WO2025223551A1

WO2025223551A1 - Formulations, crystalline forms and dosage regimens of a malt1 inhibitor

Info

Publication number: WO2025223551A1
Application number: PCT/CN2025/091228
Authority: WO
Inventors: Chongmin JI; Donghua Zhu; Sune Klint Andersen; Cristophe Henri J TISTAERT; Katie Ingrid Eduard Amssoms; Nico Frederik HOLMSTOCK; Eszter TIEGER; Bart BUEKEN; Frank Bert Raf JACOBS; Lorena Fontan Gabas; Jan SNOEYS; Jian Yin; Jeffrey Stuart MOWAT; Johannes Wilhelmus J. Thuring; Fabian HULPIA; Susan LEPRI; Aldo Peschiulli; Yves Emiel Maria Van Roosbroeck; Adriana-Ingrid VELTER; Mikko Juhani Artturi Muuronen
Original assignee: Janssen Pharmaceutica NV; Johnson and Johnson China Investment Ltd
Current assignee: Janssen Pharmaceutica NV; Johnson and Johnson China Investment Ltd
Priority date: 2024-04-26
Filing date: 2025-04-25
Publication date: 2025-10-30
Anticipated expiration: 2026-10-26

Abstract

The present invention relates to the amorphous solid dispersions and crystalline forms of a MALT1 inhibitor. The present invention also relates to dosage regimens of the MALT1 inhibitor for the treatment of diseases, syndromes, conditions, and disorders affected by the inhibition of MALT1.

Description

FORMULATIONS, CRYSTALLINE FORMS AND DOSAGE REGIMENS OF A MALT1 INHIBITOR

FIELD OF THE INVENTION

The technical field of the present invention is in pharmaceuticals, particularly formulations, crystalline forms and dosage regimens.

BACKGROUND OF THE INVENTION

Many active pharmaceutical ingredients (API) have properties such as hydrophobicity and instability leading to challenges in providing suitable pharmaceutical formulations.

MALT1 (mucosa-associated lymphoid tissue lymphoma translocation 1) is a key mediator of the classical NF_KB signaling pathway. MALT1 is the only human paracaspase and transduces signals from the B cell receptor (BCR) and T cell receptor (TCR) . MALT1 is the active subunit of the CBM complex which is formed upon receptor activation. The CBM complex consists of multiple subunits of three proteins: CARD11 (caspase recruitment domain family member 11) , BCL10 (B-cell CLL/Lymphoma 10) and MALT1. MALT1 affects NF_KB signaling by two mechanisms: firstly, MALT1 functions as a scaffolding protein and recruits NF_KB signaling proteins such as TRAF6, TAB-TAK1 or NEMO-IKKα/β; and secondly, MALT1, as a cysteine protease, cleaves and thereby deactivates negative regulators of NF-_KB signaling, such as RelB, A20 or CYLD. The ultimate endpoint of MALT1 activity is the nuclear translocation of the NF-_KB transcription factor complex and activation of NF-_KB signaling.

Constitutive activation of NF-_KB signaling is the hallmark of ABC-DLBCL (Diffuse Large B cell Lymphoma of the Activated B Cell-like subtype) , the more aggressive form of DLBCL. DLBCL is the most common form of non-Hodgkin’s lymphoma (NHL) , accounting for approximately 25%of lymphoma cases while ABC-DLBCL comprises approximately 40%of DLBCL. NF-_KB pathway activation is driven by mutations of signaling components, such as CD79a/b, CARD11, MYD88 or TNFAIP3 (A20) , in ABC-DLBCL patients.

The use of BTK inhibitors, for example Ibrutinib, provides clinical proof-of-concept that inhibiting NF-_KB signaling in ABC-DLBCL is efficacious. MALT1 is downstream of BTK in the NF-_KB signaling pathway and a MALT1 inhibitor could provide a therapeutic option for ABC-DLBCL patients not responding to Ibrutinib, patients with CARD11 mutations, and patients that have acquired resistance to Ibrutinib.

There exists a need for MALT1 inhibitors that provide a therapeutic benefit to patients suffering from cancer and/or immunological diseases.

SUMMARY OF THE INVENTION

The present invention provides an amorphous solid dispersion comprising a compound and an orally pharmaceutically acceptable polymer;

wherein the compound is (1S, 3R) -3- (4- ( (R) -2-chloro-8-methyl-8- (trifluoromethyl) -7, 8-dihydro-6H-pyrazolo [1, 5-a] pyrrolo [2, 3-e] pyrimidin-6-yl) phenyl) -2, 2-difluoro-1-methyl-N- ( (trans) -3- (methylsulfonyl) cyclobutyl) cyclopropane-1-carboxamide (Compound 3) :

or a pharmaceutically acceptable salt form thereof.

The present invention also provides crystalline forms of (1S, 3R) -3- (4- ( (R) -2-chloro-8-methyl-8- (trifluoromethyl) -7, 8-dihydro-6H-pyrazolo [1, 5-a] pyrrolo [2, 3-e] pyrimidin-6-yl) phenyl) -2, 2-difluoro-1-methyl-N- ( (trans) -3- (methylsulfonyl) cyclobutyl) cyclopropane-1-carboxamide (Compound 3) :

The present invention also provides a compound for use in the treatment of a disease, syndrome, condition, or disorder in a subject in need thereof, wherein said disease, syndrome, condition, or disorder is affected by the inhibition of MALT1,

or a pharmaceutically acceptable salt form thereof or a solvate thereof.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

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

In the drawings:

Figure 1a is an X-ray powder diffraction (XRPD) pattern of a crystalline Form I.

Figure 1b is a differential scanning calorimetry (DSC) thermogram of crystalline Form I.

Figure 1c is a thermogravimetric analysis (TGA) curve of crystalline Form I.

Figure 1d is a dynamic vapor sorption (DVS) isotherm plot of crystalline Form I.

Figure 2a is an X-ray powder diffraction (XRPD) pattern of crystalline Form IIa.

Figure 2b is a differential scanning calorimetry (DSC) thermogram of crystalline Form IIa.

Figure 2c is a thermogravimetric analysis (TGA) curve of crystalline Form IIa.

Figure 3a is an X-ray powder diffraction (XRPD) pattern of a crystalline Form IIb.

Figure 3b is a differential scanning calorimetry (DSC) thermogram of crystalline Form IIb.

Figure 4 is a thermogravimetric analysis (TGA) curve of crystalline Form IIb.

Figure 6 shows the total %of degradation of various ASD concepts at 40℃/75%RH.

Figure 7 shows the total %of degradation of various ASD concepts at 50℃/10%RH.

Figure 8 shows the total %of degradation of various ASD concepts at 60℃/30%RH.

Figure 9 shows an overview of the total degradation products (%) for HPMCAS LG 1: 2 (C1) , HPMCAS LG 1: 3 (C2) , L100 1: 3 (C3) , HPMC E5 1: 3 (C4) , and crystalline API (C5) .

Figure 10 shows the dissolution profiles of HPMCAS LG 1: 2, HPMCAS LG 1: 3, L100 1: 3 and HPMC E5 1: 3 at a 35 mg dose.

Figure 11 shows the dissolution profiles of HPMCAS LG 1: 2, HPMCAS LG 1: 3, L100 1: 3 and HPMC E5 1: 3 at a 100 mg dose.

Figure 12 shows tumor growth curves of OCI-Ly3 xenografts.

Figure 13 shows tumor growth curves of OCI-Ly10 xenografts.

Figure 14 shows levels of human IL‐10 and Compound 3 in the serum of NSG mice bearing OCI‐Ly3 tumors.

Figure 15 shows levels of uncleaved BCL10 in the serum of NSG mice bearing OCI‐Ly3 tumors.

Figure 16 shows levels of human IL‐10 and Compound 3 in the serum of NSG mice bearing OCI‐Ly10 tumors.

Figure 17 shows the dissolution profiles of HPMCAS LG 1: 2 and HPMCAS LG 1: 3 at a 35 mg dose and at a 100 mg dose.

Figure 18 shows mean (SD) Compound 3 plasma concentration-time profiles at Cycle 1 Day 1

Figure 19 shows mean (SD) Compound 3 plasma concentration-time profiles at Cycle 2 Day 1

Figure 20 shows mean (SD) Compound 3 plasma predose concentrations

Figure 21 shows the simulated plasma concentration-time profiles for Compound 3 for a regimen of 160 mg BID loading dose for 2 weeks followed by 160 mg QD maintenance dose versus a 160 mg QD dose regimen.

DETAILED DESCRIPTION OF THE INVENTION

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

DEFINITIONS

Some of the quantitative expressions given herein are not qualified with the term "about" It is understood that whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value. As used herein, the term “about” means a quantity within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05%of a given value or range.

In the present disclosure the singular forms “a, ” , “an, ” and “the” include the plural reference. Furthermore, when indicating that a certain element “may be” X, Y, or Z, it is not intended by such usage to exclude in all instances other choices for the element.

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

As used herein, term “consisting of” is intended to include only the recited elements steps or ingredients and thus excludes any element, step, or ingredient not mentioned other than those recited.

As used herein, the term “consisting essentially of” is intended to mean a composition consisting of recited elements and any unavoidable impurities.

As used herein, any instance of “comprising” may also include “consisting essentially of” and “consisting of” . For example, a composition described herein as “comprising” certain components can also to be taken as disclosure of a composition “consisting essentially of” and “consisting of” those components.

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

As used herein, the term “room temperature” (RT) refers to a temperature of from about 15 ℃to about 30 ℃, in particular from about 20 ℃ to about 30 ℃. An example of room temperature is a temperature of about 25 ℃.

When a crystalline form is identified using one or more XRPD peaks given as angles 2θ (two theta) , each of the 2θ values is understood to mean the given value ± 0.2 degrees two theta, unless otherwise expressed.

As used herein, the term “seeding” refers to the addition of crystalline material to a solution or mixture to initiate crystallisation or recrystallisation.

As used herein, the term “solvate” comprises solvent addition forms. A “solvate” may be a solvate with water (i.e., a hydrate) or with an organic solvent.

In the context of the present invention, the “free base” form of the compound described herein means (1S, 3R) -3- (4- ( (R) -2-chloro-8-methyl-8- (trifluoromethyl) -7, 8-dihydro-6H-pyrazolo [1, 5-a] pyrrolo [2, 3-e] pyrimidin-6-yl) phenyl) -2, 2-difluoro-1-methyl-N- ( (trans) -3- (methylsulfonyl) cyclobutyl) cyclopropane-1-carboxamide as non-salt and non-solvate form. The compound described herein may be provided in the free base form or as a salt or solvate thereof. Preferably, the compound is in the free base form (e.g., as Compound 3) . The dose of the compound or the amount of the compound in a composition may be expressed as being “calculated based on the free base form” . Where the compound is provided as a salt or a solvate and the dose or amount of the compound is expressed as being calculated based on the free base form, the dose or amount of salt or solvate provided is the equivalent amount to provide the defined amount of free base. The mass of the salt or solvent that is equivalent to a given mass of the free base can be calculated according to the formula:
mass (salt or solvate) = mass (free base) x conversion factor

The conversion factor can be calculated according to the formula:
conversion factor = molecular mass (salt or solvate) /molecular mass (free base)

The term “amorphous” refers to a non-crystalline solid phase. Examples of amorphous forms include the fully non-crystalline form, semi-crystalline forms, or a form comprising regions of crystallinity and regions of non-crystallinity.

The term “amorphous solid dispersion” (which may also be referred to as “ASD” ) as used herein refers to a solid dispersion in which the active pharmaceutical ingredient is dispersed within an excipient matrix, wherein the active pharmaceutical ingredient is present in substantially amorphous form. For example, an amorphous solid dispersion may comprise an active pharmaceutical ingredient (for example, the compound as described herein, e.g., Compound 3) , a polymer (for example, the orally pharmaceutically acceptable polymer as described herein) and optionally other components such as surface-active carriers or other pharmaceutically acceptable carriers. In any of the amorphous solid dispersions described herein, the compound (for example, Compound 3) may be present in an amorphous form in a weight percentage of at least 90%w/w, optionally at least 91%w/w, optionally at least 92%w/w, optionally at least 93%w/w, optionally at least 94%w/w, optionally at least 95%w/w, optionally at least 96%w/w, optionally at least 97%w/w, optionally at least 98%w/w, optionally at least 99%w/w, optionally at least 99.5%w/w, optionally at least 99.9%w/w; preferably at least 95%w/w, relative to the total content of the compound. When a particular percentage by weight of the compound is in amorphous form, the remainder of the compound may be in any crystalline form of the compound.

The term “molecular weight” (MW) , as referenced herein in the context of polymers, refers to average molecular weight, unless otherwise defined. An average molecular weight may, for example, refer to a number average or weight average molecular weight. Average molecular weight may, for example, be measured using gel permeation chromatography.

T_g as used herein refers to the glass transition temperature, which is the temperature at which a material changes from glassy (solid) state to a soft, rubbery state. T_g can be measured by differential scanning calorimetry (DSC) .

As used herein, unless otherwise noted, the term "affect" or "affected" (when referring to a disease, syndrome, condition or disorder affected by the inhibition of MALT1) includes a reduction in the frequency and/or severity of one or more symptoms or manifestations of said disease, syndrome, condition or disorder; and/or includes the prevention of the development of one or more symptoms or manifestations of said disease, syndrome, condition or disorder or the development of the disease, condition, syndrome or disorder.

As used herein, and unless otherwise defined, the terms “treat, ” “treating” and “treatment” include the eradication, removal, modification, management or control of a disease, syndrome, condition, or disorder (e.g., a disease, syndrome, condition, or disorder affected by the inhibition of MALT1) .

As used herein, and unless otherwise defined, the phrase “therapeutically effective amount” means an amount of Compound 3, or a pharmaceutically acceptable salt form thereof or a solvate thereof, effective for treating a disease, syndrome, condition, or disorder affected by the inhibition of MALT1. In one embodiment, the term “therapeutically effective amount” refers to the amount of Compound 3, or a pharmaceutically acceptable salt form thereof or a solvate thereof, that when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent, and/or ameliorate a condition, or a disorder or a disease (i) mediated by MALT1; or (ii) associated with MALT1 activity; or (iii) characterized by activity (normal or abnormal) of MALT1; or (2) reduce or inhibit the activity of MALT1; or (3) reduce or inhibit the expression of MALT1; or (4) modify the protein levels of MALT1.

The term “pharmaceutically acceptable” means that which is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which are approved or approvable for human pharmaceutical use as well as veterinary use, by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans. The term “orally pharmaceutically acceptable” means that which is generally safe, non-toxic and neither biologically nor otherwise undesirable when administered orally.

As used herein, the term “carrier” refers to any component, other than the active pharmaceutical ingredient, present in a formulation or used in the manufacture of the formulation. Carriers may also be referred to as excipients. The intended function of a carrier is to act as a vehicle for transporting the active pharmaceutical ingredient within or to the subject such that the active pharmaceutical ingredient can perform its intended function. Examples of carriers include fillers, glidants, lubricants, disintegrants, disintegrant aids, and the like.

The term “surface-active carrier” refers to a carrier that lowers the surface tension of a formulation.

is a registered trade mark and refers to polymers marketed by Evonik. polymers are copolymers derived from esters of acrylic and methacrylic acid.

E 100 as used herein refers to poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1: 2: 1 (CAS number: 24938-16-7) polymer. E 100 has a weight average molecular weight of about 47,000 g/mol (as determined by size exclusion chromatography (SEC) ) .

L 100 as used herein refers to poly (methacrylic acid-co-methyl methacrylate) 1: 1 (CAS number: 25086-15-1) polymer. L 100 has a weight average molecular weight of about 125,000 g/mol.

L 100-55 as used herein refers to poly (methacrylic acid-co-ethyl acrylate) 1: 1 (CAS number: 25212-88-8) polymer. L 100-55 has a weight average molecular weight of about 320,000 g/mol (as determined by size exclusion chromatography (SEC) ) .

PVP as used herein refers to polyvinylpyrrolidone.

PVP K30 as used herein refers to a homopolymer of vinylpyrrolidone (polyvinylpyrrolidone; CAS number: 9003-39-8) having a weight average molecular weight of 44,000-54,000 g/mol.

PVP VA64 as used herein refers to a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a ratio of 6: 4 by mass (CAS number: 25086-89-9) . In particular, PVP VA64 refers to a polymer having a weight average molecular weight of 45,000-70,000 g/mol.

is a registered trademark and refers to a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (CAS number 402932-23-4) marketed by BASF. The average molecular weight ofis about 118,000 g/mol (nominally in the range of 90,000 –140,000 g/mol) , as determined by gel permeation chromatography. displays a T_g of about 70 ℃ and a K-value of 31-41 (1%in ethanol, obtained from measurements of relative viscosity according to Fikentscher) .

HPMC as used herein refers to hydroxypropyl methylcellulose, also known as hypromellose (CAS number: 9004-65-3) . Hypromellose is a cellulose derived non-ionic polymer. The glucose monomers of the polymer are partly methylated and 2-hydroxypropylated. Different hypromellose grades are characterized by their degree of substitution and viscosity. In some embodiments, HPMC comprises 28 wt%to 30 wt%methoxyl and 7 wt%to 12 wt%hydroxypropyl and has an apparent viscosity when dissolved at 2.0%in water of 4 to 6 mPa. s. An example of commercially available HPMC having these properties is HPMC E5, available from IFF. The methoxyl and hydroxypropyl contents of HPMC may be determined by methods known in the art, for example, Fourier transform infrared (FTIR) spectroscopy and NMR spectroscopy.

HPMC E5 as used herein refers to HPMC having a methoxyl content of 28 wt%to 30 wt%and a hydroxypropyl content of 7 wt%to 12 wt%. HPMC E5 has a viscosity of 4 to 6 mPa. swhen measured for a 2%solution in water at 20 ℃. HPMC E5 may have a weight average molecular weight in the range of 20,000-30,000 g/mol (for example, 28, 700 g/mol) .

The terms “HPMC AS” and “HPMCAS” can be used interchangeably and refer to hydroxypropylmethylcellulose acetate succinate, also known as hypromellose acetate succinate (CAS number: 71138-97-1) . It is a mixture of acetic acid and monosuccinic acid esters of hydroxypropylmethyl cellulose. HPMCAS has a weight average molecular weight ranging from 17,000-20,000 g/mol and a T_g ranging from 118 to 120 ℃.

Different grades of HMPCAS are available commercially (e.g., HPMCAS LG, HPMCAS MG, HPMCAS HG, HPMCAS LF, HPMCAS MF, HPMCAS HF, HPMCAS LMP, HPMCAS MMP, and HPMCAS-HMP) . The L, M and H grades of HPMCAS vary in acetyl and succinoyl contents and also refer to the pH at which the polymers dissolve (L=low pH > 5.5, M=medium pH > 6.0 and H=high pH > 6.5) . F, G and MP grades refer to differing mean particle diameter (F is cohesive fine powder –5 μm, MP is medium particle size –70-300 μm and G is free-flowing granules –1 mm) . The acetyl and succinoyl contents of HMPCAS may be determined by methods known in the art, for example, Fourier transform infrared (FTIR) spectroscopy and NMR spectroscopy.

HPMC AS LG refers to HPMC AS having an acetyl content of 5.0 wt%to 9.0 wt%and a succinoyl content of 14.0 wt%to 18.0 wt%. HPMC AS LG is granular HPMCAS having a mean particle diameter of 1 mm.

HPMC AS MG refers to HPMC AS having an acetyl content of 7.0 wt%to 11.0 wt%and a succinoyl content of 10.0 wt%to 14.0 wt%. HPMC AS MG is granular HPMCAS having a mean particle diameter of 1 mm.

HPMC AS HG refers to HPMC AS having an acetyl content of 10.0 wt%to 14.0 wt%and a succinoyl content of 4.0 wt%to 8.0 wt%. HPMC AS HG is granular HPMCAS having a mean particle diameter of 1 mm.

HPMC AS LF refers to HPMC AS having an acetyl content of 5.0 wt%to 9.0 wt%and a succinoyl content of 14.0 wt%to 18.0 wt%. HPMC AS LF is micronized HPMCAS having a mean particle diameter of 5 μm.

HPMC AS MF refers to HPMC AS having an acetyl content of 7.0 wt%to 11.0 wt%and a succinoyl content of 10.0 wt%to 14.0 wt%. HPMC AS MF is micronized HPMCAS having a mean particle diameter of 5 μm.

HPMC AS HF refers to HPMC AS having an acetyl content of 10.0 wt%to 14.0 wt%and a succinoyl content of 4.0 wt%to 8.0 wt%. HPMC AS HF is micronized HPMCAS having a mean particle diameter of 5 μm.

HPMC AS LMP refers to HPMC AS having an acetyl content of 5.0 wt%to 9.0 wt%and a succinoyl content of 14.0 wt%to 18.0 wt%. HPMC AS LMP has a mean particle diameter of 70-300 μm.

HPMC AS MMP refers to HPMC AS having an acetyl content of 7.0 wt%to 11.0 wt%and a succinoyl content of 10.0 wt%to 14.0 wt%. HPMC AS MMP has a mean particle diameter of 70-300 μm.

HPMC AS HMP refers to HPMC AS having an acetyl content of 10.0 wt%to 14.0 wt%and a succinoyl content of 4.0 wt%to 8.0 wt%. HPMC AS HMP has a mean particle diameter of 70-300 μm.

As used herein, “polyethylene glycol” refers to a polymer having repeat units of formula - (CH₂-CH₂-O-) and a molecular weight in the range of from about 1,500 g/mol to about 3,000,000 g/mol.

The prefix ‘C_x-y’ (where x and y are integers) as used herein refers to the number of carbon atoms in a given group. Thus, a C_1-4-alkyl group contains from 1 to 4 carbon atoms, and so on.

The term ‘C_1-4-alkyl’ as used herein as a group or part of a group represents a straight or branched chain saturated hydrocarbon radical having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.

As used herein, “poly (C_1-4-alkyl acrylate) ” refers to a polymer having the following structural formula:

wherein R is a C_1-4-alkyl group and n is the number of repeat units.

As used herein, “poly (C_1-4-alkyl methacrylate) ” refers to a polymer having the following structural formula:

wherein R is a C_1-4-alkyl group and n is the number of repeat units.

As used herein, “copolymer” means a polymer derived from more than one species of monomer. For example, “copolymer of C_1-4-alkyl acrylate" means a polymer derived from C_1-4-alkyl acrylate and at least one other species of monomer, wherein C_1-4-alkyl acrylate has the following structural formula:

wherein R is a C_1-4-alkyl group. Similarly, “copolymer of C_1-4-alkyl methacrylate" means a polymer derived from C_1-4-alkyl methacrylate and at least one other species of monomer, wherein C_1-4-alkyl methacrylate has the following structural formula: As used herein, “vinylpyrrolidone-vinyl acetate copolymer” means a polymer derived from 1-vinyl-2-pyrrolidone and vinyl acetate and having the following structural formula: wherein m and n refer to the number of repeat units As used herein, the term “graft copolymer” refers to a polymeric backbone with covalently linked polymeric side chains (of a different type) . For example, and without limitation, a graft co-polymer comprising polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol has the following structure:

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

It will be clear for a skilled person that a hashed bond and a bold bond on a 1, 3-disubstituted cyclobutyl moiety as shown below:

whereby X¹ and X² represent substituents, indicate that the substituents on the cyclobutyl moiety have trans-configuration.

The stereodescriptor label “R” or “ (R) ” at a stereocenter designates that the stereocenter is purely of the R-configuration as defined in the art; likewise, the stereodescriptor label “S” or “ (S) ” means that the stereocenter is purely of the S-configuration.

“Simulated gastric fluid” (SGF) refers to a medium that simulates gastric conditions in the fasted state. This medium contains hydrochloric acid, sodium chloride, pepsin and water, and has a pH of 1.2-1.3. “Fasted state simulated intestinal fluid” (FaSSIF) refers to a medium that simulates fasting conditions in the proximal small intestine. This medium contains sodium taurocholate, lecithin, sodium dihydrogen phosphate, sodium chloride and water, and has a pH of 6.5. Simulation of gastrointestinal conditions (e.g., by using SGF and FaSSIF) may be used to predict the in vivo behavior of drug formulations.

The abbreviation “XRPD” stands for X-ray powder diffraction.

The abbreviation “DSC” stands for differential scanning calorimetry.

The abbreviation “TGA” stands for thermogravimetric analysis.

The abbreviation “DVS” stands for dynamic vapor sorption.

The abbreviation “API” stands for active pharmaceutical ingredient.

The abbreviation “MALT1” stands for mucosa-associated lymphoid tissue lymphoma translocation 1.

The abbreviation “CARD11” stands for caspase recruitment domain family member 11.

The abbreviation “BCL10” stands for BCL10 (B-cell CLL/Lymphoma 10) .

The abbreviation “CBM” stands for a complex consisting of multiple subunits of three proteins: CARD11–BCL10–MALT1.

The abbreviations “BCR” and “TCR” stand for B cell receptor and T cell receptor, respectively.

The abbreviation “DLBCL” stands for diffuse large B cell lymphoma. The abbreviation “ABC-DLBCL” stands for diffuse large B cell lymphoma of the activated B cell-like subtype.

The abbreviation “NHL” stands for non-Hodgkin’s lymphoma.

The abbreviation “RH” stands for relative humidity.

The abbreviation “IL-10” stands for Interleukin 10.

The abbreviation “SLS” stands for sodium lauryl sulfate.

The abbreviation “SMCC” stands for silicified microcrystalline cellulose.

The abbreviation “PK” stands for pharmacokinetics.

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

The salt forms of Compound 3 presented herein are typically pharmaceutically acceptable salts. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salts forms may be useful, for example, in the purification or separation of the Compound 3.

In general, pharmaceutically acceptable salts include pharmaceutically acceptable acid and base addition salts and are meant to comprise the therapeutically active non-toxic acid and base addition salt forms that compounds are able to form.

In general, salts can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. Compounds may exist as mono-or di-salts depending upon the pKa of the acid from which the salt is formed.

Pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like) or organic acids such (as acetic acid, methanesulfonic acid, maleic acid, tartaric acid, citric acid and the like) in an anion form.

Appropriate anions comprise, for example, acetate, 2, 2-dichloroacetate, adipate, alginate, ascorbate (e.g., L ascorbate) , L-aspartate, benzenesulfonate, benzoate, 4-acetamidobenzoate, butanoate, bicarbonate, bitartrate, bromide, (+) camphorate, camphor-sulphonate, (+) - (1S) -camphor-10-sulphonate, calcium edetate, camsylate, caprate, caproate, caprylate, carbonate, chloride, cinnamate, citrate, cyclamate, dihydrochloride, dodecylsulphate, edetate, estolate, esylate, ethane-1, 2-disulphonate, ethanesulphonate, formate, fumarate, galactarate, gentisate, glucoheptonate, gluceptate, gluconate, D-gluconate, glucuronate (e.g., D-glucuronate) , glutamate (e.g., L-glutamate) , α-oxoglutarate, glycolate, glycollylarsanilate, hexylresorcinate, hippurate, hydrabamine, hydrobromide, hydrochloride, hydriodate, 2-hydroxyethane-sulphonate, hydroxynaphthoate, iodide, isethionate, lactate (e.g., (+) -L-lactate, (±) -DL-lactate) , lactobionate, malate, (-) -L-malate, maleate, malonate, mandelate, (±) -DL-mandelate, mesylate, methansulfonate, methylbromide, methylnitrate, methylsulfate, mucate, naphthalene-sulphonate (e.g. naphthalene-2 sulphonate) , naphthalene-1, 5-disulphonate, 1-hydroxy-2-naphthoate, napsylate, nicotinate, nitrate, oleate, orotate, oxalate, palmitate, pamoate (embonate) , pantothenate, phosphate/diphosphate, propionate, polygalacturonate, L pyroglutamate, pyruvate, salicylate, 4-amino-salicylate, sebacate, stearate, subacetate, succinate, sulfate, tannate, tartrate, (+) -L-tartrate, teoclate, thiocyanate, toluenesulphonate (e.g., p-toluenesulphonate) , tosylate, triethiodide, undecylenate, valeric acids, as well as acylated amino acids and cation exchange resins.

Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.

In general, compounds containing an acidic proton may also be converted into their nontoxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases in a cation form. Appropriate basic salts comprise those formed with organic cations such as arginine, benzathine, benzylamine, butylamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, diethanolamine, diethylamine, ethanolamine, ethylamine, ethylenediamine, lysine, meglumine, phenylbenzylamine, piperazine, procaine, triethylamine, tromethamine, and the like; those formed with ammonium ion (i.e., NH₄ ⁺) , quaternary ammonium ion N (CH₃) ₄ ⁺, and substituted ammonium ions (e.g., NH₃R⁺, NH₂R₂ ⁺, NHR₃ ⁺, NR₄ ⁺) ; and those formed with metallic cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and the like. Compounds containing an amine function may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person.

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

As used herein, the term “D50” refers to median particle diameter, and thus it is meant that 50%of the volume weighted particles have a diameter less than and 50%of the volume weighted particles have a diameter greater than the median particle diameter.

Particle size (e.g., diameter) can be measured by art-known particle size measuring techniques such as, for example, static light scattering, sedimentation field flow fractionation, photon correlation spectroscopy, laser diffraction or disk centrifugation.

As used herein, a “total daily dose” is the total amount administered on any given day.

As used herein, “C_trough” refers to the lowest measured concentration reached by a drug in blood, blood plasma, cerebrospinal fluid, or target organ immediately before the subsequent dose.

As used herein, “C_max” refers to the maximum concentration of a drug in blood, blood plasma, cerebrospinal fluid, or target organ after a drug has been administered.

As used herein, “AUC” refers to the “area under the curve” , i.e., the area under the plasma or blood concentration-time curve. The AUC is a measure of total systemic exposure to a drug. “AUC_0-24, ss” refers to the AUC over a 24-hour dosing interval at steady state.

As used herein, “QD” means once a day.

As used herein, “BID” means twice a day.

As used herein, the term “loading phase” refers to an initial dosage period, which is directly followed by the “maintenance phase” . Accordingly, in a daily dosage regimen the first day of the maintenance phase is the day after the last day of the loading phase. A loading phase (wherein the compound is administered at a loading dose) may be used to rapidly achieve a desired plasma concentration of the compound in the subject. This may then be followed by a maintenance phase, wherein the compound is administered at a maintenance dose which is lower than the loading dose, in order to maintain the desired plasma concentration of the compound in the subject.

The abbreviation “PD” stands for pharmacodynamics.

The abbreviation “TGI” stands for tumor growth inhibition.

The abbreviation “TR” stands for tumor regression.

The abbreviation “NOAEL” stands for no observed adverse effect level.

The abbreviation “AST” stands for aspartate aminotransferase.

The abbreviation “ALT” stands for alanine aminotransferase.

The abbreviation “GLP” stands for good laboratory practice.

Where any aspects or embodiments of the invention are referred to as comprising particular elements and/or features, it is contemplated that these aspects or embodiments of the invention may also consist, or consist essentially of, such elements and/or features.

Amorphous solid dispersions

Provided herein is an amorphous solid dispersion comprising a compound and an orally pharmaceutically acceptable polymer;

or a pharmaceutically acceptable salt form thereof.

The compound (Compound 3 or a pharmaceutically acceptable salt form thereof) may be referred to as the active pharmaceutical ingredient (API) . In any of the embodiments described herein, the compound may be present in the free base form (i.e., as Compound 3) .

An embodiment of the invention is an amorphous solid dispersion of Compound 3, wherein Compound 3 is dispersed in an orally pharmaceutically acceptable polymer.

In some embodiments of the amorphous solid dispersions described herein, the compound (e.g., Compound 3) is present in an amorphous form in a weight percentage of at least 90%w/w, optionally at least 91%w/w, optionally at least 92%w/w, optionally at least 93%w/w, optionally at least 94%w/w, optionally at least 95%w/w, optionally at least 96%w/w, optionally at least 97%w/w, optionally at least 98%w/w, optionally at least 99%w/w, optionally at least 99.5%w/w, optionally at least 99.9%w/w, relative to the total content of the compound. When a particular percentage by weight of the compound is in amorphous form, the remainder of the compound may be in any crystalline form of the compound.

In some embodiments, the weight-by-weight ratio of the compound to the orally pharmaceutically acceptable polymer is in the range of 5: 1 to 1: 100, such as 5: 1 to 1: 10, 5: 1 to 1: 5, 4: 1 to 1: 4, 2: 1 to 1: 4, 1: 1 to 1: 4, 1: 1 to 1: 3, or 1: 2 to 1: 3, calculated based on the free base form of the compound.

In some embodiments, the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is in the range of 5: 1 to 1: 100, such as 5: 1 to 1: 10, 5: 1 to 1: 5, 4: 1 to 1: 4, 2: 1 to 1: 4, 1: 1 to 1: 4, 1: 1 to 1: 3, or 1: 2 to 1: 3. In some embodiments, the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is 1: 3.

In some embodiments, the orally pharmaceutically acceptable polymer is selected from the group consisting of:

C_1-4-alkylcelluloses such as methylcellulose and ethylcellulose;

hydroxy-C_1-4-alkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose;

hydroxy-C_1-4-alkyl C_1-4-alkylcelluloses such as hydroxymethyl methylcellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose and hydroxybutyl methylcellulose;

carboxy-C_1-4-alkylcelluloses such as carboxymethylcellulose;

alkali metal salts of carboxy-C_1-4-alkylcelluloses such as sodium carboxymethylcellulose;

carboxy-C_1-4-alkyl-C_1-4-alkylcelluloses such as carboxymethylethylcellulose;

hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate phthalate and hydroxypropylmethylcellulose acetate succinate;

hydroxypropylcellulose acetate phthalate;

methylcellulose acetate phthalate;

cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate;

chitosan;

α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, (2-hydroxypropyl) -α-cyclodextrin, (2-hydroxypropyl) -β-cyclodextrin, (2-hydroxypropyl) -γ-cyclodextrin;

sodium carboxymethylamylopectin, carrageenan, galactomannan, tragacanth, agar-agar, gummi arabicum, guar gummi and xanthan gummi;

polyacrylic acid, poly (C_1-4-alkyl acrylates) and copolymers of C_1-4-alkyl acrylates; polymethacrylic acid, poly (C_1-4-alkyl methacrylates) and copolymers of C_1-4-alkyl methacrylates;

polyvinyl alcohol and copolymers of polyvinyl alcohol;

crospovidone;

polyethylene glycol, polypropylene glycol, copolymers of ethylene glycol, copolymers of propylene glycol;

polyvinyl caprolactam;

polyvinyl acetate;

polyvinylpyrrolidone;

vinylpyrrolidone-vinyl acetate copolymer;

and where possible salts of these polymers;

or any combination thereof.

In some embodiments, the orally pharmaceutically acceptable polymer is polyethylene glycol. In some embodiments, the polyethylene glycol has a molecular weight (MW) in the range of from about 1,500 g/mol to about 20,000 g/mol. In some embodiments, the polyethylene glycol has a molecular weight (MW) in the range of from about 4,000 g/mol to about 6,000 g/mol.

In some embodiments, the orally pharmaceutically acceptable polymer is polyvinylpyrrolidone. In some embodiments, the polyvinylpyrrolidone has a MW in the range of from about 2,500 g/mol to about 3,000,000 g/mol.

In some embodiments, the orally pharmaceutically acceptable polymer is selected from the group consisting of hydroxypropylmethylcellulose acetate succinate (HPMCAS) ; hydroxypropyl methylcellulose (HPMC) ; a copolymer of C_1-4-alkyl acrylate; a copolymer of C_1-4-alkyl methacrylate; vinylpyrrolidone-vinyl acetate copolymer; polyvinylpyrrolidone; and copolymer of ethylene glycol; or any combination thereof.

In some embodiments, the orally pharmaceutically acceptable polymer is HPMCAS. In some embodiments, the orally pharmaceutically acceptable polymer is HPMCAS LG. In some embodiments, the orally pharmaceutically acceptable polymer is selected from the group consisting of:

HPMCAS wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl;

HPMCAS wherein the HPMCAS comprises 7.0 wt%to 11.0 wt%acetyl and 10.0 wt%to 14.0 wt%succinoyl;

HPMCAS wherein the HPMCAS comprises 10.0 wt%to 14.0 wt%acetyl and 4.0 wt%to 8.0 wt%succinoyl;

poly (methacrylic acid-co-methyl methacrylate) (1: 1) ;

poly (methacrylic acid-co-ethyl acrylate) (1: 1) ;

poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (1: 2: 1) ;

HPMC, wherein the HPMC comprises 28 wt%to 30 wt%methoxyl and 7 wt%to 12 wt%hydroxypropyl (wherein the HPMC may have an apparent viscosity when dissolved at 2.0%in water of 4 to 6 mPa. s) ;

a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a ratio of 6: 4 by mass;

polyvinylpyrrolidone having a molecular weight of 44,000-54,000 g/mol; and

a graft copolymer of polyvinyl caprolactam, polyvinyl acetate and polyethylene glycol having a molecular weight of 90,000-140,000 g/mol, optionally wherein the graft copolymer has a K-value of 31-41 when measured at 1%in ethanol;

or a combination thereof.

HPMCAS LG;

HPMCAS MG;

HPMCAS HG;

poly (methacrylic acid-co-methyl methacrylate) (1: 1) ;

poly (methacrylic acid-co-ethyl acrylate) (1: 1) ;

polyvinylpyrrolidone having a molecular weight of 44,000-54,000 g/mol; and

or a combination thereof.

In some embodiments, the orally pharmaceutically acceptable polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS) or hydroxypropyl methylcellulose (HPMC) . In some embodiments, the orally pharmaceutically acceptable polymer is HPMCAS.

