Formulations of 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4- methyl-4[4-(oxetan-3-yl)piperazin-1-yl]-pent-2-enenitrile

Abstract

Disclosed herein are novel formulations of 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-1-yl]-pent-2-enenitrile, including formulations including various solid forms thereof. Also disclosed are processes for preparing formulations of 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-1-yl]-pent-2-enenitrile.

Description

[00149] In some embodiments, the tablet includes at least one coating layer. In some embodiments, the coating layer is a film-coating layer. The coating layer can include hydroxypropyl methylcellulose, also referred to as hypromellose. In some embodiments, the coating layer comprises at least one of titanium dioxide and polyethylene glycol. In some embodiments, the coating layer comprises titanium dioxide and polyethylene glycol. In some embodiments, the coating layer comprises hydroxypropyl methylcellulose. In some embodiments, the coating layer can mask or improve the taste of the tablet, and can include a taste masking agent.

[00150] In some embodiments, the coating layer comprises about 1% to about 8 % by weight of the tablet. In some embodiments, the coating layer comprises about 1% by weight, about 2 % by weight, about 3 % by weight, about 4 % by weight, about 5 % by weight, about 6 % by weight, about 7 % by weight, or about 8 % by weight of the tablet.

[00151] In some embodiments, the coating layer includes 36% lactose monohydrate, 28% hypromellose (15 mPa.s), 26% titanium dioxide (E171) and 10% macrogol 3000-polyethylene glycol 3000 in an amount of about 2 to 4 % by weight of the tablet. In some embodiments, the coating layer includes lactose monohydrate, hypromellose, titanium dioxide and macrogol 3000-polyethylene glycol 3000 in an amount of about 3 % by weight of the tablet.

[00152] In some embodiments, the coating layer includes 40% of polyvinyl alcohol hydrolyzed, 20.2% of macrogol / PEG, 21.5% of titanium dioxide, 14.8% of talc and 3.5% of FD&C yellow #6 (Sunset Yellow FCF Aluminum Lake, USFDA Pigment Certification AZ7623, Regulation (EC) No 1333 / 2008). In some embodiments, the coating layer includes polyvinyl alcohol hydrolyzed, macrogol / PEG, titanium dioxide, talc and a pigment in an amount of about 3 % by weight of the tablet.

[00153] In some embodiments, the pharmaceutical formulation is free of titanium dioxide.

[00154] Colorants, surfactants, anti-adhesion agents, antifoaming agents, lubricants (e g., carnauba wax or PEG) and other additives may be added to the coatings besides plasticizers to solubilize or disperse the coating material, and to improve coating performance and the coated product. In some embodiments, the coating layer is white. In some embodiments, the coating layer is orange.

[00155] In some embodiments, the tablets are packaged in a blister pack. The blister packs can be made from any appropriate material. Examples include polyvinyl polychlorotrifluoroethylene in the forming film and hardened aluminum foil as lidding.

[00156] In some embodiments, the tablets are packaged in a bottle. The bottle can be made from any appropriate material.

[00157] Therapeutic Methods

[00158] Provided herein are methods of treating a disease or condition mediated by BTK comprising administering to a subject in need thereof a formulation comprising a therapeutically effective amount of the compound of Formula (I), 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-l-yl]-pent-2-enenitrile or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments the therapeutically effective amount is about 50 mg to about 900 mg. In some embodiments the therapeutically effective amount is about 200 mg. In some embodiments the therapeutically effective amount is about 300 mg. In some embodiments the therapeutically effective amount is about 400 mg. In some embodiments the therapeutically effective amount is about 500 mg. In some embodiments the therapeutically effective amount is about 600 mg. In some embodiments the therapeutically effective amount is about 800 mg. In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human.

[00159] Also provided herein are uses of the compound of Formula (I), 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3.4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-l-yl]-pent-2-enenitrile or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament to treat a disease or condition mediated by BTK. In some embodiments, the use of the compound of Formula (I), 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-l-yl]-pent-2-enenitrile or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament to treat a disease or condition mediated by BTK, comprises use of a the therapeutically effective amount of the compound of Formula (I). In some embodiments, the therapeutically effective amount of the compound of Formula (I) is about 50 mg to about 900 mg. In some embodiments the therapeutically effective amount is about 200 mg. In some embodiments the therapeutically effective amount is about 300 mg. In some embodiments the therapeutically effective amount is about 400 mg. In some embodiments the therapeutically effective amount is about 500 mg. In some embodiments the therapeutically effective amount is about 600 mg. In some embodiments the therapeutically effective amount is about 800 mg. In some embodiments, the medicament is for use in treating a mammal. In some embodiments, the mammal is a human.

[00160] Further provided herein are uses of the compound of Formula (I), 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-l-yl]-pent-2-enenitrile or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for the treatment of a disease or condition mediated by BTK. In some embodiments, the use of the compound of Formula (I), 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-l-yl]-pent-2-enenitrile or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for the treatment of a disease or condition mediated by BTK, comprises use of a the therapeutically effective amount of the compound of Formula (I). In some embodiments, the therapeutically effective amount of the compound of Formula (I) is about 50 mg to about 900 mg. In some embodiments the therapeutically effective amount is about 200 mg. In some embodiments the therapeutically effective amount is about 300 mg. In some embodiments the therapeutically effective amount is about 400 mg. In some embodiments the therapeutically effective amount is about 500 mg. In some embodiments the therapeutically effective amount is about 600 mg. In some embodiments the therapeutically effective amount is about 800 mg. In some embodiments, the use is for the treatment of a mammal. In some embodiments, the mammal is a human.

[00161] Additionally provided herein is the compound of Formula (I). 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-l-yl]-pent-2-enenitrile or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use in the treatment of a disease or condition mediated by BTK. Also provided herein is the compound of Formula (I), 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-I-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-l-yl]-pent-2-enenitrile or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use in the manufacture of medicament for the treatment of a disease or condition mediated by BTK.

[00162] In some embodiments, a dose of about 50-100 mg, 100-150 mg. 150-200 mg. 200-250 mg, 250-300 mg, 300-350 mg, 350-400 mg, 400-450 mg, 450-500 mg, 500-550 mg, 550-600 mg, 600-650 mg, 650-700 mg, 700-750 mg, 750-800 mg, 800-850 mg, or 850-900 mg is administered. In some embodiments, the dose is about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg. about 900 mg, or about 1000 mg. In some embodiments, the dose is about 200 mg. In some embodiments, the dose is about 300 mg. In some embodiments, the dose is about 400 mg. In some embodiments the dose is about 500 mg. In some embodiments, the dose is about 600 mg. In some embodiments, the dose is about 800 mg. In some embodiments, the dose is about 900 mg.

[00163] In some embodiments, the dose is administered daily. The daily dose can be delivered as a single dose or split into multiple parts. For example, in some embodiments, the dose is administered once a day (e g., about every 24 hours). In some embodiments, the dose is administered twice daily. In some embodiments, the dose is subdivided in two parts to be administered twice per day (e g., about every 12 hours). In some embodiments, the dose is subdivided in three parts to be administered three times per day (e.g., about every' 8 hours). In some embodiments, the dose is subdivided in four parts to be administered four times per day (e.g., about every’ 6 hours).

[00164] In some embodiments, the dose is administered orally. In some embodiments, the dose is administered in a form of tablets. In some embodiments, the dose is administered in the form of pills, capsules, semisolids, powders, sustained release formulations, or any other appropriate compositions.

[00165] In some embodiments, the subject is administered the BTK inhibitor compound of Formula (I) for a period of about 4, 8, 12, 16, 20, 24, or 26 weeks. In some embodiments, the subject is administered the BTK inhibitor compound of Formula (I) for a period of about 6, 12, 18, 24, 30, 36, 42, or 48 months. In some embodiments, the dose is once daily. In some embodiments, the dose is twice daily.

[00166] In some embodiments, the BTK inhibitor compound of Formula (I) is administered as monotherapy. In some embodiments, the method comprises administering the BTK inhibitor compound of Formula (I) and at least one additional therapeutic agent. The additional therapeutic agent may be administered concurrently or sequentially with the compound of Formula (I).

[00167] Determination of the frequency of administration can be made by persons skilled in the art, such as an attending phy sician based on considerations of the condition being treated, age of the subject being treated, severity of the condition being treated, general state of health of the subject being treated and the like.

[00168] In some embodiments, the compound of Formula (I) is administered in a therapeutically effective amount for treatment of various conditions or diseases, such as, e.g, at least one of acne, allergy, alopecia areata, vitiligo, pyoderma gangrenosum, membrane pemphigoid, epidermolysis bullosa acquisita, Steven Johnson syndrome, toxic epidermal necrolysis (TEN), pemphigus vulgaris, pemphigus foliaceus, ankylosing spondylitisis, antiphospholipid antibody syndrome, vasculitis, Guillain-Barre syndrome, scleroderma, Wegener's granulomatosis, psoriasis, granulomatosis with polyangiitis, thrombotic thrombocytopenic purpura, polyarteritis nodosa, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, asthma, moderate-to-severe asthma, mild asthma, moderate asthma, severe asthma, asthma that is not well controlled, autoimmune hepatitis, Behcet's disease, Grave’s disease, nephritis, pancreatitis, primary biliary cirrhosis, ulcerative colitis, colitis, conjunctivitis, dermatitis, atopic dermatitis, drug eruptions, drug-induced thrombocytopenia (DITP), vaccine-induced thrombosis and thrombocytopenia (VITT), eczema, folliculitis decalvans, pseudofolliculitis barbae, leucoclastic vasculitis, hidradenitis supprativa, palmar platar pustulosis, Lichenoid dermatitis, mycosis fungoides, sweet syndrome, follicular lymphoma, diffuse large B cell lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplamascytic lymphoma / Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, non-Hodgkin lymphoma, warm autoimmune hemolytic anemia (wAIHA). B-cell acute lymphoblastic leukemia (B-ALL), small lymphocytic lymphoma (SLL), intravascular large B cell lymphoma, primary effusion lymphoma, burkitt lymphoma / leukemia, lymphomatoid granulomatosis, B-cell non-Hodgkin lymphoma, idiopathic thrombocytopenic purpura, IgG4-related diseases (IgG4-RD) and flares thereof, antiphospholipid syndrome (APS), membranous nephropathy (MN), immune thrombocytopenia, inflammatory' bowel disease, itch associated with atopic dermatitis, lupus, cutaneous lupus, cutaneous lupus erythematosus, lupus nephritis, mixed connective tissue disease, multiple myeloma, multiple sclerosis, systemic inflammatory' response syndrome (SIRS), acute respiratory distress syndrome (ARDS), sepsis, sepsis induced acute lung injury’, diffuse alveolar damage (DAD), macrophage activation syndrome (MAS), secondary’ hemophagocytic lymphohistiocytosis (sHIH), cytokine release syndrome (CRS), cutaneous form of systemic sclerosis (CREST), cry oglobulinemia, primary’ biliary’ sclerosis, sclerosing cholangitis, urticaria, chronic spontaneous urticaria (CSU), chronic idiopathic urticaria (CIU), Al urticaria, and IgA nephropathy.

[00169] The therapeutically effective amount is typically' dependent on the weight of the subject being treated, his or her physical or health condition, the extensiveness of the condition to be treated, or the age of the subject being treated, pharmaceutical formulation methods, and / or administration methods (e.g., administration time and administration route).

