Crystalline Forms of CC Chemokine Receptor Type 4 Antagonists and Their Uses

Abstract

The present invention provides a crystalline form of a CCR4 (CC chemokine receptor type 4) antagonist, a form for oral administration thereof, and methods for the use and manufacture thereof.

Description

Technology Field

[0001] Cross-reference regarding related applications

[0002] This application claims priority to U.S. Application No. 62 / 935,007 filed on November 13, 2019, the full text of which is incorporated herein by reference.

[0003] Technology field

[0004] Crystalline forms of CC chemokine receptor type 4 (CCR4) antagonists and methods for their preparation and use are disclosed herein. These compounds may be used as therapeutic agents in the treatment of certain diseases and disorders, for example, including cancer. Background Technology

[0005] In general, the crystalline form of a drug is preferred over its amorphous form, partly due to their superior stability. For example, in many situations, amorphous drugs are converted into crystalline forms during storage. Since the amorphous and crystalline forms of drugs typically possess different physical and chemical properties, efficacy, and / or bioavailability, such interconversion is undesirable for safety reasons during pharmaceutical administration.

[0006] A key characteristic of arbitrary crystalline drugs is their polymorphic behavior. Polymorphs are crystalline forms of the same molecule that possess distinct physical properties because their crystal lattices contain different molecular arrangements. The different properties exhibited by polymorphs influence important pharmaceutical parameters such as storage, stability, compressibility, density (important for formulation and product manufacturing), and dissolution rate (important for determining bioavailability). Differences in stability can be attributed to changes in chemical reactivity (e.g., differential hydrolysis or oxidation, which causes the formulation to discolor more rapidly when composed of a single polymorph compared to other polymorphs), mechanical changes (e.g., tablet crumbling during storage as a kinetically preferred crystal form transitions to a thermodynamically more stable crystal form), or both (e.g., tablets of one polymorph are more susceptible to destruction at high humidity). Differences in solubility between polymorphs can lead to a transition to a crystalline form that is ineffective or toxic under extreme conditions. Furthermore, the physical properties of the crystal form can be critical in pharmaceutical processes. For example, certain crystal forms may form solvates more easily or be more difficult to wash by filtering out impurities than other forms (i.e., particle shape and size distribution may differ between one crystal form compared to another).

[0007] Agencies such as the U.S. Food and Drug Administration strictly regulate the polymorph content of active ingredients in solid formulations. Generally, regulatory agencies require collective monitoring of polymorphic drugs when marketing substances other than pure and thermodynamically desirable polymorphs. Therefore, for medical and commercial reasons, it is preferred to synthesize and market solid drugs as thermodynamically stable polymorphs that are substantially free of kinetically preferred polymorphs. This application addresses these and other requirements of the art.

[0008] summation

[0009] In one embodiment, a crystalline form of 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)ethanol-1-ol is provided.

[0010] In one embodiment, a crystalline form of the benzene sulfonate salt of 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)ethanol-1-ol is provided.

[0011] In one embodiment, the crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is provided in a form designated as form A. In one embodiment, the crystal 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, crystal form A has characteristic absorption peaks at 12.2°±0.3°, 23.8°±0.3°, and 25.6°±0.3° in the X-ray powder diffraction pattern using Cu Kα radiation. In another embodiment, crystal form A has characteristic absorption peaks at 23.1°±0.3°, 20.0°±0.3°, and 16.2°±0.3° in the X-ray powder diffraction pattern using Cu Kα radiation. In another embodiment, crystal form A has an X-ray powder diffraction pattern using Cu Kα radiation as shown in FIG. 1. In another embodiment, crystal form A has a melting point of about 170°C to about 173°C when measured by differential scanning calorimetry at a scanning rate of 5°C / min.

[0012] In another embodiment, the crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is provided in a form designated as form B. In one embodiment, the crystal 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, crystal form B has characteristic absorption peaks at 12.2°±0.3°, 23.8°±0.3°, and 25.6°±0.3° in the X-ray powder diffraction pattern using Cu Kα radiation. In another embodiment, crystal form B has characteristic absorption peaks at 23.1°±0.3°, 20.0°±0.3°, and 16.2°±0.3° in the X-ray powder diffraction pattern using Cu Kα radiation. In another embodiment, crystal form B has an X-ray powder diffraction pattern using Cu Kα radiation as shown in FIG. 3. In another embodiment, crystal form B has a melting point of about 116°C to about 119°C when measured by differential scanning calorimetry at a scanning rate of 5°C / min.

[0013] In another embodiment, a pharmaceutical composition comprising the crystalline form of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is provided.

[0014] In an embodiment, the pharmaceutical composition comprises crystal form A and / or crystal form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and a pharmaceutically acceptable carrier. In an embodiment, the pharmaceutical composition comprises crystal form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and a pharmaceutically acceptable carrier. In an embodiment, the pharmaceutical composition comprises crystalline form B of 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and a pharmaceutically acceptable carrier.

[0015] In another aspect, a method is provided for treating or preventing various diseases, such as allergic, immune, inflammatory, or cancer-related diseases, disorders, or conditions using the crystalline form of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and a pharmaceutical composition thereof. These diseases, disorders, and conditions are described in detail elsewhere, as are other diseases that can be treated or prevented by the crystalline compounds described herein.

[0016] In an embodiment, the disease or disorder is an allergy-related disorder (e.g., hypersensitivity and anaphylactic reaction); gastrointestinal disorder (e.g., inflammatory bowel disease, Crohn's disease, ulcerative colitis, ileitis and enteritis); psoriasis and inflammatory dermatitis (e.g., dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria and pruritus); vasculitis; scleroderma; asthma, COPD and respiratory allergic diseases (e.g., allergic rhinitis and hypersensitivity lung disease); arthritis (e.g., rheumatoid arthritis and psoriasis), autoimmune diseases including multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, and glomerulonephritis; graft rejection (e.g., allogeneic graft rejection); graft rejection (e.g., parenchymal organ); cancer, e.g., leukemia, lymphoma and metastatic cancer, particularly solid tumors (e.g., gastric cancer); and other diseases requiring suppression of unwanted inflammation and / or immune responses, e.g., atherosclerosis, neurodegenerative diseases (e.g., Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis media, and sinusitis. In an embodiment, the disease, disorder, or condition is mediated by CCR4. In an embodiment, the CCR4-mediated disease, disorder, or condition is one of asthma, COPD, rhinitis, idiopathic pulmonary fibrosis, psoriasis, and contact dermatitis. In an embodiment, the disease or disorder is pulmonary fibrosis, hepatitis, asthma, atopic dermatitis, cancer (e.g., thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, cutaneous melanoma, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma), or granuloma development.The method generally comprises the step of administering a therapeutically effective amount of crystalline form A and / or crystalline form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate as described herein to a patient who requires such treatment or prevention.

[0017] In another embodiment, 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]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is provided.

[0018] In an embodiment, a method for preparing crystal form A of the 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate described herein is provided. In an embodiment, a method for preparing crystal form B of the 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate described herein is provided. Brief explanation of the drawing

[0019] Fig. 1 This shows the X-ray powder diffraction pattern of crystal form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate. do 2This shows the differential scanning calorimetry diagram of crystal form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate. do 3 X-ray powder diffraction of crystal form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is shown. Fig. 4 This shows the differential scanning calorimetry diagram of crystal form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate. Specific details for implementing the invention

[0020] definition

[0021] The term “pharmaceutically acceptable carrier” as used herein refers to a diluent, adjuvant, excipient, or carrier that may be administered to a patient in need with 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate.

[0022] As used herein, the term “pharmaceuticalally acceptable salt” means a salt of a compound prepared with a relatively non-toxic acid or base, depending on a specific substituent found on the compound. The crystalline compounds described herein are besylate salts. If the compound contains a relatively acidic functional group, a base-added salt may be obtained by contacting a neutral form of such compound with a sufficient amount of the desired base in a pure or suitable inert solvent. Examples of pharmaceutically acceptable base-added salts include sodium, potassium, calcium, ammonium, organoamino, or magnesium salts, or similar salts. If the compound contains a relatively basic functional group, an acid-added salt may be obtained by contacting a neutral form of such compound with a sufficient amount of the desired acid in a pure or suitable inert solvent. Examples of pharmaceutically acceptable acid-added salts include salts derived from inorganic acids such as hydrochloric acid, hydrogen bromide, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphate, dihydrophosphate, sulfuric acid, monohydrosulfuric acid, hydrogen water, or phosphoric acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, souveric acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginates, etc., and salts of organic acids such as glucuronic acid or galactonoric acid, etc. (e.g., literature [Berge et al. , "Pharmaceutical Salt", Journal of Pharmaceutical Science , 1977 , 66 See [1-19]). Certain compounds may contain both basic and acidic functional groups that cause the compound to be converted into a base or an acid addition salt.

[0023] The terms "CC chemokine receptor type 4" and "CCR4" as used herein refer to a protein (including its homologs, isoproteins, and functional fragments) and a high-affinity receptor for CC type chemokines (e.g., CCL2 (MCP-1), CCL4 (MIP-1), CCL5 (RANTES), CCL17 (TARC), and CCL22 (MDC)). This is referred to by a number of different names in the scientific literature, including "CC-CKR-4", "CC CKR-4", "K5-5", "CD194", "CMKBR4", "ChemR13", "HGCN", and "14099". The above terms include any recombinant or naturally occurring form of a CCR4 variant that retains CCR4 activity (e.g., activity within 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% compared to wild-type CCR4). The above terms include any mutant form (e.g., frameshift mutant) of a CCR4 variant that retains CCR4 activity (e.g., activity within 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% compared to wild-type CCR4). In an embodiment, CCR4The CCR4 protein encoded by the gene has an amino acid sequence presented in or corresponding to Entrez 1233, UniProt P51679, or RefSeq (protein) NP_005499.1. In an embodiment, the CCR4 gene has a nucleic acid sequence presented in RefSeq (mRNA) NM_005508. In an embodiment, the amino acid sequence or nucleic acid sequence is a sequence known at the time of filing of this application. In an embodiment, the sequence corresponds to GI:5031627. In an embodiment, the sequence corresponds to NP_005499.1. In an embodiment, the sequence corresponds to NM_005508.4. In an embodiment, the sequence corresponds to GI:48762930. In an embodiment, the CCR4 is human CCR4, such as human cancer that causes CCR4. Although frequently found in dendritic cells, macrophages, NK cells, platelets, and basophils, CCR4 is primarily associated with T cells. It contributes to the progression of numerous inflammation-related disorders and, as described herein, is also associated with numerous other diseases. The genomic sequence of CCR4 is located on chromosome 3 (NC_000003.12), and the CCR4 gene is conserved in a number of species, including chimpanzees, rhesus monkeys, dogs, cattle, mice, rats, chickens, and zebrafish. The CCR4 polypeptide contains 360 amino acid residues (NP_005499.1), and like other chemokine receptors, CCR4 is a G protein-coupled receptor found on the surface of leukocytes (see Horuk (1994) Trends Pharm. Sci. 15:159-165).

[0024] As used herein, the term "CCR4 inhibitor" refers to a compound that reduces the activity of CCR4 compared to a control (e.g., a compound described herein), e.g., the absence of a compound or a compound having known inactivity.

[0025] As used herein, terms relating to proteins such as "activation," "activate," and "activating" refer to the conversion of a protein from an initial inactive or inactive state to a biologically active derivative. These terms refer to activation, or the act of activating, sensitization, or upregulation of signaling or enzymatic activity, or a reduced amount of protein in a disease.

[0026] As used herein, terms such as "agonist," "activator," and "upregulator" refer to substances capable of detectably increasing the expression or activity of a given gene or protein. An agonist may increase expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to a control group in the absence of the agonist. In certain examples, the expression or activity is 1.5 times, 2 times, 3 times, 4 times, 5 times, 10 times, or more than the expression or activity in the absence of the agonist. In an embodiment, the agonist is a molecule that interacts with a target to induce or promote an increase in the activation of the target. In an embodiment, the activator is a molecule that increases, activates, promotes, enhances activation, sensitizes, or upregulates, for example, a gene, protein, ligand, receptor, or cell.

[0027] Terms used herein regarding protein-inhibitor interactions, such as "inhibition," "inhibit," and "inhibiting," mean having a negative effect (e.g., reduction) on the activity or function of a protein compared to the activity or function of a protein in the absence of an inhibitor. In an embodiment, inhibition refers to a negative effect (e.g., reduction) on the concentration or level of a protein compared to the concentration or level of a protein in the absence of an inhibitor. In an embodiment, inhibition refers to a reduction in a disease or symptoms of a disease. In an embodiment, inhibition refers to a reduction in the activity of a specific protein target. Thus, inhibition includes blocking, reducing, preventing, or delaying activation of a stimulus, desensitizing, or down-regulating signaling or enzymatic activity or the amount of a protein, at least partially or wholly. In an embodiment, inhibition refers to a reduction in the activity of a target protein resulting from a direct interaction (e.g., the inhibitor binding to the target protein). In an embodiment, inhibition means a reduction in the activity of a target protein resulting from an indirect interaction (e.g., an inhibitor binds to a protein that activates the target protein and prevents the activation of the target protein).

[0028] As used herein, the terms “repressor,” “repressor,” “antagonist,” or “downregulator” refer interchangeably to a substance capable of detectably reducing the expression or activity of a given gene or protein. An antagonist may reduce expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to a control group in the absence of an antagonist. In certain examples, expression or activity is 1.5 times, 2 times, 3 times, 4 times, 5 times, 10 times, or lower than the expression or activity in the absence of an antagonist. An antagonist prevents, reduces, inhibits, or neutralizes the activity of a agent, and may also prevent, inhibit, or reduce the constitutive activity of a target, e.g., a target receptor, even in the absence of an identified agent. In an embodiment, an inhibitor is a molecule that reduces, blocks, prevents, delays activation, inactivates, desensitizes, or downregulates, for example, a gene, protein, ligand, receptor, or cell. An inhibitor may also be defined as a molecule that reduces, blocks, or inactivates constitutive activity. An "antagonist" is a molecule that opposes the action of the agent.

[0029] As used herein, the terms “disease” or “condition” refer to the condition or health status of a patient or subject that can be treated by the compounds or methods provided herein. The disease may be cancer. The disease may be an autoimmune disease. The disease may be an inflammatory disease. The disease may be an infectious disease. In some additional examples, “cancer” refers to solid and lymphoid cancers, liver cancer including kidney, breast, lung, bladder, colon, ovary, prostate, pancreas, stomach, brain, head and neck, skin, uterus, testis, glioma, esophagus, and hepatocellular carcinoma, nasopharyngeal carcinoma, B-acute lymphoblastic lymphoma, non-Hodgkin lymphoma (e.g., Burkitt's, small cell, and large cell lymphoma), lymphoma including Hodgkin lymphoma, leukemia (including MDS, AML, ALL, ATLL, and CML), or multiple myeloma, sarcoma, adenocarcinoma, lymphoma, and leukemia.

[0030] The term "inflammatory disease" as used herein refers to a disease or condition characterized by abnormal inflammation (e.g., an increased level of inflammation compared to a control group, such as a healthy person without the disease). Examples of inflammatory diseases include autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile-onset diabetes mellitus, type 1 diabetes mellitus, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous alveolosis, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, ischemic reperfusion injury, stroke, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis. Such conditions are often inextricably linked with other diseases, disorders, and conditions. For example, a non-limiting list of inflammation-related diseases, disorders, and conditions that may be induced by inflammatory cytokines includes arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, surgical complications (e.g., where inflammatory cytokines prevent treatment), anemia, and fibromyalgia. Other diseases and disorders that may be associated with chronic inflammation include Alzheimer's disease, congestive heart failure, stroke, aortic valve stenosis, atherosclerosis, osteoporosis, Parkinson's disease, infection, inflammatory bowel disease (IBD), allergic contact dermatitis and other edemas, systemic sclerosis, transplantation, and multiple sclerosis. Some of the aforementioned diseases, disorders, and conditions for which the compounds of the present invention (e.g., CCR4 inhibitors) may be particularly effective are described in more detail below (e.g., due to limitations of current therapies).

[0031] As used herein, the term “cancer” refers to all types of cancer, tumors, or malignant tumors found in mammals (e.g., humans), including leukemia, carcinomas, and sarcomas. Exemplary cancers that can be treated by the compounds or methods provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, gastric cancer, ovarian cancer, lung cancer, and head cancer. Exemplary cancers that can be treated by the compounds or methods provided herein include cancers of the thyroid, endocrine system, brain, breast, cervical, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, medulloblastoma, colorectal cancer, and pancreatic cancer. Additional examples include thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, cutaneous melanoma, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal carcinoma, nasopharyngeal carcinoma, head and neck squamous cell carcinoma, invasive breast carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, Hodgkin disease, Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma pleomorphic, ovarian cancer, rhabdomyosarcoma, primary hematopoiesis, primary macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulinoma, malignant carcinoid tumor, bladder cancer, premature cutaneous lesion, testicular cancer, lymphoma, thyroid carcinoma, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, tumor of the endocrine or exocrine pancreas, medullary thyroid carcinoma, medullary thyroid carcinoma, melanoma, colorectal cancer, It includes papillary thyroid carcinoma, hepatocellular carcinoma, or prostate cancer.

