferably greater than about 5%, more preferably greater than about 10%, more preferably greater than about 15%. However, a skilled person will realize that the relative intensity of the peaks may vary between different samples and different measurements on the same sample.

[0296] Form IV may further be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 2a. Table 7 provides peak listings and relative intensity for the XRPD of Crystalline form

[0297] IV (Figure 2a).

[0298] Table 7:

[0299] Pos. [°2Th.] Rel. Int. [%]

[0300] 6.3925 4.04

[0301] 8.9558 7.1

[0302] 9.3652 15.02

[0303] 11.2908 6.12

[0304] 12.9026 11.33

[0305] 13.1853 9.09

[0306] 15.4742 15.77

[0307] 15.7266 9.51

[0308] 16.1847 49.53

[0309] 17.125 13.11

[0310] 17.5131 13.43

[0311] 17.8527 15.27

[0312] 18.679 71.13

[0313] 20.7676 64.3

[0314] 21.2202 7.4

[0315] 22.04 100

[0316] 22.866 24.09

[0317] 25.6292 18.75

[0318] 26.3463 10.56

[0319] 28.1766 36.29

[0320] 31.2963 33.16

[0321] 31.7979 20.84

[0322] 33.881 11.08

[0323] 34.3743 12.54 Form IV may also be characterized by a differential scanning calorimetry thermogram (DSC) substantially as depicted in Figure 2b.

[0324] Crystalline Form V

[0325] Crystalline Form V of Compound 3 may be characterised by an X-ray powder diffraction pattern. X-ray powder diffraction (XRPD) analyzes were carried out on a PANalytical Empyrean diffractometer using the same parameters and conditions as described before for Form III.

[0326] The X-ray powder diffraction pattern comprises peaks at 5.8, 8.0, 10.0, 10.7, 11.9, 12.3, 13.4 and 17.3 degrees two theta ± 0.2 degrees two theta. The X-ray powder diffraction pattern may further comprise at least one peak selected from 11.5, 13.7, 14.9, 15.5, 16.0, 16.6, 17.6, 17.9, 18.3, 18.4, 18.9, 19.3, 19.9, 20.6, 22.0, 23.8, 24.1 and 27.8 degrees two theta ± 0.2 degrees two theta.

[0327] Form V may further be characterized by an X-ray powder diffraction pattern having four, five, six, seven, eight, nine or more peaks selected from those peaks identified in Table 8.

[0328] Form V may further be characterized by an X-ray powder diffraction pattern comprising those peaks identified in Table 8, wherein the relative intensity of the peaks is greater than about 2%, preferably greater than about 5%, more preferably greater than about 10%, more preferably greater than about 15%. However, a skilled person will realize that the relative intensity of the peaks may vary between different samples and different measurements on the same sample.

[0329] Form V may further be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 3a.

[0330] Table 8 provides peak listings and relative intensity for the XRPD of Crystalline form V (Figure 3 a).

[0331] Table 8:

[0332] Pos. [°2Th. Rel. Int. [%]

[0333] 5.7722 6.58

[0334] 7.9939 14.46

[0335] 10.0327 75.49

[0336] 10.696 10.38

[0337] 11.502 9.2 11.8846 25.15

[0338] 12.3395 23.94

[0339] 13.4215 19.81

[0340] 13.7237 23.9

[0341] 14.8724 39.37

[0342] 15.4973 25.77

[0343] 15.9938 13.7

[0344] 16.6191 27.75

[0345] 17.2746 100

[0346] 17.615 71.17

[0347] 17.919 61.11

[0348] 18.2858 49.86

[0349] 18.4403 48.53

[0350] 18.876 50.18

[0351] 19.3278 73.01

[0352] 19.8553 34.47

[0353] 20.5845 44.19

[0354] 22.0225 58.4

[0355] 22.5034 40.85

[0356] 23.8039 39.23

[0357] 24.084 44.28

[0358] 27.8257 39.05

[0359] Form V may also be characterized by a differential scanning calorimetry thermogram (DSC) substantially as depicted in Figure 3b.

