Crystalline polymorph of an itk inhibitor

Abstract

The present application relates to a novel crystalline form of 1-((2S,5R)-5-((5-((R)-2,2-difluorocyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (Compound 1). The present application also relates to a method of preparing Compound 1 and a method of preparing crystalline polymorph Form C of Compound 1. Additional aspects of the present application relate to pharmaceutical compositions comprising Compound 1 formed from the crystalline form or the crystalline form of Compound 1.

Description

CRYSTALLINE POLYMORPH OF AN ITK INHIBITORCross-Reference To Related Applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 615,414 filed December 28, 2023, which is hereby incorporated by reference in its entirety for all purposes.Summary of the Invention

[0002] In one aspect, the present disclosure provides a novel crystalline form of 1-((2.5',5R)-5-((5-((R)-2,2-difluorocyclopropyl)-7H-pyrrolo[2.,3-d]pyriinidin-4-yl)amino)-2- methylpiperidin-l-yl)prop-2-en- 1-one (Compound 1):

[0003] Described and identified herein as crystalline polymorph Form C of Compound 1. Yet another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of Compound 1 prepared from the crystalline polymorph Form C of Compound 1 or a crystalline polymorph Form C of Compound 1, a pharmaceutically acceptable salt thereof, or a combination thereof, and a pharmaceutically acceptable carrier.

[0004] In yet another aspect, the present invention provides a method of treating an ITK and / or JAK3-mediated disease in a subject in need thereof comprising administering to tlie subject a therapeutically effective amount of Compound 1 prepared from the crystalline polymorph Form C of Compound 1 or a crystalline polymorph Form C of Compound 1, or a combination thereof.Brief Description of the Drawings

[0005] For a fuller understanding of the nature and advantages of the present, invention, reference should be made to the following detailed description taken in connection with the accompanying drawings, in which:

[0006] FIG. 1 depicts a PXRD overlay of crystalline Forms A, B, and C of Compound 1 (Form A is listed as Group A, Fonn B is listed as Group B, and Fonn C is listed as Group C).

[0007] FIG. 2 depict the FT-Raman spectrum of Fonn A of Compound 1.

[0008] FIG. 3 depicts the DSC and TGA of Form A of Compound 1.

[0009] FIG. 4 depicts that PXRD of Form A of Compound 1.

[0010] FIG. 5 depict the FT-Raman spectrum of Form B of Compound 1.

[0011] FIG. 6 depicts the DSC and TGA of Form B of Compound 1.

[0012] FIG. 7 depicts that PXRD of Form B of Compound 1.

[0013] FIG. 8 depict the FT-Raman spectrum of Form C of Compound 1.

[0014] FIG. 9 depicts the DSC and TGA of Fonn C of Compound. 1 .

[0015] FIG. 10 depicts that PXRD (with Bragg reflections) of Form C of Compound 1.

[0016] FIG. 11 depicts tire IR of Form C of Compound 1.

[0017] FIG. 12 depicts the GVS isotherm plot of Form C of Compound 1 (Fonn C is listed as Group C).

[0018] FIG. 13 depicts the FT-Raman spectrum of the relative stability products and the Form C reference (Form C is listed as Group C).

[0019] FIG. 14 depicts the ORTEP representation of one of the Fonn C of Compound 1 molecules in the asymmetric unit.

[0020] FIG. 15 depicts a three-dimensional display of Form C of Compound 1 showing the two molecules in the asymmetric unit, cell using a ball- and-stick representation.Detailed Description

[0021] Before the present compositions and methods are described, it is to be understood that the scope of the invention is not limited to these particular processes, compositions, or methodologies described, as these may vary. It is also to be understood that the terminology used, in the description is for the purpose of describing the particular versions or embodiments only and is not intended to limit the scope of the present invention, which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, the preferred methods, devices, and materials are now described. All publications mentioned herein areincorporated by reference with respect to the aspect it is identified as describing. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0022] Compound 1 is disclosed in U.S. PatentNo. 11,021,482B2 (Example 49), which is hereby incorporated by reference with respect to its disclosure of and methods of synthesizing Compound 1.

[0023] As used herein, “Compound 1” refers to 1-((2S,5R)-5-((5-((R)-2,2- difluorocyclopropyl)-7H-pyrrolo[2.,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-l-yl)prop- 2-en-1-one.

[0024] In some embodiments, the crystalline forms disclosed herein may possess useful ITK inhibiting activity. Some embodiments herein are directed to treatment or prophylaxis of a disease or condition in which ITK plays an active role using the crystalline forms disclosed herein. In some embodiments, a method of treating an ITK-mediated disease or disorder in a subject comprises administering to the subject a crystalline form of embodiments herein.

[0025] Some embodiments provide methods for treating an ITK-mediated disorder in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a crystalline form or composition according to the present disclosure. Also provided is the use of crystalline forms disclosed herein in the manufacture of a medicament for the treatment of a disease or condition ameliorated by the inhibition of ITK.Definitions

[0026] Before the present compositions and methods are described, it is to be understood that this invention is not limited to the particular processes, compositions, or methodologies described, as these may vary. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only and is not intended to limit the scope of embodiments herein which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Althoughany methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of embodiments herein, the preferred methods, devices, and materials are now described. All publications mentioned herein are incorporated by reference in their entirety. Nothing herein is to be construed as an admission that embodiments herein are not entitled to antedate such disclosure by virtue of prior invention.

[0027] It must also be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to an “ITK inhibi tor” is a reference to one or more ITK inhibitors and equivalents thereof known to those skilled in the art, and so forth.

[0028] As used herein, the term “about” means plus or minus 10% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 45% to 55%. When used to describe temperature, “about” refers to the identified temperature plus or minus 5 degrees. When used to describe PXRD peaks, the term “about” refers to tire identified 20 peak plus or minus 0.2 degrees.

[0029] In embodiments or claims where the term “comprising” is used as the transi tion phrase, such embodiments can also be envisioned with replacement of the term “comprising” with the terms “consisting of” or “consisting essentially of.”

[0030] As used herein, the term “consists of’ or “consisting of’ means that the pharmaceutical composition, composition or the method includes only the elements, steps, or ingredients specifically recited in the particular claimed embodiment or claim.

[0031] As used herein, the term “consisting essentially of’ or “consists essentially of” means that the pharmaceutical composition, or the method includes only the elements, steps or ingredients specifically recited in the particular claimed embodiment or claim and may optionally include additional elements, steps or ingredients that do not materially affect the basic and novel characteristics of the particular embodiment or claim. For example, the only active ingredient(s) in the composition or method that treats the specified condition (e.g., nutrient depletion) is the specifically recited therapeutic(s) in the particular embodiment or claim.

[0032] As used herein, two embodiments are “mutually exclusive” when one is defined to be something which is different from the other. For example, an embodiment wherein two groups combine to Form C cycloalkyl is mutually exclusive with an embodiment in which onegroup is ethyl the other group is hydrogen. Similarly, an embodiment wherein one group isCH2 is mutually exclusive with an embodiment wherein the same group is NH.

[0033] The term “inhibit” means to limit, prevent or block the action or function of a target enzyme and / or, to prevent, alleviate or eliminate the onset of one or more symptoms associated with a disease, condition or disorder, or to prevent, alleviate or eliminate a disease, condition or disorder.

[0034] Unless otherwise indicated, the term ‘"skin” means that outer integument or covering of the body, consisting of the dermis and the epidermis and resting upon subcutaneous tissue.

[0035] When ranges of values are disclosed, and the notation “from nl ... to n2” or‘"between nl ... and n2” is used, where nl and n2 are tire numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between diem. This range may be integral or continuous between and including tlie end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range “from 1 to 3 pM (micromolar),” which is intended to include 1 pM, 3 pM, and everything in between to any number of significant figures (e.g., 1.255 pM, 2.1 pM, 2.9999 pM, etc.).

[0036] Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, tire composite group alkylamido would represent an alkyl group atached to the parent molecule through an amido group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.

[0037] Stereogemc centers exist in tlie compounds and crystalline forms disclosed herein. These centers are designated by the symbols “R” or “S,” depending on the configuration of substituents around the stereogenic center. It should be understood that the invention encompasses all stereoisomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d- isomers and 1 -isomers, and mixtures thereof Individual stereoisomers of compounds and crystalline forms can be prepared synthetically from commercially available starting materials which contain defined stereochemical configurations or by separation of mixtures of stereoisomeric products by conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of stereoisomersby chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds and crystalline forms of particular configurations are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds and crystalline forms disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, endo, exo, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds and crystalline forms may exist as tautomers; all tautomeric isomers are provided by this invention. Additionally, the compounds and crystalline forms disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.

[0038] As used herein, the term “a derivative thereof’ refers to a salt thereof, a pharmaceutically acceptable salt thereof, an ester thereof, a free acid form thereof, a free base form thereof, a solvate thereof, a co-crystal thereof, a deuterated derivative thereof, a hydrate thereof, an N -oxide thereof, a clathrate thereof, a prodrug thereof, a polymorph thereof, a stereoisomer thereof, a geometric isomer thereof, a tautomer thereof, a mixture of tautomers thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a mixture of stereoisomers thereof, an isotope thereof (e.g., tritium, deuterium), or a combination thereof.

[0039] By “pharmaceutical] y acceptable”, it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

[0040] As used herein, the term “pharmaceutically acceptable salt” refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal. The term “pharmaceutically acceptable salts” embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Such salts can be derived from pharmaceutically- acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.

[0041] Suitable pharmaceutically acceptable acid addition salts of the crystalline forms of embodiments herein may be prepared from an inorganic acid or an organic acid. All of these salts may be prepared by conventional means from the corresponding compounds and crystalline forms of embodiments herein by treating, for example, the compounds and crystalline forms with the appropriate acid or base.

[0042] Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, phosphoric and diphosphoric acid; and organic acids, for example formic, acetic, trifluoroacetic, propionic, succinic, glycolic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, p-hydroxy butyric, malonic, galactic, galacturonic, citric, fumaric, gluconic, glutamic, lactic, maleic, malic, mandelic, mucic, ascorbic, oxalic, pantothenic, succinic, tartaric, benzoic, acetic, xinafoic (l-hydroxy-2-naphthoic acid), napadisilic (1,5- naphthalenedisulfonic acid) and the like.

[0043] Salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically- acceptable organic bases include salts of primary, secondary and tertiary amines, including alkyl amines, aryl alkyl amines, heterocyclic amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, chloroprocaine, diethanolamine, N- methylglucamine, N,N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, A-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0044] The crystalline forms of embodiments herein may exist in both unsolvated and solvated forms. The term solvate is used herein to describe a molecular complex comprising a crystalline form of embodiments herein and an amount of one or more pharmaceutically acceptable solvent molecules. The term hydrate is employed when said solvent is water. Examples of solvate forms include, but are not limited to, crystalline forms of embodiments herein in association with water, acetone, dichloromethane, tetrahydrofuran, 1,4-dioxane, n- butanol, 2-propanoi, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. It is specifically contemplated that in embodiments herein one solvent molecule can be associated with one molecule of the crystalline forms of embodiments herein, such as a hydrate.

[0045] Furthermore, it is specifically contemplated that in embodiments herein, more than one solvent molecule may be associated with one molecule of the crystalline forms ofembodiments herein, such as a dihydrate. Additionally, it is specifically contemplated that in embodiments herein less than one solvent molecule may be associated with one molecule of the crystalline forms of embodiments herein, such as a hemihydrate. Furthermore, solvates of embodiments herein are contemplated as solvates of crystalline forms of embodiments herein that retain the biological effectiveness of the non-solvate form of the crystalline forms.

[0046] Embodiments herein also include isotopically-labeled crystalline forms of embodiments herein, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the crystalline forms of embodiments herein include isotopes of hydrogen, such as2H and3H, carbon, such as11C,13C and14C, chlorine, such as31C1, fluorine, such as18F, iodine, such as123I andl25I, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S. Certain isotopically-labeled crystalline forms of embodiments herein, for example, those incorporating a radioactive isotope, are useful in drag and / or substrate tissue distribution studies. The radioactive isotopes tritium, H. and carbon-14,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium,2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased tn vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0047] Isotopically-labeled crystalline forms of embodiments herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent m place of the non-labeled reagent otherwise employed.

[0048] Preferred isotopically-labeled crystalline forms include deuterated derivatives of the crystalline forms of embodiments herein. As used herein, the term deuterated derivative embraces crystalline forms of embodiments herein where m a particular position at least one hydrogen atom is replaced by deuterium. Deuterium (D or 2H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.

[0049] Hydrogen deuterium exchange (deuterium incorporation) is a chemical reaction in which a covalently bonded hydrogen atom is replaced by a deuterium atom. Said exchange (incorporation) reaction can be total or partial.

[0050] Typically, a deuterated derivative of a crystalline form of embodiments herein has an isotopic enrichment factor (ratio between the isotopic abundance and the natural abundance of that isotope, i.e. the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen) for each deuterium present at a site designated as a potential site of deuteration on the compounds and crystalline forms of at least 3500 (52.5% deuterium incorporation).

[0051] In some embodiments, the isotopic enrichment factor is at least 5000 (75% deuterium). In some embodiments, the isotopic enrichment factor is at least 6333.3 (95% deuterium incorporation). In some embodiments, the isotopic enrichment factor is at least 6633.3 (99.5% deuterium incorporation). It is understood that the isotopic enrichment factor of each deuterium present at a site designated as a site of deuteration is independent from the other deuteration sites.

[0052] The isotopic enrichment factor can be determined using conventional analytical methods known to one of ordinary skilled in the art, including mass spectrometry (MS) and nuclear magnetic resonance (NMR).

[0053] The terms “excipient” and ‘"pharmaceutically acceptable excipient” as used herein are intended to be generally synonymous, and is used interchangeably with, the terms “earner,” “pharmaceutically acceptable earner,” “diluent,” “pharmaceutically acceptable diluent.”

[0054] The compounds and crystalline forms disclosed herein can exist as and therefore include all stereoisomers, conformational isomers and mixtures thereof in all proportions as well as isotopic forms such as deuterated compounds and crystalline forms.