[00170] In some embodiments, the dose is administered with food. In some embodiments, the dose is administered once daily with food. In some embodiments, the dose of 200 mg, 300 mg. 400 mg, 600 mg, or 800 mg is administered with food. In some embodiments, the dose of 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg is administered once daily with food. In some embodiments, the dose of 400 mg is administered once daily with food. In some embodiments, the dose of 600 mg is administered once daily with food. In some embodiments, the dose is administered in tablets. In some embodiments, the dose is administered in tablets with food. In some embodiments, the dose is administered once daily in tablets. In some embodiments, the dose is administered once daily in tablets with food. In some embodiments, the dose of 400 mg is administered in tablets. In some embodiments, the dose of 400 mg is administered in tablets with food. In some embodiments, the dose of 400 mg is administered once daily in tablets. In some embodiments, the dose of 400 mg is administered once daily in tablets with food. In some embodiments, the dose of 600 mg is administered in tablets. In some embodiments, the dose of 600 mg is administered in tablets with food. In some embodiments, the dose of 600 mg is administered once daily in tablets. In some embodiments, the dose of 600 mg is administered once daily in tablets with food.

[00171] In some embodiments, the dose is administered twice daily with food. In some embodiments, the dose of 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg is administered with food. In some embodiments, the dose of 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg is administered twice daily with food. In some embodiments, the dose of 400 mg is administered twice daily with food. In some embodiments, the dose of 600 mg is administered twice daily with food. In some embodiments, the dose is administered in tablets. In some embodiments, the dose is administered in tablets with food. In some embodiments, the dose is administered twice daily in tablets. In some embodiments, the dose is administered twice daily in tablets with food. In some embodiments, the dose of 400 mg is administered twice daily in tablets. In some embodiments, the dose of 400 mg is administered twice daily in tablets with food. In some embodiments, the dose of 600 mg is administered twice daily in tablets. In some embodiments, the dose of 600 mg is administered twice daily in tablets with food.

[00172] In some embodiments, the dose is administered without food. In some embodiments, the dose is administered once daily without food. In some embodiments, the dose of 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg is administered without food. In some embodiments, the dose of 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg is administered once daily without food. In some embodiments, the dose of 400 mg is administered once daily without food. In some embodiments, the dose of 600 mg is administered once daily without food. In some embodiments, the dose is administered in tablets without food. In some embodiments, the dose is administered once daily in tablets without food. In some embodiments, the dose of 400 mg is administered in tablets without food. In some embodiments, the dose of 400 mg is administered once daily in tablets without food. In some embodiments, the dose of 600 mg is administered in tablets without food. In some embodiments, the dose of 600 mg is administered once daily in tablets without food.

[00173] In some embodiments, the dose is administered twice daily without food. In some embodiments, the dose of 200 mg. 300 mg, 400 mg, 600 mg, or 800 mg is administered twice daily without food. In some embodiments, the dose of 400 mg is administered twice daily without food. In some embodiments, the dose of 600 mg is administered twice daily without food. In some embodiments, the dose is administered twice daily in tablets without food. In some embodiments, the dose of 400 mg is administered twice daily in tablets without food. In some embodiments, the dose of 600 mg is administered twice daily in tablets without food.

[00174] In some embodiments, the dose is 400 mg administered once daily. In some embodiments, the dose is 600 mg administered once daily.

[00175] In some embodiments, the dose is 400 mg administered twice daily. In some embodiments, the dose is 600 mg administered twice daily.

[00176] The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity7 and understanding. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the disclosure should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled. EXAMPLES

[00177] The following Examples are presented by way of illustration, not limitation. One skilled in the art can modify the procedures set forth in the illustrative examples to arrive at the desired products.

[00178] In accordance with the current disclosure, formulations including the compound of Formula (I) can be prepared as described herein.

[00179] Example 1: Immediate Release Tablet Formulation (400 mg, amorphous)

[00180] A film-coated tablet containing 400 mg of amorphous rilzabrutinib was prepared, with the components listed in Table 3. below. A homothetical formulation of the tablets will be prepared containing 300 mg of amorphous rilzabrutinib, for use in Example 7. Table 3. Composition of amorphous rilzabrutinib 400 mg tablet, film-coated Component Unit weight (mg / tablet) % (w / w) Function Intragranular Extragranular Rilzabrutinib drug substance 400.00 50.0 - Drug Substance Microcrystalline cellulose PH101 304.00 38.0 - Diluent Crospovidone. Type A 80.00 5.0 5.0 Disintegrant Sodium stearyl fumarate 16.00 1.0 1.0 Lubricant Total weight of core tablet 800.00 100 Film coating Ready-to-use orange or white film-coating ,b,c agent ’ 24.0 3.0 Filmcoating Material Total weight of film-coated tablet 824.00 g a The microcrystalline cellulose amount is adjusted to compensate for rilzabrutinib drug substance weight. b Purified water from the spray coating suspension is removed by drying during the process. c Represents 3% weight gain on the tablet core weight. Opadry II 85F130006 or Opadry II 85F18422 white may be used.

[00181] Microcrystalline cellulose. Microcrystalline cellulose (MCC) was used as a diluent for direct compression and roller compaction. Microcrystalline cellulose is used in approved tablet drug products, primarily as a diluent in oral tablet formulations. In addition to its use as a diluent, microcrystalline cellulose also has good compressibility properties that make it useful in tableting. In rilzabrutinib tablet manufacturing, MCC is added to the formulation to provide good compaction / compressibility and adhesion.

[00182] The MCC used in the rilzabrutinib tablets described herein is Avicel PHI01.

[00183] Crospovidone. Crospovidone is a water-insoluble cross-linked polyvinyl N-pyrrolidone. It is a nonionic disintegrant and dissolution enhancement agent that can be used in tablets prepared by direct-compression and dry-granulation methods. It is considered a super disintegrant as it rapidly exhibits high capillary activity and pronounced hydration capacity. In the formulation described herein, the rilzabrutinib is designed as an immediate-release tablet so that rapid disintegration can occur to ensure maximum bioavailability.

[00184] The particle size of crospovidone affects the disintegration process, and larger particles can provide a faster disintegration. As size increases, the intra-particular porosity increases, leading to larger water uptake and faster disintegration. Disintegrants can be more effective if used both intra- and extra-granularly. In general, disintegrants added only intra-granularly are not as effective as disintegrants added extra-granularly. For rilzabrutinib tablets, crospovidone is used at a 5% level intra-granularly and another 5% is added extra-granularly. This ensures that the tablet disintegrates quickly and improves dissolution.

[00185] The crospovidone grade selected for this product is Type A grade, a multicompendial grade crospovidone which has a large particle size, swell pressure and fast disintegration time.

[00186] Sodium stearyl fumarate. Sodium stearyl fumarate (SSF) is a tablet lubricant designed for formulations in which a high-speed direct compression of tablets is desired. SSF can be used to minimize sticking of the blend to the rollers and facilitate tablet ejection during compression. Using SSF can be beneficial as compared to other lubricants, e.g., magnesium stearate, including a high degree of drug compatibility and robustness to over-lubrication. In addition, SSF can be preferred over magnesium stearate because it can enhance faster dissolution rates, harder tablets, and protect from over-blending.

[00187] SSF used in rilzabrutinib tablets is a multi-compendial grade SSF. manufactured by JRS Pharma.

[00188] Film Coating Agent. Ready-to-use orange film-coating agent, Opadry II 85F130006, was manufactured by Colorcon and is composed of a mixture containing polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, and aluminum lake pigments FD&C yellow #6.

[00189] In the tablet formulation described herein, the coating agent is dispersed in purified water and then sprayed on the tablet cores to form a water-soluble film-coat, which is a cosmetic coating and can allow immediate disintegration of the tablets for fast release of rilzabrutinib.

[00190] Tablets containing 400 mg of amorphous rilzabrutinib had a total mass of the core tablet of 800 mg per tablet (not including film coating). This is shown in Table 4, below. Table 4. Composition of amorphous rilzabrutinib formulation (400 mg) Component Unit weight (mg / tablet) % (w / w) Function Intragranular Extragranular Rilzabrutinib drug substance 400.0 50.0 - Drug Substance Microcrystalline cellulose 304.0 38.0 - Diluent Crospovidone, Type A 80.0 5.0 5.0 Disintegrant Sodium stearyl fumarate 16.0 1.0 1.0 Lubricant Total mass of core tablet 800.0 100 Film coating Ready-to-use orange filmcoating agentc 24.0 b 3.0 b Filmcoating component Purified w ater a - q.s. Filmcoating solvent Total mass of film-coated tablet 824.0 a Purified water from the spray coating suspension is removed by drying during the process. b Theoretical quantity indicated, corresponding to a targeted weight gain of 3% on the core tablet weight. Spraying is stopped once the weight gain reaches approximately 3%. c Ready to use orange film coating; Opadry II® complete film coating system 85F130006 may be used.

[00191] Example 2: Crystalline Formulation (270 mg)

[00192] A tablet containing 270 mg of crystalline Form B of rilzabrutinib was prepared, with the components listed in Table 5, below. Table 5. Rilzabrutinib 270 mg tablet (crystalline) Intragranular components Rilzabrutinib, crystalline drug substance 65.00 wt % (270 mg) Microcrystalline cellulose 50pm diluent 30.85 wt % Crospovidone Type A disintegrant 2.00 wt % Magnesium Stearate lubricant 0.25 wt % Colloidal silicon dioxide glidant 0.90 wt % Extragranular components Magnesium Stearate lubricant 1.00 wt. %

[00193] The final tablet mass was 416 mg ± 3% (404 - 428 mg).

[00194] The process for preparing the tablets described herein included weighing, sieving, mixing, compaction, tableting, and film-coating steps.

[00195] Example 3: Crystalline Formulations (400 mg, 450 mg)

[00196] Two formulations for tablets containing crystalline Form B rilzabrutinib, one with 400 mg of drug substance and one with 450 mg of drug substance, were prepared. The components for these two formulations are listed in Table 6, below. Numbers in the table represent the percentage of each component by w eight, relative to the total tablet w eight. Table 6. Composition of rilzabrutinib formulations Component Function Crystalline (400 mg) Crystalline (450 mg) Intragranular Rilzabrutinib crystalline Drug Substance 65.0 65.0 Microcrystalline Cellulose 50pm Diluent 23.0 30.2 Hydroxypropylcellulose Binder 2.0 - Crospovidone type A Disintegrant 3.0 2.0 Croscarmellose sodium Disintegrant 1.0 - Colloidal anhydrous silicon dioxide Glidant 0.9 0.9 Sodium stearyl fumarate Lubricant - - Magnesium stearate Lubricant 1.0 0.5 Extragranular Microcrystalline Cellulose 50pm Diluent 1.5 - Colloidal anhydrous silicon dioxide Glidant 0.4 0.4 Crospovidone Type A Disintegrant 1.0 - Croscarmellose Disintegrant 1.0 - Magnesium stearate Lubricant 0.20 1.0 Sodium steary l fumarate Lubricant - - TOTAL 100.0 100.0 Orange film-coating agent Coating agent 3.0 - White film-coating agent* Coating agent - 4.0 * TiO2-free

[00197] In this study, it was determined that hydroxypropylcellulose could be removed from the formulation without adversely affecting the physical characteristics of the tablet. Additionally, it was determined that one disintegrant was sufficient, that magnesium stearate and silicon dioxide are sufficient for the extragranular phase, that use of magnesium stearate in the extragranular phase can reduce sticking of the material during processing, and that a TiO2-free white film-coating agent can be used.

