Crystalline forms of c-c chemokine receptor type 4 antagonists and uses thereof

Abstract

To provide crystalline forms of a C-C chemokine receptor type 4 antagonist.SOLUTION: There is provided the compound 2 - ((R) - 3 - (1 - (1 - ((R) - 1 - (2, 4-dichlorophenyl) ethyl) - 3 - (trifluoromethyl) - 1H - pyrazolor3, 4-b] pyrazin-6-yl) azetidin-3-yl) piperidin-1-yl) ethan-1-ol benzenesulfonate in crystalline form.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] 1. CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Application No. 62 / 935,007, filed November 13, 2019, the disclosure of which is incorporated herein by reference in its entirety.

[0002] 2.Technical Field Disclosed herein are crystalline forms of CC chemokine receptor type 4 (CCR4) antagonists, and methods of making and using them. These compounds can be used as therapeutic agents in the treatment of certain diseases and disorders, including, for example, cancer. [Background technology]

[0003] 3.Background technology Generally, crystalline forms of drugs are preferred over amorphous forms of drugs, in part due to their superior stability. For example, in many situations, amorphous drugs convert to crystalline drug forms during storage. Because amorphous and crystalline forms of drugs typically have different physical / chemical properties, potency, and / or bioavailability, such interconversion is undesirable for safety reasons in pharmaceutical administration.

[0004] An important characteristic of crystalline drug substances is the polymorphic behavior of such substances. Polymorphs are crystals of the same molecule that have different physical properties because the crystal lattice contains different molecular arrangements. The different physical properties exhibited by polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density (important in formulation and product manufacturing), and dissolution rate (important in determining bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential hydrolysis or oxidation, such that a dosage form composed of one polymorph discolors more quickly than one composed of another), mechanical changes (e.g., tablets crumble upon storage because a kinetically favored crystalline form converts to a thermodynamically more stable crystalline form), or both (e.g., tablets of one polymorph are more susceptible to degradation at high humidity). Differences in solubility between polymorphs can, in extreme circumstances, result in transition to an ineffective or toxic crystalline form. In addition, the physical properties of crystalline forms can be important in pharmaceutical processing. For example, certain crystalline forms may form solvates more readily or be more difficult to filter to remove impurities than other forms (i.e., particle shape and size distribution may differ between one crystalline form and another).

[0005] Agencies such as the U.S. Food and Drug Administration strictly regulate the polymorphic content of active ingredients in solid dosage forms of drugs. Regulatory agencies generally require batch-by-batch monitoring of polymorphic drugs when other than the pure, thermodynamically preferred polymorph is sold. Therefore, medical and commercial reasons support the synthesis and sale of solid drugs as thermodynamically stable polymorphs that are substantially free of kinetically favored polymorphs. The present application addresses these and other needs in the art. Summary of the Invention

[0006] 4. Summary of the Invention In one aspect, a crystalline form of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol is provided.

[0007] In one aspect, a crystalline form of the benzenesulfonate salt of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol is provided.

[0008] In one aspect, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate is provided in a form designated as Form A. In one embodiment, crystalline Form A has characteristic absorption peaks at 18.4°±0.3°, 22.9°±0.3°, 21.2°±0.3°, and 15.9°±0.3° 2θ in an X-ray powder diffractogram using Cu Kα radiation. In another embodiment, crystalline Form A has characteristic absorption peaks at 12.2°±0.3°, 23.8°±0.3°, and 25.6°±0.3° in an X-ray powder diffractogram using Cu Kα radiation. In another embodiment, crystalline form A has characteristic absorption peaks at 23.1°±0.3°, 20.0°±0.3°, and 16.2°±0.3° in an X-ray powder diffractogram using Cu Kα radiation. In another embodiment, crystalline form A has an X-ray powder diffractogram using Cu Kα radiation as shown in Figure 1. In another embodiment, crystalline form A has a melting point of about 170°C to about 173°C as determined by differential scanning calorimetry at a scan rate of 5°C / min.

[0009] In another aspect, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate is provided in a form designated as Form B. In one embodiment, crystalline Form B has characteristic absorption peaks at 18.4°±0.3°, 22.9°±0.3°, 21.2°±0.3°, and 15.9°±0.3° 2θ in an X-ray powder diffractogram using CuKα radiation. In another embodiment, crystalline Form B has characteristic absorption peaks at 12.2°±0.3°, 23.8°±0.3°, and 25.6°±0.3° in an X-ray powder diffractogram using CuKα radiation. In another embodiment, crystalline form B has characteristic absorption peaks at 23.1°±0.3°, 20.0°±0.3°, and 16.2°±0.3° in an X-ray powder diffractogram using Cu Kα radiation. In another embodiment, crystalline form B has an X-ray powder diffractogram using Cu Kα radiation as shown in Figure 3. In another embodiment, crystalline form B has a melting point of about 116°C to about 119°C as determined by differential scanning calorimetry at a scan rate of 5°C / min.

[0010] In another aspect, a pharmaceutical composition is provided comprising a crystalline form of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate.

[0011] In embodiments, the pharmaceutical composition comprises crystalline Form A and / or Form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate, and a pharmaceutically acceptable vehicle. In embodiments, the pharmaceutical composition comprises crystalline Form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate, and a pharmaceutically acceptable vehicle. In embodiments, the pharmaceutical composition comprises crystalline Form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate, and a pharmaceutically acceptable vehicle.

[0012] In another aspect, methods of using crystalline forms of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate, and pharmaceutical compositions thereof, are provided for treating or preventing various diseases, such as allergic, immune, inflammatory, or cancer-related diseases, disorders, or conditions. Such diseases, disorders, and conditions, as well as other ailments that may be treated or prevented with the crystalline compounds described herein, are described in detail elsewhere.

[0013] In embodiments, the disease or disorder includes allergy-related disorders (e.g., hypersensitivity and anaphylactic reactions); gastrointestinal disorders (e.g., inflammatory bowel disease, Crohn's disease, ulcerative colitis, ileitis, and enteritis); psoriasis and inflammatory dermatitis (e.g., dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria, and pruritus); vasculitis; scleroderma; asthma, COPD, and respiratory allergic diseases (e.g., allergic rhinitis and hypersensitivity lung disease); arthritis (e.g., rheumatoid arthritis and psoriasis), multiple sclerosis, These include autoimmune diseases, including systemic lupus erythematosus, type I diabetes, and glomerulonephritis; graft rejection (e.g., allograft rejection); transplant rejection (e.g., solid organ); cancers, such as leukemia, lymphoma, and metastatic cancer, particularly solid tumors (e.g., gastric cancer); and other diseases in which inhibition of undesired inflammatory and / or immune responses is desired, such as atherosclerosis, neurodegenerative diseases (e.g., Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis, and sinusitis. In embodiments, the disease, disorder, or condition is mediated by CCR4. In embodiments, the CCR4-mediated disease, disorder, or condition is one of asthma, COPD, rhinitis, idiopathic pulmonary fibrosis, psoriasis, and contact dermatitis. In embodiments, the disease or disorder is pulmonary fibrosis, liver inflammation, asthma, atopic dermatitis, cancer (e.g., thyroid cancer, bile duct cancer, pancreatic adenocarcinoma, cutaneous melanoma of the skin, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma), or the development of granulomas. The method generally involves administering to a patient in need of such treatment or prevention a therapeutically effective amount of crystalline Form A and / or Form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate as described herein.

[0014] In another aspect, a method of making a crystalline form of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate is provided.

[0015] In embodiments, there is provided a method for making crystalline Form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate described herein. In embodiments, there is provided a method for making crystalline Form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate described herein. [Brief explanation of the drawings]

[0016] 5. Brief description of the drawings [Figure 1] Figure 1 shows the X-ray powder diffraction pattern of crystalline form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate. [Figure 2] Figure 1 shows a differential scanning calorimetry thermogram of crystalline form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate. [Figure 3]Figure 1 shows the X-ray powder diffraction pattern of crystalline form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate. [Figure 4] Figure 1 shows a differential scanning calorimetry thermogram of crystalline form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate. DETAILED DESCRIPTION OF THE INVENTION

[0017] 6. MODE FOR CARRYING OUT THE INVENTION 6.1 Definition As used herein, the term "pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient, or carrier with which 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate can be administered to a patient in need thereof.

[0018] As used herein, the term "pharmaceutically acceptable salt" is intended to include salts of compounds prepared using relatively non-toxic acids or bases, depending on the particular substituents found in the compound. The crystalline compounds described herein are besylate salts. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, etc. Also included are amino acid salts such as arginate salts, and organic acid salts such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds may contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0019] As used herein, the terms "CC chemokine receptor type 4" and "CCR4" refer to the protein (including homologs, isoforms, and functional fragments thereof) and are high-affinity receptors for CC-type chemokines (e.g., CCL2 (MCP-1), CCL4 (MIP-1), CCL5 (RANTES), CCL17 (TARC), and CCL22 (MDC)). It is referred to by several different names in the scientific literature, including "CC-CKR-4," "CC CKR-4," "K5-5," "CD194," "CMKBR4," "ChemR13," "HGCN," and "14099." The terms include any recombinant or naturally occurring form of CCR4 or a variant thereof that maintains CCR4 activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wild-type CCR4). The term includes any mutant form of CCR4 or variants thereof (e.g., frameshift mutations) that maintain CCR4 activity (e.g., within the range of at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wild-type CCR4). In embodiments, the CCR4 protein encoded by the CCR4 gene has an amino acid sequence set forth in or corresponding to Entrez 1233, UniProt P51679, or RefSeq (protein) NP_005499.1. In embodiments, the CCR4 gene has a nucleic acid sequence set forth in RefSeq (mRNA) NM_005508. In embodiments, the amino acid sequence or nucleic acid sequence is a sequence known at the time of filing of this application. In embodiments, the sequence corresponds to GI:5031627. In embodiments, the sequence corresponds to NP_005499.1. In embodiments, the sequence corresponds to NM_005508.4. In embodiments, this sequence corresponds to GI:48762930. In embodiments, the CCR4 is human CCR4, such as in human cancers that produce CCR4. Although frequently found on dendritic cells, macrophages, NK cells, platelets, and basophils, CCR4 is primarily associated with T cells.It plays a role in the progression of multiple inflammation-related disorders and, as described herein, is also involved in several other conditions. The genomic sequence of CCR4 is located on chromosome 3 (NC_000003.12), and the CCR4 gene is conserved in several species, including chimpanzees, rhesus monkeys, dogs, cattle, mice, rats, chickens, and zebrafish. The CCR4 polypeptide contains 360 amino acid residues (NP_005499.1), and like other chemokine receptors, CCR4 is a G protein-coupled receptor found on the surface of leukocytes (see Horuk (1994) Trends Pharm. Sci. 15:159-165).

[0020] As used herein, "CCR4 inhibitor" refers to a compound (e.g., a compound described herein) that reduces the activity of CCR4 compared to a control, such as no compound or a compound with known inactivity.

[0021] As used herein, the terms "activation," "activate," "activating," and the like, with respect to proteins, refer to converting a protein from an initial, inactive, or inactivated state to a biologically active derivative. These terms refer to activating, or activating, sensitizing, or upregulating signal transduction or enzymatic activity or the amount of a protein that is decreased in a disease.

[0022] As used herein, the terms "agonist," "activator," "up-regulator," and the like refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. An agonist can increase expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to a control in the absence of the agonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or more higher than expression or activity in the absence of the agonist. In embodiments, an agonist is a molecule that interacts with a target to cause or promote increased activation of the target. In embodiments, an activator is a molecule that increases, activates, promotes, enhances activation, sensitizes, or up-regulates, for example, a gene, protein, ligand, receptor, or cell.

[0023] As used herein, the terms "inhibition," "inhibit," "inhibiting," and the like, with respect to a protein-inhibitor interaction, refer to adversely affecting (e.g., decreasing) the activity or function of a protein compared to the activity or function of the protein in the absence of the inhibitor. In embodiments, inhibition refers to negatively affecting (e.g., decreasing) the concentration or level of a protein compared to the concentration or level of the protein in the absence of the inhibitor. In embodiments, inhibition refers to the alleviation of a disease or disease symptom. In embodiments, inhibition refers to the reduction of the activity of a specific protein target. Thus, inhibition includes at least partially or completely blocking a stimulus, reducing, preventing, or delaying activation of signaling or enzymatic activity or the amount of a protein, or inactivating, desensitizing, or downregulating. In embodiments, inhibition refers to the reduction of the activity of a target protein due to a direct interaction (e.g., an inhibitor binds to the target protein). In embodiments, inhibition refers to the reduction of the activity of a target protein due to an indirect interaction (e.g., an inhibitor binds to a protein that activates the target protein, thereby preventing activation of the target protein).

[0024] As used herein, the terms "inhibitor," "suppressor," "antagonist," or "down-regulator" refer interchangeably to a substance capable of detectably reducing the expression or activity of a given gene or protein. An antagonist can reduce expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or more lower than the expression or activity in the absence of the antagonist. An antagonist prevents, reduces, inhibits, or neutralizes the activity of an agonist, and an antagonist can also prevent, inhibit, or reduce the constitutive activity of a target, such as a target receptor, even in the absence of a recognized agonist. In embodiments, an inhibitor is a molecule that decreases, blocks, prevents, delays activation, inactivates, desensitizes, or downregulates, for example, a gene, protein, ligand, receptor, or cell. An inhibitor may also be defined as a molecule that reduces, blocks, or inactivates constitutive activity. An "antagonist" is a molecule that opposes the action of an agonist.

[0025] As used herein, the term "disease" or "condition" refers to an existing state or state of health of a patient or subject that can be treated with the compounds or methods provided herein. The disease can be cancer. The disease can be an autoimmune disease. The disease can be an inflammatory disease. The disease can be an infectious disease. In some further examples, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphatic cancers, renal cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioma, esophageal cancer, and liver cancer, including hepatocellular carcinoma, nasopharangeal carcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphoma (e.g., Burkitt's, small cell, and large cell lymphoma), Hodgkin's lymphoma, leukemia (including MDS, AML, ALL, ATLL, and CML), or multiple myeloma.

[0026] As used herein, the term "inflammatory disease" refers to a disease or condition characterized by abnormal inflammation (e.g., increased levels of inflammation compared to a control, such as a healthy individual without the disease). Examples of inflammatory diseases include autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile-onset diabetes, type 1 diabetes mellitus, Guillain-Barré syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, and ulcerative colitis. These include ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, ischemia-reperfusion injury, stroke, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis. Such conditions are often closely intertwined with other diseases, disorders, and conditions. For example, a non-limiting list of inflammation-related diseases, disorders, and conditions that may be caused by inflammatory cytokines includes arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergy, fibrosis, surgical complications (for example, when inflammatory cytokines interfere with healing), anemia, and fibromyalgia. Other diseases and disorders that may be associated with chronic inflammation include Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infectious diseases, inflammatory bowel disease (IBD), allergic contact dermatitis and other eczema, systemic sclerosis, transplantation and multiple sclerosis.Some of the aforementioned diseases, disorders and conditions that the compound of the present invention (for example, CCR4 inhibitor) can be particularly effective (for example, due to the limitations of current treatment) are described in more detail below.

