Crystalline forms of CC chemokine receptor type 4 antagonists and their uses

Abstract

Provided are crystalline forms of C-C chemokine receptor type 4 (CCR4) antagonists, oral dosage forms thereof, and methods of use and preparation thereof.

Description

[0001] 1. Cross-reference to related applications

[0002] This application claims priority to U.S. Application No. 62 / 935,007, filed on November 13, 2019, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] Disclosed herein are crystalline forms of CC chemokine receptor type 4 (CCR4) antagonists and methods of making and using the same. These compounds are useful as therapeutic agents for treating certain diseases and conditions, including, for example, cancer. Background Art

[0004] In general, crystalline forms of drugs are preferred over amorphous forms of drugs, in part due to their superior stability. For example, in many cases, amorphous drugs convert to crystalline drug forms upon storage. Because amorphous and crystalline forms of drugs often have different physical / chemical properties, potency and / or bioavailability, such interconversion is undesirable for safety reasons in drug administration.

[0005] A critical characteristic of any crystalline drug substance is the polymorphic behavior of that material. Polymorphs are crystals of the same molecule that have different physical properties because the lattice contains different arrangements of the molecules. The different physical properties exhibited by polymorphs can 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 may be due to changes in chemical reactivity (e.g., differential hydrolysis or oxidation, causing a dosage form to change color more quickly when containing one polymorph than when containing another), mechanical changes (e.g., a tablet will crumble in storage because a kinetically favorable crystalline form converts to a thermodynamically more stable crystalline form), or both (e.g., a tablet of one polymorph will decompose more easily under high humidity). In extreme cases, solubility differences between polymorphs can result in conversion to a crystalline form that lacks potency or is toxic. In addition, the physical properties of the crystalline form may be important in drug processing. For example, a particular crystalline form may be more susceptible to forming solvates than other forms, or may be more difficult to filter and wash free of impurities (ie, the particle shape and size distribution may be different for one crystalline form relative to other forms).

[0006] The polymorph content of active pharmaceutical ingredients in solid dosage forms is strictly regulated by agencies such as the U.S. Food and Drug Administration. Generally speaking, if a non-pure, thermodynamically preferred polymorph is sold on the market, regulatory agencies require batch-by-batch monitoring of polymorphic drugs. Therefore, medical and commercial reasons tend to synthesize and sell solid drugs that are substantially free of kinetically favorable polymorphs as thermodynamically stable polymorphs. The present application addresses these and other needs in the art. Summary of the invention

[0007] 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.

[0008] 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.

[0009] 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)ethane-1-ol benzenesulfonate is provided in a form designated as Form A. In one embodiment, Form A has 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. In another embodiment, 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 diffraction pattern using Cu Kα radiation. In another embodiment, 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 diffraction pattern using Cu Kα radiation. In another embodiment, Form A has a Figure 1 X-ray powder diffraction pattern using Cu Ka radiation is shown. In another embodiment, Form A has a melting point between about 170°C and about 173°C as determined by differential scanning calorimetry at a scan rate of 5°C / min.

[0010] On the other hand, 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)ethane-1-ol benzenesulfonate is provided in a form designated as Form B. In one embodiment, Form B has 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. In another embodiment, 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 diffraction pattern using Cu Kα radiation. In another embodiment, 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 diffraction pattern using Cu Kα radiation. In another embodiment, Form B has a Figure 3 X-ray powder diffraction pattern using Cu Ka radiation is shown. In another embodiment, Form B has a melting point between about 116°C and about 119°C as determined by differential scanning calorimetry at a scan rate of 5°C / min.

[0011] In another aspect, a pharmaceutical composition 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)ethane-1-ol benzenesulfonate is provided.

[0012] In an embodiment, 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)ethane-1-ol benzenesulfonate and a pharmaceutically acceptable carrier. In an embodiment, 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)ethane-1-ol benzenesulfonate and a pharmaceutically acceptable carrier. In an embodiment, the pharmaceutical composition comprises 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)ethane-1-ol benzenesulfonate and a pharmaceutically acceptable carrier.

[0013] In another aspect, methods of treating or preventing a variety of diseases, such as allergic, immune, inflammatory, or cancer-related diseases, disorders, or conditions 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)ethane-1-ol benzenesulfonate and pharmaceutical compositions thereof are provided. Such diseases, disorders, and conditions are described in detail elsewhere, as are other diseases that can be treated or prevented using the crystalline compounds described herein.

[0014] In embodiments, the diseases or conditions include allergy-related conditions (e.g., hypersensitivity and anaphylaxis); gastrointestinal conditions (e.g., inflammatory bowel disease, Crohn's disease, ulcerative colitis, ileitis, and enteritis); psoriasis and inflammatory skin diseases (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 allergic lung disease); autoimmune diseases, including arthritis (e.g., rheumatoid arthritis and psoriasis); Disease), multiple sclerosis, systemic lupus erythematosus, type I diabetes and glomerulonephritis; transplant rejection (e.g., allogeneic transplant rejection); transplant rejection (e.g., solid organ); cancer, such as leukemia, lymphoma and metastatic cancer, especially solid tumors (e.g., gastric cancer); and other diseases that require suppression of unwanted inflammation and / or immune responses, such as atherosclerosis, neurodegenerative diseases (e.g., Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis media 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 condition is pulmonary fibrosis, liver inflammation, asthma, atopic dermatitis, cancer (e.g., thyroid cancer, bile duct cancer, pancreatic adenocarcinoma, skin melanoma, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, breast invasive cancer, lung adenocarcinoma, lung squamous cell carcinoma) or granuloma development. The method generally includes administering a therapeutically effective amount of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidin-3-yl)piperidin-1-yl)ethane-1-ol benzenesulfonate crystalline form A and / or crystalline form B to a patient in need of such treatment or prevention.

[0015] In another aspect, a method for preparing 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)ethane-1-ol benzenesulfonate is provided.

[0016] In an embodiment, a method for preparing 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)ethane-1-ol benzenesulfonate described herein is provided. In an embodiment, a method for preparing 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)ethane-1-ol benzenesulfonate described herein is provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 Shown is an X-ray powder diffraction pattern of 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)ethane-1-ol benzenesulfonate.

[0018] Figure 2 Shown is a differential scanning calorimetry thermogram of 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)ethane-1-ol benzenesulfonate.

[0019] Figure 3 The x-ray powder diffraction pattern of 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)ethane-1-ol benzenesulfonate is shown.

[0020] Figure 4 Shown is a differential scanning calorimetry thermogram of 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)ethane-1-ol benzenesulfonate. DETAILED DESCRIPTION

[0021] 6.1 Definitions

[0022] As used herein, the term "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle 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)ethane-1-ol benzenesulfonate can be administered to a patient in need thereof.

[0023] As used herein, the term "pharmaceutically acceptable salt" is intended to include salts of compounds prepared with relatively nontoxic acids or bases, depending on the specific substituents present on the compound. The crystalline compound described herein is a benzenesulfonate salt. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired base (pure acid or a base in a suitable inert solvent). Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts or magnesium salts or similar salts. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid (pure acid or an acid in a suitable inert solvent). Examples of pharmaceutically acceptable acid addition salts include acid addition salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and 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-toluenesulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginine salts, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds contain both basic and acidic functional groups that allow the compounds to be converted into base addition salts or acid addition salts.

[0024] As used herein, the terms "CC chemokine receptor type 4" and "CCR4" refer to a 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)). In the scientific literature, it has many different names, including "CC-CKR-4", "CC CKR-4", "K5-5", "CD194", "CMKBR4", "ChemR13", "HGCN" and "14099". The term encompasses any recombinant or naturally occurring CCR4 variant 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 encompasses any mutant form (e.g., frameshift mutation) of CCR4 variants that maintain CCR4 activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wild-type RNF4). In embodiments, the CCR4 protein encoded by the CCR4 gene has an amino acid sequence described in or corresponding to Entrez 1233, UniProt P51679, or RefSeq (protein) NP_005499.1. In embodiments, the CCR4 gene has a nucleic acid sequence described in RefSeq (mRNA) NM_005508. In embodiments, the amino acid sequence or nucleic acid sequence is a sequence known at the time of filing 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, the sequence corresponds to GI: 48762930. In embodiments, CCR4 is human CCR4, such as human cancers that cause CCR4. Although often found in dendritic cells, macrophages, NK cells, platelets and basophils, CCR4 is mainly associated with T cells. It plays a role in the progression of a variety of inflammatory-related diseases, and as described herein, is also involved in many other disorders. The genomic sequence of CCR4 is present on chromosome 3 (NC_000003.12), and the CCR4 gene is conserved in many species, including chimpanzees, rhesus monkeys, dogs, cattle, mice, rats, chickens and zebrafish. The CCR4 polypeptide comprises 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).

[0025] As used herein, the term "CCR4 inhibitor" refers to a compound (eg, a compound described herein) that reduces CCR4 activity compared to a control, eg, the absence of the compound or a compound with known inactivity.

[0026] As used herein, the term "activation (activation / activate / activating, etc.)" with respect to a protein refers to converting a protein from an initial inactive or inactive state into a biologically active derivative. These terms refer to activation, or activation, sensitization or upregulation of signal transduction or enzyme activity or the amount of a protein reduced in a disease.

[0027] As used herein, the terms "agonist", "activator", "up-regulator" and the like refer to substances that can detectably increase the expression or activity of a given gene or protein. Compared to a control in the absence of an agonist, an agonist can increase expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more. In some cases, the expression or activity is 1.5 times, 2 times, 3 times, 4 times, 5 times, 10 times or more higher than the expression or activity in the absence of an agonist. In embodiments, an agonist is a molecule that interacts with a target to cause or promote an increase in target activation. In embodiments, an activator is a molecule that increases, activates, promotes, enhances activation, sensitizes or upregulates, for example, a gene, protein, ligand, receptor or cell.

[0028] As used herein, with respect to protein-inhibitor interactions, the term "inhibition (inhibit / inhibiting)" and the like means to negatively affect (e.g., reduce) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In embodiments, inhibition means to negatively affect (e.g., reduce) the concentration or level of the protein relative 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 a reduction in the activity of a specific protein target. Therefore, inhibition at least partially includes partially or completely blocking stimulation, reducing, preventing or delaying activation, desensitizing or downregulating the amount of signal transduction or enzyme activity or protein. In embodiments, inhibition refers to a reduction in the activity of a target protein caused by a direct interaction (e.g., an inhibitor binds to a target protein). In embodiments, inhibition refers to a reduction in the activity of a target protein caused by an indirect interaction (e.g., an inhibitor binds to a protein that activates the target protein, thereby preventing the target protein from activating).

[0029] As used herein, the term "inhibitor", "repressor" or "antagonist" or "down-regulator" refers interchangeably to a substance that can detectably reduce the expression or activity of a given gene or protein. Antagonists can reduce expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to controls in the absence of antagonists. In some cases, expression or activity is 1.5 times, 2 times, 3 times, 4 times, 5 times, 10 times or less lower than expression or activity in the absence of antagonists. Antagonists prevent, reduce, inhibit or neutralize the activity of agonists, and antagonists can also prevent, inhibit or reduce the constitutive activity of targets (e.g., target receptors), even in the absence of determined agonists. In embodiments, inhibitors are molecules that reduce, block, prevent, delay activation, inactivate, desensitize or downregulate, for example, genes, proteins, ligands, receptors or cells. Inhibitors can also be defined as molecules that reduce, block or inactivate constitutive activity. An "antagonist" is a molecule that opposes the action of an agonist.

[0030] As used herein, the term "disease" or "condition" refers to a state of being or health condition 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 other instances, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, and the like, including solid and lymphoid 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 hepatocarcinoma), nasopharyngeal cancer, lymphoma (including acute B lymphoblastic lymphoma, non-Hodgkin's lymphoma (e.g., Burkitt's lymphoma, small cell lymphoma and large cell lymphoma), Hodgkin's lymphoma, leukemia (including AML, ALL and CML)) or multiple myeloma.

[0031] As used herein, the term "inflammatory disease" refers to a disease or condition characterized by abnormal inflammation, such as increased levels of inflammation compared to a control, such as compared to 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 diabetes, type 1 diabetes, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Gravesophthalmopathy, inflammatory bowel disease, Addison's disease, 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. These conditions are often inextricably intertwined with other diseases, disorders and conditions. A non-limiting list of inflammatory-related diseases, disorders and conditions that may be caused, for example, by inflammatory cytokines includes arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, surgical complications (e.g., inflammatory cytokines prevent healing), anemia and fibromyalgia. Other diseases and conditions that may be associated with chronic inflammation include Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infection, inflammatory bowel disease (IBD), allergic contact dermatitis and other eczemas, systemic sclerosis, transplantation and multiple sclerosis. Some of the above-mentioned diseases, disorders and conditions for which the compounds of the invention (eg, CCR4 inhibitors) may be particularly effective (eg, due to limitations of current therapies) are described in more detail below.

