Crystalline forms of n-(1-(TERT-butyl)-1h-pyrazol-4-YL)-2-(4-((6-((methylsulfonyl)quinolin-4-YL)OXY)-3-methylphenyl)acetamide and salts thereof as RIPK2 inhibitors for the treatment of inflammatory diseases

Abstract

The present disclosure relates to crystalline forms of N-(l-(tert-butyl)-lH-pyrazol-4-yl)-2-( 4-((6-((methylsulfonyl)quinolin-4-yl)oxy)-3-methylphenyl)acetamide of formula (II) and crystalline forms of salts thereof. The compound of formula (II) is a RIPK2 inhibitor for the treatment of e.g. inflammatory diseases, autoimmune diseases, granulomatous disease, neurodegenerative diseases or cancer, and more specifically for the treatment of inflammatory bowel disease, such as Crohn's disease or ulcerative colitis, rheumatoid arthritis, inflammatory arthritis, peritonitis, ischemia reperfusion injury in kidney transplant, non-alcohol steatohepatitis, alcohol steatohepatitis, insulin-resistant type 2 diabetes, allergic rhinitis, asthma, atopic dermatitis, Sjogren's syndrome, spondyloarthritis, ankylosing spondylitis, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, thrombosis, alpha-synucleinopathy, Parkinson's disease, dementia with Lewy body, multiple system atrophy, Alzheimer's disease, amyotrophic lateral sclerosis, and chronic obstructive pulmonary disease

Description

[0001] CRYSTALLINE FORMS OF N-(1-(TERT-BUTYL)-1 H-PYRAZOL-4-YL)-2-(4-((6-((METHYLSULFONYL)QUINOLIN-4-YL)OXY)-3-METHYLPHENYL)ACETAMIDE AND SALTS THEREOF AS RIPK2 INHIBITORS FOR THE TREATMENT OF INFLAMMATORY DISEASES

[0002] RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 653,142, filed May 29, 2024. The entire teachings of the above application are incorporated herein by reference.

[0004] BACKGROUND OF THE INVENTION

[0005] Autoinflammatory disorders are diseases characterized by systemic and organ- specific inflammation due to abnormalities in the innate immune system. These abnormalities are associated with numerous inflammatory disorders such as inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), sarcoidosis, inflammatory arthritis, peritonitis, multiple sclerosis, rheumatoid arthritis, and Wegener’s granulomatosis. These disorders affect millions of people.

[0006] NODI and NOD2 (nucleotide-binding oligomerization domains 1 and 2) are members of the NOD-like receptor (NLR) family, which represent important components of the mammalian innate immune system, serving as intracellular receptors for peptidoglycan (PGN), a component of bacterial cell walls. NODI and NOD2 detect the presence of intracellular bacteria by binding to PGN fragments. Heredity polymorphisms in the genes encoding NODI and NOD2 have been associated with inflammatory disorders. Once activated, NOD signaling leads to activation of NF-kB and MAP kinases, resulting in the transcription of pro- inflammatory kinases and the induction of autophagy.

[0007] NODI and NOD2 require RIPK2 as a common scaffolding (adaptor) protein to propagate downstream signals that lead to aberrant proinflammatory innate immune activation. In particular, RIPK2 is critical for NF-kB activation and subsequent cytokine production. Inhibition of RIPK2 resolves abnormal inflammation states such as intestinal inflammation. Accordingly, inhibitors of RIPK2 have potential to act as therapeutic agents, for example, to reduce or resolve inflammation for inflammatory disorders such as inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), sarcoidosis, inflammatory arthritis, peritonitis, multiple sclerosis, rheumatoid arthritis, and Wegener’s granulomatosis.

[0008] In the context of malignant transformation, knockdown of RIPK2 downregulated RNA expression of E-cadherin and vimentin, proteins involved in epithelial-to-mesenchymal transition (EMT) and the promotion of the metastatic phenotype indicating that RIPK2 is involved in cell migration and metastasis.

[0009] Inhibitors of RIPK2 activity can block RIPK2-dependent pro-inflammatory signaling and thereby provide a therapeutic benefit in auto-inflammatory diseases and other disorders characterized by increased and / or dysregulated RIPK2 activity. An example of a RIPK2 inhibitor is the compound represented by Structural Formula II:

[0010] The solid form of a compound can be important in the formulation of pharmaceutical compositions. For example, different crystalline forms of a compound or a salt thereof can have different physical properties (e.g., stability, dissolution rate, density, etc.) relating to their suitability for use in pharmaceutical compositions.

[0011] There is a need for crystalline forms of the compound of Structural Formula II or a salt thereof that are thermodynamically stable and suitable for use in pharmaceutical compositions (e.g., are readily dissolvable, exhibit low hygroscopicity, good flow properties and / or good chemical and thermal stability). There is a further need for crystalline forms of the compound of Structural Formula II or a salt thereof having physical properties that enable the manufacture of the compound of Structural Formula II and its pharmaceutical compositions in high yield and high purity with long shelflife.

[0012] SUMMARY OF THE INVENTION

[0013] In some embodiments, the present disclosure relates to a crystalline form of a salt of the compound represented by Structural Formula (II): wherein the salt is selected from the group consisting of a chloride, a succinate, a sulfate, a methanesulfonate, a fumarate, and a citrate of the compound represented by Structural Formula (II).

[0014] In some embodiments, the present disclosure relates to a crystalline form of the compound represented by Structural Formula (II):

[0015] In some embodiments, the present disclosure relates to a composition, comprising particles of one or more crystalline forms of a compound represented by Structural Formula

[0016] (II): wherein the one or more crystalline forms are selected from:

[0017] Form Ila characterized by at least three x-ray powder diffraction peaks at 29 angles selected from 13.81°, 16.73°, 18.11°, and 20.12°, and

[0018] Form lib characterized by at least three x-ray powder diffraction peaks at 29 angles selected from 4.39°, 20.39°, 21.10°, and 24.14°.

[0019] In some embodiments, the present disclosure relates to a pharmaceutical composition, comprising a crystalline form or a composition described herein and a pharmaceutically acceptable carrier.

[0020] In some embodiments, the present disclosure relates to a method of treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline form described herein, a composition described herein, or a pharmaceutical composition described herein, wherein the disease or disorder is selected from an inflammatory disease, autoimmune disease, granulomatous disease, cancer, and neurodegenerative disease.

[0021] In some embodiments, the present disclosure relates to a method of treating a RIP2 kinase-mediated disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline form described herein, a composition described herein, or a pharmaceutical composition described herein. In one aspect, the RIP2 kinase-mediated disease or disorder is a disease or disorder wherein inhibition of RIP2 kinase would provide benefit. In a particular aspect, the disease or disorder is selected from an inflammatory disease, autoimmune disease, granulomatous disease, cancer, and neurodegenerative disease.

[0022] BRIEF DESCRIPTION OF THE DRAWINGS

[0023] The foregoing will be apparent from the following more particular description of example embodiments of the invention.

[0024] FIG. 1 is an x-ray powder diffraction (XPRD) pattern of the crystalline Form la.

[0025] FIG. 2 is a graph depicting a differential scanning calorimetry (DSC) thermogram and a thermogravimetric analysis (TGA) thermogram of the crystalline Form la.

[0026] FIG. 3 is an XPRD pattern of the crystalline Form lb.

[0027] FIG. 4 is a graph depicting a DSC thermogram and a TGA thermogram of the crystalline Form lb.

[0028] FIG. 5 is an XPRD pattern of the crystalline Form Ic.

[0029] FIG. 6 is a graph depicting a DSC thermogram and a TGA thermogram of the crystalline Form Ic.

[0030] FIG. 7 is an XPRD pattern of the crystalline Form Id.

[0031] FIG. 8 is a graph depicting a DSC thermogram and a TGA thermogram of the crystalline Form Id.

[0032] FIG. 9 is an XPRD pattern of the crystalline Form le.

[0033] FIG. 10 is a graph depicting a DSC thermogram and a TGA thermogram of the crystalline Form le.

[0034] FIG. 11 is an XPRD pattern of the crystalline Form If.

[0035] FIG. 12 is a graph depicting a DSC thermogram and a TGA thermogram of the crystalline Form If. FIG. 13 is an XPRD pattern of the crystalline Form Ig.

[0036] FIG. 14 is an XPRD pattern of the crystalline Form Ila.

[0037] FIG. 15 is a graph depicting a DSC thermogram and a TGA thermogram of the crystalline Form Ila.

[0038] FIG. 16 is an XPRD pattern of the crystalline Form lib.

[0039] FIG. 17 is a graph depicting a DSC thermogram and a TGA thermogram of the crystalline Form lib.

[0040] FIG. 18 is a polymorph map detailing the crystalline Forms la - la-7.

[0041] FIG. 19 is a polymorph map detailing the crystalline Forms Ila - lib.

[0042] FIG. 20A shows a plot of dynamic vapor sorption (DVS) of crystalline Form la.

[0043] FIG. 20B shows weight change over time at constant temperature 25 °C during DVS analysis of crystalline Form la.. Absorption and desorption curves are shown at constant temperature (25 °C).

[0044] FIG. 21 is an XPRD pattern of the crystalline Form IIa-1.

[0045] FIG. 22 is a graph depicting a DSC thermogram and a TGA thermogram of the crystalline Form IIa-1.

[0046] FIG. 23 is an XPRD pattern of the crystalline Form IIa-2.

[0047] FIG. 24 is a graph depicting a DSC thermogram and a TGA thermogram of the crystalline Form IIa-2.

[0048] FIG. 25 is an XPRD pattern of the crystalline Form la-1.

[0049] FIG. 26 is a graph depicting a DSC thermogram and a TGA thermogram of the crystalline Form la-1.

[0050] FIG. 27 is an XPRD pattern of the crystalline Form la-2.

[0051] FIG. 28 is a graph depicting a DSC thermogram and a TGA thermogram of the crystalline Form la-2.

[0052] FIG. 29 is an XPRD pattern of the crystalline Form la-3.

[0053] FIG. 30 is a graph depicting a DSC thermogram and a TGA thermogram of the crystalline Form la-3.

[0054] FIG. 31 is an XPRD pattern of the crystalline Form la-4.

[0055] FIG. 32 is a graph depicting a DSC thermogram and a TGA thermogram of the crystalline Form la-4.

[0056] FIG. 33 is an XPRD pattern of the crystalline Form la-5. FIG. 34 is a graph depicting a DSC thermogram and a TGA thermogram of the crystalline Form la-5.

[0057] FIG. 35 is an XPRD pattern of the crystalline Form la-6.

[0058] FIG. 36 is a graph depicting a DSC thermogram and a TGA thermogram of the crystalline Form la-6.

[0059] FIG. 37 is an XPRD pattern of the crystalline Form la-7.

[0060] FIG. 38 is a graph depicting a DSC thermogram and a TGA thermogram of the crystalline Form la-7.

[0061] FIG. 39 is an XPRD pattern of the crystalline Form Ib-1.

[0062] FIG. 40 is a graph depicting a DSC thermogram and a TGA thermogram of the crystalline Form Ib-1.

[0063] FIG. 41 is an XPRD pattern of the crystalline Form Ic-1.

[0064] FIG. 42 is a graph depicting a DSC thermogram and a TGA thermogram of the crystalline Form Ic-1.

[0065] FIG. 43 is an XRPD pattern of amorphous form of the compound represented by Structural Formula (II).

[0066] FIG. 44 is a modulated differential scanning calorimetry (mDSC) pattern of amorphous form of the compound represented by Structural Formula (II).

[0067] FIG. 45 is a plot demonstrating XRPD traces of crystalline Form la after stability studies for 12 months under different temperatures and conditions.

[0068] DETAILED DESCRIPTION OF THE INVENTION

[0069] RIP Kinases

[0070] Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a wide variety of signal transduction processes in the cell. They have been shown to be key regulators in most cellular functions including proliferation, cell metabolism, cell survival, apoptosis, DNA damage repair, and cell motility. Uncontrolled signaling due to defective control of protein phosphorylation has been implicated in a number of diseases, including, for example, cancer, inflammation, allergies, immune diseases, CNS disorders, and angiogenesis.

[0071] Amongst the families of protein kinases, one particular example is the Receptor- Interacting Serine / Threonine Kinases including RIPK2. RIPK2 is composed of an N-terminal kinase domain and a C-terminal caspase-recruitment domain (CARD) linked via an intermediate (IM) region. The CARD domain of RIP2 kinase mediates interaction with other CARD-containing proteins, such as NODI and N0D2. NODI and N0D2 are cytoplasmic receptors which are activated by specific bacterial peptidoglycan motifs and play a key role in innate immune surveillance. Upon intracellular bacterial exposure, NODI or N0D2 binds to RIPK2 to coordinate NF-kB (nuclear factor k B)-mediated cytokine responses. Once associated with N0D1 / 2, RIPK2 undergoes autophosphorylation on Tyr 474 (Y474), and acts as a molecular scaffold to bring together other kinases (TAK1, IKKb involved in NF-kB, and MAPK activation).

[0072] Both NOD 1 / 2 and RIPK2 are NF-kB regulated genes, and as such, their activation causes a positive feedback loop in which activation of NOD1 / 2:RIPK2 stimulates further activation and further inflammation. Additionally, NOD 1 / 2 and RIPK2 expression are stimulated by a variety of mediators of inflammation, including TNF (Tumor Necrosis Factor) and IFN (Interferon). In addition to NF-kB pathway activation, the NOD1 / 2:RIPK2 complex stimulates autophagy, bactericidal activity, MHC Class II presentation and MAPK (Mitogen- Activated Protein Kinase) activation. Overall, this pathway modulates the innate immune system to help tailor the adaptive immune response to eradicate the offending pathogen.

[0073] Dysregulation of RIPK2-dependent signaling has been linked to autoinflammatory diseases. Patients with loss-of-function N0D2 alleles are prone to the development of Crohn’s disease (CD), an inflammatory disorder of the gastrointestinal tract. NOD2 / RIPK2 pathway is involved in the pathogenesis of inflammatory bowel disease (IBD). Both N0D2 and RIPK2 are upregulated in colon biopsies from CD patients as well as ulcerative colitis (UC) pediatric population. A selective RIPK2 inhibitor has been shown to block the spontaneous pro- inflammatory cytokines secretion from UC / CD patient’s biopsies. This result underlines that RIPK2 activation in the UC / CD patient’s mucosa leads to the pro-inflammatory status of these biopsies.

[0074] Rheumatoid arthritis (RA) is a disease where NOD2 / RIPK2 plays a role. NOD2 / RIPK2 pathway has been shown to be upregulated in immune cells of RA patients, suggesting that RIPK2 inhibition could be beneficial in this population. Gain-of-function N0D2 mutations have been genetically linked to other inflammatory diseases, such as Blau Syndrome / Early Onset Sarcoidosis (EOS), a pediatric granulomateous disease characterized by uveitis, dermatitis, and arthritis. Broad genotyping of young patients suffering from allergic rhinitis and atopic dermatitis highlighted common N0D2 polymorphism with Crohn’s as probable leading cause of the excessive immune response against skin tissues observed. Mutations in NODI have been associated with asthma and early-onset and extra- intestinal inflammatory bowel disease. Genetic and functional studies have also suggested a role for RIP2-dependent signaling in a variety of other granulomateous disorders, such as sarcoidosis.

[0075] Metabolic syndrome, a pathology closely related to obesity and overweight, results from a chronic inflammation and is characterized by hypertension, hyperglycemia and lipolysis dysfunction. Activation of the immune system through NODI pathway was observed in patients suffering from metabolic syndrome. A recent functional study highlighting the impact of RIPK2 inhibitors on lipolysis suggested a role for RIP2-dependent signaling in dysglycemia and lipolysis.

[0076] In cardiac hypertrophy, a complex and multifactorial pathology, inflammation was shown as important hallmark of the disease, notably through the activation of NF-kB signaling. Knockout studies of RIPK2 on hypertrophic heart mice models suggested a role of RIPK2 in the regulation of the inflammation and subsequent tissue fibrosis and hypertrophy.

[0077] Beyond immuno-inflammatory diseases, RIPK2 modulation has also been described in several cancers. In triple negative breast cancer (TNBC), RIPK2 high expression has been associated to worse progression-free survival as well as a worse overall survival. It has been shown that RIPK2 knockdown increases docetaxel sensitivity and decreases tumor and lung metastasis. Another study focusing on a new cancer gene cassette on breast cancer patients’ chromosome 8 discovered RIPK2 coamplification with other tested oncogenes (such as MYC). TNBC biopsies performed in order to find druggable kinases beyond HER2 demonstrated that RIPK2 was hyper-phosphorylated in basal-like and luminal B breast cancer biopsies suggesting that this pathway could be activated in these type of TNBC. More recently, phospho-RIPK2 levels as well as NF-kB activity were shown elevated in biopsies of Inflammatory Breast Cancer. 34 head and neck squamous cell carcinoma cell lines showed that RIPK2 knockdown led to cell death, indicating central roles of the protein for cell survival. It has been proposed that RIPK2 promotes glioma cell growth by regulating TRAF3 and activating the NF-kB pathway and p38 signaling.

[0078] A new role for RIPK2 in osteosarcoma invasion was demonstrated when Gefitinib, via RIPK2 inhibition, prevented progression of pulmonary metastasis. Further, non-canonical NF- kB plays a pivotal role in non-Hodgkin’s lymphoma. Finally, using a three-dimensional lymphatic endothelial cell tube formation, RIPK2 was identified as a kinase involved in lymphatic vessel remodeling, a key factor for the metastatic spread of cancer. Taken together these data strongly support the development of RIPK2 inhibitors in oncology.

[0079] RIPK2 and RIP2 kinase are used interchangeably herein and refer to Receptorinteracting protein kinase 2.

[0080] A description of example embodiments of the invention follows.

[0081] Definitions

[0082] It is to be understood that the term “about”, when referring to a numerical value for temperature, means that the numerical value has a range ±5 °C of the recited numerical value, unless specified otherwise. For example, when a described embodiment or a claim recites a temperature of “about 20 °C”, this is to be understood to mean 20 °C ± 5 °C, that is, a temperature from 15 °C to 25 °C.