[0027] As used herein, the term "cancer" refers to all types of cancer, neoplasm, or malignant tumor found in mammals (e.g., humans), including leukemia, carcinoma, and sarcoma. Exemplary cancers that can be treated with the compounds or methods provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, gastric cancer, ovarian cancer, lung cancer, and head cancer. Exemplary cancers that can be treated with the compounds or methods provided herein include thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, medulloblastoma, colorectal cancer, and pancreatic cancer. Further examples include thyroid cancer, bile duct cancer, pancreatic adenocarcinoma, cutaneous melanoma of the skin, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, nasopharyngeal cancer, squamous cell carcinoma of the head and neck, invasive carcinoma of the breast, lung adenocarcinoma, lung squamous cell carcinoma, Hodgkin's disease, non-Hodgkin's disease, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocythemia, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic neoplasms, medullary thyroid cancer, carcinoma), melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

[0028] As used herein, the term "autoimmune disease" refers to a disease or condition in which a subject's immune system mounts an abnormal immune response to a substance that does not normally elicit an immune response in healthy individuals. Examples of autoimmune diseases that can be treated with the compounds, pharmaceutical compositions, or methods described herein include acute disseminated encephalomyelitis (ADEM), acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome (APS), autoimmune angioedema, autoimmune aplastic anemia, autoimmune autonomic neuropathy, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED), autoimmune myocarditis, and autoimmune inflammatory bowel disease (AIED). Autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura (ATP), autoimmune thyroid disease, autoimmune urticaria, axonal or neuronal neuropathy, Barrow's disease, Behçet's disease, bullous pemphigoid, cardiomyopathy, Castleman's disease, celiac disease, Chagas' disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multiple myelitis (CRMO), Churg-Strauss syndrome, cicatricial pemphigoid / benign mucous membrane pemphigoid, Crohn's disease, Cogan's syndrome, cold agglutinin disease, congenital heart disease Block, Coxsackie myocarditis, CREST disease, essential mixed cryoglobulinemia, demyelinating neuropathy, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, experimental allergic encephalomyelitis, Evans' syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis (GPA) (formerly known as Wegener's granulomatosis), Glomerulonephritis, Rebes' disease, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura, herpes gestationis, hypogammaglobulinemia, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease, immunoregulatory lipoproteins, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, lignified conjunctivitis, linear immunoglobulin A disease (LAD), lupus (SLE), Lyme disease,Chronic, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease (MCTD), Mooren's ulcer, Much-Habermann disease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica (Devic), neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatoid arthritis, PANDAS (Streptococcus-associated childhood autoimmune neuropsychiatric disorders), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH) , Paris-Romberg syndrome, Parsonage-Turner syndrome, pars planitis (peripheral uveitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, type I, type II, type III autoimmune polyglandular syndrome, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, progesterone dermatitis, primary biliary cirrhosis, primary sclerosing encephalopathy Cholangitis, psoriasis, psoriatic arthritis, idiopathic pulmonary fibrosis, pyoderma gangrenosum, pure red cell aplasia, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, Reiter's syndrome, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity, stiff-body syndrome, These include subacute bacterial endocarditis (SBE), Susac syndrome, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, transverse myelitis, type 1 diabetes, ulcerative colitis, undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, bullous dermatoses, vitiligo, or Wegener's granulomatosis (i.e., granulomatosis with polyangiitis (GPA)).

[0029] As used herein, the term "treating" or "treatment" refers to an indication of success in treating or ameliorating an injury, disease, condition, or state, and includes any objective or subjective parameter, such as remission, remission, alleviating symptoms, or making the injury, disease, or state more tolerable to the patient, slowing the rate of degeneration or decline; making the end point of degeneration less debilitating; or improving the patient's physical or mental health. The treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric testing, and / or psychiatric evaluation. The term "treating" and its conjugations can include prevention of an injury, disease, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing.

[0030] As used herein (and as is well understood in the art), "treating" or "treatment" broadly encompasses any approach to achieving beneficial or desired results in a subject's condition, including clinical outcomes. Beneficial or desired clinical outcomes may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether partial or complete, detectable or undetectable, reduction in the extent of disease, stabilization of disease conditions (i.e., not worsening), prevention of disease infection or spread, delay or slowing of disease progression, improvement or relief of disease conditions, reduction in disease recurrence, and remission. In other words, "treatment" as used herein includes any cure, amelioration, or prevention of disease. Treatment may prevent disease from developing, inhibit the spread of disease, relieve symptoms of disease (e.g., eye pain, seeing halos around lights, bloodshot eyes, high intraocular pressure), completely or partially eliminate the underlying cause of disease, shorten the duration of disease, or a combination thereof.

[0031] As used herein, "treating" and "treatment" include preventive treatment. The treatment method includes administering a therapeutically effective amount of a compound described herein to a subject. The administration step can consist of a single administration or can include a series of administrations. The length of the treatment period depends on various factors, such as the severity of the condition, the age of the patient, the concentration of the compound, the activity of the composition used for treatment, or a combination thereof. It will also be understood that the effective dosage of the agent used for treatment or prevention can increase or decrease during a specific treatment or prevention plan. Changes in dosage can be made and become evident by standard diagnostic assays known in the art. In some cases, chronic administration may be required. For example, the composition is administered to the subject in an amount and for a duration sufficient to treat the patient.

[0032] As used herein, the term "preventing" refers to a reduction in the occurrence of disease symptoms in a patient. As noted above, prevention can be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely develop without treatment. In embodiments, prevention refers to slowing or inhibiting the progression of a disease, disorder, or condition to an adverse or otherwise undesirable state.

[0033] As used herein, the term "modulator" refers to a composition that increases or decreases the level of a target molecule, the function of a target molecule, or the physical state of a molecular target. In embodiments, a CCR4-associated disease modulator is a compound that reduces the severity of one or more symptoms of a disease associated with CCR4 (e.g., cancer, inflammatory disease, autoimmune disease, or infectious disease). A CCR4 modulator is a compound that increases or decreases the activity or function or level of activity or function of CCR4. Modulators may act alone or may use cofactors, such as proteins, metal ions, or small molecules. Examples of modulators include small molecule compounds and other bioorganic molecules. Numerous libraries of small molecule compounds (e.g., combinatorial libraries) are commercially available and serve as a starting point for identifying modulators. One skilled in the art can develop one or more assays (e.g., biochemical or cell-based assays) that can screen such compound libraries to identify one or more compounds with desired properties, and a skilled medicinal chemist can then optimize such one or more compounds, for example, by synthesizing and evaluating analogs and derivatives thereof. Synthesis and / or molecular modeling studies can also be used to identify activators.

[0034] The term "modulate" is used according to its plain and ordinary meaning and refers to the act of changing or varying one or more properties. "Modulation" refers to the process of changing or varying one or more properties. For example, as applied to the effect of a modulator on a target protein, modulating means changing by increasing or decreasing the property or function of the target molecule or the amount of the target molecule. In embodiments, terms such as "modulate," "modulation," and the like refer to the ability of a molecule (e.g., an activator or inhibitor) to increase or decrease, either directly or indirectly, the function or activity of CCR4 compared to the absence of the molecule.

[0035] A "patient" or "subject in need of treatment" refers to an organism suffering from or susceptible to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammals. In an embodiment, the patient is a human. The terms "human" and "patient" are used interchangeably herein.

[0036] As used herein, the term "effective amount" refers to an amount of a compound sufficient to achieve its stated purpose (e.g., achieve the effect for which the compound is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signal transduction pathway, or reduce one or more symptoms of a disease or condition) compared to the absence of the compound. An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom of a disease, which may also be referred to as a "therapeutically effective amount." "Reduction" of a symptom (and grammatical equivalents of this phrase) refers to a decrease in the severity or frequency of the symptom, or the elimination of the symptom. A "prophylactically effective amount" of a drug is an amount of a drug that, when administered to a subject, will have its intended preventative effect, for example, an amount of a drug that prevents or delays the onset (or recurrence) of an injury, disease, pathology, or condition, or reduces the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition, or a symptom thereof. A complete preventative effect does not necessarily occur by administration of a single dose, but may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. As used herein, "activity-reducing amount" refers to the amount of antagonist required to reduce the activity of an enzyme compared to the absence of antagonist. As used herein, "function-disrupting amount" refers to the amount of antagonist required to disrupt the function of an enzyme or protein compared to the absence of antagonist. The exact amount depends on the purpose of treatment and can be determined by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).A therapeutically effective amount can be ascertained by measuring relevant physiological effects and can be adjusted in conjunction with dosing regimens, diagnostic analyses of a subject's condition, etc. By way of example, measuring serum levels of a CCR4 inhibitor (or, e.g., a metabolite thereof) at particular times after administration can indicate whether a therapeutically effective amount has been administered.

[0037] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. The target concentration will be the concentration of active compound that is capable of achieving the methods described herein, as measured using methods described herein or known in the art.

[0038] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, human doses can be formulated to achieve concentrations found to be effective in animals. Human dosages can be adjusted by monitoring the efficacy of the compound and adjusting the dosage upward or downward, as described above. Adjusting dosages to achieve maximum efficacy in humans based on the above and other methods is well within the capabilities of one skilled in the art. Adjusting dosages to achieve maximum therapeutic window efficacy or toxicity in humans based on the above and other methods is well within the capabilities of one skilled in the art.

[0039] The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent sufficient to improve a disorder, as described above. For example, for a given parameter, a therapeutically effective amount may exhibit an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic effectiveness may also be expressed as a "-fold" increase or decrease. For example, a therapeutically effective amount may be at least 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effective than a control.

[0040] Dosage may vary depending on the patient's requirements and the compound used. In the context of the present invention, the dosage administered to a patient must be sufficient to induce a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects. Determining the appropriate dosage for a particular situation is within the capabilities of those skilled in the art. Generally, treatment is initiated with a lower dosage that is less than the optimal dose of the compound. Thereafter, the dosage is gradually increased until the optimal effect is reached under the circumstances. Dosage amount and interval can be individually adjusted to provide an effective level of the administered compound for the specific clinical indication being treated. This provides a treatment regimen that is appropriate for the severity of the individual's condition.

[0041] As used herein, the term "administering" refers to oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal, or subcutaneous administration to a subject, or implantation of a sustained-release device, such as a mini-osmotic pump. Administration can be by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other delivery modes include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. "Coadministration" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapies (e.g., anti-cancer agents, chemotherapeutic agents, or treatments for neurodegenerative diseases). The compounds of the present invention can be administered alone or co-administered to a patient. Coadministration is intended to include simultaneous or sequential administration of compounds, individually or in combination (two or more compounds or agents). Thus, preparations can be combined with other active substances, if desired (e.g., to reduce metabolic degradation). The compositions of the present invention can be delivered transdermally or topically, and can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, nanoparticles, pastes, jellies, liniments, powders, and aerosols. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, and the like, suitable for ingestion by the patient. Solid preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form preparations include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. The compositions of the present invention can further include components for sustained release and / or comfort. Such components include high molecular weight anionic mucomimetic polymers, gelling polysaccharides, and finely divided drug carrier matrices.These components are discussed in further detail in U.S. Pat. Nos. 4,911,920, 5,403,841, 5,212,162, and 4,861,760, the entire contents of which are incorporated herein by reference in their entirety for all purposes. The compositions of the present invention can also be delivered as microspheres for sustained release in the body. For example, the microspheres can be administered via intradermal injection of drug-containing microspheres that slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995), as biodegradable and injectable gel formulations (see, e.g., Gao, Pharm. Res. 12:857-863, 1995), or as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In another embodiment, formulations of the compositions of the present invention can be delivered by the use of liposomes that fuse with or are endocytosed by cell membranes, i.e., by using receptor ligands attached to the liposomes that bind to surface membrane protein receptors of the cell, triggering endocytosis. In particular, liposome surfaces are specifically targeted to target cells. Liposomes can be used to focus delivery of the compositions of the invention to target cells in vivo if they carry specific receptor ligands or are otherwise preferentially directed to a particular organ. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989.) The compositions of the invention can also be delivered as nanoparticles.

[0042] "Co-administered" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapeutic agents. The compounds of the present invention can be administered alone or simultaneously to a patient. For example, the compounds of the present invention can be co-administered with an anti-cancer agent in the treatment of cancer. Co-administration is intended to include simultaneous or sequential administration of the compounds, individually or in combination (two or more compounds). The compositions of the present invention can be delivered transdermally by topical routes or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, liniments, powders, and aerosols.