[0032] The term "autoimmune disease" as used herein refers to a disease or condition in which a subject's immune system exhibits an abnormal immune response to a substance that does not normally induce an immune response in a healthy subject. Examples of autoimmune diseases that can be treated by the compounds, pharmaceutical compositions, or methods described herein include acute disseminated encephalitis (ADEM), acute necrotizing hemorrhagic leukocytitis, Addison's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome (APS), autoimmune angioedema, autoimmune aplastic anemia, autoimmune pancreatitis, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED), autoimmune pericarditis, autoimmune oophoritis, autoimmune blepharitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura (ATP), autoimmune thyroid disease, autoimmune urticaria, axonal or neuroneuropathy, Vallo's disease, Behcet's disease, bullous pustular pustulosis, cardiomyopathy, Castleman's disease. Celiac disease, Chagas disease, Chronic Fatigue Syndrome, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Chronic Relapsing Polyperiostitis Mouth Disease (CRMO), Strauss Syndrome, Benign Polypustular Mucositis / Benign Mucositis, Crohn's Disease, Cogans Syndrome, Cold Agglutinin Disease, Congenital Pericarditis, Coxsackie Cardiomyopathy, Crest's Disease, Essential Mixed Cryoglobulinemia, Demyelinating Neuropathy, Dermatomyelitis, Dermatomyositis, Debick's Disease (Neuromyelitis Opticis), Discoid Lupus, Dressler Syndrome, Endometriosis, Eosinophilic Esophagitis, Eosinophilic Fasciitis, Erythema Nourishingis, Experimental Allergic Encephalomyelitis, Evans Syndrome, Fibromyalgia, Fibroalveolitis, Giant Cell Arteritis (Temporal Arteritis), Giant Cell Nephritis, Glomerulonephritis, Goodpasture Syndrome, with Polyangiitis Granulomatosis (GPA) (formerly Wegener's granulomatosis), Graves' disease, Güley-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura, gestational herpes, hypogammaglobulinemia, idiopathic thrombocytopenia (ITP), IgA nephropathy,IgG4-related sclerotic disease, immunomodulatory lipoprotein, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes (Type 1 diabetes), juvenile myositis, Kawasaki syndrome, Lambert-Aton syndrome, leukocytoclectomycosis, lichen planus, lichen sclerosus, mungocytic conjunctivitis, linear IgA disease (LAD), lupus (SLE), Lyme disease, chronic, Meniere's disease, micropolyvasculitis, mixed connective tissue disease (MCTD), Muren ulcer, Mukar-Habermann disease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica (DEVIC), neutropenia, pituitary pemphigoid, optic neuritis, relapsing rheumatism, PANDAS (Streptococcus-associated pediatric autoimmune neurological disease), paraneoplastic cerebellar degeneration, paroxysmal nocturnal pigmenturia (PNH), Paryl-Romberg syndrome, Parsonage-Turner syndrome, planoarthritis (peripheral uveitis), pemphigus, peripheral neuropathy, peripheral encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosum, autoimmune polygland syndromes I, II, and III, polymyalgia rheumatica, polymyositis, post-myocardial syndrome, post-premature ejaculation, progesterone dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, idiopathic pulmonary fibrosis, pyoderma subcutaneousis, aplasia sibilantis, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, Reiter's syndrome, recurrent polyarthritis, retroperitoneal fibrosis, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, rigid man syndrome, subacute bacterial endocarditis Includes (SBE), Susac syndrome, sympathetic ophthalmitis, Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, transverse myelitis, type 1 diabetes mellitus, ulcerative colitis, undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, bullous dermatitis, vitiligo, or Wegener's granuloma (e.g., granulomatosis with polyangiitis (GPA)).

[0033] As used herein, the terms “treating” or “treatment” refer to any indicator of success in the treatment or improvement of an injury, disease, pathology, or condition, including any objective or subjective parameters such as remission; remission; reduction of symptoms or making the injury, pathology, or condition more tolerable to the patient; slowing the rate of deterioration or decline; making the end point of deterioration less debilitating; or promoting the physical or mental well-being of the patient. Treatment or improvement of symptoms may be based on objective or subjective parameters including physical examinations, neuropsychiatric examinations, and / or psychiatric evaluation results. The term “treating” and its application may include the prevention of an injury, pathology, condition, or disease. In an embodiment, treatment is prevention. In an embodiment, treatment does not include prevention.

[0034] As used herein, “treating” or “treatment” also includes any approach to obtain a beneficial or desired outcome in the subject’s condition, which broadly includes clinical outcomes. Beneficial or desired clinical outcomes may include, but are not limited to, the alleviation or improvement of one or more symptoms or conditions; a reduction in the extent of the disease; the stabilization of the condition of the disease (i.e., not exacerbating it); the prevention of the spread or transmission of the disease; the delay or slowing of disease progression; the improvement or alleviation of the condition of the disease; a reduction in the recurrence of the disease; and remission, whether partial or total and detectable or undetectable. In other words, as used herein, “treatment” includes any treatment, improvement, or prevention of the disease. Treatment prevents the occurrence of the disease; inhibits the spread of the disease; alleviates the symptoms of the disease (e.g., eye pain, sprained vision around lights, red eyes, very high intraocular pressure); completely or partially eliminates the underlying cause of the disease; shortens the duration of the disease, or performs a combination thereof.

[0035] As used herein, "treating" or "treatment" includes prophylactic treatment. A treatment method involves administering a therapeutically effective amount of the compound described herein to a subject. The administration step may consist of a single dose or may involve a series of doses. The length of the treatment period depends on various factors, e.g., the severity of the condition, the age of the patient, the concentration of the compound, the activity of the composition used for treatment, or a combination thereof. Additionally, it will be recognized that the effective dose of the preparation used for treatment or prevention may increase or decrease over the course of a specific treatment or prophylactic method. Changes in dosage may be caused by and become apparent through standard diagnostic tests known in the art. In some examples, chronic administration may be required. For example, the composition is administered to the subject for a sufficient amount and duration to treat the patient.

[0036] As used herein, the term "prevention" refers to the reduction of the occurrence of symptoms of a patient's disease. As indicated above, prevention may be complete (no detectable symptoms) or partial, so that fewer symptoms are observed than would be likely to occur without treatment. In an embodiment, prevention refers to slowing the progression of a disease, disorder, or condition, or inhibiting its progression to a harmful or other unwanted state.

[0037] As used herein, the term "modulator" refers to a composition that increases or decreases the level of a target molecule, the function of a target molecule, or the physical state of the molecule's target. In an embodiment, a CCR4-related disease modulator is a compound that reduces the severity of one or more symptoms of a disease associated with CCR4 (e.g., cancer, inflammatory disease, autoimmune disease, or infectious disease). A CCR4 modulator is a compound that increases or decreases the activity or function of CCR4, or the level of activity or function. The modulator may act alone or may use cofactors, e.g., proteins, metal ions, or small molecules. Examples of modulators include small molecule compounds, other bio-organic molecules, etc. A number of libraries of small molecule compounds (e.g., combination libraries) are commercially available and may serve as a starting point for identifying modulators. Those skilled in the art may develop one or more assays (e.g., biochemical or cell-system assays) capable of screening such libraries of compounds to identify one or more compounds having desired properties; Subsequently, a person skilled in the art may optimize one or more of these compounds by, for example, synthesizing and evaluating their analogs and derivatives. Synthetic and / or molecular modeling studies may also be utilized for the identification of activators.

[0038] The term "modulate" is used in its ordinary and common sense and refers to the act of altering or changing one or more characteristics. "Regulation" refers to the process of altering or changing one or more characteristics. For example, as applied to the effect of a modulator on a target protein, the modulator modulates the means to alter the characteristics or function of a target molecule or the amount of the target molecule by increasing or decreasing it. In embodiments, the terms "modulate," "regulate," etc. refer to the ability of a molecule (e.g., activator or inhibitor) to increase or decrease the function or activity of CCR4 directly or indirectly compared to the absence of the molecule.

[0039] “Patient” or “individual in need” refers to a living organism suffering from or likely to suffer from a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammalian animals. In an embodiment, the patient is a human. The terms “person” and “patient” are used interchangeably herein.

[0040] As used herein, the term "effective dose" refers to an amount of a compound sufficient to achieve the stated purpose compared to the absence of the compound (e.g., to achieve the effect of administration, to treat a disease, to reduce enzyme activity, to increase enzyme activity, to reduce signaling pathways, or to reduce one or more symptoms of a disease or condition). An example of an "effective dose" is an amount sufficient to contribute to the treatment, prevention, or reduction of symptoms or signs of a disease, which may also be referred to as a "therapeutic effective dose." "Reduction" of symptoms or signs (and grammatical equivalents of this phrase) means reducing the severity or frequency of symptoms or eliminating symptoms. A "prophylactic effective dose" of a drug is an amount of drug that, when administered to a subject, has the intended prophylactic effect, for example, to prevent or delay the onset (or recurrence) of an injury, disease, pathology, or condition, or to reduce the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition, or symptoms thereof. A complete prophylactic effect does not necessarily occur with a single dose administration, but may occur only after the administration of a series of doses. Therefore, a prophylactically effective amount may be administered in one or more doses. As used herein, "reduced activity amount" refers to the amount of antagonist required to reduce the activity of an enzyme compared to the absence of the antagonist. As used herein, "inhibitory amount" refers to the amount of antagonist required to interfere with the function of an enzyme or protein compared to the absence of the antagonist. The exact amount will vary depending on the purpose of treatment and can be determined by a person skilled in the art using known techniques (e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992)]; [Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999)]; [Pickar, Dosage Calculations (1999)]; and [ Remington: The Science and Practice of Pharmacy[Refer to , 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins]). The therapeutically effective dose can be identified by measuring the associated physiological effects, which may be adjusted in relation to the administration regimen and diagnostic analysis of the subject's condition. For example, measurement of serum levels of a CCR4 inhibitor (or, e.g., its metabolites) may indicate whether a therapeutically effective dose has been administered.

[0041] For any compound described herein, the therapeutically effective dose may be initially measured from a cell culture assay. The target concentration will be the concentration of the active compound(s) capable of achieving the method described herein, as measured using the method described herein or methods known in the art.

[0042] As is well known in the art, the therapeutically effective dose for use in humans can also be determined from animal models. For example, the dose for humans may be formulated to achieve a concentration found to be effective in animals. The dosage in humans may be adjusted by monitoring the effect of the compound and adjusting the dosage up or down as described above. Adjusting the dosage to achieve maximum efficacy in humans based on the methods described above and other methods is within the capability of those skilled in the art. Adjusting the dosage to achieve maximum titratable drug concentration efficacy or toxicity in humans based on the methods described above and other methods is within the capability of those skilled in the art.

[0043] The term "therapeutic effective dose" as used herein refers to an amount of therapeutic agent sufficient to improve the disorder as described above. For example, for a given parameter, the therapeutic effective dose will represent an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic efficacy may also be expressed as a "-fold" increase or decrease. For example, the therapeutic effective dose may have an effect of at least 1.2 times, 1.5 times, 2 times, 5 times, or more compared to the control group.

[0044] The dosage may be varied depending on the requirements of the patient and the compound used. In the context of the present invention, the dose administered to the patient must be sufficient to achieve a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the presence, nature, and degree of any side effects. Determining the appropriate dosage for a specific situation is within the skill of the practitioner. Generally, treatment is initiated with a smaller dose than the optimal dose of the compound. Subsequently, the dosage is increased in small increments until the optimal effect is reached under the circumstances. The dosage and intervals are individually adjusted to provide a level of administered compound effective for the specific clinical indication being treated. This will provide a therapeutic regimen corresponding to the severity of the individual's disease state.

[0045] As used herein, the term "administration" refers to oral administration, administration as a suppository, local contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intradural, intracranial, intranasal, or subcutaneous administration, or sustained-release device to a target, e.g. It refers to the implantation of a mini-osmotic pump. Administration is 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, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other delivery methods include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. "Concomitant administration" means that the compositions described herein are administered simultaneously immediately before or immediately after the administration of one or more additional therapies (e.g., anticancer agents, chemotherapy, or treatment of neurodegenerative diseases). The compounds of the present invention may be administered alone or in combination to a patient. Concomitant administration means administering compounds (one or more compounds or formulations) individually or in combination, simultaneously or sequentially. Thus, formulations may be combined with other active substances if desired (e.g., to reduce metabolic degradation). The compositions of the present invention may be delivered transdermally by a topical route, formulated as topical sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. Oral formulations include tablets, pills, powders, sugars, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., which are suitable for ingestion by the patient. Solid formulations include powders, tablets, pills, capsules, cachets, suppositories, dispersible granules, etc. Liquid formulations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. The compositions of the present invention may further include components to provide sustained release and / or comfort. Such components include high molecular weight, anionic polysaccharide polymers, gelled polysaccharides, and finely divided drug carrier substrates.These components are discussed in detail in U.S. Patents No. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference for all purposes. Compositions of the present invention may also be delivered as microspheres for sustained release in the body. For example, microspheres may be delivered via intradermal injection of drug-containing microspheres for sustained subcutaneous release (Reference [Rao,. J. Biomater Sci. Polym. Ed Refer to . 7:623-645, 1995]); as a biodegradable and injectable gel formulation (e.g., literature [Gao Pharm. Res. See 12:857-863, 1995); Or, as microspheres for oral administration (e.g., literature [Eyles, J. Pharm. Pharmacol. (Refer to [49:669-674, 1997]) it may be administered. In another embodiment, the formulation of the composition of the present invention may be delivered by using liposomes that fuse with or endocytize the cell membrane, that is, by using a receptor ligand attached to a liposome that binds to a surface membrane protein receptor of the cell causing endocytization. In particular, by using liposomes on which the liposome surface carries a receptor ligand specific to the target cell, or otherwise preferentially guided to a specific organ, focus may be placed on delivering the composition of the present invention into the target cell in vivo (e.g., the literature [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] (Refer to ). The composition of the present invention can also be delivered as nanoparticles.