In some embodiments, the orally pharmaceutically acceptable polymer is HPMCAS, wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl; poly (methacrylic acid-co-methyl methacrylate) (1: 1) ; or HPMC, wherein the HPMC comprises 28 wt%to 30 wt%methoxyl and 7 wt%to 12 wt%hydroxypropyl and wherein the HPMC has an apparent viscosity when dissolved at 2.0%in water of 4 to 6 mPa. s; or a combination thereof.

In some embodiments, the orally pharmaceutically acceptable polymer is HPMCAS, wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl.

In some embodiments, the orally pharmaceutically acceptable polymer is HPMCAS, wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl, and wherein the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is in the range of 1: 2 to 1: 3.

In some embodiments, the orally pharmaceutically acceptable polymer is HPMCAS, wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl, and wherein the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is 1: 3.

In some embodiments, the amorphous solid dispersion further comprises a surface-active carrier. The surface-active carrier may be selected from lauroyl PEG-32 glycerides, vitamin E R-alpha-tocopheryl polyethylene glycol 100 succinate (TPGS) , polysorbate 80, alkali dodecylsulphate surfactants, dioctyl sulfosuccinate sodium salt, cholic acid, deoxycholic acid, lithocholic acid, cholesterol and esters thereof. In some embodiments, the surface-active carrier is sodium lauryl sulfate (SLS) .

In some embodiments, the amorphous solid dispersion is in particulate form. In some embodiments, the amorphous solid dispersion in particulate form has a volume weighted particle size distribution D50, as measured by a static light scattering method, of from about 10 μm to about 60 μm, such as from about 30 μm to about 60 μm.

In some embodiments, the present invention relates to a particle comprising the amorphous solid dispersion as described herein. The particle comprising the amorphous solid dispersion as described herein, may have a volume weighted particle size distribution D50, as measured by a static light scattering method, of from about 10 μm to about 60 μm, such as from about 30 μm to about 60 μm.

An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles comprising the amorphous solid dispersion as described herein. In particular, an aspect of the invention is any specific pharmaceutical formulation described herein comprising a pharmaceutically acceptable carrier and particles comprising the amorphous solid dispersion as described herein.

An aspect of the invention is a tablet comprising a pharmaceutically acceptable carrier and particles comprising the amorphous solid dispersion as described herein. In particular, an aspect of the invention is any tablet described herein comprising a pharmaceutically acceptable carrier and particles comprising the amorphous solid dispersion as described herein.

The amorphous solid dispersion described herein may have beneficial properties in terms of dissolution rate and stability.

In some embodiments, when the amorphous solid dispersion is contacted with simulated gastric fluid (SGF) for about 15 minutes followed by contacting with fasted state simulated intestinal fluid (FaSSIF) , at least 60% (optionally at least 70%, optionally at least 80%) of the amorphous solid dispersion is dissolved after 20 minutes. In some embodiments, when the amorphous solid dispersion comprises 100 mg of Compound 3 and is contacted with simulated gastric fluid (SGF) for about 15 minutes followed by contacting with fasted state simulated intestinal fluid (FaSSIF) , at least 60% (optionally at least 70%, optionally at least 80%) of the amorphous solid dispersion is dissolved after 20 minutes.

In some embodiments, the amorphous solid dispersion exhibits no crystalline conversion after exposure at 40 ℃, 75%relative humidity (RH) , for 28 days. In some embodiments, the amorphous solid dispersion exhibits no crystalline conversion after exposure at 50 ℃, 75%relative humidity (RH) , for 28 days. In some embodiments, the amorphous solid dispersion exhibits no crystalline conversion after exposure at 60 ℃, 10%relative humidity (RH) , for 28 days. In some embodiments, the amorphous solid dispersion exhibits no crystalline conversion after exposure at 60 ℃, 30%relative humidity (RH) , for 28 days. In some embodiments, the amorphous solid dispersion exhibits no crystalline conversion after exposure at 60 ℃, 75%relative humidity (RH) , for 28 days. In some embodiments, the amorphous solid dispersion exhibits no crystalline conversion after exposure at 40 ℃, 75%relative humidity (RH) , for 3 months. In some embodiments, the amorphous solid dispersion exhibits no crystalline conversion after exposure at 50 ℃, 75%relative humidity (RH) , for 3 months. In some embodiments, the amorphous solid dispersion exhibits no crystalline conversion after exposure at 60 ℃, 10%relative humidity (RH) , for 3 months. In some embodiments, the amorphous solid dispersion exhibits no crystalline conversion after exposure at 60 ℃, 30%relative humidity (RH) , for 3 months. In some embodiments, the amorphous solid dispersion exhibits no crystalline conversion after exposure at 60 ℃, 75%relative humidity (RH) , for 3 months. In some embodiments, the amorphous solid dispersion exhibits no crystalline conversion after exposure at 40 ℃, 75%relative humidity (RH) , for 6 months. In some embodiments, the amorphous solid dispersion exhibits no crystalline conversion after exposure at 50 ℃, 75%relative humidity (RH) , for 6 months. In some embodiments, the amorphous solid dispersion exhibits no crystalline conversion after exposure at 60 ℃, 10%relative humidity (RH) , for 6 months. In some embodiments, the amorphous solid dispersion exhibits no crystalline conversion after exposure at 60 ℃, 30%relative humidity (RH) , for 6 months. In some embodiments, the amorphous solid dispersion exhibits no crystalline conversion after exposure at 60 ℃, 75%relative humidity (RH) , for 6 months.

Copolymers of C_1-4-alkyl acrylates and C_1-4-alkyl methacrylates

The orally pharmaceutically acceptable polymer may be a copolymer derived from esters of acrylic and methacrylic acid. In some embodiments, the orally pharmaceutically acceptable polymer may be a copolymer of C_1-4-alkyl acrylate. In some embodiments, the orally pharmaceutically acceptable polymer may be a copolymer of C_1-4-alkyl methacrylate.

In some embodiments, the orally pharmaceutically acceptable polymer is poly (methacrylic acid-co-ethyl acrylate) (1: 1) . This is an anionic copolymer based on methacrylic acid and ethyl acrylate (CAS number 25212–88–8; chemical/IUPAC name: poly (methacrylic acid-co-ethyl acrylate) 1: 1) . An example of commercially available poly (methacrylic acid-co-ethyl acrylate) (1: 1) is L 100-55.

In some embodiments, the orally pharmaceutically acceptable polymer is poly (methacrylic acid-co-methyl methacrylate) (1: 1) . This is an anionic copolymer based on methacrylic acid and methyl methacrylate (CAS number 25086-15-1; chemical/IUPAC name: poly (methacrylic acid-co-methyl methacrylate) 1: 1) . An example of commercially available poly (methacrylic acid-co-methyl methacrylate) (1: 1) is L 100.

In some embodiments, the orally pharmaceutically acceptable polymer is poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (1: 2: 1) . This is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (CAS number 24938-16-7; chemical/IUPAC name: poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1: 2: 1) . An example of commercially available poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (1: 2: 1) is E 100.

HPMCAS

In some embodiments, the orally pharmaceutically acceptable polymer is hydroxypropylmethylcellulose acetate succinate (HPMCAS) . HPMCAS is available commercially in various grades, which are named differently depending on the manufacturer.

For example, Shin-Etsu Chemical Co., Ltd. Defines these grades as follows:

Further grades of HPMCAS provided by Shin-Etsu includeHPMCAS: HPMCAS-LMP, HPMCAS-MMP, and HPMCAS-HMP, having a mean particle diameter from about 70 to about 300 μm.

In some embodiments, the HPMCAS is:

a) HPMCAS , wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl;

b) HPMCAS , wherein the HPMCAS comprises 7.0 wt%to 11.0 wt%acetyl and 10.0 wt%to 14.0 wt%succinoyl;

c) HPMCAS , wherein the HPMCAS comprises 10.0 wt%to 14.0 wt%acetyl and 4.0 wt%to 8.0 wt%succinoyl;

d) HPMCAS , wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl;

e) HPMCAS , wherein the HPMCAS comprises 7.0 wt%to 11.0 wt%acetyl and 10.0 wt%to 14.0 wt%succinoyl;

f) HPMCAS , wherein the HPMCAS comprises 10.0 wt %to 14.0 wt%acetyl and 4.0 wt%to 8.0 wt%succinoyl;

g) HPMCAS, wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl;

h) HPMCAS, wherein the HPMCAS comprises 7.0 wt%to 11.0 wt%acetyl and 10.0 wt%to 14.0 wt%succinoyl; or

i) HPMCAS, wherein the HPMCAS comprises 10.0 wt%to 14.0 wt%acetyl and 4.0 wt%to 8.0 wt%succinoyl.

The particle size of HPMCAS may be measured using methods well known to a person skilled in the art, such as laser diffraction.

In some embodiments, the HPMCAS has a viscosity of 3 mm²/s. The viscosity may be determined by capillary tube viscometer using a 2% (w/w) solution in dilute NaOH (test solution) at 20 ℃, as described in the Japanese Pharmacopoeia (18^th edition) . In some embodiments, the HPMCAS is:

a) HPMCAS, wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl;

b) HPMCAS, wherein the HPMCAS comprises 7.0 wt%to 11.0 wt%acetyl and 10.0 wt%to 14.0 wt%succinoyl; or

c) HPMCAS, wherein the HPMCAS comprises 10.0 wt %to 14.0 wt%acetyl and 4.0 wt %to 8.0 wt%succinoyl.

HPMC

In some embodiments, the orally pharmaceutically acceptable polymer is hydroxypropyl methylcellulose (HPMC) (also known as hypromellose) .

Polyvinylpyrrolidone and vinylpyrrolidone-vinyl acetate copolymers

In some embodiments, the orally pharmaceutically acceptable polymer is a polyvinylpyrrolidone. In some embodiments, the orally pharmaceutically acceptable polymer is a vinylpyrrolidone-vinyl acetate copolymer.

Names and abbreviations for polyvinylpyrrolidone include, but are not limited to, PVP, povidone and crospovidone. Crospovidone is a crosslinked homopolymer of vinyl pyrrolidone.

The average molecular weight of PVP may be expressed in terms of the K-value, which is calculated from the relative viscosity in water. The average molecular weight of polyvinylpyrrolidone (PVP) is not critical and any average molecular weight of PVP (see e.g., Handbook of Pharmaceutical Excipients, 3rd Ed (2000) , 433-439, American Pharmaceutical Association Washington and The Pharmaceutical Press London) , may be used, but preferably PVP ranges from 10,000 to 100,000 (K=17-96) .

The crospovidone (or cross-polyvinylpyrrolidone, cross-PVP) described in reference of Handbook of Pharmaceutical Excipients, 3nd Ed (2000) , 163-164, American Pharmaceutical Association Washington and The Pharmaceutical Press London) may be used.

In some embodiments, the the orally pharmaceutically acceptable polymer is polyvinylpyrrolidone (CAS 9003-39-8) . The polyvinylpyrrolidone may have a molecular weight of 44,000-54,000 g/mol. This may be referred to as PVP K30. Examples of commercially available PVP K30 are30 and Plasdone K-29/32.

In some embodiments, the vinylpyrrolidone-vinyl acetate copolymer is a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a ratio of 6: 4 by mass. Names and abbreviations for a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a ratio of 6: 4 by mass (PVP-VA64) include, but are not limited to, copolyvidone, copovidum, and copovidone. Examples of commercially available PVP-VA64 areVA64, VA64 Fine, Luviskol and Plasdone

Graft copolymers of polyvinyl caprolactam, polyvinyl acetate and polyethylene glycol

In some embodiments, the orally pharmaceutically acceptable polymer is a graft copolymer of polyvinyl caprolactam, polyvinyl acetate and polyethylene glycol. This may have an amphiphilic chemical structure, a K-value of 31-41 (1%in ethanol, obtained from measurements of relative viscosity according to Fikentscher) and a molecular weight in the range of 90,000 –140,000 g/mol (as determined by gel permeation chromatography, with an average molecular weight of approximately 118,000 g/mol) . A commercially available example of such graft copolymers is

Additional pharmaceutically acceptable carriers

The amorphous solid dispersions as described herein may further comprise one or more pharmaceutically acceptable carriers such as, for example, plasticizers, flavors, colorants, preservatives and the like.

Plasticizers may be beneficial, for example, when the amorphous solid dispersion is prepared by melt extrusion. Plasticizers lower the temperature at which a melt is formed, and this lowering of the melting point is advantageous where the polymer has limited thermal stability.

Suitable plasticizers are pharmaceutically acceptable and include polyalcohols such as ethylene glycol, propylene glycol, 1, 2-butylene glycol, 2, 3-butylene glycol, styrene glycol; polyethylene glycols such as diethylene glycol, triethylene glycol, tetraethylene glycol; other polyethylene glycols having a molecular weight of 1,000 g/mol or less; polypropylene glycols having a molecular weight of 200 g/mol or less; glycol ethers such as monopropylene glycol monoisopropyl ether; propylene glycol monoethyl ether; diethylene glycol monoethyl ether; ester type plasticizers such as sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, allyl glycollate; and amines such as monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine; triethylenetetramine, 2-amino-2-methyl-1, 3-propanediol and the like. In some embodiments, the plasticizer may be a polyethylene glycol having a molecular weight having a molecular weight of 1,000 g/mol or less, ethylene glycol, a polypropylene glycol having a molecular weight of 200 g/mol or less, or propylene glycol.

In some embodiments, the amorphous solid dispersions as described herein do not contain a plasticizer.

Processes for preparing amorphous solid dispersions

Various techniques exist for preparing amorphous solid dispersions including melt-extrusion, spray-drying, antisolvent precipitation, solution-evaporation, fusion-based processes (e.g., ) , and the like.

The melt-extrusion process may comprise the following steps:

a) mixing Compound 3, or a pharmaceutically acceptable salt form thereof, and an orally pharmaceutically acceptable polymer,

b) optionally blending additives with the thus obtained mixture,

c) heating the thus obtained blend until one obtains a homogenous melt,

d) forcing the thus obtained melt through one or more nozzles; and

e) cooling the melt until it solidifies.

The terms “melt” and “melting” should be interpreted broadly. For the purposes of the present disclosure, these terms may mean the alteration from a solid state to a liquid state, but may also refer to a transition to a glassy state or a rubbery state.

One important parameter of melt extrusion is the temperature at which the melt-extruder is operating. The operating temperature can range, for example, between about 20 ℃ and about 300 ℃, such as between about 70 ℃ and 250 ℃, or between about 160 ℃ and about 190 ℃. The lower temperature limit depends on the solubility of Compound 3 (or the pharmaceutically acceptable salt form thereof) in the orally pharmaceutically acceptable polymer and on the viscosity of the mixture. When Compound 3 (or the pharmaceutically acceptable salt form thereof) is not completely dissolved in the orally pharmaceutically acceptable polymer, the extrudate will not have the required bioavailability; when the viscosity of the mixture is too high, the process of melt extrusion will be difficult.

The throughput rate is also of importance, i.e., even at relatively low temperatures the orally pharmaceutically acceptable polymer may start to decompose when it remains in contact with the heating element for too long.

It will be appreciated that the person skilled in the art will be able to optimize the parameters of the melt extrusion process. The working temperatures will also be determined by the kind of extruder or the kind of configuration within the extruder that is used. Most of the energy needed to melt, mix and dissolve the components in the extruder can be provided by the heating elements. However, the friction of the material within the extruder may also provide a substantial amount of energy to the mixture and aid in the formation of a homogenous melt of the components.

A person skilled in the art can determine the most appropriate extruder, such as, for example, a single screw, a twin-screw extruder or a multi-screw extruder, for the preparation of the subject-matter of the present invention. Suitable extruders that may be used are the Haake mini-extruder, Leistritz 18 mm extruder, and the Leistritz 27 mm extruder.

Spray-drying of a solution of the components also yields an amorphous solid dispersion of said components and may be a useful alternative to the melt-extrusion process, particularly in those cases where the orally pharmaceutically acceptable polymer is not sufficiently stable to withstand the extrusion conditions and where residual solvent can effectively be removed from the amorphous solid dispersion. Yet another possible preparation is solution-evaporation, which consists of preparing a solution of the components, pouring said solution onto a large surface so as to form a thin film, and evaporating the solvent therefrom.

Solvents suitable for spray-drying can be any solvent (e.g., an organic solvent) in which Compound 3 (or a pharmaceutically acceptable salt form thereof or a solvate thereof) and the orally pharmaceutically acceptable polymer are miscible. The boiling point of the solvent may be lower than the T_g (glass transition temperature) of the amorphous solid dispersion. In addition, the solvent should have relatively low toxicity and be removed from the dispersion to a level that is acceptable according to The International Committee on Harmonization (ICH) guidelines. Removal of solvent to this level may require a post drying step such as for instance tray-drying, subsequent to the spray-drying process. Solvents include alcohols such as methanol, ethanol, n-propanol, iso-propanol, and butanol, in particular methanol; ketones such as acetone, methyl ethyl ketone and methyl iso-butyl ketone; esters such as ethyl acetate and propylacetate; and various other solvents such as acetonitrile, dichloromethane, toluene, and 1, 1, 1-trichloroethane. Lower volatility solvents such as dimethyl acetamide or dimethylsulfoxide can also be used. Solvents can be used in any combination. Accordingly, the solvent may be a mixture of solvents. In some embodiments, the solvent is a mixture of methanol and dichloromethane or a mixture of acetone and water. In some embodiments, the solvent is a mixture of methanol and dichloromethane. In some embodiments, the volume ratio of methanol and dichloromethane in the mixture is from about 1: 1 to about 1: 4. In some embodiments, the volume ratio of methanol and dichloromethane in the mixture is about 1: 3.

The amorphous solid dispersion product may be milled or ground to particles. Alternatively, the particles obtained from the methods described herein may already have the desired particle size, without the need for a subsequent milling or grinding step. For example, milling or grinding may not be required when the amorphous solid dispersion is prepared by spray-drying.

In some embodiments, the amorphous solid dispersion in particulate form may have a volume weighted particle size distribution D50, as measured by a static light scattering method, of from about 10 μm to about 60 μm, such as from about 30 μm to about 60 μm.

The particle size proves to be an important factor determining the speed, in particular the flowability, with which a particular dosage form can be manufactured on a large scale of a particular dosage form or formulation, and the quality of the final product. The smaller the particles, the faster the tableting speed can be, without detrimental effects on their quality.

Particles of the dimensions mentioned herein can be obtained by sieving them through nominal standard test sieves as described in the CRC Handbook, 64^th ed., page F-114. Nominal standard sieves are characterized by the mesh/hole width (μm) , DIN 4188 (mm) , ASTM E 11-70 (No) , (mesh) or BS 410 (mesh) values. Particle sizes may be designated by reference to the mesh/hole width in μm and to the corresponding Sieve No. in the ASTM E11-70 standard.

Pharmaceutical compositions

When the compound or amorphous solid dispersion described herein is formulated in a pharmaceutical composition, the composition also comprises a pharmaceutically acceptable carrier. The particular carrier will depend on the route of administration and may be determined by those skilled in the art. The carrier must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof. Examples of carriers include fillers, glidants, lubricants and disintegrants.

Pharmaceutical compositions designed for oral administration may be in the form of a tablet, capsule, sachet, pill, lozenge, caplet, or troche.

To prepare the pharmaceutical compositions, an effective amount of the particular compound as the active pharmaceutical ingredient (or an amorphous solid dispersion comprising the compound) is combined with a pharmaceutically acceptable carrier.

Provided herein is a pharmaceutical composition comprising the amorphous solid dispersion described herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may be a solid oral dosage form.

The solid oral dosage form may comprise a core, wherein the core comprises the pharmaceutically acceptable carrier and the amorphous solid dispersion. In some embodiments, the solid oral dosage form may further comprise a coating or casing.

In some embodiments, the solid oral dosage form is a tablet, optionally comprising a coating. Accordingly, the tablet may be an uncoated tablet, consisting or consisting essentially of the core. Alternatively, the tablet may be a coated tablet comprising the core and the coating.

The pharmaceutically acceptable carrier may comprise a filler, a disintegrant, a glidant, and a lubricant.

Fillers for use in the pharmaceutical compositions and dosage forms described herein include fillers typically used in the formulation of pharmaceuticals. Examples are lactose, sucrose, dextrose, glucose, starches, isomalt, cellulose (e.g., microcrystalline cellulose, silicified microcrystalline cellulose) , polysaccharides (including dextrates and maltodextrin) , polyols (including mannitol, xylitol, and sorbitol) , cyclodextrins, calcium carbonates, dihydrated or anhydrous dibasic calcium phosphate, magnesium carbonate, and others known in the art, and mixtures thereof (e.g., spray-dried mixture of lactose monohydrate (75%) with microcrystalline cellulose (25%) , which is commercially available as ) . Several types of microcrystalline cellulose are suitable for use in the compositions described herein, for example, microcrystalline cellulose selected from the group consisting of types: PH101, PH102, PH103, PH105, PH 112, PH113, PH200, PH301, and other types of microcrystalline cellulose, such as silicified microcrystalline cellulose. Several types of lactose are suitable for use in the compositions described herein, for example, lactose selected from the group consisting of anhydrous lactose, lactose monohydrate, lactose fast flo, directly compressible anhydrous lactose, and modified lactose monohydrate. In some embodiments, the filler comprises silicified microcrystalline cellulose (SMCC) , microcrystalline cellulose (MCC) , mannitol, lactose, dicalcium phosphate, isomalt, corn starch, pregelatinized starch, magnesium carbonate, or a combination thereof. In some embodiments, the filler is selected from the group consisting of silicified microcrystalline cellulose (SMCC) , microcrystalline cellulose (MCC) , mannitol, lactose, dicalcium phosphate, isomalt, corn starch, pregelatinized starch, magnesium carbonate, or a combination thereof. For example, the filler may be selected from the group consisting of silicified microcrystalline cellulose (SMCC) , microcrystalline cellulose (MCC) , mannitol, lactose, corn starch, pregelatinized starch, or a combination thereof. In some embodiments, the filler is silicified microcrystalline cellulose.

Examples of lubricants and glidants are hydrogenated vegetable oils, e.g., hydrogenated cottonseed oil, magnesium stearate, stearic acid, sodium lauryl sulfate, magnesium lauryl sulfate, colloidal silica, colloidal anhydrous silica, talc, combinations thereof, and others known in the art.

In some embodiments, the lubricant comprises magnesium stearate, sodium stearyl fumarate (SSF) , stearic acid, a glyceryl derivative (such as glyceryl monostearate) , sodium lauryl sulfate, talc, or a combination thereof. In some embodiments, the lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate (SSF) , stearic acid, a glyceryl derivative (such as glyceryl monostearate) , sodium lauryl sulfate, talc, or a combination thereof, such as magnesium stearate or sodium stearyl fumarate (SSF) . In some embodiments, the lubricant is magnesium stearate.

In some embodiments, the glidant comprises colloidal silica (such as colloidal hydrophobic silica or colloidal anhydrous silica) , talc, or a combination thereof. In some embodiments, the glidant is selected from the group consisting of colloidal silica, talc, or a combination thereof. In some embodiments, the glidant is colloidal anhydrous silica.

Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches, and crosslinked starches, celluloses and polymers, combinations thereof and the like. Representative disintegrants include microcrystalline cellulose, croscarmellose sodium, alginic acid, sodium alginate, crosprovidone, cellulose, agar and related gums, sodium starch glycolate, corn starch, potato starch, Veegum HV, methylcellulose, L-HPC (low substituted hydroxypropylcellulose) , agar, bentonite, sodium carboxymethylcellulose, calcium carboxymethylcellulose, carboxymethylcellulose, alginic acid, guar gum, maize starch, pregelatinized starch, combinations thereof, and the like.

In some embodiments, the pharmaceutically acceptable carrier may further comprise a disintegrant aid. Examples of pharmaceutically acceptable disintegrant aids include any salt having a solubility that is sufficiently high to serve the purpose of aiding disintegration. The disintegrant aid may be selected from sodium chloride, sodium sulfate (e.g., anhydrous sodium sulfate) , sodium phosphate (e.g., tri-sodium phosphate dodecahydrate) , sodium bicarbonate, sodium bromide, sodium iodide, or a combination thereof. In some embodiments, the disintegrant aid is sodium chloride.

Additional suitable pharmaceutically acceptable carriers and their properties may be found in texts such as Handbook of Pharmaceutical Excipients, Edited by R.C. Rowe, P.J. Sheskey &M.E. Quinn, Sixth Edition (Published by Pharmaceutical Press, a Division of Royal Pharmaceutical Society of Great Britain) . One skilled in the art will recognize that the appropriate pharmaceutically acceptable carriers should be selected such that they are compatible with other carriers and do not bind with the active pharmaceutical ingredient or cause degradation.

In some embodiments of the pharmaceutical compositions and solid oral dosage forms (e.g., tablets) described herein, the pharmaceutically acceptable carrier comprises a filler, a disintegrant, a glidant, and a lubricant, wherein the filler is silicified microcrystalline cellulose (SMCC) , the disintegrant is croscarmellose sodium, the glidant is anhydrous colloidal silica, and the lubricant is magnesium stearate. In some embodiments of such pharmaceutical compositions and solid oral dosage forms (e.g., tablets) , the amorphous solid dispersion comprises Compound 3 and an orally pharmaceutically acceptable polymer, wherein the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is 1: 3 and the orally pharmaceutically acceptable polymer is HPMCAS, in particular wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl.

The solid oral dosage form described herein may comprise from about 5 mg to about 150 mg of Compound 3 or a pharmaceutically acceptable salt form thereof, calculated based on the free base form. For example, the solid oral dosage form may comprise from about 10 mg to about 100 mg, such as 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, or 100 mg of Compound 3 or a pharmaceutically acceptable salt form thereof, calculated based on the free base form.

The solid oral dosage form described herein may be a tablet, wherein the tablet comprises from about 5 mg to about 150 mg of Compound 3 or a pharmaceutically acceptable salt form thereof, calculated based on the free base form. For example, the tablet may comprise from about 10 mg to about 100 mg, such as 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, or 100 mg of Compound 3 or a pharmaceutically acceptable salt form thereof, calculated based on the free base form. For example, the tablet may comprise from about 10 mg to about 100 mg, such as 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, or 100 mg of Compound 3.

The amorphous solid dispersion may be present in the solid oral dosage form (e.g., tablet) in an amount of from about 30%to about 80% (w/w) relative to the total weight of the core. For example, the amorphous solid dispersion may be present in the solid oral dosage form in an amount of from about 40%to about 60% (w/w) or from about 45%to about 55% (w/w) relative to the total weight of the core. In some embodiments, the amorphous solid dispersion may be present in the solid oral dosage form in an amount of about 50% (w/w) relative to the total weight of the core.

The filler may be present in the solid oral dosage form (e.g., tablet) in an amount of from about 10%to about 70% (w/w) relative to the total weight of the core. For example, the filler is present in the solid oral dosage form in an amount of from about 30%to about 60% (w/w) , from about 35%to about 55% (w/w) , or from about 35%to about 45% (w/w) relative to the total weight of the core. In some embodiments, the filler is present in the solid oral dosage form in an amount of about 40.5% (w/w) relative to the total weight of the core.

The disintegrant may be present in the solid oral dosage form (e.g., tablet) in an amount of from about 4%to about 10% (w/w) relative to the total weight of the core. For example, the disintegrant may be present in the solid oral dosage form in an amount of from about 5%to about 8% (w/w) relative to the total weight of the core. In some embodiments, the disintegrant may be present in the solid oral dosage form in an amount of about 6% (w/w) relative to the total weight of the core.

The glidant may be present in the solid oral dosage form (e.g., tablet) in an amount of from about 0.2%to about 7% (w/w) relative to the total weight of the core. For example, the glidant may be present in the solid oral dosage form in an amount of from about 1%to about 4% (w/w) relative to the total weight of the core. In some embodiments, the glidant may be present in the solid oral dosage form in an amount of about 2% (w/w) relative to the total weight of the core.

The lubricant may be present in the solid oral dosage form (e.g., tablet) in an amount of from about 0.2%to about 7% (w/w) relative to the total weight of the core. For example, the lubricant may be present in the solid oral dosage form in an amount of from about 0.2%to about 3%(w/w) relative to the total weight of the core. In some embodiments, the lubricant may be present in the solid oral dosage form in an amount of about 1.5% (w/w) relative to the total weight of the core.

The solid oral dosage form (e.g., tablet) may comprise a total of about 45%to about 55% (w/w) of the amorphous solid dispersion, a total of about 35%to about 45% (w/w) of the filler, a total of about 5%to about 8% (w/w) of the disintegrant, a total of about 1%to about 4% (w/w) of the glidant, and a total of about 0.2%to about 3% (w/w) of the lubricant, relative to the total weight of the core. In some embodiments, the solid oral dosage form may comprise a total of about 50% (w/w) of the amorphous solid dispersion, a total of about 40.5% (w/w) of the filler, a total of about 6% (w/w) of the disintegrant, a total of about 2% (w/w) of the glidant, and a total of about 1.5% (w/w) of the lubricant, relative to the total weight of the core.

In some embodiments, the pharmaceutical composition is a solid oral dosage form, wherein the solid oral dosage form is a tablet consisting of a core, wherein the core comprises the pharmaceutically acceptable carrier and the amorphous solid dispersion, wherein the pharmaceutically acceptable carrier comprises a filler, a disintegrant, a glidant, and a lubricant, wherein the amorphous solid dispersion comprises Compound 3 and HPMCAS, wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl, wherein the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is 1: 3, wherein the tablet comprises a total of about 45%to about 55% (w/w) of the amorphous solid dispersion, a total of about 35%to about 45% (w/w) of the filler, a total of about 5%to about 8% (w/w) of the disintegrant, a total of about 1%to about 4% (w/w) of the glidant, and a total of about 0.2%to about 3% (w/w) of the lubricant, relative to the total weight of the core, and wherein the filler is silicified microcrystalline cellulose, the disintegrant is croscarmellose sodium, the glidant is anhydrous colloidal silica, and the lubricant is magnesium stearate.In some embodiments, the pharmaceutical composition is a solid oral dosage form, wherein the solid oral dosage form is a tablet consisting of a core, wherein the core comprises the pharmaceutically acceptable carrier and the amorphous solid dispersion, wherein the pharmaceutically acceptable carrier comprises a filler, a disintegrant, a glidant, and a lubricant, wherein the amorphous solid dispersion comprises Compound 3 and HPMCAS, wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl, wherein the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is 1: 3, wherein the tablet comprises a total of about 50% (w/w) of the amorphous solid dispersion, a total of about 40.5% (w/w) of the filler, a total of about 6% (w/w) of the disintegrant, a total of about 2% (w/w) of the glidant, and a total of about 1.5% (w/w) of the lubricant, relative to the total weight of the core, wherein the filler is silicified microcrystalline cellulose, the disintegrant is croscarmellose sodium, the glidant is anhydrous colloidal silica, and the lubricant is magnesium stearate.

A tablet dosage form may be prepared by a process comprising compressing a blend of an amorphous solid dispersion and a pharmaceutically acceptable carrier. The dosage form, amorphous solid dispersion and pharmaceutically acceptable carrier may be as described herein.

The process may further comprise preparing the amorphous solid dispersion as described herein, prior to the compression.

The process may further comprise blending the amorphous solid dispersion with the pharmaceutically acceptable carrier. In embodiments where the pharmaceutically acceptable carrier comprises a filler, a disintegrant, a glidant, and a lubricant, the blending may comprise blending the amorphous solid dispersion, filler, disintegrant, glidant, and lubricant. Alternatively, in embodiments where the pharmaceutically acceptable carrier comprises a filler, a disintegrant, a glidant, and a lubricant, the process may comprise: blending the amorphous solid dispersion, glidant, a portion of the lubricant, a portion of the filler, and a portion of the disintegrant to provide a first mixture; dry granulating the first mixture; adding the remainder of the filler and the remainder of the disintegrant to provide a second mixture; adding the remainder of the lubricant to provide a third mixture; and compressing the third mixture into a tablet.

The compression may be direct compression. The dry granulation may comprise roller compaction.

The blending steps may be carried out using a suitable blender, e.g., a diffusion mixer (tumbler) , such as a bin blender, V-blender, double cone blender, slant cone blender, cube blender, horizontal/vertical/drum blender, static continuous blender, or dynamic continuous blender. In some embodiments, the blender is a bin blender.

In another embodiment, the invention comprises a tablet comprising an amorphous solid dispersion of Compound 3 and HPMCAS, wherein the mass of Compound 3 as the free base is 35 mg and the mass of HPMCAS is 105 mg.

In another embodiment, the invention comprises a tablet comprising an amorphous solid dispersion of Compound 3 and HPMCAS, wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl, wherein the mass of Compound 3 as the free base is 35 mg and the mass of HPMCAS is 105 mg.

In another embodiment, the invention comprises a tablet comprising an amorphous solid dispersion of Compound 3 and HPMCAS, wherein the mass of Compound 3 as the free base is 40 mg and the mass of HPMCAS is 120 mg.

In another embodiment, the invention comprises a tablet comprising an amorphous solid dispersion of Compound 3 and HPMCAS, wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl, wherein the mass of Compound 3 as the free base is 40 mg and the mass of HPMCAS is 120 mg.

In another embodiment, the invention comprises a tablet comprising an amorphous solid dispersion of Compound 3 and HPMCAS, wherein the mass of Compound 3 as the free base is 50 mg and the mass of HPMCAS is 150 mg.

In another embodiment, the invention comprises a tablet comprising an amorphous solid dispersion of Compound 3 and HPMCAS, wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl, wherein the mass of Compound 3 as the free base is 50 mg and the mass of HPMCAS is 150 mg.

In some embodiments, the process may further comprise applying a coating to the tablet.

Methods of treatment and medical uses

The pharmaceutical formulations and dosage forms of the present invention are useful in methods of treatment.

For example, the pharmaceutical formulations and dosage forms described herein are useful in methods for treating, ameliorating and/or preventing a disease, a syndrome, a condition that is affected by the inhibition of MALT1. The pharmaceutical formulations and dosage forms described herein are useful in treating diseases, syndromes, conditions, or disorders that are ameliorated by the inhibition of MALT1.

One embodiment of the present invention is directed to a method of treating a MALT1-dependent or MALT1-mediated disease or condition in a subject in need thereof, including an animal, a mammal, and a human in need of such treatment, comprising administering to the subject a therapeutically effective amount of a pharmaceutical formulation or dosage form described herein.

The MALT1-dependent or MALT1-mediated disease or condition may be selected from cancers of hematopoietic origin or solid tumors such as chronic myelogenous leukemia, myeloid leukemia, non-Hodgkin lymphoma (NHL) , NF-_KB-driven B cell malignancies, and other B cell lymphomas.

Cancers that may benefit from a treatment with pharmaceutical formulations and dosage forms described herein include, but are not limited to, lymphomas, leukemias, carcinomas, and sarcomas, e.g., non-Hodgkin’s lymphoma (NHL (including B-cell NHL) ) , diffuse large B-cell lymphoma (DLBCL) , mantle cell lymphoma (MCL) , follicular lymphoma (FL) , mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma (MZL) , T-cell lymphoma, Hodgkin’s lymphoma, Burkitt’s lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL) , small lymphocytic lymphoma (SLL) , macroglobulinemia, lymphoblastic T cell leukemia, chronic myelogenous leukemia (CML) , hairy-cell leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocyte leukemia, promyelocytic leukemia, erythroleukemia, brain (gliomas) , glioblastomas, breast cancer, colorectal/colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head &neck cancer, testicular cancer, Ewing’s sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, esophageal cancer, salivary gland cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, and GIST (gastrointestinal stromal tumor) .

In an alternate embodiment, the disorder or condition is selected from non-Hodgkin’s lymphoma (NHL) , diffuse large B-cell lymphoma (DLBCL) , marginal zone lymphoma, mantle cell lymphoma (MCL) , follicular lymphoma (FL) , transformed follicular lymphoma, chronic lymphocytic leukemia, and macroglobulinemia.

In yet another embodiment of the invention, the disorder or condition is lymphoma. In another embodiment of the invention, the disorder or condition is the activated B cell like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) . In another embodiment of the invention, the disorder or condition is germinal center B cell like (GCB) subtype of diffuse large B-cell lymphoma (DLBCL) . In another embodiment of the invention, the disorder or condition is non-germinal center B cell like (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL) .

In an additional embodiment of the invention, the disorder or condition is chronic lymphocytic leukemia (CLL) . In another embodiment, the disorder or condition small lymphocytic lymphoma (SLL) .

In another embodiment of the invention, the lymphoma is MALT lymphoma.

In another embodiment of the invention, the disorder or condition is macroglobulinemia (WM) .

In yet another embodiment, the disorder or condition is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL) , mantle cell lymphoma (MCL) , follicular lymphoma (FL) , and mucosa-associated lymphoid tissue (MALT) lymphoma.

In an alternate embodiment, the disorder or condition is non-Hodgkin’s lymphoma (NHL) . In a further embodiment, the non-Hodgkin’s lymphoma (NHL) is B-cell NHL. In another embodiment, the non-Hodgkin’s lymphoma (NHL) is relapsed/refractory B-cell NHL.

In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is selected from the group consisting of relapsed/refractory non-germinal center B cell like (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL) , relapsed/refractory macroglobulinemia (WM) , relapsed/refractory mantle cell lymphoma (MCL) , relapsed/refractory follicular lymphoma (FL) , and relapsed/refractory mucosa-associated lymphoid tissue (MALT) lymphoma.

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

In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is relapsed/refractory macroglobulinemia (WM) .

In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is relapsed/refractory mantle cell lymphoma (MCL) .

In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is relapsed/refractory follicular lymphoma (FL) .

In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is relapsed/refractory mucosa-associated lymphoid tissue (MALT) lymphoma.

In yet another embodiment, the disorder or condition is primary and secondary central nervous system lymphoma, transformed follicular lymphoma, or API2-MALT1 fusion dependent disease.