[0055] The term “disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and "‘condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.

[0056] The term “combination therapy ” means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the presentdisclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

[0057] The term “ITK. inhibitor” is used herein to refer to a compound or crystalline form of said compound that exhibits an ICso with respect to ITK activity of no more than about 100 gM and more typically not more than about 50 gM, as measured in the ITK enzyme assay described generally herein. ICso is that concentration of inhibitor that reduces the activity of an enzyme (e.g., ITK) to half-maximal level. Certain compounds and crystalline forms disclosed herein have been discovered to exhibit inhibition against ITK. In certain embodiments, compounds and crystalline forms will exhibit an ICso with respect to ITK of no more than about 10 uM; in further embodiments, compounds and crystalline forms will exhibit an ICso with respect to ITK of no more than about 5 gM; in yet further embodiments, compounds and crystalline forms will exhibit an ICso with respect to ITK of not more than about 1 gM; in yet further embodiments, compounds and crystalline forms will exhibit an ICso with respect to ITK of not more than about 200 nM, as measured in the ITK binding assay described herein.

[0058] The term “immune checkpoint inhibitor” means a crystalline form or pharmaceutical composition that inhibit immune checkpoint molecules.

[0059] “Administering” when used in conjunction with a therapeutic means to administer a therapeutic directly into or onto a target tissue or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted. Thus, as used herein, the term “administering”, when used in conjunction with a crystalline form of embodiments herein, can include, but is not limited to, providing the compounds and crystalline forms into or onto the target tissue; providing the compounds and crystalline forms systemically to a patient by, e.g., intravenous injection whereby the therapeutic reaches the target tissue. “Administering” a composition may be accomplished by injection, topically, orally, or by any of these methods in combination with other known techniques.

[0060] The term “patient” is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock suchas cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0061] The phrase "therapeutically effective" is intended to qualify the amount of active ingredien ts used in the treatment of a disease or disorder or on the effecting of a clinical endpoint.

[0062] As used herein, the term “therapeutic” or “therapeutic agent” or “pharmaceutically active agent” means an agent utilized to treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a patient. In part, embodiments of the present invention are directed to the treatment of ITK-mediated diseases.

[0063] A “therapeutically effective amount” or “effective amount” of a composition is a predetermined amount calculated to achieve the desired effect, e.g., to inhibit, block, or reverse the activation, migration, or proliferation of cells. The activity contemplated by the present methods includes both medical therapeutic and / or prophylactic treatment, as appropriate. The specific dose of a crystalline Form C administered according to this invention to obtain therapeutic and / or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compounds and crystalline forms administered, the route of administration, and the condition being treated. The compounds and crystalline forms are effective over a wide dosage range and, for example, dosages per day will normally fall within the range of from 0.001 to 10 mg / kg, more usually in the range of from 0.01 to 1 mg / kg. However, it will be understood that the effective amount administered will be determined by the physician in the light of the relevant circumstances including the condition to be treated, the choice of compounds and crystalline forms to be administered, and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. A therapeutically effective am ount of compounds and crystalline forms of this invention is typically an amount such that when it is administered in a physiologically tolerable excipient composition, it is sufficient to achieve an effective systemic concentration or local concentration in the tissue.

[0064] The term “therapeutically acceptable” refers to those compounds and crystalline forms, or a derivative thereof, which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use.

[0065] The terms “treat,” “treated,” “treating”, or “treatment” as used herein refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization ( / . e.. not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total, whether induction of or maintenance of), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. Treatment may also be preemptive in nature,it may include prevention of disease. Prevention of a disease may involve complete protection from disease, for example as in the case of prevention of infection with a pathogen, or may involve prevention of disease progression. For example, prevention of a disease may not mean complete foreclosure of any effect related to the diseases at any level, but instead may mean prevention of the symptoms of a disease to a clinically significant, or detectable level. Prevention of diseases may also mean prevention of progression of a disease to a later stage of the disease and prolonging disease- free survival as compared to disease-free survival if not receiving treatment and prolonging disease-free survival as compared to disease-free survival if not receiving treatment,

[0066] The crystalline forms of embodiments herein may also refer to a salt thereof, an ester thereof, a free acid form thereof, a free base form thereof, a solvate thereof, a co-crystal thereof, a deuterated derivative thereof a hydrate thereof, an N -oxide thereof, a clathrate thereof, a prodrug thereof, a polymorph thereof, a stereoisomer thereof, a geometric isomer thereof, a tautomer thereof, a mixture of tautomers thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a mixture of stereoisomers thereof, an isotope thereof (e.g., tritium, deuterium), or a combination of the foregoing of the compounds and crystalline forms of embodiments herein.

[0067] Hie present disclosure relates to new pyrrolopyrimidine compounds and crystalline forms and compositions, and their application as pharmaceuticals for the treatmentof disease. Methods of inhibition of ITK activity in a human or animal subject are also provided for the treatment of diseases such as those caused by inflammation.

[0068] The Tec (tyrosine kinase expressed in hepatocellular carcinoma) family of tyrosine kinases (TFTK) consists of five family members: Tec, BTK (Bruton’s tyrosine kinase), BMX (bone marrow kinase on the X chromosome also known as ETK), RLK (resting lymphocyte kinase also known as TXK) and ITK (interleukin-2 -inducible T cell kinase, also known as EMT and TSK). These kinases are central to the regulation of hematopoietic cell biology and more specifically the development and activity of lymphocytes and myeloid cells. The TFTK have structural similarities to other non-receptor tyrosine kinases while exhibiting some family specific motifs resulting in a diversity of domain structures associated with complex localization, scaffolding and activation mechanisms. Generally, TFTK contain an ammo terminal plekstrin homology domain (PH domain) involved in lipid interactions and membrane targeting followed by a BTK homology domain (BH) that binds Zn2+ and an SH3 domain generally involved in proline rich domain binding, A phosphotyrosine binding SH2 domain and a carboxy terminal ATP binding kinase domain complete the TFTK structure. TFTK expression is generally limited to hematopoietic lineage cells with the exception of ETK and TEC that are expressed in the liver and endothelial cells, respectively. BMX is expressed in monocytes, granulocytes and cardiac endothelium while BTK is expressed in B cells and mast cells but not plasma cells and T cells. TEC, RLK and ITK are all expressed in T cells. To date the TFTK with the most clear biological role in T cells is ITK.

[0069] Antigen / MHC dependent activation of the T cell receptor (TCR) has been shown to transduce its signal through ITK. TCR stimulation results in the activation of the kinase LCK and subsequent phosphorylation of the immunoreceptor tyrosine-based activation motifs (ITAMs) on CD3 inducing the binding and activation of the kinase ZAP70. In turn, ZAP70 phosphorylates the adaptor proteins LAT and SLP-76, which together with LCK and other proteins forms a hetermultimeric signaling complex that activates PI3K and generates PIP3 on the plasma membrane. ITK binds to this signaling complex via SH2 and SH3 domains and to PIP3 through its PH domain, resulting in LCK dependent phosphorylation of ITK ¥511 and subsequent ITK autophosphorylation of ¥180. Activated ITK phosphorylates PLCyl that, once activated, hydrolyzes PIP2 to the second messengers IP3 and DAG. The cellular consequences of these sequelae of events include calcium mobilization and flux, PKC and MEK / ERK pathway activation, and transcriptional activation via API , NFK active NFAT. Asa critical enzyme in the TCR activation pathway, ITK impacts T cell function in a number of ways including positive and negative selection, cellular differentiation, and cytokine production and release,

[0070] The role of ITK in T cell function has been delineated through genetic knockdown / kinase inactivation of the ITK gene in rodents and through characterizing human ITK mutant individuals. Mice with a null mutation of the ITK gene expressed a decreased number of mature T cells and a block in thymocyte development as well as a decreased TCR- driven T cell proliferative response. Interestingly, IL2 and CD28 signaling, as well as PMA / ionomycin-driven responses, remained unchanged, suggesting that the ITK response is membrane proximal and stimuli specific. It appears that ITK is responsible for amplification of TCR signaling versus an "on / off switch, as dual knockdown of the T cell expressing TFTK, ITK and RLK in mice produce a more complete TCR inactivation phenotype compared with ITK genetic deletion alone. In contrast to the modulatory effect that ITK appears to have on naive T cell activation, it plays a more significant role in T helper cell differentiation. Several studies in ITK-deficient mice have demonstrated a reduction in the Th2 protective response to parasitic infection. This reduced Th2 response was linked to a decrease in concentrations of Th2 cytokines IL4, IL5, IL13, and IL10 and to a reduction in RLK expression. In contrast to the ITK requirement for mounting Th2 driven responses, its impact on Thl responses is modest. For example, IFMy production in ITK knockout cells is partially inhibited while the double ITK / RLK knockout has a more severe phenotype. Evaluation of Th l 7 T helper cells in ITK knockout in vivo and in vitro studies demonstrated a reduction of IL17A mRNA and protein while having little impact on IL17F. The role of ITK in cytotoxic CD8+ T cells was investigated using ITK knockout mice. Stimulation of CD8+ T cells deficient in ITK results in a reduction in activation of PLCgl, ERK, and p38 MAPK and loss of Ca2+ response resulting in decreased proliferative response and effector cytokine production (IL, 2, IL4, and IFNy) while not impacting cytolytic capacity of these cells. In addition to the defects observed in CD4 + and CD8+ T cells, natural killer T cell development and TCR stimulated response is reduced in ITK knockout cells and animals.

[0071] Rodent genetic knockout studies reflect the impact of enzyme expression, not necessarily its catalytic activity, on biological responses. As ITK, through its multiple domain structure, has a role in scaffolding, in addition to its catalytic role. It is important to delineate the impact of blocking each of these functions on cellular biology. Kinase activity-independentITK activities include recruitment of the guanine nucleotide exchange factor VAV to the cell membrane associated with actin polymerization (PH and SH2 domain dependent), antigen receptor stimulation, and receptor activation of SRF. However, ITK knockout mice expressing an ITK kinase domain-deleted transgene demonstrated that the kinase domain is essential for induction of a normal Th2 response.

[0072] The relationship between ITK expression and activity and human disease has recently been documented in studies characterizing individuals exhibiting mutations in the gene encoding this protein and or correlation between expression and disease. The ITK gene was found to be elevated in peripheral blood T cells from patients with moderate to severe atopic dermatitis, a Th2 -driven chronic inflammatory skin disease. An investigation of disease- associated single nucleotide polymorphisms (SNP) in seasonal allergic rhinitis identified ITK as a significant risk factor. A human primary immunodeficiency was uncovered in siblings that died from immune dysregulation resulting in lymphoproliferation following Epstein Barr Virus (EBV) infection. This disorder was linked to a missense (R335W) mutation in the SH2 domain of ITK resulting in structural instability and reduced steady state levels of the enzyme. The finding was confirmed and extended in studies that identified three patients harboring a C1764G nonsense mutation in ITK resulting in a premature stop codon and reduced expression and / or activity of the protein. These patients presented with EBV-positive Hodgkin’s Lymphoma. These two reports suggest that mutational disruption of the ITK gene in humans results in an autosomal recessive lymphoproliferative disorder and identifies this kinase as a critical modulator in T cell biology,

[0073] In addition to the human genetic data summarized above, animal models support ITK as a therapeutic target for autoimmune and inflammatory disease. ITK knockout mice demonstrate reduced airway hypersensitivity and inflammation in models of allergic asthma. In a murine model of atopic dermatitis, ITK -deficient mice do not develop inflammation while ITK inhibition reduces the response in wild type mice. The ITK -dependent regulation of TCR- dependent Cazmobilization and transcription factor induction makes it a critical factor in protecting against Influenza A and HIV infection and viral replication. ITK inhibitors have been shown to alter HIV replication at multiple stages and have the potential as effective HIV therapeutics.

[0074] From an oncology perspective, studies have demonstrated that ITK inhibitors selectively target the killing of acute lymphblastic T-cell leukemia and cutaneous T-celllymphoma while normal T cells are minimally impacted. ITK is highly expressed in transformed T-cell lines relative to normal T cells and other cancer cell lines. The impact of ITK inhibition on T cell tumors was confirmed in mouse xenograph models. Cancer evasion of the immune system as a result of tumor antigen tolerance induction versus priming is critical for tumor survival. Tumors that develop a microenvironment that induces T cell unresponsiveness demonstrate altered T cell gene expression suggesting skewing to the Th2 phenotype. ITK inhibition will favor Thl differentiation and could be used to enhance cancer immunotherapy.

[0075] The utility of simultaneously inhibiting signals downstream of both the T cell receptor and cytokines receptors is best exemplified by the field of organ transplantation (Halloran). Standard-of-care in the immediate post-transplant setting is to prevent immunological graft rejection by dosing with a cocktail of inhibitors that impinge on lymphocyte activation at different points. The most common drags used in both the initial posttransplant period, as well as the discharge setting - are a calcmeurin inhibitor such as Prograf or Neoral, which block TCR signaling, and an anti -metabolite, such mycophenolate mofetil or rapamycin, which block the proliferation induced downstream of cytokines such as IL-2 or IL- 15. These drags cannot be used as monotherapy, as it would require higher doses resulting in drug-specific toxicity. By using these drugs at sub-optimal doses simultaneously, synergistic immunosuppression is achieved with reduced toxicity. ITK is downstream of TCR, and JAK3 is downstream of tire common g chain of cytokine receptors. By virtue of covalently modifying the cysteine in the catalytic domain of both kinases, it is possible to inhibit both enzymes with a single drug and thereby synergistically inhibit the activation of T cells.

[0076] The detailed description set-forth herein is provided to aid those skilled in the art in practicing the present disclosure. However, the disclosure described and claimed herein is not to be limited in scope by the specific embodiments herein disclosed because these embodiments are intended as illustration of several aspects of the disclosure. Any equivalent embodiments are intended to be within the scope of this disclosure. Indeed, various modifications of the disclosure in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description, which do not depart from the spirit or scope of the present inventive discovery. Such modifications are also intended to fall within the scope of the appended claims.