[00198] Example 4: Additional Crystalline Formulations (500 mg)

[00199] A formulation for tablets containing 500 mg of crystalline Form B rilzabrutinib was prepared. The components for this formulation are listed in Table 7, below. Table 7. Composition of 500 mg crystalline rilzabrutinib formulation Component Centesimal composition [%] Composition per unit [mg / unit] Intragranular RILZABRUTINIB CRYSTALLINE 65.00 500.00 Microcrystalline Cellulose 50 pm 30.45 234.23 Colloidal anhydrous silicon dioxide 0.90 6.92 Crospovidone Type A 2.00 15.38 Magnesium Stearate 0.25 1.92 Extragranular Magnesium Stearate 1.00 7.69 Colloidal anhydrous silicon dioxide 0.40 3.08 Core tablet terminated at 100.00 % 769.23 mg Film-coating Opadry" 32F38977 white a 3.0 23.08 Purified water Sufficient quantity Film-coated terminated at 792.31 mg a Opadry® II 32F38977 is composed of 36% lactose monohydrate, 28% hypromellose (15 mPa.s, 26% titanium dioxide (E171), and 10% macrogol 3000-polyethylene glycol 3000. b Purified water from the spray coating suspension is removed by drying during the process.

[00200] Example 5: An Additional 500 mg Crystalline Exemplary Formulation

[00201] An additional formulation for tablets containing 500 mg of crystalline Form B rilzabrutinib was prepared. The components for this formulation are listed in Table 8, below. Table 8. A Crystalline Formulation for 500 mg Rilzabrutinib Component Function Weight % for crystalline formulation (500 mg) Intragranular Rilzabrutinib, crystalline Drug Substance 65.0 Microcrystalline Cellulose Diluent 30.45 Crospovidone type A Disintegrant 2.0 Colloidal anhydrous silicon dioxide Glidant 0.9 Magnesium stearate Lubricant 0.25 Extragranular Microcrystalline Cellulose Diluent - Colloidal anhydrous silicon dioxide Glidant 0.4 Magnesium stearate Lubricant 1.0 TOTAL 100.0 White film-coating agent Coating agent 3.0

[00202] Tablets were made with the formulation shown in Table 8. An additional batch was made with 0.50 weight % of magnesium stearate in the intragranular phase. Tablet mass was 769.23 ± 3%.

[00203] It was determined that using a white coating with titanium dioxide was beneficial to have a suitable color for the tablets. There were issues with flowing of the material during processing at the compression step.

[00204]      Example 6: Colloidal Silicon Dioxide / MCC variations (400 mg crystalline)

[00205] Six additional formulations for tablets containing 400 mg of crystalline Form B rilzabrutinib will be prepared, to evaluate the effects of varying the types of colloidal silicon dioxide and microcrystalline cellulose (MCC) used in the tablets. The components for these formulations are listed in Table 9, below. Table 9. Additional Formulations for 400 mg Crystalline Rilzabrutinib Tablets Formula w / w % 1 2 3 4 5 6 Intragranular Rilzabrutinib, crystalline 65.00 65.00 65.00 65.00 65.00 65.00 Microcrystalline cellulose 50 pm 30.45 30.45 30.45 20.45 20.45 20.45 Crospovidone Type A 2.00 2.00 2.00 2.00 2.00 2.00 colloidal silica Aerosil 200 0.9 - 0.7 0.7 0.9 - colloidal silica Aeroperl 300 - 0.9 - - - 0.9 Magnesium stearate 0.25 0.25 0.25 0.25 0.25 0.25 Extragranular colloidal silica Aerosil 200 0.4 - 0.6 0.6 0.4 - colloidal silica Aeroperl 300 - 0.4 - - - 0.4 Microcrystalline cellulose 180 pm 10.0 10.0 10.0 Magnesium stearate 1.00 1.00 1.00 1.00 1.00 1.00 TOTAL 100.00 100.00 100.00 100.00 100.00 100.00

[00206] These formulations for tablets containing 400 mg of crystalline rilzabrutinib will determine an optimum formulation for future use.

[00207] Example 7: Food effect and relative bioavailability study of rilzabrutinib in healthy participants.

[00208] A randomized, open-label, single-dose, 4-period, 4-sequence, crossover Phase I relative bioavailability study comparing crystalline formulation tablet versus reference amorphous formulation tablet of rilzabrutinib in fasted and fed conditions in healthy male and female participants was performed. IMP = investigational medicinal product.

[00209] The amorphous formulation was studied with a dose of two 300 mg amorphous tablets (for a total dose of 600 mg rilzabrutinib; IMP1) and the crystalline formulation was studied with a dose of one 500 mg crystalline tablet (IMP2).

[00210] This study was performed with healthy volunteers.

[00211] Summary of study design. This was a randomized, open-label, single dose, 4-period, 4-sequence, crossover Phase I relative bioavailability study comparing crystalline formulation tablet to reference amorphous formulation tablet of rilzabrutinib in fasted and fed (high fat meal) conditions in healthy male and female participants aged 18 to 55 years.

[00212] The total study duration per participant was approximately 36 days, including:

[00213] Screening: 28 days (Day -28 to Day -1).

[00214] Treatment periods: once successfully screened, enrolled participants will be randomized to 1 of 4 treatment sequences with 4 single dose treatment periods. Duration of each period of the study for 1 participant: 1 day of treatment followed by 1 day washout.

[00215] Washout: One day washout is planned after each treatment period hence providing 2 days between doses.

[00216] Safety follow-up: participants were asked to participate in an end-of-study safety' assessment upon discharge from the clinical study unit, i.e., on Day 8 of the study, 1 day after last IMP administration on Day 1 of the fourth treatment period.

[00217] Primary Study Objectives: To assess the relative bioavailability of crystalline formulation tablet versus reference amorphous formulation tablet of rilzabrutinib in fasted conditions in healthy male and female participants.

[00218] Secondary Study Objectives: To assess the relative bioavailability of crystalline formulation tablet versus reference amorphous formulation tablet of rilzabrutinib in fed conditions in healthy male and female participants; to assess the food effect with crystalline formulation tablet and with reference amorphous formulation tablet of rilzabrutinib in healthy male and female participants; and to assess the safety and tolerability of a single oral 600 mg amorphous dose (reference formulation) and a single oral 500 mg crystalline dose (test formulation) of rilzabrutinib administered under fed and fasted conditions.

[00219] The scope of the trial is a safety and pharmacokinetics study.

[00220] The four arms of the study are shown in Table 10, below. Table 10. The four arms of the study. Arm Label Arm description Arm type Treatment A: rilzabrutinib amorphous fasted Participants will receive single oral dose of amorphous tablet formulation rilzabrutinib under fasted conditions on Day 1 for one period Active Comparator / Reference Treatment B: rilzabrutinib crystalline fasted Participants will receive single oral dose of cry stalline tablet formulation rilzabrutinib under fasted conditions on Day 1 for one period Experimental / Test Treatment C: rilzabrutinib amorphous fed Participants will receive single oral dose of amorphous tablet formulation rilzabrutinib under fed conditions on Day 1 for one period Active Comparator / Reference Treatment D: rilzabrutinib crystalline fed Participants will receive single oral dose of cry stalline tablet formulation rilzabrutinib under fed conditions on Day 1 for one period Experimental / Test

[00221] Eligible participants were randomly assigned in Latin square design to receive the following study interventions in 1 of 4 sequences:

[00222] Treatment A: a single oral 600 mg dose of amorphous tablet formulation rilzabrutinib under fasted conditions using 2 x 300 mg tablets (= Reference in fasted condition).

[00223] Treatment B: a single oral 500 mg dose of crystalline tablet formulation rilzabrutinib under fasted conditions using 1 x 500 mg tablet (= Test in fasted condition).

[00224] Treatment C: a single oral 600 mg dose of amorphous tablet formulation rilzabrutinib under fed conditions using 2 x 300 mg tablets (= Reference in fed condition).

[00225] Treatment D: a single oral 500 mg dose of crystalline tablet formulation rilzabrutinib under fed conditions using 1 x 500 mg tablet (= Test in fed condition).

[00226] The following sequences were randomly assigned on Day 1 in a 1:1:1:1 ratio: Sequence Period 1 Period 2 Period 3 Period 4 1 A B C D 2 D A B C 3 C D A B 4 B C D A

[00227] Each administration of investigational medicinal product (IMP) was separated by a washout process with a duration of 2 days (1 day of treatment at a single dose was followed by 1 day washout).

[00228] The end of the trial was the last visit of the last participant (LSLV).

[00229] Study Population: Healthy volunteers, all genders, minimum age of 18 years and maximum age of 55 years. Number of participants (planned and analyzed): 28 healthy adult male and female participants were randomized to study interventions as planned.

[00230] Inclusion Criteria: Body weight between 50.0 and 100.0 kg, inclusive, if male, and between 40.0 and 90.0 kg, inclusive, if female, body mass index (BMI) between 18.0 and 32.0 kg / m2, inclusive. Willing to abstain from using tobacco or nicotine-containing products or consuming alcohol from check-in (Day -1) until discharge at end-of-study visit. Willing to abstain from taking any prescription drugs, dietary supplements, or non-prescription drugs within 14 days or 5 half-lives, whichever, is longer, prior to the first dose of study drug through the follow-up phone call. Use of hormonal contraception and aspirin (at doses of <2000 mg / day) or ibuprofen (at doses of <1200 mg / day) are allowed prior to and during the study. Negative urine drug / alcohol testing at screening and check-in (Day -1). Screening urine drug / alcohol testing may be repeated once if deemed appropriate by the site Investigator. Willing to abstain from consuming grapefruit, star fruit, or Seville orange-containing products from 14 days prior to first dose of study drug until discharge from the clinical study unit.

[00231] Exclusion Criteria: Any history or presence of clinically relevant cardiovascular, pulmonary, gastrointestinal, hepatic, renal, metabolic, hematological, neurological, osteomuscular, articular, psychiatric, systemic, ocular, gynecologic (if female), infectious disease, or signs of acute illness. Participant has clinical signs and symptoms consistent with COVID-19, e.g, fever, dry cough, dyspnea, loss of taste and smell, sore throat, fatigue or confirmed infection by appropriate laboratory test within the last 4 weeks prior to Screening. Participant who had severe course of COVID-19 (i.e., hospitalization, extracorporeal membrane oxygenation [ECMO], mechanically ventilated). Participant has a positive test result for SARS-CoV-2 (measured via Real-time Reverse Transcriptase Polymerase Chain Reaction [RT-PCR] or Rapid Antigen Test [RAT]).

[00232] Frequent headaches and / or migraine, recurrent nausea and / or vomiting (for vomiting only: more than twice a month). Blood donation, any volume, within 1 month before inclusion. Symptomatic postural hypotension, irrespective of the decrease in blood pressure, or asymptomatic postural hypotension defined as a decrease in systolic blood pressure <30 mmHg within 3 minutes when changing from supine to standing position.

[00233] Presence or history of drug hypersensitivity, or allergic disease diagnosed and treated by a physician. Participants with known hypersensitivity to any component of the IMP formulation or allergic disease diagnosed and treated by a physician. History or presence of drug or alcohol abuse (alcohol consumption more than 40 g per day on a regular basis). Regular intake of nicotine (via patch, smoking, vaping or other forms) more than 10 mg per day (based on the average nicotine content of 10-12 mg of nicotine per cigarette and inhalation of up to 2 mg of nicotine per cigarette), and unable to stop smoking during the study (occasional smoker can be enrolled). Excessive consumption of beverages containing xanthine bases (more than 4 cups or glasses per day). If female, pregnancy (defined as positive 0-HCG blood test), or breast-feeding.

[00234] Any medication (including St John’s Wort or ginseng) within 14 days before inclusion or within 5 times the elimination half-life or pharmacodynamic half-life of the medication, with the exception of aspirin / ibuprofen, hormonal contraception, and menopausal hormone replacement therapy. Any vaccination (except COVID-19 vaccination, see below) within the last 28 days and any biologies (antibody or its derivatives) given within 4 months before inclusion. Non-live vaccines, including COVID-19: last administration of a vaccine within 4 weeks before randomization. Live vaccines: last administration of a vaccine within 3 months before randomization.