[0046] "Concomitant administration" means that the compositions described herein are administered simultaneously immediately before or immediately after the administration of one or more additional therapies. The compounds of the present invention may be administered alone or may be administered to a patient in combination. For example, the compounds of the present invention may be administered in combination with anticancer agents in the treatment of cancer. Concomitant administration means administering the compounds individually or in combination (one or more compounds) simultaneously or sequentially. The compositions of the present invention may be delivered transdermally by a local route or may be formulated as topical sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0047] As used herein, the term "anticancer agent" refers to a composition (e.g., compound, drug, antagonist, inhibitor, modifier) ​​having antitumor properties or the ability to inhibit cell growth or proliferation. In an embodiment, the anticancer agent is a chemotherapy agent. In an embodiment, the anticancer agent is a preparation identified herein that is useful in a method for treating cancer. In an embodiment, the anticancer agent is a preparation approved by the FDA or a similar regulatory agency in a country other than the United States for treating cancer. 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, BAY 869766), an alkylating agent (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosourea, nitrogen mustard (e.g., mechlorethamine, Cyclophosphamide, chlorambucil, mayphalan), ethyleneimines and methylamines (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmerstin, romeursin, semerstin, streptozosin), triagenes (decarbazine)), anti-metabolites (e.g., 5-azathiophrine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, fluorouridine, cytarabine), purine analogs (e.g., mercaptopurines, thioguanine, pentostatin) etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesin, podophyllotoxin, paclitaxel, dotaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrin, etoposide)(VP16), etoposide phosphate, tenifoside, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g., cisplatin, oxaloplatin, carboplatin), anthracendiones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocorticotropic inhibitors (e.g., mitothan, aminoglutetiimide), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors of mitogen-activated protein kinase signaling (e.g. For, U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmantine or LY294002, Syk inhibitors, mTOR inhibitors, antibodies (e.g., rituximab), gossypol, genasense, polyphenol E, chlorofusin, all-trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-associated apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycitidine, all-trans-retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec RTM), geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), Flavopyridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352, 20-epi-1, 25 Dihydroxyvitamin D3; 5-ethinyluracil; abiraterone; aclarubicin; acylfulbene; adesiphenol; adozelesin; aldehydeslukin; ALL-TK antagonist; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagleride; anastrozole; andrographolide; angiogenesis inhibitor; antagonist D; antagonist G; antarelix; anti-dostrophic morphogenesisProtein-1; Antiandrogen, Prostate Carcinoma; Antiestrogen; Antineoplastic Agent; Antisense Oligonucleotide; Apidicholine Glycinate; Apoptosis Gene Regulator; Apoptosis Regulator; Apuric Acid; ara-CDP-DL-PTBA; Arginine Deaminase; Asulacrine; Atamestein; Atrimustine; Axinastatin 1; Axinastatin 2; Axinastatin 3; Azasterone; Azatoxin; Azatyrosine; Bacatin III Derivatives; Balanol; Vatimestad; BCR / ABL Antagonists; Benzochlorine; Benzoylstaurosporine; Beta-Lactam Derivatives; Beta-Alletin; Beta-Clamycin B; Betulinic Acid; bFGF Inhibitors; Baicalutamide; Bisantren; Bisaziridinylspermine; Bisnafid; Bistraten A; Wiselesin; Breplate; Bropyrimin; Budotitan; Butionine Sulfoximine; Calcipotriol; Carfostin C; Camptothecin Derivatives; Canarifox IL-2; Capecitabine; Carboxamide-amino-triazole; Carboxyamidotriazole; CaRest M3; CARN 700; Chondrogeneic Inhibitors; Caselesin; Casein Kinase Inhibitors (ICOS); Castanospermin; Cecropin B; Cetrorelix; Chlorins; Chloroquinoxalin Sulfonamide; Cicaprost; Cis-Porphyrin; Cladribin; Clomiphene Analogs; Clotrimazole; Colismycin A; Colismycin B; Combretastatin A4; Combretastatin Analogs; Conagenin; Crembecidin 816; Crisnatol; Cryptopicin 8; Cryptopicin A Derivatives; Curacin A; Cyclopentatraquinone; Cycloplatam; Cyfemycin; Cytarabine Oxphosphate; Cell Damage Factor; Cytostatin; Dacliximab; Decitabine; Dehydrodidemnin B; Desloreline; Dexamethasone; Dexiphosphamide; Dexrazoxane; Dexverapamil; Diaziquone; Didemnin B; Didox; Diethylnospermin; Dihydro-5-Azacitidine; 9-Dioxamycin; Diphenylspiromustin; Docosanol; Dolasetron; Doxyfluridine; Droroxifene; Dronabinol; Duocamycin SA; Abselen; Ecomustin; Edylfosin; Edrecolomab; Eflonitine; Elemen; Emiteper; Epirubicin; Epristeride;Estramustine analogs; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; padrozol; pazarabine; fenretinide; filgrastim; finasteride; flavopyridol; flegelastine; fluasterone; fludarabine; fluorodaunorunisin hydrochloride; pofenimex; pomestan; postriesin; potmustine; gadolinium texapyrin; gallium nitrate; gallositabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfame; heregulin; hexamethylene bisacetamide; hypericin; ibandronate; idarubicin; iodoxifen; hydramathan; ilmorphosin; ilomastat; imidazoacridone; imiquimod; immunostimulating peptides; Insulin-like growth factor-1 receptor inhibitors; interferon agonists; interferon; interleukin; iobenzuan; iodoxorubicin; iforminol, 4-; iroflact; isogladin; isobenzazole; isohomohalicondrin B; itasetron; jasflaquinolide; cahalaride F; lamellarin-N triacetate; lanreotide; reinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia suppressor factor; leukocyte alpha interferon; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarosole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; lysoclinamide 7; lovaplatin; lombrycin; rometrexole; ronidamine; losoxantrone; Lovastatin; Loxorbin; Lutotecan; Lutetium Texapyrin; Lysophylline; Lytic Peptide; Meitansin; Mannostatin A; Marimastat; Masoprocol; Maspin; Matrisin Inhibitor; Matrix Metalloproteinase Inhibitor; Menogaril; Mervarone; Mederellin; Methioninase; Metoclopramide; MIF Inhibitor; Mifepristone; Miltefosin; Myrimostim; Mismatched Double-Stranded RNA; Mitoguazone; Mitoractol; Mitomycin Analog; Mitonapid; Mitotoxin Fibroblast Growth Factor-Saporin; Mitoxantrone; Moparotene; Molgramostim; Monoclonal Antibody, Human Chorionic Gonadotropin; Monophosphoryl Lipid A+ Myobacterium Cell Wall Sk;Morpidamol; Multidrug Resistance Gene Inhibitor; Multi-tumor Suppressive First-Class Therapy; Mustard Anticancer Agent; Micaperoxide B; Mycobacterium Cell Wall Extract; Myriaporone; N-Acetyldinaline; N-Substituted Benzamide; Naparelin; Nagrestip; Naloxone + Pentazocine; Nafavin; Nafterpine; Natograstim; Nedaplatin; Nemolubicin; Neridronic Acid; Neutral Endopeptidase; Nilutamide; Nisamycin; Nitric Oxide Modulator; Nitroxide Antioxidant; Nitrulline; O6-Benzylguanine; Octreotide; Oxenone; Oligonucleotide; Onapristone; Ondansetron; Ondansetron; Oracin; Orokine Inducer; Omaplatin; Osateron; Oxaliplatin; Oxaunomycin; Palauamine; Palmitoylisoxin; Palmidronic Acid; Panaxitriol; Panomiphene; Parabactin; Fazeliptin; Pegasapase; Feldecin; Pembrolizumab; Sodium pentosan polysulfate; Pentostatin; Pentrosole; Perflubrone; Perphosphamide; Perillyl alcohol; Fenazinomycin; Phenylacetate; Phosphatase inhibitors; Pisibanil; Pilocarpine hydrochloride; Pirarubicin; Pyritrexime; Placetin A; Placetin B; Plasminogen activator inhibitors; Platinum complex; Platinum compound; Platinum-triamine complex; Porfimer sodium; Porphyromycin; Prednisone; Propyl bis-acridone; Prostaglandin J2; Proteasome inhibitors; Protein A-type immunomodulators; Protein kinase C inhibitors; Protein kinase C inhibitors, microalgae; Protein tyrosine phosphatase inhibitors; Purine nucleoside phosphorylase inhibitors; Purpurin; Pyrazoloacridine; Pyridoxylated hemoglobin polyoxyethyl conjugate; RAF antagonist; Raltitrex; Ramosetron; Ras-farnesil protease inhibitor; Ras inhibitor; Ras-GAP inhibitor; Leteliptin dimethylated; Renium Re 186 etidronate; Lyzosin; Ribozyme; RII retinaamide; Logletimide; Rohitucaine; Romurtide; Roquinimex; Rubiginon B1; Luboxil; Safingol; Saitopine; SarCNU; Sarcopitol A; Sagramostim; Sdi 1 mimetic; Semerstin; Aging-derivedInhibitor 1; Sense oligonucleotide; Signal transduction inhibitor; Signal transduction modulator; Short-chain antigen-binding protein; Sizofuran; Sobuzolic acid; Sodium borocaptate; Sodium phenylacetate; Sorverol; Somatomedin-binding protein; Sonermin; Spafosic acid; Spicamycin D; Spiromustin; Splenopeptin; Spongestatin 1; Squalamine; Stem cell inhibitor; Stem cell division inhibitor; Stipiamide; Stromelisin inhibitor; Sulfinosine; Hyperactive vasoactive intestinal peptide antagonist; Suradista; Suramine; Swainsonine; Synthetic glycosaminoglycan; Thalimustin; Tamoxifen iodide; Touromustin; Tazarotene; Tecogalan sodium; Tegafur; Tellurapyrillium; Telomerase inhibitor; Temoporfin; Temozolomide; Tenifoside; Tetrachlorodecaoxide; Tetrazomin; Taliblastine; Thiocoraline; Thrombopoietin; Thrombopoietin mimics; Timalfacine; Thymopoietin receptor agonists; Timotrinan; Thyroid-stimulating hormone; Tin ethyl thiofurpurine; Tirapazamine; Titanocene bichloride; Topcentin; Toremifene; Pluripotent stem cell factor; Translation inhibitors; Tretinoin; Triacetyluridine; Trisyribin; Trimetrexate; Triptorelin; Trophisetron; Turosteride; Tyrosine kinase inhibitors; Tirfostine; UBC inhibitors; Uvenimex; Urogenital-derived growth inhibitory factor; Urokinase receptor antagonists; Baprootide; Bariolin B; Vector systems, erythrocyte gene therapy; Bellaresol; Veramin; Verdin; Verteporfin; Vinorelbine; Vinsaltin; Vitacin; Borozol; Zanoteron; Geniplatin; Zilascov; Gynostatin Stimaleimer, Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, Asibicin; Aclarubicin; Acodazole Hydrochloride; Acronin; Adozelesin; Aldeslukin; Altretamine; Ambomycin; Ametantrone Acetate; Aminoglutecimide; Amsacrine; Anastrozole; Antramycin; Asparaginase; Asperin; Azacitidine; Azetepa; Azotomycin; Vatimestad; Benzodepa; Baicalutamide; Bisantren Hydrochloride; Bisnafid Dimesylate; Bizelesin; BleomycinSulfate; Brequina sodium; Bropyrimin; Busulfan; Cashinomycin; Calosterone; Carasemide; Carbetimer; Carboplatin; Camerstine; Carubicin hydrochloride; Caselesin; Sedefingol; Chlorambucil; Sirolemycin; Cladribine; Crisnatol mesylate; Cyclophosphamide; Cytarabine; Dacarbazine; Daunorubicin hydrochloride; Decitabine; Dexormaplatin; Desaguanine; Desaguanine mesylate; Diaziquone; Doxorubicin; Doxorubicin hydrochloride; Droroxifene; Droroxifene citrate; Dromostanolone propionate; Duazomycin; Edatrexate; Eflornitine hydrochloride; Elsamitrusin; Enroplatin; Enpromate; Epipropidine; Epirubicin hydrochloride; Erbulozol; Esorubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; etoprine; padrozol hydrochloride; pazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; phosidone; postriesin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimorphosin; interleukin I1 (including recombinant interleukin II, or rlL.sub.2), interferon alpha-2a; interferon alpha-2b; interferon alpha-n1; interferon alpha-n3; interferon beta-1a; interferon gamma-1b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; Leuprolide acetate; Riarozol hydrochloride; Lometrexole sodium; Romestine; Losoxantrone hydrochloride; Masoprocol; Meitansine; Mechlorethamine hydrochloride; Megestrol acetate; Melengestrol acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate sodium; Metoprine; Meturedepa; Mitindoamide; Mitocarcin; Mitocromin; Mitogiline; Mitomalcin; Mitomycin; Mitosper; Mitotan; Mitoxantrone hydrochloride; Mycophenolic acid; Nocodazoie; Nogalamycin; Omaplatin; Oxysuran; Pegaspagase; Peliomycin; Pentamustine; Peplomycin sulfate; Perphosphamide; Pipobroman; Piposulfan; Pyroxantrone hydrochloride; Plicamycin;Plamestan; Porfimer sodium; Porphyromycin; Prednimustine; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Pyrazopurine; Ribophrine; Logletimide; Safingol; Safingol hydrochloride; Semustine; Simtrazine; Sparfosate sodium; Sparsomycin; Spirogermanium hydrochloride; Spiromustine; Spiroplatin; Streptonigreen; Streptozosin; Sulofenur; Thalisomycin; Tecogalan sodium; Tegafur; Teloxantrone hydrochloride; Temoporfin; Tenifoside; Teroxylon; Testolactone; Thiamiphrine; Thioguanine; Thiotepa; Thiazopurine; Tirapazamine; Toremifene citrate; Trestolon acetate; Trisilibin phosphate; Trimetrexate; Trimetrexate glucuronate; triptorelin; tubulozol hydrochloride; uracil mustard; uredepa; bapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesin; vindesin sulfate; vinpidine sulfate; vinglycinate sulfate; vinryurosine sulfate; vinorelbine tartrate; vinocidin sulfate; vinzolidine sulfate; borozol; geniplatin; genostatin; Zorubicin hydrochloride, agents that restrain cells in the G2-M phase and / or regulate the formation or stability of microtubules (e.g., Taxol™ (i.e., paclitaxel)), Taxotere™, compounds containing a taxane backbone, erbulozol (i.e., R-55104), dolastatin 10 (i.e., DLS-10 and NSC-376128), mibobulin isethionate (i.e., as CI-980), vincristine, NSC-639829, discodermolid (i.e., as NVP-XX-A-296), ABT-751 (Abbott, i.e., E-7010), altohirtin (e.g., altohirtin A and altohirtin C), spongestatin (e.g., spongestatin 1, spongestatin 2, spongestatin 3, spongestatin 4, spongestatin 5, spongestatin 6, spongestatin 7), Spongestatin 8, and spongestatin 9), semadotine hydrochloride (i.e., LU-103793 and NSC-D-669356), epotillon (e.g., epotillonA, Epotillon B, Epotillon C (i.e., desoxiepotillon A or dEpoA), Epotillon D (i.e., KOS-862, dEpoB, and desoxiepotillon B), Epotillon E, Epotillon F, Epotillon B N-oxide, Epotillon A N-oxide, 16-Aza-Epotillon B, 21-Aminoepotillon B (i.e., BMS-310705), 21-Hydroxypotillon D (i.e., E, desoxiepotillon F and dEpoF), 26-Fluoroepotillon, Auristatin PE (i.e., NSC-654663), Soblidotin (i.e., TZT-1027), LS-4559-P (Pharmacia, i.e., LS-4577), LS-4578 (Pharmacia, i.e. LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, i.e. WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, i.e. ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), Cryptopicin 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), Bitibawamide, Tubulicin A, Canadensol, Centauredin (i.e., NSC-106969), T-138067 (Tularik, i.e., T-67, TL-138067 and TI-138067), COBRA-1 (Parker HughesLaboratories, 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 Laboratories), Pythianolide B, Laurimalide, SPA-2 (Parker Hughes Laboratories), SPA-1 (Parker Hughes Laboratories, i.e., SPIKET-P), 3-IAABU (Cytoskeleton / Mount Sinai School of Medicine, i.e., MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterin, 3-BAABU (Cytoskeleton / Mount Sinai School of Medicine, i.e., MF-191), TMPN (Arizona State University), Barnadosene Acetylacetonate, T-138026 (Tularik), Monsatrol, Inanosine (i.e., NSC-698666), 3-IAABE (Cytoskeleton / Mount Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, i.e., T-900607), RPR-115781 (Aventis), Eleutherobin (e.g., Desmethyl-eleutherobin, Desacetyl-eleutherobin, Iso-eleutherobin A, and Z-eleutherobin), Caribaoside, Caribeolin, Halicondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Tacalonolide A, TUB-245 (Aventis), A-259754 (Abbott), diozostatin, (-)-phenylahistine (i.e., NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), myoseverin B, D-43411 (Zentaris, i.e., D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (i.e., SPA-110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris),D-82318 (Zentaris), SC-12983 (NCI), resverasatin sodium phosphate, BPR-OY-007 (National Health Research Institations), 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, medoxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), anti-estrogens (e.g., tamoxifen), and androgens (e.g., testosterone propionate, fluoxymesterone), anti-androgens (e.g., Flutamide), immunostimulants (e.g., Bacillus calmette-gerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), humanized pembrolizumab antibodies, immunotoxins (e.g., anti-CD33 monoclonal antibody-calisemycin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., 111 In, 90 Y, or 131Anti-CD20 monoclonal antibodies conjugated to I, etc.), triptolide, homoharingtonin, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesin, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytriptamine, vemurafenib, dabrafenib, eroteinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR)-targeted therapies or treatments (e.g., gefitinib (Iressa™), eroteinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib / BIBW2992, CI-1033 / canertinib, Neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, Dacomitinib / PF299804, OSI-420 / Desmethyl Erotinib, AZD8931, AEE788, Felitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, or similar compounds, but are not limited thereto. In one embodiment, the crystalline compound disclosed herein is co-administered with pembrolizumab to a patient undergoing cancer treatment.

[0048] The terms "chemotherapy" or "chemotherapy agent" as used herein are used in the ordinary sense and refer to chemical compositions or compounds having antitumor properties or the ability to inhibit cell growth or proliferation. In an embodiment, the chemotherapy agent is an antiproliferative / antitumor drug, an antimetabolite, an antitumor antibiotic, a mitotic inhibitor, a topoisomerase inhibitor, a cell proliferation inhibitor, an estrogen receptor downregulator, an antiandrogen, an LHRH antagonist or LHRH agonist, a progestogen, an aromatase inhibitor, an alpha-reductase inhibitor, a cancer cell invasion inhibitor, a growth factor function inhibitor, a farnesyl transferase inhibitor, a tyrosine kinase inhibitor, a serine / threonine kinase inhibitor, an epidermal growth factor family inhibitor, a platelet-derived growth factor family inhibitor, a hepatocyte growth factor family inhibitor; It is an anti-angiogenic agent, a vascular injury agent, a preparation used in antisense therapy, an anti-ras antisense agent, a preparation used in gene therapy, an immunotherapeutic agent, or an antibody.