[0043] As used herein, "anti-cancer agent" refers to a composition (e.g., a compound, drug, antagonist, inhibitor, modulator) that has anti-neoplastic properties or the ability to inhibit cell growth or proliferation. In embodiments, the anti-cancer agent is a chemotherapeutic agent. In embodiments, the anti-cancer agent is an agent identified herein that is useful in methods of treating cancer. In embodiments, the anti-cancer agent is an agent approved by the FDA or a similar regulatory agency in a country other than the United States to treat cancer. In embodiments, the anticancer agent is a MEK (e.g., MEK1, MEK2, or MEK1 and MEK2) inhibitor (e.g., XL518, CI-1040, PD035901, selumetinib / AZD6244, GSK1120212 / trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BA Y869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, chlorambucil, uramustine), ethyleneimines and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkylsulfonates (e.g., busulfan, melphalan, mechlorethamine, uramustine, thiotepa), phan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozocin), triazenes (decarbazine)), antimetabolites (e.g., 5-azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxolidine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin, etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin,Daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g., cisplatin, oxaloplatin, carboplatin), anthracenediones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical suppressants (e.g., mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors of mitogen-activated protein kinase signaling (e.g., U0126, PD98059, PD184352, PD0325901, AR RY-142886, SB239063, SP600125, BAY43-9006, wortmannin, or LY294002, Syk inhibitors, mTOR inhibitors, antibodies (e.g., Rituxan), gossyfol, genasense, polyphenol E, chlorofusin, all-trans retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all-trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec®), geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352, 20-epi-1,25-dihydroxyvitamin D3, 5-ethynyluracil, abiraterone, aclarubicin, acylfulvene, adecipenol, adzelesin, aldesleukin, ALL-TK antagonist, altretamine, ambamustine, amidox, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, andrographolide, angiogenesis inhibitor, antagonist D, antagonist G, antarelix, dorsal dorsal morphogenetic protein-1, antiandrogen, prostate cancer, antiestrogens, antineoplastic agents, antisense oligonucleotides, aphidicolin glycinate, apoptosis gene modulators, apoptosis regulators,Apurinic acid, ara-CDP-DL-PTBA, arginine deaminase, asulaculin, atamestane, atlimustine, axinastatin 1, axinastatin 2, axinastatin 3, azasetron, azatoxin, azatyrosine, baccatin III derivatives, balanol, batimastat, BCR / ABL antagonists, benzochlorins, benzoylstaurosporines, beta-lactam derivatives, beta-arretin, betaclamycin B, betulinic acid, bFGF inhibitors, bicalutamide, bisantrene, bisaziridinylspermine, bisnafide, bistrene A, bizelesin, brefullate, bropirimine, budotitanium, buthionine sulfoximine, calcipotriol, calphostin C, camptothecin derivatives, canarypox IL-2, capecitabine, carboxamido-amino-triazole, carboxyamidotriazole, CaRest M3, CARN 700, cartilage-derived inhibitor, carzelesin, casein kinase inhibitor (ICOS), castanospermine, cecropin B, cetrorelix, clorins, chloroquinoxaline sulfonamide, cicaprost, cis-porphyrin, cladribine, clomiphene analogue, clotrimazole, colismycin A, colismycin B, combretastatin A4, combretastatin analogue, conagenin, clambecidin 816, crisnatol, cryptophycin 8, cryptophycin A derivative, curacin A, cyclopentanethraquinone, cycloplatam, sipemycin, cytarabine ocfosfate, cytolytic factor, cytostatin, dacliximab, decitabine, dehydrogenase Didemnin B, deslorelin, dexamethasone, dexphosphamide, dexrazoxane, dexverapamil, diaziquone, didemnin B, didox, diethylnorspermine, dihydro-5-azacytidine, 9-dioxamycin, diphenylspiromustine, docosanol, dolasetron, doxifluridine, droloxifene, dronabinol, duocarmycin SA, ebselen, ecomustine, edelfosine, edrecolomab, eflornithine, elemene, emitefur, epirubicin, epristeride, estramustine analogues, estrogen agonists, estrogen antagonists, etanidazole, etoposide phosphate, exemestane,Fadrozole, fazarabine, fenretinide, filgrastim, finasteride, flavopiridol, flezelastine, fluasterone, fludarabine, fluorodaunorubicin hydrochloride, forfenimex, formestane, fostriecin, fotemustine, gadolinium texaphyrin, gallium nitrate, gallocitabine, ganirelix, gelatinase inhibitors, gemcitabine, glutathione inhibitors, hepsulfam, heregulin, hexamethylenebisacetamide bisacetamide), hypericin, ibandronic acid, idarubicin, idoxifene, idramantone, ilmofosine, ilomastat, imidazoacridone, imiquimod, immunostimulatory peptides, insulin-like growth factor-1 receptor inhibitors, interferon agonists, interferons, interleukins, iobenguane, iododoxorubicin, ipomeanol, 4-, ilopract, irsogladine, isobengazole, isohomohalichondrin B, itasetron, jasplakinolide, kahalalide F, lamellarin-N triacetate, lanreotide, leinamycin, lenograstim, lentinan sulfate, leptolstatin, letrozole, leukemia inhibitory factor, leukocyte alpha interferon, leuprolide + estrogen + progesterone, leuprorelin, levamisole, liarozole, linear polyamine analogues, lipophilic disaccharide peptides, Lipid-soluble platinum compounds, lysocrine amide 7, lobaplatin, lombricine, lometrexol, lonidamine, losoxantrone, lovastatin, loxoribine, lurtotecan, lutetium texaphyrin, lysofylline, lytic peptides, maytansine, mannostatin A, marimastat, massoprocol, maspin, matrilysin inhibitors, matrix metalloproteinase inhibitors, menogaril, mervalon methionin, meterelin, methioninase, metoclopramide, MIF inhibitors, mifepristone, miltefosine, millimostim, mismatched double-stranded RNA, mitoguazone, mitolactol, mitomycin analogs, mitonafide, mitotoxin fibroblast growth factor-saporin, mitoxantrone, mofalotene, molgramostim, monoclonal antibodies, human chorionic gonadotropin, monophosphoryl lipid A+ Myobacterium cell wall sk,Mopidamol, multidrug resistance gene inhibitors, multiple tumor suppressor 1-based therapeutics, mustard anticancer drugs, mycaperoxide B, mycobacterium cell wall extract, myriaporone, N-acetyldinaline, N-substituted benzamides, nafarelin, nagressip, naloxone + pentazocine, napavine, naphterpine, nartograstim, nedaplatin, nemorubicin, neridronic acid, neutral endopeptidase, nilutamide, nisamycin, nitric oxide modulators, nitroxide antioxidants, nitruli O6-benzylguanine, octreotide, oxenon, oligonucleotide, onapristone, ondansetron, ondansetron, oracin, oral cytokine inducer, ormaplatin, osaterone, oxaliplatin, oxaunomycin, palauamine, palmitoylrhizoxin, pamidronate, panaxytriol, panomyphen, parabactin, pazelliptin, pegaspargase, perdecin, pembrolizumab, pentosan polysulfate sodium, pentostatin, pen Trozole, perflubron, perfosfamide, perillyl alcohol, phenazinomycin, phenylacetate, phosphatase inhibitors, picibanil, pilocarpine hydrochloride, pirarubicin, piritrexim, prasetin A, prasetin B, plasminogen activator inhibitors, platinum complexes, platinum compounds, platinum-triamine complexes, porfimer sodium, porfiromycin, prednisone, propyl bis-acridone, prostaglandin J2, proteasome inhibitors, protein A-based Immunomodulators, protein kinase C inhibitors, protein kinase C inhibitors, microalgae, protein tyrosine phosphatase inhibitors, purine nucleoside phosphorylase inhibitors, purpurins, pyrazoloacridines, pyridoxylated hemoglobin polyoxyethylene conjugates, raf antagonists, raltitrexed, ramosetron, ras farnesyl protein transferase inhibitors, ras inhibitors, ras-GAP inhibitors, demethylated leteriptin, rhenium etidronate Re 186, rhizoxin, ribozymes, RII retinamide, rogletimide, rohitukin, romurtide, roquinimex, rubiginone B1, ruboxil, safingol, saintpine, SarCNU, sarcophytol A,Sargramostim, Sdi 1 mimetic, semustine, senescence-derived inhibitor 1, sense oligonucleotide, signal transduction inhibitor, signal transduction modulator, single-chain antigen binding protein, schizofuran, sobuzoxane, borocaptate sodium, sodium phenylacetate, sorbero, le, somatomedin binding protein, sonermin, sparfosic acid, spicamycin D, spiromustine, splenopentin, spongistatin 1, squalamine, stem cell inhibitors, stem cell division inhibitors, stipiamide, stromelysin inhibitors, sulfinosine, superactive vasoactive intestinal peptide antagonists, suradista, suramin, swainsonine, synthetic glycosaminoglycans, talimustine, tamoxifen methiodide, tauromustine, tazarotene, tecogalan sodium, tegafur, tellurapyrylium, telomerase inhibitors Antineoplastic agents, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, tetrazomine, saliblastin, thiocoraline, thrombopoietin, thrombopoietin mimetics, thymalfasin, thymopoietin receptor agonist, thymotrin, thyroid-stimulating hormone, tin ethyl etiopurpurin, tirapazamine, titanocene dichloride, topsentin, toremifene, totipotent stem cell factor, translation inhibitors, tretinoin, triacetyluridine, triciribine, trimetrexate, triptorelin, tropisetron, turosteride, tyrosine kinase enzyme inhibitors, tyrphostin, UBC inhibitors, ubenimex, urogenital sinus-derived growth inhibitory factor, urokinase receptor antagonists, vapreotide, variolin B, vector systems, erythrocyte gene therapy drugs, veraresol, veramine, verdins, verteporfin, vinorelbine, vinxartin, vitaxin, vorozole, zanoteron, zeniplatin, zilascorb, zinostatin stimalamer, adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, aciclovir Bicine, aclarubicin, acodazole hydrochloride, acronine, adzelesin, aldesleukin, altretamine, ambomycin, amethantrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacytidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bzelesin, bleomycin sulfate, brequinar sodium, bropirimine, busulfan, cactinomycin, calsterone, carasemide,Carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, chlorambucil, ciloremycin, cisplatin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, daunorubicin hydrochloride, decitabine, dexorumaplatin, dezaguanine, dezaguanine mesylate, diaziquone, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, drostanolone propionate, duazomycin, edatrexate, eflornithine hydrochloride, eltrombopag Samitrucin, enloplatin, enpromate, epipropizine, epirubicin hydrochloride, elbrozole, esorubicin hydrochloride, estramustine, estramustine sodium phosphate, etanidazole, etoposide, etoposide phosphate, etopurine, fadrozole hydrochloride, fazarabine, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, fluorocitabine, foskidone, phosphotriestreacin sodium, gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, imofosine (ii) mofosine), interleukin I1 (including recombinant interleukin II or rlL.sub.2), interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon alpha-n3, interferon beta-1a, interferon gamma-1b, iproplatin, irinotecan hydrochloride, lanreotide acetate, letrozole, leuprolide acetate, liarozole hydrochloride, lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol, maytansine hydrochloride Mechlorethamine, megestrol acetate, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, methotrexate sodium, metoprine, meturedepa, mitindomide, mitocalcin, mitochromin, mitodilline, mitomarcin, mitomycin, mitospar, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazoie, nogalamycin, ormaplatin, oxisuran, pegaspargase, periomycin, pentamustine, peploycin sulfate, perfosfamide,Pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, promestane, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, rhizoxin, rogletimide, safingol, safingol hydrochloride, semustine, simtrazene, sparphosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrin, streptozocin, sulofenur, tallysomycin, tecogalan sodium , tegafur, teloxantrone hydrochloride, temoporfin, teniposide, teroxilon, testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, toremifene citrate, trestrone acetate, triciribine phosphate, trimetrexate, trimetrexate glucuronate, triptorelin, tuburosol hydrochloride, uracil mustard, uredepa, vapreotide, verteporfin, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, vinedipine sulfate, vinglistine sulfate, vinleurosine sulfate, sake Vinorelbine nitrate, vinrocidin sulfate, vinzolidine sulfate, vorozole, zeniplatin, zinostatin, zorubicin hydrochloride, agents that arrest cells in the G2-M phase and / or modulate the formation or stability of microtubules (e.g., Taxol™ (i.e., paclitaxel), Taxotere™, compounds containing a taxane skeleton, elbrozole (i.e., R-55104), dolastatin 10 (i.e., DLS-10 and NSC-376128), mibobrin isethionate (i.e., as CI-980), vincristine, NSC-639829 , discodermolide (i.e., as NVP-XX-A-296), ABT-751 (Abbott, i.e., E-7010), altruchtin (e.g., altruchtin A and altruchtin C), spongistatins (e.g., spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6, spongistatin 7, spongistatin 8, and spongistatin 9), cemadotin hydrochloride (i.e., LU-103793 and NSC-D-669356), epothilones (e.g.,Epothilone A, epothilone B, epothilone C (i.e., deoxyepothilone A or dEpoA), epothilone D (i.e., KOS-862, dEpoB, and deoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (i.e., BMS-310705), 21-hydroxyepothilone D (i.e., deoxyepothilone F and dEpoF), 26-fluoroepothilone, auristatin PE (i.e., NSC-654663), soblidotin (i.e., TZT-1027), LS-4559-P (Pharmacia, i.e., LS-4577), LS-4578 (Pharmacia, i.e., LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, i.e., WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, i.e., ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko) Hakko), IDN-5005 (Indena), cryptophycin 52 (i.e., LY-355703), AC-7739 (Ajinomoto, i.e., AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, i.e., AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), vitilevuamide, tubulysin A, canadensol, centaureidin (i.e., NSC-106969), T-138067 (Tularik, i.e., T-67, TL-138067, and TI-138067), COBRA-1 (Parker Hughes Institute, i.e.,DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), oncocidin A1 (i.e., BTO-956 and DIME), DDE-313 (Parker Hughes Institute), physianolide B, laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, i.e., SPIKET-P), 3-IAABU (cytoskeleton / Mt. Sinai School of Medicine, i.e., MF-569), narcosine (also known as NSC-5366), nascapine, D-24851 (Asta Medica), A-105972 (Abbott), hemiasterlin, 3-BAABU (cytoskeleton / Mt. Sinai School of Medicine, i.e., MF-191), TMPN (Arizona State University), vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, inanosin (i.e., NSC-698666), 3-IAABE (cytoskeleton / Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, i.e., T-900607), RPR-115781 (Aventis), eleutherobin (such as desmethyleleutherobin, desacetyleleutherobin, isoeleutherobin A, and Z-eleutherobin), caribeoside, caribeolin, halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), diozostatin, (-)-phenylahistine (i.e., NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), myoseverin B, D-43411 (Zentaris, i.e., D-81862), A-289099 (Abbott),A-318315 (Abbott), HTI-286 (i.e., SPA-110, trifluoroacetate) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), resverastatin sodium phosphate, sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi)), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, corticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), pembrolizumab humanized antibody, immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., 111 In, 90 Y, or 131anti-CD20 monoclonal antibodies conjugated to IFN-γ, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR) targeted therapies or therapeutic agents (e.g., gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitum Mab (Vectibix™), vandetanib (Caprelsa™), afatinib / BIBW2992, CI-1033 / canertinib, neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299804, OS In one embodiment, the crystalline compounds disclosed herein are co-administered with pembrolizumab to a patient for the treatment of cancer.

[0044] As used herein, the term "chemotherapeutic" or "chemotherapeutic agent" is used according to its plain and ordinary meaning to refer to a chemical composition or compound having antitumor properties or the ability to inhibit cell growth or proliferation. In embodiments, the chemotherapeutic agent is an antiproliferative / antineoplastic drug, antimetabolite, antitumor antibiotic, antimitotic agent, topoisomerase inhibitor, cytostatic agent, estrogen receptor down-regulator, antiandrogen, LHRH antagonist or agonist, progestogen, aromatase inhibitor, inhibitor of 5.alpha.-reductase, agent inhibiting cancer cell invasion, inhibitor of growth factor function, farnesyltransferase inhibitor, tyrosine kinase inhibitor, serine / threonine kinase inhibitor, inhibitor of epidermal growth factor family, inhibitor of platelet-derived growth factor family, inhibitor of hepatocyte growth factor family, antiangiogenic agent, vascular damaging agent, agent used in antisense therapy, anti-ras antisense, agent used in gene therapy, immunotherapeutic agent, or antibody.

[0045] As used herein, the term "anti-inflammatory agent" is used according to its plain and ordinary meaning and refers to a composition (e.g., a compound, drug, antagonist, inhibitor, modulator) used in any manner to reduce inflammation or swelling. In embodiments, the anti-inflammatory agent is an agent identified herein that has utility in methods for treating inflammatory diseases or disorders. In embodiments, the anti-inflammatory agent is an agent approved by the FDA or a similar regulatory agency in a country other than the United States to reduce swelling and inflammation. In embodiments, the anti-inflammatory agent is a nonsteroidal anti-inflammatory drug (hereinafter NSAID) including thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol, a non-selective cyclooxygenase COX-1 / COX-2 inhibitor, whether applied topically or systemically (piroxicam, diclofenac, naproxen, propionic acids such as flurbiprofen, fenoprofen, ketoprofen and ibuprofen, mefenamic acid, indomethacin, sulindac, fenamates such as azapropazone, pyrazolones such as phenylbutazone, salicylic acid such as aspirin). acid salts); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib, and etoricoxib); cyclooxygenase inhibiting nitric oxide donors (CINOD); glucocorticoids (whether administered by topical, oral, intramuscular, intravenous, or intra-articular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular therapies such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine.

[0046] As used herein, the term "solid form" refers to a form of a compound in which the atoms or molecules are tightly connected through chemical bonds, so that its shape and volume are relatively stable.

[0047] As used herein, the term "crystalline form of a compound" refers to a compound having a crystalline structure, i.e., the compound components are arranged in a highly ordered microscopic structure that forms a crystal lattice that extends in all directions.

[0048] As used herein, the term "amorphous form of a compound" refers to a compound having an amorphous structure, i.e., a structure that lacks the long-range order of a crystalline compound.

[0049] As used herein, the term "therapeutic index" refers to the dose ratio between toxic and therapeutic effects.

[0050] 6.2 Crystalline compounds When referring herein to a compound according to the invention that is crystalline, suitably the degree of crystallinity as determined by X-ray powder diffraction data is greater than about 60%, such as, for example, greater than about 80%, particularly greater than about 90%, more particularly greater than about 95%. In an embodiment of the invention, the degree of crystallinity as determined by X-ray powder diffraction data is greater than about 98%, and the percentage of crystallinity refers to the weight percent of the total sample mass that is crystalline.

[0051] Preferably, the crystalline modifications of the compounds according to the invention are substantially free of other crystalline modifications of the compounds. Preferably, the described crystalline modifications of the compounds described herein contain, for example, less than 20%, less than 15%, less than 10%, less than 5%, less than 3%, or especially less than 1% by weight of other crystalline forms of the compound.

[0052] The crystalline compound disclosed herein is a salt of benzenesulfonate, also known as the besylate salt of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol. The besylate salt form of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol can be made by reacting the free base, 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol, with benzenesulfonic acid. The free base of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol can be made according to the procedures disclosed in Example 42 of U.S. Pat. No. 10,179,787, issued January 15, 2019, to Beck et al., and International Application No. 2018 / 022992, published February 1, 2018, both entitled "Chemokine Receptor Modulators and Uses Thereof," to Beck et al.

[0053] 6.2.A. Crystalline Form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate, and its preparation In embodiments, crystalline Form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate is provided. In embodiments, crystalline form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate has characteristic absorption peaks at 18.4°±0.3°, 22.9°±0.3°, 21.2°±0.3°, and 15.9°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

[0054] In another embodiment, crystalline form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate has characteristic absorption peaks at 18.4°±0.3°, 22.9°±0.3°, 21.2°±0.3°, 15.9°±0.3°, 12.2°±0.3°, 23.8°±0.3°, and 25.6°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

[0055] In another embodiment, crystalline form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate has characteristic absorption peaks at 18.4°±0.3°, 22.9°±0.3°, 21.2°±0.3°, 15.9°±0.3°, 12.2°±0.3°, 23.8°±0.3°, 25.6°±0.3°, 23.1°±0.3°, 20.0°±0.3°, and 16.2°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

[0056] In embodiments, crystalline Form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate has a melting point of about 159° C. to about 183° C. In other embodiments, crystalline Form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate has a melting point of about 165° C. to about 177° C. In still other embodiments, crystalline form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo)[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate has a melting point of about 168° C. to about 174° C. In still other embodiments, crystalline form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo)[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate has a melting point of about 169° C. to about 173° C. In still other embodiments, crystalline form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo)[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate has a melting point of about 170° C. to about 173° C. In still other embodiments, crystalline form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo)[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate has a melting point of about 171° C. to about 173° C.In still other embodiments, crystalline form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo)[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate has a melting point of 172°C.

[0057] In embodiments, crystalline Form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo)[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate can be prepared by first adding 2-((R)-3-(1-(1)-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate to a solvent to form a solution or suspension. As used herein, the terms solution and suspension are used interchangeably and are meant to include situations in which 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate is placed in a solvent or solvent mixture regardless of solubility. The solvent used for crystallization can be either a homogeneous solvent, a combination of solvents, or a solvent or solvent combination in which 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate exhibits temperature-dependent solubility.

[0058] In embodiments, the dissolution process is carried out at elevated temperatures. In embodiments, the dissolution process is carried out at temperatures up to and including the boiling point of the solvent or combination of solvents. In embodiments, 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b)]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate is dissolved in a solvent or solvent mixture with heating, and optionally with shaking and stirring. In embodiments, the heated solution may be kept at an elevated temperature to ensure complete dissolution of the 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate. In embodiments, the heated solution may also be filtered at an elevated temperature to remove any undissolved components.

[0059] In embodiments, the solution is slowly cooled to provide 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo)[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate crystalline Form A. In embodiments, 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo)[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate crystalline Form A is separated from residual solvent by filtration and / or drying under reduced pressure. Other methods known to those skilled in the art of crystallization (e.g., solvent evaporation, drowning, chemical reaction, seeding with a small amount of the desired crystalline form, etc.) can also be used to provide crystalline Form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo)[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate.