[0077] All references cited in this specification are hereby incorporated by reference. The discussion of the references herein is intended merely to summarize the assertions made by their authors and no admission is made that any reference constitutes prior art relevant to patentability. Applicant reserves the right to challenge the accuracy and pertinency of the cited references.Crystalline Forms

[0078] Polymorphism is the ability of solid materials to exist in two or more crystalline forms with different, arrangements or conformations of the constituents in the crystal lattice. Polymorphism and pseudomorphism are very' common amongst drags and are responsible for differences in many properties. While convention dictates selection of the lowest energypolymorph for incorporation into a formulation due to its chemical stability, considerations must be given to the excipients in the formulation to achieve desired chemical and physical stability and therefore efficacy. Disclosed herein is a particularly useful polymorph of Compound 1, named polymorph Form C.

[0079] Embodiments herein are directed to a crystalline form of 1 -((25,52D~5-((5-((A)- 2,2.-difluorocyclopropyl)-7H~pyrrolo[2,3-a]pyrimidin~4-yl)amino)-2-methylpiperidin-l- yl)prop-2-en-l-one (Compound 1), which has been found to inhibit ITK and / or JAK3 Kinase.

[0080] Some embodiments are directed towards a crystalline polymorph Form C of Compound 1 (1-((2S,5A)-5-((5-((R)-2,2-difluorocyclopropyl)-7H-pyrrolo[2,3-i.7]pyrimidin-4- yl)am ino)-2-methylpiperidin- 1 -yl)prop-2-en- 1 -one) .

[0081] In some embodiments, Form C is characterized by a PXRD pattern comprising a significant peak at 20 angle of about 15.59°.

[0082] In some embodiments. Form C is further characterized by a PXRD pattern comprising a. significant peak at 20 angle of about 7.39°.

[0083] In some embodiments, Form C is further characterized by a PXRD pattern comprising a significant peak at 20 angle of about 1 1 .66°.

[0084] In some embodiments, Form C is further characterized by a PXRD pattern comprising significant peaks at 20 of about 14.25°, about 14.74°, about 16.06°, and about 18.77°.

[0085] In some embodiments. Form C is further characterized by a PXRD pattern comprising significant peaks at 20 of about 20.63°, about 21 .53°, and about 23.35°.

[0086] In some embodiments, Form C is characterized by a PXRD pattern substantially as shown in FIG. 10.

[0087] In some embodiments. Form C is characterized by an IR spectra pattern comprising a significant peak at about 1587 cm-1.

[0088] In some embodiments, Form C is further characterized by an IR spectra pattern comprising a significant peak at about 1454 cm-1.

[0089] In some embodiments, Form C is further characterized by an IR spectra pattern comprising a significant peak at about 1638 cm-1.

[0090] In some embodiments. Form C is further characterized by an IR spectra pattern comprising significant peaks at about 1467 cm-1and at about 1474 cm-1.

[0091] In some embodiments. Form C is further characterized by an IR spectra pattern comprising significant peaks at about 3204 cm-1and at about 3464 cm-1.

[0092] In some embodiments, Form C is further characterized by an IR spectra pattern comprising significant peaks at about 1210 cm-1, at about 1254 cm-1, and at about 1314 cm-1.

[0093] In some embodiments. Form C is characterized by an IR spectrum substantially as shown in FIG. 11.

[0094] In some embodiments. Form C is characterized by a FT-Raman spectrum substantially as shown in FIG. 8.

[0095] In some embodiments. Form C is characterized by a DSC thermograms exhibiting a sharp endotherm at about 182.2°C.

[0096] In some embodiments, Form C is characterized by a DSC thermogram substantially as shown in FIG. 9.

[0097] In some embodiments. Form C is characterized by a water loss as measured by thermogravimetric analysis (TGA) of about 0.1 wt. %.

[0098] In some embodiments. Form C is characterized by a TGA spectrum substantially as shown in FIG. 9.

[0099] In some embodiments, wherein Form C is characterized by 0.5% water uptake as measured by gravimetric vapor sorption (GVS).

[0100] In some embodiments. Form C has a chemical purity of about 90%.

[0101] In some embodiments. Form C has a chemical purity of about 91%.

[0102] In some embodiments, Form C has a chemical purity of about 92%.

[0103] In some embodiments, Form C has a chemical purity of about 93%.

[0104] In some embodiments. Form C has a chemical purity of about 94%.

[0105] In some embodiments. Form C has a chemical purity of about 95%.

[0106] In some embodiments, Form C has a chemical purity of about 96%.

[0107] In some embodiments, Form C has a. chemical purity of about 97%.

[0108] In some embodiments. Form C has a chemical purity of about 98%.

[0109] In some embodiments. Form C has a chemical purity of about 99%.

[0110] In some embodiments. Form C has a chemical purity of about 99, 1 %.

[0111] In some embodiments. Form C has a chemical purity of about 99,2%.

[0112] In some embodiments. Form C has a chemical purity of about 99.3%.

[0113] In some embodiments, Form C has a chemical purity of about 99.4%.

[0114] In some embodiments, Form C has a chemical purity of about 99.5%.

[0115] In some embodiments, Form C has a chemical purity of about 99.6%.

[0116] In some embodiments. Form C has a chemical purity of about 99.7%.

[0117] In some embodiments. Form C has a chemical purity of about 99,8%.

[0118] In some embodiments. Form C has a chemical purity of about 99,9%.

[0119] In some embodiments. Form C has a chemical purity of about 99.99%.

[0120] The crystalline form of Compound 1 or a pharmaceutical composition prepared from the crystalline polymorph Form C of Compound 1 disclosed herein possesses useful ITK and / or JAK3 inhibiting activity and may be used in the treatment or prophylaxis of a disease or condition in which ITK and / or IAK3 plays an active role. Thus, embodiments are also directed to pharmaceutical compositions comprising the crystalline form disclosed herein or prepared from the crystalline form disclosed herein together with a pharmaceutically acceptable earner, as well as methods of making and using the crystalline Form C and compositions comprising the same. Certain embodiments are directed to methods for inhibiting ITK and / or JAK3. Other embodiments are directed to methods for treating an ITK and / or JAK3-mediated disorder in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of the crystalline form or composition prepared from the crystalline form disclosed herein according to the present, invention. Also provided is the use of the crystalline form disclosed herein in the manufacture of a medicament tor the treatment of a disease or condition ameliorated by the inhibition of ITK and / or JAK3.

[0121] Also provided are embodiments wherein any embodiment herein may be combined with any one or more of the other embodiments, unless otherwise stated and provided the combination is not mutually exclusive,

[0122] The crystalline form of embodiments herein may also refer to a salt thereof, an ester thereof, a free acid form thereof, a free base form thereof, a solvate thereof, a deuterated derivative thereof, a hydrate thereof, an N-oxide thereof, a clathrate thereof, a prodrug thereof, a polymorph thereof, a stereoisomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a mixture of stereoisomers thereof, a tautomer thereof, a mixture of tautomers thereof, or a combination of the foregoing of the compounds and crystalline forms of embodiments herein.

[0123] The crystalline form of Compound 1 described herein may contain a stereogenic center and may be chiral and thus exist as enantiomers. Where the compounds and crystalline forms according to embodiments herein possess two or more stereogenic centers, they may additionally exist as diastereomers. Embodiments herein includes all possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers. In some embodiments, the formulas are shown without a definitive stereochemistry at certain positions. Embodiments herein include all stereoisomers of such formulas and pharmaceutically acceptable salts thereof. Diastereomers may be separated by, for example, fractional crystallization from a suitable solvent, and pairs of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid or base as a resolving agent or on a chiral HPLC column. Further, any enantiomer or diastereomer of the crystalline form may be obtained by stereospecific or stereoselective synthesis using optically pure or enantioenriched starting materials or reagents of known configuration. The scope of embodiments herein as described and claimed encompasses the racemic forms of the compounds and crystalline forms as well as the individual enantiomers, diastereomers, and stereoisomer-enriched mixtures.

[0124] Suitable pharmaceutically acceptable acid addition salts of the crystalline form herein may be prepared from an inorganic acid or an organic acid. All of these salts may be prepared by conventional means from the corresponding compounds and crystalline forms of embodiments herein by treating, for example, the compounds and crystalline forms with the appropriate acid or base.

[0125] Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, phosphoric and diphosphoric acid; and organic acids, for example formic, acetic, trifluoroacetic, propionic, succinic, glycolic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, p-hydroxy butyric, malonic, galactic, galacturonic, citric, fumaric, gluconic, glutamic, lactic, maleic, malic, mandelic, mucic, ascorbic, oxalic, pantothenic, succinic, tartaric, benzoic, acetic, xinafoic (l-hydroxy-2-naphthoic acid), napadisilic (1,5- naphthalenedisulfonic acid) and the like.

[0126] The crystalline form herein may exist in both unsolvated and solvated forms. The term solvate is used herein to describe a molecular complex comprising the crystalline form herein and an amount of one or more pharmaceutically acceptable solvent molecules. The term hydrate is employed when said solvent is water. Examples of solvate forms include, but are not limited to, the crystalline Form C as disclosed herein in association with water, acetone, dichloromethane, tetrahydrofuran, 1,4-dioxane, n-butanol, 2-propanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. It is specifically contemplated that in embodiments herein one solvent molecule can be associated with one molecule of the crystalline form disclosed herein, such as a hydrate.

[0127] Furthermore, it is specifically contemplated that in embodiments herein, more than one solvent molecule may be associated with one molecule of the crystalline form, such as a dihydrate. Additionally, it is specifically contemplated that in embodiments herein less than one solvent molecule may be associated with one molecule of the crystalline form of embodiments herein, such as a hemihydrate. Furthermore, solvates of embodiments herein are contemplated as solvates of compounds and crystalline forms of embodiments herein that retain the biological effectiveness of the non-solvate form of the compounds and crystalline forms.

[0128] The compounds and crystalline forms disclosed herein can exist as and therefore include all stereoisomers, conformational isomers and mixtures thereof in all proportions as well as isotopic forms such as deuterated compounds and crystalline forms.

[0129] The compounds and crystalline forms disclosed herein can exist as therapeutically acceptable salts. The present invention includes compounds and crystalline forms listed above in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally bepharmaceutically acceptable. However, salts of non- pharmaceutically acceptable salts may be of utility in the preparation and purification of the compounds and crystalline forms in question. Basic addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).Pharmaceutical Compositions

[0130] Some embodiments herein are directed to a pharmaceutical composition comprising the crystalline form of Compound 1 or a pharmaceutical composition prepared from the crystalline polymorph Form C of Compound 1 and a pharmaceutically acceptable excipient.

[0131] Also provided is a pharmaceutical composition comprising the crystalline form of Compound 1 as disclosed herein or a pharmaceutical composition prepared from the crystalline polymorph Form C of Compound 1 as disclosed herein in a non-aqueous formulation, together with a pharmaceutically acceptable carrier or excipient.

[0132] In some embodiments, the pharmaceutical compositions for use in accordance with embodiments herein can be formulated in conventional manner using one or more physiologically acceptable carriers or excipients.

[0133] Also provided is a pharmaceutical composition comprising a crystalline form as disclosed herein, together with a pharmaceutically acceptable excipient.

[0134] In certain embodiments, the pharmaceutical composition may comprise about 0.01% to about 50% of the crystalline forms as disclosed herein. In some embodiments, the crystalline forms as disclosed herein is in an amount of about 0.01%to about 50%, about 0.01% to about 45%, about 0.01% to about 40%, about 0.01% to about 30%, about 0.01% to about 20%, about 0.01% to about 10%, about 0.01% to about 5%, about 0.05% to about 50%, about 0.05% to about 45%, about 0.05% to about 40%, about 0.05% to about 30%, about 0.05% to about 20%, about 0.05% to about 10%, about 0.1% to about 50%, about 0. 1% to about 45%, about 0.1% to about 40%, about 0.1 % to about 30%, about 0. 1 % to about 20%, about 0. 1 % to about 10%, about 0.1% to about 5%, about 0.5% to about 50%, about 0.5% to about 45%, about 0.5% to about 40%, about 0.5% to about 30%, about 0.5% to about 20%, about 0.5% to about 10%, about 0.5% to about 5%, about 1% to about 50%, about 1% to about 45%, about 1 % to about 40%, about 1 % to about 35%, about 1% to about 30%, about 1% to about 25%, about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, about 1% to about 5%,about 5% to about 45%, about 5% to about 40%, about 5% to about 35%, about 5% to about30%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, about 5% to about 10%, about 10% to about 45%, about 10% to about 40%, about 10% to about 35%, about 10% to about 30%, about 10% to about 25%, about 10% to about 20%, about 10% to about 15%, or a value within one of these ranges. Specific examples may include about 0.01%, about 0.05%, about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 5%, about 10%, about 15%, about 20%, about 2.5%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, or a range between any two of these values. The foregoing all representing weight percentages of the pharmaceutical composition.

[0135] In some embodiments, the crystalline forms as disclosed herein is in a therapeutically effective amount. In some embodiments, the therapeutically effective amount may be about 1 mg to about 1000 mg, about 1 mg to about 900 mg, about 1 mg to about 800 mg, about 1 mg to about 700 mg, about 1 mg to about 600 mg, about 1 mg to about 500 mg, about 1 mg to about 400 mg, about 1 mg to about 300 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, about 50 mg to about 1000 mg, about 100 mg to about 1000 mg, about 200 mg to about 1000 mg, about 300 mg to about 1000 mg, about 400 mg to about 1000 mg, about 500 mg to about 1000 mg, about 10 mg to about 500 mg, about 50 mg to about 500 mg, about 100 mg to about 500 mg, about 10 mg to about 300 mg, about 50 mg to about 300 mg, from about 100 mg to about 300 mg, about 10 mg to about 150 mg, about 50 mg to about 150 mg, about 60 mg to about 120 mg, about 50 mg to about 12.0 mg or a range between any two of these values. Specific examples include, for example, about 1000 mg, about 900 mg, about 800 mg, about 700 mg, about 750 mg, about 600 mg, about 500 mg, about 400 mg, about 450 mg, about 300 mg, about 250 mg, about 200 mg, about 175 mg, about 150 mg, about 125 mg, about 120 mg, about 110 mg, about 100 mg, about 90 mg, about 80 mg, about 70 mg, about 60 mg, about 50 mg, about 30 mg, about 20 mg, or any value between the ranges disclosed above.