In another embodiment of the invention, the disorder or condition (cancer or immunological disease (such as any of the cancers listed above) ) is relapsed or refractory to prior treatment.

In another embodiment of the invention, the disorder or condition is cancer (such as any of the cancers mentioned above) and the subject has received prior treatment with a Bruton tyrosine kinase inhibitor (BTKi) .

In an alternate embodiment of the invention, the disorder or condition is cancer (such as any of the cancers mentioned above) and the subject is relapsed or refractory to prior treatment with a Bruton tyrosine kinase inhibitor (BTKi) .

In some embodiments, the subject may have received at least two prior lines of therapy, including a BTK inhibitor. In some embodiments, the subject may have received Ibrutinib prior to administration of Compound 3. In some embodiments, the subject may have received first line chemotherapy and at least one subsequent line of systemic therapy, including autologous stem cell transplantation (autoSCT) , prior to administration of Compound 3. In some embodiments, the subject may have received at least two prior lines of systemic therapy, including a standard anti CD20 antibody, prior to administration of Compound 3. In some embodiments, the subject may have received at least two prior lines of systemic therapy, prior to administration of Compound 3.

In an embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is diffuse large B-cell lymphoma (DLBCL) . In some embodiments, the DLBCL is relapsed or refractory DLBCL.

In an embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is mantle cell lymphoma (MCL) . In some embodiments, the MCL is relapsed or refractory MCL.

In an embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is follicular lymphoma (FL) . In some embodiments, the FL is relapsed or refractory FL.

In an embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is transformed follicular lymphoma (tFL) . In some embodiments, the tFL is relapsed or refractory tFL.

In an embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is marginal zone lymphoma (MZL) . In some embodiments, the MZL is relapsed or refractory MZL.

In an embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is chronic lymphocytic leukemia (CLL) . In some embodiments, the CLL is relapsed or refractory CLL.

In an embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is small lymphocytic lymphoma (SLL) . In some embodiments, the SLL is relapsed or refractory SLL.

In an embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 ismacroglobulinemia (WM) . In some embodiments, the WM is relapsed or refractory WM.

In an embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is MALT lymphoma. In some embodiments, the MALT lymphoma is relapsed or refractory MALT lymphoma.

In an embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is relapsed/refractory GCB-DLBCL. In an embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is relapsed/refractory non-GCB-DLBCL. In an embodiment, the disorder or condition is relapsed/refractory ABC-DLBCL.

In some embodiments, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is non-GCB DLBCL and the subject has received or is not eligible for high dose chemotherapy or autologous stem cell transplantation with curative intent and does not have access to other standard of care therapies, such as CAR-T. Participants who have DLBCL that has transformed from a lower grade lymphoproliferative disorder will not be eligible for the study.

In some embodiments, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is follicular lymphoma (FL) or Macroglobulinemia and the subject is previously treated with at least 2 prior lines of systemic therapy using different treatment regimens with at least one line being an anti-CD20 antibody-containing combination regimen.

In some embodiments, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is mantle cell lymphoma and the subject is previously treated with at least one prior line of systemic therapy including an anti-CD20 antibody combination regimen.

In some embodiments, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is MALT lymphoma and the subject is previously treated with at least one line of therapy appropriate for the individual’s disease.

In particular, pharmaceutical formulations and dosage forms of the invention are useful for treating or ameliorating diseases, syndromes, conditions, or disorders such as diffuse large B-cell lymphoma (DLBCL) , mantle cell lymphoma (MCL) , follicular lymphoma (FL) , mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia (CLL) including 17p-depleted CLL, small lymphocytic lymphoma (SLL) , and macroglobulinemia (WM) . In particular, pharmaceutical formulations and dosage forms of the invention are useful for treating or ameliorating DLBCL tumors with CD79a/b or CARD11 mutations, including tumors with acquired resistance to ibrutinib (BTK, PLCG2 or CARD11 mutations) , ibrutinib resistant CLL/MCL/WM tumors and MALT lymphoma (MALT translocation) . Pharmaceutical formulations and dosage forms of the invention are also useful for treating or ameliorating diffuse large B-cell lymphoma, activated B cell-like subtype (ABC-DLBCL) .

Pharmaceutical formulations and dosage forms of the invention may be used for the treatment of a subject that is relapsed or refractory to a prior treatment. This prior treatment may be a treatment with a Bruton tyrosine kinase inhibitor (BTKi) like ibrutinib. Particular cohorts of patients suitable for treatment with the pharmaceutical formulations and dosage forms of the invention include: i) relapsed and refractory patients with CLL, MCL, or WM following ibrutinib progression; ii) relapsed and refractory DLBCL patients; iii) relapsed and refractory patients with indolent NHL such as FL or MZL.

Pharmaceutical formulations and dosage forms of the invention may be used for the treatment of immunological diseases including, but not limited to, autoimmune and inflammatory disorders, e.g., arthritis, rheumatoid arthritis (RA) , psoriatic arthritis (PsA) , inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn’s disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplant rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet’s diseases, uveitis, myasthenia gravis, Grave’s disease, Hashimoto thyroiditis, Sjoergen’s syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) , cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, and polymyositis.

In another embodiment, the invention comprises a method of treating diffuse large B-cell lymphoma in a patient in need thereof, comprising the steps of:

a) Selecting two lesions from the patient with the largest measurable diameters;

b) administering to the patient a therapeutically effective amount of Compound 3, resulting in at least a 30%decrease in the sum of the largest diameters of the two lesions selected in step a) .

b) administering to the patient a therapeutically effective amount of an amorphous solid dispersion comprising Compound 3 and HPMCAS, resulting in at least a 30%decrease in the sum of the largest diameters of the two lesions selected in step a) .

b) administering to the patient a therapeutically effective amount of Compound 3, wherein the therapeutically effective amount is 35 mg Compound 3, calculated as the free base, administered BID, resulting in at least a 30%decrease in the sum of the largest diameters of the two lesions selected in step a) .

b) administering to the patient a therapeutically effective amount of Compound 3, wherein the therapeutically effective amount is 35 mg Compound 3, calculated as the free base, administered QD, resulting in at least a 30%decrease in the sum of the largest diameters of the two lesions selected in step a) .

b) administering to the patient a therapeutically effective amount of Compound 3, wherein the therapeutically effective amount is 40 mg Compound 3, calculated as the free base, administered BID, resulting in at least a 30%decrease in the sum of the largest diameters of the two lesions selected in step a) .

b) administering to the patient a therapeutically effective amount of Compound 3, wherein the therapeutically effective amount is 40 mg Compound 3, calculated as the free base, administered QD, resulting in at least a 30%decrease in the sum of the largest diameters of the two lesions selected in step a) .

b) administering to the patient a therapeutically effective amount of Compound 3, wherein the therapeutically effective amount is at least 35 mg Compound 3, calculated as the free base, administered BID, resulting in at least a 30%decrease in the sum of the largest diameters of the two lesions selected in step a) .

b) administering to the patient a therapeutically effective amount of Compound 3, wherein the therapeutically effective amount is at least 35 mg Compound 3, calculated as the free base, administered QD, resulting in at least a 30%decrease in the sum of the largest diameters of the two lesions selected in step a) .

In another embodiment, the invention comprises a method of treating macroglobulinemia in a patient in need thereof, comprising the steps of:

b) administering to the patient a therapeutically effective amount of Compound 3, wherein the therapeutically effective amount is at least 40 mg Compound 3, calculated as the free base, administered BID, resulting in at least a 30%decrease in the sum of the largest diameters of the two lesions selected in step a) .

b) administering to the patient a therapeutically effective amount of Compound 3, wherein the therapeutically effective amount is at least 40 mg Compound 3, calculated as the free base, administered QD, resulting in at least a 30%decrease in the sum of the largest diameters of the two lesions selected in step a) .

Efficacy

The efficacy of the methods and uses described herein may be measured e.g., by determining the overall response rate (ORR) , CR rate, duration of response (DOR) , duration of CR, and time to response (TTR) .

Overall response rate (ORR) is defined as the percentage of participants who have a best response of partial response (PR) or better per investigator assessment according to disease-specific response criteria.

CR rate is defined as the percentage of participants achieving a CR at any time post-treatment. DOR is defined for participants who achieved a response of PR or better as the time between the date of initial documentation of first response of PR or better to the date of first documented evidence of progressive disease or death. For the purposes of the statistical analysis of this endpoint, participants who did not achieve a response of PR or better are considered as not having responded (ie, DOR is not defined for participants who did not achieve a response of PR or better) . For the purposes of the statistical analysis of this endpoint as a time-to-event endpoint, participants who achieved a response of PR or better but for which there is no documented evidence of progressive disease or death will be considered censored at the date of the latest disease evaluation.

TTR is defined for participants who achieved a response of PR or better as the time from the first dose of study treatment to the first response of PR or better; for the purposes of the statistical analysis of this endpoint, participants who did not achieve a response of PR or better are considered as not having responded (ie, TTR is not defined for participants who did not achieve a response of PR or better) .

In some embodiments, the dosage regimen is a dosage regimen that provides an overall response rate of at least 20%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%or at least 95%in a population of subjects receiving treatment according to the dosage regimen. The overall response rate may be 30%to 100%, 30%to 75%, 35 to 100%, 35 to 75%, 40 to 100%, 40 to 75%, 45 to 100%or 45 to 75%, 50 to 100%, 50 to 75%, 55 to 100%, 55 to 75%, 60 to 100%, 60 to 75%, 70 to 80%, 60 to 95%, 70 to 95%, 80 to 95%, 60 to 100%, 70 to 100%or 80 to 100%. The overall response rate may be 74%. The overall response rate may be 70 to 80%. The overall response rate may be at least 30%. The overall response rate may be at least 35%. The overall response rate may be at least 40%. The overall response rate may be at least 45%. The overall response rate may be at least 47%. The overall response rate may be at least 50%. The overall response rate may be at least 55%. The overall response rate may be at least 70%. The overall response rate may be at least 65%. The overall response rate may be at least 72%. The overall response rate may be at least 74%.

In some embodiments, the dosage regimen is a dosage regimen that provides an improved overall response rate compared to standard of care (SOC) .

One embodiment of the present invention is directed to a method for prolonging survival of a patient with a MALT1-dependent or MALT1-mediated disease or condition, comprising administering to the patient a therapeutically effective amount of Compound 3, wherein administration of the therapeutically effective amount of Compound 3 prolongs survival of the patient compared to an untreated control subject.

One embodiment of the present invention is directed to a method for prolonging survival of a patient with a MALT1-dependent or MALT1-mediated disease or condition, comprising administering to the patient a therapeutically effective amount of Compound 3, wherein administration of the therapeutically effective amount of Compound 3 prolongs survival of the patient compared to a control subject treated with SOC.

One embodiment of the present invention is directed to a method for prolonging median survival in a population of subjects receiving treatment according to the dosage regimen described herein, when compared to a population of untreated subjects.

One embodiment of the present invention is directed to a method for prolonging median survival in a population of subjects receiving treatment according to the dosage regimen described herein, when compared to a population of subjects treated with SOC.

In some embodiments, the dosage regimen is a dosage regimen that provides a prolonged survival of a patient with a MALT1-dependent or MALT1-mediated disease or condition, when compared with an untreated patient.

In some embodiments, the dosage regimen is a dosage regimen that provides a prolonged survival of a patient with a MALT1-dependent or MALT1-mediated disease or condition, when compared with a patient treated with SOC.

In some embodiments, the dosage regimen is a dosage regimen that provides a CR rate of at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%or at least 85%in a population of subjects receiving treatment according to the dosage regimen. The CR rate may be 15%to 100%, 20%to 100%, 25%to 100%, 15%to 75%, 20 to 75%, 25 to 75%, 20 to 40%. The CR rate may be at least 40%. The CR rate may be at least 45%. The CR rate may be at least 46%. The CR rate may be 40%to 50%. The CR rate may be 40%to 60%. The CR rate may be 40%to 100%. The CR rate may be 40%to 75%. The CR rate may be 45%to 50%. The CR rate may be 45%to 100%. The CR rate may be 45%to 75%.

In some embodiments, the dosage regimen is a dosage regimen that provides an improved CR rate compared to standard of care (SOC) .

In some embodiments, the median duration of response in a population of subjects receiving treatment according to the dosage regimen is at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 52 weeks, at least 56 weeks, at least 60 weeks, at least 65 weeks, at least 70 weeks, at least 75 weeks, at least 80 weeks or at least 85 weeks. The median duration of response may be 65 weeks to 75 weeks. The median duration of response may be 65 weeks to 80 weeks. The median duration of response may be 65 weeks to 100 weeks. The median duration of response may be 70 weeks to 75 weeks. The median duration of response may be 70 weeks to 80 weeks. The median duration of response may be 70 weeks to 100 weeks. In some embodiments, the median duration of response in a population of subjects receiving treatment according to the dosage regimen is at least 100 weeks. In some embodiments, the median duration of response in a population of subjects receiving treatment according to the dosage regimen is at least 72 weeks. In some embodiments, the median duration of response in a population of subjects receiving treatment according to the dosage regimen is at least 70 weeks. In some embodiments, the median duration of response in a population of subjects receiving treatment according to the dosage regimen is at least 65 weeks.

In some embodiments, the dosage regimen is a dosage regimen that provides an improved median duration of response in a population of subjects receiving treatment according to the dosage regimen compared to standard of care (SOC) .

In some embodiments, the duration of response in a population of subjects receiving treatment according to the dosage regimen is at least 52 weeks in >50%of the responders. In some embodiments, the duration of response in a population of subjects receiving treatment according to the dosage regimen is at least 48 weeks in >50%of the responders. In some embodiments, the duration of response in a population of subjects receiving treatment according to the dosage regimen is at least 50 weeks in >50%of the responders. In some embodiments, the duration of response in a population of subjects receiving treatment according to the dosage regimen is at least 70 weeks in >50%of the responders. In some embodiments, the duration of response in a population of subjects receiving treatment according to the dosage regimen is at least 72 weeks in >50%of the responders.

In some embodiments, the dosage regimen is a dosage regimen that provides an improved duration of response in a population of subjects receiving treatment according to the dosage regimen compared to standard of care (SOC) .

In some embodiments, the median duration of CR in a population of subjects receiving treatment according to the dosage regimen is at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 52 weeks, at least 56 weeks, at least 60 weeks, at least 64 weeks, at least 68 weeks, at least 72 weeks, at least 76 weeks, or at least 80 weeks.

In some embodiments, the dosage regimen is a dosage regimen that provides an improved median duration of CR in a population of subjects receiving treatment according to the dosage regimen compared to standard of care (SOC) .

In some embodiments, the median time to response in a population of subjects receiving treatment according to the dosage regimen is between 0.5 –3 months. In some embodiments, the median time to response is <3 months. In some embodiments, the median time to response is <2 months. In some embodiments, the median time to response is <1 month.

In some embodiments, the dosage regimen is a dosage regimen that provides an improved median time to response in a population of subjects receiving treatment according to the dosage regimen compared to standard of care (SOC) .

In some embodiments, the median overall survival in a population of subjects receiving treatment according to the dosage regimen is at least 24 weeks, at least 40 weeks, at least 50 weeks, at least 60 weeks, at least 70 weeks, at least 77 weeks, at least 80 weeks, at least 85 weeks, at least 90 weeks, or at least 95 weeks. The median overall survival may be 50 weeks to 144 weeks, 70 weeks to 144 weeks, 77 weeks to 144 weeks, 80 weeks to 144 weeks, 85 weeks to 144 weeks, 90 weeks to 144 weeks, or 92 weeks to 144 weeks. In some embodiments, the median overall survival in a population of subjects receiving treatment according to the dosage regimen is at least 77 weeks. In some embodiments, the median overall survival in a population of subjects receiving treatment according to the dosage regimen is at least 80 weeks. In some embodiments, the median overall survival in a population of subjects receiving treatment according to the dosage regimen is at least 85 weeks. In some embodiments, the median overall survival in a population of subjects receiving treatment according to the dosage regimen is at least 90 weeks. In some embodiments, the median overall survival in a population of subjects receiving treatment according to the dosage regimen is at least 92 weeks. In some embodiments, the median overall survival in a population of subjects receiving treatment according to the dosage regimen is at least 95 weeks. The median overall survival may be 12 weeks to 120 weeks, 50 weeks to 120 weeks, 77 to 120 weeks, 80 to 120 weeks, 85 to 120 weeks, or 90 to 120 weeks.

In some embodiments, the dosage regimen is a dosage regimen that provides an improved median overall survival in a population of subjects receiving treatment according to the dosage regimen compared to standard of care (SOC) .

In some embodiments, the median progression-free survival in a population of subjects receiving treatment according to the dosage regimen is at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, or at least 24 weeks. The median progression-free survival may be 8 weeks to 144 weeks, 12 weeks to 144 weeks, 12 weeks to 96 weeks, 12 weeks to 48 weeks, 16 to 144 weeks, 16 to 96 weeks, 16 to 48 weeks, 18 to 144 weeks, 18 to 96 weeks or 18 to 48 weeks. In some embodiments, the median progression-free survival in a population of subjects receiving treatment according to the dosage regimen is at least 20 weeks. In some embodiments, the median progression-free survival in a population of subjects receiving treatment according to the dosage regimen is 20 weeks.

In some embodiments, the dosage regimen is a dosage regimen that provides an improved median progression-free survival in a population of subjects receiving treatment according to the dosage regimen compared to standard of care (SOC) .

Response assessment for Non-Hodgkin Lymphoma (Lugano Classification) and Macroglobulinemia is set out in Tables A and B, respectively. The criteria for response assessment in Table A are based on Lugano Classification (Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014; 32 (27) : 3059-3068. ) . The criteria for response assessment in Table B are updated from the VIth International Workshop (Owen RG, Kyle RA, Stone MJ, et al. Response assessment inmacroglobulinaemia: update from the VIth International Workshop. Br J Haematol. 2013; 160 (2) : 171-176. ) Overall Response Rate, Time to Response, and Duration of Response per investigator assessment according to disease-specific response criteria of Tables A and B.

Table A: Response Criteria for Non-Hodgkin Lymphoma (Phase 1)

a. A score of 3 in many participants indicates a good prognosis with standard treatment, especially if at the time of an interim scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment) . Measured dominant lesions: Up to 6 of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in 2 diameters. Nodes should preferably be from disparate regions of the body and should include, where applicable, mediastinal, and retroperitoneal areas. Non-nodal lesions include those in solid organs (eg, liver, spleen, kidneys, lungs) , GI involvement, cutaneous lesions, or those noted on palpation. Non-measured lesions: Any disease not selected as measured, dominant disease and truly assessable disease should be considered not measured. These sites include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not meet the requirements for measurability but are still considered abnormal, as well as truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal

disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In Waldeyer's ring or in extranodal sites (eg, GI tract, liver, bone marrow) , FDG uptake may be greater than in the mediastinum with complete metabolic response but should be no higher than surrounding normal physiologic uptake (eg, with marrow activation as a result of chemotherapy or myeloid growth factors) .

b. PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤liver; 4, uptake moderately > liver; 5, uptake markedly higher than liver or new lesions; X, new areas of uptake unlikely to be related to lymphoma.

Table B: Response Criteria forMacroglobulinemia (Phase 1)

a. Sequential changes in IgM levels may be determined either by M protein quantitation by densitometry or total serum IgM quantitation by nephelometry.

Crystalline forms of Compound 3

The present invention is directed to a crystalline form of

or a solvate thereof.

The present invention is directed to the anhydrous crystalline Form I of

The present invention is directed to the crystalline Form II of

as a solvate, in particular an acetonitrile solvate (crystalline Form IIa) or a methanol solvate (crystalline Form IIb) .

Crystalline Form I has good flow properties and improved solubility.

Crystalline Form II has a favourable morphology and crystal habit.

The crystalline Form I may be provided in a substantially pure form, wherein the mole percent of impurities in the crystalline form is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably, less than about 0.1 mole percent. In an embodiment of the present invention, the crystalline Form I is present as a substantially pure form.

The crystalline Form IIa may be provided in a substantially pure form, wherein the mole percent of impurities in the crystalline form is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably, less than about 0.1 mole percent. In an embodiment of the present invention, the crystalline Form IIa is present as a substantially pure form.

The crystalline Form IIb may be provided in a substantially pure form, wherein the mole percent of impurities in the crystalline form is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably, less than about 0.1 mole percent. In an embodiment of the present invention, the crystalline Form IIb is present as a substantially pure form.

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

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

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

In an embodiment, the present invention is directed to a crystalline Form of

for use as a medicament.

In an embodiment, the present invention is directed to crystalline Form I, II, IIa or IIb of

for use as a medicament.

A pharmaceutical composition comprising a crystalline form as described herein, in particular any of forms I, IIa and IIb, and at least one additional ingredient selected from pharmaceutically acceptable carriers, diluents and excipients.

A pharmaceutical composition prepared starting from a crystalline form as described herein, in particular any of forms I, IIa and IIb, and at least one additional ingredient selected from pharmaceutically acceptable carriers, diluents and excipients.

A process comprising preparing any of the crystalline forms described herein, in particular any of forms I, IIa and IIb.

The use of a crystalline form as described herein, in particular any of forms I, IIa and IIb, in the manufacture of a medicament for the treatment or prevention of a disease, syndrome, condition, or disorder affected by inhibition of MALT1.

The process comprising formulating a crystalline form as described herein, in particular any of forms I, IIa and IIb, wherein the crystalline form is formulated into an oral dosage form. A tablet, pill or capsule obtainable by said process.

Dosage regimens and use in treatment

Provided herein is a compound for use in the treatment of a disease, syndrome, condition, or disorder in a subject in need thereof,

or a pharmaceutically acceptable salt form thereof or a solvate thereof.

Provided herein is a compound for use in the treatment of a disease, syndrome, condition, or disorder in a subject in need thereof, wherein said disease, syndrome, condition, or disorder is affected by the inhibition of MALT1,

or a pharmaceutically acceptable salt form thereof or a solvate thereof.

Provided herein is a compound for use in the treatment of a disease, syndrome, condition, or disorder in a subject in need thereof, wherein said disease, syndrome, condition, or disorder is ameliorated by the inhibition of MALT1,

or a pharmaceutically acceptable salt form thereof or a solvate thereof.

Also provided herein is a method of treating a disease, syndrome, condition, or disorder, wherein said disease, syndrome, condition, or disorder is affected by the inhibition of MALT1, comprising administering to a subject in need thereof a therapeutically effective amount of (1S, 3R) -3- (4- ( (R) -2-chloro-8-methyl-8- (trifluoromethyl) -7, 8-dihydro-6H-pyrazolo [1, 5-a] pyrrolo [2, 3-e] pyrimidin-6-yl) phenyl) -2, 2-difluoro-1-methyl-N- ( (trans) -3- (methylsulfonyl) cyclobutyl) cyclopropane-1-carboxamide (Compound 3) :

or a pharmaceutically acceptable salt form thereof or a solvate thereof.

Also provided herein is a method of treating a disease, syndrome, condition, or disorder, wherein said disease, syndrome, condition, or disorder is ameliorated by the inhibition of MALT1, comprising administering to a subject in need thereof a therapeutically effective amount of (1S, 3R) -3- (4- ( (R) -2-chloro-8-methyl-8- (trifluoromethyl) -7, 8-dihydro-6H-pyrazolo [1, 5-a] pyrrolo [2, 3-e] pyrimidin-6-yl) phenyl) -2, 2-difluoro-1-methyl-N- ( (trans) -3- (methylsulfonyl) cyclobutyl) cyclopropane-1-carboxamide (Compound 3) :

or a pharmaceutically acceptable salt form thereof or a solvate thereof.

or a pharmaceutically acceptable salt form thereof or a solvate thereof, and wherein the compound is administered to the subject at a dose of at least about 10 mg.

or a pharmaceutically acceptable salt form thereof or a solvate thereof, and

wherein the compound is administered to the subject at a dose of at least about 10 mg.

or a pharmaceutically acceptable salt form thereof, and

wherein the compound is in the form of an amorphous solid dispersion.

or a pharmaceutically acceptable salt form thereof, and

wherein the compound is in the form of an amorphous solid dispersion.

In any of the medical uses and methods described herein, Compound 3 or a pharmaceutically acceptable salt form thereof may be in the form of an amorphous solid dispersion (e.g., an amorphous solid dispersion as described herein) . The amorphous solid dispersion may be provided as a pharmaceutical composition (e.g., a pharmaceutical composition as described herein) comprising the amorphous solid dispersion and a pharmaceutically acceptable carrier. For example, the pharmaceutical composition may be a solid oral dosage form (e.g., a solid oral dosage form as described herein) . For example, the solid oral dosage form may be a tablet (e.g., a tablet as described herein) .

An embodiment relates to the use of dosing regimens, formulations and crystalline forms as described herein in the manufacture of a medicament for treating a disease, syndrome, condition, or disorder by inhibition of MALT1 as described herein.

The compound may be administered to the subject in a dosage regimen. The dosage regimen may comprise administering the compound at a dose from about 10 mg to about 500 mg.

In some embodiments, the compound is administered to the subject at a dose from about 10 mg to about 500 mg. For example, the compound may be administered to the subject at a dose from about 10 mg to about 450 mg, from about 10 mg to about 400 mg, from about 10 mg to about 350 mg, from about 10 mg to about 300 mg, from about 10 mg to about 250 mg, or from about 10 mg to about 200 mg.

In some embodiments, the dosing regimen may comprise administering the compound at a dose from about 10 mg to about 500 mg. For example, the compound may be administered to the subject at a dose from about 10 mg to about 450 mg, from about 10 mg to about 400 mg, from about 10 mg to about 350 mg, from about 10 mg to about 300 mg, from about 10 mg to about 250 mg, or from about 10 mg to about 200 mg.

In some embodiments, the compound is administered to the subject at a dose from about 20 mg to about 500 mg. For example, the compound may be administered to the subject at a dose from about 20 mg to about 400 mg, from about 20 mg to about 300 mg, from about 20 mg to about 200 mg, from about 20 mg to about 180 mg, from about 20 mg to about 160 mg, or from about 20 mg to about 140 mg.

In some embodiments, the dosing regimen may comprise administering the compound at a dose from about 20 mg to about 500 mg. For example, the compound may be administered to the subject at a dose from about 20 mg to about 400 mg, from about 20 mg to about 300 mg, from about 20 mg to about 200 mg, from about 20 mg to about 180 mg, from about 20 mg to about 160 mg, or from about 20 mg to about 140 mg.

In some embodiments, the compound is administered to the subject at a dose from about 30 mg to about 120 mg. For example, the compound may be administered to the subject at a dose from about 30 mg to about 110 mg, from about 30 mg to about 100 mg, from about 30 mg to about 90 mg, from about 30 mg to about 80 mg, from about 30 mg to about 70 mg, from about 30 mg to about 60 mg, from about 30 mg to about 50 mg, or from about 30 mg to about 45 mg. In some embodiments, the compound is administered to the subject at a dose from about 35 mg to about 45 mg.

In some embodiments, the dosing regimen may comprise administering the compound at a dose from about 30 mg to about 120 mg. For example, the compound may be administered to the subject at a dose from about 30 mg to about 110 mg, from about 30 mg to about 100 mg, from about 30 mg to about 90 mg, from about 30 mg to about 80 mg, from about 30 mg to about 70 mg, from about 30 mg to about 60 mg, from about 30 mg to about 50 mg, or from about 30 mg to about 45 mg. In some embodiments, the dosing regimen may comprise administering the compound at a dose from about 35 mg to about 45 mg.

In some embodiments, the compound is administered to the subject at a dose of at least about 10 mg, at least about 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, or at least about 100 mg.

In some embodiments, the dosing regimen may comprise administering the compound at a dose of at least about 10 mg, at least about 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, or at least about 100 mg.

In some embodiments, the compound is administered to the subject at a dose of at most about 500 mg, at most about 490 mg, at most about 480 mg, at most about 470 mg, at most about 460 mg, at most about 450 mg, at most about 440 mg, at most about 430 mg, at most about 420 mg, at most about 410 mg, at most about 400 mg, at most about 390 mg, at most about 380 mg, at most about 370 mg, at most about 360 mg, at most about 350 mg, at most about 340 mg, at most about 330 mg, at most about 320 mg, at most about 310 mg, at most about 300 mg, at most about 290 mg, at most about 280 mg, at most about 270 mg, at most about 260 mg, at most about 250 mg, at most about 240 mg, at most about 230 mg, at most about 220 mg, at most about 210 mg, at most about 200 mg, at most about 190 mg, at most about 180 mg, at most about 170 mg, at most about 160 mg, at most about 150 mg, at most about 140 mg, at most about 130 mg, at most about 120 mg, at most about 110 mg, at most about 100 mg, at most about 90 mg, at most about 80 mg, at most about 70 mg, at most about 60 mg, at most about 50 mg, at most about 40 mg, or at most about 30 mg.

In some embodiments, the dosing regimen may comprise administering the compound at a dose of at most about 500 mg, at most about 490 mg, at most about 480 mg, at most about 470 mg, at most about 460 mg, at most about 450 mg, at most about 440 mg, at most about 430 mg, at most about 420 mg, at most about 410 mg, at most about 400 mg, at most about 390 mg, at most about 380 mg, at most about 370 mg, at most about 360 mg, at most about 350 mg, at most about 340 mg, at most about 330 mg, at most about 320 mg, at most about 310 mg, at most about 300 mg, at most about 290 mg, at most about 280 mg, at most about 270 mg, at most about 260 mg, at most about 250 mg, at most about 240 mg, at most about 230 mg, at most about 220 mg, at most about 210 mg, at most about 200 mg, at most about 190 mg, at most about 180 mg, at most about 170 mg, at most about 160 mg, at most about 150 mg, at most about 140 mg, at most about 130 mg, at most about 120 mg, at most about 110 mg, at most about 100 mg, at most about 90 mg, at most about 80 mg, at most about 70 mg, at most about 60 mg, at most about 50 mg, at most about 40 mg, or at most about 30 mg.

In some embodiments, the compound is administered to the subject at a dose of about 20 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, or about 490 mg.

In some embodiments, the dosing regimen may comprise administering the compound at a dose of about 20 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, or about 490 mg.

The dose may be calculated based on the free base form of the compound.

The compound may be administered orally.

The compound may be administered daily.

The dose (such as the dose of at least about 10 mg, e.g., the dose of from about 10 mg to about 500 mg) may be administered daily. The dose may be administered once a day (QD) or twice a day (BID) .

The dose (such as the dose of at least about 10 mg, e.g., the dose of from about 10 mg to about 500 mg) may be administered daily for at least 21 days. For example, the dose may be administered daily for 21 days or daily for 28 days.

The dose (such as the dose of at least about 10 mg, e.g., the dose of from about 10 mg to about 500 mg) may be a total daily dose.

In some embodiments, the compound is administered to the subject at a total daily dose from about 10 mg to about 500 mg. For example, the compound may be administered to the subject at a total daily dose from about 10 mg to about 450 mg, from about 10 mg to about 400 mg, from about 10 mg to about 350 mg, from about 10 mg to about 300 mg, from about 10 mg to about 250 mg, or from about 10 mg to about 200 mg.

In some embodiments, the dosing regimen may comprise administering the compound at a total daily dose from about 10 mg to about 500 mg. For example, the compound may be administered to the subject at a total daily dose from about 10 mg to about 450 mg, from about 10 mg to about 400 mg, from about 10 mg to about 350 mg, from about 10 mg to about 300 mg, from about 10 mg to about 250 mg, or from about 10 mg to about 200 mg.

In some embodiments, the compound is administered to the subject at a total daily dose from about 20 mg to about 500 mg. For example, the compound may be administered to the subject at a total daily dose from about 20 mg to about 400 mg, from about 20 mg to about 300 mg, from about 20 mg to about 200 mg, from about 20 mg to about 180 mg, from about 20 mg to about 160 mg, or from about 20 mg to about 140 mg.

In some embodiments, the dosing regimen may comprise administering the compound at a total daily dose from about 20 mg to about 500 mg. For example, the compound may be administered to the subject at a total daily dose from about 20 mg to about 400 mg, from about 20 mg to about 300 mg, from about 20 mg to about 200 mg, from about 20 mg to about 180 mg, from about 20 mg to about 160 mg, or from about 20 mg to about 140 mg.

In some embodiments, the compound is administered to the subject at a total daily dose from about 30 mg to about 120 mg. For example, the compound may be administered to the subject at a total daily dose from about 30 mg to about 110 mg, from about 30 mg to about 100 mg, from about 30 mg to about 90 mg, from about 30 mg to about 80 mg, from about 30 mg to about 70 mg, from about 30 mg to about 60 mg, from about 30 mg to about 50 mg, or from about 30 mg to about 45 mg.

In some embodiments, the dosing regimen may comprise administering the compound at a total daily dose from about 30 mg to about 120 mg. For example, the compound may be administered to the subject at a total daily dose from about 30 mg to about 110 mg, from about 30 mg to about 100 mg, from about 30 mg to about 90 mg, from about 30 mg to about 80 mg, from about 30 mg to about 70 mg, from about 30 mg to about 60 mg, from about 30 mg to about 50 mg, or from about 30 mg to about 45 mg.

In some embodiments, the compound is administered to the subject at a total daily dose from about 35 mg to about 45 mg.

In some embodiments, the dosing regimen may comprise administering the compound at a total daily dose from about 35 mg to about 45 mg.

In some embodiments, the compound is administered to the subject at a total daily dose of at least about 10 mg, at least about 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, or at least about 100 mg.

In some embodiments, the dosing regimen may comprise administering the compound at a total daily dose of at least about 10 mg, at least about 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, or at least about 100 mg.

In some embodiments, the compound is administered to the subject at a total daily dose of at most about 500 mg, at most about 490 mg, at most about 480 mg, at most about 470 mg, at most about 460 mg, at most about 450 mg, at most about 440 mg, at most about 430 mg, at most about 420 mg, at most about 410 mg, at most about 400 mg, at most about 390 mg, at most about 380 mg, at most about 370 mg, at most about 360 mg, at most about 350 mg, at most about 340 mg, at most about 330 mg, at most about 320 mg, at most about 310 mg, at most about 300 mg, at most about 290 mg, at most about 280 mg, at most about 270 mg, at most about 260 mg, at most about 250 mg, at most about 240 mg, at most about 230 mg, at most about 220 mg, at most about 210 mg, at most about 200 mg, at most about 190 mg, at most about 180 mg, at most about 170 mg, at most about 160 mg, at most about 150 mg, at most about 140 mg, at most about 130 mg, at most about 120 mg, at most about 110 mg, at most about 100 mg, at most about 90 mg, at most about 80 mg, at most about 70 mg, at most about 60 mg, at most about 50 mg, at most about 40 mg, or at most about 30 mg.

In some embodiments, the dosing regimen may comprise administering the compound at a total daily dose of at most about 500 mg, at most about 490 mg, at most about 480 mg, at most about 470 mg, at most about 460 mg, at most about 450 mg, at most about 440 mg, at most about 430 mg, at most about 420 mg, at most about 410 mg, at most about 400 mg, at most about 390 mg, at most about 380 mg, at most about 370 mg, at most about 360 mg, at most about 350 mg, at most about 340 mg, at most about 330 mg, at most about 320 mg, at most about 310 mg, at most about 300 mg, at most about 290 mg, at most about 280 mg, at most about 270 mg, at most about 260 mg, at most about 250 mg, at most about 240 mg, at most about 230 mg, at most about 220 mg, at most about 210 mg, at most about 200 mg, at most about 190 mg, at most about 180 mg, at most about 170 mg, at most about 160 mg, at most about 150 mg, at most about 140 mg, at most about 130 mg, at most about 120 mg, at most about 110 mg, at most about 100 mg, at most about 90 mg, at most about 80 mg, at most about 70 mg, at most about 60 mg, at most about 50 mg, at most about 40 mg, or at most about 30 mg.

In some embodiments, the compound is administered to the subject at a total daily dose of about 20 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, or about 490 mg.

In some embodiments, the dosing regimen may comprise administering the compound at a total daily dose of about 20 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, or about 490 mg.

In some embodiments, the compound is administered to the subject at a total daily dose of about 40 mg for 21 days. In some embodiments, the compound is administered to the subject at a total daily dose of about 40 mg for 28 days.

The total daily dose may be calculated based on the free base form of the compound.

In some embodiments, the compound is administered to the subject in a daily dosage regimen comprising or consisting of:

(a) a loading phase, wherein the compound is administered at a total daily loading dose; and

(b) a maintenance phase, wherein the compound is administered at a total daily maintenance dose, wherein the total daily maintenance dose is lower than the total daily loading dose.

In some embodiments, the compound is administered twice a day (BID) during the loading phase and once a day (QD) during the maintenance phase. In some embodiments, the compound is administered once a day (QD) during the loading phase and once a day (QD) during the maintenance phase.

In some embodiments, the total daily loading dose is from about 20 mg to about 500 mg. For example, the total daily loading dose may be from about 40 mg to about 320 mg or from about 60 mg to about 120 mg.

In some embodiments, the total daily maintenance dose is from about 10 mg to about 350 mg. For example, the total daily maintenance dose may be from about 10 mg to about 300 mg, from about 10 mg to about 250 mg, from about 20 mg to about 160 mg, or from about 30 mg to about 60 mg.

In some embodiments, the total daily loading dose is from about 20 mg to about 500 mg and the total daily maintenance dose is from about 10 mg to about 350 mg. The total daily loading dose may be provided by dosing from about 10 mg to about 250 mg BID and the total daily maintenance dose may be provided by dosing from about 10 mg to about 350 mg QD. Alternatively, the total daily loading dose may be provided by dosing from about 20 mg to about 500 mg QD and the total daily maintenance dose may be provided by dosing from about 10 mg to about 350 mg QD.