[0083] It is to be understood that any 29 angle specified herein means the specified value ± 0.2°. For example, when a described embodiment or a claim specifies a 29 of 4.4°, this is to be understood to mean 4.4° ± 0.2°, that is, a 29 angle of from 4.2° to 4.6°.

[0084] It is to be understood that the term “about”, when referring to a numerical value for time, means that the numerical value has a range ±5 minutes of the recited numerical value, unless specified otherwise. For example, when a described embodiment or a claim recites a period of time of “about 60 minutes”, this is to be understood to mean 60 minutes ± 5 minutes, that is, a period of time from 55 minutes to 65 minutes.

[0085] Provided herein are crystalline forms of the compound of Structural Formula (II) and salts thereof.

[0086] “Crystalline” or “crystal,” as used herein, refers to a homogeneous solid formed by a repeating, three-dimensional pattern of atoms, ions or molecules (e.g., an anhydrous molecule or a salt thereof, solvate thereof, or combination of the foregoing) having fixed distances between constituent parts. The unit cell is the simplest repeating unit in this pattern.

[0087] The crystalline forms provided herein can be identified on the basis of characteristic peaks in an x-ray powder diffraction (XRPD) analysis. XRPD is a scientific technique that measures the x-rays, neutrons or electrons scattered by a powder or microcrystalline material as a function of scattering angle. XRPD can be used to identify and characterize crystalline solids, as the diffraction pattern produced by a particular solid is typically distinctive to that solid and can be used as a “fingerprint” to identify that solid. For example, an XRPD pattern or diffractogram (e.g., a pattern or diffractogram produced by a sample, such as an unknown sample) that is substantially in accordance with a reference XRPD pattern or diffractogram can be used to determine the identity between the sample material and the reference material. Both the position and the relative intensity of the peaks in an XRPD diffractogram are indicative of the particular phase and identity of a material. XRPD diffractograms can be collected as known in the art such as by using Cu Ka radiation.

[0088] The crystalline forms provided herein can also be identified on the basis of differential scanning calorimetry (DSC) and / or thermogravimetric analysis (TGA). DSC is a thermoanalytical technique in which the difference in the amount of heat required to increase the temperature of a sample is measured as a function of temperature. DSC can be used to detect physical transformations, such as phase transitions, of a sample. For example, DSC can be used to detect the temperature(s) at which a sample undergoes crystallization, melting or glass transition.

[0089] TGA is a method of thermal gravimetric analysis in which changes in physical and chemical properties of a material are measured as a function of increasing temperature (with constant heating rate) or as a function of time (with constant temperature and / or constant mass loss). TGA can provide information about physical phenomena, such as second-order phase transitions, or about chemical phenomena, such as desolvation and / or decomposition.

[0090] It is to be understood that any temperature associated with DSC or TGA specified herein means the specified value ± 5 °C or less. For example, when an embodiment or a claim specifies an endothermic peak at about 184 °C, this is to be understood to mean 184 °C ± 5 °C or less, that is a temperature of from 179 °C to 189 °C. In preferred embodiments, a DSC or TGA temperature is the specified value ± 3 °C, in more preferred embodiments, ± 2 °C.

[0091] The crystalline forms provided can be additionally characterized by dynamic vapor sorption (DVS), wherein a sample is subjected to varying conditions of humidity and temperature, and the response of the sample is measured gravimetrically. The result of a DVS analysis particularly can be a dual curve providing sample weight percent as a function of relative humidity (RH) over time, a dual curve providing sample water content as a function of RH over time, a curve providing weight percent in relation to RH, or a curve providing water content in relation to RH. Equipment useful for measuring such data is known in the art, and any such equipment can be used to measure the compounds according to the present disclosure. In certain embodiments, DVS analysis can be carried out by scanning at a series of specific RH values. Thus, specific polymorphs according to the disclosure may be identified and described in relation to the representative graph and / or the approximate peaks obtained in DVS analysis, particularly scanning from 0% to 95% RH with a step interval of 5% or 10% RH.

[0092] Pharmaceutical Compositions

[0093] In another embodiment, the disclosure relates to a pharmaceutical composition, comprising crystalline forms of the compound of Structural Formula (II) or a salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, a composition of the disclosure is formulated for administration to a patient in need of the composition. In some embodiments, a composition of the disclosure is formulated for oral, intravenous, subcutaneous, intraperitoneal or dermatological administration to a patient in need thereof. In a particular embodiment, the composition of the disclosure is formulated for oral administration.

[0094] As used herein, the term “subject” is intended to include human and non-human animals. Exemplary human subjects include a human patient having a disorder, e.g., a disorder described herein or a normal subject. The term “non-human animals” of the disclosure includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and / or agriculturally useful animals, e.g., sheep, cow, pig, etc., and companion animals (dog, cat, horse, etc.). In a particular embodiment the subject is a human, for example, an adult male or female or a male or female child.

[0095] As used herein, an amount of a crystalline form that is effective to treat a disorder, or a “therapeutically effective amount” refers to an amount of a crystalline form which is effective, upon single or multiple dose administration to a subject or a cell, in curing, alleviating, relieving or improving one or more symptoms of a disorder.

[0096] As used herein, an amount of a crystalline form effective to prevent a disorder, or a “prophylactically effective amount” of the crystalline form refers to an amount effective, upon single- or multiple-dose administration to the subject, in preventing or delaying the onset or recurrence of a disorder or one or more symptoms of the disorder.

[0097] For administration to human subjects, the total daily dose of the crystalline forms disclosed herein is typically in the range of about O.lmg to about 3000 mg depending on the route of administration. For example, oral administration can require a total daily dose of from about 1 mg to about 3000 mg, while an intravenous dose can only require a total daily dose of from about 0.1 mg to about 300 mg. The total daily dose may be administered in a single or divided doses (e.g., 2, 3, 4, 5 or 6 times per day at evenly space or randomly spaced intervals) or on an as needed basis. The typical daily dose can fall outside the ranges above based on the discretion of the physician or drug prescriber. Although these dosages are based on an average human subject having a mass of about 60 kg to 70 kg, the physician will be able to determine the appropriate dose for a subject (e.g., an infant) whose mass falls outside this weight range.

[0098] As used herein, the term “treat” or “treatment” is defined as the application or administration of a crystalline form, alone or in combination with a second agent, to a subject, e.g., a patient, or application or administration of the crystalline form to an isolated tissue or cell, e.g., cell line, from a subject, e.g., a patient, who has a disorder (e.g., a disorder as described herein), a symptom of a disorder, or a predisposition toward a disorder, in order to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder, one or more symptoms of the disorder or the predisposition toward the disorder (e.g., to prevent at least one symptom of the disorder or to delay onset of at least one symptom of the disorder).

[0099] “Pharmaceutically or pharmacologically acceptable” includes molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards, as required by FDA Office of Biologies standards. The phrase “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, poly acrylates, waxes, polyethylenepolyoxypropylene -block polymers, polyethylene glycol and wool fat.

[0100] Compositions of the present disclosure may be administered orally, parenterally (including subcutaneous, intramuscular, intravenous and intradermal), by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. In some embodiments, provided crystalline forms or compositions are administrable intravenously and / or intraperitoneally.

[0101] The term “parenteral,” as used herein, includes subcutaneous, intracutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intra-arterial, intra- synovial, intrasternal, intrathecal, intralesional, intrahepatic, intraperitoneal intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, subcutaneously, intraperitoneally or intravenously.

[0102] Pharmaceutically acceptable compositions of this disclosure can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions and / or emulsions are required for oral use, the active ingredient can be suspended or dissolved in an oily phase and combined with emulsifying and / or suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0103] In some embodiments, an oral formulation is formulated for immediate release or sustained / delayed release.

[0104] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active crystalline form is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium salts, g) wetting agents, such as acetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

[0105] Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0106] A crystalline form of the disclosure can also be in micro-encapsulated form with one or more excipients, as noted above. In such solid dosage forms, the crystalline form of the disclosure can be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.

[0107] Compositions for oral administration may be designed to protect the active ingredient against degradation as it passes through the alimentary tract, for example, by an outer coating of the formulation on a tablet or capsule.

[0108] In another embodiment, a crystalline form of the disclosure can be provided in an extended (or “delayed” or “sustained”) release composition. This delayed-release composition comprises a crystalline form of the disclosure in combination with a delayed-release component. Such a composition allows targeted release of a provided crystalline form into the lower gastrointestinal tract, for example, into the small intestine, the large intestine, the colon and / or the rectum. In certain embodiments, the delayed-release composition comprising a crystalline form of the disclosure further comprises an enteric or pH-dependent coating, such as cellulose acetate phthalates and other phthalates (e.g., polyvinyl acetate phthalate, methacrylates (Eudragits)). Alternatively, the delayed-release composition provides controlled release to the small intestine and / or colon by the provision of pH sensitive methacrylate coatings, pH sensitive polymeric microspheres, or polymers which undergo degradation by hydrolysis. The delayed-release composition can be formulated with hydrophobic or gelling excipients or coatings. Colonic delivery can further be provided by coatings which are digested by bacterial enzymes such as amylose or pectin, by pH dependent polymers, by hydrogel plugs swelling with time (Pulsincap), by time-dependent hydrogel coatings and / or by acrylic acid linked to azoaromatic bonds coatings.

[0109] In certain embodiments, the delayed-release composition of the present disclosure comprises hypromellose, microcrystalline cellulose, and a lubricant. The mixture of a crystalline form of the disclosure, hypromellose and microcrystalline cellulose can be formulated into a tablet or capsule for oral administration. In certain embodiments, the mixture is granulated and pressed into tablets.

[0110] Alternatively, pharmaceutically acceptable compositions of this disclosure can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the crystalline form of the disclosure with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and, therefore, will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0111] Pharmaceutically acceptable compositions of this disclosure can also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0112] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches can also be used.

[0113] For other topical applications, the pharmaceutically acceptable compositions of the disclosure can be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of crystalline forms of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene crystalline form, emulsifying wax and water and penetration enhancers. Alternatively, pharmaceutically acceptable compositions of the disclosure can be formulated in a suitable lotion or cream containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active crystalline form suspended or dissolved in a carrier with suitable emulsifying agents. In some embodiments, suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. In other embodiments, suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2- octyldodecanol, benzyl alcohol and water and penetration enhancers.

[0114] For ophthalmic use, pharmaceutically acceptable compositions of the disclosure can be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.

[0115] Pharmaceutically acceptable compositions of this disclosure can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0116] In some embodiments, pharmaceutically acceptable compositions of this disclosure are formulated for oral administration.

[0117] In some embodiments, pharmaceutically acceptable compositions of this disclosure are formulated for intravenous administration.

[0118] In some embodiments, pharmaceutically acceptable compositions of this disclosure are formulated for topical administration.

[0119] The amount of crystalline forms of the present disclosure that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration and the activity of the crystalline form employed. Preferably, compositions should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving the composition.

[0120] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific crystalline form employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician and the severity of the particular disease being treated. The amount of a crystalline form of the present disclosure in the composition will also depend upon the particular crystalline form in the composition. Other pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-oc-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene -block polymers, polyethylene glycol and wool fat. Cyclodextrins such as ex-, |3-, and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3- hydroxypropyl- |3-cyclodextrins, or other solubilized derivatives can also be advantageously used to enhance delivery of crystalline forms described herein.

[0121] The pharmaceutical compositions of this disclosure are preferably administered by oral administration or by injection. The pharmaceutical compositions of this disclosure can contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation can be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated crystalline form or its delivery form.

[0122] The pharmaceutical compositions can be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and / or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.

[0123] When the compositions of this disclosure comprise a combination of a crystalline form of the formulae described herein and one or more additional therapeutic or prophylactic agents, both the crystalline form and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. The additional agent(s) can be administered separately, as part of a multiple dose regimen, from the crystalline forms of this disclosure. Alternatively, the additional agent(s) can be part of a single dosage form, mixed together with the crystalline form of this disclosure in a single composition.

[0124] The crystalline forms described herein can, for example, be administered by injection, intravenously, intraarterially, intraocularly, intravitreally, subdermally, orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg / kg of body weight or, alternatively, in a dosage ranging from about 1 mg to about 1000 mg / dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administration of an effective amount of a crystalline form of the disclosure, or a composition thereof, to achieve the desired or stated effect. Typically, the pharmaceutical compositions of this disclosure will be administered from about 1 to about 6 times per day or, alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active crystalline form (w / w). Alternatively, a preparation can contain from about 20% to about 80% active crystalline form.

[0125] Doses lower or higher than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient’s disposition to the disease, condition or symptoms, and the judgment of the treating physician. Upon improvement of a patient’s condition, a maintenance dose of a compound, composition or combination of this disclosure can be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon recurrence of disease symptoms.

[0126] Uses of Crystalline Forms and Pharmaceutically Acceptable Compositions

[0127] As used herein, “RIPK2-mediated” disease, disorder or condition means any disease or other deleterious condition in which RIPK2 plays a role. Accordingly, another embodiment of the present invention relates to treating, for example, lessening the severity of, a RIPK2- mediated disorder or condition. RIPK2-mediated disorders include inflammatory disorders, autoimmune disorders, granulomatous diseases, neurodegenerative disorders, and cancer. Specific examples of RIPK2-mediated disorders are set forth in detail below.

[0128] Crystalline forms provided by this disclosure are also useful as tools, for example, to study RIPK2 modulation in biological and pathological phenomena, to study cancer or for the identification and / or comparative evaluation of RIPK2 modulators. Accordingly, in particular embodiments, the present invention provides a method for studying an effect of a crystalline form described herein, or a salt or composition thereof, on a sample, the method comprising contacting a sample comprising cells in culture or RIPK2 with the crystalline form or a composition thereof; and measuring the effect of the crystalline form or a composition thereof, on the cells or RIPK2. For example, the crystalline forms described herein can be used as a standard or control substance in binding assays (e.g., competitive binding assays) to identify or evaluate potential RIPK2 modulators or as a discovery tool to probe the role of RIPK2 modulation in certain disorders or conditions, such as those described herein, including inflammatory disorders, autoimmune disorders, and other RIPK2-mediated disorders or conditions.

[0129] In a certain embodiment, the present invention relates to a method of treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline form described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein, wherein the disease or disorder is selected from inflammatory diseases, autoimmune diseases, granulomatous diseases, cancer and neurodegenerative diseases. In some embodiments, crystalline forms and compositions described herein are useful for treating inflammatory disorders in a subject in need thereof. Thus, in certain embodiments, the present invention provides a method for treating an inflammatory disorder, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a crystalline form of the present invention.

[0130] In certain aspects, the inflammatory disease can include, but is not limited to uveitis, interleukin- 1 converting enzyme fever syndrome, dermatitis, acute lung injury, type 2 diabetes mellitus, arthritis, inflammatory bowel disease (IBD), ischemia reperfusion injury in a solid organ transplant, sepsis, liver disease, allergic disease, and graft versus host disease.

[0131] In certain instances, the inflammatory disease is an IBD. For example, the IBD is selected from ulcerative colitis, Crohn's disease, early-onset IBD, and extraintestinal IBD. In a particular embodiment, the ulcerative colitis is moderately to severely acute ulcerative colitis.

[0132] Alternatively, the inflammatory disease can include but is not limited to rheumatoid arthritis, inflammatory arthritis, peritonitis, ischemia reperfusion injury in kidney transplant, non-alcohol steatohepatitis, alcohol steatohepatitis, insulin-resistant type 2 diabetes, allergic rhinitis, asthma, atopic dermatitis, Sjogren’s syndrome, spondyloarthritis, ankylosing spondylitis, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, thrombosis, a-synucleinopathy, Parkinson’s disease, dementia with Lewy body, multiple system atrophy, Alzheimer’s disease, amyotrophic lateral sclerosis, and chronic obstructive pulmonary disease.

[0133] In a particular embodiment, the disease or disorder is an autoimmune disease. For example, the autoimmune disease can include, but is not limited to systemic lupus erythematosus, lupus nephritis, psoriasis, diabetes mellitus type 1, Goodpasture’s syndrome, Guillain-Barre Syndrome, Hashimoto’s disease, Grave’s disease, immune thrombocytopenic purpura, and multiple sclerosis (including relap sing-remitting MS, secondary-progressive MS, primary-progressive MS, progressive-relapsing MS).

[0134] In a further embodiment, the disease or disorder is a granulomatous disease. For example, the granulomatous disease is selected from sarcoidosis, Blau syndrome, Wegner’s granulomatosis, Behcet’s disease, and interstitial pulmonary disease.

[0135] In another embodiment, the disease or disorder is a neurodegenerative disorder. For example, the neurological disorder is selected from Alzheimer’s disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig’s Disease), Parkinson’s disease, multiple sclerosis, diabetic neurophathy, poly glutamine (polyQ) diseases, stroke, Fahr disease, Menke’s disease, Wilson’s disease, cerebral ischemia, a prion disorder, dementia, corticobasal degeneration, progressive supranuclear palsy, spinocerebellar atrophies, brain injury and spinal cord injury.

[0136] In yet another embodiment, the disease or disorder is cancer. For example, the cancer is selected from a hematological cancer such as leukemia (e.g., acute myeloid leukemia, chronic myelogenous leukemia), lymphoma (e.g., non-Hodgkin’s Lymphoma, Hodgkin’s Lymphoma, diffuse large B-cell lymphoma), myeloma (e.g., multiple myeloma), myelodysplastic syndrome, myelofibrosis), breast cancer, brain cancer (e.g., glioblastoma), colorectal cancer, esophageal cancer, head and neck cancer, melanoma, pancreatic cancer, prostate cancer, stomach cancer, bone cancer, ovarian cancer, uterine cancer, renal cancer, liver cancer and lung cancer. The cancer can be a soft tissue cancer, including but not limited to, a sarcoma selected from the group consisting of a fibrosarcoma and liposarcoma (e.g., a dedifferentiated liposarcoma and a pleomorphic liposarcoma)

[0137] The crystalline forms and compositions described herein can also be administered to cells in culture, e.g., in vitro or ex vivo, or to a subject, e.g., in vivo, to treat, prevent, and / or diagnose a variety of disorders, including those described herein below.