[0136] While it may be possible for the crystalline forms as disclosed herein to be administered as the raw chemical, it is also possible to present them as a pharmaceutical composition. Accordingly, provided herein are pharmaceutical compositions which comprise the crystalline forms as disclosed herein, or a derivative thereof, together with one or more pharmaceutically acceptable excipients thereof and optionally one or more other therapeutic ingredients. The excipient(s) must be "acceptable" in the sense of being compatible with theother ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation of the pharmaceutical composition is dependent upon the route of administration chosen. Any of the well-known techniques and excipients may be used as suitable and as understood in the art. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, e.g. , by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0137] In some embodiments, the pharmaceutical compositions for use in accordance with embodiments herein can be formulated in conventional manner using one or more physiologically acceptable excipients.

[0138] When employed as pharmaceuticals, the crystalline forms as disclosed herein can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical arts, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration of the disclosed the crystalline forms as disclosed herein or compositions may be oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), pulmonary (e.g,, by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), intraperitoneal, intrathecal, intradural, transmucosal, transdermal, rectal, topical (including dermal, buccal, sublingual and intraocular), or intravaginal administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or injection or infusion; or intracranial, e.g. , intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions for topical administration may include foams, transdermal patches, ointments, lotions, creams, gels, solutions, fluid emulsions, fluid suspensions, semisolids, pastes, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Coated condoms, gloves and the like may also be useful. In some embodiments, the crystalline forms as di sclosed herein can be contained in such formulations pharmaceutical compositions with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like. The artisan can refer to various pharmacologic references for guidance. For example. Modem Pharmaceutics, 5th Edition,Banker & Rhodes, CRC Press (2009); and Goodman & Gilman's The Pharmaceutical Basis ofTherapeutics, 13th Edition, McGraw' Hill, New Y ork (2018) can be consulted.

[0139] In some embodiments, a method of treating an ITK-mediated disease comprises administering a crystalline forms as disclosed herein or a pharmaceutical composition of embodiments disclosed herein. In some embodiments, the crystalline forms as disclosed herein are m a therapeutically effective amount. In some embodiments, the therapeutically effective amount is an amount disclosed herein.

[0140] Some embodiments disclosed herein also include pharmaceutical compositions which contain, as the active ingredient, one or more of the crystalline forms as disclosed herein m combination with one or more pharmaceutically acceptable carriers (excipients).

[0141] In some embodiments, a method of making a pharmaceutical composition comprises mixing the active ingredient with an excipient, diluting the active ingredient using an excipient, or enclosing the active ingredient within a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium tor the active ingredient. Thus, the pharmaceutical compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active the crystalline forms as disclosed herein, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0142] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcry stall ine cellulose, polyvinylpyrrolidone, cellulose, water, syrup, crospovidone, silicon dioxide, and methyl cellulose, including eutectic solvents, eutectic-based ionic liquids, or ionic liquids. The pharmaceutical compositions can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; weting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy- benzoates; sweetening agents; and flavoring agents. The pharmaceutical compositions can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

[0143] lire pharmaceutical compositions can be formulated in a unit dosage form. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predetermined quantity' of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. The compositions include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, intrathecal, intradural, transmucosal, transdermal, rectal, intranasal, topical (including, for example, dermal, buccal, sublingual and intraocular), intravitreal, or mtravaginal administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The composition could include those suitable for administration by depot injections or by implants. Hie composition could include those suitable for administration by inhalation, such as, for example, a gas, vapor, or powder. The composition could include those suitable for administration, e.g., as an aerosol via a nebulizer, humidifier, inhaler and vaporizer or the like. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association the crystalline forms as disclosed herein or a derivative thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into die desired composition.

[0144] Compositions of the crystalline forms as disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary' or paste,

[0145] Pharmaceutical preparations which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing m a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powderedcrystalline forms as disclosed herein moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. Ail compositions for oral administration should be in dosages suitable for such administration. Hie push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the crystalline forms as disclosed herein may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of the crystalline forms as disclosed herein doses.

[0146] For preparing solid compositions such as tablets, the principal active ingredient can be mixed with a pharmaceutical excipient to form a solid pre -formulation composition containing a homogeneous mixture of the crystalline forms as disclosed herein of the present invention. When referring to these pre-formulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the pharmaceutical composition so that the pharmaceutical composition can be readily subdivided into equally therapeutically effective unit dosage forms such as tablets, pills and capsules. This solid pre-formulation is then subdivided into unit dosage forms of the type described above containing from, for example, about 0.1 to about 1000 mg of the active ingredient.

[0147] lire tablets or pills of the present invention can be coated or otherwise compounded to provi de a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which selves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used tor such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0148] The liquid forms in which the crystalline forms as disclosed herein and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0149] The crystalline forms as disclosed herein may be formulated for parenteral administration by injection, e.g. , by bolus injection or continuous infusion. Compositions for injection may be presented in unit dosage fonn, e.g., in ampoules or in multi-dose containers, with an added preservative. The pharmaceutical compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The compositions may be presented in unit-dose or multi-dose containers, tor example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid earner, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0150] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the crystalline forms as disclosed herein which may contain antioxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient: and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the crystalline forms as disclosed herein to allow for tire preparation of highly concentrated solutions.

[0151] In addition to the pharmaceutical compositions described previously, the crystalline forms as disclosed herein may also be formulated as a depot preparation. Such long-acting compositions may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the crystalline forms as disclosed herein may be formulated with suitable polymeric or hydrophobic materials (forexample as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0152] For buccal or sublingual administration, the pharmaceutical compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

[0153] The crystalline forms as disclosed herein may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa buter, polyethylene glycol, or other glycerides.

[0154] Certain crystalline forms as disclosed herein may be administered topically, that is by non-systemic administration. This includes the application of the crystalline forms as disclosed herein externally to the epidermis or the buccal cavity and the instillation of such the crystalline forms as disclosed herein into the ear, eye and nose, such that the crystalline forms as disclosed herein does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

[0155] In some embodiments, the pharmaceutical composition is suitable for topical administration. In some embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the composition is suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, intrathecal, intradural, transmucosal, transdermal, rectal, intranasal, topical (including, for example, dermal, buccal, sublingual and intraocular), intravitreal, or intravaginal administration.

[0156] In some embodiments, the crystalline forms as disclosed herein may be administered ophthalmically. In some embodiments, the crystalline forms as disclosed herein may be administered as an ophthalmic composition. The crystalline forms as disclosed herein may be administered as, for example, liquid preparations, including eye lotions, spray, or eye drops for topical administration. In some embodiments the crystalline forms as disclosed herein may be administered as semi-solid preparations, for example, applied to the eyelid, such as cream, lotion, gel, ointment, or paste. In some embodiments, the crystalline forms as disclosed herein may be administered as solid dosage forms, for example, applied to the eye surface to produce modified release, such as a powder. In some embodiments, the crystalline forms as disclosed herein are administered through devices for surgical implantation, parenteralproducts, (e.g., intracorneal or intravitreous products), liquids for irrigation, or the like. In some embodiments, the pharmaceutical composition comprising the crystalline forms as disclosed herein are sterile and free from particulate matters. In some embodiments, the crystalline forms as disclosed herein may be administered by intraocular injection, intraorbital injection, or an intravitreal injection. In some embodiments, the intraocular injection may be to the anterior chamber of the eye, posterior chamber of the eye, or a combination thereof. For example, the crystalline forms as disclosed herein may be administered to the posterior intraorbital region of the eye.

[0157] In some embodiments, pharmaceutical compositions suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as a solution, powder, fluid, emulsion, fluid suspension, semi-solid, gels, liniments, lotions, creams, ointment, paste, jelly, foam, and drops suitable for administration to the eye, ear or nose. The active ingredient for topical administration may comprise, for example, from 0.001 % to 10% w / w (by weight) of the composition. In certain embodiments, the active ingredient may comprise as much as 10% w / w. In other embodiments, it may comprise less than 5% w / w. In certain embodiments, the active ingredient may comprise from 2% w / w to 5% w / w. In other embodiments, it may comprise from 0.1% to 1% w / w of the composition.

[0158] Gels for topical or transdermal administration may comprise, generally, a mixture of volatile solvents, nonvolatile solvents, and water. In certain embodiments, the volatile solvent component of the buffered solvent system may include lower (C1-C6) alkyl alcohols, lower alkyl glycols and lower glycol polymers. In further embodiments, the volatile solvent is ethanol. The volatile solvent component is thought to act as a penetration enhancer, while also producing a cooling effect on the skm as it evaporates, lire nonvolatile solvent portion of the buffered solvent system is selected from lower alkylene glycols and lower glycol polymers. In certain embodiments, propylene glycol is used. The nonvolatile solvent slows the evaporation of the volatile solvent and reduces the vapor pressure of the buffered solvent system. The amount of this nonvolatile solvent component, as with the volatile solvent, is determined by the pharmaceutical compound or drug being used. When too little of the nonvolatile solvent is in the system, the pharmaceutical compound may crystallize due to evaporation of volatile solvent, while an excess may result m a lack of bioavailability due to poor release of drug from solvent mixture. The buffer component of the buffered solvent system may be selected fromany buffer commonly used in the art; in certain embodiments, water is used. A common ratio of ingredients is about 20% of the nonvolatile solvent, about 40% of the volatile solvent, and about 40% water. There are several optional ingredients which can be added to the topical composition. These include, but are not limited to, chelators and gelling agents. Appropriate gelling agents can include, but are not limited to, semisynthetic cellulose derivatives (such as hydroxypropylmethylcellulose) and synthetic polymers, and cosmetic agents.

[0159] Lotions include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and / or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.

[0160] Creams, ointments or pastes are semi-solid pharmaceutical compositions of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension m an aqueous or nonaqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base. The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel. The pharmaceutical composition may incorporate any suitable surface-active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicas, and other ingredients such as lanolin, may also be included.

[0161] Drops may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and / or fungicidal agent and / or any other suitable preservative, and, in certain embodiments, including a surface-active agent. The resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100 °C for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0,002%), benzalkonium chloride (0.01%) and cblorhexidine acetate (0.01%). Suitablesolvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol .

[0162] Pharmaceutical compositions for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.

[0163] For administration by inhalation, the crystalline forms as disclosed herein may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the crystalline forms as disclosed herein may take the form of a dry powder composition, for example a powder mix of the crystalline forms as disclosed herein and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.

[0164] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. "Die liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the pharmaceutical compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device, or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the composition in an appropriate manner.

[0165] In some embodiments, the pharmaceutical compositions administered to a patient can be in the form of pharmaceutical compositions described above. In some embodiments, these compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. In some embodiments, the pH of the preparations of the crystalline forms as disclosed herein is about 3to about 1 1, about 5 to about 9, about 5.5 to about 6.5, or about 5.5 to about 7.5. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

[0166] Preferred unit dosage pharmaceutical compositions are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.

[0167] It should be understood that, in addition to the ingredients particularly mentioned above, the pharmaceutical compositions described above may include other agents conventional in the art having regard to the type of pharmaceutical composition in question, for example those suitable for oral administration may include flavoring agents.

[0168] In some embodiments, the therapeutically effective amount can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the crystalline forms as disclosed herein, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the co. stall me forms as disclosed herein in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the crystalline forms as disclosed herein can be provided in an aqueous physiological buffer solution containing about 0. 1 to about 10% w / v of the crystalline forms as disclosed herein for parenteral administration. Some typical dose ranges for the crystalline forms as disclosed herein are from about 1 pg / kg to about 1 g / kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the crystalline forms as disclosed herein selected, composition of the excipient, and its route of administration. Effective doses can be extrapolated from doseresponse curves derived from in vitro or animal model test systems.

[0169] The amount of the crystalline forms as disclosed herein or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications.

[0170] The active crystalline forms as disclosed herein can be effective over a wide dosage range and can be generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the crystalline forms as disclosed herein actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual crystalline forms as disclosed herein administered, the age, weight, and response of the individual patient, the seventy of the patient's symptoms, and the like.

[0171] The crystalline forms as disclosed herein may be administered orally or via injection at a dose of from 0.1 to 500 mg / kg per day. The dose range for adult humans is generally from 5 mg to 2 g / day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of the crystalline forms as disclosed herein which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.

[0172] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0173] The crystalline forms as disclosed herein can be administered in various modes, e.g. orally, topically, or by injection. The precise amount of the crystalline forms as disclosed herein administered to a patient will be the responsibility of the attendant physician. The specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific crystalline forms as disclosed herein employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the indication or condition being treated. In addition, the route of administration may vary depending on tire condition and its severity.

[0174] The compositions can further include one or more additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant.Methods of Use

[0175] Some embodiments herein are directed to a method of modulation of an ITK- mediated function in a subject comprising the administration of a therapeutically effective amount of a crystalline form as disclosed herein , In some embodiments, a method of inhibitingITK in a subject comprises administering to the subject a crystalline form of embodiments herein.

[0176] Some embodiments are directed towards a method of treating an ITK-mediated or JAK3-mediated disorder in a subject in need thereof, comprising administering to the subject die crystalline polymorph as disclosed herein, in an amount effective to treat the ITK-mediated or JAK3 -mediated disorder.

[0177] The present invention also relates to a method of inhibiting at least one ITK function comprising the step of contacting ITK with a crystalline form as described herein. The cell phenotype, cell proliferation, activity of ITK, change in biochemical output produced by active ITK, expression of ITK, or binding of ITK with a natural binding partner may be monitored. Such methods may be modes of treatment of disease, biological assays, cellular assays, biochemical assays, or the like.