[0032] As used herein, the term "cancer" refers to all types of cancers, neoplasms or malignancies found in mammals (e.g., humans), including leukemias, carcinomas and sarcomas. Exemplary cancers that can be treated with the compounds or methods provided herein include brain cancer, gliomas, glioblastomas, neuroblastomas, 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, pancreatic cancer. Additional examples include thyroid cancer, bile duct cancer, pancreatic cancer, skin malignant melanoma, colon adenocarcinoma, rectal adenocarcinoma, stomach adenocarcinoma, esophageal cancer, nasopharyngeal cancer, head and neck squamous cell carcinoma, invasive breast cancer, lung adenocarcinoma, lung squamous cell carcinoma, Hodgkin's disease, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, essential macroglobulinemia, primary brain tumor, cancer, malignant pancreatic islet tumor, malignant carcinoid, urinary bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic tumor, medullary thyroid cancer, medullary thyroid cancer, carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

[0033] As used herein, the term "autoimmune disease" refers to a disease or condition in which a subject's immune system produces an abnormal immune response to a substance that would not normally elicit an immune response in a healthy subject. Examples of autoimmune diseases that can be treated using 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 dysregulation, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura (ATP), autoimmune thyroid disease, autoimmune urticaria, axonal or neuropathy, Barlow's disease, Behcet's disease, bullous pemphigoid, cardiomyopathy, Castleman's disease, celiac disease, Chagas disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), allergic granulomatous vasculitis, cicatricial pemphigoid / benign mucous membrane pemphigoid, Crohn's disease, Cogan's syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, Crest disease, essential mixed cryoglobulinemia, demyelinating neuropathy, Dermatitis herpetiformis, dermatomyositis, Devic disease (neuromyelitis optica), discoid lupus, Dressler syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, experimental allergic encephalomyelitis, Evan's syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis (GPA) (formerly Wegener's granulomatosis), Griff's disease, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpes pregnancy, hypogammaglobulinemia, idiopathic thrombocytopenic purpura (I TP), IgA nephropathy, IgG4-related sclerosing disease, immunomodulatory lipoprotein, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes (type 1 diabetes), juvenile myositis, Kawasaki syndrome, myasthenic syndrome, leukocytic vasculitis, lichen planus, lichen sclerosus, woody conjunctivitis, linear IgA disease (LAD), lupus erythematosus (SLE), Lyme disease, chronic Meniere's disease, microscopic polyangiitis, mixed connective tissue disease (MCTD), Moren's ulcer, Mu-Ha's disease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica (Devic's), neutropenia,ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatic disease, PANDAS (autoimmune neuropsychiatric disorder of childhood associated with streptococci), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry-Lomborg syndrome, Parsenager-Turner syndrome, pars plana (peripheral uveitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, autoimmune polyglandular syndromes type I, II, and III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, postpericardiotomy syndrome, progesterone dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, idiopathic pulmonary fibrosis, pyoderma gangrenosum, pure red blood cells Aplasia, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, Rett's syndrome, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, stiff-man syndrome, subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunter syndrome, rhabdomyositis, type 1 diabetes mellitus, ulcerative colitis, undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vesiculobullous dermatosis, vitiligo, or Wegener's granulomatosis (also known as granulomatosis with polyangiitis (GPA)).

[0034] As used herein, the term "treating" or "treatment" refers to the successful treatment or improvement of any sign of an injury, disease, pathology, or condition, including any objective or subjective parameter, such as reduction; relief; alleviation of symptoms or making the pathology or condition more tolerable for the patient; slowing the rate of degeneration or debilitation; or making the terminal stage of deterioration less debilitating; improving the patient's physical or mental health. The treatment or improvement of symptoms can be based on objective or subjective parameters; including the results of a physical examination, a neuropsychiatric examination, and / or a psychiatric assessment. The term "treatment" and its variants can include the prevention of injury, pathology, condition, or disease. In an embodiment, treatment is prevention. In an embodiment, treatment does not include prevention.

[0035] As used herein (and as is well understood in the art), "treating" or "treatment" also broadly encompasses any method for obtaining a beneficial or desired result (including a clinical result) in a subject's condition. Beneficial or desired clinical results may include, but are not limited to, alleviating or ameliorating one or more symptoms or conditions, alleviating the extent of the disease, stabilizing (i.e., not worsening) the disease state, preventing disease transmission or spread, delaying or slowing disease progression, improving or alleviating the disease state, reducing disease recurrence, and alleviating, whether partial or complete, and whether detectable or undetectable. In other words, "treatment" as used herein encompasses any cure, improvement, or prevention of a disease. Treatment may prevent the occurrence of a disease; inhibit the spread of a disease; alleviate symptoms of a disease (e.g., eye pain, seeing halos, red eyes, extremely high intraocular pressure), completely or partially remove the underlying cause of the disease, shorten the duration of the disease, or a combination of these things.

[0036] As used herein, "treatment" 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 may consist of a single administration, or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of the compound, the activity of the composition used in the treatment, or a combination thereof. It should also be understood that the effective dose of the agent used for treatment or prevention may increase or decrease over the course of a specific treatment or prevention regimen. By standard diagnostic assays known in the art, changes in dosage may occur and become apparent. In some cases, long-term administration may be required. For example, the composition is administered to the subject in an amount and duration sufficient to treat the patient.

[0037] As used herein, the term "prevent" refers to reducing the occurrence of symptoms of a disease in a patient. As described above, prevention can be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would be present without treatment. In embodiments, prevention refers to slowing the progression of a disease, disorder or condition or inhibiting its progression to a harmful or undesirable state.

[0038] As used herein, the term "modulator" refers to a composition that increases or decreases the level of a target molecule or a target molecule function or a molecular target physical state. In an embodiment, a CCR4-related disease modulator is a compound that reduces the severity of one or more symptoms of a CCR4-related disease (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 activity level or functional level of CCR4. The modulator can work alone, or it can also use cofactors, such as proteins, metal ions, or small molecules. Examples of modulators include small molecule compounds and other bioorganic molecules. Many small molecule compound libraries (e.g., combinatorial libraries) are commercially available and can be used as a starting point for identifying modulators. Those skilled in the art can develop one or more assays (e.g., biochemical or cell-based assays) in which such compound libraries can be screened to identify one or more compounds with desired properties; thereafter, a skilled medicinal chemist can optimize such one or more compounds by, for example, synthesizing and evaluating its analogs and derivatives. Synthesis and / or molecular modeling studies can also be used to identify activators.

[0039] The term "modulate" is used according to its common general meaning, and refers to the behavior of changing or modifying one or more properties. "Modulation" refers to the process of changing or varying one or more characteristics. For example, when applied to the effect of a modulator on a target protein, modulation means changing by increasing or decreasing the characteristic or function of the target molecule or the amount of the target molecule. In embodiments, the terms "modulate, modulation" etc. refer to the ability of a molecule (e.g., an activator or inhibitor) to directly or indirectly increase or decrease the function or activity of CCR4 relative to the absence of a molecule.

[0040] "Patient" or "subject in need thereof" refers to a living organism suffering from or susceptible to a disease or condition that can be treated by administering a pharmaceutical composition provided herein. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. In embodiments, the patient is a human. The terms "human" and "patient" are used interchangeably herein.

[0041] As used herein, an "effective amount" is an amount sufficient to achieve the purpose of the compound (e.g., to achieve its administration effect, treat a disease, reduce enzyme activity, increase enzyme activity, reduce signal transduction pathways, or alleviate one or more symptoms of a disease or condition) relative to the absence of the compound. An example of an "effective amount" is an amount sufficient to facilitate treatment, prevention, or reduction of one or more symptoms of a disease, which may also be referred to as a "therapeutically effective amount". "Reduction" of one or more symptoms (and grammatical equivalents of this phrase) means reducing the severity or frequency of one or more symptoms, or eliminating one or more symptoms. The "preventive effective amount" of a drug is the amount of the drug that will have the expected preventive effect when applied to a subject, such as preventing or delaying the onset (or recurrence) of damage, disease, pathology, or condition or reducing the possibility of the onset (or recurrence) of damage, disease, pathology, or condition or its symptoms. The complete preventive effect does not necessarily occur by administering a single dose, and may occur after only a series of doses are administered. Therefore, the preventive effective amount may be administered in one or more administration forms. As used herein, an "activity reduction amount" refers to the amount of antagonist required to reduce the activity of an enzyme relative to the absence of an antagonist. As used herein, a "function-disrupting amount" refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amount will depend on the purpose of the treatment and will be determined by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (Volumes 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). The therapeutically effective amount can be determined by measuring relevant physiological effects and can be adjusted in conjunction with the dosing regimen and diagnostic analysis of the subject's condition, etc. For example, measuring serum levels of a CCR4 inhibitor (or, e.g., a metabolite thereof) at a particular time after administration can indicate whether a therapeutically effective amount has been administered.

[0042] For any compound described herein, the therapeutically effective amount can be initially determined by cell culture assays.The target concentration will be the concentration of one or more active compounds that enables the methods described herein as measured using methods described herein or known in the art.

[0043] As is well known in the art, the therapeutically effective amount for humans can also be determined based on animal models. For example, a dosage for humans can be formulated to achieve a concentration that has been found to be effective for animals. As described above, the dosage in humans can be adjusted by monitoring the effectiveness of the compound and adjusting the dosage upward or downward. It is entirely within the capabilities of ordinary technicians to adjust the dosage based on the above methods and other methods to achieve maximum efficacy in humans. It is entirely within the capabilities of ordinary technicians to adjust the dosage based on the above methods and other methods to achieve maximum therapeutic window efficacy or toxicity in humans.

[0044] As used herein, the term "therapeutically effective amount" refers to the amount of a therapeutic agent sufficient to improve a condition as described above. For example, for a given parameter, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. The therapeutic efficacy can also be expressed as a "fold" increase or decrease. For example, a therapeutically effective amount can have an effect of at least 1.2 times, 1.5 times, 2 times, 5 times, or more relative to a control.

[0045] The dosage can vary according to the needs of the patient and the compound used. In the context of the present invention, the dosage administered to the patient should be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dosage will also depend on the presence, nature and extent of any adverse side effects. It is within the skill of the practitioner to determine the appropriate dosage for a specific situation. Typically, treatment begins with a smaller dose than the optimal dose of the compound. Thereafter, the dosage is increased in small increments until the best effect is achieved in a variety of situations. The dosage and interval can be adjusted individually to provide a level of the compound administered that is effective for the specific clinical indication being treated. This will provide a treatment regimen commensurate with the severity of the individual disease state.

[0046] As used herein, the term "administer" means oral administration to a subject, administration in the form of a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or implantation of a sustained-release device (e.g., a mini-osmotic pump). Administered 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. Other modes of delivery include, but are not limited to, the use of liposome preparations, intravenous infusions, transdermal patches, etc. "Co-administered" refers to administering a composition described herein just before or after administering one or more other therapies (e.g., anticancer agents, chemotherapeutic agents or neurodegenerative diseases). The compounds of the present invention may be administered alone or may be co-administered to a patient. Co-administration is intended to include administering the compound alone or in combination (more than one compound or agent) simultaneously or sequentially. Therefore, when necessary, these preparations can also be combined with other active substances (e.g., to reduce metabolic degradation). The compositions of the present invention can be delivered by transdermal, topical routes and can be formulated into applicators, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders and aerosols. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc. suitable for patient intake. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible particles. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. The compositions of the present invention may additionally include components that provide sustained release and / or comfort. Such components include high molecular weight, anionic mucoid polymers, gelling polysaccharides, and finely dispersed drug carrier substrates. These components are discussed in more detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions of the present invention can also be delivered in the form of microspheres for slow release in vivo. For example, the microspheres can be administered by intradermal injection of drug-containing microspheres that are slowly released subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7: 623-645, 1995); as a biodegradable and injectable gel formulation (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, the formulation of the composition of the present invention can be delivered by using liposomes that fuse with the cell membrane or are endocytosed, that is, by using receptor ligands attached to the liposomes, which bind to the surface membrane protein receptors of the cell to cause endocytosis. By using liposomes, especially when the liposome surface carries receptor ligands that are specific to the target cells or otherwise preferentially target specific organs, the composition of the present invention can be delivered to the target cells in vivo. (See, for example, 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 composition of the present invention can also be delivered as nanoparticles.

[0047] "Co-administration" refers to the administration of the compositions described herein at the same time, just before, or just after the administration of one or more additional therapies. The compounds of the present invention can be administered alone or can be co-administered to a patient. For example, the compounds of the present invention can be co-administered with an anticancer agent to treat cancer. Co-administration is intended to include administering the compounds alone or in combination (more than one compound) simultaneously or sequentially. The compositions of the present invention can be delivered by transdermal, topical routes and can be formulated into applicators, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, spreads, powders, and aerosols.