[00235] Positive result on any of the following tests: hepatitis B surface antigen (HBs Ag), anti-hepatitis C virus (anti-HCV) antibodies, anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV 1 and anti HIV2 Ab). Positive result on urine drug screen (amphetamines / methamphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates). Positive alcohol breath or alcohol urine test. Positive pregnancy test. Gilbert’s Syndrome.

[00236] Specific vulnerable populations: Women of child-bearing potential using contraception.

[00237] Interventions. See Table 11, below. Table 11. Interventions INN or placebo or any descriptive name Pharmaceutical form Route of administration IMP1: Rilzabrutinib; 300 mg amorphous tablet (reference) Film coated tablet Oral IMP2: Rilzabrutinib, 500 mg crystalline tablet (test) Film coated tablet Oral

[00238] Endpoints. See Tables 12-13, below. Primary Endpoints are relative bioavailability as assessed by rilzabrutinib plasma PK parameters following administration of the test and reference formulations in the fasted state, e.g., Cmax, AUClast, AUC. Secondary Endpoints are relative bioavailability as assessed by rilzabrutinib plasma PK parameters following administration of the test and reference formulations in the fed state, e. g., Cmax, AUClast. AUC; food effects as assessed by rilzabrutinib plasma PK parameters following administration of the test and reference formulations under the fed versus fasted state, e. g., Cmax, AUClast, AUC; and safety of reference and test formulations as assessed by physical examinations, vital signs, 12 lead ECGs, clinical laboratory tests (clinical chemistry', hematology’, coagulation, and urinalysis), and adverse events.

[00239] Abbreviations: AUC = area under the plasma concentration versus time curve extrapolated to infinity; AUClast = area under the plasma concentration versus time curve from time zero to the last measurable concentration; Cmax = maximum plasma concentration; ECG = electrocardiogram; PK = pharmacokinetic. Table 12. Primary Endpoints Endpoint title Endpoint Description Time frame for evaluation Primary Endpoints Relative bioavailability as assessed by rilzabrutinib Cmax following administration of the test and reference formulations in the fasted state Cmax: maximum plasma concentration Day 1 to Day 8 Relative bioavailability as assessed by rilzabrutinib AUCiast following administration of the test and reference formulations in the fasted state AUCiast: area under the plasma concentration versus time curve from time zero to the last measurable concentration Day 1 to Day 8 Relative bioavailability as assessed by rilzabrutinib AUC following administration of the test and reference formulations in the fasted state AUC: area under the plasma concentration versus time curve extrapolated to infinity Day 1 to Day 8 Table 13. Secondary Endpoints Secondary End points Relative bioavailability as assessed by rilzabrutinib Cmax following administration of the test and reference formulations in the fed state Cmax: maximum plasma concentration Day 1 to Day 8 Relative bioavailability as assessed by rilzabrutinib AUCiast following administration of the test and reference formulations in the fed state AUCiast: area under the plasma concentration versus time curve from time zero to the last measurable concentration Day 1 to Day 8 Relative bioavailability as assessed by rilzabrutinib AUC following administration of the test and reference formulations in the fed state AUC: area under the plasma concentration versus time curve extrapolated to infinity Day 1 to Day 8 Food effects as assessed by rilzabrutinib Cmax following administration of the test and reference formulations under the fed versus fasted state Cmax: maximum plasma concentration Day 1 to Day 8 Food effects as assessed by' rilzabrutinib AUClast following administration of the test and reference formulations under the fed versus fasted state AUClast: area under the plasma concentration versus time curve from time zero to the last measurable concentration Day 1 to Day 8 Food effects as assessed by rilzabrutinib AUC following administration of the test and reference formulations under the fed versus fasted state AUC: area under the plasma concentration versus time curve extrapolated to infinity' Day 1 to Day 8 Safety' of reference and test formulations As assessed by physical examinations, vital signs, 12 lead ECGs, clinical laboratory tests (clinical chemistry', hematology, coagulation, and urinalysis), and adverse events. Day 1 to Day 8

[00240] Statistical methods. Statistical considerations.

[00241] Primary endpoint: Pharmacokinetic. Relative bioavailability (Frei) of crystalline formulation compared to amorphous formulation in fasted condition was assessed for maximum plasma concentration (Cmax), AUC until last timepoint with quantifiable concentration (AUClast), and area under plasma concentration versus time curve extrapolated to infinity (AUC) using a linear model on log-transformed parameters, with and without dose normalization. Formulation ratios (geometric mean ratios) were estimated from the model, as well as 90% confidence intervals (Cis).

[00242] Main secondary' endpoints.

[00243] Pharmacokinetic. Relative bioavailability of crystalline formulation compared to amorphous formulation in fed condition (with and without dose normalization) and food effect for each formulation were assessed for Cmax, AUClast and AUC using a linear model on log-transformed parameters. The test / reference ratios of PK parameters after log transformation (geometric mean ratios) for the different formulation and food conditions were estimated, as well as the 90% Cis.

[00244] Safety'. Secondary endpoints were adverse events (AEs), laboratory parameters, vital signs, and electrocardiograms (ECGs). Analyses were based on the review of individual values, and descriptive statistics. The safety' analysis focused on the treatment-emergent (TE) period, defined as the time from the first IMP administration of a study period up to the next study period (excluded) or up to the end of study visit (included) for the last study period. AEs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA). Their severities were graded according to National Cancer Institute (NCI) Common Terminology' Criteria for Adverse Events (CTCAE). The numbers (%) of participants experiencing treatment emergent adverse events (TEAEs) were summarized. Potentially clinically significant abnormalities (PCSAs) in clinical laboratory test results, vital signs, and ECG were flagged and summarized using frequency tables.

[00245] Summary of results.

[00246] Participant Disposition: A total of 28 participants were randomized and exposed to rilzabrutinib in one of four treatment sequences (ABCD, BCDA, CDAB, or DABC). 27 of 28 participants completed the study while one participant withdrew consent on day 6 for personal reasons (sequence randomized ABCD, not exposed to D).

[00247] Analysis Populations: All participants (N=28) were evaluable for safety assessment and PK parameters.

[00248] Demographic and other baseline characteristics: 18 of 28 (64.3%) participants were male, 10 of 28 (35.7%) participants were female, the median (min-max) age at enrollment was 31.5 (19-53) years.

[00249] Exposure: All except one participant (27 of 28) received four, single doses of rilzabrutinib: 600 mg amorphous formulation (reference formulation) in the fed and fasted states as well as single doses of 500 mg crystalline formulation (test formulation) in the fed and fasted states. One subject withdrew from the study prior to completion of treatment sequence 1 and received single doses of 600 mg amorphous formulation in the fed and fasted states as well as a 500 mg cry stalline formulation in the fasted state. This participant was not replaced.

[00250] Safety results: The administration of rilzabrutinib in both formulations was safe and well tolerated. Overall, 21 of 28 (75%) participants experienced a total of 60 AEs (58 TEAEs and 2 post-treatment AEs). 41 of 58 (70.6%) reported TEAEs were gastrointestinal in nature. There were no deaths, serious adverse events (SAEs), or withdrawals from the study due to TEAEs.

[00251] No other clinically significant vital sign changes, ECG changes, or alterations in laboratory parameters were observed.

[00252] The most common TEAEs for subjects most recently receiving both the amorphous and crystalline formations were gastrointestinal in nature.

[00253] Following amorphous formulation in the fasted state (A), 15 of 28 (53.6%) participants reported 20 gastrointestinal TEAEs including 8 of Grade 1 diarrhea, 4 of Grade 1 nausea. 2 of Grade 1 abdominal pain, 1 of Grade 1 vomiting, and 1 of Grade 1 dyspepsia. One participant reported Grade 2 nausea and Grade 2 abdominal pain; one participant reported Grade 2 nausea; and one participant reported Grade 2 diarrhea. All TEAEs resolved without treatment beyond increased oral fluids.

[00254] Following crystalline formulation in the fasted state (B), 11 of 28 (39.3%) participants reported 14 gastrointestinal TEAEs including 8 of Grade 1 diarrhea, 4 of Grade 1 nausea, 1 of Grade 1 abdominal pain, and 1 of Grade 1 flatulence. All TEAEs resolved without treatment.

[00255] Gastrointestinal TEAEs were less frequent for each formulation in the fed state: following amorphous formulation (C), 4 of 28 (14.3%) participants reported 3 Grade 1 nausea and 1 Grade 1 abdominal pain and following crystalline formulation (D), 3 of 27 (11.1%) participants reported 2 Grade 1 nausea and 1 Grade 1 diarrhea.

[00256] Pharmacokinetic results. A total of 28 participants were included in the PK analysis population. One participant discontinued early and so had no data for the '‘500 mg crystalline Fed” study intervention.

[00257] Mean rilzabrutinib plasma concentration-time profiles following single SC doses are shown in Figure 1 (linear scale) and Figure 2 (semi-logarithmic scale). A summary of plasma PK parameters of rilzabrutinib following a single oral dose of 500 mg crystalline or 600 mg amorphous rilzabrutinib in fasted or fed condition is shown in Table 14. Table 14. Mean ±SD (geometric mean) [CV%] pharmacokinetic parameters for rilzabrutinib following single oral administration of two formulations in healthy participants in fasted or fed conditions. PK Parameters 500 mg Crystalline Fasted 500 mg Crystalline Fed 600 mg Amorphous Fasted 600 mg Amorphous Fed N 28 27 28 28 Cmax (mg / mL) 212± 192 (154)

[90] 170±124 (140)

[73] 220 ± 144(179)

[66] 182± 123 (152)

[68] Cmax / Dose (ng / mL / mg) 0.425 ± 0.384 (0.309)

[90] 0.340 ±0.248 (0.280)

[73] 0.366 ±0.240 (0.298)

[66] 0.304 ±0.206 (0.253)

[68] AUC (ng h / rnL) 689 ±756 (509)

[110] b 524 ± 353 (445)

[67] 715 ±483 (569)

[68] c 608 ±343 (525)

[56] AUC / Dose (ng h / mL / mg) 1.38 ± 1.51 1.05 ±0.705 (0.889)

[67] 1.19 ± 0.805 1.01 ± 0.572 (0.876)

[56] (1.02)

[110] b (0.948)

[68] c AUClast 648 ± 741 (457) 523 ± 352 (443) 699 ± 477 (555) 607 ±343 (524) (ng h / mL)

[114]

[67]

[68]

[56] AUClast / Dose 1.30 ± 1.48 1.05 ±0.704 1.17 ± 0.796 1.01 ± 0.571 (ng h / mL / mg) (0.914)

[114] (0.887)

[67] (0.925)

[68] (0.873)

[56] tmaxa (h) 1.50 (1.00, 4.00) 2.50(1.00, 5.00) 1.50 (1.00, 5.00) 2.50(1.00,5.00) tl / 2z (h) 3.02 ± 1.09 (2.84)

[36] b 2.74 ±0.641 (2.66)

[23] 3.21 ± 1.18 (3.03)

[37] c 2.66 ± 0.520 (2.60)

[20] CL / F (L / h) 1290 ± 1130 (983)

[88] b 1300 ±739 (1120)

[57] 1420± 1550 (1060)

[109] c 1330 ±765 (1140)

[58] Vz / F (L) 170 ± 9540 (4030)

[155] b 4880 ±2360 (4320)

[48] 7800± 13500 (4610)

[173] c 4900 ±2610 (4290)

[53] a Median (Min, Max) b N=26. For 2 participants in '‘500 mg Crystalline Fasted”, log linear terminal phase was not characterized sufficiently. c N=27. For 1 participant in “600 mg Amorphous Fasted”, log linear terminal phase was not characterized sufficiently.