[0360] Form V may further be characterized by thermal gravimetric analysis (TGA). Form V may exhibit a TGA curve substantially as depicted in Figure 3c.

[0361] Crystalline Form VI

[0362] Crystalline Form VI of Compound 3 may be characterised by an X-ray powder diffraction pattern. X-ray powder diffraction (XRPD) analyzes were carried out on a PANalytical Empyrean diffractometer using the same parameters and conditions as described before for Form III.

[0363] The X-ray powder diffraction pattern comprises peaks at 3.3, 6.6, 9.8, 13.1, 16.3, 17.9, 18.5, 18.7, 20.5 and 20.7 degrees two theta ± 0.2 degrees two theta. The X-ray powder diffraction pattern may further comprise at least one peak selected from 12.5, 14.0, 18.1, 21.1, 21.8, 22.4, 23.1, 23.9, 25.9, 26.3, 26.5, 27.0, 28.3, 29.6 and 32.4 degrees two theta ± 0.2 degrees two theta.

[0364] Form VI may further be characterized by an X-ray powder diffraction pattern having four, five, six, seven, eight, nine or more peaks selected from those peaks identified in Table 9.

[0365] Form VI may further be characterized by an X-ray powder diffraction pattern comprising those peaks identified in Table 9, wherein the relative intensity of the peaks is greater than about 2%, preferably greater than about 5%, more preferably greater than about 10%, more preferably greater than about 15%. However, a skilled person will realize that the relative intensity of the peaks may vary between different samples and different measurements on the same sample.

[0366] Form VI may further be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 4a.

[0367] Table 9 provides peak listings and relative intensity for the XRPD of Crystalline form VI (Figure 4a).

[0368] Table 9:

[0369] Pos. [°2Th,] Rel. Int. [%]

[0370] 3.2838 0.23

[0371] 6.5522 1.08

[0372] 9.8038 0.76

[0373] 12.5232 4.77

[0374] 13.1429 100

[0375] 14.0117 14.74

[0376] 16.2532 51.31

[0377] 17.8796 37.36

[0378] 18.0893 27.65

[0379] 18.5391 39.96

[0380] 18.7031 35.13

[0381] 20.4911 33.92

[0382] 20.6616 42.78

[0383] 21.0938 8.15

[0384] 21.8088 33.75

[0385] 22.3703 17.87

[0386] 23.0978 19

[0387] 23.9128 22.32

[0388] 25.8714 15.76 26.3391 12.74

[0389] 26.4777 13

[0390] 27.0047 17.26

[0391] 28.287 18.82

[0392] 29.622 24.66

[0393] 32.4365 21.95

[0394] Form VI may also be characterized by a differential scanning calorimetry thermogram (DSC) substantially as depicted in Figure 4b.

[0395] Crystalline Form VII

[0396] Crystalline Form VII of Compound 3 may be characterised by an X-ray powder diffraction pattern. X-ray powder diffraction (XRPD) analyzes were carried out on a PANalytical Empyrean diffractometer using the same parameters and conditions as described before for Form III.

[0397] The X-ray powder diffraction pattern comprises peaks at 9.1, 9.6, 10.7, 13.7, 18.3, 19.3, 19.4 and 19.8 degrees two theta ± 0.2 degrees two theta. The X-ray powder diffraction pattern may further comprise at least one peak selected from 15.0, 15.9, 17.0, 17.4, 18.9, 20.1, 20.8, 21.2, 21.7, 23.1, 26.1, 31.6 and 31.7 degrees two theta ± 0.2 degrees two theta.

[0398] Form VII may further be characterized by an X-ray powder diffraction pattern having four, five, six, seven, eight, nine or more peaks selected from those peaks identified in Table 10.