In some embodiments, the total daily loading dose is from about 20 mg to about 500 mg and the total daily maintenance dose is from about 10 mg to about 300 mg. The total daily loading dose may be provided by dosing from about 10 mg to about 250 mg BID and the total daily maintenance dose may be provided by dosing from about 10 mg to about 300 mg QD. Alternatively, the total daily loading dose may be provided by dosing from about 20 mg to about 500 mg QD and the total daily maintenance dose may be provided by dosing from about 10 mg to about 300 mg QD.

In some embodiments, the total daily loading dose is from about 20 mg to about 500 mg and the total daily maintenance dose is from about 10 mg to about 250 mg. The total daily loading dose may be provided by dosing from about 10 mg to about 250 mg BID and the total daily maintenance dose may be provided by dosing from about 10 mg to about 250 mg QD. Alternatively, the total daily loading dose may be provided by dosing from about 20 mg to about 500 mg QD and the total daily maintenance dose may be provided by dosing from about 10 mg to about 250 mg QD.

In some embodiments, the total daily loading dose is from about 40 mg to about 320 mg and the total daily maintenance dose is from about 20 mg to about 160 mg. The total daily loading dose may be provided by dosing from about 20 mg to about 160 mg BID and the total daily maintenance dose may be provided by dosing from about 20 mg to about 160 mg QD. Alternatively, the total daily loading dose may be provided by dosing from about 40 mg to about 320 mg QD and the total daily maintenance dose may be provided by dosing from about 20 mg to about 160 mg QD.

In some embodiments, the total daily loading dose is from about 60 mg to about 120 mg and the total daily maintenance dose is from about 30 mg to about 60 mg. The total daily loading dose may be provided by dosing from about 30 mg to about 60 mg BID and the total daily maintenance dose may be provided by dosing from about 30 mg to about 60 mg QD. Alternatively, the total daily loading dose is provided by dosing from about 60 mg to about 120 mg QD and the total daily maintenance dose is provided by dosing from about 30 mg to about 60 mg QD.

In some embodiments, the total daily loading dose is about 80 mg and the total daily maintenance dose is about 40 mg. The total daily loading dose may be provided by dosing about 40 mg BID and the total daily maintenance dose is provided by dosing about 40 mg QD. Alternatively, the total daily loading dose may be provided by dosing about 80 mg QD and wherein the total daily maintenance dose is provided by dosing about 40 mg QD.

In some embodiments, the loading phase is a period of at least 2 days, such as a period of at least 3 days or at least 4 days.

In some embodiments, the loading phase is a period of at most 14 days, such as a period of at most 10 days or at most 7 days.

In some embodiments, the loading phase is a period of 4 days.

In some embodiments, the maintenance phase is a period of at least 7 days, such as a period of at least 14 days.

In some embodiments, the compound is administered to the subject in a daily dosage regimen comprising or consisting of: (a) a loading phase, wherein the compound is administered at a total daily loading dose of about 10 mg to about 250 mg BID for a period of at least 2 days; and (b) a maintenance phase, wherein the compound is administered at a total daily maintenance dose of about 10 mg to about 250 mg QD. In some embodiments, the compound is administered to the subject in a daily dosage regimen comprising or consisting of: (a) a loading phase, wherein the compound is administered at a total daily loading dose of about 10 mg to about 250 mg BID for a period of at least 4 days; and (b) a maintenance phase, wherein the compound is administered at a total daily maintenance dose of about 10 mg to about 250 mg QD.

In some embodiments, the compound is administered to the subject in a daily dosage regimen comprising or consisting of: (a) a loading phase, wherein the compound is administered at a total daily loading dose of about 20 mg to about 160 mg BID for a period of at least 2 days; and (b) a maintenance phase, wherein the compound is administered at a total daily maintenance dose of about 20 mg to about 160 mg QD. In some embodiments, the compound is administered to the subject in a daily dosage regimen comprising or consisting of: (a) a loading phase, wherein the compound is administered at a total daily loading dose of about 20 mg to about 160 mg BID for a period of at least 4 days; and (b) a maintenance phase, wherein the compound is administered at a total daily maintenance dose of about 20 mg to about 160 mg QD.

In some embodiments, the compound is administered to the subject in a daily dosage regimen comprising or consisting of: (a) a loading phase, wherein the compound is administered at a total daily loading dose of about 40 mg BID for a period of at least 2 days; and (b) a maintenance phase, wherein the compound is administered at a total daily maintenance dose of about 40 mg QD.In some embodiments, the compound is administered to the subject in a daily dosage regimen comprising or consisting of: (a) a loading phase, wherein the compound is administered at a total daily loading dose of about 40 mg BID for a period of at least 4 days; and (b) a maintenance phase, wherein the compound is administered at a total daily maintenance dose of about 40 mg QD.

In some embodiments, the compound is administered to the subject in a daily dosage regimen comprising or consisting of: (a) a loading phase, wherein the compound is administered at a total daily loading dose of about 40 mg BID for a period of 4 days; and (b) a maintenance phase, wherein the compound is administered at a total daily maintenance dose of about 40 mg QD.

The total daily loading dose and the total daily maintenance dose may be calculated based on the free base form of the compound.

The subject may be an animal, preferably a mammal. In some embodiments, the subject is a human.

As described herein, the disease, syndrome, condition, or disorder is one that is affected by the inhibition of MALT1. The MALT1-dependent or MALT1-mediated disease or condition may be selected from cancers of hematopoietic origin or solid tumors such as chronic myelogenous leukemia, myeloid leukemia, non-Hodgkin lymphoma (NHL) , NF-KB-driven B cell malignancies, and other B cell lymphomas.

Cancers that may benefit from a treatment with the compound described herein include, but are not limited to, lymphomas, leukemias, carcinomas, and sarcomas, e.g., non-Hodgkin’s lymphoma (NHL (including B-cell NHL) ) , diffuse large B-cell lymphoma (DLBCL) , mantle cell lymphoma (MCL) , follicular lymphoma (FL) , mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma (MZL) , T-cell lymphoma, Hodgkin’s lymphoma, Burkitt’s lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL) , small lymphocytic lymphoma (SLL) , macroglobulinemia, lymphoblastic T cell leukemia, chronic myelogenous leukemia (CML) , hairy-cell leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocyte leukemia, promyelocytic leukemia, erythroleukemia, brain (gliomas) , glioblastomas, breast cancer, colorectal/colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head &neck cancer, testicular cancer, Ewing’s sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, esophageal cancer, salivary gland cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, and GIST (gastrointestinal stromal tumor) .

In an alternate embodiment, the disorder or condition is selected from non-Hodgkin’s lymphoma (NHL) , diffuse large B-cell lymphoma (DLBCL) , marginal zone lymphoma, mantle cell lymphoma (MCL) , follicular lymphoma (FL) , transformed follicular lymphoma, chronic lymphocytic leukemia, andmacroglobulinemia.

In another embodiment of the invention, the lymphoma is MALT lymphoma.

In yet another embodiment, the disorder or condition is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL) , mantle cell lymphoma (MCL) , follicular lymphoma (FL) , and mucosa-associated lymphoid tissue (MALT) lymphoma. In another embodiment, the non-Hodgkin’s lymphoma (NHL) is relapsed/refractory B-cell NHL.

In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is selected from the group consisting of relapsed/refractory non-germinal center B cell like (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL) , relapsed/refractorymacroglobulinemia (WM) , relapsed/refractory mantle cell lymphoma (MCL) , relapsed/refractory follicular lymphoma (FL) , and relapsed/refractory mucosa-associated lymphoid tissue (MALT) lymphoma.

In an alternate embodiment, the disorder or condition is non-Hodgkin’s lymphoma (NHL) . In a further embodiment, the non-Hodgkin’s lymphoma (NHL) is B-cell NHL.

In particular, the compound described herein is useful for treating or ameliorating diseases, syndromes, conditions, or disorders such as diffuse large B-cell lymphoma (DLBCL) , mantle cell lymphoma (MCL) , follicular lymphoma (FL) , mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia (CLL) including 17p-depleted CLL, small lymphocytic lymphoma (SLL) , and macroglobulinemia (WM) . In particular, the compound described herein is useful for treating or ameliorating DLBCL tumors with CD79a/b or CARD11 mutations, including tumors with acquired resistance to ibrutinib (BTK, PLCG2 or CARD11 mutations) , ibrutinib resistant CLL/MCL/WM tumors and MALT lymphoma (MALT translocation) . The compound described herein is also useful for treating or ameliorating diffuse large B-cell lymphoma, activated B cell-like subtype (ABC-DLBCL) .

The compound described herein may be used for the treatment of a subject that is relapsed or refractory to a prior treatment. This prior treatment may be a treatment with a Bruton tyrosine kinase inhibitor (BTKi) like ibrutinib. Particular cohorts of patients suitable for treatment with the compound described herein include: i) relapsed and refractory patients with CLL, MCL, or WM following ibrutinib progression; ii) relapsed and refractory DLBCL patients; iii) relapsed and refractory patients with indolent NHL such as FL or MZL.

The compound described herein may be used for the treatment of immunological diseases including, but not limited to, autoimmune and inflammatory disorders, e.g., arthritis, rheumatoid arthritis (RA) , psoriatic arthritis (PsA) , inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn’s disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplant rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet’s diseases, uveitis, myasthenia gravis, Grave’s disease, Hashimoto thyroiditis, Sjoergen’s syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) , cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, and polymyositis.

In an embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is relapsed/refractory GCB-DLBCL. In an embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is relapsed/refractory non-GCB-DLBCL. In an embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is relapsed/refractory ABC-DLBCL.

As described herein, the compound may be in the form of an amorphous solid dispersion. Accordingly, the treatment of a disease, syndrome, condition, or disorder in a subject in need thereof may comprise administering an amorphous solid dispersion to the subject, wherein the amorphous solid dispersion comprises the compound described herein. The amorphous solid dispersion may be as described herein. For example, the amorphous solid dispersion may comprise Compound 3 and an orally pharmaceutically acceptable polymer.

As described herein, the compound may be in the form of a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier. Accordingly, the treatment of a disease, syndrome, condition, or disorder in a subject in need thereof may comprise administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises the compound and a pharmaceutically acceptable carrier. The pharmaceutical composition may be as described herein. For example, the pharmaceutical composition may comprise an amorphous solid dispersion (wherein the amorphous solid dispersion comprises the compound, wherein the compound is Compound 3 or a pharmaceutically acceptable salt form thereof) and a pharmaceutically acceptable carrier.

In some embodiments, the compound is administered to the subject in a dosage regimen that provides a C_trough in blood plasma of at least about 10 nM, such as at least about 11 nM, at least about 12 nM, at least about 15 nM, at least about 20 nM, or at least about 30 nM.

In some embodiments, the compound is administered to the subject in a dosage regimen that provides a C_trough in blood plasma of from about 10 nM to about 170 nM, such as from about 10 nM to about 100 nM, from about 10 nM to about 55 nM, or from about 10 nM to about 20 nM.In some embodiments, the compound is administered to the subject in a dosage regimen that provides a C_trough in blood plasma of from about 11 nM to about 40 nM.

In some embodiments, the compound is administered to the subject in a dosage regimen that provides a C_trough in blood plasma at steady state of at least about 10 nM, such as at least about 11 nM, at least about 12 nM, at least about 15 nM, at least about 20 nM, or at least about 30 nM.

In some embodiments, the compound is administered to the subject in a dosage regimen that provides a C_trough in blood plasma at steady state of from about 10 nM to about 170 nM, such as from about 10 nM to about 100 nM, from about 10 nM to about 55 nM, or from about 10 nM to about 20 nM. In some embodiments, the compound is administered to the subject in a dosage regimen that provides a C_trough in blood plasma of from about 11 nM to about 40 nM.

The disclosure provides aspects and embodiments as set out in the following clauses:

1. An amorphous solid dispersion comprising a compound and an orally pharmaceutically acceptable polymer;

or a pharmaceutically acceptable salt form thereof.

2. The amorphous solid dispersion of clause 1, wherein the amorphous solid dispersion comprises Compound 3 and the orally pharmaceutically acceptable polymer.

3. The amorphous solid dispersion of clause 1, wherein the compound is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 90%w/w, relative to the total content of the compound.

4. The amorphous solid dispersion of clause 3, wherein the compound is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 91%w/w, relative to the total content of the compound.

5. The amorphous solid dispersion of clause 4, wherein the compound is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 92%w/w, relative to the total content of the compound.

6. The amorphous solid dispersion of clause 5, wherein the compound is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 93%w/w, relative to the total content of the compound.

7. The amorphous solid dispersion of clause 6, wherein the compound is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 94%w/w, relative to the total content of the compound.

8. The amorphous solid dispersion of clause 7, wherein the compound is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 95%w/w, relative to the total content of the compound.

9. The amorphous solid dispersion of clause 8, wherein the compound is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 96%w/w, relative to the total content of the compound.

10. The amorphous solid dispersion of clause 9, wherein the compound is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 97%w/w, relative to the total content of the compound.

11. The amorphous solid dispersion of clause 10, wherein the compound is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 98%w/w, relative to the total content of the compound.

12. The amorphous solid dispersion of clause 11, wherein the compound is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 99%w/w, relative to the total content of the compound.

13. The amorphous solid dispersion of clause 12, wherein the compound is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 99.5%w/w, relative to the total content of the compound.

14. The amorphous solid dispersion of clause 13, wherein the compound is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 99.9%w/w, relative to the total content of the compound.

15. The amorphous solid dispersion of clause 2, wherein Compound 3 is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 90%w/w, relative to the total content of Compound 3.

16. The amorphous solid dispersion of clause 15, wherein Compound 3 is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 91%w/w, relative to the total content of Compound 3.

17. The amorphous solid dispersion of clause 16, wherein Compound 3 is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 92%w/w, relative to the total content of Compound 3.

18. The amorphous solid dispersion of clause 17, wherein Compound 3 is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 93%w/w, relative to the total content of Compound 3.

19. The amorphous solid dispersion of clause 18, wherein Compound 3 is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 94%w/w, relative to the total content of Compound 3.

20. The amorphous solid dispersion of clause 19, wherein Compound 3 is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 95%w/w, relative to the total content of Compound 3.

21. The amorphous solid dispersion of clause 20, wherein Compound 3 is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 96%w/w, relative to the total content of Compound 3.

22. The amorphous solid dispersion of clause 21, wherein Compound 3 is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 97%w/w, relative to the total content of Compound 3.

23. The amorphous solid dispersion of clause 22, wherein Compound 3 is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 98%w/w, relative to the total content of Compound 3.

24. The amorphous solid dispersion of clause 23, wherein Compound 3 is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 99%w/w, relative to the total content of Compound 3.

25. The amorphous solid dispersion of clause 24, wherein Compound 3 is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 99.5%w/w, relative to the total content of Compound 3.

26. The amorphous solid dispersion of clause 25, wherein Compound 3 is present in an amorphous form, wherein the amorphous form is present in a weight percentage of at least 99.9%w/w, relative to the total content of Compound 3.

27. The amorphous solid dispersion of any one of clauses 1 or 3 to 14, wherein the weight-by-weight ratio of the compound to the orally pharmaceutically acceptable polymer is in the range of 5: 1 to 1: 100, calculated based on the free base form of the compound.

28. The amorphous solid dispersion of clause 27, wherein the weight-by-weight ratio of the compound to the orally pharmaceutically acceptable polymer is in the range of 5: 1 to 1: 10, calculated based on the free base form of the compound.

29. The amorphous solid dispersion of clause 28, wherein the weight-by-weight ratio of the compound to the orally pharmaceutically acceptable polymer is in the range of 5: 1 to 1: 5, calculated based on the free base form of the compound.

30. The amorphous solid dispersion of clause 29, wherein the weight-by-weight ratio of the compound to the orally pharmaceutically acceptable polymer is in the range of 4: 1 to 1: 4, calculated based on the free base form of the compound.

31. The amorphous solid dispersion of clause 30, wherein the weight-by-weight ratio of the compound to the orally pharmaceutically acceptable polymer is in the range of 2: 1 to 1: 4, calculated based on the free base form of the compound.

32. The amorphous solid dispersion of clause 31, wherein the weight-by-weight ratio of the compound to the orally pharmaceutically acceptable polymer is in the range of 1: 1 to 1: 4, calculated based on the free base form of the compound.

33. The amorphous solid dispersion of clause 32, wherein the weight-by-weight ratio of the compound to the orally pharmaceutically acceptable polymer is in the range of 1: 1 to 1: 3, calculated based on the free base form of the compound.

34. The amorphous solid dispersion of clause 33, wherein the weight-by-weight ratio of the compound to the orally pharmaceutically acceptable polymer is in the range of 1: 2 to 1: 3, calculated based on the free base form of the compound.

35. The amorphous solid dispersion of clause 34, wherein the weight-by-weight ratio of the compound to the orally pharmaceutically acceptable polymer is 1: 3, calculated based on the free base form of the compound.

36. The amorphous solid dispersion of any one of clauses 2 or 15-26, wherein the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is in the range of 5: 1 to 1: 100.

37. The amorphous solid dispersion of clause 36, wherein the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is in the range of 5: 1 to 1: 10.

38. The amorphous solid dispersion of clause 37, wherein the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is in the range of 5: 1 to 1: 5.

39. The amorphous solid dispersion of clause 38, wherein the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is in the range of 4: 1 to 1: 4.

40. The amorphous solid dispersion of clause 39, wherein the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is in the range of 2: 1 to 1: 4.

41. The amorphous solid dispersion of clause 40, wherein the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is in the range of 1: 1 to 1: 4.

42. The amorphous solid dispersion of clause 41, wherein the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is in the range of 1: 1 to 1: 3.

43. The amorphous solid dispersion of clause 42, wherein the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is in the range of 1: 2 to 1: 3.

44. The amorphous solid dispersion of clause 43, wherein the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is 1: 3.

45. The amorphous solid dispersion of any one of the preceding clauses, wherein the orally pharmaceutically acceptable polymer is selected from the group consisting of:

C_1-4-alkylcellulose;

hydroxy-C_1-4-alkylcellulose;

hydroxy-C_1-4-alkyl C_1-4-alkylcellulose;

carboxy-C_1-4-alkylcellulose;

alkali metal salt of carboxy-C_1-4-alkylcellulose;

carboxy-C_1-4-alkyl-C_1-4-alkylcellulose;

hydroxypropylcellulose acetate phthalate;

methylcellulose acetate phthalate;

chitosan;

polyacrylic acid, poly (C_1-4-alkyl acrylate) , copolymer of C_1-4-alkyl acrylate;

polymethacrylic acid, poly (C_1-4-alkyl methacrylate) , copolymer of C_1-4-alkyl methacrylate;

polyvinyl alcohol and copolymer of vinyl alcohol;

crospovidone;

polyethylene glycol, polypropylene glycol, copolymer of ethylene glycol and copolymer of propylene glycol;

polyvinyl caprolactam;

polyvinyl acetate;

polyvinylpyrrolidone;

vinylpyrrolidone-vinyl acetate copolymer;

and where possible salts of these polymers;

or any combination thereof.

46. The amorphous solid dispersion of clause 45, wherein the C_1-4-alkylcellulose is selected from the group consisting of methylcellulose and ethylcellulose, or a combination thereof.

47. The amorphous solid dispersion of clause 45, wherein the hydroxy-C_1-4-alkylcellulose is selected from the group consisting of hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxybutylcellulose, or a combination thereof.

48. The amorphous solid dispersion of clause 45, wherein the hydroxy-C_1-4-alkyl C_1-4-alkylcellulose is selected from the group consisting of hydroxymethyl methylcellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, and hydroxybutyl methylcellulose, or a combination thereof.

49. The amorphous solid dispersion of clause 45, wherein the carboxy-C_1-4-alkylcellulose is carboxymethylcellulose.

50. The amorphous solid dispersion of clause 45, wherein the alkali metal salt of carboxy-C_1-4-alkylcellulose is sodium carboxymethylcellulose.

51. The amorphous solid dispersion of clause 45, wherein the carboxy-C_1-4-alkyl-C_1-4-alkylcellulose is carboxymethylethylcellulose.

52. The amorphous solid dispersion of clause 45, wherein the polyethylene glycol has a molecular weight (MW) in the range of from about 1,500 g/mol to about 20,000 g/mol, optionally from about 4,000 g/mol to about 6,000 g/mol.

53. The amorphous solid dispersion of clause 45, wherein the polyvinylpyrrolidone has a MW in the range of from about 2,500 g/mol to about 3,000,000 g/mol.

54. The amorphous solid dispersion of clause 45, wherein the orally pharmaceutically acceptable polymer is selected from the group consisting of hydroxypropylmethylcellulose acetate succinate (HPMCAS) ; hydroxypropyl methylcellulose (HPMC) ; a copolymer of C_1-4-alkyl acrylate; a copolymer of C_1-4-alkyl methacrylate; vinylpyrrolidone-vinyl acetate copolymer; polyvinylpyrrolidone; and copolymer of ethylene glycol; or any combination thereof.

54a. The amorphous solid dispersion of clause 45, wherein the orally pharmaceutically acceptable polymer is hydroxypropylmethylcellulose acetate succinate (HPMCAS) .

55. The amorphous solid dispersion of clause 54, wherein the copolymer of C_1-4-alkyl acrylate is poly (methacrylic acid-co-ethyl acrylate) .

56. The amorphous solid dispersion of clause 54, wherein the copolymer of C_1-4-alkyl acrylate is poly (methacrylic acid-co-ethyl acrylate) (1: 1) .

57. The amorphous solid dispersion of clause 54, wherein the copolymer of C_1-4-alkyl methacrylate is poly (methacrylic acid-co-methyl methacrylate) or poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) .

58. The amorphous solid dispersion of clause 54, wherein the copolymer of C_1-4-alkyl methacrylate is poly (methacrylic acid-co-methyl methacrylate) (1: 1) or poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (1: 2: 1) .

59. The amorphous solid dispersion of clause 54, wherein the vinylpyrrolidone-vinyl acetate copolymer is a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a ratio of 6: 4 by mass.

60. The amorphous solid dispersion of clause 54, wherein the polyvinylpyrrolidone has a molecular weight of 44,000-54,000 g/mol.

61. The amorphous solid dispersion of clause 54, wherein the copolymer of ethylene glycol is a copolymer of polyvinyl caprolactam, polyvinyl acetate and polyethylene glycol.

62. The amorphous solid dispersion of clause 54, wherein the copolymer of ethylene glycol is a graft copolymer of polyvinyl caprolactam, polyvinyl acetate and polyethylene glycol.

63. The amorphous solid dispersion of clause 62, wherein the graft-copolymer has a molecular weight of 90,000-140,000 g/mol, optionally wherein the graft copolymer has a K-value of 31-41 when measured at 1%in ethanol.

64. The amorphous solid dispersion of clause 54 or 54a, wherein the HPMCAS comprises:

a) 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl;

b) 7.0 wt%to 11.0 wt%acetyl and 10.0 wt%to 14.0 wt%succinoyl; or

c) 10.0 wt%to 14.0 wt%acetyl and 4.0%to 8.0 wt%succinoyl.

65. The amorphous solid dispersion of clause 54, 54a or 64, wherein the HPMCAS has a mean particle diameter of 1 mm.

66. The amorphous solid dispersion of clause 54, 54a or 64, wherein the HPMCAS has a mean particle diameter of 5 μm.

67. The amorphous solid dispersion of clause 54, 54a or 64, wherein the HPMCAS has a mean particle diameter of 70–300 μm.

68. The amorphous solid dispersion of any one of clauses 54, 54a or 64-67, wherein the HPMCAS is:

b) HPMCAS, wherein the HPMCAS comprises 7.0 wt%to 11.0 wt%acetyl and 10.0 wt%to 14.0 wt%succinoyl;

c) HPMCAS, wherein the HPMCAS comprises 10.0 wt%to 14.0 wt%acetyl and 4.0 wt%to 8.0 wt%succinoyl;

d) HPMCAS, wherein the HPMCAS comprises 5.0 wt %to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl;

e) HPMCAS, wherein the HPMCAS comprises 7.0 wt%to 11.0 wt%acetyl and 10.0 wt%to 14.0 wt%succinoyl;

f) HPMCAS, wherein the HPMCAS comprises 10.0 wt %to 14.0 wt%acetyl and 4.0 wt%to 8.0 wt%succinoyl;

h) HPMCAS , wherein the HPMCAS comprises 7.0 wt%to 11.0 wt%acetyl and 10.0 wt%to 14.0 wt%succinoyl; or

69. The amorphous solid dispersion of any one of clauses 54, 54a or 64-68, wherein the HPMCAS has a viscosity of 3 mm²/s.

70. The amorphous solid dispersion of clause 68 or 69, wherein the HPMCAS is:

c) HPMCAS, wherein the HPMCAS comprises 10.0 wt%to 14.0 wt%acetyl and 4.0 wt%to 8.0 wt%succinoyl.

71. The amorphous solid dispersion of clause 54, wherein the HPMC comprises 28 wt%to 30 wt%methoxyl and 7 wt%to 12 wt%hydroxypropyl, optionally wherein the HPMC has an apparent viscosity when dissolved at 2.0%in water of 4 to 6 mPa. s.

72. The amorphous solid dispersion of any one of clauses 45-71, wherein the orally pharmaceutically acceptable polymer is selected from the group consisting of:

HPMCAS, wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl;

HPMCAS, wherein the HPMCAS comprises 7.0 wt%to 11.0 wt%acetyl and 10.0 wt%to 14.0 wt%succinoyl;

HPMCAS, wherein the HPMCAS comprises 10.0 wt%to 14.0 wt%acetyl and 4.0 wt%to 8.0 wt%succinoyl;

poly (methacrylic acid-co-methyl methacrylate) (1: 1) ;

poly (methacrylic acid-co-ethyl acrylate) (1: 1) ;

HPMC, wherein the HPMC comprises 28 wt%to 30 wt%methoxyl and 7 wt%to 12 wt%hydroxypropyl, optionally wherein the HPMC has an apparent viscosity when dissolved at 2.0%in water of 4 to 6 mPa. s;

polyvinylpyrrolidone having a molecular weight of 44,000-54,000 g/mol; and

or a combination thereof.

73. The amorphous solid dispersion of any one of clauses 45-72, wherein the orally pharmaceutically acceptable polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS) or hydroxypropyl methylcellulose (HPMC) .

74. The amorphous solid dispersion of clause 73, wherein the orally pharmaceutically acceptable polymer is HPMCAS.

75. The amorphous solid dispersion of any one of clauses 45-74, wherein the orally pharmaceutically acceptable polymer is selected from:

poly (methacrylic acid-co-methyl methacrylate) (1: 1) ; and

or a combination thereof.

76. The amorphous solid dispersion of any one of clauses 45-75, wherein the orally pharmaceutically acceptable polymer is HPMCAS, wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl.

77. The amorphous solid dispersion of any one of clauses 45-76, wherein the orally pharmaceutically acceptable polymer is HPMCAS, wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl, and wherein the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is in the range of 1: 2 to 1: 3.

78. The amorphous solid dispersion of any one of clauses 45-77, wherein the orally pharmaceutically acceptable polymer is HPMCAS, wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl, and wherein the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is 1: 3.

79. The amorphous solid dispersion of any one of the preceding clauses, wherein the amorphous solid dispersion further comprises a surface-active carrier.

80. The amorphous solid dispersion of clause 79, wherein the surface-active carrier is selected from lauroyl PEG-32 glycerides, vitamin E R-alpha-tocopheryl polyethylene glycol 100 succinate, polysorbate 80, alkali dodecylsulphate surfactants, dioctyl sulfosuccinate sodium salt, cholic acid, deoxycholic acid, lithocholic acid, cholesterol and esters thereof.

81. The amorphous solid dispersion of clause 79 or 80, wherein the surface-active carrier is sodium lauryl sulfate.

82. The amorphous solid dispersion of any one of the preceding clauses, wherein the amorphous solid dispersion is in particulate form.

83. The amorphous solid dispersion of clause 82, wherein the amorphous solid dispersion has a volume weighted particle size distribution D50, as measured by a static light scattering method, of from about 10 μm to about 60 μm.

84. The amorphous solid dispersion of clause 83, wherein the amorphous solid dispersion has a volume weighted particle size distribution D50, as measured by a static light scattering method, of from about 30 μm to about 60 μm.

85. The amorphous solid dispersion of any one of the preceding clauses, wherein, when the amorphous solid dispersion is contacted with simulated gastric fluid for about 15 minutes followed by contacting with fasted state simulated intestinal fluid, at least 60%of the amorphous solid dispersion is dissolved after 20 minutes.

86. The amorphous solid dispersion of any one of the preceding clauses, wherein, when the amorphous solid dispersion comprises 100 mg of Compound 3 and is contacted with simulated gastric fluid for about 15 minutes followed by contacting with fasted state simulated intestinal fluid, at least 60%of the amorphous solid dispersion is dissolved after 20 minutes

87. The amorphous solid dispersion of clause 86, wherein at least 70%of the amorphous solid dispersion is dissolved after 20 minutes.

88. The amorphous solid dispersion of clause 87, wherein at least 80%of the amorphous solid dispersion is dissolved after 20 minutes.

89. The amorphous solid dispersion of any one of the preceding clauses, wherein the amorphous solid dispersion exhibits no crystalline conversion after exposure at 40 ℃, 75%relative humidity, for 28 days.

90. The amorphous solid dispersion of any one of the preceding clauses, wherein the amorphous solid dispersion exhibits no crystalline conversion after exposure at 50 ℃, 75%relative humidity, for 28 days.

91. The amorphous solid dispersion of any one of the preceding clauses, wherein the amorphous solid dispersion exhibits no crystalline conversion after exposure at 60 ℃, 10%relative humidity, for 28 days.

92. The amorphous solid dispersion of any one of the preceding clauses, wherein the amorphous solid dispersion exhibits no crystalline conversion after exposure at 60 ℃, 30%relative humidity, for 28 days.

93. The amorphous solid dispersion of any one of the preceding clauses, wherein the amorphous solid dispersion exhibits no crystalline conversion after exposure at 60 ℃, 75%relative humidity, for 28 days.

94. The amorphous solid dispersion of any one of the preceding clauses, wherein the amorphous solid dispersion exhibits no crystalline conversion after exposure at 40 ℃, 75%relative humidity, for 3 months.

95. The amorphous solid dispersion of any one of the preceding clauses, wherein the amorphous solid dispersion exhibits no crystalline conversion after exposure at 50 ℃, 75%relative humidity, for 3 months.

96. The amorphous solid dispersion of any one of the preceding clauses, wherein the amorphous solid dispersion exhibits no crystalline conversion after exposure at 60 ℃, 10%relative humidity, for 3 months.

97. The amorphous solid dispersion of any one of the preceding clauses, wherein the amorphous solid dispersion exhibits no crystalline conversion after exposure at 60 ℃, 30%relative humidity, for 3 months.

98. The amorphous solid dispersion of any one of the preceding clauses, wherein the amorphous solid dispersion exhibits no crystalline conversion after exposure at 60 ℃, 75%relative humidity, for 3 months.

99. The amorphous solid dispersion of any one of the preceding clauses, wherein the amorphous solid dispersion exhibits no crystalline conversion after exposure at 40 ℃, 75%relative humidity, for 6 months.

100. The amorphous solid dispersion of any one of the preceding clauses, wherein the amorphous solid dispersion exhibits no crystalline conversion after exposure at 50 ℃, 75%relative humidity, for 6 months.

101. The amorphous solid dispersion of any one of the preceding clauses, wherein the amorphous solid dispersion exhibits no crystalline conversion after exposure at 60 ℃, 10%relative humidity, for 6 months.

102. The amorphous solid dispersion of any one of the preceding clauses, wherein the amorphous solid dispersion exhibits no crystalline conversion after exposure at 60 ℃, 30%relative humidity, for 6 months.

103. The amorphous solid dispersion of any one of the preceding clauses, wherein the amorphous solid dispersion exhibits no crystalline conversion after exposure at 60 ℃, 75%relative humidity, for 6 months.

104. A pharmaceutical composition comprising the amorphous solid dispersion according to any one of the preceding clauses, and a pharmaceutically acceptable carrier.

105. The pharmaceutical composition of clause 104, wherein the composition is a solid oral dosage form.

106. The pharmaceutical composition of clause 105, wherein the solid oral dosage form comprises a core and optionally a coating or casing, wherein the core comprises the pharmaceutically acceptable carrier and the amorphous solid dispersion.

107. The pharmaceutical composition of clause 106, wherein the solid oral dosage form is a tablet comprising the core and optionally a coating, optionally wherein the tablet consists of the core.

108. The pharmaceutical composition of any one of clauses 104-107, wherein the pharmaceutically acceptable carrier comprises a filler, a disintegrant, a glidant, and a lubricant.

109. The pharmaceutical composition of clause 108, wherein the filler is selected from the group consisting of silicified microcrystalline cellulose, microcrystalline cellulose, mannitol, lactose, dicalcium phosphate, isomalt, corn starch, pregelatinized starch, magnesium carbonate, or a combination thereof.

110. The pharmaceutical composition of clause 109, wherein the filler is selected from the group consisting of silicified microcrystalline cellulose, microcrystalline cellulose, mannitol, lactose, corn starch, pregelatinized starch, or a combination thereof.

111. The pharmaceutical composition of clause 110, wherein the filler is selected from the group consisting of silicified microcrystalline cellulose, mannitol, lactose, or a combination thereof.

112. The pharmaceutical composition of clause 111, wherein the filler is silicified microcrystalline cellulose.

113. The pharmaceutical composition of any one of clauses 108-112, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, and sodium starch glycolate, or a combination thereof.

114. The pharmaceutical composition of clause 113, wherein the disintegrant is croscarmellose sodium.

115. The pharmaceutical composition of any one of clauses 108-114, wherein the glidant is selected from the group consisting of colloidal silica, and talc, or a combination thereof.

116. The pharmaceutical composition of clause 115, wherein the glidant is anhydrous colloidal silica.

117. The pharmaceutical composition of any one of clauses 108-116, wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, stearic acid, a glyceryl derivative (optionally glyceryl monostearate) , sodium lauryl sulfate, and talc, or a combination thereof.

118. The pharmaceutical composition of clause 117, wherein the lubricant is magnesium stearate.

119. The pharmaceutical composition of any one of clauses 108-118, wherein the filler is silicified microcrystalline cellulose, the disintegrant is croscarmellose sodium, the glidant is anhydrous colloidal silica, and the lubricant is magnesium stearate.

119a. The pharmaceutical composition of any one of clauses 108-119, wherein the filler is silicified microcrystalline cellulose, the disintegrant is croscarmellose sodium, the glidant is anhydrous colloidal silica, and the lubricant is magnesium stearate; wherein the orally pharmaceutically acceptable polymer is HPMCAS; and wherein the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is 1: 3.

120. The pharmaceutical composition of any one of clauses 108-119, wherein the filler is silicified microcrystalline cellulose, the disintegrant is croscarmellose sodium, the glidant is anhydrous colloidal silica, and the lubricant is magnesium stearate; wherein the orally pharmaceutically acceptable polymer is HPMCAS, wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl; and wherein the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is 1: 3.

121. The pharmaceutical composition of any one of clauses 105-120, wherein the solid oral dosage form comprises from about 5 mg to about 150 mg of the compound, calculated based on the free base form.

122. The pharmaceutical composition of clause 121, wherein the solid oral dosage form comprises from about 10 mg to about 100 mg of the compound, calculated based on the free base form.

123. The pharmaceutical composition of clause 122, wherein the solid oral dosage form comprises about 10 mg of the compound, calculated based on the free base form.

124. The pharmaceutical composition of clause 122, wherein the solid oral dosage form comprises about 15 mg of the compound, calculated based on the free base form.

125. The pharmaceutical composition of clause 122, wherein the solid oral dosage form comprises about 20 mg of the compound, calculated based on the free base form.

126. The pharmaceutical composition of clause 122, wherein the solid oral dosage form comprises about 25 mg of the compound, calculated based on the free base form.

127. The pharmaceutical composition of clause 122, wherein the solid oral dosage form comprises about 30 mg of the compound, calculated based on the free base form.

128. The pharmaceutical composition of clause 122, wherein the solid oral dosage form comprises about 35 mg of the compound, calculated based on the free base form.

129. The pharmaceutical composition of clause 122, wherein the solid oral dosage form comprises about 40 mg of the compound, calculated based on the free base form.

130. The pharmaceutical composition of clause 122, wherein the solid oral dosage form comprises about 45 mg of the compound, calculated based on the free base form.

131. The pharmaceutical composition of clause 122, wherein the solid oral dosage form comprises about 50 mg of the compound, calculated based on the free base form.

132. The pharmaceutical composition of clause 122, wherein the solid oral dosage form comprises about 60 mg of the compound, calculated based on the free base form.

133. The pharmaceutical composition of clause 122, wherein the solid oral dosage form comprises about 100 mg of the compound, calculated based on the free base form.

134. The pharmaceutical composition of any one of clauses 105-120, wherein the solid oral dosage form comprises from about 5 mg to about 150 mg of Compound 3.

135. The pharmaceutical composition of clause 134, wherein the solid oral dosage form comprises from about 10 mg to about 100 mg of Compound 3.

136. The pharmaceutical composition of clause 135, wherein the solid oral dosage form comprises about 10 mg of Compound 3.

137. The pharmaceutical composition of clause 135, wherein the solid oral dosage form comprises about 15 mg of Compound 3.

138. The pharmaceutical composition of clause 135, wherein the solid oral dosage form comprises about 20 mg of Compound 3.

139. The pharmaceutical composition of clause 135, wherein the solid oral dosage form comprises about 25 mg of Compound 3.

140. The pharmaceutical composition of clause 135, wherein the solid oral dosage form comprises about 30 mg of Compound 3.

141. The pharmaceutical composition of clause 135, wherein the solid oral dosage form comprises about 35 mg of Compound 3.

142. The pharmaceutical composition of clause 135, wherein the solid oral dosage form comprises about 40 mg of Compound 3.