[00258] Summaries of the geometric mean ratios and 90% Cis for the primary PK parameters are shown in Table 15 and Table 16, with the latter presenting dose-normalized PK parameters. Table 15 - Primary analysis - Relative bioavailability and food effect - Point estimates of treatment ratio with 90% confidence intervals for rilzabrutinib Cmax, AUClast and AUC - PK population Comparison Parameter Point Estimate 90% CI Treatment B versus Log(Cmax) 0.93 (0.73 to 1.19) Treatment A Log(AUClast) 0.86 (0.68 to 1.08) Log(AUC) 0.85 (0.69 to 1.05) Treatment D versus Log(Cmax) 0.83 (0.65 to 1.07) Treatment C Log(AUClast) 0.82 (0.65 to 1.03) Log(AUC) 0.85 (0.69 to 1.04) Treatment C versus Log(Cmax) 0.86 (0.65 to 1.14) Treatment A Log(AUClast) 0.95 (0.73 to 1.23) Log(AUC) 0.85 (0.67 to 1.07) Treatment D versus Log(Cmax) 0.77 (0.58 to 1.02) Treatment B Log(AUClast) 0.90 (0.69 to 1.18) Log(AUC) 0.85 (0.67 to 1.07) Treatment A: Rilzabrutinib 600 mg Amorphous, Fasted. Treatment B: Rilzabrutinib 500 mg Cry stalline, Fasted. Treatment C: Rilzabrutinib 600 mg Amorphous, Fed. Treatment D: Rilzabrutinib 500 mg Crystalline, Fed. CI: confidence interval In primary analy sis, all available PK parameters were included. Table 16 - Primary analysis - Relative bioavailability and food effect of Rilzabrutinib Cmax. AUClast and AUC - Point estimates of treatment ratio with 90% confidence intervals for dose normalized PK parameters - PK population Comparison Parameter Point Estimate 90% CI Treatment B versus Log (Dose Normalized Cmax) 1.12 (0.88 to 1.43) Treatment A Log(Dose Normalized AUClast) 1.03 (0.82 to 1.29) Log(Dose Normalized AUC) 1.02 (0.83 to 1.26) Treatment D versus Log (Dose Normalized Cmax) 1.00 (0.78 to 1.28) Treatment C Log(Dose Normalized AUClast) 0.98 (0.78 to 1.24) Log(Dose Normalized AUC) 1.02 (0.83 to 1.25) Treatment C versus Log (Dose Normalized Cmax) 0.86 (0.65 to 1.14) Treatment A Log(Dose Normalized AUClast) 0.95 (0.73 to 1.23) Log(Dose Normalized AUC) 0.85 (0.67 to 1.07) Treatment D versus Log (Dose Normalized Cmax) 0.77 (0.58 to 1.02) Treatment B Log(Dose Normalized AUClast) 0.90 (0.69 to 1.18) Log(Dose Normalized AUC) 0.85 (0.67 to 1.07) Treatment A: Rilzabrutinib 600 mg Amorphous, Fasted. Treatment B: Rilzabrutinib 500 mg Cry stalline, Fasted. Treatment C: Rilzabrutinib 600 mg Amorphous, Fed. Treatment D: Rilzabrutinib 500 mg Crystalline, Fed. CI: confidence interval In primary analysis, all available PK parameters were included.

[00259] In fasted condition, exposure was similar in term of Cmax and slightly higher in term of AUC for 600 mg amorphous rilzabrutinib compared to 500 mg crystalline rilzabrutinib (Table 14), with test / reference ratios of 0.93 (90% CI: 0.73 to 1.19) and 0.85 (90% CI: 0.69 to 1.05), respectively (Table 15). In fed condition, exposure was slightly higher in term of Cmax and AUC for 600 mg amorphous rilzabrutinib compared to 500 mg crystalline rilzabrutinib (Table 14). with test / reference ratios of 0.83 (90% CI: 0.65 to 1.07) and 0.85 (90% CI: 0.69 to 1.04), respectively (Table 15).

[00260] The dose-normalized exposures were similar between both formulations, indicating similar bioavailability for the formulations after adjustment for dose differences (Table 16). Point estimates (90% CI) for dose-normalized crystalline / amorphous ratios were 1.12 (90% CI: 0.88 to 1.43) and 1.02 (90% CI: 0.83 to 1.26) in fasted condition, and 1.00 (90% CI: 0.78 to 1.28) and 1.02 (90% CI: 0.83 to 1.25) in the fed condition, for Cmax and AUC, respectively. All 90% Cis of the ratio of the geometric means included 1 (Table 15 and Table 16).

[00261] Following oral administration of 500 mg crystalline or 600 mg amorphous rilzabrutinib in fasted condition, median tmax of rilzabrutinib was similar (1.50 h). Median tmax was delayed when rilzabrutinib was administered in fed condition but was similar for the two formulations (2.50 h). Mean tl / 2z of rilzabrutinib appeared similar between 500 mg crystalline or 600 mg amorphous rilzabrutinib in fasted or fed condition, with mean values ranging between 2.66 and 3.21 hours.

[00262] For both formulations, exposure, in term of Cmax and AUC, was lower when rilzabrutinib was administered in fed condition than when administered in fasted condition (Table 14). Point estimates for fed / fasted ratios were 0.77 (90% CI: 0.58 to 1.02) and 0.85 (90% CI: 0.67 to 1.07) for the 500 mg crystalline, and 0.86 (90% CI: 0.65 to 1.14) and 0.85 (90% CI: 0.67 to 1.07) for the 600 mg amorphous rilzabrutinib, for Cmax and AUC, respectively (Table 15).

[00263] Total variability' (based on CV%) in plasma rilzabrutinib systemic exposure parameters was generally high (56% to 114%) and appeared generally similar between the two formulations, in fasted or fed condition (Table 14).

[00264] Conclusions. In the fasted state, the bioavailability' of rilzabrutinib following a single dose of the 500 mg crystalline tablet formulation was similar to the 600 mg amorphous tablet formulation after dose normalization. For both formulations, a high fat meal resulted in an average of 15% reduction of exposure (AUC) in comparison to fasted condition.

[00265] Overall, rilzabrutinib given as single doses of 600 mg amorphous formulation and 500 mg crystalline formulation in the fasted and fed states was safe and yvell tolerated in healthy participants. Gastrointestinal adverse events were common and observed more often in the fasted state and with amorphous formulation.

[00266] Example 8: Additional Crystalline Formulation (600 mg)

[00267] A formulation for immediate release film-coated tablets containing 600 mg of crystalline Form B rilzabrutinib was prepared. The tablets were prepared for oral administration and are white to off-white oblong film-coated tablets. The components for this formulation are listed in Table 17, below. Table 17. Composition of 600 mg crystalline rilzabrutinib tablet formulation Component Unit weight (mg / tablet) Percentage (w / w) Function Intragranular Crystalline rilzabrutinib 600.00 65.00 drug substance Microcrystalline Cellulose a 234.92 25.45 diluent Colloidal anhydrous silicon dioxide 8.31 0.90 glidant Crospovidone Type A 18.46 2.00 disintegrant Magnesium Stearate 2.31 0.25 lubricant Extragranular Microcrystalline Cellulose 46.15 5.00 diluent Colloidal anhydrous silicon dioxide 3.69 0.40 glidant Magnesium Stearate 9.23 1.00 lubricant Core tablet mass 923.08 100.00 Film-coating White ready-to-use .             c,d film-coating agent 27.69 3.00 b fdm-coating material Film-coated tablet mass 950.77 a The microcrystalline cellulose amount was adjusted to compensate for rilzabrutinib drug substance weight. b Represents 3% weight gain on the core tablet mass. c Ready to use Opadry® II 32F38977 composed of 36% lactose monohydrate, 28% hypromellose (15 mPa.s), 26% titanium dioxide (E171) and 10% macrogol 3000-polyethylene glycol 3000. d Film-coating agent was prepared as a water suspension for spraying with purified water. Water is considered as a processing agent and is removed during the process.

[00268] Although the present disclosure has been described in some detail by w ay of illustration and example for purposes of clarity' of understanding, the descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated herein in their entirety by reference.

[00269] Embodiments:

[00270] Non-limiting embodiments of the disclosure include:

[00271] Embodiment!. A tablet compnsing: atleastonecompoundchosenfrom(2- [(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-l-yl]-pent-2-enenitrile (the compound of Formula (I)), and pharmaceutically acceptable salts thereof; at least one diluent; at least one disintegrant; at least one lubricant; and optionally, at least one glidant.

[00272] Embodiment 2. The tablet of Embodiment 1, wherein the tablet comprises an intragranular phase and an extragranular phase.

[00273] Embodiment 3. The tablet of Embodiment 1 or Embodiment 2, wherein the at least one diluent is chosen from lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose, calcium phosphate, hydroxypropylmethylcellulose, sucrose, calcium sulfate, calcium lactate, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, kaolin, sodium chloride, inositol, and bentonite.

[00274] Embodiment 4. The tablet of Embodiment 3, wherein the at least one diluent comprises microcrystalline cellulose.

[00275] Embodiment 5. The tablet of Embodiment 3, wherein the at least one diluent is chosen from microcrystalline cellulose 50 pm, microcrystalline cellulose 90 pm, and microcrystalline cellulose 180 pm.

[00276] Embodiment 6. The tablet of Embodiment 3, wherein the at least one diluent is present in a total amount ranging from about 75 mg to about 400 mg.

[00277] Embodiment 7. The tablet of Embodiment 3, wherein the at least one diluent is present in a total amount ranging from about 10% to about 50% by weight.

[00278] Embodiment 8. The tablet of Embodiment 7, wherein the at least one diluent is present in the intragranular phase in a total amount ranging from about 15% to about 45% by weight.

[00279] Embodiment 9. The tablet of Embodiment 7 or Embodiment 8, wherein the at least one diluent is present in the extragranular phase in a total amount ranging from about 0% to about 15% by weight.

[00280] Embodiment 10. The tablet of Embodiment 1 or Embodiment 2, wherein the at least one glidant is chosen from colloidal silicon dioxide and talc.

[00281] Embodiment 11. The tablet of Embodiment 10. wherein the at least one glidant comprises at least one of colloidal silicon dioxide having an average specific surface area of about 200 m2 / g, and colloidal silicon dioxide having an average specific surface area of about 300 m2 / g.

[00282] Embodiment 12. The tablet of Embodiment 10, wherein the at least one glidant is present in a total amount ranging from 0 mg to about 50 mg.

[00283] Embodiment 13. The tablet of Embodiment 10, wherein the at least one glidant is present in a total amount ranging from about 0% to about 5% by weight.

[00284] Embodiment 14. The tablet of Embodiment 13, wherein the at least one glidant is present in the intragranular phase in a total amount ranging from about 0% to about 5% by weight.

[00285] Embodiment 15. The tablet of Embodiment 13, wherein the at least one glidant is present in the extragranular phase in a total amount ranging from about 0% to about 5% by weight.

[00286] Embodiment 16. The tablet of Embodiment 1 or Embodiment 2, wherein the at least one disintegrant is chosen from a starch, a cross-linked starch, a cellulose, a cross-linked cellulose, a cross-linked polymer, an alginate, a clay, a gum, a glycolate, bentonite, a natural sponge, a surfactant, a resin, citrus pulp, and sodium lauryl sulfate.

[00287] Embodiment 17. The tablet of Embodiment 16, wherein the at least one disintegrant is chosen from cross linked polyvinyl N-pyrrolidone (crospovidone) and cross linked carboxymethyl cellulose (croscarmellose).

[00288] Embodiment 18. The tablet of Embodiment 16, wherein the at least one disintegrant is present in a total amount ranging from 1 mg to about 125 mg.