[0060] In embodiments, 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate is dissolved in a solvent at elevated temperature and the solution is then cooled to room temperature to provide crystalline Form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo)[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate.

[0061] In embodiments, crystalline form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo)[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate has a high melting point.

[0062] In embodiments, crystalline form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo)[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate has low hygroscopicity.

[0063] In embodiments, crystalline form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo)[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate has good solubility.

[0064] In embodiments, crystalline Form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo)[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate has good bioavailability.

[0065] In embodiments, crystalline Form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo)[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate demonstrated excellent stability after 36 months of storage at room temperature.

[0066] 6.2.B. Crystalline Form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate, and its preparation In one embodiment, crystalline form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzene is provided. In embodiments, crystalline form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate has characteristic absorption peaks at 12.5°±0.3°, 14.6°±0.3°, 22.3°±0.3°, and 13.3°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

[0067] In another embodiment, crystalline form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate has characteristic absorption peaks at 12.5°±0.3°, 14.6°±0.3°, 22.3°±0.3°, 13.3°±0.3°, 15.8°±0.3°, 24.5°±0.3°, and 4.5°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

[0068] In another embodiment, crystalline form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate has characteristic absorption peaks at 12.5°±0.3°, 14.6°±0.3°, 22.3°±0.3°, 13.3°±0.3°, 15.8°±0.3°, 24.5°±0.3°, 4.5°±0.3°, 22.8°±0.3°, 10.6°±0.3°, and 18.6°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

[0069] In embodiments, crystalline form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate has a melting point of about 105° C. to about 129° C. In other embodiments, crystalline form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate has a melting point of about 111° C. to about 123° C. In still other embodiments, crystalline form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate has a melting point of about 114° C. to about 120° C. In still other embodiments, crystalline form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate has a melting point of about 115° C. to about 119° C. In still other embodiments, crystalline form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate has a melting point of about 116° C. to about 119° C. In still other embodiments, crystalline form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate has a melting point of about 116° C. to about 118° C.

[0070] In embodiments, crystalline Form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate can be prepared by first adding 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate to a solvent to form a solution or suspension. As used herein, the terms solution and suspension are used interchangeably and are meant to include situations in which 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate is placed in a solvent or solvent mixture regardless of solubility. The solvent used for crystallization can be either a homogeneous solvent, a combination of solvents, or a solvent or solvent combination in which 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate exhibits temperature-dependent solubility.

[0071] In embodiments, the dissolution process is carried out at elevated temperatures. In embodiments, the dissolution process is carried out at temperatures up to and including the boiling point of the solvent or combination of solvents. In embodiments, 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b)]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate is dissolved in a solvent or solvent mixture with heating, and optionally with shaking and stirring. In embodiments, the heated solution may be kept at an elevated temperature to ensure complete dissolution of the 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate. In embodiments, the heated solution may also be filtered at an elevated temperature to remove any undissolved components.

[0072] In embodiments, the solution is slowly cooled to provide 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate crystalline Form B. In embodiments, 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate crystalline Form B is separated from residual solvent by filtration and / or drying under reduced pressure. Other methods known to those skilled in the art of crystallization (e.g., solvent evaporation, drowning, chemical reaction, seeding with a small amount of the desired crystalline form, etc.) can also be used to provide crystalline Form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate.

[0073] 6.3 Therapeutic Use In embodiments, methods for the treatment and prevention of CCR4-mediated diseases, disorders, or conditions are provided, comprising administering to a patient in need thereof a therapeutically effective amount of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or a pharmaceutical composition thereof. In embodiments, the patient is an animal. In embodiments, the patient is a mammal. In embodiments, the patient is human.

[0074] In embodiments, methods are provided for treating immune, inflammatory, or cancer-related diseases or disorders, comprising administering to a patient in need of such treatment crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate.

[0075] In embodiments, methods are provided for treating immune, inflammatory, or cancer-related diseases or disorders, comprising administering to a patient in need of such treatment a pharmaceutical composition comprising crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate.

[0076] Crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof are useful in treating allergy-related disorders (e.g., hypersensitivity and anaphylactic reactions); gastrointestinal disorders (e.g., inflammatory bowel disease, Crohn's disease, ulcerative colitis, ileitis, and enterocolitis); psoriasis and inflammatory dermatitis (e.g., dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria, and pruritus); vasculitis; scleroderma; asthma, COPD, and respiratory allergic diseases. autoimmune diseases, including arthritis (e.g., rheumatoid arthritis and psoriasis), multiple sclerosis, systemic lupus erythematosus, type I diabetes, and glomerulonephritis; graft rejection (e.g., allograft rejection); transplant rejection (e.g., solid organ); cancer, such as leukemia, lymphoma, and metastatic cancer, particularly solid tumors (e.g., gastric cancer); and other diseases in which inhibition of an unwanted inflammatory and / or immune response is desired, such as atherosclerosis, neurodegenerative diseases (e.g., Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis, and sinusitis.

[0077] In embodiments, the CCR4-mediated disease, disorder, or condition is asthma, COPD, rhinitis, idiopathic pulmonary fibrosis, psoriasis, and contact dermatitis. In embodiments, the disease or disorder is pulmonary fibrosis, liver inflammation, asthma, atopic dermatitis, cancer (e.g., thyroid cancer, nasopharyngeal carcinoma, Hodgkin's lymphoma, bile duct cancer, pancreatic adenocarcinoma, cutaneous melanoma of the skin, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma), or granuloma development.

[0078] Furthermore, in certain embodiments, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof are administered to a patient, preferably a human, as a preventative measure against various diseases or disorders. Crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof are useful in treating allergy-related disorders (e.g., hypersensitivity and anaphylactic reactions); gastrointestinal disorders (e.g., inflammatory bowel disease, clotting factor-1, steroid hormone ... psoriasis and inflammatory dermatitis (e.g., dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria, and pruritus); vasculitis; scleroderma; asthma, COPD, and respiratory allergic diseases (e.g., allergic rhinitis and hypersensitivity lung disease); arthritis (e.g., rheumatoid arthritis and psoriasis), multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, and glomerulonephritis autoimmune diseases, including; graft rejection (e.g., allograft rejection); transplant rejection (e.g., solid organ); cancer, such as leukemia, lymphoma, and metastatic cancer, especially solid tumors (e.g., gastric cancer); as well as atherosclerosis, neurodegenerative diseases (e.g., Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis, and sinusitis; asthma, COPD, rhinitis, idiopathic pulmonary fibrosis, psoriasis , and contact dermatitis; pulmonary fibrosis, liver inflammation, asthma, atopic dermatitis, cancer (e.g., thyroid cancer, bile duct cancer, pancreatic adenocarcinoma, cutaneous melanoma of the skin, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma), or other diseases in which inhibition of unwanted inflammatory and / or immune responses is desired, such as granuloma development.Thus, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can be used to prevent one disease or disorder and simultaneously treat another disease or disorder (e.g., preventing psoriasis during cancer treatment; preventing asthma during contact dermatitis treatment).

[0079] Crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can be determined by methods known in the art in treating the above-mentioned diseases and disorders. Crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can be used to treat or prevent the above-mentioned diseases and disorders using known procedures described in the art.

[0080] 6.4 Admin Mode In embodiments, methods for the treatment and prevention of CCR4-mediated diseases, disorders, or conditions are provided, comprising administering to a patient in need thereof a therapeutically effective amount of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or a pharmaceutical composition thereof. In embodiments, the patient is an animal. In embodiments, the patient is a mammal. In embodiments, the patient is human.

[0081] Crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof are useful in the treatment of allergy-related disorders (e.g., hypersensitivity and anaphylactic reactions); gastrointestinal disorders (e.g., inflammatory bowel disease, Crohn's disease, ulcerative colitis, ileitis, and enterocolitis); psoriasis and inflammatory dermatitis (e.g., dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria, and pruritus); vasculitis; scleroderma; asthma, COPD, and respiratory allergies. The compounds are useful for the treatment or prevention of allergic diseases (e.g., allergic rhinitis and hypersensitivity pulmonary disease); autoimmune diseases including arthritis (e.g., rheumatoid arthritis and psoriasis), multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, and glomerulonephritis; graft rejection (e.g., allograft rejection); transplant rejection (e.g., solid organ); cancer, such as leukemia, lymphoma, and metastatic cancer, particularly solid tumors (e.g., gastric cancer), and other diseases in which inhibition of an undesired inflammatory and / or immune response is desired, such as atherosclerosis, neurodegenerative diseases (e.g., Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis, and sinusitis.

[0082] In embodiments, the CCR4-mediated disease, disorder, or condition is asthma, COPD, rhinitis, idiopathic pulmonary fibrosis, psoriasis, and contact dermatitis. In embodiments, the disease or disorder is pulmonary fibrosis, liver inflammation, asthma, atopic dermatitis, cancer (e.g., thyroid cancer, bile duct cancer, pancreatic adenocarcinoma, cutaneous melanoma of the skin, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma), or granuloma development.

[0083] Furthermore, in certain embodiments, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof are administered to a patient, preferably a human, as a preventative measure against various diseases or disorders. Crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof are useful in treating allergy-related disorders (e.g., hypersensitivity and anaphylactic reactions); gastrointestinal disorders (e.g., inflammatory bowel disease, clotting factor-1, steroid hormone ... psoriasis and inflammatory dermatitis (e.g., dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria, and pruritus); vasculitis; scleroderma; asthma, COPD, and respiratory allergic diseases (e.g., allergic rhinitis and hypersensitivity lung disease); arthritis (e.g., rheumatoid arthritis and psoriasis), multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, and glomerulonephritis autoimmune diseases, including; graft rejection (e.g., allograft rejection); transplant rejection (e.g., solid organ); cancer, such as leukemia, lymphoma, and metastatic cancer, especially solid tumors (e.g., gastric cancer); as well as atherosclerosis, neurodegenerative diseases (e.g., Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis, and sinusitis; asthma, COPD, rhinitis, idiopathic pulmonary fibrosis, psoriasis , and contact dermatitis; pulmonary fibrosis, liver inflammation, asthma, atopic dermatitis, cancer (e.g., thyroid cancer, bile duct cancer, pancreatic adenocarcinoma, cutaneous melanoma of the skin, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma), or other diseases in which inhibition of unwanted inflammatory and / or immune responses is desired, such as granuloma development.Thus, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can be used to prevent one disease or disorder and simultaneously treat another disease or disorder (e.g., preventing psoriasis during cancer treatment; preventing asthma during contact dermatitis treatment).

[0084] Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topically, particularly to the ear, nose, eye, or skin.

[0085] In embodiments, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof are administered orally. Crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal, and intestinal mucosa, etc.). In embodiments, administration can be systemic or local. Various delivery systems (e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc.) are known that can be used to administer crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof.

[0086] In embodiments, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can be delivered via a sustained release system. In embodiments, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can be delivered via an oral sustained release system. In one embodiment, the oral sustained release system is a pump (Langer, supra; Sefton, 1987, CRC Crit Ref. Biomed. Eng. 14:201; Saudek et al., 1989, N. Engl. J. Med. 321:574).

[0087] In other embodiments, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can be delivered using polymeric materials (see, for example, "Medical Applications of Controlled Release," Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); "Controlled Drug Bioavailability," Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Langer et al., 1983, J. Macromol. Sci. Rev. Macromol. Chem. 23:61; Levy et al., 1985, Science 228:190; During et al. (See also Howard et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105). In yet other embodiments, polymeric materials are used for oral sustained release delivery. Suitable polymers for use in oral delivery of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof include, but are not limited to, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and hydroxyethylcellulose. In one embodiment, the polymer is hydroxypropylmethylcellulose. Other cellulose ethers have been described (Alderman, Int. J. Pharm. Tech. & Prod. Mfr. 1984, 5(3)1-9).Factors that influence drug release are well known to those skilled in the art and have been described in the art (Bamba et al., Int. J. Pharm. 1979, 2, 307).

[0088] In other embodiments, enteric coated preparations can be used for oral sustained release administration of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof. Coating materials suitable for use for oral delivery of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof include, but are not limited to, polymers with pH-dependent solubility (i.e., pH-controlled release), polymers with slow or pH-dependent swelling, dissolution, or erosion rates (i.e., time-controlled release), polymers that are enzymatically degraded (i.e., enzyme-controlled release), and polymers that form a rigid layer that is ruptured by increased pressure (i.e., pressure-controlled release).

[0089] In yet other embodiments, an osmotic delivery system is used for oral sustained release administration of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof (Verma et al., Drug Dev. Ind. Pharm. 2000, 26:695-708. In embodiments, OROS™ osmotic devices are used for oral sustained-release delivery of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof (Theeuwes et al., U.S. Pat. No. 3,845,770; Theeuwes et al., U.S. Pat. No. 3,916,899).

[0090] In yet other embodiments, a controlled-release system can be placed near the target of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof, thereby requiring only a fraction of the systemic dose (e.g., Goodson, "Medical Applications of Controlled Release," supra, vol. 2, pp. 115-138 (1984)). Other controlled-release systems discussed in Langer, 1990, Science 249:1527-1533, can also be used.

[0091] When used to treat or prevent a CCR4-mediated disease, disorder, or condition, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can be administered or applied alone or in combination with other agents. In embodiments, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof may also be administered or applied alone or in combination with a pharmaceutically active agent, including, when treating cancer, another anti-cancer / chemotherapeutic agent.