143. The pharmaceutical composition of clause 135, wherein the solid oral dosage form comprises about 45 mg of Compound 3.

144. The pharmaceutical composition of clause 135, wherein the solid oral dosage form comprises about 50 mg of Compound 3.

145. The pharmaceutical composition of clause 135, wherein the solid oral dosage form comprises about 60 mg of Compound 3.

146. The pharmaceutical composition of clause 135, wherein the solid oral dosage form comprises about 100 mg of Compound 3.

147. The pharmaceutical composition of any one of clauses 105-120, wherein the solid oral dosage form is a tablet, wherein the tablet comprises from about 5 mg to about 150 mg of the compound, calculated based on the free base form.

148. The pharmaceutical composition of clause 147, wherein the solid oral dosage form is a tablet, wherein the tablet comprises from about 10 mg to about 100 mg of the compound, calculated based on the free base form.

149. The pharmaceutical composition of clause 148, wherein the tablet comprises about 10 mg of the compound, calculated based on the free base form.

150. The pharmaceutical composition of clause 148, wherein the tablet comprises about 15 mg of the compound, calculated based on the free base form.

151. The pharmaceutical composition of clause 148, wherein the tablet comprises about 20 mg of the compound, calculated based on the free base form.

152. The pharmaceutical composition of clause 148, wherein the tablet comprises about 25 mg of the compound, calculated based on the free base form.

153. The pharmaceutical composition of clause 148, wherein the tablet comprises about 30 mg of the compound, calculated based on the free base form.

154. The pharmaceutical composition of clause 148, wherein the tablet comprises about 35 mg of the compound, calculated based on the free base form.

155. The pharmaceutical composition of clause 148, wherein the tablet comprises about 40 mg of the compound, calculated based on the free base form.

156. The pharmaceutical composition of clause 148, wherein the tablet comprises about 45 mg of the compound, calculated based on the free base form.

157. The pharmaceutical composition of clause 148, wherein the tablet comprises about 50 mg of the compound, calculated based on the free base form.

158. The pharmaceutical composition of clause 148, wherein the tablet comprises about 60 mg of the compound, calculated based on the free base form.

159. The pharmaceutical composition of clause 148, wherein the tablet comprises about 100 mg of the compound, calculated based on the free base form.

160. The pharmaceutical composition of any one of clauses 105-120, wherein the solid oral dosage form is a tablet, wherein the tablet comprises from about 5 mg to about 150 mg of Compound 3.

161. The pharmaceutical composition of clause 160, wherein the solid oral dosage form is a tablet, wherein the tablet comprises from about 10 mg to about 100 mg of Compound 3.

162. The pharmaceutical composition of clause 161, wherein the tablet comprises about 10 mg of Compound 3.

163. The pharmaceutical composition of clause 161, wherein the tablet comprises about 15 mg of Compound 3.

164. The pharmaceutical composition of clause 161, wherein the tablet comprises about 20 mg of Compound 3.

165. The pharmaceutical composition of clause 161, wherein the tablet comprises about 25 mg of Compound 3.

166. The pharmaceutical composition of clause 161, wherein the tablet comprises about 30 mg of Compound 3.

167. The pharmaceutical composition of clause 161, wherein the tablet comprises about 35 mg of Compound 3.

168. The pharmaceutical composition of clause 161, wherein the tablet comprises about 40 mg of Compound 3.

169. The pharmaceutical composition of clause 161, wherein the tablet comprises about 45 mg of Compound 3.

170. The pharmaceutical composition of clause 161, wherein the tablet comprises about 50 mg of Compound 3.

171. The pharmaceutical composition of clause 161, wherein the tablet comprises about 60 mg of Compound 3.

172. The pharmaceutical composition of clause 161, wherein the tablet comprises about 100 mg of Compound 3.

173. The pharmaceutical composition of any one of clauses 106-172, wherein the amorphous solid dispersion is present in the solid oral dosage form in an amount of from about 30%to about 80% (w/w) relative to the total weight of the core.

174. The pharmaceutical composition of clause 173, wherein the amorphous solid dispersion is present in the solid oral dosage form in an amount of from about 40%to about 60% (w/w) relative to the total weight of the core.

175. The pharmaceutical composition of clause 174, wherein the amorphous solid dispersion is present in the solid oral dosage form in an amount of from about 45%to about 55% (w/w) relative to the total weight of the core.

176. The pharmaceutical composition of clause 175, wherein the amorphous solid dispersion is present in the solid oral dosage form in an amount of about 50% (w/w) relative to the total weight of the core.

177. The pharmaceutical composition of any one of clauses 108-176, wherein the filler is present in the solid oral dosage form in an amount of from about 10%to about 70% (w/w) relative to the total weight of the core.

178. The pharmaceutical composition of clause 177, wherein the filler is present in the solid oral dosage form in an amount of from about 30%to about 60% (w/w) relative to the total weight of the core.

179. The pharmaceutical composition of clause 178, wherein the filler is present in the solid oral dosage form in an amount of from about 35%to about 55% (w/w) relative to the total weight of the core.

180. The pharmaceutical composition of clause 179, wherein the filler is present in the solid oral dosage form in an amount of from about 35%to about 45% (w/w) relative to the total weight of the core.

181. The pharmaceutical composition of clause 180, wherein the filler is present in the solid oral dosage form in an amount of about 40.5% (w/w) relative to the total weight of the core.

182. The pharmaceutical composition of any one of clauses 108-181, wherein the disintegrant is present in the solid oral dosage form in an amount of from about 4%to about 10% (w/w) relative to the total weight of the core.

183. The pharmaceutical composition of clause 182, wherein the disintegrant is present in the solid oral dosage form in an amount of from about 5%to about 8% (w/w) relative to the total weight of the core.

184. The pharmaceutical composition of clause 183, wherein the disintegrant is present in the solid oral dosage form in an amount of about 6% (w/w) relative to the total weight of the core.

185. The pharmaceutical composition of any one of clauses 108-184, wherein the glidant is present in the solid oral dosage form in an amount of from about 0.2%to about 7% (w/w) relative to the total weight of the core.

186. The pharmaceutical composition of clause 185, wherein the glidant is present in the solid oral dosage form in an amount of from about 1%to about 4% (w/w) relative to the total weight of the core.

187. The pharmaceutical composition of clause 186, wherein the glidant is present in the solid oral dosage form in an amount of about 2% (w/w) relative to the total weight of the core.

188. The pharmaceutical composition of any one of clauses 108-187, wherein the lubricant is present in the solid oral dosage form in an amount of from about 0.2%to about 7% (w/w) relative to the total weight of the core.

189. The pharmaceutical composition of clause 188, wherein the lubricant is present in the solid oral dosage form in an amount of from about 0.2%to about 3% (w/w) relative to the total weight of the core.

190. The pharmaceutical composition of clause 189, wherein the lubricant is present in the solid oral dosage form in an amount of about 1.5% (w/w) relative to the total weight of the core.

191. The pharmaceutical composition of any one of clauses 108-190, wherein the solid oral dosage form comprises a total of about 45%to about 55% (w/w) of the amorphous solid dispersion, a total of about 35%to about 45% (w/w) of the filler, a total of about 5%to about 8%(w/w) of the disintegrant, a total of about 1%to about 4% (w/w) of the glidant, and a total of about 0.2%to about 3% (w/w) of the lubricant, relative to the total weight of the core.

192. The pharmaceutical composition of clause 191, wherein the solid oral dosage form comprises a total of about 50% (w/w) of the amorphous solid dispersion, a total of about 40.5%(w/w) of the filler, a total of about 6% (w/w) of the disintegrant, a total of about 2% (w/w) of the glidant, and a total of about 1.5% (w/w) of the lubricant, relative to the total weight of the core.

193. The pharmaceutical composition of any one of clauses 105-192, wherein the pharmaceutical composition is a solid oral dosage form;

wherein the solid oral dosage form is a tablet consisting of a core;

wherein the core comprises the pharmaceutically acceptable carrier and the amorphous solid dispersion;

wherein the pharmaceutically acceptable carrier comprises a filler, a disintegrant, a glidant, and a lubricant;

wherein the amorphous solid dispersion comprises Compound 3 and HPMCAS, wherein in particular the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl, wherein the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is 1: 3;

wherein the tablet comprises a total of about 45%to about 55% (w/w) of the amorphous solid dispersion, a total of about 35%to about 45% (w/w) of the filler, a total of about 5%to about 8% (w/w) of the disintegrant, a total of about 1%to about 4% (w/w) of the glidant, and a total of about 0.2%to about 3% (w/w) of the lubricant, relative to the total weight of the core; and

wherein the filler is silicified microcrystalline cellulose, the disintegrant is croscarmellose sodium, the glidant is anhydrous colloidal silica, and the lubricant is magnesium stearate.

194. The pharmaceutical composition of any one of clauses 105-193, wherein the pharmaceutical composition is a solid oral dosage form;

wherein the solid oral dosage form is a tablet consisting of a core;

wherein the tablet comprises a total of about 50% (w/w) of the amorphous solid dispersion, a total of about 40.5% (w/w) of the filler, a total of about 6% (w/w) of the disintegrant, a total of about 2% (w/w) of the glidant, and a total of about 1.5% (w/w) of the lubricant, relative to the total weight of the core; and

195. The pharmaceutical composition of clause 104 or 105, wherein the pharmaceutical composition is in the form of a tablet, capsule, sachet, pill, lozenge, caplet, or troche.

196. A process for preparing the amorphous solid dispersion of any one of clauses 1-103, the process comprising spray drying a mixture comprising Compound 3, or a pharmaceutically acceptable salt form thereof, the orally pharmaceutically acceptable polymer, and a solvent.

197. The process of clause 196, wherein the mixture is a mixture comprising Compound 3, the orally pharmaceutically acceptable polymer, and the solvent.

198. The process of clause 196 or 197, wherein the solvent is selected from the group consisting of alcohols selected from methanol, ethanol, n-propanol, iso-propanol, and butanol; ketones selected from acetone, methyl ethyl ketone, and methyl iso-butyl ketone; esters selected from ethyl acetate, and propylacetate; acetonitrile; dichloromethane; toluene; 1, 1, 1-trichloroethane; dimethyl acetamide; dimethylsulfoxide; combinations thereof; a mixture of methanol and dichloromethane; and a mixture of acetone and water.

199. The process of clause 198, wherein the solvent is a mixture of methanol and dichloromethane.

200. The process of clause 199, wherein the volume ratio of methanol and dichloromethane in the mixture is from about 1: 1 to about 1: 4.

201. The process of clause 200, wherein the volume ratio of methanol and dichloromethane in the mixture is about 1: 3.

202. The process of any one of clauses 296-201, wherein the process comprises:

dissolving Compound 3, or a pharmaceutically acceptable salt form thereof, in the solvent to obtain a solution;

dissolving the orally pharmaceutically acceptable polymer in the solution to obtain a spray feed mixture;

spray drying the spray feed mixture to obtain a spray dried powder; and

post drying the spray dried powder to obtain the amorphous solid dispersion.

203. The process of any one of clauses 196-202, wherein the process comprises dissolving Compound 3 in the solvent to obtain a solution, wherein Compound 3 is a crystalline form of Compound 3 as defined in any one of clauses 241-295, optionally wherein Compound 3 is a crystalline form of Compound 3 as defined in any one of clauses 242-260.

204. A process for preparing the amorphous solid dispersion of any one of clauses 1-103, the process comprising melt-extruding a mixture comprising Compound 3, or a pharmaceutically acceptable salt form thereof, and the orally pharmaceutically acceptable polymer to obtain a melt-extruded mixture.

205. The process of clause 204, wherein the mixture is a mixture comprising Compound 3 and the orally pharmaceutically acceptable polymer.

206. The process of clause 204 or 205, further comprising milling or grinding the melt-extruded mixture.

207. A process for preparing a solid oral dosage form, wherein the solid oral dosage form is a tablet, the process comprising compressing a blend of the amorphous solid dispersion of any one of clauses 1-103 and a pharmaceutically acceptable carrier.

208. The process of clause 207, wherein the solid oral dosage form is as defined in any one of clauses 107-179.

209. The process of clause 207 or 208, wherein the pharmaceutically acceptable carrier is as defined in any one of clauses 108-119 or 164-177.

210. The process of any one of clauses 207-209, further comprising preparing the amorphous solid dispersion by the process of any one of clauses 181-191, prior to the compression.

211. The process of any one of clauses 207-210, further comprising blending the amorphous solid dispersion with the pharmaceutically acceptable carrier.

212. The process of clause 211, wherein the pharmaceutically acceptable carrier comprises a filler, a disintegrant, a glidant, and a lubricant, and wherein the blending comprises blending the amorphous solid dispersion, filler, disintegrant, glidant, and lubricant.

213. The process of any one of clauses 207-212, wherein the compression is direct compression.

214. The process of any one of clauses 207-213, wherein the pharmaceutically acceptable carrier comprises a filler, a disintegrant, a glidant, and a lubricant, and wherein the process comprises:

blending the amorphous solid dispersion, glidant, a portion of the lubricant, a portion of the filler, and a portion of the disintegrant to provide a first mixture;

dry granulating the first mixture;

adding the remainder of the filler and the remainder of the disintegrant to provide a second mixture;

adding the remainder of the lubricant to provide a third mixture; and

compressing the third mixture into a tablet.

215. The process of clause 214, wherein dry granulation comprises roller compaction.

216. The process of any one of clauses 207-215, wherein the process further comprises applying a coating to the tablet.

216a. A tablet obtained via the process as described in any one of clauses 207-216.

217. The amorphous solid dispersion of any one of clauses 1-103 or the pharmaceutical composition of any one of clauses 104-195 for use in the treatment of a disease, syndrome, condition, or disorder in a subject in need thereof.

218. The amorphous solid dispersion of any one of clauses 1-103 or the pharmaceutical composition of any one of clauses 104-195 for use in the treatment of a disease, syndrome, condition, or disorder in a subject in need thereof, wherein said disease, syndrome, condition, or disorder is affected by the inhibition of MALT1.

219. The amorphous solid dispersion of any one of clauses 1-103 or the pharmaceutical composition of any one of clauses 104-195 for use in the treatment of a disease, syndrome, condition, or disorder in a subject in need thereof, wherein said disease, syndrome, condition, or disorder is ameliorated by the inhibition of MALT1.

220. A method of treating a disease, syndrome, condition, or disorder, wherein said disease, syndrome, condition, or disorder is affected by the inhibition of MALT1, comprising administering to a subject in need thereof a therapeutically effective amount of the amorphous solid dispersion of any one of clauses 1-103 or the pharmaceutical composition of any one of clauses 104-195.

221. Use of the amorphous solid dispersion of any one of clauses 1-103 in the manufacture of a medicament for the treatment of a disease, syndrome, condition, or disorder affected by the inhibition of MALT1.

222. The amorphous solid dispersion or pharmaceutical composition for use of any one of clauses 217-219, wherein the subject is a human.

223. The amorphous solid dispersion or pharmaceutical composition for use of any one of clauses 217-219 or 222, wherein the disease, syndrome, condition, or disorder is cancer.

224. The amorphous solid dispersion or pharmaceutical composition for use of clause 223, wherein the cancer is selected from the group consisting of lymphomas, leukemias, carcinomas, and sarcomas, e.g., non-Hodgkin’s lymphoma (NHL (including B-cell NHL) ) , diffuse large B-cell lymphoma (DLBCL) , mantle cell lymphoma (MCL) , follicular lymphoma (FL) , mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin’s lymphoma, Burkitt’s lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL) , small lymphocytic lymphoma (SLL) , macroglobulinemia, lymphoblastic T cell leukemia, chronic myelogenous leukemia (CML) , hairy-cell leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, brain (gliomas) , glioblastomas, breast cancer, colorectal/colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing’s sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, and GIST (gastrointestinal stromal tumor) .

225. The amorphous solid dispersion or pharmaceutical composition for use of any one of clauses 217-219 or 222-224, wherein the disease, syndrome, condition, or disorder is selected from non-Hodgkin’s lymphoma (NHL) , diffuse large B-cell lymphoma (DLBCL) , marginal zone lymphoma, mantle cell lymphoma (MCL) , follicular lymphoma (FL) , transformed follicular lymphoma, chronic lymphocytic leukemia, and macroglobulinemia.

226. The amorphous solid dispersion or pharmaceutical composition for use of any one of clauses 217-219 or 222-225, wherein the disease, syndrome, condition, or disorder is lymphoma.

227. The amorphous solid dispersion or pharmaceutical composition for use of any one of clauses 217-219 or 222-226, wherein the disease, syndrome, condition, or disorder is the activated B cell like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) , germinal center B cell like (GCB) subtype of diffuse large B-cell lymphoma (DLBCL) , or non-germinal center B cell like (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL) .

228. The amorphous solid dispersion or pharmaceutical composition for use of any one of clauses 217-219 or 222-227, wherein the disease, syndrome, condition, or disorder is chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) .

229. The amorphous solid dispersion or pharmaceutical composition for use of any one of clauses 217-219 or 222-228, wherein the disease, syndrome, condition, or disorder is MALT lymphoma.

230. The amorphous solid dispersion or pharmaceutical composition for use of any one of clauses 217-219 or 222-229, wherein the disease, syndrome, condition, or disorder is macroglobulinemia (WM) .

231. The amorphous solid dispersion or pharmaceutical composition for use of any one of clauses 217-219 or 222-230, wherein the disease, syndrome, condition, or disorder is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL) , mantle cell lymphoma (MCL) , follicular lymphoma (FL) , and mucosa-associated lymphoid tissue (MALT) lymphoma.

232. The amorphous solid dispersion or pharmaceutical composition for use of any one of clauses 217-219 or 222-231, wherein the disease, syndrome, condition, or disorder is non-Hodgkin’s lymphoma (NHL) .

233. The amorphous solid dispersion or pharmaceutical composition for use of clause 232, wherein the non-Hodgkin’s lymphoma (NHL) is B-cell NHL.

234. The amorphous solid dispersion or pharmaceutical composition for use of any one of clauses 217-219 or 222-233, wherein the disease, syndrome, condition, or disorder is primary and secondary central nervous system lymphoma, transformed follicular lymphoma, or API2-MALT1 fusion dependent disease.

235. The amorphous solid dispersion or pharmaceutical composition for use of any one of clauses 217-219 or 222-234, wherein the disease, syndrome, condition, or disorder is marginal zone lymphoma, DLBCL or macroglobulinemia.

236. The amorphous solid dispersion or pharmaceutical composition for use of any one of clauses 217-219 or 222-235, wherein the disease, syndrome, condition, or disorder is marginal zone lymphoma, non-GCB DLBCL or macroglobulinemia.

237. The amorphous solid dispersion or pharmaceutical composition for use of any one of clauses 217-219 or 222-236, wherein the disorder or condition is relapsed or refractory to prior treatment.

238. The amorphous solid dispersion or pharmaceutical composition for use of any one of clauses 217-219 or 222-237, wherein the disorder or condition is cancer and the subject has received prior treatment with a Bruton tyrosine kinase inhibitor (BTKi) , optionally wherein the subject is relapsed or refractory to prior treatment with a Bruton tyrosine kinase inhibitor (BTKi) .

239. The amorphous solid dispersion or pharmaceutical composition for use of any one of clauses 217-219 or 222-238, wherein the disease, syndrome, condition, or disorder is an immunological disease.

240. The amorphous solid dispersion or pharmaceutical composition for use of any one of clauses 217-219 or 222-239, wherein the immunological disease is selected from autoimmune and inflammatory disorders, e.g., arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn’s disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplant rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet’s diseases, uveitis, myasthenia gravis, Grave’s disease, Hashimoto thyroiditis, Sjogren’s syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) , cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, and polymyositis.

241. A crystalline form of (1S, 3R) -3- (4- ( (R) -2-chloro-8-methyl-8- (trifluoromethyl) -7, 8-dihydro-6H-pyrazolo [1, 5-a] pyrrolo [2, 3-e] pyrimidin-6-yl) phenyl) -2, 2-difluoro-1-methyl-N- ( (trans) -3- (methylsulfonyl) cyclobutyl) cyclopropane-1-carboxamide (Compound 3) :

or a solvate thereof.

242. A crystalline form of (1S, 3R) -3- (4- ( (R) -2-chloro-8-methyl-8- (trifluoromethyl) -7, 8-dihydro-6H-pyrazolo [1, 5-a] pyrrolo [2, 3-e] pyrimidin-6-yl) phenyl) -2, 2-difluoro-1-methyl-N- ( (trans) -3- (methylsulfonyl) cyclobutyl) cyclopropane-1-carboxamide (Compound 3) :

wherein the crystalline form is an anhydrous crystalline form (Form I) .

243. The crystalline form of clause 242, wherein the crystalline form produces an X-ray powder diffraction pattern comprising peaks at 7.9, 11.2, 11.9, 13.4, 14.0, 16.6, 18.0, 19.2 and 23.5 degrees two theta ± 0.2 degrees two theta.

244. The crystalline form of clause 243, wherein the X-ray powder diffraction pattern further comprises at least one peak selected from 9.9, 15.1, 15.6, 16.1, 18.4, 19.6, 20.2, 20.5, 22.0, 22.4, 22.8, 28.3, 28.7 and 34.7 degrees two theta ± 0.2 degrees two theta.

245. The crystalline form of any one of clauses 242-244, wherein the crystalline form produces an X-ray powder diffraction pattern comprising four, five, six, seven, eight, nine or more peaks selected from peaks at 7.9, 9.9, 11.2, 11.9, 13.4, 14.0, 15.1, 15.6, 16.1, 16.6, 18.0, 18.4, 19.2, 19.6, 20.2, 20.5, 22.0, 22.4, 22.8, 23.5, 28.3, 28.7 and 34.7 degrees two theta ± 0.2 degrees two theta.

246. The crystalline form of any one of clauses 242-245, wherein the X-ray powder diffraction pattern comprises peaks at 7.9, 9.9, 11.2, 11.9, 13.4, 14.0, 15.1, 15.6, 16.1, 16.6, 18.0, 18.4, 19.2, 19.6, 20.2, 20.5, 22.0, 22.4, 22.8, 23.5, 28.3, 28.7 and 34.7 degrees two theta ± 0.2 degrees two theta.

247. The crystalline form of any one of clauses 242-246, wherein the relative intensity of the peaks is greater than about 2%.

248. The crystalline form of clause 247, wherein the relative intensity of the peaks is greater than about 5%.

249. The crystalline form of clause 248, wherein the relative intensity of the peaks is greater than about 10%.

250. The crystalline form of clause 249, wherein the relative intensity of the peaks is greater than about 15%.

251. The crystalline form of any one of clauses 242-250, further characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 1a.

252. The crystalline form of any one of clauses 242-251, characterized by a differential scanning calorimetry thermogram (DSC) comprising an endotherm with an onset temperature of 183.4 ℃ and a peak temperature at 185.51 ℃.

253. The crystalline form of any one of clauses 242-252, characterized by a DSC substantially as depicted in Figure 1b.

254. The crystalline form of any one of clauses 242-253, wherein the crystalline form exhibits a thermal gravimetric analysis (TGA) curve substantially as depicted in Figure 1c.

255. The crystalline form of any one of clauses 242-254, wherein the crystalline form exhibits a dynamic vapor sorption (DVS) isotherm plot substantially as depicted in Figure 1d.

256. The crystalline form of any one of clauses 242-255, wherein the crystalline form is provided in a substantially pure form.

257. The crystalline form of any one of clauses 242-256, wherein the mole percent of impurities in the crystalline form is less than about 5 mole percent.

258. The crystalline form of clause 257, wherein the mole percent of impurities in the crystalline form is less than about 2 mole percent.

259. The crystalline form of clause 258, wherein the mole percent of impurities in the crystalline form is less than about 0.5 mole percent.

260. The crystalline form of clause 259, wherein the mole percent of impurities in the crystalline form is less than about 0.1 mole percent.

261. A crystalline form of (1S, 3R) -3- (4- ( (R) -2-chloro-8-methyl-8- (trifluoromethyl) -7, 8-dihydro-6H-pyrazolo [1, 5-a] pyrrolo [2, 3-e] pyrimidin-6-yl) phenyl) -2, 2-difluoro-1-methyl-N- ( (trans) -3- (methylsulfonyl) cyclobutyl) cyclopropane-1-carboxamide (Compound 3) :

wherein the crystalline form is a solvate (Form II) .

262. The crystalline form of clause 261, wherein the crystalline form is an acetonitrile solvate (Form IIa) .

263. The crystalline form of clause 262, wherein the crystalline form produces an X-ray powder diffraction pattern comprising peaks at 8.1, 10.8, 13.5, 14.9, 16.2, 17.4, 17.9, 19.1, 20.2 and 22.1 degrees two theta ± 0.2 degrees two theta.

264. The crystalline form of clause 263, wherein the X-ray powder diffraction pattern further comprises at least one peak selected from 7.6, 11.1, 11.5, 11.8, 12.9, 13.9, 15.2, 22.7, 23.0, 23.2, 24.7, 26.5, 27.3 and 28.2 degrees two theta ± 0.2 degrees two theta.

265. The crystalline form of any one of clauses 262-264, wherein the crystalline form produces an X-ray powder diffraction pattern comprising four, five, six, seven, eight, nine or more peaks selected from peaks at 7.6, 8.1, 10.8, 11.1, 11.5, 11.8, 12.9, 13.5, 13.9, 14.9, 15.2, 16.2, 17.4, 17.9, 19.1, 20.2, 22.1, 22.7, 23.0, 23.2, 24.7, 26.5, 27.3 and 28.2 degrees two theta ± 0.2 degrees two theta.

266. The crystalline form of any one of clauses 262-265, wherein the X-ray powder diffraction pattern comprises peaks at 7.6, 8.1, 10.8, 11.1, 11.5, 11.8, 12.9, 13.5, 13.9, 14.9, 15.2, 16.2, 17.4, 17.9, 19.1, 20.2, 22.1, 22.7, 23.0, 23.2, 24.7, 26.5, 27.3 and 28.2 degrees two theta ± 0.2 degrees two theta.

267. The crystalline form of any one of clauses 263-266, wherein the relative intensity of the peaks is greater than about 2%.

268. The crystalline form of clause 267, wherein the relative intensity of the peaks is greater than about 5%.

269. The crystalline form of clause 268, wherein the relative intensity of the peaks is greater than about 10%.

270. The crystalline form of clause 269, wherein the relative intensity of the peaks is greater than about 15%.

271. The crystalline form of any one of clauses 262-270, further characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 2a.

272. The crystalline form of any one of clauses 262-271, characterized by a differential scanning calorimetry thermogram (DSC) substantially as depicted in Figure 2b.

273. The crystalline form of any one of clauses 262-272, wherein the crystalline form exhibits a thermal gravimetric analysis (TGA) curve substantially as depicted in Figure 2c.

274. The crystalline form of any one of clauses 262-273, wherein the crystalline form is provided in a substantially pure form.

275. The crystalline form of any one of clauses 262-274, wherein the mole percent of impurities in the crystalline form is less than about 5 mole percent.

276. The crystalline form of clause 275, wherein the mole percent of impurities in the crystalline form is less than about 2 mole percent.

277. The crystalline form of clause 276, wherein the mole percent of impurities in the crystalline form is less than about 0.5 mole percent.

278. The crystalline form of clause 277, wherein the mole percent of impurities in the crystalline form is less than about 0.1 mole percent.

279. The crystalline form of clause 261, wherein the crystalline form is a methanol solvate (Form IIb) .

280. The crystalline form of clause 279, wherein the crystalline form produces an X-ray powder diffraction pattern comprising peaks at 7.6, 8.2, 10.7, 12.8, 13.5, 15.1, 15.3, 17.2, 17.5, 17.9 and 21.9 degrees two theta ± 0.2 degrees two theta.

281. The crystalline form of clause 280, wherein the X-ray powder diffraction pattern further comprises at least one peak selected from 9.5, 11.5, 16.0, 16.4, 18.4, 18.6, 19.1, 20.1, 21.5, 24.8, 26.2, 27.0 and 27.2 degrees two theta ± 0.2 degrees two theta.

282. The crystalline form of any one of clauses 279-281, wherein the crystalline form produces an X-ray powder diffraction pattern comprising four, five, six, seven, eight, nine or more peaks selected from peaks at 7.6, 8.2, 9.5, 10.7, 11.5, 12.8, 13.5, 15.1, 15.3, 16.0, 16.4, 17.2, 17.5, 17.9, 18.4, 18.6, 19.1, 20.1, 21.5, 21.9, 24.8, 26.2, 27.0 and 27.2 degrees two theta ± 0.2 degrees two theta.

283. The crystalline form of any one of clauses 279-282, wherein the X-ray powder diffraction pattern comprises peaks at 7.6, 8.2, 9.5, 10.7, 11.5, 12.8, 13.5, 15.1, 15.3, 16.0, 16.4, 17.2, 17.5, 17.9, 18.4, 18.6, 19.1, 20.1, 21.5, 21.9, 24.8, 26.2, 27.0 and 27.2 degrees two theta ± 0.2 degrees two theta.

284. The crystalline form of any one of clauses 279-283, wherein the relative intensity of the peaks is greater than about 2%.

285. The crystalline form of clause 284, wherein the relative intensity of the peaks is greater than about 5%.

286. The crystalline form of clause 285, wherein the relative intensity of the peaks is greater than about 10%.

287. The crystalline form of clause 286, wherein the relative intensity of the peaks is greater than about 15%.

288. The crystalline form of any one of clauses 279-287, further characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 3a.

289. The crystalline form of any one of clauses 279-288, characterized by a differential scanning calorimetry thermogram (DSC) substantially as depicted in Figure 3b.

290. The crystalline form of any one of clauses 279-289, wherein the crystalline form exhibits a thermal gravimetric analysis (TGA) curve substantially as depicted in Figure 4.

291. The crystalline form of any one of clauses 279-290, wherein the crystalline form is provided in a substantially pure form.

292. The crystalline form of any one of clauses 279-291, wherein the mole percent of impurities in the crystalline form is less than about 5 mole percent.

293. The crystalline form of clause 292, wherein the mole percent of impurities in the crystalline form is less than about 2 mole percent.

294. The crystalline form of clause 293, wherein the mole percent of impurities in the crystalline form is less than about 0.5 mole percent.

295. The crystalline form of clause 294, wherein the mole percent of impurities in the crystalline form is less than about 0.1 mole percent.

296. A compound for use in the treatment of a disease, syndrome, condition, or disorder in a subject in need thereof,

or a pharmaceutically acceptable salt form thereof or a solvate thereof.

297. A compound for use in the treatment of a disease, syndrome, condition, or disorder in a subject in need thereof, wherein said disease, syndrome, condition, or disorder is ameliorated by the inhibition of MALT1,

or a pharmaceutically acceptable salt form thereof or a solvate thereof.

298. A compound for use in the treatment of a disease, syndrome, condition, or disorder in a subject in need thereof, wherein said disease, syndrome, condition, or disorder is affected by the inhibition of MALT1,

or a pharmaceutically acceptable salt form thereof or a solvate thereof.

299. A compound for use in the treatment of a disease, syndrome, condition, or disorder in a subject in need thereof, wherein said disease, syndrome, condition, or disorder is affected by the inhibition of MALT1,

or a pharmaceutically acceptable salt form thereof or a solvate thereof, and

300. A compound for use in the treatment of a disease, syndrome, condition, or disorder in a subject in need thereof, wherein said disease, syndrome, condition, or disorder is affected by the inhibition of MALT1,

or a pharmaceutically acceptable salt form thereof, and

wherein the compound is in the form of an amorphous solid dispersion.

301. The compound for use of any one of clauses 296-300, wherein the compound is administered to the subject in a dosage regimen, wherein the dosage regimen comprises administering the compound at a dose from about 10 mg to about 500 mg.

302. The compound for use of any one of clauses 296-300, wherein the compound is administered to the subject at a dose from about 10 mg to about 500 mg.

303. The compound for use of clause 301 or 302, wherein the compound is administered to the subject at a dose from about 10 mg to about 450 mg.

304. The compound for use of clause 303, wherein the compound is administered to the subject at a dose from about 10 mg to about 400 mg.

305. The compound for use of clause 304, wherein the compound is administered to the subject at a dose from about 10 mg to about 350 mg.

306. The compound for use of clause 305, wherein the compound is administered to the subject at a dose from about 10 mg to about 300 mg.

307. The compound for use of clause 306, wherein the compound is administered to the subject at a dose from about 10 mg to about 250 mg.

308. The compound for use of clause 307, wherein the compound is administered to the subject at a dose from about 10 mg to about 200 mg.

309. The compound for use of clause 301 or 302, wherein the compound is administered to the subject at a dose from about 20 mg to about 500 mg.

310. The compound for use of clause 309, wherein the compound is administered to the subject at a dose from about 20 mg to about 400 mg.

311. The compound for use of clause 310, wherein the compound is administered to the subject at a dose from about 20 mg to about 300 mg.

312. The compound for use of clause 311, wherein the compound is administered to the subject at a dose from about 20 mg to about 200 mg.

313. The compound for use of clause 312, wherein the compound is administered to the subject at a dose from about 20 mg to about 180 mg.

314. The compound for use of clause 313, wherein the compound is administered to the subject at a dose from about 20 mg to about 160 mg.

315. The compound for use of clause 314, wherein the compound is administered to the subject at a dose from about 20 mg to about 140 mg.

316. The compound for use of clause 315, wherein the compound is administered to the subject at a dose from about 30 mg to about 120 mg.

317. The compound for use of clause 316, wherein the compound is administered to the subject at a dose from about 30 mg to about 110 mg.

318. The compound for use of clause 317, wherein the compound is administered to the subject at a dose from about 30 mg to about 100 mg.

319. The compound for use of clause 318, wherein the compound is administered to the subject at a dose from about 30 mg to about 90 mg.

320. The compound for use of clause 319, wherein the compound is administered to the subject at a dose from about 30 mg to about 80 mg.

321. The compound for use of clause 320, wherein the compound is administered to the subject at a dose from about 30 mg to about 70 mg.

322. The compound for use of clause 321, wherein the compound is administered to the subject at a dose from about 30 mg to about 60 mg.

323. The compound for use of clause 322, wherein the compound is administered to the subject at a dose from about 30 mg to about 50 mg.

324. The compound for use of clause 323, wherein the compound is administered to the subject at a dose from about 30 mg to about 45 mg.

325. The compound for use of clause 324, wherein the compound is administered to the subject at a dose from about 35 mg to about 45 mg.

326. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of at least about 10 mg.

327. The compound for use of clause 326, wherein the compound is administered to the subject at a dose of at least about 20 mg.

328. The compound for use of clause 327, wherein the compound is administered to the subject at a dose of at least about 30 mg.

329. The compound for use of clause 328, wherein the compound is administered to the subject at a dose of at least about 40 mg.

330. The compound for use of clause 329, wherein the compound is administered to the subject at a dose of at least about 50 mg.

331. The compound for use of clause 330, wherein the compound is administered to the subject at a dose of at least about 60 mg.

332. The compound for use of clause 331, wherein the compound is administered to the subject at a dose of at least about 70 mg.

333. The compound for use of clause 332, wherein the compound is administered to the subject at a dose of at least about 80 mg.

334. The compound for use of clause 333, wherein the compound is administered to the subject at a dose of at least about 90 mg.

335. The compound for use of clause 334, wherein the compound is administered to the subject at a dose of at least about 100 mg.

336. The compound for use of any one of clauses 296-302 or 326-335, wherein the compound is administered to the subject at a dose of at most about 500 mg.

337. The compound for use of clause 336, wherein the compound is administered to the subject at a dose of at most about 490 mg.

338. The compound for use of clause 337, wherein the compound is administered to the subject at a dose of at most about 480 mg.

339. The compound for use of clause 338, wherein the compound is administered to the subject at a dose of at most about 470 mg.

340. The compound for use of clause 339, wherein the compound is administered to the subject at a dose of at most about 460 mg.

341. The compound for use of clause 340, wherein the compound is administered to the subject at a dose of at most about 450 mg.

342. The compound for use of clause 341, wherein the compound is administered to the subject at a dose of at most about 440 mg.

343. The compound for use of clause 342, wherein the compound is administered to the subject at a dose of at most about 430 mg.

344. The compound for use of clause 343, wherein the compound is administered to the subject at a dose of at most about 420 mg.

345. The compound for use of clause 344, wherein the compound is administered to the subject at a dose of at most about 410 mg.

346. The compound for use of clause 345, wherein the compound is administered to the subject at a dose of at most about 400 mg.

347. The compound for use of clause 346, wherein the compound is administered to the subject at a dose of at most about 390 mg.

348. The compound for use of clause 347, wherein the compound is administered to the subject at a dose of at most about 380 mg.

349. The compound for use of clause 348, wherein the compound is administered to the subject at a dose of at most about 370 mg.

350. The compound for use of clause 349, wherein the compound is administered to the subject at a dose of at most about 360 mg.

351. The compound for use of clause 350, wherein the compound is administered to the subject at a dose of at most about 350 mg.

352. The compound for use of clause 351, wherein the compound is administered to the subject at a dose of at most about 340 mg.

353. The compound for use of clause 352, wherein the compound is administered to the subject at a dose of at most about 330 mg.

354. The compound for use of clause 353, wherein the compound is administered to the subject at a dose of at most about 320 mg.

355. The compound for use of clause 354, wherein the compound is administered to the subject at a dose of at most about 310 mg.

356. The compound for use of clause 355, wherein the compound is administered to the subject at a dose of at most about 300 mg.

357. The compound for use of clause 356, wherein the compound is administered to the subject at a dose of at most about 290 mg.

358. The compound for use of clause 357, wherein the compound is administered to the subject at a dose of at most about 280 mg.

359. The compound for use of clause 358, wherein the compound is administered to the subject at a dose of at most about 270 mg.