[0048] As used herein, the term "anticancer agent" refers to a composition (e.g., compound, drug, antagonist, inhibitor, modulator) that has anti-tumor properties or is capable of inhibiting cell growth or proliferation. In embodiments, the anticancer agent is a chemotherapeutic agent. In embodiments, the anticancer agent is an agent identified herein as having utility in a method for treating cancer. In embodiments, the anticancer agent is an agent approved by the FDA or similar regulatory agency in a country outside the United States for the treatment of cancer. In an embodiment, anticancer agents include, but are not limited to, MEK (e.g., MEK1, MEK2, or MEK1 and MEK2) inhibitors (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), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, chlorambucil, melphalan), ethyleneimine and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine), stine), streptozocin, triazenes (decarbazine), antimetabolites (e.g., 5-thioazaprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analogs (e.g., methotrexate) or pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin, etc.), plant alkaloids (e.g., long-acting 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.), icamycin), platinum compounds (e.g., cisplatin, oxaliplatin, carboplatin), anthracenediones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical suppressants (e.g., mitotane, aminoacetimide), 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), gossyphol, 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.RTM.), 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; adecypenol; adozelesin; aldesleukin; ALL-TK antagonist; altretamine; ambamustine; 2,4-dichlorophenoxyacetic acid (amidox) ; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitor; antagonist D; antagonist G; antarelix; anti-dorsal morphogenetic protein-1; antiandrogen, prostate cancer substance; antiestrogen; antineoplaston; antisense oligonucleotide; aphidicolin glycinate; apoptosis gene regulator; apoptosis regulator; apurinic nucleic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin1); marine cyclic peptide 2; marine cyclic peptide 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorin; benzoylstaurosporine; β-lactam derivatives; β-alethine; β-clarithromycin B; betulinic acid acid; bFGF inhibitors; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage-derived inhibitor; carzelesin; casein kinase inhibitor (ICOS); castanospermine; cecropin B; cetrorelix; chlorin; chloroquinoxalinesulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4A4); combretastatin analogs; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinone; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor factor; cytostatin; dacliximab; decitabine; dehydrogenated ecteinascidin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; ecteinascidin B; didox; diethyInorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenylspiromustinespiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristamide eride; estrogen nitrogen mustard analogs; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezellastine; fulasterone; fludarabine; fluorodaunorunicin hydrochloride hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylenediethylamide; hypericin; ibandronic acidacid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridone; imiquimod; immunostimulatory peptides; insulin-like growth factor-1 receptor inhibitors; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4- ); iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetic acid; lanreotide; leinamycin; lenograstim; lentinan sulfate sulfate; leptolstatin; letrozole; leukemia inhibitory factor; interferon alpha; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptide; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrixlysin inhibitorinhibitor; matrix metalloproteinase inhibitor; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double-stranded RNA; mitoguazone; dibromodulanol mitolactol; mitomycin analogs; mitonafide; mitotoxin; fibroblast growth factor-saponin; mitoxantrone; mofarotene; molgramostim; human chorionic gonadotropin monoclonal antibody; monophosphoryl lipid A+ mycobacterial cell wall skeleton; mopidamol; multidrug resistance gene inhibitors; multi-tumor inhibitor-1-based therapeutics; mustard anticancer agents; Indian Ocean sponge B (mycaperoxide B); mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitrous oxide antioxidants; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducers; oramaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acidacid; panaxytriol; panomifene; parabactin; pazelIiptine; pegaspargase; peldesine; pembrolizumab; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetic acid; phosphatase inhibitors; picibanil; pilocarpine hydrochloride hydrochloride; pirarubicin; piritrexim; placenta A; placenta B; plasminogen activator inhibitor; platinum complex; platinum compound; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2 J2); proteasome inhibitors; protein A-based immunomodulators; protein kinase C inhibitors; microalgae protein kinase C inhibitors; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxalated hemoglobin polyoxyethylene conjugates; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitors; demethylated retelliptine demethylated; rhenium etidronate Re186; rhizoxin; ribozyme; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi1 mimetic; semustine; senescence-derived inhibitor 1; sense oligonucleotide; signal transduction inhibitor; signal transduction modulator; single-chain antigen binding protein; sizofuran; sobuzoxane; borcarbazine sodium; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparsopartic acid acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitor; stipiamide; stromelysin inhibitor; sulfinosine; potent vasoactive intestinal peptide antagonist; suradista; suramin; suramin; synthetic mucopolysaccharide; tamustine; tamoxifen methyliodide; tauromustine; tazarotene; tecogalan sodium; tegafur ); tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocholine; thrombopoietin; thrombopoietin mimetics; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tinethyl thiazolinetiopurpurin; tirapazamine; titanium dichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitor; retinoic acid; triacetyl uridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitor; tyrphostin; UBC inhibitor; ubenimex; urogenital sinus-derived growth inhibitor; ureakinase receptor antagonist; vapreotide; varioline olin) B; vector system, red blood cell gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitamin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatinstimalamer, adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride hydrochloride; acronine; adozelesin; aldesleukin; hexamethylmelamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; binasafidedimesylate; bizelesin; bleomycin sulfate; brequinarsodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; cristal mesylate mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; drolostanone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; phosphate Etoposide; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin I1 (including recombinant interleukin II or rlL.sub.2), interferon α-2a; interferon α-2b; interferon α-n1; interferon α-n3; interferon β-1a; interferon γ-1b; iproplatin; irinotecan hydrochloride; lanreotide acetate acetate; letrozole; leuprolide acetate; liarozole hydrochloridehydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; hydrochloride; plicamycin; plomestane; porfimersodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparrosate sodium; sparsomycin; spirogermanium hydrochloridehydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate phosphate; trimetrexate; trimetrexate glucuronide; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloridehydrochloride), agents that arrest cells in the G2-M phase and / or modulate the formation or stability of microtubules (e.g., Taxol.TM (i.e., paclitaxel), Taxotere.TM, compounds containing a taxane backbone, Erbulozole (i.e., R-55104), Dolastatin 10 (i.e., DLS-10 and NSC-376128), Mivobulin isethionate (i.e., as CI-980), Vincristine, NSC-639829, Discodermolide (i.e., as NVP-XX-A-296), ABT-751 (Abbott, i.e., E-7010), Altorhyrtins (e.g., Altorhyrtin A and Altorhyrtin C), sponge statins (e.g., sponge statin 1, sponge statin 2, sponge statin 3, sponge statin 4, sponge statin 5, sponge statin 6, sponge statin 7, sponge statin 8 and sponge statin 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, riostatin PE (i.e., NSC-654663), solidotin (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, ILX-651 and LU-223651), SAH-49960 (Lillv / Novartis), SDZ-268970 (Lillv / Novartis), AM-97 (Armad / KyowaHakko), AM-132(Armad), AM-138(Armad / Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (i.e., LY-355703), AC-7739 (Aiinomoto, 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), Fijianolide 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), ofMedicine, namely MF-191), TMPN (Arizona State University), divanadium acetylacetonate, T-138026 (Tularik), Monsatrol, lnanocine (ie NSC-698666), 3-IAABE (Cytoskeleton / Mt.SinaiSchool ofMedicine), A-204197 (Abbott), T-607 (Tuiarik, i.e. T-900607), RPR-115781 (Aventis), Eleutherobin (such as demethyl Acanthopanax, deacetyl Acanthopanax, isoacanthopanax A and Z-Acanthopanax), Caribaeol, Caribaeolin, 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, (-)-Phenylahistin (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 phosphate sodium, BPR-OY-007 (National Institutes of Health), Institutes) and SSR-250411 (Sanofi), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, adrenocortical steroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol,estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guérin (BCG), levamisole, interleukin-2, α-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR and anti-VEGF monoclonal antibodies), pembrolizumab humanized antibodies, immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., with 111 In, 90 Y or 131 I-conjugated anti-CD20 monoclonal antibodies, 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) TM ), erlotinib (Tarceva TM ), cetuximab (Erbitux TM ), lapatinib (Tykerb TM ), panitumumab (Vectibix TM ), vandetanib (Caprelsa TM)、afatinib / BIBW2992、CI-1033 / canertinib、neratinib / HKI-272、CP-724714、TAK-285、AST-1306、ARRY334543、ARRY-380、AG-1478、dacomitinib / PF299804、OSI-420 / desmethyl erlotinib erlotinib), AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, etc. In one embodiment, the crystalline compound disclosed herein is co-administered to a patient with pembrolizumab in cancer treatment.

[0049] As used herein, the term "chemotherapeutic drug" or "chemotherapeutic agent" is used in accordance with its plain ordinary meaning to refer to a chemical composition or compound having anti-tumor properties or the ability to inhibit cell growth or proliferation. In an embodiment, the chemotherapeutic agent is an antiproliferative / antineoplastic agent, an antimetabolite, an antitumor antibiotic, an antimitotic agent, a topoisomerase inhibitor, a cytostatic agent, an estrogen receptor downregulator, an antiandrogen, an LHRH antagonist or an LHRH agonist, a progestin, an aromatase inhibitor, a 5.α-reductase inhibitor, an agent that inhibits cancer cell invasion, a growth factor function inhibitor, a farnesyl transferase inhibitor, a tyrosine kinase inhibitor, a serine / threonine kinase inhibitor, an inhibitor of the epidermal growth factor family, an inhibitor of the platelet-derived growth factor family, an inhibitor of the hepatocyte growth factor family; an anti-angiogenic agent, a vascular damaging agent, an agent for antisense therapy, an anti-ras antisense agent, an agent for gene therapy, an immunotherapeutic agent, or an antibody.

[0050] As used herein, the term "anti-inflammatory agent" is used according to its simple ordinary meaning and refers to a composition (e.g., compound, drug, antagonist, inhibitor, modulator) used in any way to reduce inflammation or swelling. In an embodiment, an anti-inflammatory agent is an agent identified herein that has utility in a method for treating an inflammatory disease or condition. In an embodiment, an anti-inflammatory agent is an agent approved by the FDA or similar regulatory agencies in countries outside the United States for reducing swelling and inflammation. In an embodiment, the anti-inflammatory agent is thalidomide or a derivative thereof, a retinoid, anthralin or calcipotriol, a non-steroidal anti-inflammatory agent (hereinafter referred to as NSAID), including non-selective cyclooxygenase COX-1 / COX-2 inhibitors, whether applied topically or systemically (such as piroxicam, diclofenac, propionic acid such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azaprozone, pyrazolone such as phenylbutazone, salicylates such as aspirin); select COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumacoxib, parecoxib, and etoricoxib); cyclooxygenase inhibiting nitric oxide donors (CINODs); glucocorticoids (whether administered by the topical, oral, intramuscular, intravenous, or intraarticular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular treatments, such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine.

[0051] As used herein, the term "solid form" refers to a compound form in which atoms or molecules are tightly connected by chemical bonds so that their shape and volume are relatively stable.

[0052] As used herein, the term "crystalline form of a compound" refers to a compound having a crystalline structure, ie, the components of the compound are arranged in a highly ordered microstructure, forming a lattice extending in all directions.

[0053] As used herein, the term "amorphous form of a compound" refers to a compound having an amorphous structure, ie, a structure that lacks the long-range order of a crystalline compound.

[0054] As used herein, the term "therapeutic index" refers to the dose ratio between toxic and therapeutic effects.

[0055] 6.2 Crystalline compounds

[0056] When referring to compounds according to the invention as being crystalline, suitably, the degree of crystallinity as determined by X-ray powder diffraction data is, for example, greater than about 60%, such as greater than about 80%, particularly greater than about 90%, more particularly greater than about 95%. In embodiments of the invention, the degree of crystallinity as determined by X-ray powder diffraction data is greater than about 98%, wherein the % crystallinity refers to the weight % of the total sample mass of the crystals.

[0057] Suitably, the crystalline form of the compound according to the present invention is substantially free of other crystalline forms of the compound. Suitably, the crystalline modification of the compound described herein comprises less than, for example, 20%, 15%, 10%, 5%, 3% or in particular less than 1% by weight of other crystalline forms of the compound.

[0058] The crystalline compound disclosed herein is the benzenesulfonate salt, also known as 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. The benzenesulfonate 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)ethane-1-ol can be prepared 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)ethane-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)ethane-1-ol can be prepared according to the procedures disclosed in Example 42 of U.S. Patent No. 10,179,787 to Beck et al., published on January 15, 2019, and in International Application WO2018 / 022992 to Beck et al., published on February 1, 2018, both entitled “Chemokine Receptor Modulators and Uses Thereof”.

[0059] 6.2.A. 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)ethane-1-ol benzenesulfonate and its preparation method

[0060] In an embodiment, 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)ethane-1-ol benzenesulfonate is provided. In an embodiment, 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)ethane-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 diffraction pattern using Cu Kα radiation.

[0061] In another embodiment, 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)ethane-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 the X-ray powder diffraction pattern using CuKα radiation.

[0062] In another embodiment, 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)ethane-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 the X-ray powder diffraction pattern using CuKα radiation.