[0178] The crystalline form of the present invention may be useful as JAK3 kinase inhibitors as well as inhibitors of ITK. This dual use of a single crystalline form inhibiting either ITK or JAK3 pathways individually or both pathways simultaneously may lead to a beneficial effect. As a result, the crystalline form of the present invention may find utility in treating a broad range of diseases or conditions mediated by ITK activity, JAK3 activity, or both. Accordingly, some embodiments herein are directed to treatment or prophylaxis of a disease or condition in which JAK, particularly JAK3, plays an active role using the crystalline form disclosed herein. In some embodiments, a method of treating a JAK3-mediated disease or disorder in a subject comprises administering to the subject a crystalline form of embodiments herein. Some embodiments provide methods for treating a JAK3-mediated disorder in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a crystalline form or composition according to the present disclosure. Also provided is the use of crystalline form disclosed herein for use in the manufacture of a medicament for the treatment of a disease or condition ameliorated by the inhibition of JAK3, ITK, or a combination thereof. Embodiments discussed herein which are directed to methods of treatment of ITK-mediated conditions or diseases may also apply to methods of treatment for JAK3-mediated conditions or diseases.

[0179] Also provided herein is a method of treating an ITK-mediated or J AK3 -mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of a crystalline form as disclosed herein, a derivative thereof, or a combination thereof. Incertain embodiments, the therapeutically effective amount of a crystalline form as disclosed herein, a derivative thereof, or a combination thereof, may be in tire form of a pharmaceutical composition. In embodiments, the pharmaceutical composition may include a pharmaceutically acceptable excipient.

[0180] Also provided herein is a method of inhibiting ITK or JAK3 activity in a population of cells, said method comprising: administering, to a population of cells, one or more crystalline forms as disclosed herein, a derivative thereof, or a combination thereof, in an amount effective to inhibit ITK or JAK3 activity in the population of cells. In some embodiments the population of cells is a population of human cells.

[0181] In some embodiments, the present invention provides a method for treating an ITK- mediated or JAK3 -mediated disease or disorder in a patient in need thereof, wherein said method comprises administering to said patient a therapeutically effective amount of a crystalline form of embodiments herein, or composition thereof. Such ITK-mediated diseases or disorders include, but are not limited to, those described herein.

[0182] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is an autoimmune disorder, a chronic and / or acute inflammatory disorder, and / or auto- inflammatory disorder. Exemplary autoimmune and / or inflammatory and / or autoinflammatory disorders include: arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic-onset juvenile rheumatoid arthritis, systemic onset juvenile idiopathic arthritis, Still’s disease, adultonset Still's disease, seronegative spondyloarthropathies, osteoarthritis, enthesitis, enthesopathy, infectious arthritis, Lyme disease, inflammatory arthritis, inflammatory’ bowel disease-associated arthritis, myositis, autoimmune myositis, carditis, myocarditis, dermatomyositis, juvenile dermatomyositis, idiopathic arthritis, juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, ankylosing spondylitis, gout, scleroderma, juvenile scleroderma, Reiter’s syndrome, spondylitis, spondyloarthritis, spondyloarthropathy, lupus, systemic lupus erythematosus (SLE), pediatric systemic lupus erythematosus, cutaneous lupus, subacute cutaneous lupus, chronic cutaneous lupus, discoid lupus, psoriatic arthritis, reactive arthritis, Sjogren’s syndrome, polymyositis, polymyalgia rheumatica, mixed connective tissue disease, vasculitis, large vessel vasculitis, small vessel vasculitis, vasculitis syndromes including Takayasu’s arteritis, Wegener’s granulomatosis, giant-cell arteritis, polyarteritis nodosa, sarcoidosis, familial Mediterranean fever, a cryopyrin-associated periodic syndrome (e.g), Muckle-Wells syndrome, familial cold auto-inflammatory syndrome, neonatal-onsetmultisystem inflammatory disease, TNF receptor-associated periodic syndrome; gastrointestinal disorders (e.g.) inflammatory bowel disease, irritable bowel syndrome, spastic colon, Crohn’s disease, ulcerative colitis, acute and chronic pancreatitis, celiac disease, primary biliary cirrhosis, primary sclerosing cholangitis, periodontitis, gingivitis, esophagitis, gastritis, eosinophilic gastritis, gastric and duodenal ulcers, peritonitis, periodontitis, enteritis, colitis; pulmonary-respiratory disorders (e.g. ) pulmonary inflammation, sinusitis, rhinitis, pneumonia, bronchitis, pulmonary' fibrosis, idiopathic pulmonary' fibrosis, asthma, allergic asthma, eosinophilic asthma, bronchial asthma, Churg-Strauss syndrome, bronchiolitis, bronchiolitis obliterans, chronic obstructive pulmonary disease (COPD), interstitial lung disease; endocrinologic disorders (e.g.) diabetes. Type 1 diabetes, Hashimoto’s thyroiditis. Graves' disease, Addison’s disease; autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia; neurological / neuromuscular disorders (e.g), neurodegenerative disorders, multiple sclerosis Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), familial ALS, Alzheimer's disease, myasthenia gravis (Lambert-Eaton myasthenic, syndrome (LEMS)), Guillain-Barret syndrome, meningitis, encephalitis, traumatic brain injury'; nephropathies including (e.g.) immunologically mediated glomerulonephropathy, autoimmune nephropathy, membranous glomerulopathy, chronic progressive nephropathies, diabetic, nephropathy, renal fibrosis, ischemic / reperfusion injury associated, HIV -associated nephropathy, ureteral obstructive nephropathy, glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidney disease, autosomal dominant polycystic kidney disease, diabetic kidney disease; ocular disorders including, (e.g.), dry eye, uveitis, keratoconjunctivitis sicca, scleritis, episcleritis, keratitis, keratopathy, chorditis, retinal vasculitis, optic neuritis, retinopathy, diabetic retinopathy, immune -mediated retinopathy, macular degeneration, wet macular degeneration, dry (age- related) macular degeneration, and ocular malignancies; allergy and allergic reactions including hypersensitivity reactions such as Type I hypersensitivity reactions, (e.g. including anaphylaxis). Type II hypersensitivity reactions (e.g. Goodpasture’s Disease, autoimmune hemolytic anemia), Type III hypersensitivity reaction diseases (e.g. the Arthus reaction, serum sickness), and Type IV hypersensitivity reactions (e.g. contact dermatitis, allograft rejection); disorders of fibrosis and scarring(e.g.), hepatic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, low grade scarring such as, scleroderma, increased fibrosis, keloids, post-surgical scars; dermatologic disorders (e.g.), psoriasis, atopy, atopic dermatitis, acne, acne vulgaris, cornedonal acne, inflammatory acne, nodulo-cystic acne, scarring acne, acne keloidalis nuchae, hidradenitis suppurativa, neutrophilic dermatoses, pyoderma gangrenosum, acute febrile neutrophilic dermatosis (Sweet’s syndrome), erythema elevatinum diutinum (EED), neutrophilic eccrine hidradenitis, histiocytoid neutrophilic dermatosis, bowel-bypass syndrome dermatosis, Behcet’s disease, palisading neutrophilic granulomatous dermatitis neutrophilic urticarial dermatosis, alopecia, nonscarring alopecia, alopecia areata (AA), including patchy AA, alopecia totalis (AT), alopecia universalis (AU), androgenetic alopecia (AGA), male and female pattern AGA, ophiasis pattern alopecia areata, sisaihpo pattern alopecia areata, telogen effluvium, tinea capitis, hypotrichosis, hereditary hypotrichosis simplex, scarring alopecia, lichen planopilaris, central centrifugal cicatricial alopecia, frontal fibrosing alopecia, eyebrow alopecia, intranasal hair alopecia; vitiligo including segmental vitiligo, unisegmental, bisegmental or multisegmental vitiligo, non-segmental vitiligo including acral, facial, or acrofacial vitiligo, centrofacial vitiligo, mucosal vitiligo, confetti vitiligo, trichrome vitiligo, marginal inflammatory vitiligo, quadrichrome vitiligo, blue vitiligo, Koebner phenomenon, vulgaris vitiligo, generalized vitiligo, universal vitiligo, mixed vitiligo (nonsegmental associated with segmental vitiligo), focal vitiligo, solitary mucosal vitiligo or vitiligo with or without leukotricia (involvement of body hair); immunobullous diseases such as (e.g.), bullous pemphigoid, cicatricial pemphigoid, pemphigus vulgaris, linear IgA disease; dermatologic drug reactions, and pruritus (itch) including (e.g.), atopic pruritus, xerotic pruritus, pruritus associated with psoriasis (“psoriatic itch”), acute pruritus, chronic pruritus, idiopathic pruritus, chronic idiopathic itch, hepatobiliary-associated itch, renal associated itch, lichen simplex chronicus associated pruritus, prurigo nodularis. Type II diabetes, hypophysitis, idiopathic thrombocytopenic purpura, metal-induced autoimmunity, autoimmune deafness (including, for example, Meniere's disease), interstitial cystitis, enterocolitis, ocular inflammation, non-small cell lung carcinoma, small cell lung carcinoma, skin cancer, organ transplant rejection, bone marrow transplant rejection, graft vs. host reaction (for example, graft vs. host disease), allograft rejections (for example, acute allograft rejection or chronic allograft rejection), early transplantation, diabetes, a myeloproliferative disorder, a rejection (for example, acute allograft rejection); bone resorption diseases, asthma (e.g., bronchial asthma), atopy, autoimmune thyroid disorders, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE Syndrome), SA VI (stimulator ofinterferon genes (STING) associated vasculopathy with onset in infancy), nephropathies, myocarditis, secondary hematologic manifestations of autoimmune diseases (for example, anemias), autoimmune hemolytic syndromes, autoimmune and inflammatory hepatitis, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, silicone implant associated autoimmune disease, drug-induced autoimmunity, HIV -related autoimmune syndromes; acute and chronic infection, sepsis syndromes (e.g.) sepsis, septic shock, endotoxic shock, exotoxin-induced toxic shock, Gram-negative sepsis, Gram-positive sepsis, fungal sepsis, toxic shock syndrome; hyperoxia induced inflammations, reperfusion inj ury, post-surgical trauma, tissue injury, pain (e.g. ) acute pain, chronic pain, neuropathic pain, or fibromyalgia, autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, auto-inflammatory disorders, fibrotic disorders, metabolic disorders, neoplasias, or cardiovascular or cerebrovascular disorders, a skin disorder, pruritus, a hair loss disorder, a cancer, a neoplasm, an inflammatory condition, connective tissue diseases and an autoimmune condition, a neoplasm, a malignancy, a myeloproliferative disorder, a hematopoietic neoplasm, a myeloid neoplasm, a lymphoid neoplasm, including myelofibrosis, primary' myelofibrosis, polycythemia vera, essential thrombocythemia, acute and chronic leukemias, lymphomas, cutaneous lymphomas including mycosis fungoides, other myeloid malignancies, and myelodysplastic syndrome, atopic dermatitis, psoriasis, psoriasis vulgaris, skin sensitization, skin irritation, skin rash, contact dermatitis, allergic contact sensitization, allergic dermatitis, inflammatory dermatoses, neutrophilic dermatoses, pruritis, atopic itch, atopic dermatitis- associated itch, autoimmune responses, autoimmune connective tissue disease, bacterial infection, biliary' itch, broad activation of the immune responses, body louse, bullous diseases, brachioradial pruritus, brain tumors, chronic idiopathic pruritus, contact dermatitis, cholestasis, cutaneous larva migrans, cutaneous T-cell lymphoma, nervous system damage, dandruff, delusional parasitosis, dermatomyositis, dermatosis of pregnancy, diabetes mellitus, drag eruptions, dysregulation of neuronal processes and sensory' perception, eczema, eosinophilic folliculitis, foreign objects or devices on skin, fungal infection, gestational pemphigoid, head lice, herpes, hidradenitis suppurativa, pyoderma gangrenosum, hives, Hodgkin’s disease, hyperparathyroidism, idiopathic chronic itch, inflammation, insect infestation, insect bites, insect stings, intrahepatic cholestasis of pregnancy, iron deficiency anemia, increased accumulation of exogenous opioids or synthetic opioids, internal cancer, jaundice, lichen planus, lichen sclerosus, lupus erythematosus, lymphoma, lymphoma-associated itch.leukemia-associated itch, malignancy, mastocytosis, menopause, multiple sclerosis, neoplasm, nerve irritation, neurogenic itch, neuropathic itch, notalgia paresthetica, notalgia obsessive- compulsive disorders, paresthetica, parasitic infection, popular uritcariaurticaria, pediculosis, peripheral neuropathy, photodermatitis, polycythemia vera, psychiatric disease, psychogenic itch, pruritic popular eruption of HIV, pruritic urticarial papules and plaques of pregnancy (PUPP), psoriasis-associated itch, psoriatic itch, pubic lice, punctate palmoplantar keratodenna, renal itch, rheumatoid arthritis, scabies, scar growth, shaving, seborrheic dermatitis, stasis dermatitis, sunburn, swimmer’s itch, systemic immune senescence, tactile hallucinations, Thl7-associated inflammation, thyroid illness, uremia, uremic itch, urticaria, urticarial itch, varicella, viral infection, wound or scab healing, xerosis, chilblain lupus erythematosus, polychondritis, relapsing polychondritis, an immunologically mediated nephropathy, prostate cancer, renal cancer, hepatic cancer, breast cancer, thyroid cancer, Kaposi's sarcoma, Castleman's disease, pancreatic cancer, lymphoma, leukemia, multiple myeloma, polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), systemic mast cell disease (SMCD), systemic sclerosis / scleroderma, lupus nephritis, wound healing, surgical scarring, spinal cord injury', CNS scarring, acute lung injury, cystic fibrosis, adult respiratory distress syndrome, acute lung injury, drag-induced lung injury, glomerulonephritis, chronic kidney disease (for example, diabetic nephropathy), hypertension-induced nephropathy, alimentary’ track or gastrointestinal fibrosis, hepatic or biliary' fibrosis, liver fibrosis (for example, nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma), cirrhosis (for example, primary biliary cirrhosis or cirrhosis due to fatty liver disease (for example, alcoholic and nonalcoholic steatosis)), radiation-induced fibrosis (for example, head and neck, gastrointestinal or pulmonary-'), primary sclerosing cholangitis, restenosis, cardiac fibrosis (for example, endomyocardial fibrosis or atrial fibrosis), ophthalmic scarring, fibrosclerosis, fibrotic cancers, fibroids, fibroma, fibroadenomas, fibrosarcomas, transplant arteriopathy, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, obesity, steroid-resistance, glucose intolerance, metabolic syndrome, angiogenesis disorders, multiple myeloma, leukemias (for example, acute lymphocytic leukemia, acute and chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, orpromyelocytic leukemia), lymphomas (for example, B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkit's lymphoma, mast cell tumors, Hodgkin's disease or non-Hodgkin's disease), myelodysplastic syndrome, fibrosarcoma, rhabdomyosarcoma; astrocytoma, neuroblastoma, glioma and schwannomas; melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid follicular cancer, Kaposi's sarcoma, melanoma, teratoma, rhabdomyosarcoma, metastatic and bone disorders, as well as cancer of the bone, moudi / pharynx, esophagus, larynx, stomach, intestine, colon, rectum, liver, nerve, brain (for example, glioma or glioblastoma multiforme), head and neck, throat, ovary, uterus, testis, bladder, kidney, gall bladder, cervix, atherosclerosis, restenosis of an atherosclerotic coronary artery, acute coronary syndrome, myocardial infarction, cardiac -allograft vasculopathy, stroke, spinal cord injury’, neuronal ischemia, and peripheral neuropathy.