[0049] As used herein, the term "anti-inflammatory agent" is used in the ordinary sense and refers to a composition (e.g., compound, drug, antagonist, inhibitor, modifier) ​​used in any manner to reduce inflammation or edema. In an embodiment, the anti-inflammatory agent is a preparation identified herein that is useful in a method of treating an inflammatory disease or disorder. In an embodiment, the anti-inflammatory agent is a preparation approved by the FDA or a similar regulatory agency in a country other than the United States for reducing edema and inflammation. In an embodiment, the anti-inflammatory agent is a non-steroidal anti-inflammatory agent (hereinafter NSAID) comprising thalidomide or its derivatives, retinoids, dithranol or calcipotriol, a non-selective cyclo-oxygenase COX-1 / COX-2 inhibitor depending on whether applied topically or systemically (e.g., piroxicam, diclofenac, propionic acid, e.g., naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, phenamates, e.g., mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolone, e.g., phenylbutazone, salicylates, e.g., aspirin); or a selective COX-2 inhibitor (e.g., meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); Cyclo-oxygenase that inhibits nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, or intra-articular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular therapies such as hyaluronic acid derivatives; and nutritional agents such as glucosamine.

[0050] As used herein, the term "solid form" refers to a form of a compound in which atoms or molecules are tightly connected through chemical bonds, resulting in a relatively stable shape and volume.

[0051] As used herein, the term "crystalline form of a compound" refers to a compound having a crystalline structure, that is, a compound arranged in a highly ordered microstructure in which the compound composition forms a crystal lattice extending in all directions.

[0052] As used herein, the term "amorphous form of a compound" refers to a compound having an amorphous structure, that is, a structure lacking the long-range order of crystalline compounds.

[0053] The term "therapeutic index" used here refers to the ratio of administration between toxicity and therapeutic effect.

[0054] crystalline compounds

[0055] When referring herein to a crystalline compound according to the present invention, the degree of crystallinity, suitably measured by X-ray powder diffraction data, is, for example, greater than about 60%, for example, greater than about 80%, particularly greater than about 90%, more particularly greater than about 95%. In an embodiment of the present invention, the degree of crystallinity as measured by X-ray powder diffraction data is greater than about 98%, and said % degree of crystallinity refers to a weight% of the total sample mass that is crystalline.

[0056] Suitably, the crystal variant of the compound according to the present invention is substantially free from other crystal variants of the compound. Suitably, the crystal variant of the compound described herein comprises, for example, 20 wt%, 15 wt%, 10 wt%, 5 wt%, less than 3 wt%, or particularly less than 1 wt% of other crystal forms of said compound.

[0057] The crystalline compound disclosed herein is a benzene sulfonate salt also referred to as the besylate salt of 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-ol. The besylate salt form of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidin-1-yl)ethanol-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]pyrazine-6-yl)azetidine-3-yl)piperidin-1-yl)ethanol-1-ol with benzenesulfonic acid. The free bases of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-ol are both Beck's paper titled "Chemokine Receptor Modulators and Uses Thereof," published on January 15, 2019. et al It can be manufactured according to the procedure disclosed in U.S. Patent No. 10,179,787 and Example 42 of Beck et al., International Application WO 2018 / 022992, issued February 1, 2018.

[0058] 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)

[0059] -1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)

[0060] Crystalline Form A of Ethan-1-Olbenzene Sulfonate and Its Preparation

[0061] In an embodiment, crystalline form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is provided. In an embodiment, crystal form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate has characteristic absorption peaks at 18.4°±0.3°, 22.9°±0.3°, 21.2°±0.3° and 15.9°±0.3° in X-ray powder diffraction using Cu Kα radiation.

[0062] In another embodiment, crystal form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate 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 X-ray powder diffraction using Cu Kα radiation.

[0063] In another embodiment, crystal form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate 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 X-ray powder diffraction analysis using Cu Kα radiation.

[0064] In an embodiment, crystal form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-ol benzene sulfonate has a melting point of about 159 °C to about 183 °C. In another 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)piperidine-1-yl)ethanol-1-ol benzene sulfonate has a melting point of about 165 °C to about 177 °C. In another embodiment, crystal form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate has a melting point of about 168 °C to about 174 °C. In another embodiment, crystal form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate has a melting point of about 169 °C to about 173 °C. In another embodiment, crystal form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate has a melting point of about 170 °C to about 173 °C. In another embodiment, crystal form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate has a melting point of about 171 °C to about 173 °C.In another embodiment, the melting point of crystal form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is 172 °C.

[0065] In an embodiment, crystal form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is first added to a solvent of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate to form a solution or suspension. The terms solution and suspension as used herein are used interchangeably and refer to situations involving the addition of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate to a solvent or solvent mixture regardless of solubility. The solvent used for crystallization may be a homologous solvent, a combination of solvents, or a solvent or a combination of solvents in which 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate exhibits temperature-dependent solubility.

[0066] In an embodiment, the dissolution process is performed at a raised temperature. In an embodiment, the dissolution process is performed below the boiling point of the solvent or solvent combination. In an embodiment, 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is dissolved in a solvent or solvent mixture while heating and optionally shaking and stirring. In an embodiment, the heated solution is maintained at an elevated temperature to completely dissolve 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate. In an embodiment, the heated solution is also filtered at an elevated temperature to remove any undissolved components.

[0067] In an embodiment, the solution is slowly cooled to provide crystalline form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate. In an embodiment, crystalline form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is filtered and / or dried under reduced pressure to separate it from the residual solvent. Crystal form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate can be provided by using other methods known to those skilled in the art of crystallization technology (e.g., solvent evaporation, dissolution, chemical reaction, seeding into a small amount of the desired crystal form, etc.).

[0068] 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)piperidine-1-yl)ethanol-1-olbenzenesulfonate is dissolved in a solvent at a rising temperature, and then the solution is cooled to room temperature to provide crystalline form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate.

[0069] In an embodiment, crystal form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate has a high melting point.

[0070] In an embodiment, crystal form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate has low hygroscopicity.

[0071] In an embodiment, crystal form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate has good solubility.

[0072] In an embodiment, crystal form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate has good bioavailability.

[0073] In an embodiment, crystal form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate demonstrated excellent stability after storage at room temperature for 36 months.

[0074] 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)

[0075] -1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)

[0076] Crystalline form B of ethanol-1-ol benzene sulfonate and its preparation

[0077] In one embodiment, crystalline form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is provided. In an embodiment, crystal form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate has characteristic absorption peaks at 12.5°±0.3°, 14.6°±0.3°, 22.3°±0.3° and 13.3°±0.3° in X-ray powder diffraction using Cu Kα radiation.

[0078] In another embodiment, crystal form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate 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 X-ray powder diffraction using Cu Kα radiation.

[0079] In another embodiment, crystal form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate 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 X-ray powder diffraction using Cu Kα radiation.

[0080] In an embodiment, crystal form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate has a melting point of about 105 °C to about 129 °C. In another embodiment, crystal form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate has a melting point of about 111 °C to about 123 °C. In another embodiment, crystal form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate has a melting point of about 114 °C to about 120 °C. In another embodiment, crystal form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate has a melting point of about 115 °C to about 119 °C. In another embodiment, crystal form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate has a melting point of about 116 °C to about 119 °C. In another embodiment, crystal form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate has a melting point of about 116 °C to about 118 °C.

[0081] In an embodiment, crystal form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate can be prepared by first adding 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate to a solvent to form a solution or suspension. The terms solution and suspension as used herein are used interchangeably and refer to situations involving the addition of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate to a solvent or solvent mixture regardless of solubility. The solvent used for crystallization may be a homologous solvent, a combination of solvents, or a solvent or a combination of solvents in which 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate exhibits temperature-dependent solubility.

[0082] In an embodiment, the dissolution process is performed at a raised temperature. In an embodiment, the dissolution process is performed below the boiling point of the solvent or solvent combination. In an embodiment, 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is dissolved in a solvent or solvent mixture while heating and optionally shaking and stirring. In an embodiment, the heated solution is maintained at an elevated temperature to completely dissolve 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate. In an embodiment, the heated solution is also filtered at an elevated temperature to remove any undissolved components.

[0083] In an embodiment, the solution is slowly cooled to provide crystalline form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate. In an embodiment, crystalline form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is filtered and / or dried under reduced pressure to separate it from the residual solvent. Crystal form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate can be provided by using other methods known to those skilled in the art of crystallization technology (e.g., solvent evaporation, dissolution, chemical reaction, seeding of a small amount into the desired crystal form, etc.).

[0084] therapeutic use

[0085] In an embodiment, a method for treating and preventing a CCR4-mediated disease, disorder, or condition is provided, comprising 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)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or a pharmaceutical composition thereof to a patient in need thereof. In an embodiment, the patient is an animal. In an embodiment, the patient is a mammal. In an embodiment, the patient is a human.

[0086] In an embodiment, a method for treating immune, inflammatory, or cancer-related diseases or disorders is provided, comprising administering the crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate to a patient requiring such treatment.

[0087] In an embodiment, a method for treating an immune, inflammatory, or cancer-related disease or disorder is provided, comprising administering a pharmaceutical composition comprising the crystal 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate to a patient requiring such treatment.

[0088] Crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical compositions are for allergy-related disorders (e.g., hypersensitivity and anaphylactic reactions); gastrointestinal disorders (e.g., inflammatory bowel disease, Crohn's disease, ulcerative colitis, ileitis and enteritis); psoriasis and inflammatory dermatitis (e.g., dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria and pruritus); vasculitis; scleroderma; asthma, COPD and respiratory allergic diseases (e.g., allergic rhinitis and hypersensitivity lung disease); It may be administered to patients, particularly human patients, suffering from arthritis (e.g., rheumatoid arthritis and psoriasis), multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, and glomerulonephritis; graft rejection (e.g., allogeneic graft rejection); transplant rejection (e.g., parenchymal organs); cancer, e.g., leukemia, lymphoma, and metastatic cancer, especially solid tumors (e.g., gastric cancer); and other diseases requiring suppression of unwanted inflammation and / or immune responses, e.g., atherosclerosis, neurodegenerative diseases (e.g., Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis media, and sinusitis.

[0089] In an embodiment, the CCR4-mediated disease, disorder, or condition is asthma, COPD, rhinitis, idiopathic pulmonary fibrosis, psoriasis, and contact dermatitis. In an embodiment, the disease or disorder is pulmonary fibrosis, hepatitis, asthma, atopic dermatitis, cancer (e.g., thyroid carcinoma, nasopharyngeal carcinoma, Hodgkin lymphoma, cholangiocarcinoma, pancreatic adenocarcinoma, cutaneous melanoma, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma), or granuloma development.

[0090] In addition, in certain embodiments, crystal 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical composition is administered to a patient, preferably a human, as a preventive measure against various diseases or disorders.Crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical compositions are for allergy-related disorders (e.g., hypersensitivity and anaphylactic reactions); gastrointestinal disorders (e.g., inflammatory bowel disease, Crohn's disease, ulcerative colitis, ileitis and enteritis); psoriasis and inflammatory dermatitis (e.g., dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria and pruritus); vasculitis; scleroderma; asthma, COPD and respiratory allergic diseases (e.g., allergic rhinitis and hypersensitivity lung disease); Arthritis (e.g., rheumatoid arthritis and psoriasis), autoimmune diseases including multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, and glomerulonephritis; graft rejection (e.g., allogeneic graft rejection); transplant rejection (e.g., parenchymal organs); cancer, e.g., leukemia, lymphoma, and metastatic cancer, particularly solid tumors (e.g., gastric cancer); and other diseases requiring suppression of unwanted inflammation and / or immune responses, e.g., atherosclerosis, neurodegenerative diseases (e.g., Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis media, and sinusitis; asthma, COPD, rhinitis, idiopathic pulmonary fibrosis, psoriasis, and contact dermatitis; It may be administered as a preventive measure for patients with a predisposition to pulmonary fibrosis, hepatitis, asthma, atopic dermatitis, cancer (e.g., thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, cutaneous melanoma, colorectal adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, invasive breast carcinoma, lung adenocarcinoma, lung squamous cell carcinoma), or granuloma.Accordingly, crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical compositions can be used for the prevention of one disease or disorder and simultaneously for the treatment of another disease (e.g., prevention of psoriasis during cancer treatment; prevention of asthma during contact dermatitis treatment).

[0091] The suitability of crystal 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical compositions for treating the aforementioned diseases and disorders can be determined by methods known in the art. Crystal 2-((R)-3-(1-((R)-1-((2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1)ethanol-1-olbenzenesulfonate and / or its pharmaceutical compositions can be used to treat or prevent the aforementioned diseases and disorders using procedures known in the art.

[0092] Administration method

[0093] In an embodiment, a method for treating and preventing a CCR4-mediated disease, disorder, or condition is provided, comprising 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)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or a pharmaceutical composition thereof to a patient in need thereof. In an embodiment, the patient is an animal. In an embodiment, the patient is a mammal. In an embodiment, the patient is a human.

[0094] Crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical compositions are for allergy-related disorders (e.g., hypersensitivity and anaphylactic reactions); gastrointestinal disorders (e.g., inflammatory bowel disease, Crohn's disease, ulcerative colitis, ileitis and enteritis); psoriasis and inflammatory dermatitis (e.g., dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria and pruritus); vasculitis; scleroderma; asthma, COPD and respiratory allergic diseases (e.g., allergic rhinitis and hypersensitivity lung disease); It is useful for the treatment or prevention of arthritis (e.g., rheumatoid arthritis and psoriasis), autoimmune diseases including multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, and glomerulonephritis; graft rejection (e.g., allogeneic graft rejection); transplant rejection (e.g., parenchymal organs); cancer, e.g., leukemia, lymphoma, and metastatic cancer, especially solid tumors (e.g., gastric cancer); and other diseases requiring suppression of unwanted inflammation and / or immune responses, e.g., atherosclerosis, neurodegenerative diseases (e.g., Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis media, and sinusitis.

[0095] In an embodiment, the CCR4-mediated disease, disorder, or condition is asthma, COPD, rhinitis, idiopathic pulmonary fibrosis, psoriasis, and contact dermatitis. In an embodiment, the disease or disorder is pulmonary fibrosis, hepatitis, asthma, atopic dermatitis, cancer (e.g., thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, cutaneous melanoma, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma), or granuloma development.

[0096] In addition, in certain embodiments, crystal 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical composition is administered to a patient, preferably a human, as a preventive measure against various diseases or disorders.Crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical compositions are for allergy-related disorders (e.g., hypersensitivity and anaphylactic reactions); gastrointestinal disorders (e.g., inflammatory bowel disease, Crohn's disease, ulcerative colitis, ileitis and enteritis); psoriasis and inflammatory dermatitis (e.g., dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria and pruritus); vasculitis; scleroderma; asthma, COPD and respiratory allergic diseases (e.g., allergic rhinitis and hypersensitivity lung disease); Arthritis (e.g., rheumatoid arthritis and psoriasis), autoimmune diseases including multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, and glomerulonephritis; graft rejection (e.g., allogeneic graft rejection); transplant rejection (e.g., parenchymal organs); cancer, e.g., leukemia, lymphoma, and metastatic cancer, particularly solid tumors (e.g., gastric cancer); and other diseases requiring suppression of unwanted inflammation and / or immune responses, e.g., atherosclerosis, neurodegenerative diseases (e.g., Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis media, and sinusitis; asthma, COPD, rhinitis, idiopathic pulmonary fibrosis, psoriasis, and contact dermatitis; It may be administered as a preventive measure for patients with a predisposition to pulmonary fibrosis, hepatitis, asthma, atopic dermatitis, cancer (e.g., thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, cutaneous melanoma, colorectal adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, invasive breast carcinoma, lung adenocarcinoma, lung squamous cell carcinoma), or granuloma.Accordingly, crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical compositions can be used for the prevention of one disease or disorder and simultaneously for the treatment of another disease (e.g., prevention of psoriasis during cancer treatment; prevention of asthma during contact dermatitis treatment).

[0097] Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, vaginal, transdermal, rectal, or by inhalation, or topically, particularly to the ears, nose, eyes, or skin.

[0098] In an embodiment, crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate 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]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical compositions may be administered by any other convenient route, e.g., by injection or bolus injection, by absorption through the epithelial or mucosal inner layers of the skin (e.g., oral mucosa, rectal and intestinal mucosa, etc.). In embodiments, administration may be systemic or local. Various delivery systems (e.g., liposomes, microparticles, microcapsules, capsules, etc.) that can be used to administer crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or pharmaceutical compositions thereof are known.

[0099] In an embodiment, the crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical composition may be delivered via a sustained-release system. In an embodiment, the crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical composition may be delivered via an oral sustained-release system. In one embodiment, the oral sustained-release system is a pump (Langer, supra; Sefton, 1987, CRC Crit Ref. Biomed. Eng. 14:201; Saudek et al., 1989, N. Engl. J. Med. 321:574).