[0138] The crystalline forms of this invention can be used alone or in combination with other therapeutic agents. Combination therapies according to the present invention comprise the administration of at least one crystalline form of the invention, and the use of at least one other therapeutically active agent. For example, combination therapies according to the present invention comprise the administration of at least one crystalline form of the invention (for example, Form la) and at least one other therapeutically active agent to a subject in need of treatment for a given disease or disorder, for example, the inflammatory diseases, autoimmune diseases, granulomatous diseases, cancers and neurodegenerative diseases described herein.

[0139] The crystalline forms of the invention and the other therapeutically active agent can be administered together in a single pharmaceutical composition or separately and, when administered separately this can occur simultaneously or sequentially in any order. The amounts of the crystalline forms of the invention and other therapeutically active agents and the relative timings of administration can be selected in order to achieve the desired combined therapeutic effect. Thus in a further aspect, there is provided a combination comprising a crystalline form of the invention together with one or more other therapeutically active agents.

[0140] In certain embodiments, the invention relates to a method of treating a subject suffering from an inflammatory disorder as described herein comprising administering to the subject an effective amount of a crystalline form disclosed herein or a pharmaceutically acceptable salt thereof and an anti-inflammatory agent and / or an anti-TNF agent.

[0141] In a particular embodiment, the invention relates to a method of treating a subject suffering from Crohn's disease as described herein comprising administering to the subject an effective amount of a crystalline form disclosed herein or a pharmaceutically acceptable salt thereof and optionally an anti-inflammatory agent and / or an anti-TNF agent.

[0142] In a particular embodiment, the invention relates to a method of treating a subject suffering from ulcerative colitis (e.g., moderately or severely active ulcerative colitis) as described herein comprising administering to the subject an effective amount of a crystalline form disclosed herein or a pharmaceutically acceptable salt thereof and optionally an antiinflammatory agent and / or an anti-TNF agent. In a particular aspect, the crystalline form in Form la and the anti-inflammatory agent is an anti-integrin agent (e.g., vedolizumab (Entyvio®)).

[0143] In another embodiment, the invention relates to a method of treating a subject suffering from an autoimmune disorder as described herein comprising administering to the subject an effective amount of a crystalline form disclosed herein or a pharmaceutically acceptable salt thereof and an autoimmune agent such as, but not limited to, an anti-TNF agent.

[0144] Suitable anti-inflammatory / autoimmune agents include 5-aminosalicyclic acid and mesalamine preparations, sulfasalazine, hydroxycloroquine, thiopurines (azathiopurine, mercaptopurine), methotrexate, cyclophosphamide, cyclosporine, calcineurin inhibitors (cyclosporine, pimecrolimus, tacrolimus), mycophenolic acid (CellCept®), mTOR inhibitors (temsirolimus, everolimus), JAK inhibitors (tofacitinib (Xeljan®)), Syk inhibitors (fostamatinib), corticosteroids, particularly low-dose corticosteroids (such as prednisone (Deltasone®) and bundesonide) and anti-inflammatory biologies such as anti-IL6R mAbs (Actemra® (tocilizumab)), anti-IL6 biologies, anti-IL I (anakinra (Kineret®), canakinumab (Haris®), rilonacept (Arcalyst®)), anti-IL12 or / and IL23 biologies (ustekinumab (Stelara®)), anti-IL17 biologies (secukinumab), anti-CD22 (epratuzumab), anti-integrin agents (natalizumab (Tysabri®)), vedolizumab (Entyvio®), anti-IFNa (sifalimumab), anti-CD20 mAbs (rituximab (Rituxan®) and ofatumumab (Arzerra®)), and other agents, such as abatacept (Orencia®), anakinra (Kineret®), canakinumab (Haris®), rilonacept (Arcalyst®), secukinumab, epratuzumab, sifalimumab, and belimumab (Benlysta®), CD4 biologies and other cytokine inhibitors or biologies to T-cell or B-cell receptors or interleukins. In some embodiments, the anti-inflammatory / autoimmune agent is an aminosalicylate. Examples of aminosalicylates include mesalamine (Apriso®, Asacol HD®, Canasa®, Delzicol®, Lialda®, Pentasa®, Rowasa®), balsalazide (Colazal®), olsalazine (Dipentuni®), and sulfasalazine (Azulfidine®).In some embodiments, the JAK inhibitors is selected from tofacitinib (Xeljan®) and upadacitinib (Rinvoq®). Examples of suitable anti-TNF agents include the anti-TNF biologies such as Enbrel® (etanecerpt), Humira® (adalimumab), Remicade® (infliximab), Cimzia® (certolizumab), and Simponi® (golimumab).

[0145] In a particular embodiment, the invention relates to a method of treating a subject suffering from a neurodegenerative disease as described herein such as Parkinson’s comprising administering to the subject an effective amount of a crystalline form disclosed herein or a pharmaceutically acceptable salt thereof and optionally one or more additional therapeutic agents typically used in the treatment of Parkinson’s. Such additional therapeutic agents include, but are not limited to levodopa, carbodopa or a combination thereof, pramipexole, ropinirole, rotigotine, selegiline, rasagiline, entacapone, tolcapone, benztropine, trihexyphenidyl, or amantadine, or a pharmaceutically acceptable salt thereof.

[0146] In a particular embodiment, the invention relates to a method of treating a subject suffering from a neurodegenerative disease as described herein such as Alzheimer’s comprising administering to the subject an effective amount of a crystalline form disclosed herein or a pharmaceutically acceptable salt thereof and optionally one or more additional therapeutic agents typically used in the treatment of Alzheimer’s disease. Such additional therapeutic agents include, but are not limited to donepezil, galantamine, memantine, rivastigmine, anti- Abeta (amyloid beta) therapies including aducanumab, crenezumab, solanezumab, and gantenerumab, small molecule inhibitors of BACE1 including verubecestat, AZD3293 (EY3314814), elenbecestat (E2609), EY2886721, PF- 05297909, JNJ-54861911, TAK-070, VTP-37948, HPP854, CTS-21166, or anti-tau therapies such as EMTM (leuco- methylthioninium-bis (hydromethanesulfonate)), or a pharmaceutically acceptable salt thereof.

[0147] In certain embodiments, the invention relates to a method of treating a subject with cancer comprising administering to the subject an effective amount of a crystalline form disclosed herein thereof and an anti-cancer agent. An "anti-cancer agent" is a compound, which when administered in an effective amount to a subject with cancer, can achieve, partially or substantially, one or more of the following: arresting the growth, reducing the extent of a cancer (e.g., reducing size of a tumor), inhibiting the growth rate of a cancer, and ameliorating or improving a clinical symptom or indicator associated with a cancer (such as tissue or serum components) or increasing longevity of the subject.

[0148] The anti-cancer agents suitable for use in the methods described herein include any anticancer agents that have been approved for the treatment of cancer. In one embodiment, the anticancer agent includes, but is not limited to, a targeted antibody, an angiogenesis inhibitor, an alkylating agent, an antimetabolite, a vinca alkaloid, a taxane, a podophyllotoxin, a topoisomerase inhibitor, a hormonal antineoplastic agent and other antineoplastic agents.

[0149] In one embodiment, the anti-cancer agents that can be used in methods described herein include, but are not limited to, paclitaxel, docetaxel, 5-fluorouracil, trastuzumab, lapatinib, bevacizumab, letrozole, goserelin, tamoxifen, cetuximab, panitumumab, gemcitabine, capecitabine, irinotecan, oxaliplatin, carboplatin, cisplatin, doxorubicin, epirubicin, cyclophosphamide, methotrexate, vinblastine, vincristine, melphalan, cytarabine, etoposide, daunorubicin, bleomycin, mitomycin and adriamycin and a combination thereof.

[0150] In one embodiment, the anti-cancer agent and the compound disclosed herein are administered contemporaneously. When administered contemporaneously, the anti-cancer agent and the compound can be administered in the same formulation or in different formulations. Alternatively, the compound and the additional anti-cancer agent can be administered separately at different times.

[0151] In some embodiments, the present disclosure relates to a crystalline form of a salt of the compound represented by Structural Formula (II): wherein the salt is selected from the group consisting of a chloride, a succinate, a sulfate, a methanesulfonate, a fumarate, and a citrate of the compound represented by Structural Formula (ID-

[0152] In some embodiments, the salt is a chloride of the compound represented by Structural Formula (II). For example, the salt is a monochloride of the compound represented by Structural Formula (II).

[0153] In some embodiments, the crystalline form is Form la characterized by at least three x- ray powder diffraction peaks at 29 angles selected from 10.33°, 16.77°, 19.01°, and 24.45°. In some embodiments, the crystalline form is characterized by x-ray powder diffraction peaks at 26 angles 7.99°, 10.33°, 13.23°, 16.77°, 17.70°, 19.01°, 23.48°, and 24.45°.

[0154] In some embodiments, the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles of 7.99°, 8.85°, 10.33°, 13.23°, 15.56°, 16.77°, 17.70°, 19.01°, 20.51°, 20.91°, 21.58°, 23.48°, 24.45°, 24.99°, and 26.01°.

[0155] In some embodiments, the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles of 7.99°, 8.85°, 10.33°, and 13.23°.

[0156] In some embodiments, the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 1.

[0157] In some embodiments, the crystalline form is characterized by a DSC thermogram having an endothermic event at about 258 °C.

[0158] In some embodiments, the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 2.

[0159] In some embodiments, the crystalline form is anhydrous.

[0160] In some embodiments, the salt is a succinate of the compound represented by Structural Formula (II).

[0161] In some embodiments, the crystalline form is Form lb characterized by at least three x- ray powder diffraction peaks at 26 angles selected from 8.30°, 9.29°, 18.42°, and 23.39°.

[0162] In some embodiments, the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles 6.31°, 8.30°, 9.29°, 16.72°, 18.42°, 22.80°, 23.39°, and 24.26°.

[0163] In some embodiments, the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles of 6.31°, 8.30°, 9.29°, 16.72°, 18.42°, 19.18°, 19.86°, 22.80°, 23.39°, and 24.26°.

[0164] In some embodiments, the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles 6.31°, 8.30°, and 9.29°.

[0165] In some embodiments, wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 3.

[0166] In some embodiments, the crystalline form is characterized by a DSC thermogram having an endothermic event at about 159 °C.

[0167] In some embodiments, the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 4. In some embodiments, the salt is a sulfate of the compound represented by Structural Formula (II).

[0168] In some embodiments, the crystalline form is Form Ic characterized by at least three x- ray powder diffraction peaks at 29 angles selected from 3.87°, 7.76°, 15.76°, and 19.86°.

[0169] In some embodiments, the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles 3.87°, 7.76°, 11.86°, 15.76°, and 19.86°.

[0170] In some embodiments, the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles 3.87°, 7.76°, and 11.86°.

[0171] In some embodiments, the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 5.

[0172] In some embodiments, the crystalline form is characterized by a DSC thermogram having an endothermic event at about 255 °C.

[0173] In some embodiments, the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 6.

[0174] In some embodiments, the salt is a phosphate of the compound represented by Structural Formula (II).

[0175] In some embodiments, the crystalline form is Form Id characterized by at least three x- ray powder diffraction peaks at 29 angles selected from 4.86°, 7.00°, 9.37°, and 21.07°.

[0176] In some embodiments, the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles 4.86°, 7.00°, 9.37°, 15.01°, 18.99°, and 21.07°.

[0177] In some embodiments, the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles 4.86°, 7.00°, and 9.37°,

[0178] In some embodiments, the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG 7.

[0179] In some embodiments, the crystalline form is characterized by a DSC thermogram having an endothermic event at about 147 °C.

[0180] In some embodiments, the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 8.

[0181] In some embodiments, is a fumarate of the compound represented by Structural Formula (II).

[0182] In some embodiments, the crystalline form is Form le characterized by at least three x- ray powder diffraction peaks at 29 angles selected from 8.11°, 9.42°, 22.66°, and 23.31°. In some embodiments, the crystalline form is characterized by x-ray powder diffraction peaks at 26 angles 8.11°, 8.58°, 9.42°, 16.37°, 18.68°, 22.66°, 23.31°, and 24.28°.

[0183] In some embodiments, the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles 8.11°, 8.58°, 9.42°, 16.37°, 17.71°, 18.68°, 19.03°, 19.66°, 22.66°, 23.31°, 24.02°, and 24.28°.

[0184] In some embodiments, the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles 8.11°, 8.58°, and 9.42°.

[0185] In some embodiments, the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 9.

[0186] In some embodiments, the crystalline form is characterized by a DSC thermogram having an endothermic event at about 204 °C.

[0187] In some embodiments, the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 10.

[0188] In some embodiments, the crystalline form is anhydrous.

[0189] In some embodiments, the salt is a methanesulfonate of the compound represented by Structural Formula (II).

[0190] In some embodiments, the crystalline form is Form If characterized by at least three x- ray powder diffraction peaks at 26 angles selected from 3.76°, 7.62°, 15.36°, and 19.28°.

[0191] In some embodiments, the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles 3.76°, 6.70°, 7.62°, 8.19°, 15.36°, 16.51°, and 19.28°.

[0192] In some embodiments, the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles 3.76°, 6.70°, 7.62°, and 8.19°,

[0193] In some embodiments, the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 11.

[0194] In some embodiments, the crystalline form is characterized by a DSC thermogram having an endothermic event at about 221 °C.

[0195] In some embodiments, the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 12.

[0196] In some embodiments, the crystalline form is anhydrous.

[0197] In some embodiments, the salt is a citrate of the compound represented by Structural Formula (II).

[0198] In some embodiments, the crystalline form is Form Ig characterized by at least three x- ray powder diffraction peaks at 29 angles selected from 3.68°, 7.49°, 18.81°, and 18.99°. In some embodiments, the crystalline form is characterized by x-ray powder diffraction peaks at 26 angles 3.68°, 7.49°, 10.32°, 11.31°, 18.81°, and 18.99°.

[0199] In some embodiments, the crystalline form is characterized by x-ray powder diffraction peaks at 26 angles 3.68°, 7.49°, 10.32°, and 11.31°.

[0200] In some embodiments, the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 13.

[0201] In some embodiments, the present disclosure relates to a crystalline form of the compound represented by Structural Formula (II):

[0202] In some embodiments, the crystalline form is Form Ila characterized by at least three x-ray powder diffraction peaks at 26 angles selected from 13.81°, 16.73°, 18.11°, and 20.12°.

[0203] In some embodiments, the crystalline form is characterized by x-ray powder diffraction peaks at 26 angles 7.99, 13.81°, 16.73°, 17.30°, 18.11°, 18.62°, 20.12°, and 23.77°.

[0204] In some embodiments, the crystalline form is characterized by x-ray powder diffraction peaks at 26 angles 7.99, 13.81°, and 16.73°.

[0205] In some embodiments, the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 14.

[0206] In some embodiments, the crystalline form is characterized by a DSC thermogram having an endothermic event at about 163 °C.

[0207] In some embodiments, the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 15.

[0208] In some embodiments, the crystalline form is Form lib characterized by at least three x-ray powder diffraction peaks at 26 angles selected from 4.39°, 20.39°, 21.10°, and 24.14°.

[0209] In some embodiments, the crystalline form is characterized by x-ray powder diffraction peaks at 26 angles 4.39°, 8.66°, 12.96°, 17.29°, 20.39°, 20.73°, 21.10°, and 24.14°.

[0210] In some embodiments, the crystalline form is characterized by x-ray powder diffraction peaks at 26 angles 4.39°, 8.66°, 10.90°, 12.96°, 13.54°, 16.03°, 17.29°, 19.79°, 20.39°, 20.73°, 21.10°, 21.50°, 23.09°, and 24.14°. In some embodiments, the crystalline form is characterized by x-ray powder diffraction peaks at 26 angles 4.39°, 8.66°, 10.90°, 12.96°, and 13.54°.

[0211] In some embodiments, the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 16.

[0212] In some embodiments, the crystalline form is characterized by a DSC thermogram having an endothermic event at about 128 °C.

[0213] In some embodiments, the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 17.

[0214] In some embodiments, the crystalline form is a hydrate. In some embodiments, the crystalline form is monohydrate.

[0215] In some embodiments, the present disclosure relates to a composition, comprising particles of one or more crystalline forms of a compound represented by Structural Formula (II): wherein the one or more crystalline forms are selected from:

[0216] Form Ila characterized by at least three x-ray powder diffraction peaks at 26 angles selected from 13.81°, 16.73°, 18.11°, and 20.12°, and

[0217] Form lib characterized by at least three x-ray powder diffraction peaks at 26 angles selected from 4.39°, 20.39°, 21.10°, and 24.14°.

[0218] In some embodiments, the present disclosure relates to a pharmaceutical composition, comprising a crystalline form or a composition described herein and a pharmaceutically acceptable carrier.

[0219] In some embodiments, the present disclosure relates to a method of treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline form described herein, a composition described herein, or a pharmaceutical composition described herein, wherein the disease or disorder is selected from an inflammatory disease, autoimmune disease, granulomatous disease, cancer, and neurodegenerative disease. In some embodiments, the disease or disorder is an inflammatory disease. For example, the inflammatory disease is selected from uveitis, interleukin- 1 converting enzyme fever syndrome, dermatitis, acute lung injury, type 2 diabetes mellitus, arthritis, inflammatory bowel disease (IBD), ischemia reperfusion injury in a solid organ transplant, sepsis, liver disease, allergic disease, and graft versus host disease. For example, the inflammatory disease is an IBD. For example, in certain embodiments, the IBD is selected from ulcerative colitis (e.g., moderately to severely active ulcerative colitis), Crohn's disease, early-onset IBD, and extraintestinal IBD. In some embodiments, the inflammatory disease is selected from rheumatoid arthritis, inflammatory arthritis, peritonitis, ischemia reperfusion injury in kidney transplant, non-alcohol steatohepatitis, alcohol steatohepatitis, insulin-resistant type 2 diabetes, allergic rhinitis, asthma, atopic dermatitis, Sjogren’s syndrome, spondyloarthritis, ankylosing spondylitis, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, thrombosis, a-synucleinopathy, Parkinson’s disease, dementia with Lewy body, multiple system atrophy, Alzheimer’s disease, amyotrophic lateral sclerosis, and chronic obstructive pulmonary disease.