[0399] Form VII may further be characterized by an X-ray powder diffraction pattern comprising those peaks identified in Table 10, wherein the relative intensity of the peaks is greater than about 2%, preferably greater than about 5%, more preferably greater than about 10%, more preferably greater than about 15%. However, a skilled person will realize that the relative intensity of the peaks may vary between different samples and different measurements on the same sample.

[0400] Form VII may further be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 5a.

[0401] Table 10 provides peak listings and relative intensity for the XRPD of Crystalline form VII (Figure 5 a).

[0402] Table 10:

[0403] Pos. [°2Th,] Rel. Int. [%] 9.083 1.68

[0404] 9.5963 0.41

[0405] 10.7389 1.01

[0406] 13.6827 3.42

[0407] 15.0401 1.04

[0408] 15.8736 0.73

[0409] 17.0057 0.5

[0410] 17.3986 1.09

[0411] 18.3362 11.84

[0412] 18.866 0.64

[0413] 19.2942 1.91

[0414] 19.3709 1.9

[0415] 19.7912 1.02

[0416] 20.0617 0.5

[0417] 20.7578 0.38

[0418] 21.242 0.53

[0419] 21.7174 0.94

[0420] 23.0878 1

[0421] 26.1477 0.64

[0422] 31.5984 100

[0423] 31.6853 46.81

[0424] Form VII may also be characterized by a differential scanning calorimetry thermogram (DSC) substantially as depicted in Figure 5b. Crystalline Form VIII

[0425] Crystalline Form VIII of Compound 3 may be characterised by an X-ray powder diffraction pattern. X-ray powder diffraction (XR.PD) analyzes were carried out on a PANalytical Empyrean diffractometer using the same parameters and conditions as described before for Form III.

[0426] The X-ray powder diffraction pattern comprises peaks at 5.3, 6.0, 8.0, 12.1, 12.2, 13.2, 15.9, 16.1, 18.9, 20.0, 21.1 and 26.6 degrees two theta ± 0.2 degrees two theta. The X-ray powder diffraction pattern may further comprise at least one peak selected from 10.6, 14.1, 14.5, 15.0, 17.0, 17.3, 17.6, 17.7, 21.4, 22.1, 23.3, 24.3, 25.2, 25.7, 27.4, 28.1, 28.9, 29.3, 30.0, 30.4, 31.0, 31.8, 32.5, 32.7 and 34.4 degrees two theta ± 0.2 degrees two theta.

[0427] Form VIII may further be characterized by an X-ray powder diffraction pattern having four, five, six, seven, eight, nine or more peaks selected from those peaks identified in Table 11.

[0428] Form VIII may further be characterized by an X-ray powder diffraction pattern comprising those peaks identified in Table 11, wherein the relative intensity of the peaks is greater than about 2%, preferably greater than about 5%, more preferably greater than about 10%, more preferably greater than about 15%. However, a skilled person will realize that the relative intensity of the peaks may vary between different samples and different measurements on the same sample. Form VIII may further be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 6a.

[0429] Table 11 provides peak listings and relative intensity for the XRPD of Crystalline form VIII (Figure 6a). Table 11:

[0430] Pos. [°2Th.] Rel. Int. [%]