[0100] In other embodiments, crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical compositions may be delivered using polymeric materials (see ["Medical Applications of Controlled Release," Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974)]; ["Controlled Drug Bioavailability," Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984)]; [Langer et al., 1983, J. Macromol. Sci. Rev. Macromol. Chem. 23:61]; [Levy et al., 1985, Science 228: 190; During et al., 1989, Ann. Neurol. 25:351]; [Howard et al., 1989, J. Neurosurg. [See also 71:105]). In another embodiment, the polymer material is used for oral sustained-release delivery. Polymers suitable for use in the oral delivery of crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical compositions include, but are not limited to, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and hydroxyethylcellulose. In one embodiment, the polymer is hydroxypropylmethylcellulose. Other cellulose ethers are described (Alderman, Int. J. Pharm. Tech. & Prod. Mfr. 1984, 5 (3) 1-9). Factors affecting drug release are well known to those skilled in the art and are described in the art (Bamba et al., Int. J. Pharm. 1979, 2, 307).

[0101] In another embodiment, an enteric-coated formulation may be used for oral sustained-release administration of crystal 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical compositions. Coating materials suitable for use in the oral delivery of crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical compositions include, but are not limited to, polymers having pH-dependent solubility (i.e., pH-controlled release), polymers having slow or pH-dependent rates of swelling, dissolution, or erosion (i.e., time-controlled release), polymers degraded by enzymes (i.e., enzyme-controlled release), and polymers forming a hard layer that is destroyed by an increase in pressure (i.e., pressure-controlled release).

[0102] In another embodiment, an osmotic delivery system is used for oral sustained-release administration of crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical compositions (Verma et al., Drug Dev. Ind. Pharm. 2000, 26:695-708). In an embodiment, the OROS™ osmotic device is used in an oral sustained-release delivery device for crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical compositions (Theeuwes et al., U.S. Patent No. 3,845,770; Theeuwes et al., U.S. Patent No. 3,916,899).

[0103] In another embodiment, the controlled-release system may be positioned near a target of crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical composition, and thus requires only a fraction of the systemic dose (e.g., the aforementioned Goodson, "Medical Applications of Controlled Release," 2nd ed., pp. 115-138 (1984)). Literature (Langer, 1990, Science Other control-emission systems discussed in 249:1527-1533) can also be used.

[0104] When used to treat or prevent CCR4-mediated diseases, disorders, or conditions, crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical compositions may be administered or applied alone or in combination with other agents. In an embodiment, crystal 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical composition may be administered alone or with other pharmaceutical activators, for example, when treating cancer, including other anticancer / chemotherapy agents.

[0105] 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, BAY 869766), an alkylating agent (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosourea, nitrogen mustard (e.g., mechlorethamine, Cyclophosphamide, chlorambucil, mayphalan), ethyleneimines and methylamines (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmerstin, romeursin, semerstin, streptozosin), triagenes (decarbazine)), anti-metabolites (e.g., 5-azathiophrine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, fluorouridine, cytarabine), purine analogs (e.g., mercaptopurines, thioguanine, pentostatin) etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesin, podophyllotoxin, paclitaxel, dotaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrin, etoposide (VP16), etoposide phosphate, tenifoside, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g., cisplatin, oxaloplatin, carboplatin), anthracendiones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyureas), methylhydrazine derivatives (e.g., procarbazine),Adrenocorticosteroids (e.g., mitothan, aminoglutetiimide), 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, BAY 43-9006, wortmantine or LY294002), Syk inhibitors, mTOR inhibitors, antibodies (e.g., rituximab), gossypol, genasense, polyphenol E, chlorofusin, all-trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-associated apoptosis-inducing ligand (TRAIL), 5-Aza-2'-Deoxycitidine, all trans-retinoic acids, Doxorubicin, Vincristine, Etoposide, Gemcitabine, Imatinib (Gleevec RTM), Geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), Flavopyridol, LY294002, Bortezomib, Trastuzumab, Pembrolizumab, BAY 11-7082, PKC412, PD184352, 20-epi-1, 25 Dihydroxyvitamin D3; 5-Ethinyluracil; Abiraterone; Aclarubicin; Acylfulbene; Adesiphenol; Adozelesin; Aldeslukin; ALL-TK antagonist; Altretamine; Ambamustine; Amidox; Amifostine; aminolevulinic acid; amrubicin; amsacrine; anagleride; anastrozole; andrographolide; angiogenesis inhibitor; antagonist D; antagonist G; antarelix; anti-isomorphic morphogen-1; antiandrogen, prostate carcinoma; antiestrogen; antineoplastic agent; antisense oligonucleotide; apidicolin glycinate; apoptosis gene regulator, apoptosis regulator; apuric acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestein; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasterone; azatoxin; azatyrosine; bacatin III derivative; balanol; vatimustate;BCR / ABL antagonists; benzochlorine; benzoylstaurosporine; beta-lactam derivatives; beta-alletin; beta-clammaycin B; betulinic acid; bFGF inhibitors; bicalutamide; wisantren; bisaziridinylspermine; bisnafid; bistraten A; biselesin; breplate; bropyrimin; bodotitan; butionine sulfoximine; calcipotriol; calfostin C; camptothecin derivatives; canarifox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; chondrogeneic inhibitors; caselesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; Cladribine; Clomiphene analogs; Clotrimazole; Colismycin A; Colismycin B; Combretastatin A4; Combretastatin analogs; Conagenine; Crembecidin 816; Crisnatol; Cryptopicin 8; Cryptopicin A derivatives; Curacin A; Cyclopentatraquinone; Cycloplatam; Cyfemycin; Cytarabine oxphosphate; Cell injury factor; Cytostatin; Dacliximab; Decitabine; Dehydrodidemnin B; Desloreline; Dexamethasone; Dexiphosphamide; Dexrazoxane; Dexverapamilm; Diaziquone; Didemnin B; Didox; Diethylnospermine; Dihydro-5-Azacitidine; 9-Dioxamycin; Diphenylspiromustin; Docosanol; Dolasetron; Doxyfluridine; Droroxifene; Dronabinol; Duocamycin SA; Abselen; Ecomustin; Edylfosin; Edrecolomab; Eflonitine; Elemen; Emiteper; Epirubicin; Epristide; Estramustin analogs; Estrogen agonists; Estrogen antagonists; Ethanidazole; Etoposide phosphate; Exemestane; Padrozol; Fazarabine; Fenretinide; Filgrastim; Finasteride; Flavopyridol; Flegelastine; Fluasterone; Fludarabine; Fluorodaunorunicin Hydrochloride; Pofenimex; Pomestane; Postriesin; Portmustin; Gadolinium Taxapyrin; Gallium Nitrate; Galocitabine; Ganirelix; Gelatinase inhibitors; Gemcitabine; Glutathione inhibitors;Hepsulfam; Heregulin; Hexamethylene bisacetamide; Hypericin; Ibandronate; Idarubicin; Iodoxifen; Idramanton; Ilmofosin; Ilomast; Imidazoacridone; Imiquimod; Immunostimulating peptide; Insulin-like growth factor-1 receptor inhibitor; Interferon agonist; Interferon; Interleukin; Iobenzuan; Iodoxorubicin; Ipominol, 4-; Iroplact; Isogladin; Isobenzazole; Isohomohalicondrin B; Itasetron; Jasflaquinolide; Cahalaride F; Lamellarin-N triacetate; Lanreotide; Reinamycin; Lenograstim; Lentinan sulfate; Leptolstatin; Letrozole; Leukemia suppressor factor; Leukocyte alpha interferon; Leuprolide + Estrogen + Progesterone; Leuprorelin; Levamisole; Riarozol; Linear polyamine analogs; Lipophilic disaccharide peptides; Lipophilic platinum compounds; Lysoclinamide 7; Lovaplatin; Lombricin; Lometrexole; Ronidamine; Rosoxantrone; Lovastatin; Loxorbine; Lutotecan; Lutetium Texapyrin; Lysophylline; Lytic peptide; Meitansin; Mannostatin A; Marimastat; Masoprocol; Maspin; Matrisin inhibitors; Matrix metalloproteinase inhibitors; Menogaril; Mervarone; Mederellin; Methioninase; Metoclopramide; MIF inhibitors; Mifepristone; Miltefosin; Myrimostim; Mismatched double-stranded RNA; Mitoguazone; Mitoractol; Mitomycin analogs; Mitonapid; Mitotoxin Fibroblast Growth Factor-Saporin; Mitoxantrone; Moparoten; Molgramostim; Monoclonal antibody, Human chorionic gonadotropin; Monophosphoryl lipid A+ Myobacterium cell wall sk; Morpidamol; Multidrug resistance gene inhibitor; Multi-tumor suppressor 1st-line therapy; Mustard anticancer agent; Micaperoxide B; Mycobacterium cell wall extract; Myriaporone; N-acetyldinaline; N-substituted benzamide; Naparelin; Nagrestip; Naloxone+pentazocine; Nafavin; Nafterpine; Natograstim; Nedaplatin; Nemolubicin; Neridronic acid; Neutral endopeptidase; Nilutamide; Nisamycin; Nitric oxide modulator; Nitroxide antioxidant; Nitrulline;O6-Benzylguanine; Octreotide; Oxenone; Oligonucleotide; Onapristone; Ondansetron; Ondansetron; Oracin; Oral cytokine inducers; Omaplatin; Osateron; Oxaliplatin; Oxaunomycin; Palauamine; Palmitoylizoxin; Palmidronic acid; Panaxitriol; Panomiphene; Parabactin; Fazeliptin; Pegaspagase; Feldecin; Sodium pentosan polysulfate; Pentostatin; Pentrozol; Perflubrone; Perphosphamide; Perillyl alcohol; Fenazinomycin; Phenylacetate; Phosphatase inhibitors; Pisibanil; Pilocarpine hydrochloride; Pirarubicin; Pyritrexime; Placetin A; Placetin B; Plasminogen activator inhibitors; Platinum complex; Platinum compound; Platinum-triamine complex; Porfimer sodium; Porphyromycin; Prednisone; Propyl bis-acridone; Prostaglandin J2; Proteasome inhibitors; Protein A-type immunomodulators; Protein kinase C inhibitors; Protein kinase C inhibitors, microalgae; Protein tyrosine phosphatase inhibitors; Purine nucleoside phosphorylase inhibitors; Furpurine; Pyrazoloacridine; Pyridoxylated hemoglobin polyoxyethyl conjugate; RAF antagonists; Raltitrex; Ramosetron; Ras-farnesil protein transferase inhibitors; Ras inhibitors; Ras-GAP inhibitors; Leteliptin dimethylated; Renium Re 186 etidronate; Rhizosin; Ribozyme; RII retinaamide; Logletimide; Rohitucaine; Romurtide; Roquinimex; Rubiginon B1; Luboxil; Sapingol; Cyanophene; SarCNU; Sarcopitol A; Sagramostim; Sdi 1 Mimic; Semustin; Aging-derived Inhibitor 1; Sense Oligonucleotide; Signaling Inhibitor; Signaling Modulator; Short-chain Antigen-Binding Protein; Sizofuran; Sobuzolic Acid; Sodium Borocaptate; Sodium Phenylacetate; Sorverol; Somatomedin-binding Protein; Sonermin; Spafosic Acid; Spicamycin D; Spiromustin; Splenopeptin; Spongestatin 1; Squalamine; Stem Cell Inhibitor; Stem Cell Division Inhibitor; Stipiamide; Stromelisin Inhibitor; Sulfinosine; Hyperactive Vasoactive Intestinal Peptide Antagonist;Suradista; Suramine; Swainsonine; Synthetic Glycosaminoglycans; Thalimustine; Tamoxifen Iodide; Touromustine; Tazarotene; Tecogalan Sodium; Tegafur; Tellurapyrillium; Telomerase Inhibitors; Temoporfin; Temozolomide; Tenifoside; Tetrachlorodecaoxide; Tetrazomin; Taliblastine; Thiocoraline; Thrombopoietin; Thrombopoietin Mimics; Timalfacine; Thymopoietin Receptor Agonists; Timotrinan; Thyroid-Stimulating Hormone; Tin Ethyl Ethiofurpurine; Tirapazamine; Titanocene Bichloride; Topcentin; Toremifene; Pluripotent Stem Cell Factor; Translation Inhibitors; Tretinoin; Triacetyluridine; Trisyribin; Trimetrexate; Triptorelin; Trophisetron; Turosteride; Tyrosine kinase inhibitors; tyrfostine; UBC inhibitors; uvenimex; urogenital-derived growth inhibitors; urokinase receptor antagonists; bapreotide; varioline B; vector systems, erythrocyte gene therapy; velaresol; veramin; verdin; verteporfin; vinorelbine; vinsaltin; vitacin; borozol; zanoteron; geniplatin; zillascov; genostatin stimaleimer, adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, ashibicin; aclarubicin; acodazole hydrochloride; acronin; adozelesin; aldeslukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; antramycin; asparaginase; asperin; azacitidine; azetepa; Azotomycin; Batymastat; Benzodepa; Baicalutamide; Bisantren Hydrochloride; Bisnafid Dimesylate; Wizelesin; Bleomycin Sulfate; Brequina Sodium; Bropyrimin; Busulfan; Cashinomycin; Calosterone; Carasemide; Carbetimer; Carboplatin; Camerstine; Carubicin Hydrochloride; Caselesin; Sedefingol; Chlorambucil; Sirolemycin; Cladribine; Crisnatol Mesylate; Cyclophosphamide; Cytarabine; Dacarbazine; Daunorubicin Hydrochloride; Decitabine; Dexormaplatin; Desaguanine; Desaguanine Mesylate; Diaziquone; Doxorubicin; Doxorubicin Hydrochloride; Droroxifene; DroroxifeneCitrate; dromostanolone propionate; duazomycin; edatrexate; eflornitine hydrochloride; elsamitrusin; enroplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozol; esorubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; etoprine; padrozol hydrochloride; pazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; phosidone; postriesin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; idimorphosin; Interleukin I1 (including recombinant interleukin II, or rlL.sub.2), interferon alpha-2a; interferon alpha-2b; interferon alpha-n1; interferon alpha-n3; interferon beta-1a; interferon gamma-1b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; riarosole hydrochloride; rometrexole sodium; romestin; losoxanthrone hydrochloride; masoprocol; metansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindoamide; mitocarcin; mitochromin; mitogyline; mitomalcin; mitomycin; Mitosper; Mitotan; Mitoxanthrone Hydrochloride; Mycophenolic Acid; Nocodazoie; Nogalamycin; Omaplatin; Oxysuran; Pegaspagaase; Peliomycin; Pentamustine; Peplomycin Sulfate; Perphosphamide; Pipobroman; Piposulfan; Pyroxanthrone Hydrochloride; Plicamycin; Plamestan; Porfimer Sodium; Porphyromycin; Prednimustine; Procarbazine Hydrochloride; Puromycin; Puromycin Hydrochloride; Pyrazopurine; Ribophrine; Logletimide; Safingol; Safingol Hydrochloride; Semustine; Simtrazine; Sparfosate Sodium; Sparsomycin; Spirogermanium Hydrochloride; Spiromustine; Spiroplatin; Streptonigreen; Streptozosin; Sulofenur; Thalisomycin; Tecogalan Sodium; Tegafur; Teloxantrone hydrochloride; Temoporfin; Tenifoside;Teroxylon; Testolactone; Thiamiprine; Thioguanine; Thiotepa; Thiazopurine; Tirapazamine; Toremifene Citrate; Trestolon Acetate; Trisiribin Phosphate; Trimetrexate; Trimetrexate Glucuronate; Triptorelin; Tubulozol Hydrochloride; Uracil Mustard; Uredepa; Baprootide; Verteporfin; Vinblastine Sulfate; Vincristine Sulfate; Vindecin; Vindecin Sulfate; Vinpidine Sulfate; Vinglycinate Sulfate; Vinryurosine Sulfate; Vinorelbine Tartrate; Vinocidin Sulfate; Vinzolidine Sulfate; Borozol; Geniplatin; Gynostatin; Zorubicin hydrochloride, agents that restrain cells in the G2-M phase and / or regulate the formation or stability of microtubules (e.g., Taxol™ (i.e., paclitaxel)), Taxotere™, compounds containing a taxane backbone, erbulozol (i.e., R-55104), dolastatin 10 (i.e., DLS-10 and NSC-376128), mibobulin isethionate (i.e., as CI-980), vincristine, NSC-639829, discodermolid (i.e., as NVP-XX-A-296), ABT-751 (Abbott, i.e., E-7010), altohirtin (e.g., altohirtin A and altohirtin C), spongestatin (e.g., spongestatin 1, spongestatin 2, spongestatin 3, spongestatin 4, spongestatin 5, spongestatin 6, spongestatin 7), Spongestatin 8, and Spongestatin 9), Semadotine hydrochloride (i.e., LU-103793 and NSC-D-669356), Epotillon (e.g., Epotillon A, Epotillon B, Epotillon C (i.e., Desoxipotillon A or dEpoA), Epotillon D (i.e., KOS-862, dEpoB, and Desoxipotillon B), Epotillon E, Epotillon F, Epotillon B N-oxide, Epotillon A N-oxide, 16-Aza-Epotillon B, 21-Aminoepotillon B (i.e., BMS-310705), 21-Hydroxypotillon D (i.e., E, Desoxipotillon F and dEpoF), 26-Fluoroepotillon,Auristatin PE (i.e., NSC-654663), Soblidotin (i.e., TZT-1027), LS-4559-P (Pharmacia, i.e., LS-4577), LS-4578 (Pharmacia, i.e., LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristine Sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, i.e., WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, i.e., ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), Cryptopicin 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), Bitilevauamide, Tubulicin A, Canadensol, Centauredin (i.e., NSC-106969), T-138067 (Tularik, i.e., T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Laboratories, 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 Laboratories), Fyzianolide B, Laurimalide, SPA-2 (Parker Hughes Laboratories), SPA-1 (Parker Hughes Laboratories, i.e., SPIKET-P), 3-IAABU (Cytoskeleton / Mount Sinai Medical School, i.e., MF-569),Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterin, 3-BAABU (Cytoskeleton / Mount Sinai School of Medicine, i.e., MF-191), TMPN (Arizona State University), Vanadosene Acetylacetonate, T-138026 (Tularik), Monsatrol, Inanosine (i.e., NSC-698666), 3-IAABE (Cytoskeleton / Mount Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, i.e., T-900607), RPR-115781 (Aventis), Eleutherobin (e.g., Desmethyl-eleutherobin, Desacetyl-eleutherobin, Isoeleuterobin A and Z-eleuterobin), caribaoside, cariveolin, halicondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), tacalonolide A, TUB-245 (Aventis), A-259754 (Abbott), diozostatin, (-)-phenylahistine (i.e., NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), myoseverin B, D-43411 (Zentaris, i.e., D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (i.e. SPA-110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), resverasatin sodium phosphate, BPR-OY-007 (National Health Research Institations) 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, medoxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), anti-estrogens (e.g., tamoxifen), and androgens (e.g., testosterone propionate, fluoxymesterone), anti-androgens (e.g., flutamide), immunostimulants (e.g., Bacillus calmette-gerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calisemycin conjugate, anti-CD22 monoclonal antibody-Pseudomonas Exotoxin conjugates, etc.), radiation immunotherapy (e.g., 111 In, 90 Y, or 131Anti-CD20 monoclonal antibodies conjugated to I, etc.), triptolide, homoharingtonin, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesin, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytriptamine, vemurafenib, dabrafenib, eroteinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR)-targeted therapies or treatments (e.g., gefitinib (Iressa™), eroteinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib / BIBW2992, CI-1033 / canertinib, Neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, Dacomitinib / PF299804, OSI-420 / Desmethyl Erotinib, AZD8931, AEE788, Felitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, or similar ones, including but not limited to these.