[0220] In some embodiments, the disease or disorder is an autoimmune disease. For example, in certain embodiments, the autoimmune disease is selected from systemic lupus erythematosus, lupus nephritis, psoriasis, immune thrombocytopenic purpura, and multiple sclerosis.

[0221] In some embodiments, the disease or disorder is a granulomatous disease. For example, in certain embodiments, the granulomatous disease is selected from sarcoidosis, Blau syndrome, Wegner’s granulomatosis, Behcet’s disease, and interstitial pulmonary disease.

[0222] In some embodiments, the disease or disorder is cancer. For example, in certain embodiments, the cancer is selected from leukemia, breast cancer, brain cancer, colorectal cancer, head and neck cancer, melanoma, pancreatic cancer, prostate cancer, ovarian cancer, renal cancer, and lung cancer.

[0223] In some embodiments, the disease or disorder is a neurodegenerative disease. For example, in certain embodiments, the neurodegenerative disease is selected from Alzheimer’s disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig’s Disease), Parkinson’s disease, multiple sclerosis, diabetic neurophathy, polyglutamine (polyQ) diseases, stroke, Fahr disease, Menke’s disease, Wilson’s disease, cerebral ischemia, a prion disorder, dementia, corticobasal degeneration, progressive supranuclear palsy, spinocerebellar atrophies, brain injury, and spinal cord injury. In some embodiments, the method further comprises administering second agent. For example, in some embodiments, the second agent is an anti-inflammatory agent or an anti- autoimmune agent.

[0224] In some embodiments, the second agent is selected from anti-TNF agent, anti-IL-23 agent, anti-integrin agent, and JAK inhibitor. In a particular aspect, the second agent is anti- TNF agent. In some embodiments, the second agent is selected from anti-TNF agent, anti-IL- 23 agent, anti-TLla antibody (e.g., tulisokibart), a small molecule targeting TLla, anti-integrin agent, and JAK inhibitor. In a particular aspect, the second agent is anti-TNF agent. In a particular aspect, second agent is anti- IL-23 agent. In a particular aspect, the second agent is anti-integrin agent. In a particular aspect, second agent is JAK inhibitor. In some embodiments, the JAK inhibitors is selected from tofacitinib and upadacitinib.

[0225] In some embodiments, the second agent is selected from infliximab (Remicade®), adalimumab (Humira®), golimumab (Simponi®), vedolizumab (Entyvio®), ustekinumab (Stelara®), and mirikizumab (Omvoh®). In some embodiments, the second agent is vedolizumab.

[0226] In some embodiments, the second agent is sphingosine 1-phosphate (SIP) receptor modulator. In some embodiments, the second agent is ozanimod (Zeposia®).

[0227] In some embodiments, the second agent is selected from mesalamine, balsalazide, olsalazine, and sulfasalazine.

[0228] In some embodiments, the second agent and the crystalline form described herein, the composition described herein, or the pharmaceutical composition described herein are administered contemporaneously, such as administered together in a single pharmaceutical formulation. In a particular aspect, the second agent and the crystalline form described herein, the composition described herein, or the pharmaceutical composition described herein are formulated for simultaneous administration.

[0229] In some embodiments, the second agent and the crystalline form described herein, the composition described herein, or the pharmaceutical composition described herein are administered separately. In a particular aspect, the second agent and the crystalline form described herein, the composition described herein, or the pharmaceutical composition described herein are administered separately at different times. In a particular aspect, the second agent and the crystalline form described herein, the composition described herein, or the pharmaceutical composition described herein are administered separately at the same time. In some embodiments, the present disclosure relates to a method of treating a RIP2 kinase-mediated disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline form described herein, a composition described herein, or a pharmaceutical composition described herein. In one aspect, the RIP2 kinase-mediated disease or disorder is a disease or disorder wherein inhibition of RIP2 kinase would provide benefit. In a particular aspect, the disease or disorder is selected from an inflammatory disease, autoimmune disease, granulomatous disease, cancer, and neurodegenerative disease.

[0230] In some embodiments, the present disclosure relates to the use of a crystalline form described herein, a composition described herein, or a pharmaceutical composition described herein in the manufacture of a medicament for use in treating a RIP2 kinase-mediated diseases or disorders (e.g., inflammatory diseases, autoimmune diseases, granulomatous diseases, cancer or neurodegenerative diseases).

[0231] In a some embodiments, the RIP2 kinase-mediated disease or disorder is an inflammatory disease. For example, in certain embodiments, the inflammatory disease is selected from uveitis, interleukin- 1 converting enzyme fever syndrome, dermatitis, acute lung injury, type 2 diabetes mellitus, arthritis, inflammatory bowel disease (IBD), ischemia reperfusion injury in a solid organ transplant, sepsis, liver disease, allergic disease, and graft versus host disease. For example, in certain embodiments, the inflammatory disease is an IBD. For example, the IBD is selected from ulcerative colitis, Crohn's disease, early-onset IBD, and extraintestinal IBD. For example, in certain embodiments, the inflammatory disease is selected from rheumatoid arthritis, inflammatory arthritis, peritonitis, ischemia reperfusion injury in kidney transplant, non-alcohol steatohepatitis, alcohol steatohepatitis, insulin-resistant type 2 diabetes, allergic rhinitis, asthma, atopic dermatitis, Sjogren’s syndrome, ankylosing spondylitis, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, thrombosis, a-synucleinopathy, Parkinson’s disease, dementia with Lewy body, multiple system atrophy, Alzheimer’s disease, amyotrophic lateral sclerosis, and chronic obstructive pulmonary disease.

[0232] In some embodiments, the RIP2 kinase-mediated disease or disorder is an autoimmune disease. For example, in certain embodiments, the autoimmune disease is selected from systemic lupus erythematosus, lupus nephritis, psoriasis, immune thrombocytopenic purpura, and multiple sclerosis. In some embodiments, the RIP2 kinase-mediated disease or disorder is a granulomatous disease. For example, in certain embodiments, the granulomatous disease is selected from sarcoidosis, Blau syndrome, Wegner’s granulomatosis, Behcet’s disease, and interstitial pulmonary disease.

[0233] In some embodiments, the RIP2 kinase-mediated disease or disorder is cancer. For example, in certain embodiments, the cancer is selected from leukemia, breast cancer, brain cancer, colorectal cancer, head and neck cancer, melanoma, pancreatic cancer, prostate cancer, ovarian cancer, renal cancer, and lung cancer.

[0234] In some embodiments, the RIP2 kinase-mediated disease or disorder is a neurodegenerative disease. For example, in certain embodiments, the neurodegenerative disease is selected from Alzheimer’s disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig’s Disease), Parkinson’s disease, multiple sclerosis, diabetic neurophathy, poly glutamine (polyQ) diseases, stroke, Fahr disease, Menke’s disease, Wilson’s disease, cerebral ischemia, a prion disorder, dementia, corticobasal degeneration, progressive supranuclear palsy, spinocerebellar atrophies, brain injury, and spinal cord injury.

[0235] In some embodiments, the present disclosure relates to a crystalline form described herein, a composition described herein, or a pharmaceutical composition described herein for use in treating RIP2 kinase-mediated diseases and disorders (e.g., inflammatory diseases, autoimmune diseases, granulomatous diseases, cancer or neurodegenerative diseases).

[0236] In some embodiments, the RIP2 kinase-mediated disease or disorder is an inflammatory disease. For example, in certain embodiments, the inflammatory disease is selected from uveitis, interleukin- 1 converting enzyme fever syndrome, dermatitis, acute lung injury, type 2 diabetes mellitus, arthritis, inflammatory bowel disease (IBD), ischemia reperfusion injury in a solid organ transplant, sepsis, liver disease, allergic disease, and graft versus host disease. For example, in certain embodiments, the inflammatory disease is an IBD. For example, the IBD is selected from ulcerative colitis, Crohn's disease, early-onset IBD, and extraintestinal IBD. For example, in certain embodiments, the inflammatory disease is selected from rheumatoid arthritis, inflammatory arthritis, peritonitis, ischemia reperfusion injury in kidney transplant, non-alcohol steatohepatitis, alcohol steatohepatitis, insulin-resistant type 2 diabetes, allergic rhinitis, asthma, atopic dermatitis, Sjogren’s syndrome, ankylosing spondylitis, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, thrombosis, a-synucleinopathy, Parkinson’s disease, dementia with Lewy body, multiple system atrophy, Alzheimer’s disease, amyotrophic lateral sclerosis, and chronic obstructive pulmonary disease.

[0237] In some embodiments, the RIP2 kinase-mediated disease or disorder is an autoimmune disease. For example, in certain embodiments, the autoimmune disease is selected from systemic lupus erythematosus, lupus nephritis, psoriasis, immune thrombocytopenic purpura, and multiple sclerosis.

[0238] In some embodiments, the RIP2 kinase-mediated disease or disorder is a granulomatous disease. For example, in certain embodiments, the granulomatous disease is selected from sarcoidosis, Blau syndrome, Wegner’s granulomatosis, Behcet’s disease, and interstitial pulmonary disease.

[0239] In some embodiments, the RIP2 kinase-mediated disease or disorder is cancer. For example, in certain embodiments, the cancer is selected from leukemia, breast cancer, brain cancer, colorectal cancer, head and neck cancer, melanoma, pancreatic cancer, prostate cancer, ovarian cancer, renal cancer, and lung cancer.

[0240] In some embodiments, the RIP2 kinase-mediated disease or disorder is a neurodegenerative disease. For example, in certain embodiments, the neurodegenerative disease is selected from Alzheimer’s disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig’s Disease), Parkinson’s disease, multiple sclerosis, diabetic neurophathy, poly glutamine (polyQ) diseases, stroke, Fahr disease, Menke’s disease, Wilson’s disease, cerebral ischemia, a prion disorder, dementia, corticobasal degeneration, progressive supranuclear palsy, spinocerebellar atrophies, brain injury, and spinal cord injury.

[0241] In some embodiments, the crystalline form described herein, the composition described herein, or the pharmaceutical composition described herein is formulated to be administered with a second agent. For example, in some embodiments, the second agent is an antiinflammatory agent or an anti-autoimmune agent.

[0242] In some embodiments, the second agent is selected from anti-TNF agent, anti-IL-23 agent, anti-integrin agent, and JAK inhibitor. In a particular aspect, the second agent is anti- TNF agent. In a particular aspect, second agent is anti-IL-23 agent. In a particular aspect, the second agent is anti-integrin agent. In a particular aspect, second agent is JAK inhibitor.

[0243] In some embodiments, the second agent and the crystalline form described herein, the composition described herein, or the pharmaceutical composition described herein are administered contemporaneously, such as administered together in a single pharmaceutical formulation. In a particular aspect, the second agent and the crystalline form described herein, the composition described herein, or the pharmaceutical composition described herein are formulated for simultaneous administration.

[0244] In some embodiments, the second agent and the crystalline form described herein, the composition described herein, or the pharmaceutical composition described herein are administered separately. In a particular aspect, the second agent and the crystalline form described herein, the composition described herein, or the pharmaceutical composition described herein are administered separately at different times. In a particular aspect, the second agent and the crystalline form described herein, the composition described herein, or the pharmaceutical composition described herein are administered separately at the same time.

[0245] In some embodiments, the present disclosure relates to a formulation comprising a crystalline form described herein. In some embodiments, the formulation comprises crystalline Form la. In a particular aspect, the formulation is a capsule. In certain embodiments, the formulation is a tablet. In some embodiments, the formulation further comprises one or more pharmaceutically acceptable excipients, diluents, binders, disintegrants, lubricants, coloring agents, or preservatives. In some embodiments, the formulation further comprises one or more pharmaceutically acceptable excipients selected from a diluent, binder, lubricant, plasticizer, glidant, film coat, and disintegrants or a combination thereof. In some embodiments, at least one excipient is a diluent. In some embodiments, the diluent is selected from the group consisting of lactose (either anhydrous or hydrate — e.g., monohydrate), cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, starch, gelatinized starch, calcium carbonate, cyclodextrin, calcium sulfate, calcium silicate, magnesium carbonate, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, potassium chloride, sodium chloride, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, mannitol, maltitol, sorbitol, xylitol, lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, dextrates, dextrin and mixtures thereof. Lactose used herein may be anhydrous lactose and / or hydrous lactose, such as lactose monohydrate. In some embodiments, the lactose is anhydrous lactose. In some embodiments, the lactose is hydrous lactose. In some embodiments, the lactose is lactose monohydrate. In some embodiments, the diluent is cellulose. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the diluent comprises lactose and microcrystalline cellulose In some embodiments, at least one excipient is a disintegrating agent (or disintegrant). In some embodiments, the disintegrating agent is selected from the group consisting of natural starch (such as starch wheat, rice, tapioca, com or potato starch), a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose (e.g., Methocel®), croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, alginic acid, calcium carbonate, sodium carbonate, carboxymethylcellulose sodium, agar, xylan, gellan gum, and xanthan gum. In some embodiments, the disintegrating agent is croscarmellose sodium. As used herein, croscarmellose sodium refers to internally cross-linked sodium carboxymethylcellulose.

[0246] In some embodiments, at least one excipient is a binder. In some embodiments, the binder is selected from the group consisting of carboxymethylcellulose, sodium lauryl sulfate, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), alginates, gelatin, sucrose, and acacia. In some embodiments, the formulation comprises lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropyl cellulose.

[0247] In some embodiments, at least one excipient is a lubricant or a glidant. In some embodiments, the lubricant or glidant is selected from the group consisting of magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, sucrose fatty acid ester, starch (wheat, rice, com or potato starch), talc, highly dispersed (colloidal) silica, magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl monostearate, silicon dioxide, calcium silicate, magnesium silicate, hardened vegetable oil, hard liquid paraffin, hydrogenated vegetable oil, wax, glyceryl fatty acid esters, solid polyethylene glycols, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, polyoxyethylene monostearate, glyceryl triacetate, sucrose monolaurate and mixtures thereof, but it may not be limited thereto. In a certain aspect, the lubricant may be magnesium stearate, stearic acid or highly dispersed (colloidal) silica. In some embodiments, the lubricant may be magnesium stearate. In some embodiments, the excipients comprise lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate.

[0248] In some embodiments, at least one excipient is a preservative. In some embodiments, the preservative is selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium metabisulfite (SMB), propyl gallate (PG), ascorbyl palmitate, dihydroxybenzoic acid, cysteine, ascorbic acid, and alpha tocopherol (Vit-E). In some embodiments, the formulation comprises about 2 wt% to about 20 wt% of crystalline Form la. For example, the formulation comprises about 2 wt% to about 20 wt%, about 2 wt% to about 18 wt%, about 2 wt% to about 16 wt%, about 2 wt% to about 14 wt%, about 2 wt% to about 12 wt%, about 2 wt% to about 10 wt%, about 2 wt% to about 9 wt%, about 2 wt% to about 8 wt%, about 2 wt% to about 7 wt%, about 2 wt% to about 6 wt%, about 2 wt% to about 5 wt%, about 2 wt% to about 4 wt%, about 3 wt% to about 20 wt%, about 3 wt% to about 18 wt%, about 3 wt% to about 16 wt%, about 3 wt% to about 14 wt%, about 3 wt% to about 12 wt%, about 3 wt% to about 10 wt%, about 3 wt% to about 9 wt%, about 3 wt% to about 8 wt%, about 3 wt% to about 7 wt%, about 3 wt% to about 6 wt%, about 3 wt% to about 5 wt%, about 3 wt% to about 4 wt%, about 4 wt% to about 20 wt%, about 4 wt% to about 18 wt%, about 4 wt% to about 16 wt%, about 4 wt% to about 14 wt%, about 4 wt% to about 12 wt%, about 4 wt% to about 10 wt%, about 4 wt% to about 9 wt%, about 4 wt% to about 8 wt%, about 4 wt% to about 7 wt%, about 4 wt% to about 6 wt%, about 4 wt% to about 5 wt%, about 5 wt% to about 20 wt%, about 5 wt% to about 18 wt%, about 5 wt% to about 16 wt%, about 5 wt% to about 14 wt%, about 5 wt% to about 12 wt%, about 5 wt% to about 10 wt%, about 5 wt% to about 9 wt%, about 5 wt% to about 5 wt%, about 5 wt% to about 7 wt%, about 5 wt% to about 6 wt%, about 6 wt% to about 20 wt%, about 6 wt% to about 18 wt%, about 6 wt% to about 16 wt%, about 6 wt% to about 14 wt%, about 6 wt% to about 12 wt%, about 6 wt% to about 10 wt%, about 6 wt% to about 9 wt%, about 6 wt% to about 8 wt%, about 6 wt% to about 7 wt%, about 7 wt% to about 20 wt%, about 7 wt% to about 18 wt%, about 7 wt% to about 16 wt%, about 7 wt% to about 14 wt%, about 7 wt% to about 12 wt%, about 7 wt% to about 10 wt%, about 7 wt% to about 9 wt%, about 7 wt% to about 8 wt%, about 8 wt% to about 20 wt%, about 8 wt% to about 18 wt%, about 8 wt% to about 16 wt%, about 8 wt% to about 14 wt%, about 8 wt% to about 12 wt%, about 8 wt% to about 10 wt%, about 8 wt% to about 9 wt%, about 9 wt% to about 20 wt%, about 9 wt% to about 18 wt%, about 9 wt% to about 16 wt%, about 9 wt% to about 14 wt%, about 9 wt% to about 12 wt%, about 9 wt% to about 10 wt%, about 10 wt% to about 20 wt%, about 10 wt% to about 18 wt%, about 10 wt% to about 16 wt%, about 10 wt% to about 14 wt%, or about 10 wt% to about 12 wt% of crystalline Form la. In some embodiments, the formulation comprises about 20 wt%, about 19 wt%, about 18 wt%, about 17 wt%, about 16 wt%, about 15 wt%, about 14 wt%, about 13 wt%, about 12 wt%, about 11 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, or about 2 wt% of crystalline Form la. In some embodiments, the formulation comprises about 9 wt% of crystalline Form la. In some embodiments, the formulation comprises about 4 wt% of crystalline Form la.