[0092] In embodiments, the anticancer agent is a MEK (e.g., MEK1, MEK2, or MEK1 and MEK2) inhibitor (e.g., XL518, CI-1040, PD035901, selumetinib / AZD6244, GSK1120212 / trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY869766), an alkylating agent (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, Melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan), ethyleneimines and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozocin), triazenes (decarbazine), antimetabolites (e.g., 5-azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine) , pemetrexed, raltitrexed, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxolidine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin), etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate, teni poside, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum compounds (e.g., cisplatin, oxaloplatin, carboplatin), anthracenediones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical suppressants (e.g., mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide),Antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors of mitogen-activated protein kinase signaling (e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY43-9006, wortmannin, or LY294002), Syk inhibitors, mTOR inhibitors, antibodies (e.g., Rituxan), gossyfol, genasense, polyphenol E , chlorofusin, all-trans retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all-trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec®), geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352, 20-epi-1,25-dihydroxyvitamin D3, 5-ethynyluracil, abiraterone, aclarubicin, acylfulvene, adecipenol, adzelesin, aldesleukin, ALL-TK antagonist, altretamine, ambamustine, amidox, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, andrographolide, angiogenesis inhibitor, antagonist D, antagonist G, antarelix, dorsal dorsal morphogenetic protein-1, antiandrogen, prostate cancer, antiestrogen, antineoplastic Drugs, antisense oligonucleotides, aphidicolin glycinate, apoptosis gene modulators, apoptosis regulators, apurinic acid, ara-CDP-DL-PTBA, arginine deaminase, asulaculin, atamestane, atrimustine, axinastatin 1, axinastatin 2, axinastatin 3, azasetron, azatoxin, azatyrosine, baccatin III derivatives, balanol, batimastat, BCR / ABL antagonists, benzochlorins, benzoylstaurosporines, beta-lactam derivatives, beta-arretin, betaclamycin B, betulinic acid, bFGF inhibitors,Bicalutamide, bisantrene, bisaziridinyl spermine, bisnafide, bistrene A, bizelesin, breflate, bropirimine, budotitane, buthionine sulfoximine, calcipotriol, calphostin C, camptothecin derivatives, canarypox IL-2, capecitabine, carboxamido-amino-triazole, carboxyamidotriazole, CaRest M3, CARN 700, cartilage-derived inhibitor, carzelesin, casein kinase inhibitor (ICOS), castanospermine, cecropin B, cetrorelix, clorins, chloroquinoxaline sulfonamide, cicaprost, cis-porphyrin, cladribine, clomiphene analogue, clotrimazole, collismycin A, collismycin B, combretastatin A4, combretastatin analogue, conagenin, clambecidin 816, crisnatol, crisp Cryptophycin 8, cryptophycin A derivative, curacin A, cyclopentanethraquinone, cycloplatam, sipemycin, cytarabine ocfosfate, cytolytic factors, cytostatin, dacliximab, decitabine, dehydrodydemnin B, deslorelin, dexamethasone, dexphosphamide, dexrazoxane, dexverapamil, diaziquone, didemnin B, didox, diethylnorspermine, dihydro-5-azacytidine , 9-dioxamycin, diphenylspiromustine, docosanol, dolasetron, doxifluridine, droloxifene, dronabinol, duocarmycin SA, ebselen, ecomustine, edelfosine, edrecolomab, eflornithine, elemene, emitefur, epirubicin, epristeride, estramustine analogues, estrogen agonists, estrogen antagonists, etanidazole, etoposide phosphate, econamides Semestan, fadrozole, fazarabine, fenretinide, filgrastim, finasteride, flavopiridol, flezelastine, fluasterone, fludarabine, fluorodaunorubicin hydrochloride, forfenimex, formestane, fostriecin, fotemustine, gadolinium texaphyrin, gallium nitrate, gallocitabine, ganirelix, gelatinase inhibitors, gemcitabine, glutathione inhibitors, hepsulfam, heregulin,Hexamethylene bisacetamide, hypericin, ibandronic acid, idarubicin, idoxifene, idramantone, ilmofosine, ilomastat, imidazoacridone, imiquimod, immunostimulatory peptides, insulin-like growth factor-1 receptor inhibitors, interferon agonists, interferons, interleukins, iobenguane, iododoxorubicin, ipomeanol, 4-, ilopract, irsogladine, isobengazole, isohomohalichondrin B, itasetron, jasplakinolide, kahalalide F, lamellarin-N trimethoprim acetate, lanreotide, leinamycin, lenograstim, lentinan sulfate, leptolstatin, letrozole, leukemia inhibitory factor, leukocyte alpha interferon, leuprolide + estrogen + progesterone, leuprolide, levamisole, liarozole, linear polyamine analogues, lipid-soluble disaccharide peptides, lipid-soluble platinum compounds, lysocrine amide 7, lobaplatin, lombricine, lometrexol, lonidamine, losoxantrone, lovastatin, loxoribine, lurtotecan, lutetium texaf lysofylline, lytic peptides, maytansine, mannostatin A, marimastat, masoprocol, maspin, matrilysin inhibitors, matrix metalloproteinase inhibitors, menogaril, melbarone, meterelin, methioninase, metoclopramide, MIF inhibitors, mifepristone, miltefosine, millimostim, mismatched double-stranded RNA, mitoguazone, mitolactol, mitomycin analogues, mitonafide, mitotoxin fibroblast growth factor-saporin, mitoxantrone, mofalotene, molgramostim, mono Clonal antibodies, human chorionic gonadotropin, monophosphoryl lipid A + Myobacterium cell wall sk, mopidamol, multidrug resistance gene inhibitors, multiple tumor suppressor 1-based therapeutic agents, mustard anticancer drugs, mycaperoxide B, mycobacterium cell wall extract, myriapolone, N-acetyldinaline, N-substituted benzamides, nafarelin, nagressip, naloxone + pentazocine, napavine, naphterpine, nartograstim, nedaplatin, nemorubicin, neridronic acid, neutral endopeptidase, nilutamide, nisamycin,Nitric oxide modulators, nitroxide antioxidants, nitrulline, O6-benzylguanine, octreotide, oxenone, oligonucleotides, onapristone, ondansetron, oracin, oral cytokine inducers, ormaplatin, osateron, oxaliplatin, oxaunomycin, palauamine, palmitoylrhizoxin, pamidronate, panaxytriol, panomyphen, parabactin, pazelliptin, pegaspargase, perdecin, pembrolizumab, pentosan polysulfate sodium, pentostatin, pentrolizumab, perflubron, perfosfamide, perillyl alcohol, phenazinomycin, phenylacetate, phosphatase inhibitors, picibanil, pilocarpine hydrochloride, pirarubicin, piritrexim, placebo Platin A, Plasetin B, Plasminogen activator inhibitors, Platinum complexes, Platinum compounds, Platinum-triamine complexes, Porfimer sodium, Porfiromycin, Prednisone, Propylbis-acridone, Prostaglandin J2, Proteasome inhibitors, Protein A-based immunomodulators, Protein kinase C inhibitors, Protein kinase C inhibitors, Microalgae, Protein tyrosine phosphatase inhibitors, Purine nucleoside phosphorylase inhibitors, Purpurin, Pyrazoloacridine, Pyridoxylated hemoglobin polyoxyethylene conjugates, Raf antagonists, Raltitrexed, Ramosetron, Ras farnesyl protein transferase inhibitors, Ras inhibitors, Ras-GAP inhibitors, Demethylated Reteriptin, Renium etidronate 186, rhizoxin, ribozyme, RII retinamide, rogletimide, rohitukin, romurtide, roquinimex, rubiginone B1, ruboxil, safingol, saintpine, SarCNU, sarcophytol A, sargramostim, Sdi 1 mimetic, semustine, senescence-derived inhibitor 1, sense oligonucleotide, signal transduction inhibitor, signal transduction modulator, single-stranded antigen binding protein, schizofuran, sobuzoxane, borocaptate sodium, sodium phenylacetate, sorberol, somatomedin binding protein, sonermin, sparfosic acid, spicamycin D, spiromustine, splenopentin, spongistatin 1, squalamine,Stem cell inhibitors, stem cell division inhibitors, stypamide, stromelysin inhibitors, sulfinosine, superactive vasoactive intestinal peptide antagonists, suradista, suramin, swainsonine, synthetic glycosaminoglycans, talimustine, tamoxifen methiodide, tauromustine, tazarote, tetrachloroquine, tecogalan sodium, tegafur, tellapyrylium, telomerase inhibitors, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, tetrazomine, saliblastine, thiocoraline, thrombopoietin, thrombopoietin mimetics, thymalfasin, thymopoietin receptor agonists, thymotrin, thyroid-stimulating hormone, tin ethyl etiopurpurin, tirapazamine, titanocene dichloride, topsentin, toremifene, totipotent stem cell factor, translation inhibitors, tretinoin, triacetyluridine, triciribine, trimetrexate Xanthan, triptorelin, tropisetron, turosteride, tyrosine kinase inhibitors, tyrphostin, UBC inhibitors, ubenimex, urogenital sinus-derived growth inhibitory factor, urokinase receptor antagonists, vapreotide, variolin B, vector-based, erythrocyte gene therapy drugs, veraresol, veramine, verdins, verteporfin, vinorelbine, vinxartin, vitaxin, vorozole, zanoteron, zeniplatin, zilascorub, zinostatin stimalamer, adriamycin, Dactinomycin, bleomycin, vinblastine, cisplatin, acivicin, aclarubicin, acodazole hydrochloride, acronine, adzelesin, aldesleukin, altretamine, ambomycin, amethantrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacytidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizeresin, bleomycin sulfate, brequinar sodium, burethromycin, ... Lopirimine, busulfan, cactinomycin, calsterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, chlorambucil, ciloremycin, cisplatin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, daunorubicin hydrochloride, decitabine, dexorumaplatin, dezaguanine, dezaguanine mesylate, diaziconazole, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, drostanolone propionate,Duazomycin, edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin, enpromate, epipropidine, epirubicin hydrochloride, elbrozole, esorubicin hydrochloride, estramustine, estramustine sodium phosphate, etanidazole, etoposide, etoposide phosphate, etopurine, fadrozole hydrochloride, fazarabine, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, fluorocitabine, foskidone, phosphotriesin sodium, gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, iimofosine, interleukin I1 (including recombinant interleukin II or rlL.sub.2), interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon Alpha-n3, interferon beta-1a, interferon gamma-1b, iproplatin, irinotecan hydrochloride, lanreotide acetate, letrozole, leuprolide acetate, liarozole hydrochloride, lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol, maytansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate Trexate, methotrexate sodium, metoprine, meturedepa, mitindomide, mitocalcin, mitochromin, mitodilline, mitomarcine, mitomycin, mitospar, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazoie, nogalamycin, ormaplatin, oxisuran, pegaspargase, periomycin, pentamstine, peploycin sulfate sulfate), perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, promestane, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, rhizoxin, rogletimide, safingol, safingol hydrochloride, semustine, simtrazene, sparphosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrin,Streptozocin, sulofenur, tallysomycin, tecogalan sodium, tegafur, teroxantrone hydrochloride, temoporfin, teniposide, teroxylone, testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, toremifene citrate, trestrone acetate, triciribine phosphate, trimetrexate, trimetrexate glucuronate, triptorelin, tuburosol hydrochloride, uracil mustard, uredepa, vapreotide, verteporfin, bile sulfate vinblastine, vincristine sulfate, vindesine, vindesine sulfate, vinedipine, vinglisinate sulfate, vinleurosine sulfate, vinorelbine tartrate, vinrocidine sulfate, vinzolidine sulfate, vorozole, zeniplatin, zinostatin, zorubicin hydrochloride, agents that arrest cells in the G2-M phase and / or modulate the formation or stability of microtubules (e.g., Taxol™ (i.e., paclitaxel), Taxotere™, compounds containing a taxane skeleton, elbrozole (i.e., R -55104), dolastatin 10 (i.e., DLS-10 and NSC-376128), mibobrine isethionate (i.e., as CI-980), vincristine, NSC-639829, discodermolide (i.e., as NVP-XX-A-296), ABT-751 (Abbott, i.e., E-7010), altruchitin (e.g., altruchitin A and altruchitin C), spongistatins (e.g., spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6, spongistatin 7, spongistatin 8, and spongistatin 9), cemadotin hydrochloride (i.e., LU-103793 and NSC-D-669356), epothilones (e.g., epothilone A, epothilone B, epothilone C (i.e., deoxyepothilone A or dEpoA), epothilone D (i.e., KOS-862, dEpoB, and deoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (i.e., BMS-310705), 21-hydroxyepothilone D (i.e., deoxyepothilone F and dEpoF),26-Fluoroepothilone, auristatin PE (i.e., NSC-654663), sobridotin (i.e., TZT-1027), LS-4559-P (Pharmacia, i.e., LS-4577), LS-4578 (Pharmacia, i.e., LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, i.e., WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), cryptophycin 52 (i.e., LY-355703), AC-7739 (Ajinomoto, i.e., AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, i.e., AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), vitilevuamide, tubulysin A, canadensol, centaureidin (i.e., NSC-106969), T-138067 (Tularik, i.e., T-67, TL-138067, and TI-138067), COBRA-1 (Parker Hughes Institute, i.e., DDE-261 and WHI-261), H10 (Kansas State University), University), H16 (Kansas State University), oncocidin A1 (i.e., BTO-956 and DIME), DDE-313 (Parker Hughes Institute), physianolide B, laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute,i.e., SPIKET-P), 3-IAABU (cytoskeleton / Mt. Sinai School of Medicine i.e., MF-569), narcosine (also known as NSC-5366), nascapine, D-24851 (Asta Medica), A-105972 (Abbott), hemiasterlin, 3-BAABU (cytoskeleton / Mt. Sinai School of Medicine i.e., MF-191), TMPN (Arizona State University), vanadocene acetylacetonate, T-138026 (Tularik), monsatrol, inanosin (i.e., NSC-698666), 3-IAABE (cytoskeleton / Mt. Sinai School of Medicine Medicine), A-204197 (Abbott), T-607 (Tuiarik, i.e., T-900607), RPR-115781 (Aventis), eleutherobin (such as desmethyleleutherobin, desacetyleleutherobin, isoeleutherobin A, and Z-eleutherobin), caribeoside, caribeolin, halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), diozostatin, (-)-phenylahisteine ​​(i.e., NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), myoseverin B, D-43411 (Zentaris, i.e., D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (i.e., SPA-110, trifluoroacetate) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), resverastatin sodium phosphate, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).Steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH), such as goserelin or leuprolide, corticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrin acetate, Antibodies include, but are not limited to, anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies, immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), androgens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., 111 In, 90 Y, or 131anti-CD20 monoclonal antibodies conjugated to IFN-γ, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR) targeted therapies or therapeutic agents (e.g., gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitum Mab (Vectibix™), vandetanib (Caprelsa™), afatinib / BIBW2992, CI-1033 / canertinib, neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299804, OS These include, but are not limited to, I-420 / desmethylerlotinib, AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, and dasatinib.

[0093] 6.5 Pharmaceutical Compositions In embodiments, a pharmaceutical composition is provided that includes a therapeutically effective amount of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and a suitable amount of a pharmaceutically acceptable vehicle to provide a form for proper administration to a patient. In embodiments, the crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and the pharmaceutically acceptable vehicle are sterile when administered to a patient. In embodiments, when crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate is administered intravenously, the vehicle is water. In other embodiments, saline and aqueous dextrose and glycerol solutions are used as liquid vehicles for injectable solutions. In still other embodiments, suitable pharmaceutical vehicles include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like. In other embodiments, the pharmaceutical composition of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate contains a wetting or emulsifying agent, or a pH buffering agent.In other embodiments, the pharmaceutical composition of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate contains an adjuvant, stabilizer, thickener, lubricant, and colorant.

[0094] In embodiments, pharmaceutical compositions comprising crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate can be manufactured by means of conventional mixing, dissolving, granulating, dragee-making, levitating, emulsifying, encapsulating, entrapping, or lyophilizing processes. In embodiments, pharmaceutical compositions comprising crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate can be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients, or auxiliaries that facilitate processing of the crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate into a pharmaceutically usable preparation. As will be appreciated by those skilled in the art, appropriate formulations will depend upon the selected route of administration.

[0095] In embodiments, the pharmaceutical composition comprising crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate is in the form of a solution, suspension, emulsion, tablet, pill, pellet, capsule, liquid-containing capsule, powder, sustained-release formulation, suppository, emulsion, aerosol, spray, or any other form suitable for use. In embodiments, the pharmaceutically acceptable vehicle is a capsule (e.g., Grosswald et al., U.S. Pat. No. 5,698,155). Other examples of suitable pharmaceutical vehicles are described in the art (see Remington's Pharmaceutical Sciences, Philadelphia College of Pharmacy and Science, 19th Edition, 1995). In embodiments, the pharmaceutical composition of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate is formulated for oral delivery. In embodiments, the pharmaceutical composition of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate is formulated for oral sustained release administration.

[0096] In embodiments, pharmaceutical compositions comprising crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate for oral administration may be in the form of, for example, tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs. Orally administered compositions may contain one or more optional agents to provide a pharmaceutically palatable preparation, such as sweeteners such as fructose, aspartame, or saccharin, flavoring agents such as peppermint, wintergreen, or cherry oil, coloring agents, and preservatives. Moreover, when in tablet or pill form, pharmaceutical compositions comprising crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate can be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time. The selectively permeable membrane surrounding the osmotically active driving compound is also suitable for oral administration of compounds and compositions containing crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate disclosed herein. In these later platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, causing it to swell and displace the drug or drug composition through an opening. These delivery platforms can provide an essentially zero-order delivery profile, as opposed to the spiked profiles of immediate-release formulations. Time-delay materials, such as glycerol monostearate or glycerol stearate, can also be used.Oral compositions containing crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. In embodiments, such vehicles are of pharmaceutical grade.

[0097] In embodiments, for oral liquid preparations such as suspensions, elixirs, and solutions, suitable carriers, excipients, or diluents include water, saline, alkylene glycols (e.g., propylene glycol), polyalkylene glycol (e.g., polyethylene glycol), oils, alcohol, weakly acidic buffer solutions of pH 4 to pH 6 (e.g., about 5 mM to about 50 mM acetate, citrate, ascorbate), etc. In embodiments, flavoring agents, preservatives, coloring agents, bile salts, acylcarnitines, etc. are further added.

[0098] Pharmaceutical compositions for administration via other routes may also be contemplated. In embodiments, for buccal administration, compositions containing crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate may take the form of tablets, lozenges, and the like formulated in a conventional manner. Liquid drug formulations suitable for use in nebulizers and liquid spray devices and EHD aerosol devices typically comprise crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate together with a pharmaceutically acceptable vehicle. In embodiments, the pharmaceutically acceptable vehicle is a liquid such as alcohol, water, polyethylene glycol, or a perfluorocarbon. In embodiments, another material can be added to modify the aerosol properties of a solution or suspension of a compound disclosed herein. In embodiments, the material is a liquid such as an alcohol, glycol, polyglycol, or fatty acid. Other methods of formulating liquid drug solutions or suspensions suitable for use in aerosol devices are known to those skilled in the art (see, e.g., Biesalski, U.S. Pat. No. 5,112,598; Biesalski, U.S. Pat. No. 5,556,611). In embodiments, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate can also be formulated into rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.In a further embodiment, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate can also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or intramuscular injection. In embodiments, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as a sparingly soluble derivative.

[0099] In embodiments, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate is formulated as the pure active agent. In other embodiments, the crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate is formulated as a mixture with other crystalline forms of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate. In embodiments, the pharmaceutical compositions provided herein comprise crystalline Form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate. In embodiments, the pharmaceutical compositions provided herein comprise crystalline Form B of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate. In embodiments, the pharmaceutical compositions provided herein comprise a mixture of crystalline Form A and Form B of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate.