[0106] Pharmaceutical composition

[0107] In an embodiment, a pharmaceutical composition comprising a therapeutically effective amount of 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and a suitable amount of a pharmaceutically acceptable carrier is provided, which can provide a form for appropriate administration to a patient. In an embodiment, when administered to a patient, the crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and a pharmaceutically acceptable carrier are sterilized. In an embodiment, when the crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is administered intravenously, the carrier is water. In another embodiment, saline solution and aqueous dextrose and glycerol solutions are used as liquid carriers for injectable solutions. In yet another embodiment, suitable pharmaceutical carriers include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, etc. In another embodiment, the pharmaceutical composition of crystal 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate contains a wetting agent or an emulsifier or a pH buffer.In another embodiment, the pharmaceutical composition of crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate contains auxiliary, stabilizing, thickening, lubricating, and coloring agents.

[0108] In an embodiment, a pharmaceutical composition comprising the crystal 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate can be prepared by conventional mixing, dissolving, granulating, sugaring, grinding, emulsifying, encapsulating, capturing, or freeze-drying processes. In an embodiment, a pharmaceutical composition comprising the crystal 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate may be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients, or adjuvants that facilitate the processing of the crystal 2-((R)-3-(1-((R)-1-((2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1)ethanol-1-olbenzenesulfonate into a pharmaceutically usable formulation. As is recognized by those skilled in the art, the appropriate formulation depends on the selected route of administration.

[0109] In an embodiment, the pharmaceutical composition comprising the crystalline 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is a solution, suspension, emulsion, tablet, pill, pellet, capsule, liquid, powder, sustained-release formulation, suppository, emulsion, aerosol, spray, or a capsule containing any other form suitable for use. In an embodiment, the pharmaceutically acceptable carrier is a capsule (e.g., Grosswald et al., U.S. Patent No. 5,698,155). Other examples of suitable pharmaceutical carriers are described in the art (see Remington's Pharmaceutical Sciences, Philadelphia College of Pharmacy and Science, 19th Edition, 1995). In an embodiment, a pharmaceutical composition of the crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is formulated for oral delivery. In an embodiment, a pharmaceutical composition of crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is formulated for oral sustained-release administration.

[0110] In an embodiment, a pharmaceutical composition comprising the crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate for oral delivery may be in the form, for example, tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs. The orally administered composition may contain one or more optional agents, such as a sweetener like fructose, aspartame, or saccharin, a flavoring agent like peppermint, an oil of wintergreen or cherry coloring agent, and a preservative to provide a pharmaceutically palatable formulation. In addition, a pharmaceutical composition comprising crystalline 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate in the form of a tablet or pill can be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action for a long period. A selectively permeable membrane surrounding an osmotically active driving compound is also suitable for oral administration of compounds and compositions comprising the crystal 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate disclosed herein. In these later platforms, fluid from the environment surrounding the capsule is absorbed by the driving compound, and the driving compound expands to displace the formulation or formulation composition through the pores. These delivery platforms can provide an essentially zero-order delivery profile in contrast to the spiked profile of immediate-release formulations. Time-delaying materials such as glycerol monostearate or glycerol stearate may also be used.An oral composition comprising the crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzene sulfonate may include a standard carrier, e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. In an embodiment, such a carrier is of pharmaceutical grade.

[0111] In an embodiment, for oral liquid formulations such as suspensions, elixirs, and solutions, suitable carriers, excipients, or diluents include water, brine, alkylene glycol (e.g., propylene glycol), polyalkylene glycol (e.g., polyethylene glycol), oil, alcohol, mildly acidic buffer with a pH of 4 to 6 (e.g., acetate, citrate, ascorbate with an amount of about 5 mM to about 50 mM), etc. Specifically, flavoring agents, preservatives, coloring agents, bile salts, acylcarnitine, etc. are additionally added.

[0112] Pharmaceutical compositions for administration via other routes may also be considered. In an embodiment, for buccal administration, a composition comprising crystalline 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate may be in the form of tablets, lozenges, etc., formulated in a conventional manner. Liquid drug formulations suitable for use with nebulizers, liquid spray devices, and EHD aerosol devices will typically comprise crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate together with a pharmaceutically acceptable carrier. In embodiments, the pharmaceutically acceptable carrier is a liquid such as an alcohol, water, polyethylene glycol, or perfluorocarbon. In embodiments, other substances may be added to alter the aerosol properties of a solution or suspension of the compound disclosed herein. In embodiments, such substances are liquids, e.g., alcohols, glycols, polyglycols, or fatty acids. Other methods for formulating liquid drug solutions or suspensions suitable for use in aerosol devices are known to those skilled in the art (see, for example, Biesalski, U.S. Patent No. 5,112,598; Biesalski, U.S. Patent No. 5,556,611). In an embodiment, the crystal 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate may be formulated into a rectal or vaginal composition, such as a suppository or maintenance enema containing, for example, a conventional suppository base, for example, cocoa butter or other glycerides.In a further embodiment, the crystal 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate may be formulated as a depot formulation. Such long-acting formulations may be administered via implant (e.g., subcutaneous or intramuscular) or by intramuscular injection. In an embodiment, the crystal 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate may be formulated into a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or into a sparingly soluble derivative.

[0113] In an embodiment, crystal 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is formulated as a pure activator. In another embodiment, the crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is formulated as a mixture with another crystalline form of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate. In an embodiment, the pharmaceutical composition provided herein comprises form A of the crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate. In an embodiment, the pharmaceutical composition provided herein comprises form B of the crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate. In an embodiment, the pharmaceutical composition provided herein comprises a mixture of forms A and B of crystalline 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate.

[0114] In an embodiment, the pharmaceutical composition of crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is formulated into an oral tablet formulation.

[0115] In an embodiment, the pharmaceutical composition of crystalline 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate in an oral tablet formulation comprises 75 mg of the crystalline compound.

[0116] In an embodiment, the pharmaceutical composition of crystalline 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate in an oral tablet formulation comprises 25 mg of the crystalline compound.

[0117] In an embodiment, the pharmaceutical composition of the crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate comprises a wetting agent. In an embodiment, the wetting agent is sodium lauryl sulfate (SLS).

[0118] In an embodiment, the pharmaceutical composition of the crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate comprises a water-soluble excipient. In an embodiment, the water-soluble excipient is lactose monohydrate. In an embodiment, the water-soluble excipient is at least 50% by weight of the oral tablet formulation.

[0119] In an embodiment, the pharmaceutical composition of the crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate comprises a disintegrant. In an embodiment, the disintegrant is cros-carmellose sodium.

[0120] Dosage

[0121] Crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical compositions will be used in an effective amount to achieve the intended purpose. In an embodiment, for use to treat or prevent the CCR4-mediated disease or disorder disclosed herein, crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical composition is administered or applied in a therapeutically effective amount.

[0122] The amount of 2-((R)-3-(1-((R)-1-((2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1)ethanol-1-olbenzenesulfonate and / or its pharmaceutical compositions effective for the treatment of specific disorders or conditions disclosed herein will vary depending on the nature of the disorder or condition and may be determined by standard clinical techniques known in the art as previously described. In addition, In a test tube or In vivoThe test may be selectively used to help determine the optimal dosage range. The amount of the determined 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical composition administered will vary depending on the subject being treated, the subject's weight, the severity of pain, the method of administration, and the prescribing physician's judgment, among other factors.

[0123] In an embodiment, a dose of crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate can be delivered to a pharmaceutical composition by a single administration. In an embodiment, a dose of crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate can be delivered to a pharmaceutical composition by multiple applications. In an embodiment, a dose of the crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate can be delivered into a pharmaceutical composition by controlled release. In an embodiment, the crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical composition is delivered by oral sustained-release administration. In a specific embodiment, the crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical composition is administered twice daily. In an embodiment, the crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical composition 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 an embodiment, administration may continue as long as required for the effective treatment of the CCR4-mediated disease state or disorder described herein.

[0124] In an embodiment, the dosage of crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical composition may be adjusted to provide about 25 mg / day to about 500 mg / day. In another embodiment, the dosage of crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical composition may be adjusted to provide about 50 mg / day to about 150 mg / day. In another embodiment, the dosage of crystal 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical composition may be adjusted to provide about 75 mg / day to about 125 mg / day. The dosage range can be easily measured by methods known to those skilled in the art.

[0125] Crystals 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or their pharmaceutical compositions are tested in vitro and in vivo for desired therapeutic or prophylactic activity before use in humans. In an embodiment, the therapeutically effective dose of the crystal 2-((R)-3-(1-((R)-1-((2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1)ethanol-1-olbenzenesulfonate and / or its pharmaceutical composition described herein will provide therapeutic benefits without causing substantial toxicity. The toxicity of crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical composition can be measured using standard pharmaceutical procedures and can be easily identified by those skilled in the art. In an embodiment, the dosage of the crystal 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical composition described herein is within a range of circulating concentrations containing an effective dosage with little or no toxicity.

[0126] Combination therapy

[0127] In a specific embodiment, the crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical composition is used in combination with at least one other therapeutic agent. In an embodiment, 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. In an embodiment, co-administration comprises administering two therapeutic agents simultaneously or nearly simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other). In an embodiment, concomitant administration comprises administering two therapeutic agents sequentially in any order. In an embodiment, concomitant administration may be achieved by preparing a concomitant formulation, i.e., a single pharmaceutical composition comprising both therapeutic agents. In another embodiment, the therapeutic agents may be formulated separately. In another embodiment, the active and / or adjuvant may be linked or conjugated to each other. In an embodiment, the compound described herein may be combined with the therapeutic agent for CCR4-mediated disease disclosed herein.

[0128] In an embodiment, the crystal 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)ethanol-1-olbenzenesulfonate and / or its pharmaceutical composition and other therapeutic agents further act. In an embodiment, the crystal 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)ethanol-1-olbenzenesulfonate and / or its pharmaceutical composition and other therapeutic agents act synergistically.

[0129] In an embodiment, other therapeutic agents are anticancer agents, chemotherapy agents, or anti-inflammatory agents.