360. The compound for use of clause 359, wherein the compound is administered to the subject at a dose of at most about 260 mg.

361. The compound for use of clause 360, wherein the compound is administered to the subject at a dose of at most about 250 mg.

362. The compound for use of clause 361, wherein the compound is administered to the subject at a dose of at most about 240 mg.

363. The compound for use of clause 362, wherein the compound is administered to the subject at a dose of at most about 230 mg.

364. The compound for use of clause 363, wherein the compound is administered to the subject at a dose of at most about 220 mg.

365. The compound for use of clause 364, wherein the compound is administered to the subject at a dose of at most about 210 mg.

366. The compound for use of clause 365, wherein the compound is administered to the subject at a dose of at most about 200 mg.

367. The compound for use of clause 366, wherein the compound is administered to the subject at a dose of at most about 190 mg.

368. The compound for use of clause 367, wherein the compound is administered to the subject at a dose of at most about 180 mg.

369. The compound for use of clause 368, wherein the compound is administered to the subject at a dose of at most about 170 mg.

370. The compound for use of clause 369, wherein the compound is administered to the subject at a dose of at most about 160 mg.

371. The compound for use of clause 370, wherein the compound is administered to the subject at a dose of at most about 150 mg.

372. The compound for use of clause 371, wherein the compound is administered to the subject at a dose of at most about 140 mg.

373. The compound for use of clause 372, wherein the compound is administered to the subject at a dose of at most about 130 mg.

374. The compound for use of clause 373, wherein the compound is administered to the subject at a dose of at most about 120 mg.

375. The compound for use of clause 374, wherein the compound is administered to the subject at a dose of at most about 110 mg.

376. The compound for use of clause 375, wherein the compound is administered to the subject at a dose of at most about 100 mg.

377. The compound for use of clause 376, wherein the compound is administered to the subject at a dose of at most about 90 mg.

378. The compound for use of clause 377, wherein the compound is administered to the subject at a dose of at most about 80 mg.

379. The compound for use of clause 378, wherein the compound is administered to the subject at a dose of at most about 70 mg.

380. The compound for use of clause 379, wherein the compound is administered to the subject at a dose of at most about 60 mg.

381. The compound for use of clause 380, wherein the compound is administered to the subject at a dose of at most about 50 mg.

382. The compound for use of clause 381, wherein the compound is administered to the subject at a dose of at most about 40 mg.

383. The compound for use of clause 382, wherein the compound is administered to the subject at a dose of at most about 30 mg.

384. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 20 mg.

385. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 30 mg.

386. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 35 mg.

387. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 40 mg.

388. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 50 mg.

389. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 60 mg.

390. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 70 mg.

391. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 80 mg.

392. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 90 mg.

393. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 100 mg.

394. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 120 mg.

395. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 140 mg.

396. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 160 mg.

397. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 180 mg.

398. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 200 mg.

399. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 220 mg.

400. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 240 mg.

401. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 260 mg.

402. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 280 mg.

403. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 300 mg.

404. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 320 mg.

405. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 340 mg.

406. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 360 mg.

407. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 380 mg.

408. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 400 mg.

409. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 420 mg.

410. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 440 mg.

411. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 460 mg.

412. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 480 mg.

413. The compound for use of any one of clauses 296-302, wherein the compound is administered to the subject at a dose of about 490 mg.

414. The compound for use of any one of clauses 299 or 301-413, wherein the dose is calculated based on the free base form of the compound.

415. The compound for use of any one of clauses 296-414, wherein the compound is administered orally.

416. The compound for use of any one of clauses 296-414, wherein the compound is administered daily.

417. The compound for use of any one of clauses 299 or 301-416, wherein the dose is administered daily.

418. The compound for use of any one of clauses 299 or 301-417, wherein the dose is administered once a day (QD) .

419. The compound for use of any one of clauses 299 or 301-418, wherein the dose is administered twice a day (BID) .

420. The compound for use of any one of clauses 299 or 301-419, wherein the dose is administered daily for at least 21 days.

421. The compound for use of any one of clauses 299 or 301-420, wherein the dose is administered daily for 21 days.

422. The compound for use of any one of clauses 299 or 301-420, wherein the dose is administered daily for 28 days.

423. The compound for use of any one of clauses 299, 301-418 or 420-422, wherein the dose is a total daily dose.

424. The compound for use of any one of clauses 296-423, wherein the compound is administered to the subject at a total daily dose from about 10 mg to about 500 mg.

425. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose from about 10 mg to about 450 mg.

426. The compound for use of clause 425, wherein the compound is administered to the subject at a total daily dose from about 10 mg to about 400 mg.

427. The compound for use of clause 426, wherein the compound is administered to the subject at a total daily dose from about 10 mg to about 350 mg.

428. The compound for use of clause 427, wherein the compound is administered to the subject at a total daily dose from about 10 mg to about 300 mg.

429. The compound for use of clause 428, wherein the compound is administered to the subject at a total daily dose from about 10 mg to about 250 mg.

430. The compound for use of clause 429, wherein the compound is administered to the subject at a total daily dose from about 10 mg to about 200 mg.

431. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose from about 20 mg to about 500 mg.

432. The compound for use of clause 431, wherein the compound is administered to the subject at a total daily dose from about 20 mg to about 400 mg.

433. The compound for use of clause 432, wherein the compound is administered to the subject at a total daily dose from about 20 mg to about 300 mg.

434. The compound for use of clause 433, wherein the compound is administered to the subject at a total daily dose from about 20 mg to about 200 mg.

435. The compound for use of clause 434, wherein the compound is administered to the subject at a total daily dose from about 20 mg to about 180 mg.

436. The compound for use of clause 435, wherein the compound is administered to the subject at a total daily dose from about 20 mg to about 160 mg.

437. The compound for use of clause 436, wherein the compound is administered to the subject at a total daily dose from about 20 mg to about 140 mg.

438. The compound for use of clause 437, wherein the compound is administered to the subject at a total daily dose from about 30 mg to about 120 mg.

439. The compound for use of clause 438, wherein the compound is administered to the subject at a total daily dose from about 30 mg to about 110 mg.

440. The compound for use of clause 439, wherein the compound is administered to the subject at a total daily dose from about 30 mg to about 100 mg.

441. The compound for use of clause 440, wherein the compound is administered to the subject at a total daily dose from about 30 mg to about 90 mg.

442. The compound for use of clause 441, wherein the compound is administered to the subject at a total daily dose from about 30 mg to about 80 mg.

443. The compound for use of clause 442, wherein the compound is administered to the subject at a total daily dose from about 30 mg to about 70 mg.

444. The compound for use of clause 443, wherein the compound is administered to the subject at a total daily dose from about 30 mg to about 60 mg.

445. The compound for use of clause 444, wherein the compound is administered to the subject at a total daily dose from about 30 mg to about 50 mg.

446. The compound for use of clause 445, wherein the compound is administered to the subject at a total daily dose from about 30 mg to about 45 mg.

447. The compound for use of clause 446, wherein the compound is administered to the subject at a total daily dose from about 35 mg to about 45 mg.

448. The compound for use of any one of clauses 296-423, wherein the compound is administered to the subject at a total daily dose of at least about 10 mg.

449. The compound for use of clause 448, wherein the compound is administered to the subject at a total daily dose of at least about 20 mg.

450. The compound for use of clause 449, wherein the compound is administered to the subject at a total daily dose of at least about 30 mg.

451. The compound for use of clause 450, wherein the compound is administered to the subject at a total daily dose of at least about 40 mg.

452. The compound for use of clause 451, wherein the compound is administered to the subject at a total daily dose of at least about 50 mg.

453. The compound for use of clause 452, wherein the compound is administered to the subject at a total daily dose of at least about 60 mg.

454. The compound for use of clause 453, wherein the compound is administered to the subject at a total daily dose of at least about 70 mg.

455. The compound for use of clause 454, wherein the compound is administered to the subject at a total daily dose of at least about 80 mg.

456. The compound for use of clause 455, wherein the compound is administered to the subject at a total daily dose of at least about 90 mg.

457. The compound for use of clause 456, wherein the compound is administered to the subject at a total daily dose of at least about 100 mg.

458. The compound for use of any one of clauses 296-423 or 448-457, wherein the compound is administered to the subject at a total daily dose of at most about 500 mg.

459. The compound for use of clause 458, wherein the compound is administered to the subject at a total daily dose of at most about 490 mg.

460. The compound for use of clause 459, wherein the compound is administered to the subject at a total daily dose of at most about 480 mg.

461. The compound for use of clause 460, wherein the compound is administered to the subject at a total daily dose of at most about 470 mg.

462. The compound for use of clause 461, wherein the compound is administered to the subject at a total daily dose of at most about 460 mg.

463. The compound for use of clause 462, wherein the compound is administered to the subject at a total daily dose of at most about 450 mg.

464. The compound for use of clause 463, wherein the compound is administered to the subject at a total daily dose of at most about 440 mg.

465. The compound for use of clause 464, wherein the compound is administered to the subject at a total daily dose of at most about 430 mg.

466. The compound for use of clause 465, wherein the compound is administered to the subject at a total daily dose of at most about 420 mg.

467. The compound for use of clause 466, wherein the compound is administered to the subject at a total daily dose of at most about 410 mg.

468. The compound for use of clause 467, wherein the compound is administered to the subject at a total daily dose of at most about 400 mg.

469. The compound for use of clause 468, wherein the compound is administered to the subject at a total daily dose of at most about 390 mg.

470. The compound for use of clause 469, wherein the compound is administered to the subject at a total daily dose of at most about 380 mg.

471. The compound for use of clause 470, wherein the compound is administered to the subject at a total daily dose of at most about 370 mg.

472. The compound for use of clause 471, wherein the compound is administered to the subject at a total daily dose of at most about 360 mg.

473. The compound for use of clause 472, wherein the compound is administered to the subject at a total daily dose of at most about 350 mg.

474. The compound for use of clause 473, wherein the compound is administered to the subject at a total daily dose of at most about 340 mg.

475. The compound for use of clause 474, wherein the compound is administered to the subject at a total daily dose of at most about 330 mg.

476. The compound for use of clause 475, wherein the compound is administered to the subject at a total daily dose of at most about 320 mg.

477. The compound for use of clause 476, wherein the compound is administered to the subject at a total daily dose of at most about 310 mg.

478. The compound for use of clause 477, wherein the compound is administered to the subject at a total daily dose of at most about 300 mg.

479. The compound for use of clause 478, wherein the compound is administered to the subject at a total daily dose of at most about 290 mg.

480. The compound for use of clause 479, wherein the compound is administered to the subject at a total daily dose of at most about 280 mg.

481. The compound for use of clause 480, wherein the compound is administered to the subject at a total daily dose of at most about 270 mg.

482. The compound for use of clause 481, wherein the compound is administered to the subject at a total daily dose of at most about 260 mg.

483. The compound for use of clause 482, wherein the compound is administered to the subject at a total daily dose of at most about 250 mg.

484. The compound for use of clause 483, wherein the compound is administered to the subject at a total daily dose of at most about 240 mg.

485. The compound for use of clause 484, wherein the compound is administered to the subject at a total daily dose of at most about 230 mg.

486. The compound for use of clause 485, wherein the compound is administered to the subject at a total daily dose of at most about 220 mg.

487. The compound for use of clause 486, wherein the compound is administered to the subject at a total daily dose of at most about 210 mg.

488. The compound for use of clause 487, wherein the compound is administered to the subject at a total daily dose of at most about 200 mg.

489. The compound for use of clause 488, wherein the compound is administered to the subject at a total daily dose of at most about 190 mg.

490. The compound for use of clause 489, wherein the compound is administered to the subject at a total daily dose of at most about 180 mg.

491. The compound for use of clause 490, wherein the compound is administered to the subject at a total daily dose of at most about 170 mg.

492. The compound for use of clause 491, wherein the compound is administered to the subject at a total daily dose of at most about 160 mg.

493. The compound for use of clause 492, wherein the compound is administered to the subject at a total daily dose of at most about 150 mg.

494. The compound for use of clause 493, wherein the compound is administered to the subject at a total daily dose of at most about 140 mg.

495. The compound for use of clause 494, wherein the compound is administered to the subject at a total daily dose of at most about 130 mg.

496. The compound for use of clause 495, wherein the compound is administered to the subject at a total daily dose of at most about 120 mg.

497. The compound for use of clause 496, wherein the compound is administered to the subject at a total daily dose of at most about 110 mg.

498. The compound for use of clause 497, wherein the compound is administered to the subject at a total daily dose of at most about 100 mg.

499. The compound for use of clause 498, wherein the compound is administered to the subject at a total daily dose of at most about 90 mg.

500. The compound for use of clause 499, wherein the compound is administered to the subject at a total daily dose of at most about 80 mg.

501. The compound for use of clause 500, wherein the compound is administered to the subject at a total daily dose of at most about 70 mg.

502. The compound for use of clause 501, wherein the compound is administered to the subject at a total daily dose of at most about 60 mg.

503. The compound for use of clause 502, wherein the compound is administered to the subject at a total daily dose of at most about 50 mg.

504. The compound for use of clause 503, wherein the compound is administered to the subject at a total daily dose of at most about 40 mg.

505. The compound for use of clause 504, wherein the compound is administered to the subject at a total daily dose of at most about 30 mg.

506. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 20 mg.

507. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 30 mg.

508. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 35 mg.

509. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 40 mg.

510. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 50 mg.

511. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 60 mg.

512. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 70 mg.

513. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 80 mg.

514. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 90 mg.

515. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 100 mg.

516. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 120 mg.

517. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 140 mg.

518. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 160 mg.

519. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 180 mg.

520. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 200 mg.

521. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 220 mg.

522. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 240 mg.

523. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 260 mg.

524. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 280 mg.

525. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 300 mg.

526. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 320 mg.

527. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 340 mg.

528. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 360 mg.

529. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 380 mg.

530. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 400 mg.

531. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 420 mg.

532. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 440 mg.

533. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 460 mg.

534. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 480 mg.

535. The compound for use of clause 424, wherein the compound is administered to the subject at a total daily dose of about 490 mg.

536. The compound for use of clause 509, wherein the compound is administered to the subject at a total daily dose of about 40 mg for at least 21 days.

537. The compound for use of clause 509, wherein the compound is administered to the subject at a total daily dose of about 40 mg for 21 days.

538. The compound for use of clause 509, wherein the compound is administered to the subject at a total daily dose of about 40 mg for 28 days.

539. The compound for use of any one of clauses 423-538, wherein the total daily dose is calculated based on the free base form of the compound.

540. The compound for use of any one of clauses 296-539, wherein the compound is administered to the subject in a daily dosage regimen comprising or consisting of:

541. The compound for use of clause 540, wherein the compound is administered twice a day (BID) during the loading phase and once a day (QD) during the maintenance phase.

542. The compound for use of clause 540, wherein the compound is administered once a day (QD) during the loading phase and once a day (QD) during the maintenance phase.

543. The compound for use of any one of clauses 540-542, wherein the total daily loading dose is from about 20 mg to about 500 mg.

544. The compound for use of clause 543, wherein the total daily loading dose is from about 40 mg to about 320 mg.

545. The compound for use of clause 544, wherein the total daily loading dose is from about 60 mg to about 120 mg.

546. The compound for use of clause 540-545, wherein the total daily maintenance dose is from about 10 mg to about 350 mg.

547. The compound for use of clause 546, wherein the total daily maintenance dose is from about 10 mg to about 300 mg.

548. The compound for use of clause 547, wherein the total daily maintenance dose is from about 10 mg to about 250 mg.

549. The compound for use of clause 548, wherein the total daily maintenance dose is from about 20 mg to about 160 mg.

550. The compound for use of clause 549, wherein the total daily maintenance dose is from about 30 mg to about 60 mg.

551. The compound for use of any one of clauses 540-543, wherein the total daily loading dose is from about 20 mg to about 500 mg and wherein the total daily maintenance dose is from about 10 mg to about 350 mg.

552. The compound for use of clause 551, wherein the total daily loading dose is provided by dosing from about 10 mg to about 250 mg BID and wherein the total daily maintenance dose is provided by dosing from about 10 mg to about 350 mg QD.

553. The compound for use of clause 551, wherein the total daily loading dose is provided by dosing from about 20 mg to about 500 mg QD and wherein the total daily maintenance dose is provided by dosing from about 10 mg to about 350 mg QD.

554. The compound for use of any one of clauses 540-543, wherein the total daily loading dose is from about 20 mg to about 500 mg and wherein the total daily maintenance dose is from about 10 mg to about 300 mg.

555. The compound for use of clause 554, wherein the total daily loading dose is provided by dosing from about 10 mg to about 250 mg BID and wherein the total daily maintenance dose is provided by dosing from about 10 mg to about 300 mg QD.

556. The compound for use of clause 554, wherein the total daily loading dose is provided by dosing from about 20 mg to about 500 mg QD and wherein the total daily maintenance dose is provided by dosing from about 10 mg to about 300 mg QD.

557. The compound for use of any one of clauses 540-543, wherein the total daily loading dose is from about 20 mg to about 500 mg and wherein the total daily maintenance dose is from about 10 mg to about 250 mg.

558. The compound for use of clause 557, wherein the total daily loading dose is provided by dosing from about 10 mg to about 250 mg BID and wherein the total daily maintenance dose is provided by dosing from about 10 mg to about 250 mg QD.

559. The compound for use of clause 557, wherein the total daily loading dose is provided by dosing from about 20 mg to about 500 mg QD and wherein the total daily maintenance dose is provided by dosing from about 10 mg to about 250 mg QD.

560. The compound for use of any one of clauses 540-544, wherein the total daily loading dose is from about 40 mg to about 320 mg and wherein the total daily maintenance dose is from about 20 mg to about 160 mg.

561. The compound for use of clause 560, wherein the total daily loading dose is provided by dosing from about 20 mg to about 160 mg BID and wherein the total daily maintenance dose is provided by dosing from about 20 mg to about 160 mg QD.

562. The compound for use of clause 560, wherein the total daily loading dose is provided by dosing from about 40 mg to about 320 mg QD and wherein the total daily maintenance dose is provided by dosing from about 20 mg to about 160 mg QD.

563. The compound for use of any one of clauses 540-544, wherein the total daily loading dose is from about 60 mg to about 120 mg and wherein the total daily maintenance dose is from about 30 mg to about 60 mg.

564. The compound for use of clause 563, wherein the total daily loading dose is provided by dosing from about 30 mg to about 60 mg BID and wherein the total daily maintenance dose is provided by dosing from about 30 mg to about 60 mg QD.

565. The compound for use of clause 563, wherein the total daily loading dose is provided by dosing from about 60 mg to about 120 mg QD and wherein the total daily maintenance dose is provided by dosing from about 30 mg to about 60 mg QD.

566. The compound for use of any one of clauses 540-544, wherein the total daily loading dose is about 80 mg and wherein the total daily maintenance dose is about 40 mg.

567. The compound for use of clause 566, wherein the total daily loading dose is provided by dosing about 40 mg BID and wherein the total daily maintenance dose is provided by dosing about 40 mg QD.

568. The compound for use of clause 566, wherein the total daily loading dose is provided by dosing about 80 mg QD and wherein the total daily maintenance dose is provided by dosing about 40 mg QD.

569. The compound for use of any one of clauses 540-568, wherein the loading phase is a period of at least 2 days.

570. The compound for use of clause 569, wherein the loading phase is a period of at least 3 days.

571. The compound for use of clause 570, wherein the loading phase is a period of at least 4 days.

572. The compound for use of any one of clauses 540-571, wherein the loading phase is a period of at most 14 days.

573. The compound for use of clause 572, wherein the loading phase is a period of at most 10 days.

574. The compound for use of clause 573, wherein the loading phase is a period of at most 7 days.

575. The compound for use of any one of clauses 540-568, wherein the loading phase is a period of 4 days.

576. The compound for use of any one of clauses 540-575, wherein the maintenance phase is a period of at least 7 days.

577. The compound for use of clause 576, wherein the maintenance phase is a period of at least 14 days.

578. The compound for use of any one of clauses 296-540 or 569-577, wherein the compound is administered to the subject in a daily dosage regimen comprising or consisting of:

(a) a loading phase, wherein the compound is administered at a total daily loading dose of about 10 mg to about 250 mg BID for a period of at least 2 days; and

(b) a maintenance phase, wherein the compound is administered at a total daily maintenance dose of about 10 mg to about 250 mg QD.

579. The compound for use of any one of clauses 296-540 or 569-577, wherein the compound is administered to the subject in a daily dosage regimen comprising or consisting of:

(a) a loading phase, wherein the compound is administered at a total daily loading dose of about 10 mg to about 250 mg BID for a period of at least 4 days; and

580. The compound for use of any one of clauses 296-540 or 569-577, wherein the compound is administered to the subject in a daily dosage regimen comprising or consisting of:

(a) a loading phase, wherein the compound is administered at a total daily loading dose of about 20 mg to about 160 mg BID for a period of at least 2 days; and

(b) a maintenance phase, wherein the compound is administered at a total daily maintenance dose of about 20 mg to about 160 mg QD.

581. The compound for use of any one of clauses 296-540 or 569-577, wherein the compound is administered to the subject in a daily dosage regimen comprising or consisting of:

(a) a loading phase, wherein the compound is administered at a total daily loading dose of about 20 mg to about 160 mg BID for a period of at least 4 days; and

582. The compound for use of any one of clauses 296-540 or 569-577, wherein the compound is administered to the subject in a daily dosage regimen comprising or consisting of:

(a) a loading phase, wherein the compound is administered at a total daily loading dose of about 40 mg BID for a period of at least 2 days; and

(b) a maintenance phase, wherein the compound is administered at a total daily maintenance dose of about 40 mg QD.

583. The compound for use of any one of clauses 296-540 or 569-577, wherein the compound is administered to the subject in a daily dosage regimen comprising or consisting of:

(a) a loading phase, wherein the compound is administered at a total daily loading dose of about 40 mg BID for a period of at least 4 days; and

584. The compound for use of any one of clauses 296-540 or 569-577, wherein the compound is administered to the subject in a daily dosage regimen comprising or consisting of:

(a) a loading phase, wherein the compound is administered at a total daily loading dose of about 40 mg BID for a period of 4 days; and

585. The compound for use of any one of clauses 540-584, wherein the total daily loading dose and the total daily maintenance dose are calculated based on the free base form of the compound.

586. The compound for use of any one of clauses 296-585, wherein the subject is a human.

587. The compound for use of any one of clauses 296-586, wherein the disease, syndrome, condition, or disorder is cancer.

588. The compound for use of any one of clauses 587, wherein the cancer is selected from the group consisting of lymphomas, leukemias, carcinomas, and sarcomas, e.g., cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing’s sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, and GIST (gastrointestinal stromal tumor) .

589. The compound for use of any one of clauses 296-588, wherein the disease, syndrome, condition, or disorder is selected from non-Hodgkin’s lymphoma (NHL) , diffuse large B-cell lymphoma (DLBCL) , marginal zone lymphoma, mantle cell lymphoma (MCL) , follicular lymphoma (FL) , transformed follicular lymphoma, chronic lymphocytic leukemia, and macroglobulinemia.

590. The compound for use of any one of clauses 296-589, wherein the disease, syndrome, condition, or disorder is lymphoma.

591. The compound for use of any one of clauses 296-590, wherein the disease, syndrome, condition, or disorder is the activated B cell like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) , germinal center B cell like (GCB) subtype of diffuse large B-cell lymphoma (DLBCL) , or non-germinal center B cell like (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL) .

592. The compound for use of any one of clauses 296-590, wherein the disease, syndrome, condition, or disorder is chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) .

593. The compound for use of any one of clauses 296-590, wherein the disease, syndrome, condition, or disorder is MALT lymphoma.

594. The compound for use of any one of clauses 296-589, wherein the disease, syndrome, condition, or disorder is macroglobulinemia (WM) .

595. The compound for use of any one of clauses 296-590, wherein the disease, syndrome, condition, or disorder is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL) , mantle cell lymphoma (MCL) , follicular lymphoma (FL) , and mucosa-associated lymphoid tissue (MALT) lymphoma.

596. The compound for use of any one of clauses 296-590, wherein the disease, syndrome, condition, or disorder is non-Hodgkin’s lymphoma (NHL) .

597. The compound for use of clause 596, wherein the non-Hodgkin’s lymphoma (NHL) is B-cell NHL.

598. The compound for use of any one of clauses 296-597, wherein the disease, syndrome, condition, or disorder is primary and secondary central nervous system lymphoma, transformed follicular lymphoma, or API2-MALT1 fusion dependent disease.

599. The compound for use of any one of clauses 296-598, wherein the disorder or condition is relapsed or refractory to prior treatment.

600. The compound for use of any one of clauses 296-599, wherein the disorder or condition is cancer and the subject has received prior treatment with a Bruton tyrosine kinase inhibitor (BTKi) .

601. The compound for use of any one of clauses 296-600, wherein the disorder or condition is cancer and the subject is relapsed or refractory to prior treatment with a Bruton tyrosine kinase inhibitor (BTKi) .

602. The compound for use of any one of clauses 296-601, wherein the disease, syndrome, condition, or disorder is an immunological disease.

603. The compound for use of any one of clauses 602, wherein the immunological disease is selected from autoimmune and inflammatory disorders, e.g., arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn’s disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplant rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet’s diseases, uveitis, myasthenia gravis, Grave’s disease, Hashimoto thyroiditis, Sjogren’s syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) , cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, and polymyositis.

604. The compound for use of any one of clauses 296-603, wherein the compound is in the form of an amorphous solid dispersion.

605. The compound for use of clause 604, wherein the amorphous solid dispersion is as defined in any one of clauses 1-103.

606. The compound for use of any one of clauses 300, 604 or 605, wherein the amorphous solid dispersion is provided as a pharmaceutical composition comprising the amorphous solid dispersion and a pharmaceutically acceptable carrier.

607. The compound for use of any one of clauses 300, 604 or 605, wherein the amorphous solid dispersion is provided as a pharmaceutical composition comprising the amorphous solid dispersion and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is a solid oral dosage form.

608. The compound for use of any one of clauses 300, 604 or 605, wherein the amorphous solid dispersion is provided as a pharmaceutical composition comprising the amorphous solid dispersion and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is a solid oral dosage form, wherein the solid oral dosage form is a tablet.

609. The compound for use of any one of clauses 296-603, wherein the compound is in the form of a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier.

610. The compound for use of any one of clauses 606-609, wherein the pharmaceutical composition is as defined in any one of clauses 104-195.

611. The compound for use of any one of clauses 296-610, wherein the compound is administered to the subject in a dosage regimen that provides a C_trough in blood plasma of at least about 10 nM.

612. The compound for use of clause 611, wherein the compound is administered to the subject in a dosage regimen that provides a C_trough in blood plasma of at least about 11 nM.

613. The compound for use of clause 612, wherein the compound is administered to the subject in a dosage regimen that provides a C_trough in blood plasma of at least about 12 nM.

614. The compound for use of clause 613, wherein the compound is administered to the subject in a dosage regimen that provides a C_trough in blood plasma of at least about 15 nM.

615. The compound for use of clause 614, wherein the compound is administered to the subject in a dosage regimen that provides a C_trough in blood plasma of at least about 20 nM.

616. The compound for use of clause 615, wherein the compound is administered to the subject in a dosage regimen that provides a C_trough in blood plasma of at least about 30 nM.

617. The compound for use of any one of clauses 296-616, wherein the compound is administered to the subject in a dosage regimen that provides a C_trough in blood plasma of from about 10 nM to about 170 nM.

618. The compound for use of clause 617, wherein the compound is administered to the subject in a dosage regimen that provides a C_trough in blood plasma of from about 10 nM to about 100 nM.

619. The compound for use of clause 618, wherein the compound is administered to the subject in a dosage regimen that provides a C_trough in blood plasma of from about 10 nM to about 55 nM.

620. The compound for use of clause 619, wherein the compound is administered to the subject in a dosage regimen that provides a C_trough in blood plasma of from about 10 nM to about 20 nM.

621. The compound for use of clause 619, wherein the compound is administered to the subject in a dosage regimen that provides a C_trough in blood plasma of from about 11 nM to about 40 nM.

622. A method of treating a disease, syndrome, condition, or disorder, wherein said disease, syndrome, condition, or disorder is affected by the inhibition of MALT1, comprising administering to a subject in need thereof a therapeutically effective amount of (1S, 3R) -3- (4- ( (R) -2-chloro-8-methyl-8- (trifluoromethyl) -7, 8-dihydro-6H-pyrazolo [1, 5-a] pyrrolo [2, 3-e] pyrimidin-6-yl) phenyl) -2, 2-difluoro-1-methyl-N- ( (trans) -3- (methylsulfonyl) cyclobutyl) cyclopropane-1-carboxamide (Compound 3) :

or a pharmaceutically acceptable salt form thereof or a solvate thereof.

623. The method of clause 622, wherein Compound 3 or a pharmaceutically acceptable salt form thereof or a solvate thereof is administered to the subject at a dose of at least about 10 mg.

624. The method of clause 622 or 623, wherein Compound 3 or a pharmaceutically acceptable salt form thereof or a solvate thereof is administered to the subject at a dose or in a dosage regimen as defined in any one of clauses 301-585 or 611-621.

625. The method of any one of clauses 622-624, wherein Compound 3 or a pharmaceutically acceptable salt form thereof is in the form of an amorphous solid dispersion.

626. The method of clause 625, wherein the amorphous solid dispersion is as defined in any one of clauses 1-103.

627. The method of clause 625 or 626, wherein the amorphous solid dispersion is provided as a pharmaceutical composition comprising the amorphous solid dispersion and a pharmaceutically acceptable carrier.

628. The method of any one of clauses 625-627, wherein the amorphous solid dispersion is provided as a pharmaceutical composition comprising the amorphous solid dispersion and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is a solid oral dosage form.

629. The method of any one of clauses 625-628, wherein the amorphous solid dispersion is provided as a pharmaceutical composition comprising the amorphous solid dispersion and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is a solid oral dosage form, wherein the solid oral dosage form is a tablet.

630. The method of any one of clauses 627-629, wherein the pharmaceutical composition is as defined in any one of clauses 104-195.

631. The method of any one of clauses 622-630, wherein the disease, syndrome, condition, or disorder is as defined in any one of clauses 587-603.

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

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

Reference is now made to the following examples, which illustrate the invention in a non-limiting fashion.

EXAMPLES

Example 1 -Synthesis of MALT1 inhibitors

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

Preparation of intermediates

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

Intermediate 1

Into a 10 L 3-necked flask was placed ethyl 2- (benzylamino) acetate (550 g, 2.85 mol, 1.00 equiv) , CHCl₃ (5.5 L) , TEA (576 g, 5.70 mmol, 2.00 equiv) . Propanoyl chloride (290 g, 3.13 mol, 1.10 equiv) in CHCl₃ (300 mL) was added dropwise at 0 ℃. The mixture was stirred for 1 h at 25 ℃. The mixture was poured into H₂O (6 L) . The resulting solution was extracted with DCM (2x 2 L) . The organic layers were combined, dried over anhydrous MgSO₄, and concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: EtOAc/PE 1: 2) to give Intermediate 1 (561 g, 79%yield) as a light-yellow oil.

Intermediate 2

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

Intermediate 3

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

Intermediate 4

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

Intermediate 5

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

Intermediate 6

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

Intermediate 7

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

Intermediate 8

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

Intermediate 9

A mixture of Intermediate 8 (100 g, 310 mmol, 1.00 equiv) , 5-chloro-2H-pyrazol-3-amine [CAS: 916211-79-5] (36.5 g, 310 mmol, 1.00 equiv) , toluene (1 L) and AcOH (100 mL) was stirred for 15 h at 95 ℃. The reaction was cooled to 25 ℃ and concentrated under vacuum. NaHCO₃ (1000 mL) was added to the mixture, and the resulting solution was extracted with EtOAc (2x 1 L) . The organic layers were combined, dried over anhydrous MgSO₄, and concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: EtOAc/PE 15: 85) to give Intermediate 9 (39.7 g, 34%yield) as a yellow oil.

Intermediate 10

A mixture of Intermediate 9 (39.7 g, 105 mmol, 1.00 equiv) , DCM (400 mL) and TFA (80 mL) was stirred for 1 h at 25 ℃. The mixture was concentrated under vacuum and NaHCO₃ (500 mL) was added. The resulting mixture was extracted with DCM (3x300 mL) . The organic layers were combined, dried over anhydrous MgSO₄, and concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: EtOAc: PE (1: 1) . This resulted in 2-chloro-8-methyl-8- (trifluoromethyl) -7, 8-dihydro-6H-pyrazolo [1, 5-a] pyrrolo [2, 3-e] pyrimidine (Intermediate 10, [CAS: 2661482-67-1] , 15.2 g, 51%yield) as a yellow solid.

Intermediate 11 and 12

Intermediate 10 (5.0 g) was separated in enantiomers via chiral SFC, using as stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO₂, EtOH + 0.4 iPrNH₂ to provide two fractions as follows:

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

Fraction 2: Intermediate 12 (2.35 g, 47%yield)

Intermediate 13

To a cooled (0 ℃) suspension of NaH (60%in mineral oil, 2.59 g, 64.85 mmol) in THF (100 mL) was added triethylphosphonopropionate (13.9 mL, 64.85 mmol) dropwise. The reaction was stirred for 30 minutes, then a solution of 4-bromobenzaldehyde [1122-91-4] (10.0 g, 54.0 mmol) in THF (20 mL) was added dropwise, keeping the internal temperature between 0 ℃and 5 ℃. The mixture was allowed to warm to RT and stirred for 16 h. The reaction was quenched with a saturated aqueous solution of NH₄Cl (60 mL) , and the aqueous layer was extracted with EtOAc (3 x 100 mL) . The combined organic layers were dried over anhydrous MgSO₄, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography over silica gel (eluent: heptane/EtOAc up to 90/10) . The fractions containing compound were combined and concentrated in vacuo to give Intermediate 13 (12.3 g, 84%yield) as a colorless oil.

Intermediate 14

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

Intermediate 15

To a solution of Intermediate 14 (8.70 g, 38.3 mmol) and imidazole (3.13 g, 46.0 mmol) in DCM (100 mL) pre-cooled to 0 ℃, was added triisopropylsilyl chloride (9.0 mL, 42.1 mmol) dropwise. The mixture was allowed to warm up to RT and stirred for 16 h. The mixture was diluted with water (100 mL) and DCM (100 mL) . The organic layer was separated, and the aqueous layer was extracted with DCM (100 mL) . The combined organic layers were washed with brine (100 mL) , dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The crude was purified by flash column chromatography over silica gel (eluent: heptane/DCM up to 90/10) to obtain Intermediate 15 (14 g, 95%yield) as a colorless oil.

Intermediate 16

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

Intermediate 17

To a solution of Intermediate 16 (3.81 g, 13.75 mmol) in water/MeCN (87 mL/87 mL) , were added TEMPO (1.07 g, 6.87 mmol) , (Diacetoxyiodo) benzene (13.29 g, 41.25 mmol) and NaHCO₃ (2.89 g, 34.37 mmol) . The mixture was stirred for 6 h at RT, the mixture was diluted with water, and aq HCl (1 M) was added until the pH reached approximately 2. EtOAc was added and the organic layer was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over anhydrous MgSO₄, filtered, and evaporated. The product was stirred in diisopropyl ether and filtered. The filtrate was evaporated and stirred in heptane to obtain a precipitate that was filtered and dried over anhydrous MgSO₄ to give Intermediate 17 (3.46 g, 86%yield) as white solid.

Intermediate 18

To a mixture of Intermediate 17 (200.0 mg, 0.687 mmol) and N- [ (Dimethylamino) -1H-1, 2, 3-triazolo- [4, 5-b] pyridin-1-ylmethylene] -N-methylmethanaminium hexafluorophosphate N-oxide (522.5 mg, 1.37 mmol) and N, N-Diethylethanamine (0.38 mL, 2.75 mmol) in MeCN (5.2 mL) was added 3- (methylsulfonyl) cyclobutan-1-amine hydrochloride [2639792-63-3] (205.0 mg, 1.37 mmol) . The reaction was stirred at RT for 1 h. The reaction was diluted with EtOAc and water. The water layer was separated, and the acqueouse phase was extracted with EtOAc. The combined organic layers were then dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography over silica gel (eluent: MeOH/DCM 0 to 7%) to give Intermediate 18 (264 mg, 91%yield) as a white solid.

Intermediate 19

Intermediate 19 was prepared by an analogous reaction protocol as Intermediate 18, starting from trans-3-methylsulfonylcyclobutylamine hydrochloride [1408075-97-7] (1.25 g, 6.73 mmol) instead of 3- (methylsulfonyl) cyclobutan-1-amine hydrochloride [2639792-63-3] to give Intermediate 19 (1.16 g, 73%yield) as a light-yellow solid.

Compound 1

A pressure tube was charged with Intermediate 19 (175 mg, 0.41 mmol) , Intermediate 11 (126.11 mg, 0.46 mmol) , BrettPhos Pd G3 (37.57 mg, 0.041 mmol) , BrettPhos (22.24 mg, 0.041 mmol) , Cs₂CO₃ (202.53 mg, 0.62 mmol) , and 1, 4-dioxane (4.05 mL) . The mixture was degassed, then stirred at 60 ℃ for 8 h. The reaction was cooled down to RT and filtered through celite. The filtrate was concentrated under reduced pressure and the crude was purified by Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10μm, 30x150mm, Mobile phase: 0.25%NH₄HCO₃ solution in water, CH₃CN) to obtain Compound 1 as a yellow solid (147 mg, 58%yield) .