[0100] In an embodiment, the crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate is formulated as an oral tablet dosage form.

[0101] In an embodiment, a pharmaceutical composition of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate in an oral tablet dosage form contains 75 mg of crystalline compound.

[0102] In an embodiment, a pharmaceutical composition of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate in an oral tablet dosage form contains 25 mg of crystalline compound.

[0103] In embodiments, the pharmaceutical composition of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate comprises a wetting agent. In embodiments, the wetting agent is sodium lauryl sulfate (SLS).

[0104] In an embodiment, the pharmaceutical composition of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate comprises a water-soluble excipient. In an embodiment, the water-soluble excipient is lactose monohydrate. In an embodiment, the water-soluble excipient is at least 50% by weight of an oral tablet dosage form.

[0105] In embodiments, the pharmaceutical composition of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate comprises a disintegrant. In embodiments, the disintegrant is croscarmellose sodium.

[0106] 6.6 Dosage The crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof are used in an amount effective to achieve the intended purpose. In embodiments, for use in treating or preventing a CCR4-mediated disease or disorder disclosed herein, the crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof are administered or applied in a therapeutically effective amount.

[0107] The amount of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof that will be effective in treating a particular disorder or condition disclosed herein will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques known in the art, as described above. Additionally, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The amount of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof administered will depend on the subject being treated, the subject's weight, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician, among other factors.

[0108] In embodiments, a dosage of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate can be delivered in a pharmaceutical composition by a single administration. In embodiments, a dosage of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate can be delivered in a pharmaceutical composition by multiple applications. In embodiments, a dosage of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate can be delivered in a pharmaceutical composition by controlled release. In embodiments, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof are delivered by oral sustained release administration. In certain embodiments, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof are administered twice daily. In embodiments, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof are administered once daily.In embodiments, the administration can be repeated intermittently. In embodiments, the administration can be provided alone. In embodiments, the administration can be provided in combination with other drugs. In embodiments, the administration can be continued as long as needed to effectively treat the CCR4-mediated conditions or disorders described herein.

[0109] In embodiments, dosage of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can be adjusted to provide from about 25 mg / day to about 500 mg / day. In other embodiments, the dosage of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo)[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can be adjusted to provide from about 50 mg / day to about 150 mg / day. In still other embodiments, dosing of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can be adjusted to provide from about 75 mg / day to about 125 mg / day. Dosage ranges can be readily determined by methods known to those skilled in the art.

[0110] Crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof are assayed in vitro and in vivo for the desired therapeutic or prophylactic activity prior to use in humans. In embodiments, a therapeutically effective dose of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof described herein will provide therapeutic benefit without causing substantial toxicity. The toxicity of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can be determined using standard pharmaceutical procedures and can be readily ascertained by one of ordinary skill in the art. In embodiments, the dosage of the crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof described herein lies within a range of circulating concentrations that include the effective dose with little or no toxicity.

[0111] 6.7 Combination therapy In certain embodiments, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof are used in combination with at least one other therapeutic agent. In embodiments, co-administration includes administering a first therapeutic agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 2 days, 4 days, 1 week, or 1 month of a second therapeutic agent. In embodiments, co-administration includes administering two therapeutic agents simultaneously or nearly simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other). In embodiments, co-administration includes administering two therapeutic agents sequentially in any order. In embodiments, simultaneous administration can be achieved by co-formulation, i.e., preparing a single pharmaceutical composition containing both therapeutic agents. In other embodiments, the therapeutic agents can be formulated separately. In another embodiment, the active agent and / or adjuvant agent may be linked or conjugated to each other. In embodiments, the compounds described herein can be combined with the treatments for CCR4-mediated diseases disclosed herein.

[0112] In embodiments, the crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical composition thereof and the other therapeutic agent act additively. In embodiments, the crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical composition thereof and the other therapeutic agent act synergistically.

[0113] In embodiments, the other therapeutic agent is an anti-cancer agent, a chemotherapeutic agent, or an anti-inflammatory agent.

[0114] In embodiments, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof are used in combination with an anticancer agent. In embodiments, the anticancer agent is a MEK (e.g., MEK1, MEK2, or MEK1 and MEK2) inhibitor (e.g., XL518, CI-1040, PD035901, selumetinib / AZD6244, GSK1120212 / trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY869766), an alkylating agent (e.g., cyclosporine ... antihistamines (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas), nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, chlorambucil, uramustine), ethyleneimines and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, romosine), cytopenic acid, semustine, streptozocin), triazene (decarbazine)), antimetabolites (e.g., 5-azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxolidine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin), etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone,plicamycin, etc.), platinum-based compounds (e.g., cisplatin, oxaloplatin, carboplatin), anthracenediones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical suppressants (e.g., mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors of mitogen-activated protein kinase signaling (e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP6001 25, BAY43-9006, wortmannin, or LY294002, Syk inhibitors, mTOR inhibitors, antibodies (e.g., Rituxan), gossyfol, genasense, polyphenol E, chlorofusin, all-trans retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all-trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec®), geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352, 20-epi-1,25-dihydroxyvitamin D3, 5-ethynyluracil, abiraterone, aclarubicin, acylfulvene, adecipenol, adzelesin, aldesleukin, ALL-TK antagonist, altretamine, ambamustine, amidox, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, and Rographolide, angiogenesis inhibitor, antagonist D, antagonist G, antarelix, dorsal dorsal morphogenetic protein-1, antiandrogen, antiestrogen, antineoplastic agent, antisense oligonucleotide, aphidicolin glycinate, apoptosis gene modulator, apoptosis regulator, apurinic acid, ara-CDP-DL-PTBA, arginine deaminase, asulaculin, atamestane, atrimustine,Axinastatin 1, Axinastatin 2, Axinastatin 3, Azasetron, Azatoxin, Azatyrosine, Baccatin III derivatives, Balanol, Batimastat, BCR / ABL antagonists, Benzochlorins, Benzoylstaurosporines, Beta-lactam derivatives, Beta-arretin, Betaclamycin B, Betulinic acid, bFGF inhibitors, Bicalutamide, Bisantrene, Bisaziridinylspermine, Bisnafide, Bistren A, Bizelesin, Breflate, Bropirimine, Budotitane, Buthionine sulfoximine, Calcipotriol, Calphostin C, Camptothecin derivatives, Canarypox IL-2, Capecitabine, Carboxamido-amino-triazoles, Carboxamidotriazoles, CaRest M3, CARN 700, cartilage-derived inhibitor, carzelesin, casein kinase inhibitor (ICOS), castanospermine, cecropin B, cetrorelix, clorins, chloroquinoxaline sulfonamide, cicaprost, cis-porphyrin, cladribine, clomiphene analogue, clotrimazole, collismycin A, collismycin B, combretastatin A4, combretastatin analogue, conagenin, clambecidin 816, crisnatol, cryptophycin 8, cryptophycin A derivative, curacin A, cyclopentanethraquinone, cycloplatam, sipemycin, cytarabine ocfosfate, cytolytic factor, cytostatin, dacliximab, decitabine, dehydrodydemnin B, deslorelin, dexamethasone, dexphos Famid, dexrazoxane, dexverapamil, diaziquone, didemnin B, didox, diethylnorspermine, dihydro-5-azacytidine, 9-dioxamycin, diphenylspiromustine, docosanol, dolasetron, doxifluridine, droloxifene, dronabinol, duocarmycin SA, ebselen, ecomustine, edelfosine, edrecolomab, eflornithine, elemene, emitefur, epirubicin, epristeride, estramustine analogues, estrogen agonists, estrogen antagonists, etanidazole, etoposide phosphate, exemestane, fadrozole, fazarabine, fenretinide, filgrastim, finasteride, flavopiridol, flezelastine,Fluasterone, fludarabine, fluorodaunorubicin hydrochloride, forfenimex, formestane, fostriecin, fotemustine, gadolinium texaphyrin, gallium nitrate, gallocitabine, ganirelix, gelatinase inhibitors, gemcitabine, glutathione inhibitors, hepsulfam, heregulin, hexamethylene bisacetamide, hypericin, ibandronic acid, idarubicin, idoxifene, idramantone, ilmofosine, ilomastat, imidazoacridone, imiquimod, immunostimulatory peptides, insulin-like growth factor-1 receptor inhibitors, interferon agonists, interferons, interleukins, iobenguane, iododoxorubicin, ipomeanol, 4-, ilopract, irsogladine, isobengazole, isohomohalichondrin B, itasetron, jasplakinolide, kahalalide F, lamellarin-N triacetate, lanreotide, leinamycin, lenograstim, lentinan sulfate, leptolstatin, letrozole, leukemia inhibitory factor, leukocyte alpha interferon, leuprolide + estrogen + progesterone, leuprorelin, levamisole, liarozole, linear polyamine analogs, lipid-soluble disaccharide peptides, lipid-soluble platinum compounds, lysocrine amide 7, lobaplatin, rombuclofenac Lysine, lometrexol, lonidamine, losoxantrone, lovastatin, loxoribine, lurtotecan, lutetium texaphyrin, lisofylline, lytic peptides, maytansine, mannostatin A, marimastat, massoprocol, maspin, matrilysine inhibitors, matrix metalloproteinase inhibitors, menogaril, mervalone, meterelin, methioninase, metoclopramide, MIF inhibitors, mifepristone, mir Tefosine, millimostim, mismatched double-stranded RNA, mitoguazone, mitolactol, mitomycin analogues, mitonafide, mitotoxin fibroblast growth factor-saporin, mitoxantrone, mofalotene, molgramostim, monoclonal antibodies, human chorionic gonadotropin, monophosphoryl lipid A+ Myobacterium cell wall sk, mopidamol, multidrug resistance gene inhibitors, multiple tumor suppressor 1-based therapeutic agents, mustard anticancer drugs, mycaperoxide B,Mycobacterium cell wall extract, myriaporone, N-acetyldinaline, N-substituted benzamides, nafarelin, nagressip, naloxone + pentazocine, napavine, naphterpine, nartograstim, nedaplatin, nemorubicin, neridronic acid, neutral endopeptidase, nilutamide, nisamycin, nitric oxide modulators, nitroxide antioxidants, nitrulline, O6-benzylguanine, octreotide, oxenone, oligonucleotides, onapuri Stone, ondansetron, ondansetron, oracin, oral cytokine inducer, ormaplatin, osateron, oxaliplatin, oxaunomycin, parauamine, palmitoylrhizoxin, pamidronate, panaxytriol, panomyphen, parabactin, pazelliptin, pegaspargase, perdecin, pembrolizumab, pentosan polysulfate sodium, pentostatin, pentrolizumab, perflubron, perfosfamide, perililal Alcohol, phenazinomycin, phenylacetate, phosphatase inhibitors, picibanil, pilocarpine hydrochloride, pirarubicin, piritrexim, prasetin A, prasetin B, plasminogen activator inhibitors, platinum complexes, platinum compounds, platinum-triamine complexes, porfimer sodium, porfiromycin, prednisone, propyl bis-acridone, prostaglandin J2, proteasome inhibitors, protein A-based immunomodulators, protein kinase C inhibitors, protein kinase C inhibitors, microalgae, protein tyrosine phosphatase inhibitors, purine nucleoside phosphorylase inhibitors, purpurin, pyrazoloacridine, pyridoxylated hemoglobin polyoxyethylene conjugates, raf antagonists, raltitrexed, ramosetron, ras farnesyl protein transferase inhibitors, ras inhibitors, ras-GAP inhibitors, demethylated reterliptin, rhenium etidronate 186, rhizoxin, ribozyme, RII retinamide, rogletimide, rohitukin, romurtide, roquinimex, rubiginone B1, ruboxil, safingol, saintpine, SarCNU, sarcophytol A, sargramostim, Sdi 1 mimetic, semustine, senescence-derived inhibitor 1, sense oligonucleotide, signal transduction inhibitor,Signal transduction modulators, single-chain antigen binding proteins, schizofuran, sobuzoxane, borocaptate sodium, sodium phenylacetate, sorberol, somatomedin binding proteins, sonermin, sparfosic acid, spicamycin D, spiromustine, splenopentin, s, Ponzistatin 1, squalamine, stem cell inhibitors, stem cell division inhibitors, stipiamide, stromelysin inhibitors, sulfinosine, superactive vasoactive intestinal peptide antagonists, suradista, suramin, swainsonine, synthetic glycosaminoglycans, tallimustine, tamoxifen methiodide, tauromustine, tazarotene, tecogalan sodium, tegafur, tellapyrylium, telomerase inhibitors, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, tetrazomine, saliblastin, thio Coraline, thrombopoietin, thrombopoietin mimetics, thymalfasin, thymopoietin receptor agonist, thymotrin, thyroid-stimulating hormone, tin ethyl etiopurpurin, tirapazamine, titanocene dichloride, topsentin, toremifene, totipotent stem cell factor, translation inhibitors, tretinoin, triacetyluridine, triciribine, trimetrexate, triptorelin, tropisetron, turosteride, tyrosine kinase inhibitors, tyrphostin, UBC inhibitors, ubenimex, urogenital sinus-derived growth inhibitor, urokinase Receptor antagonist, vapreotide, variolin B, vector system, red blood cell gene therapy drug, veraresol, veramine, verdins, verteporfin, vinorelbine, vinxartin, vitaxin, vorozole, zanoteron, zeniplatin, zilascorb, zinostatin stimalamer, adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin, aldesleukin, altretamine, amboma Isin, amethantrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacytidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bropirimine, busulfan, cactinomycin, calsterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, chlorambucil,Cilolemycin, cisplatin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, daunorubicin hydrochloride, decitabine, dexorumaplatin, dezaguanine, dezaguanine mesylate, diaziconazole, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, drostanolone propionate, duazomycin, edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin, enpromate, epipropidine, epirubicin hydrochloride, Elbrozole, esorubicin hydrochloride, estramustine, estramustine sodium phosphate, etanidazole, etoposide, etoposide phosphate, etopurine, fadrozole hydrochloride, fazarabine, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, fluorocitabine, foskidone, phosphotriesin sodium, gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, iimofosine, interleukin I1 (recombinant interleukin I2) -leukin II or rlL.sub.2), interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon alpha-n3, interferon beta-1a, interferon gamma-1b, iproplatin, irinotecan hydrochloride, lanreotide acetate, letrozole, leuprolide acetate, liarozole hydrochloride, lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol, maytansine, mechlorethamine hydrochloride, megest acetate rol, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, methotrexate sodium, metoprine, meturedepa, mitindomide, mitocalcin, mitochromin, mitodilline, mitomarcin, mitomycin, mitospar, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazoie, nogalamycin, ormaplatin, oxisuran, pegaspargase, periomycin, pentamstine, peploycin sulfate, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, promestane, porfimer sodium,Porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, rhizoxin, rogletimide, safingol, safingol hydrochloride, semustine, simtrazene, sparphosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrin, streptozocin, sulofenur, tallysomycin, tecogalan sodium, tegafur, teloxantrone hydrochloride, temoporfin, teniposide, teroxilon, testolactone, thiamiprine, thiamin Oguanine, thiotepa, tiazofurin, tirapazamine, toremifene citrate, trestron acetate, triciribine phosphate, trimetrexate, trimetrexate glucuronate, triptorelin, tuburozole hydrochloride, uracil mustard, uredepa, vapreotide, verteporfin, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, vinedipine sulfate, vinglisinate sulfate, vinleurosine sulfate, vinorelbine tartrate, vinrocidin sulfate, vinzolidine sulfate, vorozole, zeniplatin, zinostatin, zorubicin hydrochloride, Agents that arrest cells in the G2-M phase and / or modulate microtubule formation or stability (e.g., Taxol™ (i.e., paclitaxel), Taxotere™, compounds containing a taxane skeleton, elbrozole (i.e., R-55104), dolastatin 10 (i.e., DLS-10 and NSC-376128), mibobrin isethionate (i.e., as CI-980), vincristine, NSC-639829, discodermolide (i.e., as NVP-XX-A-296), ABT-751 (Abbott, i.e., E-701) 0), altoruchitins (e.g., altoruchitin A and altoruchitin C), spongistatins (e.g., spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6, spongistatin 7, spongistatin 8, and spongistatin 9), cemadotin hydrochloride (i.e., LU-103793 and NSC-D-669356), epothilones (e.g., epothilone A, epothilone B, epothilone C (i.e., deoxyepothilone A or dEpoA), epothilone D (i.e.,KOS-862, dEpoB, and deoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (i.e., BMS-310705), 21-hydroxyepothilone D (i.e., deoxyepothilone F and dEpoF), 26-fluoroepothilone, auristatin PE (i.e., NSC-654663), soblidotin (i.e., TZT-1027), LS-4559-P (Pharmacia, i.e., LS-4577), LS-4578 (Pharmacia, i.e., LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, i.e., WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, i.e., ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko) Hakko), IDN-5005 (Indena), cryptophycin 52 (i.e., LY-355703), AC-7739 (Ajinomoto, i.e., AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, i.e., AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), vitilevuamide, tubulysin A, canadensol, centaureidin (i.e., NSC-106969), T-138067 (Tularik, i.e., T-67, TL-138067, and TI-138067), COBRA-1 (Parker Hughes Institute, i.e., DDE-261 and WHI-261), H10 (Kansas State University),H16 (Kansas State University), oncocidin A1 (i.e., BTO-956 and DIME), DDE-313 (Parker Hughes Institute), physianolide B, laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, i.e., SPIKET-P), 3-IAABU (cytoskeleton / Mt. Sinai School of Medicine, i.e., MF-569), narcosine (also known as NSC-5366), nascapine, D-24851 (Asta Medica), A-105972 (Abbott), hemiasterlin, 3-BAABU (cytoskeleton / Mt. Sinai School of Medicine, i.e., MF-191), TMPN (Arizona State University), vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, inanosin (i.e., NSC-698666), 3-IAABE (cytoskeleton / Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, i.e., T-900607), RPR-115781 (Aventis), eleutherobin (such as desmethyleleutherobin, desacetyleleutherobin, isoeleutherobin A, and Z-eleutherobin), caribeoside, caribeolin, halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), diozostatin, (-)-phenylahistine (i.e., NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), myoseverin B, D-43411 (Zentaris, i.e., D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (i.e., SPA-110,trifluoroacetate (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), resverastatin sodium phosphate, BPR-OY-007 (National Health Research Institutes), and S, SR-250411 (Sanofi)), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH), such as goserelin or leuprolide, corticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., 111 In, 90 Y, or 131anti-CD20 monoclonal antibodies conjugated to IFN-γ, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, pembrolizumab (Keytruda™), EGFR inhibitors, epidermal growth factor receptor (EGFR) targeted therapies or therapeutic agents (e.g., gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tyker) b™), panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib / BIBW2992, CI-1033 / canertinib, neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299 804, OSI-420 / desmethylerlotinib, AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, and the like.