[0063] In an embodiment, 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)ethane-1-ol benzenesulfonate has a melting point of about 159° C. to about 183° C. In another embodiment, 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)ethane-1-ol benzenesulfonate has a melting point of about 165° C. to about 177° C. In another embodiment, 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)ethane-1-ol benzenesulfonate has a melting point of about 168° C. to about 174° C. In another embodiment, 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)ethane-1-ol benzenesulfonate has a melting point of about 169° C. to about 173° C. In another embodiment, 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)ethane-1-ol benzenesulfonate has a melting point of about 170° C. to about 173° C. In another embodiment, 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)ethane-1-ol benzenesulfonate has a melting point of about 171° C. to about 173° C. In another embodiment, 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)ethane-1-ol benzenesulfonate has a melting point of 172°C.

[0064] In an embodiment, 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)ethane-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)ethane-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 intended to include the case where 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)ethane-1-olbenzenesulfonate is placed in a solvent or solvent mixture regardless of solubility. The solvent used in the crystallization may be 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)ethane-1-olbenzenesulfonate exhibits temperature-dependent solubility.

[0065] In an embodiment, the dissolution process is carried out at an elevated temperature. In an embodiment, the dissolution process is carried out at a temperature up to and including the boiling point of a solvent or a combination of solvents. In an embodiment, 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidin-1-yl)ethane-1-ol benzenesulfonate is dissolved in a solvent or a solvent mixture, while heating and optionally shaking and stirring. In an embodiment, the heated solution can be maintained at a high temperature to ensure that 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidin-1-yl)ethane-1-ol benzenesulfonate is completely dissolved. In embodiments, the heated solution may also be filtered at an elevated temperature to remove any undissolved components.

[0066] In embodiments, the solution is slowly cooled to provide 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)ethane-1-ol benzenesulfonate. In embodiments, 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)ethane-1-ol benzenesulfonate 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, immersion, chemical reaction, seeding with a small amount of the desired crystalline form, etc.) can also be used to provide 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)ethane-1-ol benzenesulfonate.

[0067] In an embodiment, 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)ethane-1-ol benzenesulfonate is dissolved in a solvent at an elevated temperature and the solution is then cooled to room temperature to provide 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)ethane-1-ol benzenesulfonate.

[0068] In an embodiment, 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)ethane-1-ol benzenesulfonate has a high melting point.

[0069] In an embodiment, 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)ethane-1-ol benzenesulfonate has low hygroscopicity.

[0070] In an embodiment, 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)ethane-1-ol benzenesulfonate has good solubility.

[0071] In an embodiment, 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)ethane-1-ol benzenesulfonate has good bioavailability.

[0072] In an embodiment, 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)ethane-1-ol benzenesulfonate exhibits excellent stability after storage at room temperature for 36 months.

[0073] 6.2.B. 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)ethane-1-ol benzenesulfonate and its preparation method

[0074] In one embodiment, 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-olbenzene is provided. In an embodiment, 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)ethane-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 diffraction pattern using Cu Kα radiation.

[0075] In another embodiment, 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)ethane-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 the X-ray powder diffraction pattern using CuKα radiation.

[0076] In another embodiment, 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)ethane-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 the x-ray powder diffraction pattern using CuKα radiation.

[0077] In an embodiment, 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)ethane-1-ol benzenesulfonate has a melting point of about 105° C. to about 129° C. In another embodiment, 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)ethane-1-ol benzenesulfonate has a melting point of about 111° C. to about 123° C. In another embodiment, 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)ethane-1-ol benzenesulfonate has a melting point of about 114° C. to about 120° C. In another embodiment, 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)ethane-1-ol benzenesulfonate has a melting point of about 115° C. to about 119° C. In another embodiment, 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)ethane-1-ol benzenesulfonate has a melting point of about 116° C. to about 119° C. In another embodiment, 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)ethane-1-ol benzenesulfonate has a melting point of about 116° C. to about 118° C.

[0078] In an embodiment, 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)ethane-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)ethane-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 intended to include the case where 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)ethane-1-olbenzenesulfonate is placed in a solvent or solvent mixture regardless of solubility. The solvent used in the crystallization may be 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)ethane-1-olbenzenesulfonate exhibits temperature-dependent solubility.

[0079] In an embodiment, the dissolution process is carried out at an elevated temperature. In an embodiment, the dissolution process is carried out at a temperature up to and including the boiling point of a solvent or a combination of solvents. In an embodiment, 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidin-1-yl)ethane-1-ol benzenesulfonate is dissolved in a solvent or a solvent mixture, while heating and optionally shaking and stirring. In an embodiment, the heated solution can be maintained at a high temperature to ensure that 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidin-1-yl)ethane-1-ol benzenesulfonate is completely dissolved. In embodiments, the heated solution may also be filtered at an elevated temperature to remove any undissolved components.

[0080] In embodiments, the solution is slowly cooled to provide 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)ethane-1-ol benzenesulfonate. In embodiments, 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)ethane-1-ol benzenesulfonate 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, immersion, chemical reaction, breeding with a small amount of the desired crystalline form, etc.) can also be used to provide 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)ethane-1-ol benzenesulfonate.

[0081] 6.3 Therapeutic Uses

[0082] In embodiments, methods of treating and preventing 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)ethane-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 a human.

[0083] In an embodiment, a method of treating an immune, inflammatory or cancer-related disease or condition is provided, the method comprising administering 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)ethane-1-ol benzenesulfonate to a patient in need of such treatment.

[0084] In an embodiment, a method of treating an immune, inflammatory or cancer-related disease or condition is provided, 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)ethane-1-ol benzenesulfonate.

[0085] 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can be administered to patients, particularly human patients, suffering from allergy-related disorders (e.g., hypersensitivity and anaphylaxis); gastrointestinal disorders (e.g., inflammatory bowel disease, Crohn's disease, ulcerative colitis, ileitis and enteritis); psoriasis and inflammatory skin diseases (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 allergic lung disease); autoimmune diseases, including arthritis (such as rheumatoid and psoriasis), multiple sclerosis, systemic lupus erythematosus, type I diabetes and glomerulonephritis; transplant rejection (e.g., allogeneic transplant rejection); transplant rejection (e.g., solid organ); cancer, such as leukemia, lymphoma and metastatic cancer, especially solid tumors (e.g., gastric cancer); and other diseases that require suppression of unwanted inflammatory and / or immune responses, such as atherosclerosis, neurodegenerative diseases (e.g., Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis media and sinusitis.

[0086] 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, skin cutaneous melanoma, 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.

[0087] In addition, 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof are administered to patients, preferably humans, as preventive measures against various diseases or conditions. 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can be administered as a preventive measure to patients prone to: allergy-related conditions (e.g., hypersensitivity and anaphylaxis); gastrointestinal conditions (e.g., inflammatory bowel disease, Crohn's disease, ulcerative colitis, ileitis, and enteritis); psoriasis and inflammatory skin diseases (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 allergic lung disease); autoimmune diseases, including arthritis (e.g., rheumatoid arthritis and psoriasis), multiple sclerosis, systemic lupus erythematosus, type I diabetes and glomerulonephritis; transplant rejection (e.g., allogeneic transplant 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 requiring suppression of unwanted inflammatory and / or immune responses, such as atherosclerosis, neurodegenerative diseases (e.g., Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis media and sinusitis; asthma, chronic obstructive pulmonary disease, 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, skin cutaneous melanoma, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, breast invasive cancer, lung adenocarcinoma, lung squamous cell carcinoma) or granuloma development. Therefore, 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can be used to prevent one disease or condition and simultaneously treat another (e.g., preventing psoriasis while treating cancer; preventing asthma while treating contact dermatitis).

[0088] The suitability 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof in treating the above-mentioned diseases and conditions can be determined by methods known in the art. 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can be used to treat or prevent the above-mentioned diseases and conditions using known methods described in the art.

[0089] 6.4 Mode of administration

[0090] In embodiments, methods of treating and preventing 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)ethane-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 a human.

[0091] 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can be used to treat or prevent: allergy-related disorders (e.g., hypersensitivity and anaphylaxis); gastrointestinal disorders (e.g., inflammatory bowel disease, Crohn's disease, ulcerative colitis, ileitis and enteritis); psoriasis and inflammatory skin diseases (e.g., dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria and pruritus); vasculitis; scleroderma; asthma, CO PD and respiratory allergic diseases (e.g., allergic rhinitis and allergic lung disease); autoimmune diseases, including arthritis (such as rheumatoid and psoriasis), multiple sclerosis, systemic lupus erythematosus, type I diabetes and glomerulonephritis; transplant rejection (e.g., allogeneic transplant rejection); transplant rejection (e.g., solid organ); cancer, such as leukemia, lymphoma and metastatic cancer, especially solid tumors (e.g., gastric cancer); and other diseases that require suppression of unwanted inflammatory and / or immune responses, such as atherosclerosis, neurodegenerative diseases (e.g., Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis media and sinusitis.

[0092] 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, skin melanoma, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, breast invasive cancer, lung adenocarcinoma, lung squamous cell carcinoma) or granuloma development.

[0093] In addition, 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof are administered to patients, preferably humans, as preventive measures against various diseases or conditions. 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can be administered as a preventive measure to patients prone to: allergy-related conditions (e.g., hypersensitivity and anaphylaxis); gastrointestinal conditions (e.g., inflammatory bowel disease, Crohn's disease, ulcerative colitis, ileitis, and enteritis); psoriasis and inflammatory skin diseases (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 allergic lung disease); autoimmune diseases, including arthritis (e.g., rheumatoid arthritis and psoriasis), multiple sclerosis, systemic lupus erythematosus, type I diabetes and glomerulonephritis; transplant rejection (e.g., allogeneic transplant 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 requiring suppression of unwanted inflammatory and / or immune responses, such as atherosclerosis, neurodegenerative diseases (e.g., Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis media and sinusitis; asthma, chronic obstructive pulmonary disease, 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, skin cutaneous melanoma, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, breast invasive cancer, lung adenocarcinoma, lung squamous cell carcinoma) or granuloma development. Therefore, 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can be used to prevent one disease or condition and simultaneously treat another (e.g., preventing psoriasis while treating cancer; preventing asthma while treating contact dermatitis).

[0094] Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectal, inhalation or topically, particularly to the ear, nose, eye or skin.

[0095] 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)ethane-1-ol benzenesulfonate salt and / or a pharmaceutical composition thereof is 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof may 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 mucosa, intestinal mucosa, etc.). In embodiments, administration may be systemic or local. A variety of delivery systems 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof are known (e.g., encapsulated in liposomes, microparticles, microcapsules, capsules, etc.).

[0096] In an 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)ethane-1-ol benzenesulfonate and / or a pharmaceutical composition thereof can be delivered by a sustained release system. In an 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)ethane-1-ol benzenesulfonate and / or a pharmaceutical composition thereof can be delivered by 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).

[0097] 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can be delivered using polymeric materials ("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; see also Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105). In other embodiments, the polymeric material is used for oral sustained release delivery. Polymers suitable 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof include, but are not limited to, sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and hydroxyethyl cellulose. In one embodiment, the polymer is hydroxypropyl methylcellulose. Other cellulose ethers have been described (Alderman, Int. J. Pharm. Tech. & Prod. Mfr. 1984, 5(3)1-9). Factors influencing 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).

[0098] In other embodiments, enteric coated formulations 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof. Coating materials suitable 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof include, but are not limited to, polymers having pH-dependent solubility (i.e., pH-controlled release), polymers having slow or pH-dependent swelling, dissolution or erosion rates (i.e., time-controlled release), polymers that are degraded by enzymes (i.e., enzyme-controlled release), and polymers that form a strong layer that is destroyed by increased pressure (i.e., pressure-controlled release).

[0099] In 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)ethane-1-ol benzenesulfonate salt and / or pharmaceutical compositions thereof (Verma et al., Drug Dev. Ind. Pharm. 2000, 26: 695-708). In an embodiment, OROS TM Osmotic devices are oral sustained-release delivery devices for 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)ethane-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).

[0100] In other embodiments, a controlled release system can be placed near the target 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)ethane-1-ol benzenesulfonate and / or pharmaceutical composition thereof, thereby requiring only a fraction of the systemic dose (e.g., Goodson, in "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.

[0101] 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can be administered or applied alone, or in combination with other agents. In an 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof may also be administered or applied alone or in combination with other pharmaceutically active agents, including, in the case of treating cancer, another anticancer agent / one or more chemotherapeutic agents.