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

Compound 2 and Compound 3

Compound 1 (147 mg) was separated via chiral SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO₂, EtOH + 0.4 iPrNH₂) . The fractions containing compound were combined and the solvent was concentrated in vacuo to provide two fractions as follows:

Fraction 1: Compound 2 (61 mg, 24%yield starting from intermediate 19)

¹H NMR (CHLOROFORM-d, 400 MHz) δ ppm: 8.26 (d, J=1.3 Hz, 1H) , 7.26 -7.22 (m, 1H) , 7.15 (d, J=11.9 Hz, 1H) , 7.08 (d, J=8.3 Hz, 1H) , 6.71 (s, 1H) , 6.08 (br d, J=6.4 Hz, 1H) , 4.55 (sxt, J=7.6 Hz, 1H) , 4.26 (d, J=10.5 Hz, 1H) , 4.06 (d, J=11.4 Hz, 1H) , 3.79 (tt, J=4.7, 9.5 Hz, 1H) , 3.64 -3.59 (m, 1H) , 3.00 -2.92 (m, 2H) , 2.87 (s, 3H) , 2.70 -2.61 (m, 2H) , 2.00 (s, 3H) , 1.25 (s, 3H) .

Fraction 2: Compound 3 (63 mg, 25%yield starting from intermediate 19)

¹H NMR (CHLOROFORM-d, 400 MHz) δ ppm: 8.26 (d, J=1.3 Hz, 1H) , 7.25 -7.05 (m, 3H) , 6.70 (s, 1H) , 6.06 (d, J=6.2Hz, 1H) , 4.59 -4.50 (m, 1H) , 4.24 (d, J=10.5 Hz, 1H) , 4.06 (d, J=11.5 Hz, 1H) , 3.83 -3.75 (m, 1H) , 3.61 (d, J=16.0 Hz, 1H) , 2.99 -2.92 (m, 2H) , 2.86 (s, 3H) , 2.69 -2.60 (m, 2H) , 1.99 (s, 3H) , 1.24 (s, 3H) .

¹H NMR spectra were recorded on Bruker Avance III 400MHz and Avance NEO 400MHz spectrometers. CHLOROFORM-d was used as solvent, unless otherwise mentioned. The chemical shifts are expressed in ppm relative to tetramethylsilane.

Crystalline Form I of Compound 3

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

Crystalline Form II (IIa and IIb) of Compound 3

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

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

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

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

Analytical Analysis

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

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

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

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

LCMS methods are set out in Table 1, with flow expressed in mL/min, column temperature (T) in ℃, run time in minutes. ‘ACN' refers to acetonitrile.

Table 1: Methods used for LCMS analysis of compounds.

LCMS results for Compounds 1-3 are set out in Table 2, wherein R_t means retention time (in minutes) ; [M+H] ⁺ means the protonated mass of the compound; method refers to the method used for LCMS analysis of compounds; No. means number.

Table 2: LCMS results.

Example 2 -Pharmacological analysis of MALT1 inhibitors

Biological Examples

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

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

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

In Vitro Assays

Biological Example 1

MALT1 Biochemical Protease Assay

MALT1 protease activity was assessed in an in vitro assay using a tetrapeptide as substrate and full-length MALT1 protein (Strep-MALT1 (1-824) -His) purified from baculovirus-infected insect cells. The tetrapeptide LRSR is coupled to AMC (7-amino-4-methylcoumarin) and provides a quenched, fluorescent substrate for the MALT1 protease (SM Biochemicals) . Cleavage of AMC from the Arginine residue results in an increase in coumarin fluorescence measured at 460 nm (excitation 355 nm) . The final assay buffer consisted of 10 nM FL MALT1 protein, 200 μM Ac-LRSR-AMC, 50 mM Tris pH 7.5, 0.6 M Citrate, 1 mM dithiothreitol (DTT) , 1 mM ethylenediaminetetraacetic acid (EDTA) , 0.05%bovine serum albumin (BSA) and 1.5%dimethyl sulfoxide (DMSO) . Test compounds were spotted at 50 nL in 100%DMSO per well of a black 384-Proxiplate (Perkin Elmer) . Test compound concentrations ranged from 30 μM to 0.5 nM using 11 dilution steps (1: 3) . Background signal was measured from control wells containing assay buffer without enzyme which functions as low control (LC) . High control (HC) values were generated using the reaction with enzyme but no compound treatment. Compounds were pre-incubated with MALT1 enzyme for 50 minutes at RT. Substrate was added subsequently, and fluorescence was measured in Labsystems fluoroskan at excitation 355 nm and emission 460 nm to determine time 0. The reaction was subsequently incubated for 4 h at RT and fluorescence was measured. For IC₅₀ calculations, timepoint 0 was subtracted from the 4 h timepoint to correct for any potential autofluorescence of the compounds. The enzyme reaction was linear during the 4 h incubation period. Characterization of the substrate Ac-LRSR-AMC determined the Michaelis constant K_M at 200 μM.

IC₅₀ values were calculated using the following formula (Z prime should be >0.5) :
LC = Median of the low control values
= Low control: Reaction without enzyme
HC = Median of the High control values
= High Control: Reaction with enzyme
%Effect = 100- [ ( (sample-LC) / (HC-LC) ) x 100]
%Control = (sample /HC) x 100
%Controlmin = ( (sample-LC) / (HC-LC) ) x 100

A best-fit curve was fitted by a minimum sum of squares method to the plot of %Controlmin vs. compound concentration. From this an IC₅₀ value (inhibitory concentration causing 50 %inhibition) can be obtained. An estimate of the slope of the plot in terms of the Hill coefficient was also obtained.

IC₅₀ Calculation:

with

y = estimated response

UB = upper bound

LB = lower bound

h = Hill slope of curve

CONC = concentration

Used in “Lexis Dose Response Curve Fitting” Version 1.0.

Resultant data are shown in Table 3.

Table 3: IC₅₀ values for Compounds 1-3.

Biological Example 2

GloSensor reporter MALT1-mediated cleavage In Jurkat Cells

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

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

IC₅₀ values were calculated using SmartFit in GeneData

SmartFit uses the 4p curve fit equation seen below:

where:

x = concentration

y = activity

S₀ = activity at bottom plateau of curve

S_inf = activity at top plateau of curve

S₅₀ = inflection point, halfway between S0 and Sinf

h = Hill slope of curve

Resultant data are shown in Table 4.

Table 4: IC₅₀ values for Compounds 1-3.

Biological Example 3

Human IL-6/IL-10 Mesoscale Assay

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

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

Table 5: IC₅₀ data for Compounds 1-3.

Biological Example 4

Proliferation Assays

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

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

IC₅₀ values were calculated using SmartFit in GeneData

SmartFit uses the 4p curve fit equation seen below:

where:

x = concentration

y = activity

S₀ = activity at bottom plateau of curve

S_inf = activity at top plateau of curve

S₅₀ = inflection point, halfway between S0 and Sinf

h = Hill slope of curve

Resultant data are shown in Table 6.

Table 6: IC₅₀ data for Compounds 1-3.

Example 3 -Crystalline Form I of Compound 3

Crystalline Form I of Compound 3 may be characterised by an X-ray powder diffraction pattern.

X-ray powder diffraction (XRPD) analyses were carried out on a PANalytical Empyrean diffractometer. The instrument is equipped with a Cu-Kα X-ray tube using iCore and dCore tunable optics for the incident and the diffracted beam, respectively. The compound was spread on the center of a zero-background holder assuring a flat surface.

INSTRUMENT PARAMETERS

MEASUREMENT CONDITIONS

Incident beam path (iCore)

Program. divergence slit: automatic

Irradiated length: 10 mm

Soller slit: 0.03 rad

Mask 1: 14 mm

Mask 2: 14 mm

Width: 15.7 mm

Diffracted beam path (dCore)

Anti scatter slit: automatic

Irradiated length: 10 mm

Soller slit: 0.04 rad

Detector: PIXcel3D-Medipix3 1x1

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

The X-ray powder diffraction pattern comprises peaks at 7.9, 11.2, 11.9, 13.4, 14.0, 16.6, 18.0, 19.2 and 23.5 degrees two theta ± 0.2 degrees two theta. The X-ray powder diffraction pattern may further comprise at least one peak selected from 9.9, 15.1, 15.6, 16.1, 18.4, 19.6, 20.2, 20.5, 22.0, 22.4, 22.8, 28.3, 28.7 and 34.7 degrees two theta ± 0.2 degrees two theta.

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

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

Form I may further be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 1a.

Table 7 provides peak listings and relative intensity for the XRPD of Crystalline form I (Figure 1a) .

Table 7:

Form I may also be characterized by a differential scanning calorimetry thermogram (DSC) comprising an endotherm with an onset temperature of 183.4 ℃ and a peak temperature at 185.51 ℃. Form I may be characterised by a DSC substantially as depicted in Figure 1b.

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

Form I may further be characterized by dynamic vapor sorption (DVS) . Form I may exhibit a DVS isotherm plot substantially as depicted in Figure 1d.

Example 4 -Crystalline Form IIa of Compound 3

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

The X-ray powder diffraction pattern comprises peaks at 8.1, 10.8, 13.5, 14.9, 16.2, 17.4, 17.9, 19.1, 20.2 and 22.1 degrees two theta ± 0.2 degrees two theta. The X-ray powder diffraction pattern may further comprise at least one peak selected from 7.6, 11.1, 11.5, 11.8, 12.9, 13.9, 15.2, 22.7, 23.0, 23.2, 24.7, 26.5, 27.3 and 28.2 degrees two theta ± 0.2 degrees two theta.

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

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

Form IIa may further be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 2a.

Table 8 provides peak listings and relative intensity for the XRPD of Crystalline form IIa (Figure 2a) .

Table 8:

Form IIa may also be characterized by a differential scanning calorimetry thermogram (DSC) substantially as depicted in Figure 2b.

Form IIa may further be characterized by thermal gravimetric analysis (TGA) . Form IIa may exhibit a TGA curve substantially as depicted in Figure 2c.

Example 5 -Crystalline Form IIb of Compound 3

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

The X-ray powder diffraction pattern comprises peaks at 7.6, 8.2, 10.7, 12.8, 13.5, 15.1, 15.3, 17.2, 17.5, 17.9 and 21.9 degrees two theta ± 0.2 degrees two theta. The X-ray powder diffraction pattern may further comprise at least one peak selected from 9.5, 11.5, 16.0, 16.4, 18.4, 18.6, 19.1, 20.1, 21.5, 24.8, 26.2, 27.0 and 27.2 degrees two theta ± 0.2 degrees two theta.

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

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

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

Table 9 provides peak listings and relative intensity for the XRPD of Crystalline form IIb (Figure 3a) .

Table 9:

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

Form IIb may further be characterized by thermal gravimetric analysis (TGA) . Form IIa may exhibit a TGA curve substantially as depicted in Figure 4.

Example 6 -Methods for characterizing crystalline forms

Differential scanning calorimetry (DSC)

About 3 mg of the compound was transferred into a standard aluminum TA-Instrument sample pan. The sample pan was closed with the appropriate cover and the DSC curve was recorded on a TA-Instruments Q2500 MTDSC equipped with a RCS cooling unit. The following parameters were used for the DSC measurements reported herein:

TGA Method

About 10 mg of the compound was transferred into a TA Instruments platinum TGA pan. The TGA curve was recorded on a TA Instruments TGA 550. The following parameters were used for the TGA measurements reported herein:

Bulk stability

Bulk stability experiments were performed for crystalline Form I (Table 10) . All anhydrates (Form I) showed physical stability upon stability testing. They are kinetically stable.

Table 10: Bulk stability of crystalline Form I.

Form II desolvates readily, resulting in Form I anhydrate. This anhydrous form showed physical stability under various conditions.

Example 7 -Preparation of amorphous solid dispersions of Compound 3 by solvent evaporation

Amorphous solid dispersions of Compound 3 (also referred to as API) and the orally pharmaceutically acceptable polymer were prepared in 10 mL glass vials by a solvent evaporation method. The orally pharmaceutically acceptable polymers were:

● E100 (poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (1: 2: 1) ) ;

● PVP K30 (polyvinylpyrrolidone) ;

● (agraft copolymer of polyvinyl caprolactam, polyvinyl acetate and polyethylene glycol) ;

● L100 (poly (methacrylic acid-co-methyl methacrylate) (1: 1) ) ;

● HPMC AS LG (HPMC AS comprising 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl) ;

● HPMC AS MG (HPMC AS comprising 7.0 wt%to 11.0 wt%acetyl and 10.0 wt%to 14.0 wt%succinoyl) ;

● HPMC AS HG (HPMC AS comprising 10.0 wt%to 14.0 wt%acetyl and 4.0 wt%to 8.0 wt%succinoyl) ;

● HPMC E5 (HPMC comprising 28 wt%to 30 wt%methoxyl and 7 wt%to 12 wt%hydroxypropyl) ;

● PVP VA64 (acopolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a ratio of 6: 4 by mass) .

Starting material Compound 3 (crystalline Form I) and the orally pharmaceutically acceptable polymer were both dissolved in a mixture of dichloromethane and methanol (50/50, v/v) or ethanol. Appropriate ratios of the API and polymer solutions were mixed and dispensed into the vials. After dispensing, amorphous API-polymer films were generated by rapid evaporation of the organic solvent. This was achieved by evaporation under reduced pressure for one hour using a vacuum oven set at 70℃ and 200 mbar. The resulting films, containing approximately 1 mg of API, were cooled down and kept at room temperature for one day before starting the dissolution assay. Films were prepared at a 1/2 and 1/3 API to polymer ratio. A neat amorphous API concept was included as reference.

Example 9 -Physical stability testing of ASD concepts

Films containing 100 μg of the API were prepared in 1 mL glass vials by solvent evaporation similar as described above and evaluated for their physical stability. This was done by stressing the films for 4 weeks at 40℃/75%relative humidity (RH) . The stability assessment was performed by polarized light microscopy (PLM) prior to and after stressing. 4 replicates were prepared of each concept.

Analysis using polarized light microscopy (PLM) , indicated formation of stable ASDs immediately after film casting. After 4 weeks storage at 40℃/75%RH no crystalline material could be detected for any of the ASD concepts.

Example 10 -Chemical stability testing of ASD concepts

Various ASD concepts were evaluated for their chemical stability. This was done by stressing the ASDs for 4 weeks at 40℃/75%RH, 50℃/10%RH, and 60℃/30%RH.

For this study, final sample concentrations of 0.5 mg/mL of the API in water/acetonitrile were used. All samples were analysed with a chiral HPLC method using a PDA detector at 298 nm.

LC Method

Column: Phenomenex Lux Cellulose-2

Column Length: 150 mm Column Diameter: 4.6 mm

Column Temperature: 45 ℃ Particle Size: 3.0 μm

Flow: 0.8 mL/min Injection

Volume: 4.0 -6.0 mL

Solvent A: 15 mM NH4TFA in water + 0.1%TFA

Solvent B: Acetonitrile

Gradient Time:

The total %of degradation for various concepts is shown in Figures 6-8. The polymers can be divided in roughly two classes: polymers with hydrogen bond donors and acceptors (e.g., HPMC-AS LG) stabilize the API best at 40℃/75%RH, but stability is decreased at higher temperature. Choosing the right polymer and ratio increases the chemical stability: 1/3 ～ 1/2 >1/1 > amorphous API.

Example 11 -Process for preparation of amorphous solid dispersions by spray-drying

Methanol and methylene chloride were transferred into a suitable container and stirred using a mixer. While stirring, Compound 3 (crystalline Form I) was added to the solvent. This was stirred until dissolved. While stirring, hypromellose acetate succinate (HPMCAS LG) was added into the same container. The mixture was stirred until fully dissolved.

The spray feed mixture (containing Compound 3, hypromellose acetate succinate, methanol and methylene chloride) was spray dried using a spray dryer (ProCept SD-2) . The spray dried powder was collected in a suitable container. Following this, the spray dried powder was post dried in a tray dryer (vacuum oven) and collected.

The spray drying conditions are set out in more detail in Table 15 below.

Table 15: Spray drying conditions.

An example of a batch formula for a spray dried amorphous solid dispersion of Compound 3 (250 mg/g) is provided in Table 16 below.

Table 16: Batch formula for an exemplary amorphous solid dispersion of Compound 3 (250 mg/g) .

An alternative solvent system that was used is acetone/water 9/1 with following spray dry conditions in Table 15b:

An example of a batch formula for a spray dried amorphous solid dispersion of Compound 3 (250 mg/g) is provided in Table 16b below.

Table 16b: Composition of Compound 3 250mg/g spray dried product (SDP) .

Example 12 -Evaluation of spray-dried ASD concepts

Based on the available physical stability, chemical stability and dissolution results obtained for the ASD films, the following concepts were selected for evaluation via spray-drying: HPMCAS LG 1: 2 (Concept 1) , HPMCAS LG 1: 3 (Concept 2) , L100 1: 3 (Concept 3) and HPMC E5 1: 3 (Concept 4) .

The ASDs were spray-dried under the conditions provided in Table 17.

Table 17: Spray drying conditions.

Physical stability

The amorphous nature of the ASD powders was assessed by XRD. The ASDs were stored at RT, 40℃/75%RH, 50℃/75%RH, 60℃/10%RH, 60℃/30%RH and 60℃/75%RH.

The method has been developed using the following equipment, but equivalent equipment can be used. If equivalent instrumentation is used it may be necessary to adapt some of the instrument components (e.g., settings and/or optics) .

Bruker D8 Advance X-ray diffractometer

X-ray tube Cu: K-Alpha

Detector: PSD: LYNXEYE_XE_T or equivalent

Sample Holder: Si low background sample holder with cavity (C79298A3244B261) . Cavity diameter 20 mm, cavity height 0.5 mm

Instrument Settings and Parameters

Optical Components

After 6 months, no crystallisation of any ASD was detected by XRD.

Chemical stability

The four concepts were evaluated for their chemical stability. The ASDs were stored for 4 weeks at 5℃, 50℃/75%RH, 60℃/10%RH, 60℃/30%RH, and 60℃/75%RH.

The chemical stability was assessed using the chromatographic method as set out in Table 18.

Table 18: Details of the chromatographic method.

The results of the testing are shown in Figure 9. In this figure, C1 refers to HPMCAS LG 1: 2, C2 refers to HPMCAS LG 1: 3, C3 refers toL100 1: 3, C4 refers to HPMC E5 1: 3, and C5 refers to crystalline API. There is an increasing trend in chemical degradation with increasing temperature and increasing %RH. Of all ASD concepts, Concept 3 (L100 1: 3) showed the greatest percentage of degradation products. Concept 1 (HPMCAS LG 1: 2) is equally chemically stable to Concept 2 (HPMCAS LG 1: 3) , with the API/polymer ratio having no impact on the chemical stability.

Dissolution assay

ASDs containing 35 mg and 100 mg of API underwent dissolution testing in 2-phase SGF/FaSSIF. The results are shown in Figures 10 and 11. It was observed that the dissolution rate of HPMCAS LG 1/3 was higher than that of HPMCAS LG 1/2 at both 35 mg and 100 mg dose levels.

ASDs containing 35 mg and 100 mg of API were also tested by dissolution testing in 1-phase. The results are shown in Figure 17. As an example, a typical method description of the 1-phase testing is below:

Dissolution Medium (FaSSIF pH 6.5 1 L preparation)

3.953 g Sodium phosphate monobasic anhydrous, 6.187 g Sodium Chloride and 0.348 g Sodium Hydroxide pellets were dissolved in a 1-L volumetric flask with about approximately 500 mL of demineralized water. 1.650 g sodium taurocholate was weighed accurately in a beaker, dissolved with some demineralized water and transfered quantitatively to the volumetric flask. 0.590 g lecithin lipoid was weighed accurately on a weighing paper and transferred quantitatively to the volumetric flask. The solution was stirred in a water bath at 37 ℃ until the lecithin was completely solubilized and a transparent solution was obtained. The solution was allowed to cool down to room temperature. pH was adjusted to pH 6.50 ± 0.05 using Phosphoric Acid or Sodium Hydroxide solutions. Demineralized water was added to dilute to volume. It was verified that the pH is 6.50 ± 0.05 units.

Dissolution testing:

Dissolution studies (n=3) were conducted on tablet formulations of 35 mg and 100 mg using 900 mL of medium in a USP Apparatus 2, set at 50 rpm and maintained at 37℃. During the test, approximately 5 mL samples were withdrawn at intervals of 5, 15, 30, 45, 60, and 120 minutes using a stainless-steel cannula and plastic syringe. The syringe was then detached from the cannula and connected to a 0.02 μm regenerated cellulose membrane filter. After discarding the initial 3 mL of filtrate, the remaining sample was filtered immediately following collection.

Chromatographic Condition for Detection:

Drug concentrations in FaSSIF were determined using an ultra-high-performance liquid chromatography (UHPLC) system. The analysis was performed on a Waters AcquityCSH C18 column with a 1.7-μm particle size and dimensions of 50 x 2.1 mm. The column temperature was maintained at 55℃. Gradient elution was employed with a mobile phase consisting of 10 mM ammonium acetate in purified water and acetonitrile. The flow rate was set at 0.8 mL/min, and the injection volume was 7 μL. UV detection was conducted at a wavelength of 297 nm.

Example 13 -General process for preparation of tablets

An amorphous solid dispersion (prepared as described in the example above) , silicified microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silica and magnesium stearate were sieved and blended in a bin blender. The blend was roller compacted using a roller compactor (WP120) to collect granules.

Croscarmellose sodium and silicified microcrystalline cellulose were sieved, added to the dry granules, and blended using a suitable blender. Following this, magnesium stearate was sieved and added to the blend, which was then blended in the blender. The final blend was compressed into tablets using Rotary Korch XL100.

Example 14 -Pharmacokinetics in dogs

The pharmacokinetics of Compound 3 in various formulations (as shown in Table 19) was investigated in Beagle dogs.

Table 19: Formulations tested in PK studies.

IV –intravenous; PO –oral; ASD –amorphous solid dispersion; API –active pharmaceutical ingredient; HPMCAS LG –hydroxypropylmethylcellulose acetate succinate L grade

Intravenous administration

For the intravenous route, three male Beagle dogs were used to obtain a complete concentration time-profile from each individual animal. The body weight of the dogs ranged from 9.58 to 13.52 kg. Animals were fasted overnight for at least 16 h prior to dosing, standard food was returned ～ 2 h post dose, tap water was available ad libitum.

For the intravenous formulation, Compound 3 was dissolved in PEG400/water (70/30) solution at a final concentration of 0.25 mg/mL, the final pH was 7.83. The formulation was kept stirring overnight at room temperature and was protected from light, until dosing the next day. After dosing the formulation was kept at 2-8℃ until quantitative analysis one day after dosing by LC-MS/MS. The final concentration of the formulation was within 10%of theoretical, hence nominal dose was used for data analysis. Animals were dosed intravenously in a cephalic vein at 2 mL/kg to obtain a final dose of 0.5 mg/kg. From each intravenously dosed animal, blood samples were taken at 1, 6 and 20 min, and 1, 2, 4, 7, 24, 48 and 72 h post dose.

Blood was collected by multiple sampling from a jugular vein into tubes containing K2EDTA. Samples were placed immediately on melting ice. Plasma was collected following centrifugation at approximately 2000 g for 10 minutes at 4 ℃. Samples were stored at –75±15 ℃ until analysis. Plasma was analysed for Compound 3 using a qualified research LC-MS/MS method. The lower limit of quantification (LLOQ) for plasma was 0.5 ng/mL. A limited pharmacokinetic analysis was performed using Phoenix^TM WinNonlin. A non-compartmental analysis using the Linear Up Log Down calculation method was used for all data. An overview of the mean plasma concentrations and the pharmacokinetic parameters can be found in Table 20.

After intravenous administration at 0.5 mg/kg, plasma concentrations were detectable up to the last sample time point of 72 h post dose. Mean extrapolated C₀ value was 1979 ng/mL. Mean clearance was 0.583 mL/min/kg and mean V_ss 1.03 L/kg. Half-life was on average 21.6 h.

Table 20: Mean (n = 3) plasma concentrations and basic pharmacokinetic parameters of Compound 3 after single intravenous administration at 0.5 mg/kg of Compound 3 in fasted male Beagle dogs.

Last time point for AUC_last: 72 h.

Last three time points were included in the terminal elimination t_1/2.

NA = not available. This applies e.g., in cases where individual values were excluded from statistics due to AUC_extrap > 20%.

Oral administration

The pharmacokinetics of Compound 3 after single oral (PO) administration was investigated at 3.5 mg eq. /kg dosed as an ASD suspension and at 35 mg eq. dosed as ASD tablets in fasted male Beagle dogs. The ASDs contained Compound 3 and HPMC AS LG at ratios of 1: 2 and 1: 3 (as shown in Table 19) .

Twelve male Beagle dogs with a body weight range of 8.0 to 12.7 kg at the start of the experimental phase were used and randomly divided as n = 3 per dose group. A complete plasma concentration time-profile was obtained from each individual animal. Prior to dosing, animals were fasted overnight. Standard food was returned to them at 2 h post dose. Tap water was available ad libitum.

The ASD suspensions was prepared in 0.5%methocel F4M in McIlvaine buffer pH 4.0 at a final concentration of 1.75 mg eq. /mL, the final pH was 3.94-3.98. The suspensions were stored in the refrigerator and were protected from light until dosing. The formulations were analyzed with (ultra) high performance liquid chromatography (UHPLC) , the final concentration was 87-90%of theoretical, nominal dose was used for data analysis.

Tablets were filled with ASD powder containing 35 mg eq. of Compound 3 per tablet.

The animals were administered with 20 mL of HCl/KCl buffer (pH 1.41) at 10 min before dosing of the ASD suspensions and tablets. Animals were dosed orally by gavage at 2 mL/kg of the ASD suspensions to obtain a final dose of 3.5 mg eq. /kg. For the tablets, one tablet containing 35 mg eq. was dosed to obtain a dose of ～ 3.5 mg eq. /kg based on an animal weight of 10 kg. From each individual dosed animal, blood samples were taken at 15 and 30 min, and 1, 2, 4, 7, 24, 48 and 72 h post dose.

Blood was collected by multiple sampling from a cephalic vein into micro haematocrit tubes (32-64 μL) containing EDTA. Samples were placed immediately on melting ice and protected from light. Samples were centrifuged at ～ 1500 x g for 10 min at 4 ℃ for plasma separation. Plasma samples were collected with end-to-end pipettes (10 μL) and stored at approx. –20 ℃until analysis.

Plasma samples were analysed for Compound 3 using a qualified research LC-MS/MS method. The lower limit of quantification (LLOQ) for plasma was 1, 4 or 10 ng/mL. A limited pharmacokinetic analysis was performed using PhoenixTM WinNonlin. A non-compartmental analysis using the Linear Up Log Down calculation method was used for all data. An overview of the mean plasma concentrations and the pharmacokinetic parameters can be found in Tables 21 to 24. AUC values at 0.5 mg/kg intravenous administration were used for calculation of the oral bioavailability.

Table 21: Mean (n = 3) plasma concentrations and basic pharmacokinetic parameters of Compound 3 after single oral administration as an ASD suspension (1: 2) at 3.5 mg eq. /kg of Compound 3 in fasted male Beagle dogs.

NA = not available. This applies e.g., in cases where individual values were excluded from statistics due to AUC_extrap > 20%and/or R_sq < 0.85.

^c = Oral bioavailability was calculated using the IV data, AUC_0-72h was 13787 ng. h/mL after IV dosing at 0.5 mg/kg.

Table 22: Mean (n = 3) plasma concentrations and basic pharmacokinetic parameters of Compound 3 after single oral administration as an ASD suspension (1: 3) at 3.5 mg eq. /kg of Compound 3 in fasted male Beagle dogs.

Table 23: Mean (n = 3) plasma concentrations and basic pharmacokinetic parameters of Compound 3 after single oral administration as an ASD (1: 2) tablet at 35 mg eq. of Compound 3 in fasted male Beagle dogs.

Table 24: Mean (n = 3) plasma concentrations and basic pharmacokinetic parameters of Compound 3 after single oral administration as an ASD (1: 3) tablet at 35 mg eq. of Compound 3 in fasted male Beagle dogs.

After oral dosing of both ASD suspensions of Compound 3 at 3.5 mg eq. /kg, plasma concentrations could be determined from 0.25 h onwards (first sampling time point) . T_max was observed at 1, 2 or generally 4 h for both ASD suspensions and plasma levels slowly declined thereafter, hence only limited terminal phase and PK could be determined (especially for HPMC AS LG 1: 2 ratio suspension) .

For ASD suspension HPMC AS LG 1: 2 ratio, dosed at 3.5 mg eq. /kg, C_max ranged from 3400 to 3600 ng/mL and AUC_last varied from 110000 to 171000 ng. h/mL, mean half-life was 23.0 h (n=1) . Oral bioavailability was > 100%.

For ASD suspension HPMC AS LG 1: 3 ratio, dosed at 3.5 mg eq. /kg, C_max ranged from 2260 to 4370 ng/mL and AUC_last varied from 82600 to 94500 ng. h/mL, mean half-life was 20.0 h (n=2) . Oral bioavailability was on average 93%. The exposure of the ASD suspensions, based on mean C_max and AUC_last, was slightly higher to comparable for ASD 1: 2 when compared to ASD 1: 3 (1.5-fold higher for AUC_last and 1.2-fold higher for C_max) .

After oral administration of both Tablet forms of Compound 3 at 35 mg eq. /tablet (actual doses ranging between 3.3 and 4.4 mg eq. /kg) , plasma concentrations could be determined from 0.25 h onwards. T_max was observed at 1 or 2 h for both tablet forms and plasma levels slowly declined thereafter, hence only limited terminal phase and PK could be determined.

For Tablet HPMC AS LG 1: 3 ratio, dosed at 35 mg eq. /tablet (mean actual dose of 3.9 mg eq./kg) , C_max ranged from 3160 to 5160 ng/mL and AUC_last varied from 105000 to 146000 ng.h/mL, mean half-life was 25.2 h (n=1) . Oral bioavailability ranged from 98 to > 100%.

For Tablet HPMC AS LG 1: 2 ratio, dosed at 35 mg eq. /tablet (mean actual dose of 3.8 mg eq./kg) , C_max ranged from 3000 to 4260 ng/mL and AUC_last varied from 111000 to 119000 ng.h/mL, mean half-life was 28.8 h (n=2) . Oral bioavailability was > 100%.

The exposure of the tablet forms, based on mean C_max and AUC_last, was comparable between ratios 1: 2 and 1: 3 (AUC_last ratio of 0.87 and C_max ratio of 0.79) .

In summary, the data indicate close to 100%bioavailability for the ASD concepts after oral administration of a 3.5 mg/kg dose in fasted state (both suspension and tablet) .

Example 15 -Pharmacokinetics (PK) , pharmacodynamics (PD) and efficacy of Compound 3 in Diffuse Large B-cell Lymphoma Xenografts

Test Agents and Controls

The test agent (Compound 3) was formulated as a solution for oral administration in 100%polyethylene glycol (PEG) 400 for all studies. The vehicle control groups were treated with 100%PEG 400. Working stocks were formulated every 2 weeks by adding the required volume of 100%PEG 400 to pre-weighed compound, stirring until compound was dissolved and stored at room temperature (RT) . Doses were adjusted by individual body weight each day and were delivered at 5 mL/kg.

Animals

For all studies, female non-obese diabetic (NOD) severe combined immunodeficiency (scid) gamma or NOD. Cg-Prkdcscid Il2rgtmlWjl/SzJ gamma (NSG) mice (Charles River Laboratories) were used at approximately 6 to 8 weeks of age (body weight range 20-25 grams) . All animals were allowed to acclimate and recover for a minimum of 7 days prior to experimental use. Autoclaved water and irradiated food were provided ad libitum, and animals were maintained on a 12-hour light and dark cycle. Cages, bedding, and water bottles were autoclaved before use and changed weekly. All experiments were carried out in accordance with The Guide for the Care and Use of Laboratory Animals, the European Communities Council Directives 2010/63/EU and were approved by the local ethics committee of Janssen Pharmaceutica NV, Beerse, Belgium.

Reagents

BCA, bicinchoninic acid; BCL, B-cell lymphoma/leukemia; M-PER, mammalian protein extraction reagent; MSD, Meso Scale Discovery; RPMI, Roswell Park Memorial Institute; TBS, tris buffered saline.

Experimental Procedure

The human activated B-cell subtype-diffuse large B-cell lymphoma (ABC-DLBCL) cell line OCI-Ly3 was obtained from Dr. Miguel A Piris, Hospital Universitario Marques de Valdecilla, Santander, Spain. The human ABC-DLBCL cell line OCI-Ly10 was obtained from Dr Mark Minden at the University Health Network (University of Toronto, Toronto, Canada) . Cell lines were maintained at 37℃, 5%CO2 in a humidified atmosphere, in Roswell Park Memorial Institute (RPMI) 1640 medium with GlutaMAX, supplemented with 10%heat-inactivated fetal bovine serum. Cells were harvested while in logarithmic growth. On the day of tumor implantation, OCI-Ly3 and OCI-Ly10 cells were resuspended in cold (4℃) serum-free RPMI 1640 medium with Matrigel (diluted 1: 1) . Each mouse received 1×10⁷ OCI-Ly3 or 1×10⁶ OCI-Ly10 cells in the right flank, in a total volume of 0.15 mL. Cells were implanted SC using a 1-mL syringe and a 26-gauge needle.

Tumor-bearing mice were randomized according to tumor sizes (for PK/PD studies: OCI-Ly3 mean of 700 mm³; n=5/group and OCI-Ly10 mean of 550 mm³; n=5/group; and for efficacy studies: OCI-Ly3 mean of 159 mm³; n=10/group and OCI-Ly10 mean of 120 mm³; n=10/group) . Treatment with vehicle, or test article at 1, 3, 10, 30, or 100 mg/kg was initiated on the same day (OCI-Ly3) or the day following randomization (OCI-Ly10) , with oral dosing twice a day for 23 (OCI-Ly10) or 28 (OCI-Ly3) days.

For PK/PD studies, blood was collected by saphenous vein or retro-orbital plexus sampling and processed to serum by centrifugation at 6,000 revolutions per minute (rpm) for 10 minutes at 4℃ from 5 animals per time point at 6, 12, and 24 hours post treatment, and stored at -80℃ for subsequent PK/PD analysis. Tumors were collected 24 hours post treatment, snap frozen, and stored at -80℃ for subsequent PD analysis.

For efficacy studies, body weight and tumor volume were measured 2 times per week throughout each study. Tumor volume was calculated using the formula: Tumor volume (mm³) = (D×d2/2) ; where ‘D’ represents the larger diameter and ‘d’ the smaller diameter of the tumor as determined by caliper measurements. Blood was collected by saphenous vein sampling and processed to plasma from 5 animals per time point for pharmacokinetic analysis at 0 (pre-dose) , 4, and 24 hours post last dose. Serum samples were analyzed to evaluate pharmacokinetic (PK) properties of test agents using a qualified research non-chiral LC-MS/MS method. The lower limit of quantification (LLOQ) for serum was 4 ng/ml (OCI-Ly3) or 0.8 ng/ml (OCI-Ly10) . PK analysis was performed using Phoenix Professional (Version 6.3) . A noncompartmental analysis using the linear up /log down trapezoidal rule was used for all data.

Data Analysis

The percent tumor growth inhibition (TGI) was defined as 1 minus the ratio of the mean tumor burden of the treated group and mean tumor burden of the control group times 100, calculated as %TGI = [1 -mean (TV_T) /mean (TV_C) ] × 100 where ‘TV_C’ are the tumor burdens of the vehicle control group at a given day and ‘TV_T’ are the tumor burdens of the treatment group at a given day.

The percent delta tumor growth inhibition (ΔTGI) was defined as 1 minus the ratio of the baseline corrected mean tumor burden of the treatment and control groups times 100, calculated as %ΔTGI = (1 [mean (TV_T) mean (TV_T0) ] / [mean (TV_C) mean (TV_C0) ] ) ×100, where ‘TV_C’ is the tumor burden of the vehicle control group at a given day, ‘TV_C0’ is the tumor burden of the vehicle control group at initiation of treatment, ‘TV_T’ is the tumor burden of the treatment group at a given day, and ‘TV_T0’ is the tumor burden of the treatment group at initiation of treatment.

The percent tumor regression (TR) was defined as 1 minus the mean of the tumor burdens of the treatment group at Day i (TV_i) divided by the tumor burdens of the treatment group at initiation of treatment (TV₀) times 100, calculated as [1 -mean (T_i/T₀) ] x 100.

For tumor volume, percent change in baseline-corrected mean tumor burdens was assessed using %ΔTGI (OCI-Ly3 and OCI-Ly10) or %TGI (OCI-Ly10) . A 2-sided hypothesis test was used to compare %ΔTGI or %TGI to 0. Specifically, a Wald-type statistic was compared to a Student’s t distribution with degrees of freedom calculated using the Satterthwaite approximation. The variance was estimated using the delta method assuming mean tumor burdens were normally distributed.

All p-values were adjusted using the false discovery rate method. Differences between groups were considered statistically significant when adjusted p values < 0.05.

Human IL-10 Assay

Serum samples from OCI-Ly3 or OCI-Ly10 tumor-bearing mice were assayed for cytokine levels using a custom V-PLEX Proinflammatory Panel 1 Human kit from Meso Scale Discovery (MSD) , following the manufacturer’s recommendations. The cytokines tested using this kit were IL-6 and IL-10. Serum was thawed on ice, and 25 μL of each sample was transferred to an MSD plate that contained 25 μL/well of Diluent 2, as per plate layout. Plates were incubated for 2 hours at RT, followed by incubation at RT for 2 hours with the detection antibody solution. Plates were read on a SECTOR imager (MSD) . Interpolation of sample values from the standard curve for each cytokine was performed using the DISCOVERY WORKBENCH software (MSD, Version 4.0.13) . Results were plotted using GraphPad Prism (Version 9) .