[0183] In some embodiments, diseases or disorders associated with an ITK kinase or a JAK3 kinase that are treated by one or more crystalline forms of the present invention include autoimmune disorders, immune-mediated disorders, chronic inflammatory disorders, acute inflammatory disorders, and / or auto-inflammatory disorders.

[0184] In some embodiments, the ITK-mediated or J AK3 -mediated disease or disorder is arthritis and arthropathies. Arthritis and arthropathies include but are not limited to: idiopathic arthritis; osteoarthritis; rheumatoid arthritis; juvenile idiopathic arthritis; systemic-onset juvenile idiopathic arthritis; adult-onset Still’s disease; seronegative spondyloarthropathies; spondyloarthropathy; ankylosing spondylitis; spondylitis; spondyloarthritis; enthesitis; enthesopathy; psoriatic arthritis; reactive arthritis; inflammatory’ arthritis; inflammatory bowel disease-associated arthritis; cystic fibrosis associated arthritis; gout; Reiter’s syndrome; and Lyme-associated arthritis.

[0185] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is myositis and inflammatory myopathies. Myositis and inflammatory- myopathies include but are not limited to: autoimmune myositis; dermatomyositis; polymyositis; and juvenile dermatomyositis .

[0186] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is scleroderma. Scleroderma include but is not limited to: systemic sclerosis / scleroderma; progressive systemic sclerosis; CREST syndrome (calcinosis; raymauds; esophageal dysfunction; sclerodactyly; telangiectasias); systemic sclerosis sine scleroderma; localizedscleroderma; morphea; linear scleroderma; en coup de sabre scleroderma; and juvenile scleroderma.

[0187] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is lupus. Lupus includes but is not limited to: systemic lupus erythematosus; pediatric systemic lupus erythematosus; cutaneous lupus; subacute cutaneous lupus; chronic cutaneous lupus; discoid lupus; lupus erythematosus; chilblain lupus erythematosus; and lupus-associated specific organ manifestations (e.g., lupus nephritis; lupus arthritis; CNS lupus; etc.).

[0188] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is an autoinflammatory condition. Autoinflammatory conditions include but are not limited to: VEXAS syndrome; Muckle-Wells syndrome; familial cold auto-inflammatory syndrome; neonatal -onset multisystem inflammatory disease (NOMID); TNF -receptor associated periodic syndrome (TRAPS); familial Mediterranean fever; cryopyrin-associated periodic syndrome (CAPS); auto-inflammatory disorders; and hyper IgD syndrome / mevalonate kinase deficiency.

[0189] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is vasculitis. Vasculitis includes but is not limited to: large vessel vasculitis; medium vessel vasculitis; small vessel vasculitis; ANCA+ vasculitis; ANCA negative vasculitis; Takayasu’s arteritis; Wegener’s granulomatosis; giant-cell arteritis; polyarteritis nodosa; and Kawasaki Disease.

[0190] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is a gastrointestinal and / or a liver disorder. Gastrointestinal and liver disorders include but are not limited to: enteritis; colitis; enterocolitis; gastritis; esophagitis; inflammatory’ bowel disease; Crohn’s disease; ulcerative colitis; irritable bowel syndrome; spastic colon; acute and chronic pancreatitis; celiac disease; periodontitis; gingivitis; eosinophilic gastritis; gastric and duodenal ulcers; peritonitis; autoimmune atrophic gastritis of pernicious anemia; alimentary track or gastrointestinal fibrosis; primary biliary cholangitis; primary sclerosing cholangitis; hepatic or biliary fibrosis; liver fibrosis (secondary' to, for example, nonalcoholic steatohepatitis; hepatitis C; or hepatocellular carcinoma); cirrhosis (secondary to, for example, primary biliary cholangitis or cirrhosis due to fatty liver disease (for example, alcoholic and nonalcoholic steatosis); autoimmune and inflammatory hepatitis / liver disease; cholestasis; cholestatic liver injury / disease; and intrahepatic cholestasis of pregnancy.

[0191] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is a pulmonary-respiratory’ disorder. Pulmonary-respiratory' disorders include but are not limitedto: pulmonary' inflammation; sinusitis; rhinitis; pneumonia; bronchitis; pulmonary fibrosis; idiopathic pulmonary fibrosis; asthma; bronchial asthma; allergic asthma; eosinophilic asthma; bronchial asthma; Churg-Strauss syndrome; bronchiolitis; bronchiolitis obliterans; chronic obstructive pulmonary disease (COPD); interstitial lung disease); acute lung injury; adult respiratory distress syndrome; drag-induced lung injur. . and autoimmune interstitial lung disease.

[0192] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is an endocrine and / or a metabolic disorder. Endocrine and metabolic disorders include but are not limited to: diabetes mellitus; diabetes; Type I diabetes; autoimmune thyroid disorders; Hashimoto's thyroiditis; Graves' disease; Addison’s disease; autoimmune ovarian failure; obesity; steroid-resistance; glucose intolerance; metabolic syndrome; metabolic bone disorders; thyroid illness; metabolic disorders; hyperparathyroidism; and menopause.

[0193] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is a hematologic disorder. Hematologic disorders include but are not limited to: autoimmune hemolytic syndromes; autoimmune hemolytic anemia; autoimmune thrombocytopenia; secondary hematologic manifestations of autoimmune diseases (e.g., anemias); polycythemia vera; essential thrombocythemia; iron deficiency anemia; myeloid metaplasia with myelofibrosis (MMM); primary myelofibrosis (PMF); and immune-mediated bone marrow failure disorders.

[0194] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is a neurologic disorder and / or a psychiatric disorder. Neurologic disorders and psychiatric disorders include but are not limited to: autoimmune encephalomyelitis; PANDA syndrome; neuromuscular disorders; neurodegenerative disorders; multiple sclerosis; Parkinson's disease; Huntington's disease; amyotrophic lateral sclerosis (ALS); familial ALS; Alzheimer's disease; myasthenia gravis Lambert-Eaton myasthenic syndrome (LEMS); Guillain-Barre syndrome; meningitis; encephalitis; traumatic brain injury; stroke; spinal cord injury; neuronal ischemia; peripheral neuropathy; CNS scarring; nerve irritation; nervous system damage; dysregulation of neuronal processes and sensory' perception; peripheral neuropathy; psychogenic itch; tactile hallucinations; paresthetica; cerebrovascular disorders; delusional parasitosis; notalgia obsessive-compulsive disorders; transverse myelitis; optic neuritic; and neuromyelitis optic.

[0195] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is a renal disease. Renal diseases include but are not limited to: nephropathies; IgA nephropathy;immunologically mediated glomerulonephropathy; autoimmune nephropathy; membranous glomerulopathy; chronic progressive nephropathies; diabetic nephropathy; renal fibrosis; ischemic / reperfusion injury associated; HIV-associated nephropathy; ureteral obstructive nephropathy; glomerulosclerosis; nephrotic syndrome; proteinuria; polycystic kidney disease; autosomal dominant polycystic kidney disease; diabetic kidney disease; nephritis; glomerulonephritis; diffuse proliferative glomerulonephritis; focal segmental glomerulonephritis; membranous glomerulonephritis; lupus glomerulonephritis; immune complex glomerulonephritis; fibrillary glomerulonephritis; chronic kidney disease; diabetic nephropathy; hypertension-induced nephropathy; an immunologically mediated nephropathy; uremia; and glomerulosclerosis disorders.

[0196] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is an ocular disorder. Ocular disorders include but are not limited to: dry eye; anterior uveitis; posterior uveitis; acute uveitis; chronic uveitis; keratoconjunctivitis sicca; scleritis; episcleritis; keratitis; keratopathy; chorditis; retinal vasculitis; optic neuritis; retinopathy; diabetic retinopathy; immune-mediated retinopathy; macular degeneration; wet macular degeneration; dry (age related) macular degeneration; ocular malignancies; ocular inflammation; ophthalmic scarring; and sympathetic ophthalmia.

[0197] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is an allergy and / or an allergic reaction. Allergy and allergic reactions include but are not limited to: atopy; hypersensitivity reactions such as Type I hypersensitivity reactions including anaphylaxis; Type II hypersensitivity’ reactions including Goodpasture’s Disease and autoimmune hemolytic anemia; Type III hypersensitivity reaction diseases including the Arthus reaction and serum sickness; and Type IV hypersensitivity reactions including contact dermatitis; and allograft rejection.

[0198] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is dermatologic condition. Dermatologic condi tions include but are not limited to: a skin disorder; atopy; atopic dermatitis; eczema; contact dermatitis; allergic contact sensitization; allergic dermatitis; acne; acne vulgaris; comedonal acne; inflammatory acne; nodulo-cystic acne; scarring acne; acne keloidalis nuchae; hidradenitis suppurativa; neutrophilic dermatoses; pyoderma gangrenosum; acute febrile neutrophilic dermatosis (Sweet’s syndrome); erythema elevatinum diutinum (EED); neutrophilic eccrine hidradenitis; histiocytoid neutrophilic dermatosis; bowel-bypass syndrome dermatosis; palisading neutrophilic granulomatousdermatitis; neutrophilic urticarial dermatosis; chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE Syndrome); a hair loss disorder; alopecia; nonscarring alopecia; alopecia areata (AA); patchy AA; alopecia totalis (AT); alopecia universalis (AU); androgenetic alopecia (AGA); male and female pattern AGA; ophiasis pattern alopecia areata; sisaihpo pattern alopecia areata; telogen effluvium; tinea capitis; hypotrichosis; hereditary hypotrichosis simplex; scarring alopecia; lichen planopilaris; central centrifugal cicatricial alopecia; frontal fibrosing alopecia; eyebrow alopecia; intranasal hair alopecia; vitiligo; segmental vitiligo; unisegmental; bisegmental or multisegmental vitiligo; non-segmeirtal vitiligo including acral; facial; or acrofacial vitiligo; centrofacial vitiligo; mucosal vitiligo; confetti vitiligo; trichrome vitiligo; marginal inflammatory vitiligo; quadrichrome vitiligo; blue vitiligo; Koebner phenomenon; vulgaris vitiligo; generalized vitiligo; universal vitiligo; mixed vitiligo (non segmental associated with segmental vitiligo); focal vitiligo; solitary mucosal vitiligo or vitiligo with or without leukotricia (involvement of body hair); bullous diseases; immunobullous diseases; bullous pemphigoid; cicatricial pemphigoid; pemphigus vulgaris; linear IgA disease; dermatologic drug reactions; idiopathic chronic itch; pruritus (itch) conditions; atopic pruritus; atopic dermatitis-associated itch; xerotic pruritus; pruritus associated with psoriasis (“psoriatic itch”); acute pruritus; chronic pruritus; idiopathic pruritus; brachioradial pruritus; neurogenic itch; neuropathic itch; chronic idiopathic pruritus; hepatobiliary-associated itch; biliary itch; renal-associated itch; uremic itch; lichen simplex chronicus associated pruritus; prurigo nodularis; Type II diabetes- associated itch; hypophysitis-associated itch; idiopathic thrombocytopenic purpura-associated itch; pruritic urticarial papules and plaques of pregnancy (PUPP); swimmer’s itch; lymphoma- associated itch; leukemia-associated itch; eruption of HIV; punctate palmoplantar keratoderma; psoriasis; psoriasis vulgaris; skin sensitization; skin irritation; skin rash; inflammatory dermatoses; drag eruptions; dermatosis of pregnancy; eosinophilic folliculitis; foreign objects or devices on skin; fungal infection of the skin; gestational pemphigoid; dandruff; photodermatitis; scar growth; seborrheic dermatitis; stasis dermatitis; sunburn; hives; urticaria; urticarial itch; papular urticaria; chronic idiopathic urticaria; chronic urticaria; wound healing; wound or scab healing; surgical scarring; lichen planus; lichen sclerosis; insect bites; insect stings; notalgia paresthetica; and xerosis.

[0199] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is an infection and / or an infestation. Infections and infestations include but are not limited to:acute and chronic infection; sepsis syndromes; sepsis; septic shock; endotoxic shock; exotoxin- induced toxic shock; Gram-negative sepsis; Gram-positive sepsis; fungal sepsis; toxic shock syndrome; bacterial infection; body louse; pruritic popular pubic lice; head lice; herpes; cutaneous larva migrans; scabies; varicella; viral infection; parasitic infection; pediculosis; insect infestation; infectious arthritis; and Lyme disease.