[0102] In an embodiment, anticancer agents include, but are not limited to, MEK (e.g., MEK1, MEK2, or MEK1 and MEK2) inhibitors (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), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, chlorambucil, melphalan), ethyleneimine and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine), stine), streptozocin, triazenes (decarbazine), antimetabolites (e.g., 5-thioazaprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analogs (e.g., methotrexate) or pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin, etc.), plant alkaloids (e.g., long-acting 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.), icamycin), platinum compounds (e.g., cisplatin, oxaliplatin, carboplatin), anthracenediones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical suppressants (e.g., mitotane, aminoacetimide), 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., rituximab), gossyphol, 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 acinus, vincristine, etoposide, gemcitabine, imatinib (Gleevec.RTM.), geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, pembrolizumab, BAY 11-7082, PKC412, PD184352, 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonist; altretamine; ambamustine; 2,4-dichlorophenoxyacetic acid dox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitor; antagonist D; antagonist G; antarelix; anti-dorsal morphogenetic protein-1; antiandrogen, antiestrogen; antineoplaston; antisense oligonucleotide; aphidicolin glycinate; apoptosis gene regulator; apoptosis regulator; apurinic nucleic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin1); marine cyclic peptide 2; marine cyclic peptide 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorin; benzoylstaurosporine; β-lactam derivatives; β-alethine; β-clarithromycin B; betulinic acid acid; bFGF inhibitors; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage-derived inhibitor; carzelesin; casein kinase inhibitor (ICOS); castanospermine; cecropin B; cetrorelix; chlorin; chloroquinoxalinesulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4A4); combretastatin analogs; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinone; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor factor; cytostatin; dacliximab; decitabine; dehydrogenated ecteinascidin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; ecteinascidin B; didox; diethyInorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenylspiromustinespiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristamide eride; estrogen nitrogen mustard analogs; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezellastine; fulasterone; fludarabine; fluorodaunorunicin hydrochloride hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylenediethylamide; hypericin; ibandronic acidacid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridone; imiquimod; immunostimulatory peptides; insulin-like growth factor-1 receptor inhibitors; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4- ); iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetic acid; lanreotide; leinamycin; lenograstim; lentinan sulfate sulfate; leptolstatin; letrozole; leukemia inhibitory factor; interferon alpha; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptide; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrixlysin inhibitorinhibitor; matrix metalloproteinase inhibitor; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double-stranded RNA; mitoguazone; dibromodulanol mitolactol; mitomycin analogs; mitonafide; mitotoxin; fibroblast growth factor-saponin; mitoxantrone; mofarotene; molgramostim; human chorionic gonadotropin monoclonal antibody; monophosphoryl lipid A+ mycobacterial cell wall skeleton; mopidamol; multidrug resistance gene inhibitors; multi-tumor inhibitor-1-based therapeutics; mustard anticancer agents; Indian Ocean sponge B (mycaperoxide B); mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitrous oxide antioxidants; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducers; oramaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acidacid; panaxytriol; panomifene; parabactin; pazelIiptine; pegaspargase; peldesine; pentosanpolysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetic acid; phosphatase inhibitors; picibanil; pilocarpine hydrochloride hydrochloride; pirarubicin; piritrexim; placenta A; placenta B; plasminogen activator inhibitor; platinum complex; platinum compound; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2 J2); proteasome inhibitors; protein A-based immunomodulators; protein kinase C inhibitors; microalgae protein kinase C inhibitors; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxalated hemoglobin polyoxyethylene conjugates; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitors; retelliptinede methylated); rhenium etidronate Re186; rhizoxin; ribozyme; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi1 mimetic; semustine; senescence-derived inhibitor 1; sense oligonucleotide; signal transduction inhibitor; signal transduction modulator; single-chain antigen binding protein; sizofuran; sobuzoxane; borcarbazine sodium; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparsopartic acid acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitor; stipiamide; stromelysin inhibitor; sulfinosine; potent vasoactive intestinal peptide antagonist; suradista; suramin; suramin; synthetic mucopolysaccharide; tamustine; tamoxifen methyliodide; tauromustine; tazarotene; tecogalan sodium; tegafur fur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocholine; thrombopoietin; thrombopoietin mimetics; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl esterethyletiopurpurin; tirapazamine; titanium dichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitor; retinoic acid; triacetyl uridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitor; tyrphostin; UBC inhibitor; ubenimex; urogenital sinus-derived growth inhibitor; ureakinase receptor antagonist; vapreotide; vapreotide ariolin) B; vector system, red blood cell gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitamin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatinstimalamer, adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride hydrochloride; acronine; adozelesin; aldesleukin; hexamethylmelamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; binasafidedimesylate; bizelesin; bleomycin sulfate; brequinarsodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; cristal mesylate mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; drolostanone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; phosphate Etoposide; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin I1 (including recombinant interleukin II or rlL.sub.2), interferon α-2a; interferon α-2b; interferon α-n1; interferon α-n3; interferon β-1a; interferon γ-1b; iproplatin; irinotecan hydrochloride; lanreotide acetate acetate; letrozole; leuprolide acetate; liarozole hydrochloridehydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; hydrochloride; plicamycin; plomestane; porfimersodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparrosate sodium; sparsomycin; spirogermanium hydrochloridehydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate phosphate; trimetrexate; trimetrexate glucuronide; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloridehydrochloride), agents that arrest cells in the G2-M phase and / or modulate the formation or stability of microtubules (e.g., Taxol.TM (i.e., paclitaxel), Taxotere.TM, compounds containing a taxane backbone, Erbulozole (i.e., R-55104), Dolastatin 10 (i.e., DLS-10 and NSC-376128), Mivobulin isethionate (i.e., as CI-980), Vincristine, NSC-639829, Discodermolide (i.e., as NVP-XX-A-296), ABT-751 (Abbott, i.e., E-7010), Altorhyrtins (e.g., Altorhyrtin A and Altorhyrtin C), sponge statins (e.g., sponge statin 1, sponge statin 2, sponge statin 3, sponge statin 4, sponge statin 5, sponge statin 6, sponge statin 7, sponge statin 8 and sponge statin 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, riostatin PE (i.e., NSC-654663), solidotin (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, ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / KyowaHakko), 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), H16 (Kansas State University), Oncocidin A1 (i.e. BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide 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-569), School of Medicine, namely MF-191), TMPN (Arizona State University), divanadium acetylacetonate, T-138026 (Tularik), Monsatrol, lnanocine (ie NSC-698666), 3-IAABE (Cytoskeleton / Mt. Sinai School ofMedicine), A-204197 (Abbott), T-607 (Tuiarik, i.e. T-900607), RPR-115781 (Aventis), Eleutherobin (such as demethyl Acanthopanax, deacetyl Acanthopanax, isoacanthopanax A and Z-Acanthopanax), Caribaeol, Caribaeolin, 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, (-)-Phenylahistin (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 phosphate sodium, BPR-OY-007 (National Institutes of Health), Institutes) and SSR-250411 (Sanofi), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, adrenocortical steroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol,The invention relates to the treatment of leukemia, leukemia and leukemia in combination with immunosuppressants (e.g., estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Gudrin (BCG), levamisole, interleukin-2, α-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., with 111 In, 90 Y or 131 I-conjugated anti-CD20 monoclonal antibodies, 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) TM ), erlotinib (Tarceva TM ), cetuximab (Erbitux TM ), lapatinib (Tykerb TM ), panitumumab (Vectibix TM ), vandetanib (Caprelsa TM)、afatinib / BIBW2992、CI-1033 / canertinib、neratinib / HKI-272、CP-724714、TAK-285、AST-1306、ARRY334543、ARRY-380、AG-1478、dacomitinib / PF299804、OSI-420 / desmethyl erlotinib erlotinib), AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, etc.

[0103] 6.5 Pharmaceutical Compositions

[0104] In an embodiment, a pharmaceutical composition is provided comprising 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)ethane-1-ol benzenesulfonate and a suitable amount of a pharmaceutically acceptable carrier to provide a form suitable for administration to a patient. 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)ethane-1-ol benzenesulfonate and the pharmaceutically acceptable carrier are sterile when administered to a patient. In an embodiment, 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)ethane-1-ol benzenesulfonate is administered intravenously, the carrier is water. In other embodiments, saline solutions and aqueous glucose and glycerol solutions are used as liquid carriers for injectable solutions. In other embodiments, suitable pharmaceutical carriers include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, ethylene 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)ethane-1-ol benzenesulfonate comprises a wetting agent or an emulsifier or a pH buffer. 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)ethane-1-ol benzenesulfonate comprises an adjuvant, a stabilizer, a thickener, a lubricant, and a colorant.

[0105] In an embodiment, 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)ethane-1-ol benzenesulfonate can be manufactured by conventional mixing, dissolving, granulating, dragee-making, grinding, emulsifying, encapsulating, entrapping or lyophilizing processes. In an embodiment, 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)ethane-1-ol benzenesulfonate may be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients or adjuvants 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)ethane-1-ol benzenesulfonate into a pharmaceutically acceptable preparation. As will be appreciated by those skilled in the art, appropriate formulations depend on the route of administration chosen.

[0106] In an embodiment, 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)ethane-1-ol benzenesulfonate is a solution, suspension, emulsion, tablet, pill, pills, capsule, capsule containing a liquid, powder, sustained release formulation, suppository, emulsion, aerosol, spray, or any other form suitable for use. In an embodiment, the pharmaceutically acceptable carrier is a capsule (e.g., Grosswald et al., U.S. Pat. No. 5,698,155). Other examples of suitable pharmaceutical carriers have been described in the art (see Remington's Pharmaceutical Sciences, Philadelphia College of Pharmacy and Science, 19th Edition, 1995). 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)ethane-1-ol benzenesulfonate is formulated for oral delivery. 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)ethane-1-ol benzenesulfonate is formulated for oral sustained release administration.

[0107] In an embodiment, 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)ethane-1-ol benzenesulfonate for oral delivery can be in the form of, for example, tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs. The orally administered composition can include one or more optional agents, such as sweeteners such as fructose, aspartame, or saccharin, flavoring agents such as peppermint, wintergreen oil, or cherry coloring agents, and preservatives to provide a pharmaceutically palatable preparation. In addition, 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)ethane-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. Selectively permeable membranes surrounding osmotically active driving compounds are also suitable for oral administration of compounds and 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)ethane-1-ol benzenesulfonate disclosed herein. In these later platforms, the fluid from the capsule surrounding environment is absorbed by the driving compound, and the driving compound expands to replace the medicament or pharmaceutical composition through the hole. Contrary to the spike curve of the immediate release preparation, these delivery platforms can provide a delivery curve of zero order. Time delay materials, such as glyceryl monostearate or glyceryl stearate can also be used. The oral composition comprising crystallization 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl) ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidin-3-yl)piperidin-1-yl)ethane-1-ol benzene sulfonate can include standard carriers, such as mannitol, lactose, starch, magnesium stearate, saccharin sodium, cellulose, magnesium carbonate, etc. In an embodiment, such carrier is pharmaceutical grade.

[0108] In an embodiment, 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 glycols (e.g., polyethylene glycol) oils, alcohols, slightly acidic buffers between pH 4 and pH 6 (e.g., acetate, citrate, ascorbate at about 5 mM to about 50 mM), etc. In an embodiment, flavoring agents, preservatives, colorants, bile salts, acylcarnitines, etc. are additionally added.

[0109] Pharmaceutical compositions for administration by other routes may also be contemplated. In an embodiment, for buccal administration, 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)ethane-1-ol benzenesulfonate may be in the form of tablets, lozenges, etc. formulated in a conventional manner. Liquid drug formulations suitable for nebulizers and liquid spray devices and EHD aerosol devices typically include 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)ethane-1-ol benzenesulfonate and a pharmaceutically acceptable carrier. In embodiments, pharmaceutically acceptable carriers are liquids, such as alcohol, water, polyethylene glycol, or perfluorocarbon. In embodiments, another material may be added to change the aerosol properties of a solution or suspension of a compound disclosed herein. In embodiments, the material is a liquid, such as alcohol, ethylene glycol, polyethylene glycol, or a fatty acid. Other methods of preparing liquid drug solutions or suspensions suitable for aerosol devices are known to those skilled in the art (see, e.g., Biesalski, U.S. Patent No. 5,112,598; Biesalski, U.S. Patent 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)ethane-1-ol benzenesulfonate may also be formulated into rectal or vaginal compositions, such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides. 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)ethane-1-ol benzenesulfonate may also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by 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)ethane-1-ol benzenesulfonate can be formulated with a suitable polymeric or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin or as a sparingly soluble derivative.

[0110] In an 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)ethane-1-ol benzenesulfonate salt is formulated as a pure active agent. 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)ethane-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)ethane-1-ol benzenesulfonate. In embodiments, pharmaceutical compositions provided herein 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)ethane-1-ol benzenesulfonate, Form A. In embodiments, pharmaceutical compositions provided herein 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)ethane-1-ol benzenesulfonate, Form B. In an embodiment, the pharmaceutical composition provided herein comprises a mixture of Forms A and 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)ethane-1-ol benzenesulfonate.

[0111] 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)ethane-1-ol benzenesulfonate is formulated as an oral tablet dosage form.

[0112] 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)ethane-1-ol benzenesulfonate in an oral tablet dosage form comprises 75 mg of the crystalline compound.

[0113] 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)ethane-1-ol benzenesulfonate in an oral tablet dosage form comprises 25 mg of the crystalline compound.