[0431] 5.2688 5.97

[0432] 6.0149 43.8

[0433] 7.9877 12.25

[0434] 10.568 5.33

[0435] 12.0719 51.04

[0436] 12.1929 30.9

[0437] 13.1662 33.06

[0438] 14.0899 1.55

[0439] 14.537 0.68

[0440] 15.0474 1.64

[0441] 15.8891 47.35

[0442] 16.1001 100

[0443] 17.0223 8.75

[0444] 17.2841 14.51

[0445] 17.6074 25.61

[0446] 17.7258 25.57

[0447] 18.9302 82.58

[0448] 20.0411 48.11

[0449] 21.0622 35.82

[0450] 21.3811 19.39

[0451] 22.1275 38.8

[0452] 23.2608 7.43 24.3171 16.46

[0453] 25.245 11.21

[0454] 25.6744 7.68

[0455] 26.5648 24.37

[0456] 27.3985 5.85

[0457] 28.1146 1.62

[0458] 28.8939 2.16

[0459] 29.3461 3.5

[0460] 29.9674 11.92

[0461] 30.3751 15.14

[0462] 30.9907 12.15

[0463] 31.78 3.77

[0464] 32.4502 3.27

[0465] 32.7252 7.09

[0466] 34.4225 1.02

[0467] Form VIII may also be characterized by a differential scanning calorimetry thermogram (DSC) substantially as depicted in Figure 6b.

[0468] Form VIII may further be characterized by thermal gravimetric analysis (TGA). Form VIII may exhibit a TGA curve substantially as depicted in Figure 6c. Based on the TGA weight loss it is a hemi methyl cyclohexane solvate (stoichiometry API: solvent 1:0.5).

[0469] Differential scanning calorimetry (DSC)

[0470] About 3 mg of the compound was transferred into a standard aluminum TA-Instrument sample pan. The sample pan was closed with the appropriate cover and the DSC curve was recorded on a TA-Instruments Q2500 MTDSC equipped with a RCS cooling unit. The following parameters were used for the DSC measurements reported herein: initial temperature: 25°C heating rate: 10°C / min final temperature : 210°C nitrogen flow: 50 ml / min

[0471] DSC was measured for Crystalline Forms III, IV, V, VI, VII and VIII. TGA Method

[0472] About 10 mg of the compound was transferred into a TA Instruments platinum TGA pan. The

[0473] TGA curve was recorded on a TA Instruments TGA 550. The following parameters were used for the TGA measurements reported herein:

[0474] Initial temperature: room temperature

[0475] Heating rate: 10°C / min

[0476] Final condition: 250°C or < 80(w / w)%

[0477] Nitrogen flow: 25 mL / min TGA was measured for Crystalline Forms III, V and VIII.

Claims

CLAIMS1. The compound with the structureor a solvate thereof, wherein the compound is crystalline form III, IV, V, VI, VII or VIII.

2. The compound according to claim 1, wherein the compound is crystalline form III as a solvate.

3. The compound according to claim 2, wherein the solvate is selected from 1 -butanol, 1- pentanol, 1 -propanol, 2-butanol, 2-butanon, 2-propanol, 4-methyl-2-pentanone, acetone, anisole, butyl acetate, 1,4-di oxane, ethanol, ethyl acetate, isopropyl acetate, isobutyl acetate, n- propyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, toluene, p-xylene, formic acid, acetic acid, methyl acetate, tert-butylmethyl ether, dimethylsulfoxide, diethyl ether, dichloromethane, propylene glycol, polyethylene glycol, cyclopentyl methyl ether, and mixtures thereof.

4. The compound according to claim 2 or 3, wherein the crystalline form produces an X- ray powder diffraction pattern comprising peaks at 4.7, 9.4, 14.1, 14.3, 15.2, 17.7, 18.8 and 23.6 degrees two theta ± 0.2 degrees two theta.

5. The compound according to claim 4, wherein the X-ray powder diffraction pattern may further comprise at least one peak selected from 11.2, 11.8, 13.4, 16.4, 16.8, 20.6, 22.5, 26.5, 26.9, and 27.6 degrees two theta ± 0.2 degrees two theta.

6. The compound according to claim 1, wherein the compound is anhydrous crystalline form IV.

7. The compound according to claim 6, wherein the crystalline form produces an X-ray powder diffraction pattern comprising peaks at 9.4, 12.9, 15.5, 16.2, 18.7, 20.8, 22.0, 22.9, 28.2 and 31.3 degrees two theta ± 0.2 degrees two theta.