[0200] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is an oncologic condition. Oncologic conditions include but are not limited to: a cancer; neoplasias; internal cancer; malignancy; a myeloproliferative disorder; a hematopoietic neoplasm; a myeloid neoplasm; a lymphoid neoplasm; non-smail cell lung carcinoma; small cell lung carcinoma; skin cancer; a myeloproliferative disorder; myelodysplastic syndrome; leukemias (e.g., acute and chronic leukemias; acute lymphocytic leukemia; acute and chronic myelogenous leukemia; chronic lymphocytic leukemia; acute lymphoblastic leukemia; or promyelocytic leukemia; chronic myelomonocytic leukemia); lymphomas (e.g., B-cell lymphoma; T-cell lymphoma; mantle cell lymphoma; hairy cell lymphoma; Burkitt’s lymphoma; mast cell tumors; Hodgkin’s disease or non-Hodgkin’s disease; cutaneous lymphomas including mycosis fungoides and cutaneous T-cell lymphoma; myeloid malignancies; myelodysplastic syndrome; fibrosarcoma; rhabdomyosarcoma; brain and nervous system tumors (e.g. , glioma or glioblastoma multiforme; astrocytoma; neuroblastoma; glioma; schwannomas; retinoblastoma) melanoma; seminoma; teratoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoacanthoma; thyroid cancer; thyroid follicular cancer; Kaposi's sarcoma; prostate cancer; renal cancer; hepatic / hepatobiliary cancer; breast cancer; pancreatic cancer; multiple myeloma; cancer of the bone; mouth / pharynx; esophagus; larynx; stomach; intestine; colon; rectum; liver; nerve; head and neck; throat; ovary; uterus; testis; bladder; kidney; gall bladder; cervix; fibrotic cancers; fibroids; fibroma; fibroadenomas; fibrosarcomas; metastatic bone disorders and lesions.

[0201] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is a transplant-related treatment or preventative measure. Transplant-related treatments or preventative measures include but are not limited to: prevention or treatment of organ transplant rejection; prevention or treatment of bone marrow transplant rejection; graft vs. host reaction; graft vs. host disease; chronic graft versus host disease; acute graft vs host disease; allograft rejections; acute allograft rejection; and chronic allograft rejection.

[0202] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is a cardiovascular disorders Cardiovascular disorders include but are not limited to: atherosclerosis; restenosis; restenosis of an atherosclerotic coronary artery; acute coronary syndrome; myocardial infarction; cardiac -allograft vasculopathy; cardiac fibrosis; endomyocardial fibrosis; atrial fibrosis; recurrent pericarditis; chronic pericarditis; myocarditis; carditis; myocarditis; and angiogenesis disorders.

[0203] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is pain disorder (e.g., acute pain; chronic pain; neuropathic pain; or fibromyalgia).

[0204] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is a fibrotic disorder. Fibrotic disorders include but are not limited to: disorders of fibrosis and scarring (e.g., hepatic fibrosis; pulmonary fibrosis; idiopathic pulmonary fibrosis; low grade scarring such as; scleroderma; increased fibrosis; keloids; post-surgical scars); myelofibrosis; primary myelofibrosis; idiopathic myelofibrosis (IMF); radiation-induced fibrosis (e.g., head and neck; gastrointestinal or pulmonary'); fibrosclerosis; mediastinal fibrosis; retroperitoneal fibrosis; progressive massive fibrosis; and nephrogenic systemic fibrosis.

[0205] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is an inflammatory condition.

[0206] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is inflammation; an inflammatory condition; chronic inflammatory disorders; acute inflammatory disorders; connective tissue diseases; autoimmune conditions / disorders / responses; autoimmune connective tissue disease; Sjogren’s syndrome; mixed connective tissue disease; polymyalgia rheumatica; sarcoidosis; autoimmune orchitis; Goodpasture's disease; Behcet’s disease; metal-induced autoimmunity; autoimmune deafness (including, for example, Meniere's disease); interstitial cystitis; polychondritis; relapsing polychondritis; autoimmune orchitis; silicone implant-associated autoimmune disease; drug-induced autoimmunity; HIV- related autoimmune syndromes; broad activation of the immune responses; bone resorption diseases; SAVI (stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy); hyperoxia-induced inflammations; reperfusion injury ; post-surgical trauma; tissue injury ; cystic fibrosis; Th17-associated inflammation; increased accumulation of exogenous opioids or synthetic opioids; jaundice; mastocytosis; Castleman's disease; systemic immune senescence; transplant arteriopathy; hypereosinophilic syndrome (HES); systemic mast cell disease (SMCD); and macrophage activation syndrome.

[0207] In some embodiments, the ITK-mediated or JAK3-mediated disease is selected from the group consisting of atopic dermatitis, palmoplantar pustulosis, fibrosing interstitial lung disease, peripheral T-cell lymphoma. Celiac disease, asthma, cryopyrin-associated periodic syndrome (CAPS), recurrent pericarditis, VEXAS syndrome, ulcerative colitis, acute severe ulcerative colitis, Crohn’s disease, inflammatory bowel disease, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acute inflammatory psoriasis, genital psoriasis, autoimmune hepatitis, systemic lupus erythematosus (SEE), organ transplant rejection, chronic graft versus host disease (cGvHD), primary' sclerosing cholangitis, or a combination thereof.

[0208] In some embodiments, the inflammatory condition is selected from the group consisting of a chronic inflammatory' condition, an acute inflammatory condition, an immuno- inflammatory' condition, an autoimmune inflammatory condition, an inflammasomopathy, or a combination thereof.

[0209] In some embodiments, the inflammatory condition is selected from the group consisting of atopic dermatitis, palmoplantar pustulosis, fibrosing interstitial lung disease, peripheral T-cell lymphoma, Celiac disease, asthma, cryopyrin-associated periodic syndrome (CAPS), recurrent pericarditis, VEXAS syndrome, ulcerative colitis, acute severe ulcerative colitis, Crohn’s disease, inflammatory bowel disease, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acute inflammatory psoriasis, genital psoriasis, autoimmune hepatitis, systemic lupus erythematosus (SLE), organ transplant rejection, chronic graft versus host disease (cGvHD), primary sclerosing cholangitis, or a combination thereof.

[0210] In some embodiments, the inflammatory condition is atopic dermatitis.

[0211] In some embodiments, the inflammatory condition is palmoplantar pustulosis.

[0212] In some embodiments, the inflammatory condition is fibrosing interstitial lung disease.

[0213] In some embodiments, the inflammatory condition is peripheral T-cell lymphoma.

[0214] In some embodiments, the inflammatory condition is Celiac disease.

[0215] In some embodiments, the inflammatory condition is asthma.

[0216] In some embodiments, the inflammatory condition is acute severe ulcerative colitis.

[0217] In some embodiments, the inflammatory condition is Crohn’s disease.

[0218] In some embodiments, the inflammatory condition is psoriatic arthritis.

[0219] In some embodiments, the inflammatory condition is ankylosing spondylitis.

[0220] In some embodiments, the inflammatory condition is acute inflammatory psoriasis.

[0221] In some embodiments, the inflammatory condition is genital psoriasis.

[0222] In some embodiments, the inflammatory condition is autoimmune hepatitis.

[0223] In some embodiments, the inflammatory condition is systemic lupus erythematosus(SLE).

[0224] In some embodiments, the inflammatory condition is organ transplant rejection.

[0225] In some embodiments, the inflammatory condition is chronic graft versus host disease (cGvHD).

[0226] In some embodiments, the inflammatory condition is primary'- sclerosing cholangitis.

[0227] In some embodiments, the inflammatory condition is cryopyrin-associated periodic syndrome (CAPS).

[0228] In some embodiments, the inflammatory condition is recurrent pericarditis.

[0229] In some embodiments, the inflammatory condition is VEXAS syndrome.

[0230] In some embodiments, the inflammatory condition is ulcerative colitis,

[0231] In some embodiments, the inflammatory condition is rheumatoid arthritis.

[0232] In some embodiments, the inflammatory condition is inflammatory bowel disease.

[0233] In some embodiments, the inflammation resulting from the inflammatory bowel disease is treated.

[0234] In some embodiments, the inflammation resulting from inflammatory bowel disease is in the proximal portion of the bowel.

[0235] In some embodiments, the inflammation resulting from inflammatory bowel disease is in the distal portion of the bowel.

[0236] In some embodiments, the inflammation resulting from inflammatory bowel disease is in the ileum portion of the bowel.

[0237] In some embodiments, the inflammation resulting from inflammatory bowel disease is in the entirety of the bowel.

[0238] Some embodiments are directed to a method of inhibiting ITK or JAK3 activity in a biological sample comprising contacting the biological sample with a crystalline form or pharmaceutical composition as described herein.

[0239] Besides being useful for human treatment, the crystalline form and compositions disclosed herein may also be useful for veterinary treatment of companion animals, exoticanimals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.

[0240] To facilitate a better understanding of the embodiments of the present invention, the following examples of preferred or representative embodiments are given . In no way should tlie following examples be read to limit, or to define, the scope of the invention.EXAMPLES

[0241] Example 1: Crystal Form Screen

[0242] The crystal-form screening study employed the following crystallization modes:• Stirring Compound 1 suspensions while cycling the temperature between 40- 5°C for four days (TC, n 48;-® Cooling clarified Compound 1 solutions from 45°C to 5°C, followed by a hold for three days. Next, the samples were equilibrated at -20°C, then a held for three days (RC, n=48)® Slow evaporation of solvents from Compound 1 solutions at RT over 7-10 days (EV, n 48 )® Anti-solvent addition to saturated and clarified solutions of Compound 1 at RT (ASA, n=12)

[0243] FT-Raman spectroscopy was chosen as the primary method for analysis and grouping of samples. Representative samples from the groupings were analyzed by PXRD to verify their uniqueness. Where possible / practical, a representative sample of the unique group was further characterized by PLM, DSC, and TGA-1R.

[0244] As shown in Table 1 and Table 2, the crystal-form screen of Compound 1 produced three crystal forms:« Form A - Non -solvated« Form B - Hydrated® Form C - Non-solvated

[0245] A PXRD pattern overlay of Forms A-C is shown in Figure 1 .

[0246] Table 2 shows the results of slurry (TC), cooling (RC), and evaporation crystallizations (EV).Table 1

[0247] Table 2 shows the results of anti-solvent addition.Table 2

[0248] Example 2: Characterization of Forms A, B, and C of Compound 1

[0249] Instrumentation

[0250] FT-Raman Spectroscopy: Raman spectra were collected with a Nicolet NXR9650 or NXR 960 spectrometer (Thermo Electron) equipped with 1064 nm Nd:YVO4 excitation laser, InGaAs and liquid-Ni cooled Ge detectors, and a MicroStage. All spectra were acquired at 4 cm-1resolution, 64 scans, using Happ-Genzel apodization function and 2 -level zero-filling through a glass cover.

[0251] Powder X-Ray Diffraction (PXRD): The powder X-ray diffraction (PXRD) measurements were be carried out using a PANalytical X'Pert Pro MPD diffractometer. The measurements were carried out at room temperature with the samples thoroughly ground to powder in an agate mortar. Each PXRD measurement was conducted over the angle range 29 = 4°- 42°, with a step size of 0.02° using copper CuKa with a wavelength of 1 .5406 A.

[0252] Differentia] Scanning Calorimetry (DSC): DSC was conducted with a TA Instruments QI 00 differential scanning calorimeter equipped with an autosampler and a refrigerated cooling system under 40 mL / min N2 purge. DSC thermograms were obtained in crimped Al pans at 15°C / min in Al pans, unless noted otherwise.

[0253] Thennogravimetric Analysis (TGA): TGA thermograms were obtained with a TA Instruments Q500 thermogravimetric analyzer under 40 mL / min N2 purge at 15°C / min in Al pans, unless noted otherwise.

[0254] Thermogravimetric Analysis with IR Off-Gas Detection (TGA-1R): TGA-1R was conducted with a TA Instruments Q5000 thermogravimetric analyzer interfaced to a Nicolet 6700 FT-1R spectrometer (Thermo Electron) equipped with an external TGA1R module with a gas flow cell and DTGS detector. TGA was conducted with 60 mL / min N2 flow and heating rate of 15°C / min in Pt or Al pans, unless noted otherwise. IR spectra were collected at 4 cm-1resolution and 32 scans at each time point.

[0255] Gravimetric V apor Sorption (GVS) : GVS experiments were conducted on a Surface Measurement Systems DVS-Advantage (SN: P22F00054). The experiments were performed at 25 °C. The instrument was operated in step mode, and the relative humidity (RH) was increased in 10% RH increments from 40% RH to 75% RH, then decreased from 75% RH to 5% RH, then increased a second time from 5% RH to 95% RH, then decreased from 95% RH to 5% RH. The mass equilibrium criterion was set at 0.003% change in mass overtime (drn / dt). A minimum step time of 20 minutes and a maximum step time of 240 minutes were specified.

[0256] High-performance Liquid Chromatography (HPLC): HPLC analyses were conducted with an HP1100 system equipped with a G 1131 Quad pump, G1367A autosampler, G1316A Thermostatted Column Compartment, and G1315B diode array detector. Column: Luna Cl 8(2) (50 x 2.0 mm, 3 pm). Mobile phase: 100% water (0.05%TFA) to 95% ACN (0.05% TFA) over 8 min and 2 min re-equilibration. Flow rate: 1 mL / min; Column temperature: 40 °C; Detection: 239 nm.

[0257] Form A is the non-solvated form that was the predominant output of the screen. However, it was observed to be thermodynamically unstable converting to Form C. Form A is crystalline by PXRD and PLM analysis shows very small birefringent particles (< 5 pm). DSC shows a small endotherm at 137.3 °C followed by a final, sharp endotherm at 181.1 °C, The relative stability data (Example 3) suggests the small endotherm at 137.3 °C is a solid-solid transition, resulting in conversion to Form C after 137.3 °C. TGA-1R indicates 1.2% weightloss of water from 25-190 °C. FIG. 2 depicts the FT-Raman of Form A of Compound 1. FIG. 3 depicts the DSC and TGA of Form A of Compound 1, and FIG. 4 depicts that PXRD of Form A of Compound 1 .

[0258] Form B is a hydrated crystal form identified in one experiment during the form screen. Form B is moderately crystalline by PXRD. PLM analysis shows very small birefrmgent particles (< 5 pn). DSC analysis shows complex thermal behavior with several low energy broad endothermic events. TGA-1R indicates 50.1% weight loss from water even though the material was dried under vacuum for four hours. The data suggests the crystal form is hygroscopic. FIG. 5 depicts the FT-Raman of Form B of Compound 1, FIG. 6 depicts the DSC and TGA of Form B of Compound 1, and FIG. 7 depicts that PXRD of Form B of Compound 1.