[0130] In an embodiment, crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical composition 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, BAY 869766), an alkylating agent (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosourea, nitrogen mustard (e.g., mechlorethamine, Cyclophosphamide, chlorambucil, mayphalan), ethyleneimines and methylamines (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmerstin, romeursin, semerstin, streptozosin), triagenes (decarbazine)), anti-metabolites (e.g., 5-azathiophrine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, fluorouridine, cytarabine), purine analogs (e.g., mercaptopurines, thioguanine, pentostatin) etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, Vindecin, podophyllotoxin, paclitaxel, dotaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrin, etoposide (VP16), etoposide phosphate, tenifoside, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin,Bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g., cisplatin, oxaloplatin, carboplatin), anthracendiones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocorticotropic inhibitors (e.g., mitothan, aminoglutetiimide), 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, BAY 43-9006, Wortmantine or LY294002, Syk inhibitor, mTOR inhibitor, antibody (e.g., Rituxan), Gossypol, Genasense, Polyphenol E, Chlorofucin, All-Retinoic Acid (ATRA), Bryostatin, Tumor Necrosis Factor-Associated Apoptosis-Inducing Ligand (TRAIL), 5-Aza-2'-Deoxycitidine, All-Retinoic Acid, Doxorubicin, Vincristine, Etoposide, Gemcitabine, Imatinib (Gleevec RTM), Geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), Flavopyridol, LY294002, Bortezomib, Trastuzumab, Pembrolizumab, BAY 11-7082, PKC412, PD184352, 20-epi-1, 25 Dihydroxyvitamin D3; 5-ethinyluracil; abiraterone; aclarubicin; acylfulbene; adesiphenol; adozelesin; aldehydeslukin; ALL-TK antagonist; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagleride; anastrozole; andrographolide; angiogenesis inhibitor; antagonist D; antagonist G; antarelix; anti-isotropic morphogenetic protein-1; antiandrogen, prostate carcinoma; antiestrogen; antineoplastic agent; antisense oligonucleotide; apidicolin glycinate; apoptosis geneRegulators, apoptosis regulators; apuric acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestein; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasterone; azatoxin; azatyrosine; bacatin III derivatives; balanol; vatimustate; BCR / ABL antagonists; benzochlorine; benzoylstaurosporine; beta-lactam derivatives; beta-alletin; beta-clammaycin B; betulinic acid; bFGF inhibitors; bicalutamide; bisantren; bisaziridinylspermine; bisnafid; bistraten A; biselesin; breplate; bropyrimin; bodotitan; butionine sulfoximine; calcipotriol; calfostin C; camptothecin derivatives; canarifox IL-2; Capecitabine; Carboxamide-amino-triazole; Carboxyamidotriazole; CaRest M3; CARN 700; Chondrogeneic inhibitor; Caselesin; Casein kinase inhibitor (ICOS); Castanospermin; Secropin B; Cetrorelix; Chlorins; Chloroquinoxaline sulfonamide; Cicaprost; Cis-porphyrin; Cladribine; Clomiphene analog; Clotrimazole; Colismycin A; Colismycin B; Combretastatin A4; Combretastatin analog; Conagenin; Crembecidin 816; Crisnatol; Cryptopicin 8; Cryptopicin A derivative; Curacin A; Cyclopentatraquinone; Cycloplatam; Cyfemycin; Cytarabine oxphosphate; Cell injury factor; Cytostatin; Dacliximab; Decitabine; Dehydrodidemnine B; Desloreline; Dexamethasone; Dexiphosphamide; Dexrazoxic acid; Dexverapamil; Diaziquone; Didemnin B; Didox; Diethylnospermine; Dihydro-5-Azacitidine; 9-Dioxamycin; Diphenylspiromustin; Docosanol; Dolasetron; Doxyfluridine; Droroxifene; Dronabinol; Duocamycin SA; Abselen; Ecomustin; Edylfosin; Edrecolomab; Eflonitine; Elemen; Emiteper; Epirubicin; Epristride; Estramustin analogs; Estrogen agonists; Estrogen antagonists; Ethanidazole; Etoposide phosphate; Exemestane; Padrozol; Fazarabine; Fenretinide;Filgrastim; Finasteride; Flavopyridol; Flegelastin; Fluasterone; Fludarabine; Fluorodaunorunicin Hydrochloride; Porfenimex; Pomestane; Postriesin; Potmustin; Gadolinium Texapyrin; Gallium Nitrate; Galocitabine; Ganirelix; Gelatinase Inhibitor; Gemcitabine; Glutathione Inhibitor; Hepsulfame; Heregulin; Hexamethylene Bisacetamide; Hypericin; Ibandronate; Idarubicin; Iodoxifen; Idramanton; Ilmofosin; Ilomastat; Imidazoacridone; Imiquimod; Immunostimulating Peptide; Insulin-like Growth Factor-1 Receptor Inhibitor; Interferon Agonist; Interferon; Interleukin; Iobenzuan; Iodoxorubicin; Ipominol, 4-; Iroplact; Isogladin; Isobenzazole; Isohomohalicondrin B; Itasetron; Jasflaquinolide; Cahalaride F; Lamelarin-N Triacetate; Lanreotide; Reinamycin; Lenograstim; Lentinan Sulfate; Leptolstatin; Letrozole; Leukemia Suppressor Factor; Leukocyte Alpha Interferon; Leuprolide + Estrogen + Progesterone; Leuprorelin; Levamisole; Riarozole; Linear Polyamine Analogue; Lipophilic Disaccharide Peptide; Lipophilic Platinum Compound; Lysoclinamide 7; Lovaplatin; Lombricin; Lometrexole; Ronidamine; Rosoxantrone; Lovastatin; Loxorbine; Lutotecan; Lutetium Taxapyrin; Lysophylline; Lytic Peptide; Meitansine; Mannostatin A; Marimastert; Masoprocol; Maspin; Matrisin inhibitors; Matrix metalloproteinase inhibitors; Menogaril; Mervarone; Methellin; Methioninase; Metoclopramide; MIF inhibitors; Mifepristone; Miltefosin; Myrimostim; Mismatched double-stranded RNA; Mitoguazone; Mitoractol; Mitomycin analogs; Mitonapid; Mitotoxin Fibroblast Growth Factor-Saporin; Mitoxantrone; Moparotene; Molgramostim; Monoclonal antibody, Human chorionic gonadotropin; Monophosphoryl lipid A+ Myobacterium cell wall sk; Morpidamol; Multidrug resistance gene inhibitors; Multiple tumor suppressor 1-line therapy; Mustard anticancer agent; Micaperoxide B; Mycobacterium cell wall extract;Myriaporone; N-acetyldinaline; N-substituted benzamide; Naparelin; Nagrestip; Naloxone+pentazocine; Nafavin; Nafterpine; Natograstim; Nedaplatin; Nemolubicin; Neridronic acid; Neutral endopeptidase; Nilutamide; Nisamycin; Nitric oxide modulator; Nitroxide antioxidant; Nitrulline; O6-benzylguanine; Octreotide; Oxenone; Oligonucleotide; Onapriston; Ondansetron; Ondansetron; Oracin; Orokine inducer; Omaplatin; Osateron; Oxaliplatin; Oxaunomycin; Palauamine; Palmitoylisoxin; Palmidronic acid; Panaxitriol; Panomiphene; Parabactin; Fazeliptin; Pegaspagase; Feldecin; Sodium pentosan polysulfate; Pentostatin; fentrozol; perflubrone; perphosphamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; pyrytrexime; placetin A; placetin B; plasminogen activator inhibitors; platinum complexes; platinum compounds; platinum-triamine complexes; porfimer sodium; porpyromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-type immunomodulators; protein kinase C inhibitors; protein kinase C inhibitors, microalgae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; furpurine; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethyl conjugates; raf antagonists; raltitrexd; ramosetron; Ras farnesil protease inhibitor; Ras inhibitor; Ras-GAP inhibitor; Leteliptin dimethylated; Renium Re 186 etidronate; Lyzosin; Ribozyme; RII retinaamide; Logletimide; Rohitucaine; Romurtide; Roquinimex; Rubiginon B1; Luboxil; Sapingol; Cyanophene; SarCNU; Sarcopitol A; Sagramostim; Sdi 1 mimetic; Semerstin; Aging-derived inhibitor 1; Sense oligonucleotide; Signaling inhibitor; Signaling regulator; Short-chain antigen-binding protein; Sizofuran; Sobuzolic acid; Sodium borocaptate;Sodium phenylacetate; Sorverol; Somatomedin binding protein; Sonermin; Spafosic acid; Spicamycin D; Spiromustin; Splenopeptin; Spongestatin 1; Squalamine; Stem cell inhibitor; Stem cell division inhibitor; Stipiamide; Stromellysin inhibitor; Sulfinosine; Hyperactive vasoactive intestinal peptide antagonist; Suradista; Suramine; Swainsonine; Synthetic glycosaminoglycans; Thalimustin; Tamoxifen iodide; Toromustin; Tazarotene; Tecogalan sodium; Tegafur; Tellurapyrillium; Telomerase inhibitor; Temoporfin; Temozolomide; Tenifoside; Tetrachlorodecaoxide; Tetrazomin; Taliblastine; Thiocoraline; Thrombopoietin; Thrombopoietin mimic; Timalfacine; Thymopoietin receptor agonists; timotrinan; thyroid-stimulating hormone; thyroethyl ethiofurpurine; tirapazamine; titanocene bichloride; topcentin; toremifene; pluripotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; trisyribin; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tirfostine; UBC inhibitors; uvenimex; urogenital-derived growth inhibitory factor; urokinase receptor antagonists; bapreotide; varioline B; vector systems, erythrocyte gene therapy; velaresol; veramin; verdin; verteporfin; vinorelbine; vinsaltin; vitacin; borozol; zanoteron; geniplatin; zillascov; Gynostatin, Stimaleimer, Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, Ashibicin; Aclarubicin; Acodazole Hydrochloride; Acronin; Adozelesin; Aldeslukin; Altretamine; Ambomycin; Ametantrone Acetate; Aminoglutechimide; Amsacrine; Anastrozole; Antramycin; Asparaginase; Asperin; Azacitidine; Azetepa; Azotomycin; Vatimestat; Benzodepa; Bicalutamide; Bisantren Hydrochloride; Bisnafid Dimesylate; Bizelesin; Bleomycin Sulfate; Brequina Sodium; Bropyrimin; Busulfan; Cashinomycin; Calosterone; Carasemide; Carbetimer; Carboplatin; Camerstine; Carubicin Hydrochloride;Caselesin; Sedefingol; Chlorambucil; Sirolemycin; Cladribine; Crisnatol Mesylate; Cyclophosphamide; Cytarabine; Dacarbazine; Daunorubicin Hydrochloride; Decitabine; Dexormaplatin; Desaguanine; Desaguanine Mesylate; Diaziquone; Doxorubicin; Doxorubicin Hydrochloride; Droroxifene; Droroxifene Citrate; Dromostanolone Propionate; Duazomycin; Edatrexate; Eflornitine Hydrochloride; Elsamitrusin; Enroplatin; Enpromate; Epipropidine; Epirubicin Hydrochloride; Erbulozol; Esolubicin Hydrochloride; Estramustine; Estramustine Sodium Phosphate; Ethanidazole; Etoposide; Etoposide Phosphate; Etoprine; Padrozol Hydrochloride; Pazarabine; Fenretinide; Floxuridine; Fludarabine phosphate; Fluorouracil; Fluorocitabine; Fosidone; Postriesin sodium; Gemcitabine; Gemcitabine hydrochloride; Hydroxyurea; Idarubicin hydrochloride; Ifosfamide; Eimorphosin; Interleukin I1 (including recombinant interleukin II, or rlL.sub.2), Interferon alpha-2a; Interferon alpha-2b; Interferon alpha-n1; Interferon alpha-n3; Interferon beta-1a; Interferon gamma-1b; Iproplatin; Irinotecan hydrochloride; Lanreotide acetate; Letrozole; Leuprolide acetate; Riarozole hydrochloride; Lometrexole sodium; Romestine; Losoxantrone hydrochloride; Masoprocol; Meitansine; Mechloretamine hydrochloride; Megestrol acetate; Melengestrol acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate sodium; Metoprine; Meturedepa; Mitindoamide; Mitocarcin; Mitocromin; Mitogyline; Mitomalcin; Mitomycin; Mitosper; Mitotan; Mitoxanthrone hydrochloride; Mycophenolic acid; Nocodazoie; Nogalamycin; Omaplatin; Oxysuran; Pegaspagase; Peliomycin; Pentamustine; Peflomycin sulfate; Perphosphamide; Pipobroman; Piposulfan; Pyroxanthrone hydrochloride; Plicamycin; Plamestan; Porfimer sodium; Porphyromycin; Prednimustine; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Pyrazopurine; Ribophrine;Logletimide; Sappingol; Sappingol Hydrochloride; Semustine; Simtrazine; Sparfosate Sodium; Sparsomycin; Spirogermanium Hydrochloride; Spiromustine; Spiroplatin; Streptonigreen; Streptozosin; Sulofenur; Thalisomycin; Tecogalan Sodium; Tegafur; Teloxantrone Hydrochloride; Temoporfin; Tenifoside; Teroxylon; Testolactone; Thiamiprine; Thioguanine; Thiotepa; Thiazopurine; Tirapazamine; Toremifene Citrate; Trestolon Acetate; Trisilibin Phosphate; Trimetrexate; Trimetrexate Glucuronate; Triptorelin; Tubulozol Hydrochloride; Uracil Mustard; Uredepa; Baprootide; Verteporfin; Vinblastine Sulfate; Vincristine Sulfate; Vindesin; Vindesin sulfate; Vinpidine sulfate; Vinglycinate sulfate; Vinleurosine sulfate; Vinorelbine tartrate; Vinocidin sulfate; Vinzolidine sulfate; Borozol; Geniplatin; Gynostatin; Zorubicin hydrochloride, agents that restrain cells in the G2-M phase and / or regulate the formation or stability of microtubules (e.g., Taxol™ (i.e., paclitaxel)), Taxotere™, compounds containing a taxane backbone, erbulozol (i.e., R-55104), dolastatin 10 (i.e., DLS-10 and NSC-376128), mibobulin isethionate (i.e., as CI-980), vincristine, NSC-639829, discodermolid (i.e., as NVP-XX-A-296), ABT-751 (Abbott, i.e., E-7010), altohirtin (e.g., altohirtin A and altohirtin C), spongestatin (e.g., spongestatin 1, spongestatin 2, spongestatin 3, spongestatin 4, spongestatin 5, spongestatin 6, spongestatin 7), Spongestatin 8, and Spongestatin 9), Semadotine hydrochloride (i.e., LU-103793 and NSC-D-669356), Epotillons (e.g., Epotillon A, Epotillon B, Epotillon C (i.e., Desoxipotillon A or dEpoA), Epotillon D (i.e., KOS-862, dEpoB, andDesoxiepotillone B), Epotillone E, Epotillone F, Epotillone B N-oxide, Epotillone A N-oxide, 16-Aza-Epotillone B, 21-Aminoepotillone B (i.e., BMS-310705), 21-Hydroxypotillone D (i.e., E, Desoxiepotillone F, and dEpoF), 26-Fluoroepotillone, Auristatin PE (i.e., NSC-654663), Soblidotin (i.e., TZT-1027), LS-4559-P (Pharmacia, i.e., LS-4577), LS-4578 (Pharmacia, i.e., LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristine Sulfates, DZ-3358 (Daiichi), FR-182877 (Fujisawa, i.e. WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, i.e. ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), Cryptophysin 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), Bitiebauamide, Tubulicin A, Canadensol, Centauredin (i.e., NSC-106969), T-138067 (Tularik, i.e., T-67, TL-138067, and TI-138067), COBRA-1 (Parker Hughes Laboratories, 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 Laboratories), pyzianolide B, laurimalide, SPA-2 (Parker Hughes Laboratories), SPA-1 (Parker Hughes Laboratories, i.e., SPIKET-P), 3-IAABU (Cytoskeleton / Mount Sinai School of Medicine, i.e., MF-569), narcosine (also known as NSC-5366), nascapine, D-24851 (Asta Medica), A-105972 (Abbott), hemiasterin, 3-BAABU (Cytoskeleton / Mount Sinai School of Medicine, i.e., MF-191), TMPN (Arizona State University), vanadocene acetylacetonate, T-138026 (Tularik), monsatrol, inanosine (i.e., NSC-698666), 3-IAABE (Cytoskeleton / Mount Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, i.e., T-900607), RPR-115781 (Aventis), eluterobin (e.g., desmethyleluterobin, desacetyleluterobin, isoeluterobin A and Z-eluterobin), caribaoside, cariveolin, halicondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), tacalonolide A, TUB-245 (Aventis), A-259754 (Abbott), diozostatin, (-)-phenylahistine (i.e., NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, i.e., D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (i.e., SPA-110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resveratatin sodium phosphate, BPR-OY-007 (National HealthResearch Institations) 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, medoxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), anti-estrogens (e.g., tamoxifen), and androgens (e.g., testosterone propionate, fluoxymesterone), anti-androgens (e.g., flutamide), immunostimulants (e.g., Bacillus calmette-gerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calisemycin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., 111 In, 90 Y, or 131Anti-CD20 monoclonal antibodies conjugated to I, etc.), triptolide, homoharingtonin, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesin, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytriptamine, vemurafenib, dabrafenib, erotenib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR)-targeted therapies or treatments (e.g., gefitinib (Iressa™), erotenib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib / BIBW2992, CI-1033 / canertinib, neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299804, OSI-420 / desmethyl erotinib, AZD8931, AEE788, felitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, or similar ones.

[0131] In an embodiment, crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical composition is used in combination with a chemotherapeutic agent. In an embodiment, the chemotherapy agent is an antiproliferative / antitumor drug, an antimetabolite, an antitumor antibiotic, a mitotic inhibitor, a topoisomerase inhibitor, a cell proliferation inhibitor, an estrogen receptor downregulator, an antiandrogen, an LHRH antagonist or LHRH agonist, a progestogen, an aromatase inhibitor, an alpha-reductase inhibitor, a cancer cell invasion inhibitor, a growth factor function inhibitor, a farnesyl transferase inhibitor, a tyrosine kinase inhibitor, a serine / threonine kinase inhibitor, an epidermal growth factor family inhibitor, a platelet-derived growth factor family inhibitor, a hepatocyte growth factor family inhibitor; an antiangiogenic agent, a vascular injury agent, a preparation used in antisense therapy, an anti-ras antisense agent, a preparation used in gene therapy, an immunotherapeutic agent, or an antibody.

[0132] In an embodiment, crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and / or its pharmaceutical composition is used in combination with an anti-inflammatory agent. In an embodiment, the anti-inflammatory agent comprises a non-steroidal anti-inflammatory agent (hereinafter NSAID) comprising thalidomide or its derivatives, retinoids, dithranol or calcipotriol, a non-selective cyclo-oxygenase COX-1 / COX-2 inhibitor (e.g., piroxicam, diclofenac, propionic acid, e.g., naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen), a phenamate, e.g., mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolone, e.g., phenylbutazone, salicylates, e.g., aspirin) whether applied topically or systemically; and a selective COX-2 inhibitor (e.g., meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); Cyclo-oxygenase that inhibits nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, or intra-articular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular therapies such as hyaluronic acid derivatives; and nutritional agents such as glucosamine.

[0133] In an embodiment, a pharmaceutical composition comprising crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is administered simultaneously with the administration of another therapeutic agent, which may be part of the same pharmaceutical composition as crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate. In an embodiment, a pharmaceutical composition comprising the crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is administered simultaneously with the administration of another therapeutic agent, which may be part of a different pharmaceutical composition. In another embodiment, a pharmaceutical composition comprising the crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is administered before the administration of another therapeutic agent. In another embodiment, a pharmaceutical composition comprising the crystal 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate is administered along with the administration of another therapeutic agent.

[0134] In another embodiment, another therapeutic agent is pembrolizumab.

[0135] In another embodiment, crystalline 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate may be administered in combination with the amorphous form of 2-((R)-3-(1-((R)-1-((2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1)ethanol-1-olbenzenesulfonate. In another embodiment, crystal form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate may be administered in combination with crystal form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate.

[0136] Numbered implementation examples

[0137] Example 1. A compound in crystalline form, 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate.

[0138] Example 2. The compound of Example 1 having characteristic absorption peaks (2θ) at 18.4°±0.3°, 22.9°±0.3°, 21.2°±0.3° and 15.9°±0.3° in the X-ray powder diffraction pattern using Cu Kα radiation.

[0139] Example 3. The compound of Example 1 having characteristic absorption peaks (2θ) at 12.2°±0.3°, 23.8°±0.3°, and 25.6°±0.3° in the X-ray powder diffraction pattern using Cu Kα radiation.