[0249] In some embodiments, the formulation comprises about 5 mg to about 50 mg of crystalline Form la. In some embodiments, the formulation comprises about 5 mg to about 45 mg, about 5 mg to about 40 mg, about 5 mg to about 35 mg, about 5 mg to about 30 mg, about 5 mg to about 25 mg, about 5 mg to about 20 mg, about 5 mg to about 15 mg, about 5 mg to about 10 mg, about 7 mg to about 50 mg, about 7 mg to about 45 mg, about 7 mg to about 40 mg, about 7 mg to about 35 mg, about 7 mg to about 30 mg, about 7 mg to about 25 mg, about 7 mg to about 20 mg, about 7 mg to about 15 mg, about 10 mg to about 50 mg, about 10 mg to about 45 mg, about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 10 mg to about 30 mg, about 10 mg to about 25 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 15 mg to about 50 mg, about 15 mg to about 45 mg, about 15 mg to about 40 mg, about 15 mg to about 35 mg, about 15 mg to about 30 mg, about 15 mg to about 25 mg, about 15 mg to about 20 mg, about 20 mg to about 50 mg, about 20 mg to about 45 mg, about 20 mg to about 40 mg, about 20 mg to about 35 mg, about 20 mg to about 30 mg, about 20 mg to about 25 mg, about 25 mg to about 50 mg, about 25 mg to about 45 mg, about 25 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, about 30 mg to about 50 mg, about 30 mg to about 45 mg, about 30 mg to about 40 mg, about 30 mg to about 35 mg, about 20 mg to about 30 mg, about 35 mg to about 50 mg, about 35 mg to about 45 mg, about 35 mg to about 40 mg, about 40 mg to about 50 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of crystalline Form la. In some embodiments, the formulation comprises about 2 mg, about 5 mg, about 7 mg, about 10 mg, about 12 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, or about 45 mg of crystalline Form la. In some embodiments, the formulation comprises about 11 mg of crystalline Form la. In some embodiments, the formulation comprises about 22 mg of crystalline Form la. In some embodiments, the formulation comprises about 32 mg of crystalline Form la. The amount of Form la in the formulation can be calculated using the HC1 salt of Form la or the free base. For example, production of a 10 mg capsule comprising Form la means that there is 10 mg of what is the free base form which corresponds to 10.9 mg of the HC1 salt.

[0250] In some embodiments, the formulation comprises microcrystalline cellulose. In some embodiments, the microcrystalline cellulose is silicified microcrystalline cellulose. In some embodiments, the formulation comprises about 30 wt% to about 70 wt% microcrystalline cellulose. In some embodiments, the formulation comprises about 40 wt% to about 60 wt% microcrystalline cellulose. In some embodiments, the formulation comprises about 40 wt% to about 50 wt% microcrystalline cellulose. In some embodiments, the formulation comprises about 30 wt%, about 40 wt%, about 50 wt%, about 60 wt%, or about 70 wt% microcrystalline cellulose. In some embodiments, the formulation comprises about 38 wt% or about 48 wt% microcrystalline cellulose.

[0251] In some embodiments, the formulation comprises mannitol. In some embodiments, the mannitol is Pearlitol® 200SD. In some embodiments, the mannitol is silicified mannitol. In some embodiments, the formulation comprises about 20 wt% to about 60 wt% mannitol. In some embodiments, the formulation comprises about 30 wt% to about 50 wt% mannitol. In some embodiments, the formulation comprises about 30 wt%, about 40 wt%, about 50 wt%, or about 60 wt%, In some embodiments, the formulation comprises about 35 wt%, about 46 wt%, or about 48 wt% mannitol.

[0252] In some embodiments, the formulation comprises magnesium stearate. In some embodiments, the formulation comprises about 1 wt% to about 4 wt% magnesium stearate. In some embodiments, the formulation comprises about 1 wt% to about 4 wt%, about 1 wt% to about 3 wt%4about 1 wt% to about 2 wt%4about 2 wt% to about 4 wt%4about 2 wt% to about 3 wt%4about 3 wt% to about 4 wt% magnesium stearate. In some embodiments, the formulation comprises about 1 wt%, about 2 wt%, or about 3 wt% magnesium stearate. In some embodiments, the formulation comprises about 1.5 wt% or about 2.4 wt% magnesium stearate.

[0253] In some embodiments, the formulation comprises croscarmellose sodium. In some embodiments, the formulation comprises about 2 wt% to about 15 wt% croscarmellose sodium. In some embodiments, the formulation comprises about 2 wt% to about 12 wt%, about 2 wt% to about 10 wt%4about 2 wt% to about 8 wt%4about 2 wt% to about 6 wt%4about 2 wt% to about 4 wt%44 wt% to about 12 wt%, about 4 wt% to about 10 wt%4about 4 wt% to about 8 wt%4about 4 wt% to about 6 wt%46 wt% to about 12 wt%, about 6 wt% to about 10 wt%4about 6 wt% to about 8 wt%48 wt% to about 12 wt%, about 8 wt% to about 10 wt%4or about 10 wt% to about 12 wt%, croscarmellose sodium. In some embodiments, the formulation comprises about 1 wt%, about 2 wt%, or about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt% about 7 wt%, about 7 wt%, about 9 wt%, about 10 wt% about 11 wt%, or about 12 wt% croscarmellose sodium. In some embodiments, the formulation comprises about 5 wt% or about 10 wt% croscarmellose sodium. In some embodiments, the formulation comprises hydroxypropyl cellulose. In some embodiments, the formulation comprises about 1 wt% to about 8 wt% hydroxypropyl cellulose. In some embodiments, the formulation comprises about 1 wt% to about 6 wt%, about 1 wt% to about 5 wt%4about 1 wt% to about 4 wt%4about 2 wt% to about 6 wt%4about 2 wt% to about 5 wt%4about 2 wt% to about 4 wt% hydroxypropyl cellulose. In some embodiments, the formulation comprises about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, or about 6 wt% hydroxypropyl cellulose.

[0254] In some embodiments, the formulation comprises about 3 wt% to about 5 wt% crystalline Form la, about 35 wt% to about 45 wt% microcrystalline cellulose, about 45 wt% to about 55 wt% mannitol, about 1 wt% to about 3 wt% hydroxypropyl cellulose, about 3 wt% to about 5 wt% croscarmellose sodium, and about 1.5 wt% to about 2.5 wt% magnesium stearate.

[0255] In some embodiments, the formulation comprises about 7 wt% to about 11 wt% crystalline Form la, about 33 wt% to about 43 wt% microcrystalline cellulose, about 43 wt% to about 53 wt% mannitol, about 1 wt% to about 3 wt% hydroxypropyl cellulose, about 3 wt% to about 5 wt% croscarmellose sodium, and about 1.5 wt% to about 2.5 wt% magnesium stearate.

[0256] In some embodiments, the formulation comprises about 7 wt% to about 11 wt% crystalline Form la, about 42 wt% to about 52 wt% microcrystalline cellulose, about 30 wt% to about 40 wt% mannitol, about 1 wt% to about 3 wt% hydroxypropyl cellulose, about 4 wt% to about 6 wt% croscarmellose sodium, and about 1 wt% to about 2 wt% magnesium stearate.

[0257] EXEMPLIFICATION

[0258] General Materials and Methods

[0259] Instruments and equipment used to obtain certain data presented in this disclosure are provided in the table below.

[0260] Table 1. Instruments and Laboratory Equipment used when executing the developed method.

[0261] Example la: Synthesis of the compound represented by Structural Formula (II), N- l-(tert- butyl)-177-pyrazol-4-yl)-2-(3-methyl-4-((6-(methylsulfonyl)quinolin-4- y l)oxy )pheny 1) acetamide :

[0262] Part I - Synthesis of 4-chloro-6-(methylthio)quinoline

[0263] A solution of 6-bromo-4-chloroquinoline (commercially available, 50 g, 206 mmol, 1.00 equiv.), sodium thiomethoxide (28.9 g, 412 mmol, 2.00 equiv.), Pd2(dba)3 (4.72 g, 5.15 mmol, 0.025 equiv.), Xantphos (5.97 g, 10.3 mmol, 0.05 equiv.), and triethylamine (143 mmol, 1.03 mol, 5 equiv.) in 1,4-dioxane (300 mL) was heated to 80 °C for 5 h under an inert atmosphere of nitrogen. EtOAc was added and insoluble materials were filtered off. Next, the organic phase was washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. EtOAc and hexanes were added (100 mL each), followed by silica gel (20 g). The slurry was stirred at room temperature for 30 min and the silica gel was subsequently filtered off and washed with EtOAc / hexanes (1:1). The solvent was removed under reduced pressure. The intended product was obtained as a red solid (43.5 g), which was used in the next reaction without further purification.

[0264] Part II - Synthesis of 4-chloro-6-(methylsulfonyl)quinoline

[0265] Oxone (139 g, 227 mmol, 1.1 equiv.) was added to a solution of 4-chloro-6- (methylthio)quinoline (43.2 g, 206 mmol, 1.00 equiv.) in THF (350 mL) and water (350 mL). The reaction mixture was stirred at room temperature for 2 h. Subsequently, water and EtOAc were added, and the organic phase was separated. The aqueous solution was neutralized with K2CO3 and extracted with EtOAc. The combined organic phases were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure. The obtained material was treated with DCM (200 mL) and hexanes (400 mL) to remove impurities. Next, the product was filtered off, washed with a small amount of EtOAc (ca. 40-50 mL) and hexanes and dried under reduced pressure. The intended product was obtained as a slightly yellowish solid (34.4 g, 69% yield), which was used in the next reaction without further purification.

[0266] Part III - Synthesis of 2-(4-hydroxy-3-methylphenyl)acetic acid

[0267] A solution of methyl 2-(4-hydroxy-3-methylphenyl)acetate (28.4 g, 158 mmol, 1.00 equiv.) and lithium hydroxide (9.44 g, 394 mmol, 2.50 equiv.) in THF (200 mL) and water (100 mL) was stirred at room temperature for 2 h. Subsequently, water was added, and the aqueous solution was washed with DCM. The pH was adjusted to 1-2 and the product was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The intended product was obtained as a white solid (26.3 g, quantitative yield), which was used in the next reaction without further purification.

[0268] Part IV - Synthesis of V-(l-(tert-butylpyrazol-4-yl)-2-(4-hydroxy-3- methylphenyl)acetamide

[0269] HATU (72.2 g, 190 mmol, 1.20 equiv.) was added to a solution of 2-(4-hydroxy-3- methylphenyl)acetic acid (26.3 g, 158 mmol, 1.00 equiv.), l-tert-butylpyrazol-4-amine hydrochloride (30.6 g, 174 mmol, 1.10 equiv.), and DIPEA (82.7 mL, 474 mmol, 3.00 equiv.) in DMF (140 mL) and the mixture was stirred at room temperature for 2 h. Subsequently, water and EtOAc were added, and the organic phase was separated. The product was extracted with an aqueous NaOH solution. Subsequently, the pH was adjusted to 5-6 with HC1 and the product was extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was washed with EtOAc and dried under reduced pressure. The intended product was obtained as a white solid (27.1 g, 60%), which was used in the next reaction without further purification.

[0270] Part V - Synthesis of \-( 1 -( / ( / / -butyl)- 1 / / -pyrazol-4-yl)-2-(3-methyl-4-((6- (methylsulfonyl)quinolin-4-yl)oxy)phenyl)acetamide

[0271] A solution of 4-chloro-6-methylsulfonylquinoline (22.8 g, 94.3 mmol, 1.00 equiv.), A-(l-tert-butylpyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamide (27.1 g, 94.3 mmol, 1.00 equiv.), DMAP (1.15 g, 9.43 mmol, 0.10 equiv.), and K2CO3 (19.5 g, 141 mmol, 1.50 equiv.) in DMF (90 mL) was heated to 120 °C for 3.5 h. More 4-chloro-6- methylsulfonylquinoline (2.28 g, 9.43 mmol, 0.10 equiv.) and K2CO3 (1.95 g, 14.1 mmol, 0.15 equiv.) were added and the heating was continued for another 1.5 h. Water and EtOAc were added, and the organic phase was separated. The organic phase was washed with water and the product was extracted with aqueous HC1 (pH 1). The aqueous phase was washed with EtOAc and the pH was adjusted to 5-7. The product was extracted with EtOAc and the organic phase was washed with water, brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was dissolved in DCM, and the organic solution was washed with an aqueous NaOH solution (pH 11-12) to remove remaining phenol starting material impurities. The organic phase was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified via column chromatography (DCM / MeOH 95:5). The intended product was obtained as a slightly yellowish solid (17.3 g, 37% yield). LCMS (ESI) calculated for C26H29N4O4S (M+H)+: 493.2, found: 493.1. ’ H NMR (400 MHz, DMSO-tfe) 510.20 (s, 1H), 8.91 (dd, J = 1.9, 0.9 Hz, 1H), 8.84 (d, J = 5.3 Hz, 1H), 8.29 - 8.27 (m, 2H), 7.95 (s, 1H), 7.46 (s, 1H), 7.39 (d, J= 2.1 Hz, 1H), 7.32 (dd, J= 8.3, 2.2 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 6.55 (d, J = 5.2 Hz, 1H), 3.62 (s, 2H), 3.39 (s, 3H), 2.14 (s, 3H), 1.49 (s, 9H).

[0272] The compound represented by Structural Formula (II) was also prepared by neutralization of its HC1 salt. Specifically, crystalline Form la was first suspended in acetone at ca. 200 mg / ml concentration. To that, 0.1 equiv. (by volume) of saturated sodium bicarbonate solution was added. The appearance changed from the initial slurry to a mainly clear solution with a minimal amount of residual solid observed. DI water was then added to the solution and precipitation was observed. The resulting solid was collected by centrifuging, then washed with DI water to remove residual salts. The material was dried in vacuum oven at 40 °C overnight for removing of residual solvent.

[0273] The resulting material was amorphous, as indicated by the XRPD analysis (Fig. 43). Modulated differential scanning calorimetry indicated a glass transition temperature (Tg) ca. 91 °C (Fig. 44).

[0274] Example lb: Synthesis of amorphous chloride salt of the compound represented by Structural Formula (II).

[0275] Into a 500 mL 3-necked round-bottom flask were added N- 1 -tert-butylpyrazol-4-yl)- 2-(4-hydroxy-3-methylphenyl)acetamide (21.0 g, 73.078 mmol, 1.0 equiv, prepared according to Part IV in Example la), CS2CO3 (47.62 g, 146.156 mmol, 2.0 equiv), 4-chloro-6- methane sulfonylquinoline (18.55 g, 76.732 mmol, 1.05 equiv) and DMF (200 mL) at room temperature. The resulting mixture was stirred for additional overnight at room temperature. The reaction was quenched by the addition of water (200 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous MgSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA to afford V-( l -tcrt-butylpyrazol-4-yl)-2-{4-[(6- methanesulfonylquinolin-4-yl)oxy] -3 -methylphenyl (acetamide as a light yellow solid. A solution of HC1 in dioxane (4 M, 44 mL) was added to a solution of the product in EtOH (300 mL) to convert the material into the hydrochloride. EtOAc (200 mL) was added, and the precipitate was filtered off and dried under reduced pressure. The intended product was obtained as a slightly yellowish solid (30.82 g, 85.3%). LC-MS: (ES, m / z): 493.15 [M+H]+; ^-NMR: (300 MHz, DMSO-tfe, ppm) 5 10.55 (s, 1H), 9.16 (d, J = 6.5 Hz, 1H), 9.12 - 9.05 (m, 1H), 8.71 - 8.58 (m, 2H), 7.95 (s, 1H), 7.53 - 7.45 (m, 2H), 7.41 (dd, J = 8.3, 2.1 Hz, 1H), 7.34 (d, J= 8.3 Hz, 1H), 6.91 (d, J= 6.4 Hz, 1H), 3.68 (s, 2H), 3.44 (s, 3H), 2.18 (s, 3H), 1.49 (s, 9H). Example 2: Synthesis and Characterization of Crystalline Forms of the Compound Represented by Structural Formula (II) (Freebase)

[0276] Form IIa-1

[0277] Process: Crystalline Form Ila- 1 , having the XRPD pattern detailed below and as shown in FIG. 21, was made at the 100 mg scale via iterative neutralization of crystalline Form la-1 with IN

[0278] NaOH to -pH 7.0 while in a water slurry at lOmg / mE in ambient conditions over several days. The solids were harvested by centrifugation and dried for multiple days in a 25°C vacuum oven. The resulting crystalline Form IIa-1 gave a DSC / TGA plot as shown in FIG. 22.

[0279] Table 2.2. All XRPD Peaks for Form IIa-1

[0280] Form lla-2 (Large Scale Preparation of Form lla-1 )

[0281] Process: Crystalline Form IIa-2 was made at 3g scale via iterative neutralization of crystalline Form la- 1 with IN NaOH to -pH 7.0 while in a water slurry at 10 mg / mL in ambient conditions over several days, The solids were harvested by centrifugation and dried for multiple days in a 25°C vacuum oven. The resulting crystalline Form IIa-2 gave an XRPD pattern as shown in FIG. 23, and a DSC / TGA plot as shown in FIG. 24.