[0114] 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)ethane-1-ol benzenesulfonate comprises a wetting agent. In an embodiment, the wetting agent is sodium lauryl sulfate (SLS).

[0115] 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)ethane-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 comprises at least 50% by weight of the oral tablet dosage form.

[0116] 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)ethane-1-ol benzenesulfonate comprises a disintegrant. In an embodiment, the disintegrant is croscarmellose sodium.

[0117] 6.6 Dosage

[0118] 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof will be used in an amount effective to achieve the intended purpose. In an embodiment, for use in the treatment or prevention of a CCR4-mediated disease or condition disclosed herein, 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof are administered or applied in a therapeutically effective amount.

[0119] 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)ethane-1-ol benzenesulfonate and / or pharmaceutical composition 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. In addition, in vitro or in vivo assays may optionally be employed to help determine 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)ethane-1-ol benzenesulfonate and / or pharmaceutical composition thereof administered will depend on, among other factors, the subject being treated, the subject's weight, the severity of the disease, the mode of administration and the judgment of the prescribing physician.

[0120] In an embodiment, a 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)ethane-1-ol benzenesulfonate can be delivered in a pharmaceutical composition by a single administration. In an embodiment, a 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)ethane-1-ol benzenesulfonate can be delivered in a pharmaceutical composition by multiple applications. In an embodiment, a 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)ethane-1-ol benzenesulfonate can be delivered in a pharmaceutical composition by controlled release. In an 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)ethane-1-ol benzenesulfonate and / or a pharmaceutical composition thereof is delivered by oral sustained release administration. In a specific 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)ethane-1-ol benzenesulfonate and / or a pharmaceutical composition thereof is administered twice daily. In a specific 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)ethane-1-ol benzenesulfonate and / or a pharmaceutical composition thereof is administered once daily. In an embodiment, administration may be repeated intermittently. In an embodiment, administration may be provided alone. In an embodiment, administration may be provided in combination with other drugs. In embodiments, administration may continue as long as necessary to effectively treat a CCR4-mediated disease state or condition described herein.

[0121] In 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)ethane-1-ol benzenesulfonate and / or a pharmaceutical composition thereof can be adjusted to provide 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)ethane-1-ol benzenesulfonate and / or a pharmaceutical composition thereof can be adjusted to provide about 50 mg / day to about 150 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can be adjusted to provide about 75 mg / day to about 125 mg / day. The dosage range can be readily determined by methods known to the skilled artisan.

[0122] Prior to use in humans, the desired therapeutic or prophylactic activity 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof are determined in vitro and in vivo. In embodiments, the therapeutically effective dose 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof described herein will provide therapeutic benefit without causing significant 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof can be determined using standard pharmaceutical procedures and can be readily determined by a skilled artisan. In 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof described herein is within a circulating concentration range that includes an effective dose with little or no toxicity.

[0123] 6.7 Combination therapy

[0124] 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof are used in combination with at least one other therapeutic agent. In embodiments, co-administration comprises administering one 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 comprises administering two therapeutic agents simultaneously or nearly simultaneously (e.g., within approximately 1, 5, 10, 15, 20, or 30 minutes). In embodiments, co-administration comprises administering two therapeutic agents sequentially in any order. In embodiments, co-administration may be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition comprising two therapeutic agents. In other embodiments, the therapeutic agent may be formulated alone. In another embodiment, the active agent and / or the adjuvant may be linked or conjugated to one another. In an embodiment, the compounds described herein may be combined with the treatment of a CCR4-mediated disease disclosed herein.

[0125] 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof act in an additive manner with other therapeutic 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)ethane-1-ol benzenesulfonate and / or pharmaceutical compositions thereof act in a synergistic manner with other therapeutic agents.

[0126] In embodiments, the additional therapeutic agent is an anti-cancer agent, a chemotherapeutic agent, or an anti-inflammatory agent.

[0127] In an 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)ethane-1-ol benzenesulfonate salt and / or a pharmaceutical composition thereof is used in combination with an anticancer agent. In an embodiment, 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), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, chlorambucil, melphalan), ethyleneimine and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine), stine), streptozocin, triazenes (decarbazine), antimetabolites (e.g., 5-thioazaprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analogs (e.g., methotrexate) or pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin, etc.), plant alkaloids (e.g., long-acting 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.), icamycin), platinum compounds (e.g., cisplatin, oxaliplatin, carboplatin), anthracenediones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical suppressants (e.g., mitotane, aminoacetimide), 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), gossyphol, 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.RTM.), 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; adecypenol; adozelesin; aldesleukin; ALL-TK antagonist; altretamine; ambamustine; 2,4-dichlorophenoxyacetic acid dox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitor; antagonist D; antagonist G; antarelix; anti-dorsal morphogenetic protein-1; antiandrogen; antiestrogen; antineoplaston; antisense oligonucleotide; aphidicolin glycinate; apoptosis gene regulator; apoptosis regulator; apurinic nucleic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin1); marine cyclic peptide 2; marine cyclic peptide 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorin; benzoylstaurosporine; β-lactam derivatives; β-alethine; β-clarithromycin B; betulinic acid acid; bFGF inhibitors; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage-derived inhibitor; carzelesin; casein kinase inhibitor (ICOS); castanospermine; cecropin B; cetrorelix; chlorin; chloroquinoxalinesulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4A4); combretastatin analogs; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinone; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor factor; cytostatin; dacliximab; decitabine; dehydrogenated ecteinascidin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; ecteinascidin B; didox; diethyInorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenylspiromustinespiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristamide eride; estrogen nitrogen mustard analogs; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezellastine; fulasterone; fludarabine; fluorodaunorunicin hydrochloride hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylenediethylamide; hypericin; ibandronic acidacid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridone; imiquimod; immunostimulatory peptides; insulin-like growth factor-1 receptor inhibitors; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4- ); iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetic acid; lanreotide; leinamycin; lenograstim; lentinan sulfate sulfate; leptolstatin; letrozole; leukemia inhibitory factor; interferon alpha; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptide; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrixlysin inhibitorinhibitor; matrix metalloproteinase inhibitor; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double-stranded RNA; mitoguazone; dibromodulanol mitolactol; mitomycin analogs; mitonafide; mitotoxin; fibroblast growth factor-saponin; mitoxantrone; mofarotene; molgramostim; human chorionic gonadotropin monoclonal antibody; monophosphoryl lipid A+ mycobacterial cell wall skeleton; mopidamol; multidrug resistance gene inhibitors; multi-tumor inhibitor-1-based therapeutics; mustard anticancer agents; Indian Ocean sponge B (mycaperoxide B); mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitrous oxide antioxidants; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducers; oramaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acidacid; panaxytriol; panomifene; parabactin; pazelIiptine; pegaspargase; peldesine; pentosanpolysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetic acid; phosphatase inhibitors; picibanil; pilocarpine hydrochloride hydrochloride; pirarubicin; piritrexim; placenta A; placenta B; plasminogen activator inhibitor; platinum complex; platinum compound; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2 J2); proteasome inhibitors; protein A-based immunomodulators; protein kinase C inhibitors; microalgae protein kinase C inhibitors; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxalated hemoglobin polyoxyethylene conjugates; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitors; retelliptinede methylated); rhenium etidronate Re186; rhizoxin; ribozyme; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi1 mimetic; semustine; senescence-derived inhibitor 1; sense oligonucleotide; signal transduction inhibitor; signal transduction modulator; single-chain antigen binding protein; sizofuran; sobuzoxane; borcarbazine sodium; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparsopartic acid acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitor; stipiamide; stromelysin inhibitor; sulfinosine; potent vasoactive intestinal peptide antagonist; suradista; suramin; suramin; synthetic mucopolysaccharide; tamustine; tamoxifen methyliodide; tauromustine; tazarotene; tecogalan sodium; tegafur fur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocholine; thrombopoietin; thrombopoietin mimetics; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl esterethyletiopurpurin; tirapazamine; titanium dichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitor; retinoic acid; triacetyl uridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitor; tyrphostin; UBC inhibitor; ubenimex; urogenital sinus-derived growth inhibitor; ureakinase receptor antagonist; vapreotide; vapreotide ariolin) B; vector system, red blood cell gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitamin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatinstimalamer, adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride hydrochloride; acronine; adozelesin; aldesleukin; hexamethylmelamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; binasafidedimesylate; bizelesin; bleomycin sulfate; brequinarsodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; cristal mesylate mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; drolostanone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; phosphate Etoposide; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin I1 (including recombinant interleukin II or rlL.sub.2), interferon α-2a; interferon α-2b; interferon α-n1; interferon α-n3; interferon β-1a; interferon γ-1b; iproplatin; irinotecan hydrochloride; lanreotide acetate acetate; letrozole; leuprolide acetate; liarozole hydrochloridehydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; hydrochloride; plicamycin; plomestane; porfimersodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparrosate sodium; sparsomycin; spirogermanium hydrochloridehydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate phosphate; trimetrexate; trimetrexate glucuronide; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloridehydrochloride), agents that arrest cells in the G2-M phase and / or modulate the formation or stability of microtubules (e.g., Taxol.TM (i.e., paclitaxel), Taxotere.TM, compounds containing a taxane backbone, Erbulozole (i.e., R-55104), Dolastatin 10 (i.e., DLS-10 and NSC-376128), Mivobulin isethionate (i.e., as CI-980), Vincristine, NSC-639829, Discodermolide (i.e., as NVP-XX-A-296), ABT-751 (Abbott, i.e., E-7010), Altorhyrtins (e.g., Altorhyrtin A and Altorhyrtin C), sponge statins (e.g., sponge statin 1, sponge statin 2, sponge statin 3, sponge statin 4, sponge statin 5, sponge statin 6, sponge statin 7, sponge statin 8 and sponge statin 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, riostatin PE (i.e., NSC-654663), solidotin (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, ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / KyowaHakko), 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), H16 (Kansas State University), Oncocidin A1 (i.e. BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide 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), ofMedicine, namely MF-191), TMPN (Arizona State University), divanadium acetylacetonate, T-138026 (Tularik), Monsatrol, lnanocine (ie NSC-698666), 3-IAABE (Cytoskeleton / Mt.SinaiSchool ofMedicine), A-204197 (Abbott), T-607 (Tuiarik, i.e. T-900607), RPR-115781 (Aventis), Eleutherobin (such as demethyl Acanthopanax, deacetyl Acanthopanax, isoacanthopanax A and Z-Acanthopanax), Caribaeol, Caribaeolin, 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, (-)-Phenylahistin (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 phosphate sodium, BPR-OY-007 (National Institutes of Health), Institutes) and SSR-250411 (Sanofi), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, adrenocortical steroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol,The invention relates to the treatment of leukemia, leukemia and leukemia in combination with immunosuppressants (e.g., estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guérin (BCG), levamisole, interleukin-2, α-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., with 111 In, 90 Y or 131 I-conjugated anti-CD20 monoclonal antibodies, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, pembrolizumab (Keytruda TM ), EGFR inhibitors, epidermal growth factor receptor (EGFR)-targeted therapies or therapeutic agents (e.g., gefitinib (Iressa TM ), erlotinib (Tarceva TM ), cetuximab (Erbitux TM ), lapatinib (Tykerb TM ), panitumumab (Vectibix TM ), vandetanib (Caprelsa TM)、afatinib / BIBW2992、CI-1033 / canertinib、neratinib / HKI-272、CP-724714、TAK-285、AST-1306、ARRY334543、ARRY-380、AG-1478、dacomitinib / PF299804、OSI-420 / desmethyl erlotinib erlotinib), AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, etc.

[0128] In an 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)ethane-1-ol benzenesulfonate salt and / or a pharmaceutical composition thereof is used in combination with a chemotherapeutic agent. In an embodiment, the chemotherapeutic agent is an antiproliferative / antineoplastic agent, an antimetabolite, an antitumor antibiotic, an antimitotic agent, a topoisomerase inhibitor, a cytostatic agent, an estrogen receptor downregulator, an antiandrogen, an LHRH antagonist or an LHRH agonist, a progestin, an aromatase inhibitor, a 5.α-reductase inhibitor, an agent that inhibits cancer cell invasion, an inhibitor of growth factor function, a farnesyl transferase inhibitor, a tyrosine kinase inhibitor, a serine / threonine kinase inhibitor, an inhibitor of the epidermal growth factor family, an inhibitor of the platelet-derived growth factor family, an inhibitor of the hepatocyte growth factor family; an anti-angiogenic agent, a vascular damaging agent, an agent for antisense therapy, an anti-ras antisense agent, an agent for gene therapy, an immunotherapeutic agent, or an antibody.