[0259] Form C is a non-solvated form identified in one ASA experiment during the form screen. It is the thermodynamically stable non-solvated form at 25 °C (Example 3). Form C was successfully scaled-up to 11 g for further assessment.

[0260] Form C scale up: Amorphous Compound 1 (12.2g) was stirred in IPA (30mL) at RT for Ih. The resulting solution was seeded with Form C. Seeds persisted. The resulting slurry was stirred at RT for 6h, then heptane (180 mL) was added dropwise. The slurry was stirred at RT for 2 days, then isolated and dried under vacuum at 40 °C for 3h to afford Form C (10.8 g, 88% yield).

[0261] Form C is crystalline by PXRD and PLM analysis shows small birefrmgent particles. DSC shows a single sharp endotherm at 182.2 °C and TGA-1R indicates 0. 1% weight loss from 25-185 °C. HPLC- analysis determined the scale-up Form C material had a purity of 99.67%. GVS analysis indicated 0.5% water uptake between 5-95% RH indicating Form C is non-hygroscopic. FIG. 8 depicts the FT-Raman of Form C of Compound 1, FIG. 9 depicts the DSC and TGA of Form C of Compound 1, FIG. 10 depicts that PXRD (with Bragg reflections) of Form C of Compound 1, FIG. 11 depicts the IR of Form C of Compound 1, and FIG. 12 depicts the GVS isotherm plot of Form C of Compound 1. No form change was detected by PXRD on the post-GVS material. Table 3 show the values and significant Bragg reflections and their 29 positions of Form C of Compound 1 as compared to the results from simulated data for Form C of Compound 1 .Table 3

[0262] Example 3: Relative Stability Studies

[0263] Relative stability studies were conducted at 25 °C to determine tire most thermodynamically stable non-solvated form. Both non-solvated forms (Form A and Form C) were ripened during the study.

[0264] Saturated suspensions of Compound 1 were prepared by stirring excess Compound 1 in the specified solvent system . Seeds of Form A were added, and the thin suspension was stirred overnight at 25 °C resulting in a thick suspension. A clarifying filtration was performed, and the filtrate was added to a 2 ml vial containing seeds of Form A and Form C. The resulting suspensions were stirred at 25 °C for five days. The solids were isolated, air-dried for 45 minutes, and analyzed by FT-Raman.

[0265] The FT-Raman spectra are shown in FIG. 13 and indicate Form C was the only crystal form remaining after the ripening study. The results of the study are summarized in Table 4.Table 4

[0266] Example 4: X-Ray Structure Determination:

[0267] Compound 1 was provided as Form C as a colorless, crystalline solid. A small, single crystal of Form C of Compound Iwas identified from the bulk sample and its absolute configuration was determined by the method of X-ray crystallography.

[0268] The single cry stal structure was also used to generate a simulated Powder X-ray Diffraction (sPXRD) pattern using the program Mercury' for use in comparison with an experimental PXRD pattern generated from the bulk sample of Compound 1.

[0269] A comparison of the two PXRD patterns clearly demonstrated that the crystal form described by the single crystal X-ray structed determined in this study is of Form C, the desired polymorph of Compound 1 .

[0270] Crystallization: A very small, single crystal of Compound 1 was identified from the bulk sample using a high-powered light microscope with a polarizing lens.

[0271] X-ray Data Collection: X-ray data collection was conducted at the University of Toledo Instrumentation Center (UTIC). A very small triangular crystal with the approximate dimensions 0.015 mm x 0.015 mm x 0.005 mm was mounted under oil on a MiTeGen™ cryoloop. Preliminary' analysis and data collection were performed at a temperature of 200 K using Copper Ka radiation (1.54178 A) with a Bruker APEX II Duo™ diffractometer equipped with an IpS Cu source and an Oxford Cryostream™ low temperature device.

[0272] X-ray Structure Determination and Crystallographic Refinement: The total exposure time was 159.02 hours. The frames were integrated with the Bruker SAINT software package using a narrow-frame algorithm. The integration of the data using an orthorhombic unit cell yielded a total of 22,231 reflections to a maximum 0 angle of 59.71° (0.89 A resolution), of which 3,982 were independent (average redundancy' 5.583, completeness = 81.0%, Rint = 3.96%, Rsig = 4.19%) and 3,340 (83.88%) were greater than 2o(F2). The final cell constants of a - 8.9882(3) A, b - 16.7734(9) A, c - 23.9425(10) A, volume - 3609.6(3) A3, are based upon the refinement of the XYZ-centroids of 6,133 reflections above 20 o(l) with 7.381° < 20 < 106.1°. Data were corrected for absorption effects using the Multi-Scanmethod (S ADABS). The ratio of minimum to maximum apparent transmission was 0.907. The calculated minimum and maximum transmission coefficients (based on crystal size) are 0.6809 and 0.7517.

[0273] The final anisotropic full-matrix least-squares refinement on F2 with 477 variables converged at R1 ::: 3.91%, for the observed data and wR2 ::: 8.70% for all data. The goodness-of-fit was 1.036. The largest peak in the final difference electron density synthesis was 0.193 e- / A3 and the largest hole was -0.211 e- / A3 with an RMS deviation of 0.043 e- / A3. On the basis of the final model, the calculated density was 1 .330 g / cm3 and F(000), 1520 e-.

[0274] The asymmetric unit contains two crystallographically independent molecules bonded via hydrogen bonds. All non-hydrogen atoms were refined with anisotropic displacement factors. Hydrogen atoms bonded to N4 and N9 were located in the Difference Fourier maps, respectively, and included in the refinement with their isotropic displacement parameter fixed to be 1.2 times the LI equivalent of the bonded atom.

[0275] The absolute configuration was determined to be R(C3)R(C10),S(C12) and R(C21)R(C28),S(30) from 1 183 selected quotients (Parsons' method) as indicated by a Flack parameter of -0.04(7). Further analysis based on Bayesian Statistics reveal a probability of 1 that the assigned enantiomer is correct, assuming that the compound is enantiopure.

[0276] Experimental details and results at 150K, including atomic coordinates and intermolecular H-bonds, are given in Tables 5-1 1. FIG. 14 depicts the ORTEP representation of one of the Form C of Compound 1 molecules in the asymmetric unit. The representation demonstrates the low degree of thermal motion within the crystal.. FIG. 15 depicts a three- dimensional display of Form C of Compound 1 showing the two molecules in the asymmetric unit cell using a ball-and-stick representation of Form C of Compound 1 in which the atoms are color-coded with gray representing carbons, yellow representing fluorines, white representing hydrogens, and red and blue representing oxygens and nitrogens, respectively. An intermolecular bond between molecules in the asymmetric unit is shown as a gold dashed line. Table 5 - Sample and crystal dataTable 6 - Data collection and structure refinementTable 7 - Atomic coordinates and equivalent isotropic atomic displacement parameters (A2)U(eq) is defined as one third of the trace of the orthogonalized Uij tensorTable 8 - Bond lengths (A)Table 9 - Bond angles (°)Table

[0277] Although the present invention has been described in considerable detail with reference to certain preferred embodiments thereof, other versions are possible. Therefore the spirit and scope of the appended claims should not be limited to the description and the preferred versions contained wathm this specification.

Claims

CLAIMS1. A crystalline polymorph Form C of Compound 1 (1-((2S,5R)-5-((5-((R)-2,2- difluorocyc]opropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-l~yl)prop- 2-en-l-one).

2. The crystalline polymorph of claim 1, wherein Form C is characterized by a PXRD pattern comprising a significant peak at 20 angle of about 15.59°.

3. Hie crystalline polymorph of claim 2, wherein Form C is further characterized by a PXRD pattern comprising a significant peak at 20 angle of about 7.39°.

4. The crystalline polymorph of any one of claims 1-3, wherein Form C is further characterized by a PXRD pattern comprising a significant peak at 20 angle of about 11.66°.

5. The crystalline polymorph of any one of claims 1-4, wherein Form C is further characterized by a PXRD pattern comprising significant peaks at 20 of about 14.25°, about 14.74°, about 16.06°, and about 18.77°.

6. The crystalline polymorph of any one of claims 1-5, wherein Form C is further characterized by a PXRD pattern comprising significant peaks at 20 of about 20.63°, about 21 .53°, and about 23.35°.

7. The crystalline polymorph of claim 1, wherein Form C is characterized by a PXRD pattern substantially as shown in FIG. 10.

8. The crystalline polymorph of claim 1, wherein Form C is characterized by an IR spectra pattern comprising a significant peak at about 1587 cm-1.

9. The crystalline polymorph of claim 8, wherein Form C is further characterized by an IR spectra pattern comprising a significant peak at about 1454 cm-1.

10. The crystalline polymorph of claim 8 or claim 9, wherein Form C is further characterized by an IR spectra pattern comprising a significant peak at about 1638 cm-1.

11. Hie crystalline polymorph of any one of claims 8-10, wherein Form C is further characterized by an IR spectra pattern comprising significant peaks at about 1467 cm-1and at about 147412. The crystalline polymorph of any one of claims 8-11, wherein Form C is further characterized by an IR spectra pattern comprising significant peaks at about 3204 cm-1and at about 3464 cm-1.

13. The crystalline polymorph of any one of claims 8-12, wherein Form C is further characterized by an IR spectra patern comprising significant peaks at about 1210 cm-1, at about 1254 cm-1, and at about 1314 cm-1.

14. Hie crystalline polymorph of claim 1 , wherein Form C is characterized by an IR spectrum substantially as shown in FIG. 11.

15. The crystalline polymorph of claim 1, wherein Form C is characterized by an FT-Raman spectrum substantially as shown m FIG. 8.

16. The crystalline polymorph of claim 1, wherein Form C is characterized by a DSC thermogram exhibiting a sharp endotherm at about 182.2°C.

17. Hie crystal line polymorph of claim 1, wherein Form C is characterized by a DSC thermogram substantially as shown in FIG, 9.

18. The crystalline polymorph of claim 1, wherein Form C is characterized by a water loss as measured by thermogravi metric analysis (TGA) of about 0.1 wt. %.

19. The ciystalline polymorph of claim 1, wherein Form C is characterized by a TGA spectrum substantially as shown in FIG . 9.

20. The ciystalline polymorph of claim 1, wherein Form C is characterized by 0,5% water uptake as measured by gravimetric vapor sorption (GVS).21 . The crystalline polymorph of claim 1 , wherein Form C has a chemical purity of about 90%,22. The ciystalline polymorph of claim 1, wherein Form C has a chemical purity' of about 95%.

23. The crystalline polymorph of claim 1, wherein Form C has a chemical purity of about 97%.

24. The crystalline polymorph of claim 1, wherein Form C has a chemical purity of about 99%.

25. The crystalline polymorph of claim 1, wherein Form C has a chemical purity of about 99.5%.

26. A pharmaceutical composition comprising the crystalline polymorph of claim 1 and a pharmaceutically acceptable excipient.

27. A method of treating an ITK-mediated or J AK3 -mediated disorder in a subject in need thereof, composing: administering to the subject the crystalline polymorph of claim 1, in an amount effective to treat the ITK-mediated or JAK3-mediated disorder.

28. The method of claim 27, wherein ITK -mediated or JAK3 mediated disorder is selected from inflammation, an inflammatory condition, chronic inflammatory disorders, acute inflammatory disorders, connective tissue diseases, autoimmune conditions / disorders / responses, autoimmune connective tissue disease, Sjogren’s syndrome, mixed connective tissue disease, polymyalgia rheumatica, sarcoidosis, autoimmune orchitis, Goodpasture's disease, Behcet’s disease, metal-induced autoimmunity, autoimmune deafness (including, for example, Meniere's disease), interstitial cystitis, polychondritis, relapsing polychondritis, autoimmune orchitis, silicone implant-associated autoimmune disease, drag-induced autoimmunity, HIV- related autoimmune syndromes, broad activation of the immune responses, bone resorption diseases, SA VI (stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy), hyperoxia-induced inflammations, reperfusion injury, post-surgical trauma, tissue injury, cystic fibrosis, Th l7~associated inflammation, increased accumulation of exogenous opioids or synthetic opioids, jaundice, mastocytosis, Castleman's disease, systemic immune senescence, transplant arteriopathy, hypereosinophilic syndrome (HES), systemic, mast cell disease (SMCD), or macrophage activation syndrome.

29. The method of claim 28, wherein the inflammatory condition is selected from the group consisting of a chronic inflammatory condition, an acute inflammatory condition, an immuno- inflammatory condition, an autoimmune inflammatory condition, an inflammasomopathy, or a combination thereof.

30. The method of claim 28, wherein the inflammatory condition is selected from the group consisting of atopic dermatitis, palmoplantar pustulosis, fibrosing interstitial lung disease, peripheral T-cell lymphoma, Celiac disease, asthma, recurrent pericarditis, VEXAS syndrome, ulcerative colitis, acute severe ulcerative colitis, Crohn’s disease, inflammatory bowel disease, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acute inflammatory psoriasis, genital psoriasis, autoimmune hepatitis, systemic lupus erythematosus (SEE), organ transplant rejection, chronic graft versus host disease (cGvHD), primary’ sclerosing cholangitis, or a combination thereof.

31. The method of claim 30, wherein the inflammatory condition is recurrent pericarditis.

32. Hie method of claim 30, wherein the inflammatory condition is VEXAS syndrome.

33. The method of claim 30, wherein the inflammatory condition is ulcerative colitis.

34. The method of claim 30, wherein the inflammatory condition is rheumatoid arthritis.

35. The method of claim 30, wherein the inflammatory condition is inflammatory bowel disease,36. The method of claim 35, wherein inflammation resulting from inflammatory bowel disease is in the proximal portion of the bowel,37. The method of claim 35, wherein inflammation resulting from inflammatory bowel disease is in the distal portion of the bowel.

38. The method of claim 35, wherein inflammation resulting from inflammatory bowel disease is in the ileum portion of the bowel.

39. The method of claim 35, wherein inflammation resulting from inflammatory bowel disease is in the entirety of the bowel.

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