[00289] Embodiment 19. The tablet of Embodiment 16, wherein the at least one disintegrant is present in a total amount ranging from about 0.1% to about 15% by weight.

[00290] Embodiment 20. The tablet of Embodiment 19, wherein the at least one disintegrant is present in the intragranular phase in a total amount ranging from about 0.1 % to about 10% by weight.

[00291] Embodiment 21. The tablet of Embodiment 19, wherein the at least one disintegrant is present in the extragranular phase in a total amount ranging from about 0% to about 10% by weight.

[00292] Embodiment 22. The tablet of Embodiment 1 or Embodiment 2, wherein the at least one lubricant is chosen from stearic acid, calcium hydroxide, talc, a hydrocarbon, a hydrogenated vegetable oil, higher fatty acids, a stearate, glycerol, talc, waxes, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol, a methoxypolyethylene glycol, sodium oleate, sodium benzoate, glyceryl behenate, magnesium or sodium laury l sulfate, colloidal silica, a starch, silicone oil, and a surfactant.

[00293] Embodiment 23. The tablet of Embodiment 22, wherein the at least one lubricant is chosen from magnesium stearate and sodium stearyl fumarate.

[00294] Embodiment 24. The tablet of Embodiment 22, wherein the at least one lubricant is present in a total amount ranging from 0.1 mg to about 50 mg.

[00295] Embodiment 25. The tablet of Embodiment 22, wherein the at least one lubricant is present in a total amount ranging from about 0.01% to about 5% by weight.

[00296] Embodiment 26. The tablet of Embodiment 25, wherein the at least one lubricant is present in the intragranular phase in a total amount ranging from about 0.1% to about 5% by weight.

[00297] Embodiment 27. The tablet of Embodiment 25, wherein the at least one lubricant is present in the extragranular phase in a total amount ranging from about 0% to about 5% by weight.

[00298] Embodiment 28. The tablet of Embodiment 2, wherein the intragranular phase comprises at least one compound chosen from (2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3.4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-l-yl]-pent-2-enenitrile (the compound of Formula (I)), and pharmaceutically acceptable salts thereof, at least one diluent, at least one disintegrant, and at least one lubricant.

[00299] Embodiment 29. The tablet of Embodiment 28, wherein the at least one diluent comprises microcrystalline cellulose 50 pm.

[00300] Embodiment 30. The tablet of Embodiment 28, wherein the at least one lubricant comprises magnesium stearate.

[00301] Embodiment 31. The tablet of Embodiment 28, wherein the at least one lubricant comprises sodium stearyl fumarate.

[00302] Embodiment 32. The tablet of Embodiment 28, wherein the at least one disintegrant comprises cross linked polyvinyl N-pyrrolidone (crospovidone).

[00303] Embodiment 33. The tablet of Embodiment 28. wherein the intragranular phase further comprises at least one glidant.

[00304] Embodiment 34. The tablet of Embodiment 33, wherein the at least one glidant comprises at least one of colloidal silicon dioxide having an average specific surface area of about 200 m2 / g and colloidal silicon dioxide having an average specific surface area of about 300 m2 / g.

[00305] Embodiment 35. The tablet of Embodiment 2. wherein the extragranular phase comprises at least one lubricant.

[00306] Embodiment 36. The tablet of Embodiment 35, wherein the at least one lubricant comprises magnesium stearate.

[00307] Embodiment 37. The tablet of Embodiment 35, wherein the at least one lubricant comprises sodium stearyl fumarate.

[00308] Embodiment 38. The tablet of Embodiment 35, wherein the extragranular phase further comprises at least one diluent.

[00309] Embodiment 39. The tablet of Embodiment 38, wherein the at least one diluent comprises microcrystalline cellulose 180 pm.

[00310] Embodiment 40. The tablet of Embodiment 35, wherein the extragranular phase further comprises at least one glidant.

[00311] Embodiment 41. The tablet of Embodiment 40, wherein the at least one glidant comprises at least one of colloidal silicon dioxide having an average specific surface area of about 200 m2 / g and colloidal silicon dioxide having an average specific surface area of about 300 m2 / g.

[00312] Embodiment 42. The tablet of Embodiment 35, wherein the extragranular phase further comprises at least one disintegrant.

[00313] Embodiment 43. The tablet of Embodiment 42, wherein the at least one disintegrant comprises cross linked polyvinyl N-pyrrolidone (crospovidone).

[00314] Embodiment 44. The tablet of any one of the preceding Embodiments, wherein the compound of Formula (I) comprises an amorphous form.

[00315] Embodiment 45. The tablet of any one of Embodiments 1-43, wherein the compound of Formula (I) is present in at least 50% cry stalline form, such as at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, 99.5%, or 100% crystalline.

[00316] Embodiment 46. The tablet of Embodiment 45, wherein the compound of Formula (I) comprises crystalline Form B.

[00317] Embodiment 47. The tablet of any one of the preceding Embodiments, wherein the compound of Formula (I) is present in an amount ranging from about 200 mg to about 650 mg.

[00318] Embodiment 48. The tablet of any one of the preceding Embodiments, wherein the compound of Formula (I) is present in an amount of about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg. about 370 mg. about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg. about 610 mg. about 620 mg, about 630 mg, about 640 mg, or about 650 mg.

[00319] Embodiment 49. The tablet of Embodiment 48, wherein the compound of Formula (I) is present in an amount of about 300 mg.

[00320] Embodiment 50. The tablet of Embodiment 48, wherein the compound of Formula (I) is present in an amount of about 500 mg.

[00321] Embodiment 51. The tablet of Embodiment 48, wherein the compound of Formula (I) is present in an amount of about 600 mg.

[00322] Embodiment 52. The tablet of any one of the preceding Embodiments, wherein the compound of Formula (I) is present in an amount of about 40% to about 75% by weight.

[00323] Embodiment 53. The tablet of Embodiment 52, wherein the compound of Formula (I) is present in an amount of about 50% by weight.

[00324] Embodiment 54. The tablet of Embodiment 52, wherein the compound of Formula (I) is present in an amount of about 65% by weight.

[00325] Embodiment 55. The tablet of Embodiment 52, wherein the compound of Formula (I) is present in the intragranular phase.

[00326] Embodiment 56. The tablet of any one of the preceding Embodiments, further comprising at least one coating layer.

[00327] Embodiment 57. The tablet of Embodiment 56, wherein the coating layer comprises a taste masking agent.

[00328] Embodiment 58. The tablet of Embodiment 1, wherein the tablet comprises: about 60% to about 70% by weight crystalline Form B of the compound of Formula (I), about 25% to about 35% by weight microcrystalline cellulose, about 0.5% to about 5% by weight crospovidone, about 0.1% to about 5% by weight magnesium stearate, and about 0.1% to about 5% by weight colloidal silicon dioxide.

[00329] Embodiment 59. The tablet of Embodiment 1, wherein the tablet comprises: about 60% to about 70% by weight of the compound of Formula (I), about 25% to about 35% by weight microcrystalline cellulose, about 0.5% to about 5% by weight crospovidone, about 0.1% to about 5% by weight magnesium stearate, and about 0.1% to about 5% by weight colloidal silicon dioxide.

[00330] Embodiment 60. The tablet of Embodiment 58 or 59. wherein the tablet comprises an intragranular phase and an extragranular phase.

[00331] Embodiment 61. The tablet of Embodiment 60, wherein the intragranular phase comprises about 65% by weight of the compound of Formula (I), about 31% by weight microcrystalline cellulose, about 2% by weight crospovidone, about 0.25% by weight magnesium stearate, and about 1% by weight colloidal silicon dioxide.

[00332] Embodiment 62. The tablet of Embodiment 60, wherein the extragranular phase comprises about 1 % by weight magnesium stearate.

[00333] Embodiment 63. The tablet of any one of Embodiments 58-62, wherein the compound of Formula (I) is present in an amount of about 270 mg.

[00334] Embodiment 64. The tablet of any one of Embodiments 59-63, wherein the compound of Formula (I) comprises a crystalline form, and preferably comprises crystalline Form B.

[00335] Embodiment 65. The tablet of any one of Embodiments 59-63, wherein the compound of Formula (I) comprises an amorphous form.

[00336] Embodiment 66. The tablet of Embodiment 1, wherein the tablet comprises: about 45% to about 55% by weight amorphous compound of Formula (I), about 35% to about 40% by weight microcrystalline cellulose, about 5% to about 15% by weight crospovidone, and about 0.5% to about 5% by weight sodium stearyl fumarate.

[00337] Embodiment 67. The tablet of Embodiment 1. wherein the tablet comprises: about 45% to about 55% by weight of the compound of Formula (I), about 35% to about 40% by weight microcrystalline cellulose, about 5% to about 15% by weight crospovidone, and about 0.5% to about 5% by weight sodium stearyl fumarate.

[00338] Embodiment 68. The tablet of Embodiment 66 or 67, wherein the tablet comprises an intragranular phase and an extragranular phase.

[00339] Embodiment 69. The tablet of Embodiment 68, wherein the intragranular phase comprises about 50% by weight of the compound of Formula (I), about 38% by weight microcrystalline cellulose, about 10% by weight crospovidone, and about 2% by weight sodium stearyl fumarate.

[00340] Embodiment 70. The tablet of Embodiment 68, wherein the extragranular phase comprises about 5% by weight crospovidone and about 1% by weight sodium stearyl fumarate.

[00341] Embodiment 71. The tablet of any one of Embodiments 66-70, wherein the compound of Formula (I) is present in an amount of about 300 mg or about 400 mg.

[00342] Embodiment 72. The tablet of any one of Embodiments 67-71, wherein the compound of Formula (I) comprises a crystalline form, and preferably comprises crystalline Form B.

[00343] Embodiment 73. The tablet of any one of Embodiments 67-71, wherein the compound of Formula (I) comprises an amorphous form.

[00344] Embodiment 74. The tablet of Embodiment 1, wherein the tablet comprises: about 60% to about 70% by weight crystalline Form B of the compound of Formula (T), about 20% to about 35% by weight microcry stalline cellulose, about 0.5% to about 10% by weight disintegrant, about 0.1% to about 5% by w eight magnesium stearate, and about 0.1% to about 5% by weight colloidal silicon dioxide, wherein the disintegrant comprises at least one of crospovidone and croscarmellose.

[00345] Embodiment 75. The tablet of Embodiment 1, wherein the tablet comprises: about 60% to about 70% by weight of the compound of Formula (I), about 20% to about 35% by weight microcrystalline cellulose, about 0.5% to about 10% by weight disintegrant, about 0.1% to about 5% by weight magnesium stearate, and about 0.1% to about 5% by weight colloidal silicon dioxide, wherein the disintegrant comprises at least one of crospovidone and croscarmellose.

[00346] Embodiment 76. The tablet of Embodiment 74 or 75, wherein the tablet comprises an intragranular phase and an extragranular phase.

[00347] Embodiment 77. The tablet of Embodiment 76, wherein the intragranular phase comprises about 65% by weight of the compound of Formula (I), about 23% to about 31% by weight microcrystalline cellulose, about 2.0% to about 4.0% by weight disintegrant, about 0.5% to about 1.0% by weight magnesium stearate, and about 0.9% colloidal silicon dioxide.

[00348] Embodiment 78. The tablet of Embodiment 76, wherein the extragranular phase comprises about 1.5% by weight microcrystalline cellulose, about 0% to about 2.0% by weight disintegrant, about 0.2% to about 1.0% by weight magnesium stearate, and about 0.4% colloidal silicon dioxide.

[00349] Embodiment 79. The tablet of any one of Embodiments 74-78, wherein the compound of Formula (I) is present in an amount of about 400 mg or about 450 mg.