[0129] In an 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)ethane-1-ol benzenesulfonate salt and / or a pharmaceutical composition thereof is used in combination with an anti-inflammatory agent. In an embodiment, the anti-inflammatory agent is thalidomide or a derivative thereof, a retinoid, anthralin or calcipotriol, a nonsteroidal anti-inflammatory agent (hereinafter referred to as NSAID), including non-selective cyclooxygenase COX-1 / COX-2 inhibitors, whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azaprozone, pyrazolones such as phenylbutazone, salicylates such as aspirin); select COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumacoxib, parecoxib, and etoricoxib); cyclooxygenase inhibiting nitric oxide donors (CINODs); glucocorticoids (whether administered by the topical, oral, intramuscular, intravenous, or intraarticular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular treatments, such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine.

[0130] In an embodiment, 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)ethane-1-ol benzenesulfonate is administered concurrently with administration of another therapeutic agent, which may be part of the same pharmaceutical composition as 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)ethane-1-ol benzenesulfonate. In an embodiment, 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)ethane-1-ol benzenesulfonate is administered simultaneously with 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)ethane-1-ol benzenesulfonate is administered prior to 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)ethane-1-ol benzenesulfonate is administered after administration of another therapeutic agent.

[0131] In other embodiments, the other therapeutic agent is pembrolizumab.

[0132] 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)ethane-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)ethane-1-ol benzenesulfonate. In other embodiments, 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)ethane-1-ol benzenesulfonate can be administered in combination with 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)ethane-1-ol benzenesulfonate.

[0133] 7. Numbered implementation plan

[0134] Embodiment 1. 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)ethane-1-ol benzenesulfonate in crystalline form.

[0135] Embodiment 2. The compound of Embodiment 1, which has 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 CuKα radiation.

[0136] Embodiment 3. The compound of Embodiment 1, which has 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.

[0137] Embodiment 4. The compound of Embodiment 1, which has 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.

[0138] Embodiment 5. The compound of Embodiment 1, which has Figure 1X-ray powder diffraction pattern using CuKα radiation is shown.

[0139] Embodiment 6. The compound of Embodiment 1 having a melting point between about 170°C and about 173°C as determined by differential scanning calorimetry at a scan rate of 5°C / minute.

[0140] Embodiment 7. The compound of Embodiment 2, which has a characteristic absorption peak (2θ) at 12.2°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0141] Embodiment 8. The compound of Embodiment 2, which has a characteristic absorption peak (2θ) at 23.8°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0142] Embodiment 9. The compound of Embodiment 2, which has a characteristic absorption peak (2θ) at 25.6°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0143] Embodiment 10. The compound of Embodiment 2, which has a characteristic absorption peak (2θ) at 23.1°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0144] Embodiment 11. The compound of Embodiment 2, which has a characteristic absorption peak (2θ) at 20.0°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0145] Embodiment 12. The compound of Embodiment 2, which has a characteristic absorption peak (2θ) at 16.2°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0146] Embodiment 13. The compound of Embodiment 1, which has 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 CuKα radiation.

[0147] Embodiment 14. The compound of Embodiment 13, which has 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.

[0148] Embodiment 15. The compound of Embodiment 14, which has 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.

[0149] Embodiment 16. The compound of Embodiment 1, which has Figure 3 X-ray powder diffraction pattern using Cu Kα radiation is shown.

[0150] Embodiment 17. The compound of Embodiment 1 having a melting point between about 116°C and about 119°C as determined by differential scanning calorimetry at a scan rate of 5°C / minute.

[0151] Embodiment 18. The compound of Embodiment 13, which has a characteristic absorption peak (2θ) at 15.8°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0152] Embodiment 19. The compound of Embodiment 13, which has a characteristic absorption peak (2θ) at 24.5°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0153] Embodiment 20. The compound of Embodiment 13, which has a characteristic absorption peak (2θ) at 4.5°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0154] Embodiment 21. The compound of Embodiment 13, which has a characteristic absorption peak (2θ) at 22.8°±0.3° in an x-ray powder diffraction pattern using Cu Ka radiation.

[0155] Embodiment 22. The compound of Embodiment 13, which has a characteristic absorption peak (2θ) at 10.6°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0156] Embodiment 23. The compound of Embodiment 13, which has a characteristic absorption peak (2θ) at 18.6°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0157] Embodiment 24. A pharmaceutical composition comprising the crystalline compound of any one of Embodiments 1 to 23 and a pharmaceutically acceptable carrier.

[0158] Embodiment 25. A pharmaceutical composition comprising the crystalline compound of any one of Embodiments 2 to 12 and a pharmaceutically acceptable carrier.

[0159] Embodiment 26. A pharmaceutical composition comprising the crystalline compound of any one of Embodiments 13 to 23 and a pharmaceutically acceptable carrier.

[0160] Embodiment 27. The pharmaceutical composition of any one of Embodiments 24 to 26, wherein the composition is in the form of an oral tablet.

[0161] Embodiment 28. The pharmaceutical composition of Embodiment 27, wherein the composition comprises 75 mg of the crystalline compound.

[0162] Embodiment 29. The pharmaceutical composition of Embodiment 27, wherein the composition comprises 25 mg of the crystalline compound.

[0163] Embodiment 30. The pharmaceutical composition of any one of Embodiments 24 to 26, wherein the composition comprises a wetting agent.

[0164] Embodiment 31. The pharmaceutical composition of Embodiment 30, wherein the wetting agent is sodium lauryl sulfate.

[0165] Embodiment 32. The pharmaceutical composition of any one of Embodiments 24 to 26, wherein the composition comprises a water-soluble excipient.

[0166] Embodiment 33. The pharmaceutical composition of Embodiment 32, wherein the water-soluble excipient is lactose monohydrate.

[0167] 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.

[0168] Embodiment 35. The pharmaceutical composition of any one of Embodiments 24 to 26, wherein the composition comprises a disintegrant.

[0169] Embodiment 36. The pharmaceutical composition of Embodiment 35, wherein the disintegrant is croscarmellose sodium.

[0170] 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 to 23.

[0171] Embodiment 38. A method of treating an immune, inflammation or cancer related disease or disorder comprising administering the pharmaceutical composition of any one of embodiments 24 to 27 to a patient in need of such treatment.

[0172] Embodiment 39. The method of embodiment 37 or 38, wherein the disease or condition is selected from allergy-related disorders, hypersensitivity reactions, anaphylactic reactions, gastrointestinal diseases, respiratory allergic diseases, allergic lung diseases, autoimmune diseases, inflammatory skin diseases, transplant rejection, allograft rejection, transplant rejection, cancer, metastatic cancer and neurodegenerative diseases.

[0173] Embodiment 40. The method of embodiment 37 or 38, wherein the disease or condition is selected from 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, allergic rhinitis, arthritis (rheumatoid and psoriasis), multiple sclerosis, systemic lupus erythematosus, type I diabetes, glomerulonephritis, leukemia, lymphoma papilloma, 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, skin cutaneous melanoma, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, nasopharyngeal carcinoma, Hodgkin's lymphoma, breast invasive cancer, lung adenocarcinoma, lung squamous cell carcinoma and granuloma development.

[0174] Embodiment 41. The method of Embodiment 37 or 38, wherein the crystalline compound is co-administered with another therapeutic agent.

[0175] Embodiment 42. The method of Embodiment 41, wherein the additional therapeutic agent is pembrolizumab.

[0176] 8. Examples

[0177] Stable crystalline solid forms of organic molecules facilitate processing of the API into final drug products, such as oral tablet dosage forms, and therefore require such physical forms. As described in U.S. Pat. No. 10,179,787, 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)ethane-1-ol was first isolated in its free base form. 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.

[0178] A number of different 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 salts were prepared using other acids. Salt formation experiments were conducted and evaluated using 14 different acids and 13 different solvents listed in Table 1 below, either alone or in some combination.

[0179] Table 1 Summary of acids and solvents used for screening 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)ethane-1-ol salt

[0180]

[0181]

[0182] This work showed that only two acids produced consistent solid forms. The p-toluenesulfonate salt gave 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 lower solubility of the p-toluenesulfonate salt would inhibit dissolution of the drug and prevent adequate intestinal absorption. At pH 2, the kinetic solubility of the p-toluenesulfonate salt was only 1 / 5 of the same parameter for the HCl salt. The bioavailability of this salt in rats was less than half of that observed with the amorphous HCl salt. Low solubility and low bioavailability are not desirable properties for a drug product.

[0183] 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)ethane-1-ol was isolated and two crystalline polymorphs were observed depending on the crystallization conditions. A higher melting point polymorph (170°C) was obtained by using a mixture of methyl tert-butyl ether and ethanol and could be consistently isolated on a production scale. The high melting point of this polymorph is advantageous as it is easier to manufacture at higher temperatures. This polymorph exhibits low hygroscopicity and greater solubility in water at pH 2 (411 μM) compared to the p-toluenesulfonate salt (190 uM). The bioavailability of the benzenesulfonate salt in rats was higher than that observed for the p-toluenesulfonate 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)ethane-1-ol (34% vs 22%). In addition, 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)ethane-1-ol exhibited excellent stability after storage at room temperature for 36 months. This unexpected combination of reproducible formation, low hygroscopicity, high solubility, bioavailability and high stability for long-term storage makes 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)ethane-1-ol benzenesulfonate unique and makes it an ideal candidate for drug development.

[0184] The following examples describe in 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)ethane-1-ol benzenesulfonate and its crystalline form. It will be apparent to those skilled in the art that many modifications may be made to the materials and methods without departing from the scope of the present invention.

[0185] In the following examples, the following abbreviations have the following meanings. If an abbreviation is not defined, the generally accepted meaning applies.

[0186] Atm = Atmosphere

[0187] Boc = tert-butyloxycarbonyl

[0188] Cbz = benzyloxy

[0189] DCC = Dicyclohexylcarbodiimide

[0190] DMAP = 4-N,N-dimethylaminopyridine

[0191] DMF = N, N-dimethylformamide

[0192] DMSO = Dimethyl sulfoxide

[0193] Fmoc = 9-fluorenylmethoxycarbonyl

[0194] g = grams

[0195] h = hours

[0196] HPLC = High Pressure Liquid Chromatography

[0197] L = Liters

[0198] LC / MS = Liquid Chromatography / Mass Spectrometry

[0199] M = mole

[0200] min = minutes

[0201] mL = milliliters

[0202] mmol = millimole

[0203] NHS = N-hydroxysuccinimide

[0204] THF = Tetrahydrofuran

[0205] TFA = trifluoroacetic acid

[0206] TLC = Thin layer chromatography

[0207] TMS = trimethylsilyl

[0208] μL = microliter

[0209] μM = micromolar

[0210] v / v = volume / volume

[0211] Example 1. Synthesis of non-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)ethane-1-ol benzenesulfonate.

[0212]

[0213] 2-[(3R)-3-[1-[1-[(1R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)pyrazolo[3,4-b]pyrazine-6-yl]azetidin-3-yl]-1-piperidine]ethanol (1.0 g, 1.84 mmol) was dissolved in ethanol (10 mL) and the solution was cooled to -10 ° C (acetone / ice bath). Benzenesulfonic acid (291.09 mg, 1.84 mmol) was then added dropwise over 5 minutes and dissolved in ethanol (10 mL). After the addition was complete, the reaction mixture was warmed to 22 ° C and stirred for 5 minutes. No precipitate was formed. The mixture was concentrated under reduced pressure to give the title compound as an off-white non-crystalline solid (1.29 g, 99.9% yield). 1 H NMR (400 MHz, methanol-d 4 ): 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=5.2Hz, 2H), 3.6 2(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.

[0214] Example 2. Synthesis of 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)ethane-1-ol benzenesulfonate.

[0215] A 2L flask was charged with non-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)ethane-1-ol benzenesulfonate (230 g, 327.83 mmol). Ethanol (345 mL) was added and the flask was equipped with a reflux condenser and then heated to 60° C. to obtain a clear solution. Tert-butyl methyl ether (1035 mL) was immediately added and the mixture was 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)ethane-1-ol benzenesulfonate (216.35 g, 308.37 mmol, 94% yield) as a white crystalline solid (Form A).

[0216] Example 3. Synthesis of 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)ethane-1-ol benzenesulfonate.

[0217] 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)ethane-1-ol benzenesulfonate (5 g) was added to 15 ml of isopropanol (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. 45 ml of methyl ethyl ketone (anti-solvent) was then 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 crystals forming. A sample of the solution was removed and stirred in a vial, resulting in a precipitate. The slurry sample was returned to the original flask for seeding, but the slurry solids dissolved.

[0218] The solution was then cooled to 35°C and then quenched at 50°C in a similar manner to that described above, resulting in a slurry with solid crystals formed. The slurry was stirred at 35°C for 1 hour and then cooled 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 remained constant, yielding 4.4 g of a white crystalline solid (crystalline form B).

[0219] Example 4. X-ray powder diffraction analysis 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)ethane-1-ol benzenesulfonate salt form A.