[0282] Table 2.3. Top XRPD Peaks for Form IIa-2 Table 2.4. All XRPD Peaks for Form IIa-2 Form Ila

[0283] Process: A solution of 4-chloro-6-methylsulfonylquinoline (22.8 g, 94.3 mmol, 1.00 equiv.), V-( l -tcrt-butylpyrazol-4-yl)-2-(4hydroxy-3-mcthylphcnyl)acctamidc (27.1 g, 94.3 mmol, 1.00 equiv., prepared as described in Example 1), DMAP (1.15 g, 9.43 mmol, 0.10 equiv.), and K2CO3 (19.5 g, 141 mmol, 1.50 equiv.) in DMF (90 mF) was heated to 120 °C for 3.5 h. More 4-chloro-6-methylsulfonylquinoline (2.28 g, 9.43 mmol, 0.10 equiv.) and K2CO3 (1.95 g, 14.1 mmol, 0.15 equiv.) were added and the heating was continued for another 1.5 h. To this crude reaction mixture, water (10 V) was added, and the compound was extracted with z-PrOAc twice. The combined organic layers were washed with water (2x5V), and extracted again with z-PrOAc (5.0V). The resulting mixture was distilled (at approx. 35 °C - 45 °C) until a volume of approximately 2V was obtained. Isopropyl alcohol (8V) was added at 20 °C -25 °C, and the resulting mixture was distilled under vacuum to from about 2.0V to about 3.0V. To the resulting mixture, 1% seed crystals) were added, followed by methyl / -butyl ether (4x4V, adjusted as needed based on the concentration of the mixture) at 35 °C-40 °C. The resulting mixture was aged for 1 h at 40 °C. The resulting mixture was cooled to 0 °C over the course of 1 h and aged at 0 °C for 2 h. The concentration of the layer comprising the desired product was monitored and to preferably less than about 3.0 mg / mL to about 5.0 mg / mL during recrystallization. The resulting crystalline solids were obtained via filtration and washed with methyl / -butyl ether (3xl.5V) and the mother liquor for 1 h.

[0284] Form Ila can also be isolated according to the process described above, omitting the step of seed addition. The addition of the seeds is optional and is done to improve the control over Form Ila formation.

[0285] The resulting solids were dried at 40 °C-45 °C under vacuum to yield Form Ila as crystalline solid in an isolated yield of about 80%. The resulting crystalline Form Ila had XRPD pattern as detailed below and in FIG. 14, as well as a DSC / TGA plot as shown in FIG. 15.

[0286] Form 11b Process: A solution of 4-chloro-6-methylsulfonylquinoline (22.8 g, 94.3 mmol, 1.00 equiv.), A-(l-tert-butylpyrazol-4-yl)-2-(4hydroxy-3-methylphenyl)acetamide (27.1 g, 94.3 mmol, 1.00 equiv., prepared as described in Example 1), DMAP (1.15 g, 9.43 mmol, 0.10 equiv.), and K2CO3 (19.5 g, 141 mmol, 1.50 equiv.) in DMF (90 mL) was heated to 120 °C for 3.5 h. More 4-chloro-6-methylsulfonylquinoline (2.28 g, 9.43 mmol, 0.10 equiv.) and K2CO3 (1.95 g, 14.1 mmol, 0.15 equiv.) were added and the heating was continued. The reaction to form the crude product mixture was monitored via HPLC, and upon completion of the reaction, water was added (5.0V, approx. 25 mL), followed by 10V of 14% dichloromethane in z-PrOAc and 4.0V of H2O. The aqueous layer of the resulting mixture was collected and extracted with 14% dichloromethane in z-PrOAc (1x5V). The combined organic layers were washed with a 2% brine solution (2V) and water (2V). The resulting organic layer was collected, to which was added 1% of seeds. The resulting mixture was stirred for 12 h, during which the concentration of the target compound remaining in the mother liquor was monitored at 1 h, 3 h, and 12 h. The resulting crystalline solid was collected via filtration and washed with methyl / -butyl ether (3x1.5V), allowed to deliqour on the filter for 1 h, and dried under vacuum at 50 °C - 55 °C to yield Form lib as a crystalline solid.

[0287] Form lib can also be isolated according to the process described above omitting the step of seed addition. The addition of the seeds is optional and is done to improve the control over Form lib formation.

[0288] Crystalline Form lib had an XRPD pattern as detailed below and in FIG. 16, as well as a DSC / TGA plot as shown in FIG. 17.

[0289] Table 2.7. Top XRPD Peaks for Form lib

[0290]

[0291] Example 3: Synthesis and Characterization of Crystalline Forms of Chloride Salts of the Compound Represented by Structural Formula (II) Form la

[0292] Process: Crystalline Form la of a chloride salt of the compound represented by Structural Formula I, having an XRPD pattern as detailed below and in FIG. 1, was prepared according to the following procedures:

[0293] Procedure I. In a 500 mL round bottom flask containing the amorphous chloride salt of the compound represented by Structural Formula (II) prepared according to Example lb (26.6 g) was added 200 mL of absolute EtOH, and the resulting suspension was allowed to reflux for 3 hours. The suspension was filtered hot and the solids were washed with 100 mL of room temperature absolute EtOH. The solids were air dried over vacuum funnel for 3 hours, then transferred to a bottle and placed under vacuum at room temperature overnight.1H NMR indicates a clean product with 1.4% of EtOH remaining. Recovered mass of crystalline Form la: 21.22 g.

[0294] Procedure II. The amorphous chloride salt of the compound represented by Structural Formula (II) prepared according to Example lb was suspended in 6.0V absolute EtOH and stirred at 70- 80 °C for 90 min to 2 h. The solids were cooled slowly over 1 h to 20 -25 °C. The slurry was aged for 1-2 h at 20-25 °C, filtered then washed with EtOH (3X2V) and MTBE (3X3 V), deliquored over filter flask, then dried under vacuum at 30-40 °C for 16 h to afford crystalline Form la.

[0295] Procedure III. HC1 in IPA at 20-25 °C was added to the compound represented by Structural Formula (II) prepared according to Example la in iPrOAc:MeOH (2:1.25V), and the resulting mixture was aged at 20 -25 °C before filtration followed by washing with MTBE (3X1.5 V), deliquoring over filter flask, then drying under vacuum at 30-40 °C for 16 h to afford crystalline Form la.

[0296] Procedure IV. Crystalline anhydrous freebase form of the compound represented by Structural Formula (II) was combined with 7.0 V of IPA:H2O (8:5) in a reactor at an internal temperature of 20-25 °C. Any crystalline anhydrous freebase form (e.g., Form Il-a, IIa-1, or IIa-2 disclosed herein) can be used. The mixture was allowed to stir to dissolve the solids (optional: if solid is not dissolving at 20-25 °C, heat to 60 °C to dissolve, cool to 20 °C). The solution was filtered under vacuum (polishing filtration). 0.60 V of HC1 solution (5M aq. HC1 or 5M HC1 in IPA) was added at an internal temperature of 20-25 °C over 2 h. The reaction mixture was agitated for no less than 1 h at an internal temperature of 20-25 °C. The slurry was filtered by the sintered glass funnel and the reactor was rinsed with mother liquor. The cake was sequentially washed via displacement / slurry / displacement with MTBE (total 3x

[0297] 2.0V). The filtration was continued via suction until majority of MTBE was removed. The solids were dried in a vacuum oven at 50 - 55 °C to afford crystalline Form la as a yellow crystalline solid.

[0298] The resulting crystalline Form la gave a DSC / TGA plot as shown in FIG. 2. Dynamic vapor sorption data of crystalline Form la are shown in FIGs. 20A and 20B.

[0299] Table 3.1. Top XRPD Peaks for Form la Table 3.2. All XRPD Peaks for Form la

[0300] Form la-1

[0301] Process: Crystalline Form la-1 of a chloride salt of the compound represented by Structural Formula I, having an XRPD pattern as detailed below and in FIG. 25, was prepared according to the following procedure. Into a 500 mL 4-necked round-bottom flask were added N-(l-tert- butylpyrazol-4-yl)-2-(4-hydroxy-3-methylphenyl)acetamide (20 g, 69.598 mmol, 1 equiv., prepared as described in Example 1) and 4-chloro-6-methanesulfonylquinoline (20.19 g, 83.518 mmol, 1.2 equiv), CS2CO3 (45.35 g, 139.196 mmol, 2 equiv) in dimethylformamide (200 mL) at room temperature. The resulting mixture was stirred for overnight at room temperature. Water (200 mL) and EtOAc (300 mL) were added, and the organic phase were separated. The aqueous layers were extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with 5% NaCl (3 x 200 mL), dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA to afford N-(l-tert-butylpyrazol-4-yl)-2-{4-[(6- methanesulfonylquinolin-4-yl)oxy] -3 -methylphenyl} acetamide as a yellow solid. HC1 in dioxane (4 M, 44 mL) was added to a solution of the product in EtOH (300 mL) to convert the material into the hydrochloride salt. EtOAc (200 mL) was added, and the precipitate was filtered off and dried under reduced pressure. Crystalline form la-1 was obtained as a slightly yellowish solid (26.7699 g, 76.91%) Crystalline Form la-1 shows an XRPD pattern as detailed below and in FIG. 25. A DSC / TGA plot for this form is shown in FIG. 26.

[0302] Table 3.3. Top XRPD Peaks for Form la-1

[0303] Form la-2 Process: Crystalline Form IIa-2 was dissolved in ethanol at ~25 mg / mL at room temperature. HC1 was slowly added to the solution via concentrated HC1 (12.08 N HC1) to a 1:5 crystalline form IIa-2:HCl input molar ratio. Precipitate was observed almost immediately after adding HC1; precipitated sample was stirred at room temperature overnight, protected from light. After 24 hr, the sample was harvested via centrifugation (14k, 5 min). The residual solids were dried overnight in a chemical hood. The resulting crystalline Form la-2 yielded an XRPD pattern as detailed below and in FIG. 27, as well as a DSC / TGA plot as shown in FIG. 28.

[0304] Form la- 3

[0305] Process: Crystalline Form la-3 was obtained via the following procedure. Amorphous freebase form of the compound of Structural Formula II prepared according to Example la was dissolved in acetone at ~25 mg / mL at room temperature. HC1 was slowly added to the solution via concentrated HC1 (12.08 N HC1) to a 1:5 freebase:HCl input molar ratio. Precipitate was observed almost immediately after adding HC1; precipitated sample was stirred at room temperature 3 days, protected from light, after which the sample was harvested via centrifugation (14k, 5 min). The residual solids were dried overnight in a chemical hood. Alternatively, amorphous free base was dissolved in acetonitrile at ~25 mg / mL at room temperature to make an acetonitrile solution. HC1 was slowly added to the solution via 2N HC1 in dioxane to a 1:1.5 freebase:HCl input molar ratio. Precipitate was observed almost immediately after adding HC1; precipitated sample was stirred at room temperature for 4 days, protected from light, after which the sample was harvested via centrifugation (14k, 5 min). The residual solids were dried overnight in a chemical hood. The resulting crystalline Form la-3 gave an XRPD pattern as detailed below and in FIG. 29, as well as a DSC / TGA plot as shown in FIG. 30.

[0306] Table 3.7. Top XRPD Peaks for Form la-3

[0307] Table 3.8. All XRPD Peaks for Form la-3

[0308] Form la-4

[0309] Process: Crystalline Form IIa-2 of the compound of Structural Formula II was dissolved in acetone at ~25 mg / mL at room temperature. HC1 was slowly added to the solution via a 2N HCl-in-diethylether to a 1:5 crystalline Form IIa-2:HCl input molar ratio. Precipitate was observed almost immediately after adding HC1; precipitated sample was stirred at room temperature overnight, protected from light. After 24 h, the sample was harvested via centrifugation (14k, 5 min). The residual solids were dried overnight in a chemical hood. The resulting crystalline Form la-4 gave an XRPD pattern as detailed below and in FIG. 31, as well as a DSC / TGA plot as shown in FIG. 32.

[0310] Table 3.9. Top XRPD Peaks for Form la-4

[0311] Table 3.10. All XRPD Peaks for Form la-4

[0312] Form la- 5 Process: An amorphous form of the compound of Structural Formula II prepared as described in Example la was dissolved in iPrOAc at ~25 mg / mL at room temperature to make an iPrOAc solution. HC1 was slowly added to the solution via a 2N HCl-in-diethylether to a 1:5 compound:HCl input molar ratio. Precipitate was observed almost immediately after adding HC1; precipitated sample was stirred at room temperature over 3 days, protected from light, after which the sample was harvested via centrifugation (14k, 5 min). The residual solids were dried overnight in a chemical hood. The resulting crystalline Form la-5 gave an XRPD pattern as detailed below and in FIG. 33, as well as a DSC / TGA plot as shown in FIG. 34.

[0313] Table 3.11. Top XRPD Peaks for Form la-5

[0314] Table 3.12. All XRPD Peaks for Form la-5

[0315] Form la-6 Process: A slurry comprising Form la was prepared in MTBE at ~25 mg / mL at room temperature. To this slurry were added 5 more equivalents of HC1 through the addition of 2N HC1 in diethyl ether. The new slurry was stirred in ambient temperature, protected from light exposure, for 4 days. After this, the slurry solution was centrifuged, and the residual solids were dried overnight in a hood. The resulting crystalline Form la-6 gave an XRPD pattern as detailed below and in FIG. 35, as well as a DSC / TGA plot as shown in FIG. 36.

[0316] Table 3.13. Top XRPD Peaks for Form la-6 Table 3.14. All XRPD Peaks for Form la-6

[0317] Form la-7

[0318] Process: A slurry comprising Form la was prepared in MTBE at ~25 mg / mL at room temperature. To this slurry were added 2 more equivalents of HC1 through the addition of 4N HC1 in 1,4-Dioxane. The new slurry was stirred in ambient temperature, protected from light exposure, for 5 days. After this, the slurry solution was centrifuged, and the residual solids were dried overnight in a hood. The resulting crystalline Form la-7 gave an XPRD pattern as detailed below and in FIG. 37, as well as a DSC / TGA plot as shown in FIG. 38.

[0319] Table 3.15. Top XRPD Peaks for Form la-7

[0320] Table 3.16. All XRPD Peaks for Form la-7

[0321] Form lb

[0322] Process: Amorphous form of the compound of Structural Formula (II), prepared as described in Example la, was dissolved in ethanol at 40 mg / mL at room temperature. To this solution were added 5 molar equivalents of solid alpha succinic acid, and the resulting mixture was stirred until clear. 20 volumes of isopropyl ether was added, and the mixture was stirred overnight at room temperature protected from light. The residual solids were isolated via centrifugation (14k, 5min) and dried overnight in a hood. The resulting crystalline Form lb gave an XRPD pattern as detailed below and in FIG. 3, as well as a DSC / TGA plot as shown in FIG. 4.

[0323] Table 3.17. Top XRPD Peaks for Form lb

[0324] Table 3.18. All XRPD Peaks for Form lb

[0325] Form Ib-1

[0326] Process: Amorphous form of the compound of Structural Formula (II), prepared as described in Example la, was dissolved in acetone plus 5% ethanol at 40 mg / mL at room temperature. To this solution were added 5 molar equivalents of solid alpha succinic acid and the resulting mixture was stirred until clear. 20 volumes of isopropyl ether was added, and the mixture was stirred overnight at room temperature protected from light. The residual solids were isolated via centrifugation (14k, 5min) and dried overnight in a hood. The resulting crystalline Form Ib-1 gave an XRPD pattern as detailed below and in FIG. 39, as well as the DSC / TGA plot as shown in FIG. 40.

[0327] Table 3.19. Top XRPD Peaks for Form Ib-1

[0328] Table 3.20. All XRPD Peaks for Form Ib-1

[0329] Form Ig Process: Crystalline Form IIa-1 was dissolved in ethanol at 20 mg / mL. 2 molar equivalents of solid citric acid were added and dissolved. Hexane was added stepwise until cloudy precipitation was observed. Sample was stirred overnight at room temperature. Samples were harvested by centrifugation (14k, 5 min) and dried overnight in a hood. The resulting crystalline Form Ig gave an XRPD pattern as detailed below and in FIG. 13. able 3.21. Top XRPD Peaks for Form Ig

[0330] Table 3.22. All XRPD Peaks for Form Ig

[0331] Form Ic

[0332] Process: Crystalline Form IIa-1 was dissolved in ethanol at 20 mg / mL. 1 molar equivalent of IN sulfuric acid in water was added. Hexane was added stepwise until cloudy precipitation was observed. The sample was stirred overnight at room temperature. Samples were harvested by centrifugation (14k, 5 min) and dried overnight in a hood. The resulting crystalline Form Ic gave an XRPD pattern as detailed below and in FIG. 5, as well as a DSC / TGA plot as shown in FIG. 6

[0333] Table 3.23. Top XRPD Peaks for Form Ic Table 3.24. All XRPD Peaks for Form Ic

[0334] Form Ic-1 Process: Form IIa-1 was dissolved in ethanol at 20 mg / mL. 2 molar equivalents of IN sulfuric acid in water were added. Hexane was added stepwise until cloudy precipitation was observed. The sample was stirred overnight at room temperature. Samples were harvested by centrifugation (14k, 5 min) and dried overnight in a hood. The resulting crystalline Form Ic-1 gave an XRPD pattern as detailed below and in FIG. 41, as well as a DSC / TGA plot as shown in FIG. 42.

[0335] Table 3.25. Top XRPD Peaks for Form Ic-1

[0336] Table 3.26. All XRPD Peaks for Form Ic-1

[0337] Form Id

[0338] Process: Form IIa-1 was dissolved in ethanol at 20 mg / mL. 2 molar equivalents IN phosphoric acid in water were added. Hexane was added stepwise until cloudy precipitation was observed. The sample was stirred overnight at room temperature. Samples were harvested by centrifugation (14k, 5 min) and dried overnight in a hood. The resulting crystalline Form Id gave an XRPD pattern as detailed below and in FIG. 7, as well as a DSC / TGA plot as shown in FIG. 8. Table 3.27. Top XRPD Peaks for Form Id

[0339] Table 3.28. All XRPD Peaks for Form Id

[0340] Form le

[0341] Process: Form IIa-2 was dissolved in ethanol at 20mg / mL. 2 molar equivalents of solid fumaric acid were added and dissolved. Hexane was added stepwise until cloudy precipitation was observed. The sample was stirred overnight at room temperature. Samples were harvested by centrifugation (14k, 5 min) and dried overnight in a hood. The resulting crystalline Form le gave an XRPD pattern as detailed below and in FIG. 9, as well as a DSC / TGA plot as shown in FIG. 10. Table 3.29. Top XRPD Peaks for Form le

[0342] Table 3.30. All XRPD Peaks for Form le

[0343] Form If

[0344] Process: Form IIa-1 was dissolved in ethanol at 20 mg / mL. 2 molar equivalents of methanesulfonic acid were added. Hexane was added stepwise until cloudy precipitation was observed. The sample was stirred overnight at room temperature. Samples were harvested by centrifugation (14k, 5 min) and dried overnight in a hood. The resulting crystalline solid gave an XRPD pattern as detailed below and in FIG. 11, as well as a DSC / TGA plot as shown in FIG. 12. Table 3.31. Top XRPD Peaks for Form If

[0345] Table 3.32. All XRPD Peaks for Form If Example 4: Characterization of crystalline forms of the chloride salt of the compound represented by Structural Formula (II) (Forms la, la-1, la-2, la-3, la-4, la-5, la-6, and la-7)

[0346] A flow chart describing the methods of obtaining crystalline forms of chloride salt of the compound represented by Structural Formula (II) described herein is provided in FIG. 18. Table 4.1, below, summarizes the representative DSC and TGA features observed during analysis of these forms.