[00350] Embodiment 80. The tablet of any one of Embodiments 75-79, wherein the compound of Formula (I) comprises a crystalline form, and preferably comprises crystalline Form B.

[00351] Embodiment 81. The tablet of any one of Embodiments 75-79, wherein the compound of Formula (I) comprises an amorphous form.

[00352] Embodiment 82. The tablet of Embodiment 1, wherein the tablet comprises: about 60% to about 70% by weight crystalline Form B of the compound of Formula (I), about 25% to about 35% by weight microcrystalline cellulose, about 0.5% to about 5% by weight crospovidone, about 0.1% to about 5% by weight magnesium stearate, and about 0.1% to about 5% by weight colloidal silicon dioxide.

[00353] Embodiment 83. The tablet of Embodiment 1, wherein the tablet comprises: about 60% to about 70% by weight of the compound of Formula (1), about 25% to about 35% by weight microcrystalline cellulose, about 0.5% to about 5% by weight crospovidone, about 0.1% to about 5% by weight magnesium stearate, and about 0.1% to about 5% by weight colloidal silicon dioxide.

[00354] Embodiment 84. The tablet of Embodiment 82 or 83, wherein the tablet comprises an intragranular phase and an extragranular phase.

[00355] Embodiment 85. The tablet of Embodiment 84, wherein the intragranular phase comprises about 65% by weight of the compound of Formula (I), about 31% by weight microcrystalline cellulose, about 2.0% by weight crospovidone. about 0.25% by weight magnesium stearate, and about 0.9% colloidal silicon dioxide.

[00356] Embodiment 86. The tablet of Embodiment 84, wherein the extragranular phase comprises about 1.0% by weight magnesium stearate, and about 0.4% colloidal silicon dioxide.

[00357] Embodiment 87. The tablet of any one of Embodiments 82-86, wherein the compound of Formula (I) is present in an amount of about 500 mg.

[00358] Embodiment 88. The tablet of any one of Embodiments 83-87, wherein the compound of Formula (I) comprises a crystalline form, and preferably comprises crystalline Form B.

[00359] Embodiment 89. The tablet of any one of Embodiments 84-87, wherein the compound of Formula (I) comprises an amorphous form.

[00360] Embodiment 90. The tablet of Embodiment 1, wherein the tablet comprises: about 60% to about 70% by weight crystalline Form B of the compound of Formula (I), about 25% to about 35% by weight microcrystalline cellulose, about 0.5% to about 5% by weight crospovidone, about 0.1% to about 5% by weight magnesium stearate, and about 0.1% to about 5% by weight colloidal silicon dioxide.

[00361] Embodiment 91. The tablet of Embodiment 1, wherein the tablet comprises: about 60% to about 70% by weight of the compound of Formula (I), about 25% to about 35% by weight microcrystalline cellulose, about 0.5% to about 5% by weight crospovidone, about 0.1% to about 5% by weight magnesium stearate, and about 0.1% to about 5% by weight colloidal silicon dioxide.

[00362] Embodiment 92. The tablet of Embodiment 90 or 91. wherein the tablet comprises an intragranular phase and an extragranular phase.

[00363] Embodiment 93. The tablet of Embodiment 92, wherein the intragranular phase comprises about 65% by weight of the compound of Formula (I), about 30% by weight microcrystalline cellulose, about 2.0% by weight crospovidone. about 0.5% by weight magnesium stearate, and about 0.9% colloidal silicon dioxide.

[00364] Embodiment 94. The tablet of Embodiment 92, w herein the extragranular phase comprises about 1.0% by weight magnesium stearate, and about 0.4% colloidal silicon dioxide.

[00365] Embodiment 95. The tablet of any one of Embodiments 90-94, wherein the compound of Formula (I) is present in an amount of about 500 mg.

[00366] Embodiment 96. The tablet of any one of Embodiments 91-95, w-herein the compound of Formula (I) comprises a crystalline form, and preferably comprises crystalline Form B.

[00367] Embodiment 97. The tablet of any one of Embodiments 91-95, wherein the compound of Formula (I) comprises an amorphous form.

[00368] Embodiment 98. The tablet of Embodiment 1, wherein the tablet comprises: about 60% to about 70% by weight of a crystalline compound of Formula (I), about 25% to about 35% by weight rmcrocrystalline cellulose, about 0.5% to about 5% by weight crospovidone, about 0.1 % to about 5% by w eight magnesium stearate, and about 0.1 % to about 5% by weight colloidal silicon dioxide, wherein the colloidal silicon dioxide comprises at least one of colloidal silicon dioxide having an average specific surface area of about 200 m2 / g and colloidal silicon dioxide having an average specific surface area of about 300 m2 / g.

[00369] Embodiment 99. The tablet of Embodiment 1, wherein the tablet comprises: about 60% to about 70% by weight of a compound of Formula (I), about 25% to about 35% by weight microcrystalline cellulose, about 0.5% to about 5% by weight crospovidone, about 0.1% to about 5% by weight magnesium stearate, and about 0.1% to about 5% by weight colloidal silicon dioxide, wherein the colloidal silicon dioxide comprises at least one of colloidal silicon dioxide having an average specific surface area of about 200 m2 / g and colloidal silicon dioxide having an average specific surface area of about 300 m2 / g.

[00370] Embodiment 100. The tablet of Embodiment 98 or 99, wherein the tablet comprises an intragranular phase and an extragranular phase.

[00371] Embodiment 101. The tablet of Embodiment 100, wherein the intragranular phase comprises about 65% by weight of the compound of Formula (I), about 20% to about 30% by weight microcrystalline cellulose, about 2.0% by weight crospovidone, about 0.25% by weight magnesium stearate, and about 0.7 to about 0.9% colloidal silicon dioxide.

[00372] Embodiment 102. The tablet of Embodiment 100, wherein the extragranular phase comprises about 1.0% by weight magnesium stearate, about 0% to about 10% microcrystalline cellulose, and about 0.4% to about 0.6% colloidal silicon dioxide.

[00373] Embodiment 103. The tablet of any one of Embodiments 98-102. wherein the compound of Formula (I) is present in an amount of about 500 mg.

[00374] Embodiment 104. The tablet of any one of Embodiments 98-102, wherein the compound of Formula (I) is present in an amount of about 600 mg.

[00375] Embodiment 105. The tablet of any one of Embodiments 99-104. wherein the compound of Formula (I) comprises a crystalline form, and preferably comprises crystalline Form B.

[00376] Embodiment 106. The tablet of any one of Embodiments 99-104, w herein the compound of Formula (I) comprises an amorphous form.

[00377] Embodiment 107. The tablet of any one of Embodiments 1-43, 45-64, 67-72. 7480, 82-88, 90-96, and 98-105, wherein the compound of Formula (I) comprises crystalline Form B.

[00378] Embodiment 108. The tablet of any one of Embodiments 1-107, further comprising a film-coating agent.

[00379] Embodiment 109. The tablet of Embodiment 108, wherein the film coating is present in an amount of about 2% to about 5% relative to the total weight of the tablet.

[00380] Embodiment 110. The tablet of Embodiment 109. wherein the film coating is present in an amount of about 3% relative to the total weight of the tablet.

[00381] Embodiment 111. A method of treating a disease or condition mediated by BTK in a patient in need thereof, comprising administering to the patient the tablet of any one of Embodiments 1 to 110.

[00382] Embodiment 112. The method of Embodiment 111. wherein the disease or condition mediated by BTK is chosen from at least one of acne, allergy, alopecia areata, vitiligo, pyoderma gangrenosum, membrane pemphigoid, epidermolysis bullosa acquisita, Steven Johnson syndrome, toxic epidermal necrolysis (TEN), pemphigus vulgaris, pemphigus foliaceus, ankylosing spondylitisis. antiphospholipid antibody syndrome, vasculitis, Guillain-Barre syndrome, scleroderma, Wegener's granulomatosis, psoriasis, granulomatosis with polyangiitis, thrombotic thrombocytopenic purpura, polyarteritis nodosa, arthritis, rheumatoid arthritis, psoriatic arthritis juvenile arthritis, asthma, moderate-to-severe asthma, mild asthma, moderate asthma, severe asthma, asthma that is not well controlled, autoimmune hepatitis, Behcet's disease, Grave’s disease, nephritis, pancreatitis, primary biliary cirrhosis, ulcerative colitis, colitis, conjunctivitis, dermatitis, atopic dermatitis, drug eruptions, drug-induced thrombocytopenia (DITP), vaccine-induced thrombosis and thrombocytopenia (VITT), eczema, folliculitis decalvans, pseudofolliculitis barbae, leucoclastic vasculitis, hidradenitis supprativa. palmar platar pustulosis. Lichenoid dermatitis, mycosis fungoides, sweet syndrome, follicular lymphoma, diffuse large B cell lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplamascytic lymphoma / Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, nonHodgkin lymphoma, warm autoimmune hemolytic anemia (wAIHA), B-cell acute lymphoblastic leukemia (B-ALL), small lymphocytic lymphoma (SLL), intravascular large B cell lymphoma, primary’ effusion lymphoma, burkitt lymphoma / leukemia. lymphomatoid granulomatosis, B-cell non-Hodgkin lymphoma, idiopathic thrombocytopenic purpura. IgG4-related diseases (IgG4-RD) and flares thereof, antiphospholipid syndrome (APS), membranous nephropathy (MN), immune thrombocytopenia, inflammatory’ bowel disease, itch associated with atopic dermatitis, lupus, cutaneous lupus, cutaneous lupus erythematosus, lupus nephritis, mixed connective tissue disease, multiple myeloma, multiple sclerosis, systemic inflammatory’ response syndrome (SIRS), acute respiratory’ distress syndrome (ARDS), sepsis, sepsis induced acute lung injury’, diffuse alveolar damage (DAD), macrophage activation syndrome (MAS), secondary' hemophagocytic lymphohistiocytosis (sHIH), cytokine release syndrome (CRS), cutaneous form of systemic sclerosis (CREST), cryoglobulinemia, primary biliary' sclerosis, sclerosing cholangitis, urticaria, chronic spontaneous urticaria (CSU), chronic idiopathic urticaria (CIU), Al urticaria, and IgA nephropathy.

[00383] Embodiment 113. Use of the tablet of any one of Embodiments 1 to 110 for treating a disease involving mediation of the BTK receptor.

[00384] Embodiment 114. A tablet comprising: at least one compound chosen from (2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-l-yl]-pent-2-enenitrile (the compound of Formula (I)), and pharmaceutically acceptable salts thereof; at least one diluent present in an amount ranging from about 10% to about 50% by weight; at least one disintegrant present in an amount ranging from about 0.1% to about 15% by weight; at least one lubricant present in an amount ranging from about 0.01% to about 5% by weight; and optionally , at least one glidant.

[00385] Embodiment 115. The tablet of Embodiment 114. wherein the tablet comprises an intragranular phase and an extragranular phase.

[00386] Embodiment 116. The tablet of Embodiment 114 or 115, wherein: the at least one diluent is chosen from lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose, calcium phosphate, hydroxypropylmethylcellulose, sucrose, calcium sulfate, calcium lactate, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, kaolin, sodium chloride, inositol, and bentonite; the at least one disintegrant is chosen from a starch, a cross-linked starch, a cellulose, a cross-linked cellulose, a cross-linked polymer, an alginate, a clay, a gum, a glycolate, bentonite, a natural sponge, a surfactant, a resin, citrus pulp, and sodium lauryl sulfate; the at least one lubricant is chosen from stearic acid, calcium hydroxide, talc, a hydrocarbon, a hydrogenated vegetable oil, higher fatty7 acids, a stearate, glycerol, talc, waxes, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol, a methoxypolyethylene glycol, sodium oleate, sodium benzoate, glycery l behenate, magnesium or sodium lauryl sulfate, colloidal silica, a starch, silicone oil, and a surfactant; and if present, the at least one glidant is chosen from colloidal silicon dioxide and talc.