[0220] The X-ray powder diffraction pattern (XRPD) of the Form A 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)ethane-1-ol benzenesulfonate produced according to Example 2 above was measured by a Malyern Panalytical X'Pert Pro X-ray powder diffractometer using Cu Kα radiation and Bragg-Bentano geometry. The instrument was equipped with line-focused parallel beam optics, using fixed divergence slits (0.5°) and anti-scatter slits (1°) and an X'Celerator detector. The tube voltage and current were set to 45 kV and 40 mA, respectively. The angular resolution of the goniometer was about 0.001°. The detector covered a range of 41° in 2-theta (2θ) with a step size of 0.0167°. The typical averaging time for each XRPD pattern collected was 3.5 minutes. A corundum sample (NIST 1976a) was used to calibrate the XRPD instrument. The sample produced Figure 1 The diffraction pattern is shown. Figure 1 The diffraction peaks are shown in Table 2 below.

[0221] Table 2.

[0222]

[0223]

[0224] 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)ethane-1-ol benzenesulfonate (Form A).

[0225] 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)ethane-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 under the appropriate temperature program (initial temperature equilibrium, isothermal, ramp rate, final temperature) to produce Figure 2 Thermogram shown in . DSC analysis showed an endothermic transition with an onset temperature of 170°C and a ΔH of 64.81 J / g.

[0226] Example 6. X-ray powder diffraction analysis of 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)ethane-1-ol benzenesulfonate.

[0227] An X-ray powder diffraction pattern (XRPD) of a Form B 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)ethane-1-ol benzenesulfonate produced according to Example 3 above was measured using the same instrumentation and methods as described earlier in Example 4. This sample produced Figure 3 The diffraction pattern shown. Figure 3 The diffraction peaks are shown in Table 3 below.

[0228] Table 3

[0229]

[0230] 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)ethane-1-ol benzenesulfonate (Form B).

[0231] Differential Scanning Calorimetry (DSC) analysis of Form B 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)ethane-1-ol benzenesulfonate produced according to Example 3 above was measured using the same method and instrumentation as used in Example 5. The material was run under the appropriate temperature program (initial temperature equilibrium, isothermal, ramp rate, final temperature) to produce Figure 4 Thermogram shown in . DSC analysis showed an endothermic transition with an onset temperature of 114°C and a ΔH of 48.82 J / g.

[0232] Example 8. Immediate Release Oral Dosage Form (Strength 5 mg)

[0233] Four different immediate release oral dosage tablets containing 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)ethane-1-ol benzenesulfonate (referred to as "Compound, Form A" and "Drug Substance" in Examples 8 to 11) were prepared, with corresponding dosage strengths of 5 mg (Example 8), 25 mg (Example 9), 50 mg (Example 10) and 75 mg (Example 11), which have the ingredients shown in Tables 3 to 6, respectively.

[0234] The composition of the 5 mg dosage strength oral tablet is shown in Table 4.

[0235] Table 4. Quantitative composition of tablets containing 5 mg of Form A

[0236]

[0237] 1. 6.45 mg of besylate salt form corresponds to 5 mg of free base form.

[0238] Granulation:

[0239] To improve the content uniformity of the tablet core formulation, a high shear wet granulation process was used to manufacture 5 mg strength tablets.

[0240] First, the API was screened through a 30-mesh screen. Hydroxypropylcellulose, sodium lauryl sulfate, lactose monohydrate, microcrystalline cellulose, and cross-linked sodium carboxymethylcellulose were then screened through a 20-mesh screen. The six materials were then high-shear granulated in a 25L pot with purified water. Water was added to a granulator running at an impeller speed of 290RPM and a chopper speed of 1760 at 350-450g / min. After reaching the end point, the wet granules were crushed in a standard mill equipped with a 375Q screen. The agglomerated granules were then dried in an oven at 40°C until the amount of water in the granules was less than 4% by weight. The dried granules were then ground in a standard grinder equipped with a 40G or 75R screen.

[0241] Lubrication and compression:

[0242] The milled granules were then added to an eight quart V-blender along with the magnesium stearate and crushed using a 30 mesh screen. The two components were blended for 4 minutes until a uniformly mixed mixture was achieved.

[0243] Tablet cores were compressed using a Korsch XL 100 rotary tablet press equipped with 0.2188" round tooling. The tablet press was operated at 70 RPM at a compression force of approximately 10 kN. The tablets had an average weight of 64.2 mg, an average thickness of 1.93 mm, and an average hardness of 3.1 kP.

[0244] Example 9. Immediate Release Oral Dosage Form (Strength 50 mg)

[0245] The composition of the 50 mg dosage strength oral tablet is shown in Table 5.

[0246] Table 5. Quantitative composition of tablets containing 50 mg of Form A

[0247]

[0248] 1. 64.50 mg of besylate salt form corresponds to 50 mg of free base form.

[0249] Granulation:

[0250] A similar granulation procedure as described in Example 8 was followed.

[0251] Lubrication and compression:

[0252] The ground granules were then added to a 16 quart V-blender along with magnesium stearate and crushed using a 30 mesh screen. The two components were mixed for 4 minutes until a uniformly mixed mixture was achieved. Tablet cores were compressed using a Korsch XL 100 rotary tablet press equipped with a 0.6496x0.3504 inch caplet tool. The tablet press was run at 30RPM at a compression force of approximately 29.5kN. The average weight of the tablets was 647.5mg, the average thickness was 4.84mm, and the average hardness was 12.3kP.

[0253] Example 10. Immediate Release Oral Dosage Form (Strength 25 mg)

[0254] The composition of the 25 mg dosage strength oral tablet is shown in Table 6.

[0255] Table 6. Quantitative composition of tablets containing 25 mg of Form A

[0256]

[0257] 1. 33.07 mg of besylate salt form corresponds to 25 mg of free base form.

[0258] Granulation and Lubrication:

[0259] First, the raw material was screened through a 30-mesh screen. Hydroxypropylcellulose, sodium lauryl sulfate, lactose monohydrate, microcrystalline cellulose, and cross-linked sodium carboxymethylcellulose were then screened through a 20-mesh screen. The six materials were then high-shear granulated in a 25L pot with purified water. Water was added to a granulator running at an impeller speed of 290RPM and a chopper speed of 1760 at 350-450g / min. After reaching the end point, the wet granules were crushed in a standard mill equipped with a 375Q screen. The agglomerated granules were then dried in an oven at 40°C until the amount of water in the granules was less than 4% by weight. The dried granules were then ground in a standard grinder equipped with a 75R screen. The ground granules were then added to a one-cubic-foot V-type mixer together with magnesium stearate and crushed using a 30-mesh screen. The two components were mixed for 4 minutes until a uniformly mixed mixture was achieved.

[0260] compression:

[0261] Tablet cores were compressed using a Korsch XL 100 rotary tablet press equipped with 7.5 mm round tooling. The tablet press was operated at 40 RPM at a compression force of approximately 15 kN. The average weight of the tablets was 166.4 mg, the average thickness was 3.52 mm, and the average hardness was 9.0 kP.

[0262] Coating:

[0263] Water and Opadry II amb film coating agent were added to a 1 / 2 gallon container and mixed 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.

[0264] Example 11. Immediate Release Oral Dosage Form (Strength 75 mg)

[0265] The composition of the 75 mg dosage strength oral tablet is shown in Table 7.

[0266] Table 7. Quantitative composition of tablets containing 75 mg of Form A

[0267]

[0268]

[0269] 1. 99.20 mg of the besylate salt form corresponds to 75 mg of the free base form.

[0270] Granulation and Lubrication:

[0271] For the granulation and lubrication steps, a similar procedure as described in Example 10 was followed.

[0272] compression:

[0273] Tablet cores were compressed using a Korsch XL 100 rotary tablet press equipped with 15 mm x 7.5 mm caplet tooling. The tablet press was operated at 40 RPM at a compression force of approximately 9.3 kN. The average tablet weight was 494.2 mg, the average thickness was 5.46 mm, and the average hardness was 15.2 kP.

[0274] It should be noted that there are alternative ways of implementing the present invention. Therefore, the present embodiments are considered to be illustrative rather than restrictive, and the present invention is not limited to the details given herein, but may be modified within the scope and equivalents of any claims issued therefrom. All publications and patents cited herein are incorporated by reference in their entirety.

Claims

1. 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)ethane-1-ol benzenesulfonate in crystalline form A; The compound has characteristic absorption peaks (2θ) 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°, 16.2°±0.3°, 27.9°±0.3° and 28.1°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

2. The compound according to claim 1, which further has characteristic absorption peaks (2θ) at 9.2°±0.3°, 9.3°±0.3°, 14.6°±0.3°, 16.5°±0.3° and 25.1°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation. 3 . The compound according to claim 1 , which has an X-ray powder diffraction pattern using Cu Kα radiation as shown in FIG. 1 .

4. A compound according to any one of claims 1 to 3 having a melting point between 170°C and 173°C as determined by differential scanning calorimetry at a scan rate of 5°C / min.

5. A pharmaceutical composition comprising the compound in crystalline form A according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition according to claim 5, wherein the composition is in the form of an oral tablet.

7. A pharmaceutical composition according to claim 6, comprising at least 75 mg of the compound in crystalline form A.

8. The pharmaceutical composition according to claim 6, comprising at least 25 mg of the compound in crystalline form A.

9. The pharmaceutical composition according to claim 6, comprising a wetting agent.

10. The pharmaceutical composition according to claim 9, wherein the wetting agent is sodium lauryl sulfate.

11. The pharmaceutical composition according to claim 6, comprising a water-soluble excipient.

12. The pharmaceutical composition according to claim 11, wherein the water-soluble excipient is lactose monohydrate.

13. The pharmaceutical composition of claim 12, wherein the water-soluble excipient is at least 50% by weight of the pharmaceutical composition.

14. The pharmaceutical composition according to claim 6, comprising a disintegrant.

15. The pharmaceutical composition according to claim 14, wherein the disintegrant is croscarmellose sodium.

16. Use of a compound of crystalline form A according to any one of claims 1 to 4 for the preparation of a medicament for treating a CCR4-mediated immune disease or disorder, an inflammatory disease or disorder, cancer or a neurodegenerative disease.

17. Use of the pharmaceutical composition according to any one of claims 5 to 15 in the preparation of a medicament for treating a CCR4-mediated immune disease or condition, an inflammatory disease or condition, cancer or a neurodegenerative disease.

18. The use according to claim 16, wherein the compound in crystalline form A is co-administered with another therapeutic agent.

19. The use according to claim 18, wherein the other therapeutic agent is pembrolizumab.

20. The use according to claim 17, wherein the compound in crystalline form A is co-administered with another therapeutic agent.

21. The use according to claim 20, wherein the other therapeutic agent is pembrolizumab.

22. The use according to claim 16 or 17, wherein the immune disease or disorder, inflammatory disease or disorder is a gastrointestinal disease, transplant rejection, multiple sclerosis or allergic lung disease.

23. The use according to claim 16 or 17, wherein the immune disease or disorder, inflammatory disease or disorder is selected from inflammatory bowel disease, hypersensitivity reactions, allergic reactions, pulmonary fibrosis, autoimmune diseases, inflammatory skin diseases and allograft rejection.

24. The use according to claim 16 or 17, wherein the immune disease or disorder, inflammatory disease or disorder is selected from Crohn's disease, ulcerative colitis, ileitis, psoriasis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria, pruritus, vasculitis, scleroderma, COPD, allergic rhinitis, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, type I diabetes, glomerulonephritis, atherosclerosis, encephalitis, meningitis, hepatitis, sepsis, sarcoidosis, allergic conjunctivitis, otitis, sinusitis, idiopathic pulmonary fibrosis and asthma.

25. The use according to claim 16 or 17, wherein the immune disease or disorder, inflammatory disease or disorder is respiratory allergic disease, liver inflammation, transplant rejection, enteritis or contact dermatitis.

26. The use according to claim 16 or 17, wherein the inflammatory disease or disorder is dermatitis or nephritis.

27. The use according to claim 16 or 17, wherein the use is for the preparation of a medicament for treating CCR4-mediated cancer.

28. The use according to claim 27, wherein the cancer is selected from leukemia, lymphoma and gastric cancer.

29. The method of claim 27, wherein the cancer is selected from the group consisting of thyroid cancer, bile duct cancer, pancreatic adenocarcinoma, skin melanoma, colon adenocarcinoma, rectal adenocarcinoma, stomach adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, nasopharyngeal carcinoma, Hodgkin's lymphoma, invasive breast cancer, lung adenocarcinoma, and lung squamous cell carcinoma.

30. The use according to claim 16 or 17, wherein the use is for preparing a medicament for treating a CCR4-mediated neurodegenerative disease.

31. The use according to claim 30, wherein the neurodegenerative disease is Alzheimer's disease.

32. Use of a compound of crystalline form A according to any one of claims 1 to 4 or a pharmaceutical composition according to any one of claims 5 to 15 for the preparation of a medicament for the treatment of CCR4-mediated granuloma development.

33. A process for the preparation of a compound in crystalline form A according to any one of claims 1 to 4, comprising crystallizing the compound from a mixture of tert-butyl methyl ether and ethanol.

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