[0347] Table 4.1. DSC and TGA features of various crystalline forms of the chloride salt of the compound represented by Structural Formula (II)

[0348] Example 5: Characterization of crystalline forms of freebase compound represented by Structural Formula (II) (Forms Ila, lib, IIa-1, and IIa-2)

[0349] A flow chart describing the methods of obtaining crystalline forms of freebase compound represented by Structural Formula (II) described herein is provided in FIG. 19. Table 5.1, below, summarizes the representative DSC and TGA features observed during analysis of these forms.

[0350] Table 5.1. Comparison of DSC and TGA features of various freebase crystalline Forms Example 6: Characterization of crystalline forms of salts of the compound represented by Structural Formula (II)

[0351] The table below summarizes the representative DSC and TGA features observed during analysis of these forms, as well as the ratio of API to counterion used in the crystallization mixture from which the crystalline forms were obtained. Table 6.1. Comparison of DSC and TGA features of crystalline forms of salts of the compound represented by Structural Formula (II)

[0352] Example 7 : Characterization and Stability Studies of Crystalline Form la

[0353] The data from dynamic vapor sorption (DVS) analysis showed that there was a 0.15% loss in weight upon equilibration to 5% RH, 1.39% gain from 5 to 95% RH and 1.41% loss from 95 to 5% RH. A plot of weight as a function of time is shown in FIG. 20A, and a plot showing % weight change as a function of % relative humidity (%RH) during adsorption and desorption is given in FIG. 20B. Post DVS XRPD showed no change in the diffraction pattern. Stability studies of crystalline Form la were performed. The solid state physical and chemical stability of crystalline Form la was evaluated under the following conditions: 2-8°C closed, 25°C / 60%RH open and closed vessels up to 12 months, and 40°C / 75%RH open and closed vessels up to 6 months. Crystalline Form la was shown to be physically and chemically stable over 12 months across all stability conditions, as determined by visual appearance, XRPD, DSC, and TGA.

[0354] XRPD traces of crystalline Form la stored at different temperatures and under different conditions for 12 months show that crystalline Form la did not lose crystallinity (see Fig. 44). Water content studies showed that crystalline form la exhibits minimal hy gro scopicity (Table 7.1 )

[0355] Table 7.1. Water content of crystalline form la.

[0356] At the 12-month time point, crystalline Form la was confirmed to be physically stable in all conditions, with no change in visual appearance of the powers and XRPD results consistent with the starting crystalline Form la. TGA and DSC are also consistent with prior results. For all conditions, the melting peak temperature is between 251 °C and 252 °C. No detectable weight loss was observed for all stability samples before 100 °C. Around 11-12% weight loss was found after the melting peak for all samples.

[0357] Example 8 - Analysis Method Details

[0358] XRPD Table 8.1 provides the general parameters for the XRPD methods used to obtain certain

[0359] XRPD data provided herein.

[0360] Table 8.1: X-ray powder diffraction (XRPD) method parameters

[0361] °DSC Table 8.2 provides the general parameters for the DSC methods used to obtain certain

[0362] DSC data provided herein.

[0363] Table 8.2: Differential scanning calorimetry (DSC) method parameters TGA

[0364] Table 8.3 provides the general parameters for the TGA methods used to obtain certain TGA data provided herein.

[0365] Table 8.3: Thermal gravitational analysis (TGA) method parameters

[0366] Example 9 - RIPK2 Inhibition by compound represented by Structural Formula (II) RIPK2 inhibition was measured as follows:

[0367] Materials: RIPK2 enzyme was purchased from Carna (catlogue number 09-128). The V9102 ADP-Glo Kinase Assay (including ultrapure ATP, lOmM) was purchased from Promega. Native swine MBP was used as the substrate for the reaction and was purchased from SignalChem Biotech (catalogue number M42-51N). Assay buffer used for the assay consisted of the following components: MgCh (final concentration of 10 mM), Brij-35 (0.01%), DTT (final concentration of 2mM), BSA (0.05%), EGTA (final concentration of 1 mM), and HEPE (pH 7.5 at final concentration of 50 mM).

[0368] Method: In a 384 well plate, 10 nL of test compound was dispensed using Echo550 and mixed with RIPK2 enzyme (final concentration of 5nM) in assay buffer for 30 minutes at room temperature. Subsequently, ATP (final concentration of 150 pM) and MBP (final concentration of 0.02 pg / pL) were dissolved in assay buffer, added, and the mixture was incubated for 180 min at room temperature. Then ADP-Glo reagent was added and incubated for 60 min at room temperature. Last, Kinase Detection Reagent was added to the mixture and incubated for 60 min. The resulting luminescent signal was measured with an Envision reader to determine the amount of ADP produced. All plates contained vehicle control (10 nL DMSO only) was used as a reference for the high control (0% kinase inhibition), and a well with no RIPK2 enzyme as reference for low control (100% kinase inhibition). Data were analyzed to determine the percent inhibition of ADP production in the presence of test compound using both low and high controls. Percent inhibition of test compound = 100 - (test compound RLU (relative luminescence units) - low control RLU) / (high control RLU - low control RLU). 4-parametric curve fit was used to determine the test compound concentration that results in 50% of RIPK2 kinase inhibition.

[0369] RIPK2 IC50 of the compound represented by Structural Formula (II) was determined to be <2.5 nM.

[0370] Example 10 - Inhibition of human NOD2 signaling by compound represented by Structural Formula (II)

[0371] Materials: Human NOD2-expressing HEK293 cells, HEK-Blue™-hNOD2 cells, were developed by Invivogen (catalogue number: hkb-hnod2) using co-transfection of the human NOD2 gene and an optimized secreted embryonic alkaline phosphatase (SEAP) reporter gene into HEK293 cells. The cell maintenance medium consisted of DMEM (Giboc, 21063-029), heat inactivated FBS, penicillin (100 U / mL), streptomycin (100 pg / mL), Normocin (100 pg / mL), Blasticidin (30 pg / mL), and Zeocin (100 pg / mL). HEK-Blue™-hNOD2 cells were transferred to assay medium consisting of DMEM (Giboc, 21063-029), heat inactivated FBS, penicillin (100 U / mL) and streptomycin (100 pg / mL) prior to stimulation. Stimulation with a NOD2 ligand, L18-MDP (Invivogen, catalogue number: tlrl-lmdp) activated NF-KB and AP-1 which induced the production of SEAP. Levels of SEAP were determined with HEK-Blue™ Detection (referred to as QUANTI-Blue solution), a cell culture medium that allows for realtime detection of SEAP. QUANTI-Blue solution was prepared by adding 1 mL of QB reagent and 1 mL of QB buffer to 98 mL of sterile H2O. Test compound was prepared into a 10 mM DMSO solution and was serially diluted into 10 points using a 3-fold dilution using a TECAN EV0200.

[0372] Method: In a 384 well plate, 40 nL of test compound was dispensed using Echo550. HEK-Blue™-hNOD2 cells (Invivogen) were prepared into a cell suspension and 40 pL of the cell suspension (12500 cells per well) was dispensed into the 384 well plate. To activate NOD2 signaling, 40 nL of L18-MDP (final concentration of 0.5 ng / mL) was added and the plate was incubated at 37 °C in a CO2 incubator for 24 hours. After the 24-hour incubation, 5 pL of the induced HEK-Blue hNOD2 cell supernatant was transferred to a new 384-well plate, centrifuged, and 45 pL of QUANTI-Blue solution was added per well and incubated for 3 hours at 37 °C. SEAP levels were measured using an Ensight at 620 nm. Percent inhibition of NOD2 signaling was determined using the following equation: (high control - test compound signal) / (High control - low control) X 100. The reaction high control was determined using wells with DMSO, cells, L18-MDP, and QUANTI-Blue solution. The reaction low control was determined using wells with DMSO, cells, and QUANTI-Blue solution. 4-parametric curve fit was used to determine the test compound concentration that results in 50% reduction of L18-MDP-driven human NOD2 signaling. hNOD2 IC50 of the compound represented by Structural Formula (II) was determined to be 0.7 nM.

[0373] Using the assay described above, inhibition of hNOD2 signaling was also evaluated for GSK 2983559 (Haile at al., J. Med. Chem. 2019, 62, 14, 6482-6494), a known RIPK2 kinase inhibitor:

[0374] Unlike the compound represented by Structural Formula (II) that exhibits desirable hNOD2 inhibition IC50 value, hNOD2 inhibition IC50 for GSK 2983559 was determined to be greater than 10 pM.

[0375] Example 11 - Inhibition of TNF- alpha secretion in human whole blood by the compound represented by Structural Formula (II)

[0376] Materials: Assay medium consisted of RPMI 1640 medium (catalogue number: 11875119) and 10% heat inactivated FBS (Cytvia). U-PLEX Biomarker Assay (cat# K15067L-4) to detect levels of TNF-alpha was purchased from Meso Scale Discovery. Heparinized whole blood from healthy donors / volunteers was obtained through Research Blood Components, LLC.

[0377] Method: Priming of human whole blood with IFN-gamma (catalogue number: 285-IF- 100) followed by stimulation with a NOD2 ligand, L18-MDP (Invivogen, catalogue number: tlrl-lmdp), resulted in secretion of TNF-alpha. Test compound was prepared into a 10 mM DMSO solution and serially diluted into 9 points using a 3-fold dilution in a 96 well plate. A 10X working stock solution of recombinant human IFN-gamma (final concentration of 10 ng / mL) was prepared in assay medium and used to prepare a 10X solution of test compound. 20uL of 10X IFN-gamma and test compound (or DMSO control) was added to a 96-well plate. 160 uL of heparinized whole blood obtained from healthy donors was dispensed into individual wells of the 96-well plate and placed on a plate shaker (150 rpm) and incubated for 60 min at 37 °C in a CO2 incubator. Subsequently, 20uL of L18-MDP (final concentration of 100 ng / mL) was added to the appropriate wells and further incubated for 16 hours on a plate shaker (150 rpm) at 37 °C in a CO2 incubator. The final concentration of DMSO was 0.05% (v / v) in all wells. After incubation, 100 pL of DPBS was added per well, mixed by shaking at 500 rpm for 2 minutes, followed by centrifugation (400xg for 10 minutes) and collection of the supernatant. TNF-alpha in the supernatant was measured using MSD immunoassay (MesoScale Discovery). 4-parametric curve fit was used to determine the test compound concentration that results in 50% reduction of TNF-alpha concentration in supernatant relative to assay controls.

[0378] Human whole blood TNFa IC50 of the compound represented by Structural Formula (II) was determined to be 9 nM.

[0379] Example 12 - Inhibition of the interaction of RIPK2 with XIAP by the compound represented by Structural Formula (II)

[0380] An assay measuring the RIPK2 and XIAP protein-protein interaction was generated using the NanoBRET proteimprotein interaction system (Promega) which measures the energy transfer from a bioluminescent protein donor (NanoLuc fusion protein) to a fluorescent protein acceptor (Halotag fusion protein). In this assay, the C-terminus of full- length XIAP was appended with the NanoLuc fusion protein and the N-terminus of full- length RIPK2 was appended with the HaloTag fusion protein. Assay medium consistsed of Opti-MEM I reduced serum medium with no phenol red plus 4% heat inactivated FBS. Transfection reagents were combined in a microfuge tube as follows: 400 uL of assay medium, 8 pL of vector with N-terminus of RIPK2 HaloTag fusion protein (vector concentration at 1 pg / pL), 0.8 uL of vector with C-terminus of XIAP NanoLuc fusion protein (vector concentration at 1 pg / pL), and 24 pL of FuGENE HD transfection reagent (Promega, catalogue number E2312). NanoBRET Nano-Gio Detection System was purchased from Promega (catalogue number N1663) and contained the HaloTag NanoBRET 618 ligand and NanoBRET Nano-Gio substrate. Test compound was prepared into a 10 mM DMSO solution and was serially diluted into 10 points using a 3-fold dilution in a 384 well plate using a TECAN EV0200. Method: HEK293T cells were transfected with the RIPK2 HaloTag fusion and XIAP NanoLuc fusion vectors in suspension. Briefly, a 16 mL cell suspension of HEK293T cells (final density of 125 000 cells / mL) in assay medium was prepared in a 50 mL tube. Transfection reagents were pre-mixed and incubated at room temperature for 30 minutes. Then the total transfection reagent mixture was added drop wise to the 16 mL cell suspension and mixed gently. 40 pL of the cells and transfection reagent suspension was plated into a white 384 well plate and incubated at 37 °C in a CO2 incubator for 24 hours. The next day, transfected cells were first treated with test compound (total volume of 40 nL) and incubated for 2 hours followed by addition of the HaloTag NanoBRET 618 ligand (100 nM, total volume of 40 nL) and again incubated for 2 hours. Lastly, a 3X solution of NanoBRET Nano- Glo substrate in Opti-MEM I reduced serum media (no phenol red; 20 pL total volume) was added to each well and incubated for 2-3 minutes at room temperature. The plate was then measured using 460 nm filter (donor emission) and 618 nm filter (acceptor emission) in an EnVision multimode plate reader (PerkinElmer). The NanoBRET ratio values were determined by dividing the acceptor emission value by the donor emission value for each sample. 4-parametric curve fit was used to determine the test compound concentration that results in 50% reduction of the RIPK2 and XIAP protein-protein interaction relative to assay controls.

[0381] NanoBRET Scaffolding IC50 of the compound represented by Structural Formula (II) was determined to be 12 nM.

[0382] Using the assay described above, inhibition of the RIPK2 and XIAP protein-protein interaction was also evaluated for GSK 2983559. Unlike the compound represented by Structural Formula (II), GSK 2983559 showed no inhibition of the RIPK2 and XIAP proteinprotein interaction.

[0383] Example 13 - In vivo inhibition of Monocyte Chemoattractant Protein- 1 (MCP-1) by the compound represented by Structural Formula (II)

[0384] The compound represented by Structural Formula (II) was tested for its ability to inhibit RIPK2 activity in vivo, as measured by plasma levels of cytokine MCP-1. C57BL / 6 mice were dosed orally with the compound represented by Structural Formula (II) one hour prior to intra-peritoneal administration of muramyldipeptide (MDP), a NOD2 agonist. Intraperitoneal (i.p.) injection of MDP in mice induces an increase in circulating levels of proinflammatory cytokines, such as MCP-1, in a RIPK2-dependent manner. This acute mouse MDP challenge represents a screening model to measure the ability of compounds to inhibit RIPK2 in vivo.

[0385] Materials: Female C57BL / 6 mice (6-13 weeks of age) were purchased from the Jackson Laboratory. All mice were maintained under a 12 h light / dark cycle and had food and water ad libitum. Muramyldipeptide (MDP) was purchased from Invivogen (catalog No. tlrl- mdp; lot No. 6231-43-02). Mouse MCP-1 was measured using U-PLEX MSD kit (Meso Scale Discovery (MSD), catalog No. K15069M-2). Carboxymethyl cellulose was purchased from Sigma-Aldrich (catalog No. C5678-500 ml), Tween80 was purchased from Sigma- Aldrich (catalog No. P1754-500 ml), (Hydroxypropyl)-P-cyclodextrin (HP-P-CD) was purchased from Sigma-Aldrich (catalog No. C332607-500G), PBS was purchased from Thermo Fisher Scientific (catalog No. 14190250).

[0386] Methods:

[0387] Oral Dosing Formulation

[0388] The vehicle was prepared by mixing carboxymethyl cellulose and Tween80 to achieve a final solution of 0.5% CMC or 20% HP-P-CD in water. The compounds of the disclosure were weighed out and mixed with the vehicle to yield final working suspensions. Working suspensions of the compounds were prepared once at the beginning of the study, and vortexed and sonicated prior to each dosing to ensure the material was in fine suspension.

[0389] Oral Dosing and MDP Administration

[0390] Mice were acclimated to the facility for at least 5 days before the start of the study. On day 0, mice were weighed and assigned to groups in a balanced manner to achieve similar average weight across the groups at the start of the study. Oral dosing (p.o.) with the compounds of the disclosure was administered as shown in Table 8. On day 0, hour -1 (1 hours before MDP injection), all mice were given a single p.o. dose with vehicle or the compound represented by Structural Formula (II). At hour 0 (1 hour after dosing), mice were injected intraperitoneally (IP) with 8 mpk MDP in PBS. Two hours after MDP injection (3 hours after drug treatment), blood was collected via cardiac puncture for all mice into EDTA microtainer collection tubes. Plasma was prepared from blood and stored at -80 °C.

[0391] Measurement of Plasma MCP-1

[0392] MCP-1 levels in mouse plasma were measured using U-PLEX MSD kit according to manufacturer’s instructions. A single analysis was performed for each sample. Concentrations were determined relative to a standard calibration curve, and total analyte levels in pg / mL. The MCP-1 data in pg / mL were normalized in GraphPad Prism 9.2 using the normalize function and entering the 0% and 100% inhibition control groups for the study. 0% inhibition was defined as mean MCP-1 pg / mL in MDP vehicle group, and 100% inhibition was defined as mean MCP-1 pg / mL in the unstimulated vehicle group.

[0393] In mice treated with MDP inhibited production of the cytokine MCP-1 by 101%.

[0394] Example 14 - Large scale preparation of crystalline Form Ila.