Uncleaved BCL10 Assay

Cleavage of the MALT1 substrate BCL10 (B-cell CLL/Lymphoma 10) , was evaluated in OCI-Ly3 tumor samples after treatment with Compound 3 using an in-house electrochemiluminescent assay. OCI-Ly3 tumors were cryopulverized in a tissueTUBE using the cryoPREP system (Covaris) following manufacturer’s instructions, then transferred to a 1.5 mL eppendorf tube. Pulverized tumors were then lysed in 300 μL MSD lysis buffer for 30 minutes at 4℃. Lysates were centrifuged at 14,000 rpm for 20 minutes at 4℃ and supernatants were collected into fresh tubes. Protein concentration was measured using the bicinchoninic (BCA) protein assay kit according to the manufacturer’s instructions.

Goat, anti-rabbit antibody-coated MSD plates were blocked for 1 hour at RT with 3%bovine serum albumin in TBS-T buffer (Tris buffered saline-0.1%Tween 20) , and then incubated with 50 μL of rabbit monoclonal anti-BCL10 (clone EP606Y) capture antibody (diluted 1: 1,000 in 1%bovine serum albumin [BSA] in TBS-T) , which binds noncleaved BCL10, for 2 hours at RT. Plates were washed three times with TBS-T, and tumor lysates (25 μg of protein/well) were transferred to the anti-BCL10-coated MSD plate and incubated for 24 hours at 4℃. Next, plates were washed 3 times with TBS-T followed by a 2-hour incubation at RT with 50 μL/well of mouse monoclonal BCL10 (clone 151) antibody (diluted 1: 500 in 1%BSA in TBS-T) , which detects both cleaved and noncleaved BCL10. Plates were then washed 3 times with TBS-T followed by a 2-hour incubation at RT with 50 μL of goat anti-mouse-Sulfo-tag antibody (diluted 1: 100 in 1%BSA in TBS-T) . Plates were washed 4 times with TBS-T and 150 μL/well of MSD Read buffer was added. Plates were incubated for 60 minutes at RT then read on a SECTOR imager. Absorbance units for noncleaved BCL10 were plotted using GraphPad Prism (Version 9) .

Results

Figure 12 shows average tumor volumes in OCI-Ly3 xenografts graphed as the mean ± standard error of the mean (SEM) (n=10/group) . Tumor cells were implanted on Day 0 and NSG mice were treated orally (PO) twice a day (BID) on Days 22‐50 for a total of 56 doses at the indicated dose levels. The dosing period is indicated by the bar below the X‐axis. *Denotes significant difference on Day 50 (p≤0.05) compared to vehicle control. Further details are provided in Table 25.

Table 25: Tumor growth inhibition (%ΔTGI) , tumor regression (%TR) and C_trough in OCI-Ly3 xenografts.

Figure 13 shows average tumor volumes in OCI-Ly10 xenografts graphed as the mean ± SEM (n=10/group) . Tumor cells were implanted on Day 0 and NSG mice were treated PO BID on Days 16-39 for a total of 46 doses at the indicated dose levels. The dosing period is indicated by the bar below the X‐axis. *Denotes significant difference on Day 38 (p≤0.05) compared to vehicle control. Further details are provided in Table 26.

Table 26. Tumor growth inhibition (%ΔTGI) , tumor regression (%TR) and C_trough in OCI-Ly3 xenografts.

Figure 14 shows levels of human interleukin 10 (hIL‐10) and Compound 3 in the serum of NSG mice bearing OCI‐Ly3 tumors after a single dose of Compound 3 at the indicated doses. The left Y‐axis represents hIL‐10 levels and the right Y‐axis represents unbound Compound 3 concentrations. IL‐10 and compound levels were measured by MSD and LC‐MS/MS, respectively, and results are presented as the mean ± SEM (n=5/group) .

Figure 15 shows levels of uncleaved BCL10 in the serum of NSG mice bearing OCI‐Ly3 tumors at 24 hours after a single dose of Compound 3 at the indicated doses. Uncleaved BCL10 expression was assessed by MSD. Data are presented as the mean ± SD (n=5/group) .Figure 16 shows levels of hIL‐10 and Compound 3 in the serum of NSG mice bearing OCI‐Ly10 tumors after a single dose of Compound 3 at the indicated doses. The left Y‐axis represents hIL‐10 levels and the right Y‐axis represents unbound Compound 3 concentrations. IL‐10 and compound levels were measured by MSD and LC‐MS/MS, respectively, and results are presented as the mean ± SEM (n=5/group) .

Pharmacokinetic (PK) projections were performed using allometric approaches where preclinical pharmacokinetic parameters from non-compartmental analyses are plotted against body weight on a log-log scale. The linear relationship that could be derived was subsequently used to model the PK parameter in man (assuming a human body weight of 80.7 kg)

For the scaling of volume of distribution (Vd) , a correction for fu_p was applied (Eq1) . For the scaling of clearance, appropriate correction factors were applied to allow for interspecies scaling (fraction unbound in plasma (fu_p) , maximum life span potential (MLP) ; Eq2)
(Eq. 1) CL = a (BW) ^b fu_p

Where BW is the body weight, fu_p is the free fraction in plasma and a and b are the coefficient and exponent of the allometric equation, respectively.
(Eq. 2) CL = a (BW) ^b fu_p /MLP

MLP (10 ⁵h)

When corrected for both MLP and fu_p, the CLu*MLP was plotted against the body weight (BW) on a log-log scale, and the allometric equation (Eq. 2) is used to simulate clearance (CL) in human.

The resulting projected PK parameters in man are shown in Table 27.

Table 27. Projected human PK parameters using allometric scaling

Human projected plasma concentrations at steady-state following once-daily oral dosing were derived using the below formulas

and

Using these inputs, a projected efficacious human dose of 35 mg could be derived to reach free plasma concentrations at steady state following once daily oral dosing (i.e., 11 nM) that equal exposures observed to result in desired tumor growth inhibition (%ΔTGI) and/or tumor regression (%TR) in murine OCI-Ly3 xenografts models.

Example 16 -First-in-human study

The first-in-human (FIH) study will start with dose escalation phase (Part A) to establish the RP2D (s) based on the safety/tolerability, PK, PD, and treatment activity. The expansion phase (Part B) will further evaluate the RP2D (s) in dose expansion cohorts. This is a FIH, open-label, non-randomized, multicenter, Phase 1 study to evaluate the safety, PK, PD, and clinical activity of Compound 3 monotherapy administered to adult participants with relapsed or refractory B‐cell NHL. The overall objective of the study is to identify the optimal dose (s) and treatment schedule (s) that may be used in future clinical development.

The study will be conducted in 2 Parts: dose escalation (Part A) and dose expansion (Part B) . The study treatment will be administered orally at a dose assigned by the sponsor according to the dose escalation or dose expansion strategy outlined in the sections below. The study treatment will be administered on an outpatient basis or per local requirements in an in-patient setting at the start of treatment. Throughout Compound 3 treatment administration, study procedures and laboratory assessments will be performed to monitor safety, PK, PD, and clinical activity.

Part A (Dose Escalation)

Dose escalation will start with dose 20 mg once a day. Subsequent dose levels and schedules will be selected based on the review of all available data including, but not limited to, PK, PD, safety, and preliminary clinical activity. Dose escalation will be guided using the BOIN design. Cohorts may be opened in parallel or staggered to study multiple dose levels and treatment schedules including the addition of loading doses. The proposed human starting dose of 20 mg is lower than the calculated maximum recommended starting dose (MRSD, equal to 1/10 of the human equivalent dose (HED) ) of 24 and 32 mg based on the rat and dog NOAEL (no-observed-adverse-effect-level) at 25 mg/kg and 10 mg/kg respectively. The estimated exposures of 20 mg starting dose in human (estimated total Cmax of ～960 ng/mL and total AUC0-24h, SS of ～21700 ng h/mL) provides at least 36-fold (total) and 25-fold (unbound) exposure margins relative to exposures observed at the NOAEL of 10 mg/kg in dog, and 90-fold (total) and 34-fold (unbound) exposure margins relative to exposures observed at the NOAEL of 25 mg/kg in rat. A modelled terminal half-life of approximately 100 hours, supports once daily administration. Thus, the proposed 20 mg once daily starting dose in this Phase 1 study is considered to be reasonable.

Part B (Dose Expansion)

In Part B, approximately 20 participants may be enrolled in each cohort with B-cell NHL histologies, defined based on emerging data from Part A of the study.

Additional expansion cohort (s) may be added, with a lower RP2D (s) , or different dose schedule (s) based on all available safety, clinical activity, and PK/PD data.

The inclusion and exclusion criteria for the first-in-human study are copied below:

Inclusion criteria:

Participants can only be included in this study if they meet the following criteria.

1. Be greater than or equal to (>=) 18 years of age at the time of informed consent.

2. Have histologically or cytologically confirmed B-cell non-Hodgkin’s lymphoma (NHL) .

3. Have measurable disease or meet all requirements for adequate response assessment.

4. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

5. Life expectancy of >=12 weeks.

6. Hematology laboratory parameters must meet the required values.

7. Hepatic laboratory parameters must meet the required values for aspartateaminotransferase (AST) , alanine aminotransferase (ALT) , and serum total bilirubin.

8. Have an estimated glomerular filtration rate (eGFR) of greater than (>) 40 milliliter/minute mL/min based on the Modified Diet in Renal Disease (MDRD) 4-variable formula.

9. While on study treatment and for at least 3 months after the last dose of study treatment, a participant must:

· Not breast feed or be pregnant.

· Not donate gametes (that is, eggs or sperm) or freeze for future use for the

purposes of assisted reproduction.

· Wear an external condom.

· If of childbearing potential,

- have a negative highly sensitive pregnancy test at screening and within 24 hours before the first dose of study treatment, and agree to further

pregnancy tests,

- practice at least 1 highly effective method of contraception.

· If a participant’s partner is of childbearing potential, partner must practice a highly effective method of contraception unless the participant is vasectomized.

10. Must sign an informed consent form (ICF) indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.

11. Be willing and able to adhere to the lifestyle restrictions specified in this protocol.

Exclusion criteria:

Participants cannot be included in this study if they meet the following criteria.

1. Participant with active or prior history of B-cell NHL involving the central nervous system (CNS) or leptomeningeal involvement.

2. History of malignancy (other than the disease under study) within 1 year prior to the first administration of study treatment.

3. Known allergies, hypersensitivity, or intolerance to the excipients.

4. Had major surgery or had significant traumatic injury within 30 days before first dose of study treatment or has not recovered from surgery. Must not have major surgery planned during the study treatment.

5. Received an autologous stem cell transplant less than or equal to (<=3) months before the first dose of study treatment.

6. Received an allogenic stem cell transplant <=6 months before the first dose of study treatment.

7. Evidence within 7 days prior to the first dose of study treatment of active viral, bacterial, or uncontrolled systemic fungal infection requiring initiation of parenteral treatment as medical intervention.

8. Have cardiovascular disease within 6 months prior to first dose of study treatment.

9. Clinically significant pulmonary compromise, including the need for supplemental oxygen use to maintain adequate oxygenation.

10. Active or chronic hepatitis B or hepatitis C infection.

11. Human immunodeficiency virus-positive participants if they have any of the required parameters described in the protocol.

12. Any other anticancer treatments or investigational agents must be discontinued for at least 2 weeks before the first dose.

13. Requires a prohibited medication that cannot be interrupted or substituted during the study.

14. Received or plans to any live, attenuated vaccine within 4 weeks before the first dose of study treatment or within 4 weeks after the last dose of study treatment.

15. Receiving corticosteroids >25 mg daily prednisone equivalents

16. Received a prior solid organ transplantation.

17. Active autoimmune disease within the past 12 months that requires systemic immunosuppressive medications.

18. Toxicities from previous anticancer therapies that have not resolved to baseline levels or to <= Grade 1.

19. Participant received prior systemic anticancer therapy with a mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) inhibitor.

20. Inability to take an orally administered drug, or medical disorder or prior surgical resection that may affect the absorption of the study treatment.

21. Any serious underlying medical or psychiatric condition (example., alcohol or drug abuse) ,

dementia or altered mental status, or any issue that would contraindicate participation in the study.

22. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant.

Complete inclusion/exclusion criteria

Inclusion Criteria

Each potential participant must satisfy all of the following criteria to be enrolled in the study:

Age

1. Be ≥18 years of age (or the legal age of majority in the jurisdiction in which the study is taking place, whichever is greater) at the time of informed consent.

Type of participant &Disease Characteristics

2. Have histologically or cytologically confirmed B-cell NHL according to the 2022 World Health Organization (WHO) classification with relapsed or refractory disease and no other approved therapies available that would be more appropriate in the investigator’s judgment. Tumor tissue availability is required at baseline unless clinically contraindicated.

In addition, the following disease-specific criteria outlined below must be met.

3. Have measurable disease or meet all requirements for adequate response assessment as defined by the appropriate disease response criteria at screening.

4. Have an ECOG performance status of 0 or 1

5. Life expectancy of ≥12 weeks

6. Hematology laboratory parameters must meet the following

● Hemoglobin ≥ 8.0 g/dL

● Neutrophils ≥ 1.0 x 10⁹/L (≥0.75×10⁹/L for participants with documented bone marrow involvement of disease)

● Platelets ≥75 x 10⁹/L (≥50×10⁹/L for participants with documented bone marrow involvement of disease)

Values must be without transfusion or growth factors for at least 7 days prior to first dose of study treatment.

7. Hepatic laboratory parameters must meet the following

● Aspartate aminotransferase (AST) ≤3 x ULN (if known liver involvement /known hepatic metastases <5 x ULN)

● Alanine aminotransferase (ALT) ≤3 x ULN (if known liver involvement /known hepatic metastases <5 x ULN)

● Serum total bilirubin ≤1.5×ULN (participants with Gilbert’s syndrome can enroll if conjugated bilirubin is within normal limits) .

8. Have an estimated glomerular filtration rate (eGFR) of >40 mL/min based on the Modified Diet in Renal Disease (MDRD) 4-variable formula.

Sex and Contraceptive/Barrier Requirements

9. 9.1 While on study treatment and for at least 7 months (for participants of childbearing potential) or for at least 4 months (for participants with a partner of childbearing potential) after the last dose of study treatment, a participant must:

● Not breastfeed or be pregnant.

● Not donate gametes (ie, eggs or sperm) or freeze for future use for the purposes of assisted reproduction.

● Wear an external condom.

● If of childbearing potential,

○ have a negative highly sensitive (eg, beta-human chorionic gonadotropin [β-hCG] ) pregnancy test at screening and within 24 hours before the first dose of study treatment, and agree to further pregnancy tests,

○ practice at least 1 highly effective method of contraception; if oral contraceptives are used, a barrier method of contraception must also be used.

● If a participant’s partner is of childbearing potential,

○ the partner must practice a highly effective method of contraception unless the participant is vasectomized.

Informed Consent

10. Must sign an ICF (Informed Consent Form) indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study. Consent is to be obtained prior to the initiation of any study-related tests or procedures that are not part of standard of care for the participant’s disease.

Exclusion Criteria

Any potential participant who meets any of the following criteria will be excluded from participating in the study:

1. Participant with active or prior history of B-cell NHL involving the CNS or leptomeningeal involvement.

2. 2.1 History of malignancy (other than the disease under study in the cohort to which the participant is assigned) within 1 year prior to the first administration of study treatment. Exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy which in the opinion of the investigator, with concurrence with the sponsor’s medical monitor, is considered cured with minimal risk of recurrence within 1 year before the first dose of study treatment. Co-existence of 2 histologies of B-cell NHL is not excluded.

3. Known allergies, hypersensitivity, or intolerance to the excipients.

4. Had major surgery or had significant traumatic injury within 30 days before first dose of study treatment or has not recovered from surgery. Must not have major surgery planned during the time the participant is receiving study treatment.

5. Received an autologous stem cell transplant ≤3 months before the first dose of study treatment

6. Received an allogenic stem cell transplant ≤6 months before the first dose of study treatment, has evidence of graft versus host disease, or required immunosuppressant therapy for graft versus host disease within the last 4 weeks.

7. Evidence within 7 days prior to the first dose of study treatment of active viral, bacterial, or uncontrolled systemic fungal infection requiring initiation of parenteral treatment as medical intervention. Any infection within 7 days of the first dose of study treatment, regardless of whether medical intervention is indicated, must be discussed with the sponsor prior to the participant receiving the first dose of study treatment.

8. Any of the following within 6 months prior to first dose of study treatment:

● severe or unstable angina,

● myocardial infarction,

● major thromboembolic events (eg, pulmonary embolism, cerebrovascular accident) ,

● clinically significant ventricular arrhythmias or heart failure New York Heart Association functional classification Class III to IV clinically significant pericardial effusion myocarditis or endocarditis,

● clinically significant hypokalemia,

● hypomagnesemia, or

● hypocalcemia (corrected for hypoalbuminemia) .

Uncomplicated deep vein thrombosis is not exclusionary.

9. Prolonged corrected QT interval by Fredericia (QTcF) >480 msec based on the average of triplicate assessments (Section 8.3.4) .

10. Clinically significant pulmonary compromise, including the need for supplemental oxygen use to maintain adequate oxygenation.

11. 11.1 Active or chronic hepatitis B or hepatitis C infection.

● Participants who test positive for anti-HBc must have hepatitis B DNA testing by polymerase chain reaction performed and confirmed as negative prior to study treatment administration.

● Participants who test positive for hepatitis C antibody are eligible if previously treated and achieved a sustained viral response, defined as a negative viral load for hepatitis C tested 12 weeks after completion of the treatment for hepatitis C.

12. 12.1 Human immunodeficiency virus-positive participants if they have any of the following:

● Detectable viral load (ie, >50 copies/mL) at screening

● CD4+ count <300 cells/mm³ at screening

● Acquired immunodeficiency syndrome (AIDS) -defining opportunistic infection within 6 months of screening

● Not receiving highly active antiretroviral therapy (HAART) . Any changes in HAART due to resistance/progression should occur at least 3 months prior to screening. A change in HAART due to toxicity is allowed up to 4 weeks prior to screening.

Note: HAART that could interfere with study treatment is excluded (consult the sponsor for a review of medications prior to enrollment) .

13. 13.1 Any other anticancer treatments or investigational agents (with the exclusion of palliative radiation to limited sites that do not interfere with response assessment based on a sufficient number of other sites) must be discontinued for at least 2 weeks, and at least 4 weeks for CAR-T cell therapy and monoclonal antibodies, including bi-specifics, with long half-lives (ie, at least 5 to 7 days) , before the first dose of the compound of the present invention.

14. Requires a prohibited medication that cannot be interrupted or substituted during the study.

15. Received or plans to receive any live, attenuated vaccine within 4 weeks before the first dose of study treatment or within 4 weeks after the last dose of study treatment. Non-live and non-replication-competent vaccines approved or authorized for emergency use (eg, COVID-19, Mpox) by local health authorities are allowed.

16. Receiving corticosteroids >25 mg daily prednisone equivalents:

● A short course (ie, >25 mg daily prednisone equivalents for less than 7 days) of corticosteroids is permitted. Inhaled or topical steroids, and adrenal replacement doses ≤25 mg daily prednisone equivalents, are permitted in the absence of active autoimmune disease.

● If corticosteroids are used to treat immune-related adverse events associated with prior therapy, ≥7 days must have elapsed since the last dose of corticosteroid and the first dose of study treatment.

17. Received a prior solid organ transplantation.

18. Active autoimmune disease within the past 12 months that requires systemic immunosuppressive medications (ie, chronic corticosteroid, methotrexate, or tacrolimus) .

19. Toxicities from previous anticancer therapies that have not resolved to baseline levels, or to Grade ≤1 except for alopecia and peripheral neuropathy, vitiligo, or endocrinopathies that are stable on hormone replacement, which may be Grade ≤2.

20. Participant received prior systemic anticancer therapy with a MALT1 inhibitor.

21. Inability to take an orally administered drug, or medical disorder or prior surgical resection that may affect the absorption of the study treatment. Such conditions include, but are not limited to, malabsorption syndrome, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or resection of the stomach or small bowel. If any of these conditions exist, the investigator should discuss with the sponsor to determine participant eligibility.

22. Any serious underlying medical or psychiatric condition (eg, alcohol or drug abuse) , dementia or altered mental status; or any issue that would impair the ability of the participant to receive or tolerate the planned treatment at the study site, to understand informed consent, or that in the opinion of the investigator would contraindicate participation in the study or confound the protocol-specified assessments or results of the study.

23. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.

In an embodiment, the subject complies with the inclusion and/or exclusion criteria as described herein. In an embodiment, the subject complies with one or more of the inclusion and/or exclusion criteria as described herein.

Phase 1 clinical study

As of 10^th March 2025, a total of 35 participants with histologically or cytologically confirmed relapsed or refractory non-germinal center B cell-like diffuse large B cell lymphoma, not otherwise specified (non-GCB DLBCL, NOS) , according to the 2022 World Health Organization (WHO) classification, with no other approved therapies available per investigator’s judgment, were enrolled in the ongoing Phase 1, First-in-human, Dose escalation study. The median age of the participants was 63.3 years (range: 25 to 85 years) . 19 (54.3%) of the participants were aged ≥65 years. 20 (42.9%) were male and 15 (57.1%) were female.

All participants received at least one dose of Compound 3 (ASD) in one of the doses and regimens. The main cohorts: 20 mg QD (n=3) , 40 mg QD (n=11) , 80 mg QD (n=11) , 160 mg QD (n=9) . Participants were treated until disease progression, intolerable toxicity, withdrawal of consent or investigator’s determination.

Preliminary results indicated that Compound 3 was safe and well-tolerated across all tested dose-level and regimens. No dose-limiting toxicities were observed. Overall, 34 (97.1%) participants experienced one or more treatment-emergent adverse events (TEAEs) . The most commonly reported TEAEs by preferred term (PT) were neutropenia (12 [34.3%] ) , leukopenia (10 participants, [28.6%] ) , anemia (9 [25.7%] ) , lymphopenia (9 [25.7%] ) , and nausea (8 [22.9%] ) . Nine participants experienced treatment-emergent serious adverse events (SAEs) . One SAE (PT pneumonia) was considered related to study treatment. Thirty (85.7%) participants experienced one or more TEAEs which were considered related to the study treatment. The most commonly reported related TEAEs were leukopenia (10 [28.6%] ) , neutropenia (10 [28.6%] ) , lymphopenia (7 [20%] ) , stomatitis (6 [17.1%] ) , nausea (5 [14.3%] ) , and rash maculo-papular (5 [14.3%] ) .

Grade 3 or higher AEs were reported in 20 (50%) participants, and majority of the events recovered or resolved without treatment interruption or dose modification. Two patients discontinued study treatment due to TEAE, COVID-19 pneumonia hypercalcemia and renal failure) , and none of them are treatment related.

As of the cutoff date 21^st March 2025, 19 participants have discontinued study treatment: 16 due to disease progression, 2 due to unrelated TEAEs and 1 who withdrew from the study.

Anti-tumor activities were observed at all dose levels, with 13 (40%) participants achieving at least a partial response among the 32 participants who had at least one disease evaluation or/and clinical progression (as assessed by the investigator) . Participants who discontinued study without disease assessment are considered as non-responder (discontinued the study for reasons other than disease progression without a disease assessment) . Table 12 below provides efficacy information by the investigator grouped by the dosing strengths

Table 12:

**all pts who received at least one dose of study treatment (3 patients are ongoing, but did not have the first disease evaluation yet)

SD: stable disease; PR: partial response; CR: complete response; NR: non-responder; PD: progress of disease.

PK in ongoing phase 1 study

In an ongoing Phase 1, First-in-human, Dose escalation study, participants were dosed in cohorts on the basis of 21-day treatment cycles: 20 mg QD (Cohort 1) , 40 mg QD (Cohort 2) , 80 mg QD (Cohort 3) , and 160 mg QD (Cohort 4) .

Intensive plasma PK samples were collected on Cycle 1 Day 1 and Cycle 2 Day 1 predose and at 0.5, 1, 2, 3, 4, 6, 24 hours after dosing. In addition, predose plasma PK samples were collected on Cycle 1 Day 4, Day 8, Day 15, Cycle 3 Day 1, Cycle 4 Day 1.

Plasma PK samples were analyzed using a validated, specific, and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioanalysis method to quantify Compound 3.

For bioanalysis, a 20-μL plasma sample aliquot was fortified with internal standard working solution of 2500 ng/mL in DMSO. Analytes were isolated through liquid/liquid extraction with water as extraction modifier and methyl-tert-butyl ether (MTBE) as extraction solvent. After centrifugation, a portion of the supernatant was evaporated to dryness under a nitrogen stream and the remaining residue was reconstituted in water/acetonitrile 50/50.

The final sample extracts were analysed using an LC-MS/MS system to determine the concentration of Compound 3: Ultra-performance liquid chromatography (UPLC) system with Phenomenex Luna C8, 5 μm, 2*30 mm column coupled to a triple quadrupole mass spectrometer with Turbo Ionspray source operated in the positive ion mode at 600℃. Gradient elution was applied using A) 10mM Ammonium Acetate in water and B) acetonitrile as mobile phases. For MS, multiple reaction monitoring was applied. Sample concentrations were calculated by interpolation from a calibration standard curve, generated by fitting a linear, 1 /concentration² weighted, least-squares regression algorithm.

Plasma PK parameters for Compound 3 were calculated for Cohorts 1 to 4 using non-compartmental analysis.

Mean (SD) C_max, AUC_tau and C_trough values for Compound 3 obtained on intensive PK days were summarized in Table 11.

Table 11: Mean (SD) PK parameters for Compound 3 at Cycle 1 Day 1 and Cycle 2 Day 1

^a N=8 for AUC_tau and C_trough

^b N=7 for AUC_tau and C_trough

Plasma concentration-time profiles of Compound 3 on Cycle 1 Day 1 and Cycle 2 Day 1 are shown in Figures 18 and 19, respectively. Mean (SD) predose concentrations of Compound 3 are shown in Figure 20.

Compound 3 C_max, AUC_tau and predose concentrations increased with increasing dose levels. Accumulation was observed for C_max and AUC_tau at Cycle 2 Day 1 versus Cycle 1 Day 1. Steady state concentrations were reached around 21 days (Cycle 2 Day 1) for Cohorts 1 and 2, while continued accumulation was observed for Cohorts 3 and 4.

PK simulations for loading dose regimen

To evaluate the effect of a 2-week BID loading dose on the plasma concentration-time profile of Compound 3 at a dose of 160 mg, PK simulations were performed using the Phoenix^TMsoftware. An extravascular 1-compartment model was used for the simulations with PK input parameters derived from observed PK data in patients receiving 160 mg QD (Cohort 4) , as shown in Table 13. For k_a, a standard value of 0.6/h was used, while CL/F and V_d/F were derived from the accumulation ratio observed for predose concentrations of Compound 3 at Cycle 3 Day 1 versus Cycle 1 Day 2, assuming steady state was reached at Cycle 3 Day 1.

Table 13: PK parameters used for BID loading dose simulations

k_a: absorption constant; CL/F: apparent clearance; V_d/F: apparent distribution volume; AR: accumulation ratio; C_predose: predose concentration of Compound 3; C3D1: Cycle 3 Day 1; C1D2: Cycle 1 Day 2

Claims

An amorphous solid dispersion comprising a compound and an orally pharmaceutically acceptable polymer;

wherein the compound is

or a pharmaceutically acceptable salt form thereof.
The amorphous solid dispersion of claim 1, wherein the weight-by-weight ratio of the compound to the orally pharmaceutically acceptable polymer is in the range of 1: 2 to 1: 3, calculated based on the free base form of the compound.
The amorphous solid dispersion of any one of claims 1-2, wherein the orally pharmaceutically acceptable polymer is selected from the group consisting of:

hydroxypropylmethylcellulose acetate succinate (HPMCAS) , wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl;

HPMCAS, wherein the HPMCAS comprises 7.0 wt%to 11.0 wt%acetyl and 10.0 wt%to 14.0 wt%succinoyl;

HPMCAS, wherein the HPMCAS comprises 10.0 wt%to 14.0 wt%acetyl and 4.0 wt%to 8.0 wt%succinoyl;

poly (methacrylic acid-co-methyl methacrylate) (1: 1) ;

poly (methacrylic acid-co-ethyl acrylate) (1: 1) ;

poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (1: 2: 1) ;

HPMC, wherein the HPMC comprises 28 wt%to 30 wt%methoxyl and 7 wt%to 12 wt%hydroxypropyl, optionally wherein the HPMC has an apparent viscosity when dissolved at 2.0%in water of 4 to 6 mPa. s;

a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a ratio of 6: 4 by mass;

polyvinylpyrrolidone having a molecular weight of 44,000-54,000 g/mol; and

a graft copolymer of polyvinyl caprolactam, polyvinyl acetate and polyethylene glycol having a molecular weight of 90,000-140,000 g/mol, optionally wherein the graft copolymer has a K-value of 31-41 when measured at 1%in ethanol;

or a combination thereof.
The amorphous solid dispersion of any one of claims 1-3, wherein the orally pharmaceutically acceptable polymer is HPMCAS.
The amorphous solid dispersion of claim 3, wherein the orally pharmaceutically acceptable polymer is selected from:

HPMCAS, wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl;

poly (methacrylic acid-co-methyl methacrylate) (1: 1) ; and

HPMC, wherein the HPMC comprises 28 wt%to 30 wt%methoxyl and 7 wt%to 12 wt%hydroxypropyl, optionally wherein the HPMC has an apparent viscosity when dissolved at 2.0%in water of 4 to 6 mPa. s;

or a combination thereof.
The amorphous solid dispersion of any one of claims 1-5, wherein the orally pharmaceutically acceptable polymer is HPMCAS, wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl, and wherein the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is 1: 3.
The amorphous solid dispersion of any one of clauses claim 1-6, wherein the amorphous solid dispersion is in particulate form and has a volume weighted particle size distribution D50, as measured by a static light scattering method, of about 10 μm to about 60 μm.
A pharmaceutical composition comprising the amorphous solid dispersion according to any one of claims 1-7 and a pharmaceutically acceptable carrier.
The pharmaceutical composition of claim 8, wherein the composition is a solid oral dosage form comprising a core and optionally a coating or casing, wherein the core comprises the pharmaceutically acceptable carrier and the amorphous solid dispersion.
The pharmaceutical composition of claim 9, wherein the solid oral dosage form is a tablet comprising the core and optionally the coating, optionally wherein the tablet consists of the core.
The pharmaceutical composition of any one of claims 8-10, wherein the pharmaceutically acceptable carrier comprises a filler, a disintegrant, a glidant, and a lubricant.
The pharmaceutical composition of claim 11, wherein the filler is selected from the group consisting of silicified microcrystalline cellulose, microcrystalline cellulose, mannitol, lactose, dicalcium phosphate, isomalt, corn starch, pregelatinized starch, magnesium carbonate, or a combination thereof, optionally wherein the filler is silicified microcrystalline cellulose.
The pharmaceutical composition of claim 11 or 12, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, and sodium starch glycolate, or a combination thereof, optionally wherein the disintegrant is croscarmellose sodium.
The pharmaceutical composition of any one of claims 11-13, wherein the glidant is selected from the group consisting of colloidal silica, talc, or a combination thereof, optionally wherein the glidant is anhydrous colloidal silica.
The pharmaceutical composition of any one of claims 11-14, wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, stearic acid, a glyceryl derivative, sodium lauryl sulfate, talc, or a combination thereof, optionally wherein the lubricant is magnesium stearate.
The pharmaceutical composition of any one of claims 11-15, wherein the filler is silicified microcrystalline cellulose, the disintegrant is croscarmellose sodium, the glidant is anhydrous colloidal silica, and the lubricant is magnesium stearate; wherein the orally pharmaceutically acceptable polymer is HPMCAS, wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl; and wherein the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is 1: 3.
The pharmaceutical composition of any one of claims 9-16, wherein the solid oral dosage form comprises from about 5 mg to about 150 mg of the compound, calculated based on the free base form.
The pharmaceutical composition of any one of claims 9-17, wherein the amorphous solid dispersion is present in the solid oral dosage form in an amount of from about 30%to about 80%(w/w) relative to the total weight of the core.
The pharmaceutical composition of any one of claims 11-18, wherein the solid oral dosage form comprises a total of about 45%to about 55% (w/w) of the amorphous solid dispersion, a total of about 35%to about 45% (w/w) of the filler, a total of about 5%to about 8% (w/w) of the disintegrant, a total of about 1%to about 4% (w/w) of the glidant, and a total of about 0.2%to about 3% (w/w) of the lubricant, relative to the total weight of the core.
The pharmaceutical composition of any one of claims 8-19, wherein the pharmaceutical composition is a solid oral dosage form;

wherein the solid oral dosage form is a tablet consisting of a core;

wherein the core comprises the pharmaceutically acceptable carrier and the amorphous solid dispersion;

wherein the pharmaceutically acceptable carrier comprises a filler, a disintegrant, a glidant, and a lubricant;

wherein the amorphous solid dispersion comprises Compound 3 and HPMCAS, wherein the HPMCAS comprises 5.0 wt%to 9.0 wt%acetyl and 14.0 wt%to 18.0 wt%succinoyl, wherein the weight-by-weight ratio of Compound 3 to the orally pharmaceutically acceptable polymer is 1: 3;

wherein the tablet comprises a total of about 50% (w/w) of the amorphous solid dispersion, a total of about 40.5% (w/w) of the filler, a total of about 6% (w/w) of the disintegrant, a total of about 2% (w/w) of the glidant, and a total of about 1.5% (w/w) of the lubricant, relative to the total weight of the core; and

wherein the filler is silicified microcrystalline cellulose, the disintegrant is croscarmellose sodium, the glidant is anhydrous colloidal silica, and the lubricant is magnesium stearate.
A process for preparing the amorphous solid dispersion of any one of claims 1-7, the process comprising spray drying a mixture comprising Compound 3, or a pharmaceutically acceptable salt form thereof, the orally pharmaceutically acceptable polymer, and a solvent.
The process of claim 30, wherein the process comprises:

dissolving Compound 3, or a pharmaceutically acceptable salt form thereof, in the solvent to obtain a solution;

dissolving the orally pharmaceutically acceptable polymer in the solution to obtain a spray feed mixture;

spray drying the spray feed mixture to obtain a spray dried powder; and

post drying the spray dried powder to obtain the amorphous solid dispersion.
The amorphous solid dispersion of any one of claims 1-7 or the pharmaceutical composition of any one of claims 8-20 for use in the treatment of a disease, syndrome, condition, or disorder in a subject in need thereof, wherein said disease, syndrome, condition, or disorder is affected by the inhibition of MALT1.
A crystalline form I of

wherein the crystalline form is an anhydrous crystalline form (Form I) .
The crystalline form of claim 24, wherein the crystalline form produces an X-ray powder diffraction pattern comprising peaks at 7.9, 11.2, 11.9, 13.4, 14.0, 16.6, 18.0, 19.2 and 23.5 degrees two theta ± 0.2 degrees two theta.
A crystalline form II of

wherein the crystalline form is a solvate (Form II) .
The crystalline form of claim 26, wherein the crystalline form is an acetonitrile solvate (Form IIa) that produces an X-ray powder diffraction pattern comprising peaks at 8.1, 10.8, 13.5, 14.9, 16.2, 17.4, 17.9, 19.1, 20.2 and 22.1 degrees two theta ± 0.2 degrees two theta.
The crystalline form of claim 26, wherein the crystalline form is a methanol solvate (Form IIb) that produces an X-ray powder diffraction pattern comprising peaks at 7.6, 8.2, 10.7, 12.8, 13.5, 15.1, 15.3, 17.2, 17.5, 17.9 and 21.9 degrees two theta ± 0.2 degrees two theta.
A compound for use in the treatment of a disease, syndrome, condition, or disorder in a subject in need thereof, wherein said disease, syndrome, condition, or disorder is affected by the inhibition of MALT1,

wherein the compound is

or a pharmaceutically acceptable salt form thereof or a solvate thereof, and

wherein the compound is administered to the subject in a dosage regimen comprising administration of the compound at a dose of at least about 10 mg.
A compound for use in the treatment of a disease, syndrome, condition, or disorder in a subject in need thereof, wherein said disease, syndrome, condition, or disorder is affected by the inhibition of MALT1,

wherein the compound is

or a pharmaceutically acceptable salt form thereof, and

wherein the compound is in the form of an amorphous solid dispersion.
The compound for use of claim 29 or 30, wherein the compound is administered to the subject in a dosage regimen comprising administration of the compound at a dose from about 10 mg to about 500 mg.
The compound for use of claim 31, wherein the compound is administered to the subject in a dosage regimen comprising administration of the compound at a dose from about 20 mg to about 160 mg.
The compound for use of any one of claims 29-32, wherein the compound is administered orally.
The compound for use of any one of claims 29 or 31-33, wherein the dose is administered once a day (QD) .
The compound for use of any one of claims 29 or 31-33, wherein the dose is administered twice a day (BID) .
The compound for use of any one of claims 29-35, wherein the compound is administered to the subject in a dosage regimen comprising administration of the compound at a total daily dose from about 10 mg to about 500 mg.
The compound for use of claim 36, wherein the compound is administered to the subject in a dosage regimen comprising administration of the compound at a total daily dose from about 20 mg to about 160 mg.
The compound for use of any one of claims 29-37, wherein the compound is administered to the subject in a daily dosage regimen comprising or consisting of:

(a) a loading phase, wherein the compound is administered at a total daily loading dose; and

(b) a maintenance phase, wherein the compound is administered at a total daily maintenance dose, wherein the total daily maintenance dose is lower than the total daily loading dose.
The compound for use of any one of claims 29-38, wherein the compound is in the form of an amorphous solid dispersion.
The compound for use of any one of claims 29-39, wherein the compound is administered to the subject in a dosage regimen that provides a C_trough in blood plasma of at least about 10 nM.