[0115] In embodiments, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof are used in combination with a chemotherapeutic agent. In embodiments, the chemotherapeutic agent is an antiproliferative / antineoplastic agent, antimetabolite, antitumor antibiotic, antimitotic agent, topoisomerase inhibitor, cytostatic agent, estrogen receptor down-regulator, antiandrogen, LHRH antagonist or agonist, progestogen, aromatase inhibitor, inhibitor of 5α-reductase, agent that inhibits cancer cell invasion, inhibitor of growth factor function, farnesyltransferase inhibitor, tyrosine kinase inhibitor, serine / threonine kinase inhibitor, inhibitor of epidermal growth factor family, inhibitor of platelet-derived growth factor family, inhibitor of hepatocyte growth factor family, anti-angiogenic agent, vascular damaging agent, agent used in antisense therapy, anti-ras antisense, agent used in gene therapy, immunotherapeutic agent, or antibody.

[0116] In embodiments, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and / or pharmaceutical compositions thereof are used in combination with an anti-inflammatory agent. In embodiments, the anti-inflammatory agent is a nonsteroidal anti-inflammatory drug (hereinafter NSAID) including thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol, a non-selective cyclooxygenase COX-1 / COX-2 inhibitor, whether applied topically or systemically (piroxicam, diclofenac, naproxen, propionic acids such as flurbiprofen, fenoprofen, ketoprofen and ibuprofen, mefenamic acid, indomethacin, sulindac, fenamates such as azapropazone, pyrazolones such as phenylbutazone, salicylic acid such as aspirin). acid salts); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib, and etoricoxib); cyclooxygenase inhibiting nitric oxide donors (CINOD); glucocorticoids (whether administered by topical, oral, intramuscular, intravenous, or intra-articular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular therapies such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine.

[0117] In embodiments, a pharmaceutical composition comprising crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate is administered concurrently with the administration of another therapeutic agent, which may be part of the same pharmaceutical composition as the crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate. In embodiments, a pharmaceutical composition comprising crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate is administered simultaneously with the administration of another therapeutic agent, which may be part of a different pharmaceutical composition. In other embodiments, a pharmaceutical composition comprising crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo)[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate is administered prior to the administration of another therapeutic agent. In other embodiments, a pharmaceutical composition comprising crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo)[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate is administered, followed by administration of another therapeutic agent.

[0118] In other embodiments, the additional therapeutic agent is pembrolizumab.

[0119] In other embodiments, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate can be administered in combination with an amorphous form of 2-((R)-3-(1-)(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate. In other embodiments, crystalline Form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate can be administered in combination with crystalline Form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate.

[0120] 7. Numbered Embodiments Embodiment 1. The compound 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate in crystalline form. Embodiment 2. The compound of embodiment 1 having characteristic absorption peaks (2θ) at 18.4°±0.3°, 22.9°±0.3°, 21.2°±0.3°, and 15.9°±0.3° in an X-ray powder diffractogram using Cu Kα radiation. Embodiment 3. The compound of embodiment 1 having characteristic absorption peaks (2θ) at 12.2°±0.3°, 23.8°±0.3°, and 25.6°±0.3° in an X-ray powder diffractogram using Cu Kα radiation. Embodiment 4. The compound of embodiment 1 having characteristic absorption peaks (2θ) at 23.1°±0.3°, 20.0°±0.3°, and 16.2°±0.3° in an X-ray powder diffractogram using Cu Kα radiation. Embodiment 5. The compound of embodiment 1, having an X-ray powder diffraction pattern using Cu Kα radiation as shown in FIG. Embodiment 6. The compound of embodiment 1, having a melting point of about 170° C. to about 173° C. as determined by differential scanning calorimetry at a scan rate of 5° C. / min. Embodiment 7. The compound of embodiment 2, having a characteristic absorption peak (2θ) at 12.2°±0.3° in an X-ray powder diffractogram using Cu Kα radiation. Embodiment 8. The compound of embodiment 2, having a characteristic absorption peak (2θ) at 23.8°±0.3° in an X-ray powder diffractogram using Cu Kα radiation. Embodiment 9. The compound of embodiment 2, having a characteristic absorption peak (2θ) at 25.6°±0.3° in an X-ray powder diffractogram using Cu Kα radiation. Embodiment 10. The compound of embodiment 2, having a characteristic absorption peak (2θ) at 23.1°±0.3° in an X-ray powder diffractogram using Cu Kα radiation. Embodiment 11. The compound of embodiment 2, having a characteristic absorption peak (2θ) at 20.0°±0.3° in an X-ray powder diffractogram using Cu Kα radiation. Embodiment 12. The compound of embodiment 2, having a characteristic absorption peak (2θ) at 16.2°±0.3° in an X-ray powder diffractogram using Cu Kα radiation. Embodiment 13. The compound of embodiment 1 having characteristic absorption peaks (2θ) at 12.5°±0.3°, 14.6°±0.3°, 22.3°±0.3°, and 13.3°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

[0002] Embodiment 14. The compound of embodiment 13 having characteristic absorption peaks (2θ) at 15.8°±0.3°, 24.5°±0.3°, and 4.5°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation. Embodiment 15. The compound of embodiment 14 having characteristic absorption peaks (2θ) at 22.8°±0.3°, 10.6°±0.3°, and 18.6°±0.3° in an X-ray powder diffractogram using Cu Kα radiation. Embodiment 16. The compound of embodiment 1 having an X-ray powder diffraction pattern using Cu Kα radiation as shown in FIG. Embodiment 1. The compound of embodiment 1, having a melting point of about 116°C to about 119°C as determined by differential scanning calorimetry at a scan rate of 7.5°C / min. Embodiment 18. The compound of embodiment 13, having a characteristic absorption peak (2θ) at 15.8°±0.3° in an X-ray powder diffractogram using Cu Kα radiation. Embodiment 19. The compound of embodiment 13, having a characteristic absorption peak (2θ) at 24.5°±0.3° in an X-ray powder diffractogram using Cu Kα radiation. Embodiment 20. The compound of embodiment 13, having a characteristic absorption peak (2θ) at 4.5°±0.3° in an X-ray powder diffractogram using Cu Kα radiation. Embodiment 21. The compound of embodiment 13, having a characteristic absorption peak (2θ) at 22.8°±0.3° in an X-ray powder diffractogram using Cu Kα radiation. Embodiment 22. The compound of embodiment 13, having a characteristic absorption peak (2θ) at 10.6°±0.3° in an X-ray powder diffractogram using Cu Kα radiation. Embodiment 23. The compound of embodiment 13, having a characteristic absorption peak (2θ) at 18.6°±0.3° in an X-ray powder diffractogram using Cu Kα radiation. Embodiment 24. A pharmaceutical composition comprising the crystalline compound of any one of embodiments 1-23 and a pharmaceutically acceptable vehicle. Embodiment 25. A pharmaceutical composition comprising the crystalline compound of any one of embodiments 2-12 and a pharmaceutically acceptable vehicle. Embodiment 26. A pharmaceutical composition comprising the crystalline compound of any one of embodiments 13-23 and a pharmaceutically acceptable vehicle. Embodiment 27. The pharmaceutical composition of any one of embodiments 24-26, wherein the composition is in the form of an oral tablet. Embodiment 28. The pharmaceutical composition of embodiment 27, wherein the composition comprises 75 mg of crystalline compound. Embodiment 29. The pharmaceutical composition of embodiment 27, wherein the composition comprises 25 mg of crystalline compound. Embodiment 30. The pharmaceutical composition of any one of embodiments 24 to 26, wherein the composition comprises a wetting agent. Embodiment 31. The pharmaceutical composition of embodiment 30, wherein the wetting agent is sodium lauryl sulfate. Embodiment 32. The pharmaceutical composition of any one of embodiments 24 to 26, wherein the composition comprises a water-soluble excipient. Embodiment 33 The pharmaceutical composition of embodiment 32, wherein the water-soluble excipient is lactose monohydrate. Embodiment 34 The pharmaceutical composition of embodiment 32, wherein the water-soluble excipient is at least 50% by weight of the oral tablet dosage form. Embodiment 35. The pharmaceutical composition of any one of embodiments 24 to 26, wherein the composition comprises a disintegrant. Embodiment 36. The pharmaceutical composition of embodiment 35, wherein the disintegrant is croscarmellose sodium. Embodiment 37. A method of treating an immune, inflammatory, or cancer-related disease or disorder, comprising administering to a patient in need of such treatment a crystalline compound of any one of embodiments 1-23. Embodiment 38. A method of treating an immune, inflammatory, or cancer-related disease or disorder, comprising administering to a patient in need of such treatment the pharmaceutical composition of any one of embodiments 24-27. Embodiment 39. The method of embodiment 37 or 38, wherein the disease or disorder is selected from an allergy-related disorder, hypersensitivity, anaphylactic response, gastrointestinal disorder, respiratory allergic disease, hypersensitivity lung disease, autoimmune disease, inflammatory skin disease, graft rejection, allograft rejection, transplant rejection, cancer, metastatic cancer, and neurodegenerative disease. Embodiment 40. The disease or disorder is inflammatory bowel disease, Crohn's disease, ulcerative colitis, ileitis, enteritis, psoriasis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria, pruritus, vasculitis, scleroderma, asthma, COPD, allergic rhinitis, arthritis (rheumatoid and psoriatic), multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, glomerulonephritis, leukemia, lymphoma, gastric cancer, atherosclerosis, Alzheimer's disease, encephalitis, meningitis. 39. The method of embodiment 37 or 38, wherein the prognosis is selected from: inflammation, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis, and sinusitis, idiopathic pulmonary fibrosis, contact dermatitis, pulmonary fibrosis, liver inflammation, asthma, thyroid cancer, bile duct cancer, pancreatic adenocarcinoma, cutaneous melanoma of the skin, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, nasopharyngeal carcinoma, Hodgkin's lymphoma, invasive breast carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, and granuloma development. Embodiment 41 The method of embodiment 37 or 38, wherein the crystalline compound is co-administered with another therapeutic agent. Embodiment 42 The method of embodiment 41, wherein the additional therapeutic agent is pembrolizumab. [Example]

[0121] 8. Working Example A stable crystalline solid form of an organic molecule is desirable because it facilitates the processing of the drug substance into a final drug product, such as an oral tablet dosage form. The compound 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol was first isolated in its free base form as outlined in U.S. Pat. No. 10,179,787. A crystalline solid form could not be produced from this free base form. Initial attempts to form the HCl salt of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol also failed to produce a crystalline solid.

[0122] Several different salts of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol were made using other acids. Salt formation experiments were performed and evaluated using 14 different acids and 13 different solvents, either alone or in several combinations, as listed in Table 1 below. [Table 1]

[0123] This study revealed that only two acids produced consistent solid forms. The paratoluenesulfonate salt yielded a stable, crystalline salt with a single polymorph and a melting point of 220°C. This highly crystalline form was less soluble than the amorphous HCl salt. The low solubility of the paratoluenesulfonate salt may inhibit drug dissolution and prevent adequate intestinal absorption. At pH 2, the dynamic solubility of the paratoluenesulfonate salt was only one-fifth that of the HCl salt. The bioavailability of this salt in rats was less than half that observed for the amorphous HCl salt. Low solubility and low bioavailability are undesirable properties for a pharmaceutical product.

[0124] The benzenesulfonate salt of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol was isolated, and two crystalline polymorphs were observed depending on the crystallization conditions. The higher melting polymorph (170 °C) was obtained by using a mixture of methyl t-butyl ether and ethanol and could be consistently isolated on a production scale. The higher melting point of this polymorph is advantageous because it facilitates manufacturing at high temperatures. This polymorph showed lower hygroscopicity and higher solubility (411 μM) than the para-turnenesulfonate salt (190 μM) in water at pH 2. The bioavailability of the benzenesulfonate salt in rats was greater than that observed with the paratoluenesulfonate salt of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (34% vs. 22%). Furthermore, the benzenesulfonate salt of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol demonstrated excellent stability after 36 months of storage at room temperature. This unexpected combination of reproducible formation, low hygroscopicity, high solubility, bioavailability, and high stability on long-term storage distinguishes this polymorph of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and makes it ideal for pharmaceutical development.

[0125] The following examples detail the preparation of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate and its crystalline forms. It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be practiced without departing from the scope of the invention.

[0126] In the examples below, the following abbreviations have the following meanings: If an abbreviation is not defined, its generally accepted meaning applies. [Table 2]

[0127] Example 1. Synthesis of amorphous 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate. [ka]

[0128] 2-[(3R)-3-[1-[1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-3-(trifluoromethyl)pyrazolo[3,4-b]pyrazin-6-yl]azetidin-3-yl]-1-piperidyl]ethanol (1.0 g, 1.84 mmol) was dissolved in ethanol (10 mL), and the solution was then cooled to -10 °C (acetone / ice bath). Benzene sulfonic acid (291.09 mg, 1.84 mmol) was then dissolved in ethanol (10 mL) by dropwise addition over 5 minutes. After the addition was complete, the reaction mixture was allowed to warm to 22 °C and stirred for 5 minutes. No precipitate formed. The mixture was concentrated under reduced pressure to give the title compound as an off-white amorphous solid (1.29 g, 99.9% yield). 1H NMR (400MHz, methanol-d4): 7.90 (s, 1H), 7.85-7.78 (m, 2H), 7.47 (d, J=2.1Hz, 1H), 7.41-7.33 (m, 4H), 7. 29(dd, J=8.5, 2.1Hz, 1H), 6.44(q, J=7.1Hz, 1H), 4.35-4.19(m, 2H), 4.05-3.94(m, 2H), 3.90(t, J=5.2H) z, 2H), 3.62(dd, J=26.7, 12.2Hz, 2H), 3.29-3.20(m, 2H), 2.94(t, J=12.6Hz, 1H), 2.77-2.58(m, 2H), 2 .22-2.08(m, 1H), 2.07-1.94(m, 2H), 1.91(d, J=7.0Hz, 3H), 1.83(t, J=13.7Hz, 1H), 1.28-1.12(m, 1H). LCMS[M+H]543.0.

[0129] Example 2. Synthesis of crystalline form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate.