[0395] Precursor A Precursor B

[0396] Dimethylacetamide (DMAC, 16.92 kg), Precursor A (1. 0 eq, 3.6 kg), Precursor B (0.95 eq, 2.88 kg), and KOH (1.08 eq, 0.76 kg) were loaded in a 100 L reactor under nitrogen. Additional 6.84 kg of DMAC were used to rinse the reactor ports. The reaction mixture was heated to 65 °C and stirred for 3 hrs. The reaction mixture was cooled to 11 °C. Water (18.00 kg) was added to the reaction mixture. A mixture of isopropyl acetate (zPrOAc, 53.86 kg) and dichloromethane (DCM, 13.39 kg) was prepared. The zPrOAc / DCM mixture (33.62 kg of) was added to the reaction mixture, followed by addition of 14.4 kg of water. The resulting mixture was stirred for 10 min. The mixture was allowed to separate for 5 min, and the top organic layer was collected (organic layer #1). The zPrOAc / DCM mixture (16.81 kg of) was added to the remaining aqueous layer and the resulting mixture was stirred for 10 min. The mixture was allowed to separate for 5 min, and the top organic layer was collected (organic layer #2). The zPrOAc / DCM mixture (16.81 kg of) was added to the remaining aqueous layer and the resulting mixture was stirred for 10 min. The mixture was allowed to separate for 5 min, and the aqueous layer was removed. Organic layers #1 and #2 were added back to the reactor, followed by 2% brine solution (7.34 kg). The resulting mixture was stirred for 10 min and then allowed to separate for 5 min. The aqueous layer was removed and water (7.20 kg) was added to the reactor. The resulting mixture was stirred for 10 min and then allowed to separate for 5 min. The aqueous layer was removed and the resulting mixture was stirred for 12 hrs. The mixture was filtered and the wet cake was washed with methyl- / -butyl ether (MTBE, 2x4 kg). The wet cake was de-liquored for 0.5 hrs under suction. The product was dried in a vacuum dryer at 50-55 °C and 0.3 bar for 12 hrs to afford crystalline Form Ila (2.65 kg).

[0397] Example 14 - Large scale preparation of crystalline Form la.

[0398] Three batches of crystalline Form Ila (each 5.25 kg) were dissolved and filtered as follows. In a 50 L reactor IPA (19.24 kg) and water (12.24 kg) were combined under nitrogen. Crystalline Form Ila (5.25 kg) was added to the reactor and the resulting mixture was heated to 65 °C and stirred for 10 min. A solution of isopropanol (IPA, 19.24 kg) and water (12.24 kg) was prepared. Additional 2.23 kg of the IPA / water solution was added to the mixture, which turned clear. The clear solution was cooled to 55 °C and polish filtered through a 0.2 micron PTFE filter. The polish filtered solutions from the three batches were combined in a 150 L reactor equipped with a wet mill and the reactor contents were cooled to 30 °C.

[0399] Aqueous 3N HC1 solution was polish filtered through a 0.2 micron PTFE filter. 3.5 kg of the polish filtered aqueous 3N HC1 solution were added to the reactor over 15 min under stirring. Seeds of Form la (159g) were added to the reactor followed by stirring for 15 min. The wet mill was started and the mixture in the reactor was stirred for 1 h while circulating through the wet mill. The wet mill was turned off and aqueous 3N HC1 solution (6.95 kg) was added to the reactor followed by stirring for 0.5 hrs. The mixture was cooled to 22 °C and stirred for 11 hrs.

[0400] MTBE was polish filtered through a 0.2 micron PTFE filter. The reactor contents were filtered and washed with polish filtered MTBE (3x17.8 kg). The wet cake was de-

[0401] liquored for 2 hrs under suction. The product was dried in a vacuum dryer at 0.1 bar, 25-30 °C for 4 hrs and 55-60 °C for 12 hrs to afford crystalline Form la (13.86 kg).

[0402] Example 15 - Formulation comprising crystalline Form la. Capsules comprising crystalline Form la were prepared according to the compositions described in Tables 15.1 and 15.2. Tablets comprising crystalline Form la were prepared according to the compositions described in Tables 15.3 and 15.4.

[0403] Table 15.1. 10 mg Capsule

[0404] Table 15.1. 20 mg Capsule

[0405] Table 15.3. Tablets 10 mg and 30 mg

[0406] Table 15. 4 Tablet 30 mg

[0407] INCORPORATION BY REFERENCE

[0408] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0409] EQUIVALENTS While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

CLAIMSWhat is claimed is:

1. A crystalline form of a salt of the compound represented by Structural Formula (II):wherein the salt is selected from the group consisting of a chloride, a succinate, a sulfate, a methanesulfonate, a fumarate, and a citrate of the compound represented by Structural Formula (II).

2. The crystalline form of claim 1, wherein the salt is a chloride of the compound represented by Structural Formula (II).

3. The crystalline form of claim 2, wherein the crystalline form is Form la characterized by at least three x-ray powder diffraction peaks at 29 angles selected from 10.33°, 16.77°, 19.01°, and 24.45°.

4. The crystalline form of claim 2 or 3, wherein the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles 7.99°, 10.33°, 13.23°, 16.77°, 17.70°, 19.01°, 23.48°, and 24.45°.

5. The crystalline form of any one of claims 2-4, wherein the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles of 7.99°, 8.85°, 10.33°, 13.23°, 15.56°, 16.77°, 17.70°, 19.01°, 20.51°, 20.91°, 21.58°, 23.48°, 24.45°, 24.99°, and 26.01°.

6. The crystalline form of claim 2, wherein the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles of 7.99°, 8.85°, 10.33°, and 13.23°.

7. The crystalline form of any one of claims 2-6, wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 1.

8. The crystalline form of any one of claims 2-7, wherein the crystalline form is characterized by a DSC thermogram having an endothermic event at about 258 °C.

9. The crystalline form of any one of claims 2-8, wherein the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 2.

10. The crystalline form of any one of claims 2-9, wherein the crystalline form is anhydrous.

11. The crystalline form of claim 1, wherein the salt is a succinate of the compound represented by Structural Formula (II).

12. The crystalline form of claim 11, wherein the crystalline form is Form lb characterized by at least three x-ray powder diffraction peaks at 29 angles selected from 8.30°, 9.29°, 18.42°, and 23.39°.

13. The crystalline form of claim 11 ort 12, wherein the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles 6.31°, 8.30°, 9.29°, 16.72°, 18.42°, 22.80°, 23.39°, and 24.26°.

14. The crystalline form of any one of claims 11-13, wherein the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles of 6.31°, 8.30°, 9.29°, 16.72°, 18.42°, 19.18°, 19.86°, 22.80°, 23.39°, and 24.26°.

15. The crystalline form of claim 11, wherein the crystalline form is characterized by x- ray powder diffraction peaks at 29 angles 6.31°, 8.30°, and 9.29°.

16. The crystalline form of any one of claims 11-15, wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 3.

17. The crystalline form of any one of claims 11-16, wherein the crystalline form is characterized by a DSC thermogram having an endothermic event at about 159 °C.

18. The crystalline form of any one of claims 11-17, wherein the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 4.

19. The crystalline form of claim 1, wherein the salt is a sulfate of the compound represented by Structural Formula (II).

20. The crystalline form of claim 19, wherein the crystalline form is Form Ic characterized by at least three x-ray powder diffraction peaks at 29 angles selected from 3.87°, 7.76°, 15.76°, and 19.86°.

21. The crystalline form of claim 19 or 20, wherein the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles 3.87°, 7.76°, 11.86°, 15.76°, and 19.86°.

22. The crystalline form of claim 19, wherein the crystalline form is characterized by x- ray powder diffraction peaks at 29 angles 3.87°, 7.76°, and 11.86°.

23. The crystalline form of any one of claims 19-22, wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 5.

24. The crystalline form of any one of claims 19-23, wherein the crystalline form is characterized by a DSC thermogram having an endothermic event at about 255 °C.

25. The crystalline form of any one of claims 19-24, wherein the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 6.

26. The crystalline form of claim 1, wherein the salt is a phosphate of the compound represented by Structural Formula (II).

27. The crystalline form of claim 26, wherein the crystalline form is Form Id characterized by at least three x-ray powder diffraction peaks at 29 angles selected from 4.86°, 7.00°, 9.37°, and 21.07°.

28. The crystalline form of claim 26 or 27, wherein the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles 4.86°, 7.00°, 9.37°, 15.01°, 18.99°, and 21.07°.

29. The crystalline form of claim 26, wherein the crystalline form is characterized by x- ray powder diffraction peaks at 29 angles 4.86°, 7.00°, and 9.37°,30. The crystalline form of any one of claims 26-29, wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG 7.

31. The crystalline form of any one of claims 26-30, wherein the crystalline form is characterized by a DSC thermogram having an endothermic event at about 147 °C.

32. The crystalline form of any one of claims 26-31, wherein the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 8.

33. The crystalline form of claim 1, wherein the salt is a fumarate of the compound represented by Structural Formula (II).

34. The crystalline form of claim 33, wherein the crystalline form is Form le characterized by at least three x-ray powder diffraction peaks at 29 angles selected from 8.11°, 9.42°, 22.66°, and 23.31°.

35. The crystalline form of claim 33 or 34, wherein the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles 8.11°, 8.58°, 9.42°, 16.37°, 18.68°, 22.66°, 23.31°, and 24.28°.

36. The crystalline form of any one of claims 33-35, wherein the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles 8.11°, 8.58°, 9.42°, 16.37°, 17.71°, 18.68°, 19.03°, 19.66°, 22.66°, 23.31°, 24.02°, and 24.28°.

37. The crystalline form of claim 33, wherein the crystalline form is characterized by x- ray powder diffraction peaks at 29 angles 8.11°, 8.58°, and 9.42°.

38. The crystalline form of any one of claims 33-37, wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 9.

39. The crystalline form of any one of claims 33-38, wherein the crystalline form is characterized by a DSC thermogram having an endothermic event at about 204 °C.

40. The crystalline form of any one of claims 33-39, wherein the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 10.

41. The crystalline form of any one of claims 33-40, wherein the crystalline form is anhydrous.

42. The crystalline form of claim 1, wherein the salt is a methanesulfonate of the compound represented by Structural Formula (II).

43. The crystalline form of claim 42, wherein the crystalline form is Form If characterized by at least three x-ray powder diffraction peaks at 29 angles selected from 3.76°, 7.62°, 15.36°, and 19.28°.

44. The crystalline form of claim 42 or 43, wherein the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles 3.76°, 6.70°, 7.62°, 8.19°, 15.36°, 16.51°, and 19.28°.

45. The crystalline form of claim 42, wherein the crystalline form is characterized by x- ray powder diffraction peaks at 29 angles 3.76°, 6.70°, 7.62°, and 8.19°.

46. The crystalline form of any one of claims 42-45, wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 11.

47. The crystalline form of any one of claims 42-46, wherein the crystalline form is characterized by a DSC thermogram having an endothermic event at about 221 °C.

48. The crystalline form of any one of claims 42-47, wherein the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 12.

49. The crystalline form of any one of claims 42-48, wherein the crystalline form is anhydrous.

50. The crystalline form of claim 1, wherein the salt is a citrate of the compound represented by Structural Formula (II).

51. The crystalline form of claim 50, wherein the crystalline form is Form Ig characterized by at least three x-ray powder diffraction peaks at 29 angles selected from 3.68°, 7.49°, 18.81°, and 18.99°.

52. The crystalline form of claim 50 or 51, wherein the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles 3.68°, 7.49°, 10.32°, 11.31°, 18.81°, and 18.99°.

53. The crystalline form of claim 50, wherein the crystalline form is characterized by x- ray powder diffraction peaks at 29 angles 3.68°, 7.49°, 10.32°, and 11.31°.

54. The crystalline form of any one of claims 50-53, wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 13.

55. A crystalline form of the compound represented by Structural Formula (II):

56. The crystalline form of claim 55, wherein the crystalline form is Form Ila characterized by at least three x-ray powder diffraction peaks at 29 angles selected from 13.81°, 16.73°, 18.11°, and 20.12°.

57. The crystalline form of claim 55 or 56, wherein the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles 7.99, 13.81°, 16.73°, 17.30°, 18.11°, 18.62°, 20.12°, and 23.77°.

58. The crystalline form of claim 55, wherein the crystalline form is characterized by x- ray powder diffraction peaks at 29 angles 7.99, 13.81°, and 16.73°.

59. The crystalline form of any one of claims 56-58, wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 14.

60. The crystalline form of any one of claims 56-59, wherein the crystalline form is characterized by a DSC thermogram having an endothermic event at about 163 °C.

61. The crystalline form of any one of claims 56-60, wherein the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 15.

62. The crystalline form of claim 56, wherein the crystalline form is Form lib characterized by at least three x-ray powder diffraction peaks at 29 angles selected from 4.39°, 20.39°, 21.10°, and 24.14°.

63. The crystalline form of claim 56 or 62, wherein the crystalline form is characterized by x-ray powder diffraction peaks at 29 angles 4.39°, 8.66°, 12.96°, 17.29°, 20.39°, 20.73°, 21.10°, and 24.14°.

64. The crystalline form of claim 63, wherein the crystalline form is characterized by x- ray powder diffraction peaks at 29 angles 4.39°, 8.66°, 10.90°, 12.96°, 13.54°, 16.03°, 17.29°, 19.79°, 20.39°, 20.73°, 21.10°, 21.50°, 23.09°, and 24.14°.

65. The crystalline form of claim 56, wherein the crystalline form is characterized by x- ray powder diffraction peaks at 29 angles 4.39°, 8.66°, 10.90°, 12.96°, and 13.54°.

66. The crystalline form of any one of claims 62-65, wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 16.

67. The crystalline form of any one of claims 62-66, wherein the crystalline form is characterized by a DSC thermogram having an endothermic event at about 128 °C.

68. The crystalline form of any one of claims 62-67, wherein the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 17.

69. The crystalline form of any one of claims 62-68, wherein the crystalline form is a hydrate.

70. The crystalline form of any one of claims 62-70, wherein the crystalline form is monohydrate.

71. A composition, comprising particles of one or more crystalline forms of a compound represented by Structural Formula (II):wherein the one or more crystalline forms are selected from:Form Ila characterized by at least three x-ray powder diffraction peaks at 29 angles selected from 13.81°, 16.73°, 18.11°, and 20.12°, andForm lib characterized by at least three x-ray powder diffraction peaks at 29 angles selected from 4.39°, 20.39°, 21.10°, and 24.14°.

72. A pharmaceutical composition, comprising the crystalline form of any one of claims 1- 70 or the composition of claim 71 and a pharmaceutically acceptable carrier.

73. A method of treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline form of any one of claims 1-70, the composition of claim 71, or a pharmaceutical composition of claim 72, wherein the disease or disorder is selected from an inflammatory disease, autoimmune disease, granulomatous disease, cancer, and neurodegenerative disease.

74. The method of claim 73, wherein the disease or disorder is an inflammatory disease.

75. The method of claim 74, wherein the inflammatory disease is selected from uveitis, interleukin- 1 converting enzyme fever syndrome, dermatitis, acute lung injury, type 2 diabetes mellitus, arthritis, inflammatory bowel disease (IBD), ischemia reperfusion injury in a solid organ transplant, sepsis, liver disease, allergic disease, and graft versus host disease.

76. The method of claim 74, wherein the inflammatory disease is an IBD.

77. The method of claim 76, wherein the IBD is selected from ulcerative colitis, Crohn's disease, early-onset IBD, and extraintestinal IBD.

78. The method of claim 74, wherein the inflammatory disease is selected from rheumatoid arthritis, inflammatory arthritis, peritonitis, ischemia reperfusion injury in kidney transplant, non-alcohol steatohepatitis, alcohol steatohepatitis, insulin-resistant type 2 diabetes, allergic rhinitis, asthma, atopic dermatitis, Sjogren’s syndrome, ankylosing spondylitis, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, thrombosis, a-synucleinopathy, Parkinson’s disease, dementia with Lewy body, multiple system atrophy, Alzheimer’s disease, amyotrophic lateral sclerosis, and chronic obstructive pulmonary disease.

79. The method of claim 73, wherein the disease or disorder is an autoimmune disease.

80. The method of claim 79, wherein the autoimmune disease is selected from systemic lupus erythematosus, lupus nephritis, psoriasis, immune thrombocytopenic purpura, and multiple sclerosis.

81. The method of claim 73, wherein the disease or disorder is a granulomatous disease.

82. The method of claim 71, wherein the granulomatous disease is selected from sarcoidosis, Blau syndrome, Wegner’s granulomatosis, Behcet’s disease, and interstitial pulmonary disease.

83. The method of claim 73, wherein the disease or disorder is a cancer.

84. The method of claim 83, wherein the cancer is selected from leukemia, breast cancer, brain cancer, colorectal cancer, head and neck cancer, melanoma, pancreatic cancer, prostate cancer, ovarian cancer, renal cancer, and lung cancer.

85. The method of claim 73, wherein the disease or disorder is a neurodegenerative disease.

86. The method of claim 85, wherein the neurodegenerative disease is selected from Alzheimer’s disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig’s Disease), Parkinson’s disease, multiple sclerosis, diabetic neurophathy, poly glutamine (polyQ) diseases, stroke, Fahr disease, Menke’s disease, Wilson’s disease, cerebral ischemia, a prion disorder, dementia, corticobasal degeneration, progressive supranuclear palsy, spinocerebellar atrophies, brain injury, and spinal cord injury.

87. The method of any one of claims 73-86, further comprising administering a second agent.

88. The method of claim 87, wherein the second agent is an anti-inflammatory agent or an anti- autoimmune agent.

89. The method of claim 87, wherein the second agent is selected from anti-TNF agent, anti-IL-23 agent, anti-integrin agent, and JAK inhibitor.

90. The method of claim 89, wherein the second agent is anti-TNF agent.

91. The method of claim 89, wherein the second agent is anti-IL-23 agent.

92. The method of claim 89, wherein the second agent is anti-integrin agent.

93. The method of claim 89, wherein the second agent is JAK inhibitor.

94. The method of any one of claims 87-93, wherein the second agent and the crystalline form are administered together in a single pharmaceutical composition.

95. The method of any one of claims 87-93, wherein the second agent and the crystalline form are administered separately.

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