[00387] Embodiment 117. The tablet of any one of Embodiments 114-116, wherein the at least one glidant is present in an amount greater than 0% to about 5% by weight.

[00388] Embodiment 118. The tablet of any one of Embodiments 114-117, wherein the compound of Formula (I) comprises an amorphous form.

[00389] Embodiment 119. The tablet of any one of Embodiments 114-117, wherein the compound of Formula (I) is present in at least 50% crystalline form, such as at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, 99.5%, or 100% crystalline.

[00390] Embodiment 120. The tablet of any one of Embodiments 114-119, wherein the compound of Formula (I) is present in an amount ranging from about 200 mg to about 650 mg.

[00391] Embodiment 121. The tablet of Embodiment 120. wherein the compound of Formula (I) is present in an amount of about 400 mg.

[00392] Embodiment 122. The tablet of Embodiment 120, wherein the compound of Formula (I) is present in an amount of about 600 mg.

[00393] Embodiment 123. The tablet of any one of Embodiments 114-122, wherein the compound of Formula (I) is present in an amount of about 40% to about 75% by weight.

[00394] Embodiment 124. The tablet of Embodiment 123, wherein the compound of Formula (I) is present in the intragranular phase.

[00395] Embodiment 125. The tablet of any one of Embodiments 114-117, wherein the tablet comprises: about 45% to about 55% by weight amorphous compound of Formula (I), about 35% to about 40% by weight microcrystalline cellulose, about 5% to about 15% by weight crospovidone, and about 0.5% to about 5% by weight sodium stearyl fumarate, preferably wherein the compound of Formula (I) is present in an amount of about 400 mg.

[00396] Embodiment 126. The tablet of any one of Embodiments 114-117, wherein the tablet comprises: about 60% to about 70% by weight crystalline Form B of the compound of Formula (I), about 25% to about 35% by weight microcrystalline cellulose, about 0.5% to about 5% by weight crospovidone, about 0.1% to about 5% by weight magnesium stearate, and about 0.1% to about 5% by weight colloidal silicon dioxide, preferably wherein the compound of Formula (I) is present in an amount of about 600 mg.

[00397] Embodiment 127. The tablet of any one of Embodiments 114-126, further comprising a film-coating agent.

[00398] Embodiment 128. A method of treating a disease or condition mediated by BTK in a patient in need thereof, comprising administering to the patient the tablet of any one of Embodiments 114-127.

[00399] Embodiment 129. The method of Embodiment 128, wherein the disease or condition mediated by BTK is chosen from at least one of acne, allergy, alopecia areata, vitiligo, pyoderma gangrenosum, membrane pemphigoid, epidermolysis bullosa acquisita, Steven Johnson syndrome, toxic epidermal necrolysis (TEN), pemphigus vulgaris, pemphigus foliaceus, ankylosing spondylitisis, antiphospholipid antibody syndrome, vasculitis, Guillain-Barre syndrome, scleroderma, Wegener's granulomatosis, psoriasis, granulomatosis with polyangiitis, thrombotic thrombocytopenic purpura, polyarteritis nodosa, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, asthma, moderate-to-severe asthma, mild asthma, moderate asthma, severe asthma, asthma that is not well controlled, autoimmune hepatitis, Behcet's disease, Grave's disease, nephritis, pancreatitis, primary’ biliary cirrhosis, ulcerative colitis, colitis, conjunctivitis, dermatitis, atopic dermatitis, drug eruptions, drug-induced thrombocytopenia (DITP), vaccine-induced thrombosis and thrombocytopenia (VITT), eczema, folliculitis decalvans, pseudofolliculitis barbae, leucoclastic vasculitis, hidradenitis supprativa, palmar platar pustulosis, Lichenoid dermatitis, mycosis fungoides, sweet syndrome, follicular lymphoma, diffuse large B cell lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplamascytic lymphoma / Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, nonHodgkin lymphoma, warm autoimmune hemolytic anemia (wAIHA), B-cell acute lymphoblastic leukemia (B-ALL), small lymphocytic lymphoma (SLL), intravascular large B cell lymphoma, primary effusion lymphoma, burkitt lymphoma / leukemia, lymphomatoid granulomatosis, B-cell non-Hodgkin lymphoma, idiopathic thrombocytopenic purpura, IgG4-related diseases (IgG4-RD) and flares thereof, antiphospholipid syndrome (APS), membranous nephropathy (MN), immune thrombocytopenia, inflammatory bowel disease, itch associated with atopic dermatitis, lupus, cutaneous lupus, cutaneous lupus erythematosus, lupus nephritis, mixed connective tissue disease, multiple myeloma, multiple sclerosis, systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS), sepsis, sepsis induced acute lung injury, diffuse alveolar damage (DAD), macrophage activation syndrome (MAS), secondary hemophagocytic lymphohistiocytosis (sHIH), cytokine release syndrome (CRS), cutaneous form of systemic sclerosis (CREST), cry oglobulinemia, primary’ biliary' sclerosis, sclerosing cholangitis, urticaria, chronic spontaneous urticaria (CSU), chronic idiopathic urticaria (CIU), Al urticaria, and IgA nephropathy.

[00400] Embodiment 130. Use of the tablet of any one of Embodiments 114-127 for treating a disease involving mediation of the BTK receptor.

Claims

1. A tablet comprising:at least one compound chosen from (2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-l-yl]-pent-2-enenitrile (the compound of Formula (I)), and pharmaceutically acceptable salts thereof;at least one diluent present in an amount ranging from about 10% to about 50% by weight:at least one disintegrant present in an amount ranging from about 0.1% to about 15% by weight;at least one lubricant present in an amount ranging from about 0.01% to about 5% by weight: and optionally, at least one glidant.

2. The tablet of claim 1, wherein the tablet comprises an intragranular phase and an extragranular phase.

3. The tablet of claim 1 or claim 2, wherein:the at least one diluent is chosen from lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose, calcium phosphate, hydroxypropylmethylcellulose, sucrose, calcium sulfate, calcium lactate, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, kaolin, sodium chloride, inositol, and bentonite;the at least one disintegrant is chosen from a starch, a cross-linked starch, a cellulose, a cross-linked cellulose, a cross-linked polymer, an alginate, a clay, a gum, a glycolate, bentonite, a natural sponge, a surfactant, a resin, citrus pulp, and sodium lauryl sulfate;the at least one lubricant is chosen from stearic acid, calcium hydroxide, talc, a hydrocarbon, a hydrogenated vegetable oil, higher fatty acids, a stearate, glycerol, talc, waxes, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol, a methoxypoly ethylene glycol, sodium oleate, sodium benzoate, glyceryl behenate, magnesium or sodium lauryl sulfate, colloidal silica, a starch, silicone oil, and a surfactant; andif present, the at least one glidant is chosen from colloidal silicon dioxide and talc.

4. The tablet of any one of the preceding claims, wherein the at least one glidant is present in an amount greater than 0% to about 5% by weight.

5. The tablet of any one of the preceding claims, wherein the compound of Formula (I) comprises an amorphous form.

6. The tablet of any one of claims 1 to 4, wherein the compound of Formula (I) is present in at least 50% crystalline form, such as at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, 99.5%, or 100% crystalline.

7. The tablet of any one of the preceding claims, wherein the compound of Formula (I) is present in an amount ranging from about 200 mg to about 650 mg.

8. The tablet of claim 7, wherein the compound of Formula (I) is present in an amount of about 400 mg.

9. The tablet of claim 7, wherein the compound of Formula (I) is present in an amount of about 600 mg.

10. The tablet of any one of the preceding claims, wherein the compound of Formula (I) is present in an amount of about 40% to about 75% by weight.

11. The tablet of claim 10, wherein the compound of Formula (I) is present in the intragranular phase.

12. The tablet of any one of claims 1 to 4, wherein the tablet comprises:about 45% to about 55% by weight amorphous compound of Formula (I),about 35% to about 40% by weight microcrystalline cellulose,about 5% to about 15% by weight crospovidone, andabout 0.5% to about 5% by weight sodium stearyl fumarate.preferably wherein the compound of Formula (I) is present in an amount of about 400 mg.

13. The tablet of any one of claims 1 to 4, wherein the tablet comprises:about 60% to about 70% by weight crystalline Form B of the compound of Formula (I), about 25% to about 35% by weight microcrystalline cellulose,about 0.5% to about 5% by weight crospovidone,about 0.1% to about 5% by weight magnesium stearate, and about 0.1% to about 5% by weight colloidal silicon dioxide, preferably wherein the compound of Formula (I) is present in an amount of about 600 mg.

14. The tablet of any one of the preceding claims, further comprising a film-coating agent.

15. A method of treating a disease or condition mediated by BTK in a patient in needthereof, comprising administering to the patient the tablet of any one of claims 1 to 14.

16. The method of claim 15, wherein the disease or condition mediated by BTK is chosen from at least one of acne, allergy , alopecia areata, vitiligo, pyoderma gangrenosum, membrane pemphigoid, epidermolysis bullosa acquisita, Steven Johnson syndrome, toxic epidermal necrolysis (TEN), pemphigus vulgaris, pemphigus foliaceus, ankylosing spondylitisis, antiphospholipid antibody syndrome, vasculitis. Guillain-Barre syndrome, scleroderma, Wegener's granulomatosis, psoriasis, granulomatosis with polyangiitis, thrombotic thrombocytopenic purpura, polyarteritis nodosa, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, asthma, moderate-to-severe asthma, mild asthma, moderate asthma, severe asthma, asthma that is not well controlled, autoimmune hepatitis. Behcet’s disease. Grave’s disease, nephritis, pancreatitis, primary biliary cirrhosis, ulcerative colitis, colitis, conjunctivitis, dermatitis, atopic dermatitis, drug eruptions, drug-induced thrombocytopenia (DITP), vaccine-induced thrombosis and thrombocytopenia (VITT), eczema, folliculitis decalvans, pseudofolliculitis barbae, leucoclastic vasculitis, hidradenitis supprativa, palmar platar pustulosis, Lichenoid dermatitis, mycosis fungoides, sweet syndrome, follicular lymphoma, diffuse large B cell lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplamascytic lymphoma / Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, non-Hodgkin lymphoma, warm autoimmune hemolytic anemia (wAIHA), B-cell acute lymphoblastic leukemia (B-ALL), small lymphocytic lymphoma (SLL), intravascular large B cell lymphoma, primary effusion lymphoma, burkitt lymphoma / leukemia. lymphomatoid granulomatosis, B-cell non-Hodgkin lymphoma, idiopathic thrombocytopenic purpura, IgG4-related diseases (IgG4-RD) and flaresthereof, antiphospholipid syndrome (APS), membranous nephropathy (MN), immune thrombocytopenia, inflammatory bowel disease, itch associated with atopic dermatitis, lupus, cutaneous lupus, cutaneous lupus erythematosus, lupus nephritis, mixed connective tissue disease, multiple myeloma, multiple sclerosis, systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS), sepsis, sepsis induced acute lung injury, diffuse alveolar damage (DAD), macrophage activation syndrome (MAS), secondary’ hemophagocytic lymphohistiocytosis (sHIH). cytokine release syndrome (CRS). cutaneous form of systemic sclerosis (CREST), cryoglobulinemia, primary biliary sclerosis, sclerosing cholangitis, urticaria, chronic spontaneous urticaria (CSU), chronic idiopathic urticaria (CIU), Al urticaria, and IgA nephropathy.

17. Use of the tablet of any one of claims 1 to 14 for treating a disease involving mediation of the BTK receptor.

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