[0130] Amorphous 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate (230 g, 327.83 mmol) was charged to a 2 L flask. Ethanol (345 mL) was added, and the flask was fitted with a reflux condenser and then heated to 60° C. to give a clear solution. tert-Butyl methyl ether (1035 mL) was added in one portion, and the mixture was then cooled from 60° C. to room temperature (22° C.) over 2 hours to precipitate the product. The mixture was cooled to 0° C. and stirred at 0° C. for 1 hour, then the solid was isolated by filtration, rinsed with cold MTBE / EtOH (575 ml / 115 mL) and dried under high vacuum at 55° C. to constant weight to give 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate (216.35 g, 308.37 mmol, 94% yield) as a white crystalline solid (crystal form A).

[0131] Example 3. Synthesis of crystalline form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate.

[0132] Amorphous solid 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate (5 g) was added to 15 ml of isopropyl alcohol (solvent) in a 100 ml flask. The mixture was first heated to 75° C. and then further heated to 81° C. to obtain a clear solution. Next, 45 ml of methyl ethyl ketone (counter-solvent) was added to the solution. The solution was cooled to 50° C. and then stirred for 30 minutes. The solution remained clear with no signs of solid crystal formation. A sample of the solution was removed and stirred in a small vial to produce a precipitate. A slurry sample was returned to the original flask and seeded, but the solids in the slurry dissolved.

[0133] The solution was then cooled to 35°C and then seeded at 50°C in the same manner as above, resulting in a slurry from which solid crystals formed. The slurry was stirred at 35°C for 1 hour and then allowed to cool to ambient temperature. The solids were isolated by filtration, rinsed with methyl ethyl ketone (2 x 5 ml), and then dried under vacuum at 50°C until their weight was constant, yielding 4.4 g of a white crystalline solid (crystal form B).

[0134] Example 4. X-ray powder diffraction analysis of crystalline form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate.

[0135] The X-ray powder diffractogram (XRPD) of a sample of crystalline form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate, produced according to Example 2 above, was measured on a Malvern Panalytical X'PertPro X-ray powder diffractometer using CuKα radiation with Bragg-Bentano geometry. The instrument was equipped with line-focus parallel beam optics utilizing a fixed divergence slit (0.5°) with an anti-scatter slit (1°) and an X'Celerator detector. The tube voltage and amperage were set at 45 kV and 40 mA, respectively. The angular resolution of the goniometer was approximately 0.001°. The detector covered a range of 41° in two theta (2θ) with a step size of 0.0167°. Typical averaging time was 3.5 minutes per collected XRPD pattern. A corundum sample (NIST 1976a) was used to calibrate the XRPD instrument. The sample produced the diffractogram pattern shown in Figure 1. The peaks in the diffractogram of Figure 1 are as shown in Table 2 below. [Table 3-1] [Table 3-2]

[0136] Example 5. Differential scanning calorimetry (melting point) analysis of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate (crystalline form A).

[0137] Differential scanning calorimetry (DSC) analysis of a crystalline sample of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate, produced according to Example 2 above, was measured using a TA Instruments Q2000 instrument, scanning from 40°C to 250°C at a scan rate of 10°C / min. The material was run through an appropriate temperature program (initial temperature, isothermal, ramp rate, equilibration at final temperature) to produce the thermogram shown in Figure 2. The DSC analysis shows an endothermic transition with an onset temperature of 170°C and a ΔH of 64.81 J / g.

[0138] Example 6. X-ray powder diffraction analysis of crystalline form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate.

[0139] The X-ray powder diffractogram (XRPD) of a sample of crystalline form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate, produced according to Example 3 above, was measured using the same instrument and method as described above in Example 4. The sample produced the diffractogram pattern shown in Figure 3. The peaks in the diffractogram of Figure 3 are set forth below in Table 3. [Table 4-1] [Table 4-2]

[0140] Example 7. Differential scanning calorimetry (melting point) analysis of crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate (crystalline form B).

[0141] Differential scanning calorimetry (DSC) analysis of a sample of crystalline form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate, produced according to Example 3 above, was measured using the same method and instrumentation used in Example 5. The material was run through the appropriate temperature program (initial temperature, isothermal, ramp rate, equilibration at final temperature) to produce the thermogram shown in FIG. 4. The DSC analysis shows an endothermic transition with an onset temperature of 114° C. and a ΔH of 48.82 J / g.

[0142] Example 8. Immediate Release Oral Dosage Form (5 mg Strength) Four different immediate release oral dosage forms of tablets containing crystalline Form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate (referred to as "Compound, Crystalline Form A" and "Drug Substance" in Examples 8-11) corresponding to dosage forms of 5 mg (Example 8), 25 mg (Example 9), 50 mg (Example 10), and 75 mg (Example 11) were made using the ingredients shown in Tables 3-6, respectively. The composition of the 5 mg dosage strength oral tablet is shown in Table 4. [Table 5]

[0143] Granulation: To improve the content uniformity of the tablet core formulation, a high shear wet granulation process was used to manufacture the 5 mg strength tablets.

[0144] First, the drug substance was screened through a 30-mesh screen. Next, hydroxypropyl cellulose, sodium lauryl sulfate, lactose monohydrate, microcrystalline cellulose, and croscarmellose sodium were screened through a 20-mesh screen. These six ingredients were then high-shear granulated in a 25-L bowl with the addition of purified water. Water was added at 350-450 g / min to the granulator, which was operated at an impeller speed of 290 RPM and a chopper speed of 1760. After reaching the endpoint, the wet granules were de-lumped in a standard mill equipped with a 375Q screen. The de-lumped granules were then dried in an oven operated at 40°C until the amount of water in the granules was less than 4% by weight. The dried granules were then milled in a standard mill equipped with a 40G or 75R screen.

[0145] Lubrication and compression: The milled granules were then added to an 8-quart V-blender along with the magnesium stearate, and a 30-mesh screen was used to remove any lumps. These two ingredients were blended for 4 minutes until a uniform mixture was achieved. Tablet cores were compressed using a Korsch XL100 rotary tablet press equipped with 0.2188 inch round tooling. The tablet press was operated at 70 RPM with a compression force of approximately 10 kN. The average tablet weight was 64.2 mg, average thickness was 1.93 mm, and average hardness was 3.1 kP.

[0146] Example 9. Immediate Release Oral Dosage Form (50 mg Strength) The composition of the 50 mg oral tablet dosage strength is shown in Table 5. [Table 6]

[0147] Granulation: A similar granulation procedure was followed as described in Example 8.

[0148] Lubrication and compression: The milled granules were then added to a 16-quart V-blender along with the magnesium stearate and de-lumped using a 30-mesh screen. These two ingredients were mixed for 4 minutes until a uniform mixture was achieved. Tablet cores were compressed using a Korsch XL100 rotary tablet press equipped with a 0.6496 x 0.3504 inch caplet tool. The tablet press was operated at 30 RPM with a compression force of approximately 29.5 kN. The average tablet weight was 647.5 mg, average thickness was 4.84 mm, and average hardness was 12.3 kP.

[0149] Example 10. Immediate Release Oral Dosage Form (25 mg Strength) The composition of the 25 mg dosage strength oral tablet is shown in Table 6. [Table 7]

[0150] Granulation and lubrication: First, the drug substance was screened through a 30-mesh screen. Next, hydroxypropyl cellulose, sodium lauryl sulfate, lactose monohydrate, microcrystalline cellulose, and croscarmellose sodium were screened through a 20-mesh screen. These six ingredients were then high-shear granulated in a 25-L bowl with the addition of purified water. Water was added at 350-450 g / min to the granulator, which was operated at an impeller speed of 290 RPM and a chopper speed of 1760. After reaching the endpoint, the wet granules were de-lumped using a standard mill equipped with a 375Q screen. The de-lumped granules were then dried in an oven operated at 40°C until the amount of water in the granules was less than 4% by weight. The dried granules were then milled using a standard mill equipped with a 75R screen. The milled granules were then added to a 1 cubic foot V-blender along with magnesium stearate and de-lumped using a 30-mesh screen. These two ingredients were mixed for 4 minutes until a uniformly mixed mixture was reached.

[0151] compression: Tablet cores were compressed using a Korsch XL100 rotary tablet press equipped with 7.5 mm round tooling. The tablet press was operated at 40 RPM with a compression force of approximately 15 kN. The average tablet weight was 166.4 mg, average thickness was 3.52 mm, and average hardness was 9.0 kP.

[0152] coating: Water and Opadry II amb film coating agent were added to a 1 / 2 gallon container and blended until a uniform suspension was observed. The uncoated tablets were then loaded into a 24-inch Compulab coater equipped with a 15-inch coating pan. The coater was operated at a speed of 12 RPM, a spray rate of 12 g / min, and an inlet temperature of 40-60°C. The tablets were sprayed with the suspension until a weight gain of at least 3% was achieved. The average weight of the coated tablets was 171.8 mg.

[0153] Example 11. Immediate Release Oral Dosage Form (75 mg Strength) The composition of the 75 mg oral tablet dosage strength is shown in Table 7. [Table 8]

[0154] Granulation and lubrication: For the granulation and lubrication steps, similar procedures were followed as described in Example 10.

[0155] compression: Tablet cores were compressed using a Korsch XL100 rotary tablet press equipped with a 15 mm x 7.5 mm caplet tool. The tablet press was operated at 40 RPM with a compression force of approximately 9.3 kN. The average tablet weight was 494.2 mg, average thickness was 5.46 mm, and average hardness was 15.2 kP.

[0156] It should be noted that there are alternative ways of implementing the invention. Accordingly, the present embodiments are to be considered as illustrative and not restrictive, and the invention is not limited to the details given herein, but may be modified within the scope of any claims and equivalents issued therefrom. All publications and patents cited herein are incorporated by reference in their entirety.

Claims

1. A crystalline form of the compound 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzenesulfonate.

2. 10. The compound of claim 1, having characteristic absorption peaks (2θ) at 18.4°±0.3°, 22.9°±0.3°, 21.2°±0.3°, and 15.9°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

3. 10. The compound of claim 1, having characteristic absorption peaks (2θ) at 12.2°±0.3°, 23.8°±0.3°, and 25.6°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

4. 2. The compound of claim 1, having characteristic absorption peaks (2θ) at 23.1°±0.3°, 20.0°±0.3°, and 16.2°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

5. 2. The compound of claim 1 having an X-ray powder diffraction pattern using Cu Kα radiation as shown in FIG.

6. 10. The compound of claim 1, having a melting point of about 170°C to about 173°C as determined by differential scanning calorimetry at a scan rate of 5°C / min.

7. 3. The compound according to claim 2, having a characteristic absorption peak (2θ) at 12.2°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

8. 3. The compound according to claim 2, having a characteristic absorption peak (2θ) at 23.8°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

9. 3. The compound according to claim 2, having a characteristic absorption peak (2θ) at 25.6°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

10. 3. The compound according to claim 2, having a characteristic absorption peak (2θ) at 23.1°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

11. 3. The compound according to claim 2, having a characteristic absorption peak (2θ) at 20.0°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

12. 3. The compound according to claim 2, having a characteristic absorption peak (2θ) at 16.2°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

13. 2. The compound of claim 1, having characteristic absorption peaks (2θ) at 12.5°±0.3°, 14.6°±0.3°, 22.3°±0.3°, and 13.3°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

14. 14. The compound of claim 13, having characteristic absorption peaks (2θ) at 15.8°±0.3°, 24.5°±0.3°, and 4.5°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

15. 15. The compound of claim 14, having characteristic absorption peaks (2θ) at 22.8°±0.3°, 10.6°±0.3°, and 18.6°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

16. 10. The compound of claim 1 having an X-ray powder diffraction pattern using Cu Kα radiation as shown in FIG.

17. 10. The compound of claim 1, having a melting point of about 116°C to about 119°C as determined by differential scanning calorimetry at a scan rate of 5°C / min.

18. 14. The compound according to claim 13, having a characteristic absorption peak (2θ) at 15.8°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

19. 14. The compound according to claim 13, having a characteristic absorption peak (2θ) at 24.5°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

20. 14. The compound according to claim 13, having a characteristic absorption peak (2θ) at 4.5°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

21. 14. The compound according to claim 13, having a characteristic absorption peak (2θ) at 22.8°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

22. 14. The compound according to claim 13, having a characteristic absorption peak (2θ) at 10.6°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

23. 14. The compound according to claim 13, having a characteristic absorption peak at 18.6°±0.3° (2θ) in an X-ray powder diffraction pattern using Cu Kα radiation.

24. A pharmaceutical composition comprising the crystalline compound of claim 1 and a pharmaceutically acceptable vehicle.

25. A pharmaceutical composition comprising the crystalline compound of claim 2 and a pharmaceutically acceptable vehicle.

26. 14. A pharmaceutical composition comprising the crystalline compound of claim 13 and a pharmaceutically acceptable vehicle.

27. 25. The pharmaceutical composition of claim 24, wherein the composition is in the form of an oral tablet.

28. 28. The pharmaceutical composition of claim 27, wherein the composition comprises 75 mg of the crystalline compound.

29. 28. The pharmaceutical composition of claim 27, wherein the composition comprises 25 mg of the crystalline compound.

30. 25. The pharmaceutical composition of claim 24, wherein the composition comprises a wetting agent.

31. 31. The pharmaceutical composition of claim 30, wherein the wetting agent is sodium lauryl sulfate.

32. 25. The pharmaceutical composition of claim 24, wherein the composition comprises a water-soluble excipient.

33. 33. The pharmaceutical composition of claim 32, wherein the water-soluble excipient is lactose monohydrate.

34. 33. The pharmaceutical composition of claim 32, wherein the water-soluble excipient is at least 50% by weight of the oral tablet dosage form.

35. 25. The pharmaceutical composition of claim 24, wherein the composition comprises a disintegrant.

36. 36. The pharmaceutical composition of claim 35, wherein the disintegrant is croscarmellose sodium.

37. 10. A method for treating an immune, inflammatory, or cancer-related disease or disorder, comprising administering to a patient in need of such treatment the crystalline compound of claim 1.

38. 25. A method of treating an immune, inflammatory, or cancer-related disease or disorder, comprising administering to a patient in need of such treatment the pharmaceutical composition of claim 24.

39. 38. The method of claim 37, wherein the disease or disorder is selected from an allergy-related disorder, hypersensitivity, anaphylactic reaction, gastrointestinal disorder, respiratory allergic disease, hypersensitivity lung disease, autoimmune disease, inflammatory skin disease, graft rejection, allograft rejection, transplant rejection, cancer, metastatic cancer, and neurodegenerative disease.

40. The disease or disorder may be inflammatory bowel disease, Crohn's disease, ulcerative colitis, ileitis, enteritis, psoriasis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria, pruritus, vasculitis, scleroderma, asthma, COPD, allergic rhinitis, arthritis (rheumatoid and psoriatic), multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, glomerulonephritis, leukemia, lymphoma, gastric cancer, atherosclerosis, Alzheimer's disease, encephalitis, meningitis , hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis and sinusitis, idiopathic pulmonary fibrosis, contact dermatitis, pulmonary fibrosis, liver inflammation, asthma, thyroid cancer, bile duct cancer, pancreatic adenocarcinoma, cutaneous melanoma of the skin, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, nasopharyngeal carcinoma, Hodgkin's lymphoma, invasive breast cancer, lung adenocarcinoma, lung squamous cell carcinoma, and granuloma development.

41. 38. The method of claim 37, wherein the crystalline compound is co-administered with another therapeutic agent.

42. 42. The method of claim 41, wherein the additional therapeutic agent is pembrolizumab.

43. 39. The method of claim 38, wherein the disease or disorder is selected from an allergy-related disorder, hypersensitivity, anaphylactic response, gastrointestinal disorder, respiratory allergic disease, hypersensitivity lung disease, autoimmune disease, inflammatory skin disease, graft rejection, allograft rejection, transplant rejection, cancer, metastatic cancer, and neurodegenerative disease.

44. The disease or disorder may be inflammatory bowel disease, Crohn's disease, ulcerative colitis, ileitis, enteritis, psoriasis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria, pruritus, vasculitis, scleroderma, asthma, COPD, allergic rhinitis, arthritis (rheumatoid and psoriatic), multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, glomerulonephritis, leukemia, lymphoma, gastric cancer, atherosclerosis, Alzheimer's disease, encephalitis, meningitis , hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis and sinusitis, idiopathic pulmonary fibrosis, contact dermatitis, pulmonary fibrosis, liver inflammation, asthma, thyroid cancer, bile duct cancer, pancreatic adenocarcinoma, cutaneous melanoma of the skin, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, nasopharyngeal carcinoma, Hodgkin's lymphoma, invasive breast cancer, lung adenocarcinoma, lung squamous cell carcinoma, and granuloma development.

45. 39. The method of claim 38, wherein the crystalline compound is co-administered with another therapeutic agent.

46. 46. ​​The method of claim 45, wherein the additional therapeutic agent is pembrolizumab.

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