8. The compound according to claim 7, wherein the X-ray powder diffraction patternmay further comprise at least one peak selected from 6.4, 9.0, 11.3, 13.2, 15.7, 17.1, 17.5,17.9, 21.2, 25.6, 26.3, 31.8, 33.9 and 34.4 degrees two theta ± 0.2 degrees two theta.

9. The compound according to claim 1, wherein the compound is crystalline form V as a hydrate.

10. The compound according to claim 9, wherein the crystalline form produces an X-ray powder diffraction pattern comprising peaks at 5.8, 8.0, 10.0, 10.7, 11.9, 12.3, 13.4 and 17.3 degrees two theta ± 0.2 degrees two theta.

11. The compound according to claim 10, wherein the X-ray powder diffraction pattern may further comprise at least one peak selected from 11.5, 13.7, 14.9, 15.5, 16.0, 16.6, 17.6,17.9, 18.3, 18.4, 18.9, 19.3, 19.9, 20.6, 22.0, 23.8, 24.1 and 27.8 degrees two theta ± 0.2 degrees two theta.

12. The crystalline form according to claim 9, 10 or 11, further characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 3a.

13. The compound according to claim 1, wherein the compound is anhydrous crystalline form VI.

14. The compound according to claim 13, wherein the crystalline form produces an X-ray powder diffraction pattern comprising peaks at 3.3, 6.6, 9.8, 13.1, 16.3, 17.9, 18.5, 18.7, 20.5 and 20.7 degrees two theta ± 0.2 degrees two theta.

15. The compound according to claim 14, wherein the X-ray powder diffraction pattern may further comprise at least one peak selected from 12.5, 14.0, 18.1, 21.1, 21.8, 22.4, 23.1,23.9, 25.9, 26.3, 26.5, 27.0, 28.3, 29.6 and 32.4 degrees two theta ± 0.2 degrees two theta.

16. The compound according to claim 1, wherein the compound is crystalline form VII as a hydrate.

17. The compound according to claim 16, wherein the crystalline form produces an X-ray powder diffraction pattern comprising peaks at 9.1, 9.6, 10.7, 13.7, 18.3, 19.3, 19.4 and 19.8 degrees two theta ± 0.2 degrees two theta.

18. The compound according to claim 17, wherein the X-ray powder diffraction pattern may further comprise at least one peak selected from 15.0, 15.9, 17.0, 17.4, 18.9, 20.1, 20.8,21.2, 21.7, 23.1, 26.1, 31.6 and 31.7 degrees two theta ± 0.2 degrees two theta.

19. The compound according to claim 1, wherein the compound is crystalline form VIII as a methyl cyclohexane solvate.

20. The compound according to claim 19, wherein the crystalline form produces an X-ray powder diffraction pattern comprising peaks at 5.3, 6.0, 8.0, 12.1, 12.2, 13.2, 15.9, 16.1, 18.9, 20.0, 21.1 and 26.6 degrees two theta ± 0.2 degrees two theta.

21. The compound according to claim 20, wherein the X-ray powder diffraction pattern may further comprise at least one peak selected from 10.6, 14.1, 14.5, 15.0, 17.0, 17.3, 17.6, 17.7, 21.4, 22.1, 23.3, 24.3, 25.2, 25.7, 27.4, 28.1, 28.9, 29.3, 30.0, 30.4, 31.0, 31.8, 32.5, 32.7 and 34.4 degrees two theta ± 0.2 degrees two theta.

22. A compound as claimed in any one of claims 1 to 21 for use as a medicament.

23. A compound as claimed in any one of claims 1 to 21 for use in the prevention or treatment of cancer or an immunological disease.

24. The compound for use according to claim 23 wherein for use in the treatment of cancer wherein the cancer is diffuse large B-cell lymphoma.

25. A method of treating or preventing a disorder selected from cancer or an immunological disease, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound as claimed in any one of claims 1 to 21.

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