[0140] Example 4. The compound of Example 1 having characteristic absorption peaks (2θ) at 23.1°±0.3°, 20.0°±0.3°, and 16.2°±0.3° in the X-ray powder diffraction pattern using Cu Kα radiation.

[0141] Example 5. A compound having an X-ray powder diffraction pattern using Cu Kα radiation as shown in FIG. 1, in Example 1.

[0142] Example 6. The compound of Example 1 having a melting point of about 170 ℃ to about 173 ℃ when measured by differential scanning calorimetry at a scanning rate of 5 ℃ / min.

[0143] Example 7. A compound of Example 2 having a characteristic absorption peak (2θ) at 12.2°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0144] Example 8. A compound of Example 2 having a characteristic absorption peak (2θ) at 23.8°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0145] Example 9. A compound of Example 2 having a characteristic absorption peak (2θ) at 25.6°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0146] Example 10. A compound of Example 2 having a characteristic absorption peak (2θ) at 23.1°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0147] Example 11. A compound of Example 2 having a characteristic absorption peak (2θ) at 20.0°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0148] Example 12. A compound of Example 2 having a characteristic absorption peak (2θ) at 16.2°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0149] Example 13. A compound of Example 1 having characteristic absorption peaks (2θ) at 12.5°±0.3°, 14.6°±0.3°, 22.3°±0.3° and 13.3°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0150] Example 14. The compound of Example 13 having characteristic absorption peaks (2θ) at 15.8°±0.3°, 24.5°±0.3°, and 4.5°±0.3° in the X-ray powder diffraction pattern using Cu Kα radiation.

[0151] Example 15. The compound of Example 14 having characteristic absorption peaks (2θ) at 22.8°±0.3°, 10.6°±0.3° and 18.6°±0.3° in the X-ray powder diffraction pattern using Cu Kα radiation.

[0152] Embodiment 16. A compound having an X-ray powder diffraction pattern using Cu Kα radiation as shown in FIG. 3, in Embodiment 1.

[0153] Embodiment 17. The compound of Embodiment 1 having a melting point of about 116 ℃ to about 119 ℃ when measured by differential scanning calorimetry at a scanning rate of 5 ℃ / min.

[0154] Example 18. A compound of Example 13 having a characteristic absorption peak (2θ) at 15.8°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0155] Example 19. A compound of Example 13 having a characteristic absorption peak (2θ) at 24.5°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0156] Example 20. A compound of Example 13 having a characteristic absorption peak (2θ) at 4.5°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0157] Example 21. A compound of Example 13 having a characteristic absorption peak (2θ) at 22.8°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0158] Example 22. A compound of Example 13 having a characteristic absorption peak (2θ) at 10.6°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0159] Example 23. The compound of Example 13 having a characteristic absorption peak (2θ) at 18.6°±0.3° in the X-ray powder diffraction pattern using Cu Kα radiation.

[0160] Embodiment 24. A pharmaceutical composition comprising a crystalline compound of any one of Embodiments 1 to 23 and a pharmaceutically acceptable carrier.

[0161] Embodiment 25. A pharmaceutical composition comprising a crystalline compound of any one of Embodiments 2 to 12 and a pharmaceutically acceptable carrier.

[0162] Embodiment 26. A pharmaceutical composition comprising a crystalline compound of any one of Embodiments 13 to 23 and a pharmaceutically acceptable carrier.

[0163] Embodiment 27. A pharmaceutical composition in any one of Embodiments 24 to 26, wherein the composition is in the form of an oral tablet.

[0164] Embodiment 28. The pharmaceutical composition of Embodiment 27, wherein the composition comprises 75 mg of a crystalline compound.

[0165] Embodiment 29. The pharmaceutical composition of Embodiment 27, wherein the composition comprises 25 mg of a crystalline compound.

[0166] Embodiment 30. A pharmaceutical composition in any one of Embodiments 24 to 26, wherein the composition comprises a wetting agent.

[0167] Embodiment 31. A pharmaceutical composition according to Embodiment 30, wherein the wetting agent is sodium lauryl sulfate.

[0168] Embodiment 32. A pharmaceutical composition in any one of Embodiments 24 to 26, wherein the composition comprises a water-soluble excipient.

[0169] Example 33. A pharmaceutical composition according to claim 32, wherein the water-soluble excipient is lactose monohydrate.

[0170] Embodiment 34. A pharmaceutical composition according to Embodiment 32, wherein the water-soluble excipient constitutes at least 50% by weight of the oral tablet formulation.

[0171] Embodiment 35. A pharmaceutical composition comprising a disintegrant in any one of Embodiments 24 to 26.

[0172] Embodiment 36. A pharmaceutical composition according to Embodiment 35, wherein the disintegrant is cros-carmellose sodium.

[0173] Embodiment 37. A method for treating immune, inflammatory, or cancer-related diseases or disorders, comprising administering a crystal compound of any one of Embodiments 1 to 23 to a patient requiring such treatment.

[0174] Embodiment 38. A method for treating an immune, inflammatory, or cancer-related disease or disorder, comprising administering a pharmaceutical composition of any one of Embodiments 24 to 27 to a patient requiring such treatment.

[0175] Embodiment 39. The method in Embodiment 37 or 38, wherein the disease or disorder is selected from allergy-related disorders, hypersensitivity, anaphylactic reaction, gastrointestinal disorders, respiratory allergic diseases, hypersensitive lung diseases, autoimmune diseases, inflammatory skin diseases, graft rejection, allogeneic graft rejection, transplant rejection, cancer, metastatic cancer, and neurodegenerative diseases.

[0176] Embodiment 40. In Embodiment 37 or 38, the disease or disorder is inflammatory bowel disease, Crohn's disease, ulcerative colitis, ileitis, enteritis, psoriasis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria, pruritus, vasculitis, scleroderma, asthma, COPD, allergic rhinitis, arthritis (rheumatoid and psoriasis), multiple sclerosis, systemic lupus erythematosus, type I diabetes mellitus, glomerulonephritis, leukemia, lymphoma, gastric cancer, atherosclerosis, Alzheimer's disease, encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis media and sinusitis, idiopathic pulmonary fibrosis, contact dermatitis, pulmonary fibrosis, hepatitis, asthma, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, cutaneous melanoma, colon adenocarcinoma, A method selected from the development of rectal adenocarcinoma, gastric adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, nasopharyngeal carcinoma, Hodgkin lymphoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma and granuloma.

[0177] Embodiment 41. A method in which the crystal compound of Embodiment 37 or 38 is administered in combination with another therapeutic agent.

[0178] Embodiment 42. The method of Embodiment 41, wherein the other therapeutic agent is pembrolizumab.

[0179] Examples

[0180] A stable crystalline solid form of an organic molecule is desirable because it facilitates the processing of the drug substance into a final drug product, e.g., an oral tablet formulation. The compound 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol was first isolated in its free base form, as described in U.S. Patent No. 10,179,787. A crystalline solid was not 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]pyrazine-6-yl)azetidine-3-yl)piperidin-1-yl)ethanol-1-ol also did not produce a crystalline solid.

[0181] Multiple different salts of 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)ethanol were prepared using different acids. Experiments were performed to form the salts, and the following Table 1 The 14 different acids and 13 different solvents listed in were evaluated using alone or in some combination.

[0182] Table 1. Investigation of acids and solvents for the 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-ol salt screen

[0183]

[0184] This study revealed that only two acids produced a consistent solid form. Para-toluenesulfonate provided a stable crystalline salt with a monopolymorph and a melting point of 220 °C. This highly crystalline form was less soluble than the amorphous HCl salt. The low solubility of para-toluenesulfonate could inhibit drug dissolution and prevent sufficient intestinal absorption. At pH 2, the kinetic solubility of para-toluenesulfonate was only one-fifth of that of the HCl salt for the same parameter. The bioavailability of this salt in rats was less than half that observed with the amorphous HCl salt. Low solubility and low bioavailability are not desirable characteristics for pharmaceuticals.

[0185] The benzene sulfonate of 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)ethanol-1-ol was isolated, and two crystalline polymorphs were observed depending on the crystallization conditions. Methyl- t-By using a mixture of butyl ether and ethanol, a higher melting polymorph (170 °C) was obtained and could be consistently separated at production scale. The high melting point of this polymorph is advantageous as it makes preparation at higher temperatures easier. This polymorph exhibited lower hygroscopicity and better solubility (411 μM) in pH 2 water than the para-toluenesulfonate (190 μM). The bioavailability of the benzenesulfonate in rats was higher than that observed for the para-toluenesulfonate of 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)ethanol-1-ol (34% vs. 22%). In addition, the benzenesulfonate of 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)ethanol-1-ol was proven to have excellent stability after storage at room temperature for 36 months. This unexpected combination of regenerative 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]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate salt ideal for pharmaceutical development.

[0186] 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]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate and its crystalline form. It will be apparent to those skilled in the art that many variations of both the material and the method can be carried out without departing from the scope of the invention.

[0187] In the following examples, the following abbreviations have the following meanings. Where an abbreviation is not defined, the generally accepted meaning applies.

[0188] Atm = Atmospheric pressure

[0189] Boc = tert-butyloxycarbonyl

[0190] Cbz = Carbobenzyloxy

[0191] DCC = Dicyclohexylcarbodiimide

[0192] DMAP = 4-N,N-dimethylaminopyridine

[0193] DMF = N,N-dimethylformamide

[0194] DMSO = Dimethyl sulfoxide

[0195] Fmoc = 9-fluorenylmethyloxycarbonyl

[0196] g = gram

[0197] h = time

[0198] HPLC = High-pressure liquid chromatography

[0199] L = liter

[0200] LC / MS = Liquid Chromatography / Mass Spectrometry

[0201] M = mole

[0202] min = minutes

[0203] mL = milliliters

[0204] mmol = millimole

[0205] NHS = N-hydroxysuccinimide

[0206] THF = Tetrahydrofuran

[0207] TFA = Trifluoroacetic acid

[0208] TLC = Thin-layer chromatography

[0209] TMS = Trimethylsilyl

[0210] μL = microliter

[0211] μM = micromolar

[0212] v / v = Volume vs. Volume

[0213] Example 1. Synthesis of amorphous 2-((R)-3-(1-((R)-1-((2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1)ethanol-1-olbenzenesulfonate.

[0214]

[0215] 2-[(3R)-3-[1-[1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-3-(trifluoromethyl)pyrazolo[3,4-b]pyrazine-6-yl]azetidine-3-yl]-1-piperidyl]ethanol (1.0 g, 1.84 mmol) was dissolved in ethanol (10 mL) and cooled to -10 °C (acetone / ice bath). Subsequently, benzenesulfonic acid (291.09 mg, 1.84 mmol) was added dropwise to ethanol (10 mL) over 5 minutes. After the addition was complete, the reaction mixture was raised to 22 °C and stirred for 5 minutes. No precipitate was formed. The mixture was concentrated under reduced pressure, and the title compound was obtained as a grayish-white, amorphous solid (1.29 g, 99.9% yield). 1 1H NMR (400 MHz, methanol- d4): 7.90 (s, 1H), 7.85 - 7.78 (m, 2H), 7.47 (d, J = 2.1Hz, 1H), 7.41 - 7.33 (m, 4H), 7.29 (dd, J = 8.5, 2.1Hz, 1H), 6.44 (q, J = 7.1Hz, 1H), 4.35 - 4.19 (m, 2H), 4.05 - 3.94 (m, 2H), 3.90 (t, J = 5.2Hz, 2H), 3.62 (dd, J = 26.7, 1 2.2 Hz, 2H), 3.29 - 3.20 (m, 2H), 2.94 (t, J = 12.6 Hz, 1H), 2.77 - 2.58 (m, 2H), 2.22 - 2.08 (m, 1H), 2.07 - 1.94 (m, 2H), 1.91 (d, J = 7.0 Hz, 3H), 1.83 (t, J = 13.7 Hz, 1H), 1.28 - 1.12 (m, 1H). LCMS [M+H] 543.0.

[0216] Example 2. 2-((R) - 3-(1-(1-((R)-1-( 2 Synthesis of crystalline form A of ,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate.

[0217] Non-determinant 2-(( R )-3-(1-(1-(( R )-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate (230 g, 327.83 mmol) was filled into a 2 L flask. Ethanol (345 mL) was added, the flask was placed in a reflux condenser, and then heated to 60 °C to obtain a clear solution. tert1035 mL of butylmethyl ether was added all at once, 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; the solid was then separated by filtration, rinsed with cold MTBE / EtOH (575 ml / 115 mL), and dried to a constant weight under high vacuum at 55 °C. R )-3-(1-(1-(( R )-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate (216.35 g, 308.37 mmol, 94% yield) was obtained as a white crystalline solid (crystalline form A).

[0218] Example 3. 2-(( R ) - Synthesis of crystalline form B of 3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate.

[0219] A non-crystalline solid 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate (5 g) was added to 15 ml of isopropyl alcohol (solvent) in a 100 ml flask. The mixture was first heated to 75 °C and then further heated to 81 °C to obtain a clear solution. Subsequently, 45 ml of methyl ethyl ketone (counter solvent) was added to the solution. The solution was cooled to 50 °C and stirred for 30 minutes. The solution remained clear with no trace of solid crystal formation. A sample of the solution was collected and stirred in a small vial to produce a precipitate. The slurry sample was returned to the original flask for seeding, but the slurry solid dissolved.

[0220] Next, the solution was cooled to 35 °C and then seeded at 50 °C in a manner similar to that described above to produce a slurry in which solid crystals are formed. The slurry was stirred at 35 °C for 1 hour and then allowed to cool to room temperature. The solid was separated by filtration, rinsed with methyl ethyl ketone (2 x 5 ml), and then dried under vacuum at 50 °C until its weight remained constant to obtain 4.4 g of a white crystalline solid (crystal form B).

[0221] Example 4. X-ray powder diffraction of crystal form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate.

[0222] The X-ray powder diffraction (XRPD) of sample A of crystalline form 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate prepared according to Example 2 was measured using a Malvern Panalytical X'Pert Pro X-ray powder diffraction analyzer utilizing Cu Kα radiation with Bragg-Bentano geometry. This instrument is equipped with a line-focused parallel beam optical system utilizing an anti-scattering slit (1°), a fixed divergence slit (0.5°), and an X'Celerator detector. The tube voltage and current were set to 45 kV and 40 mA, respectively. The angular resolution of the protractor was approximately 0.001°. The detector covered a range of 41° with a step size of 2-theta (2θ) with a step size of 0.0167°. The typical averaging time was 3.5 minutes for each collected XRPD pattern. The XRPD instrument was calibrated using a corundum sample (NIST 1976a). The sample exhibited the diffraction pattern shown in Fig. 1. The diffraction peaks from Fig. 1 are shown in Table 2 below.

[0223] Table 2.

[0224]

[0225]

[0226] Example 5. Differential scanning calorimetry (melting point) analysis of crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate (crystal form A).

[0227] Differential scanning calorimetry (DSC) analysis of a crystal sample of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate prepared according to Example 2 was measured using a TA Instruments Q2000 instrument by scanning from 40 °C to 250 °C at a scanning rate of 10 °C / min. The material was run under an appropriate temperature program (initial temperature, isothermal, ramp rate, equilibration at final temperature) to generate the calorimeter shown in Fig. 2. The DSC analysis indicates an endothermic transition with an onset temperature of 170 °C and a ΔH of 64.81 J / g.

[0228] Example 6. X-ray powder diffraction analysis of crystal form B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate.

[0229] The X-ray powder diffraction (XRPD) of a sample of crystal form B of 2-((R)-3-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate prepared according to Example 3 was measured using the same instrument and method as described prior to Example 4. The diffraction peaks from Fig. 3 are shown in Table 3 below.

[0230] Table 3.

[0231]

[0232]

[0233] Example 7. Differential scanning calorimetry (melting point) analysis of crystal 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate (crystal form B).

[0234] Differential scanning calorimetry (DSC) analysis of crystal sample B of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate prepared according to Example 3 was measured using the same method and apparatus used in Example 5, and the material was run under an appropriate temperature program (equilibrium at initial temperature, isothermal, ramping rate, final temperature) to produce the calorimeter shown in Fig. 4. The DSC analysis indicates an endothermic transition with an onset temperature of 114 °C and a ΔH of 48.82 J / g.

[0235] Example 8. Immediate-release oral formulation (strength 5 mg)

[0236] Four different immediate-release oral tablet formulations containing crystalline form A of 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate (referred to as "compound, crystalline form A" and "drug substance" in Examples 8 to 11) were prepared to have the ingredients shown in Tables 3 to 6 corresponding to dosage strengths of 5 mg (Example 8), 25 mg (Example 9), 50 mg (Example 10), and 75 mg (Example 11), respectively.

[0237] The composition of the 5 mg dosage strength oral tablet is shown in Table 4.

[0238] Table 4. Quantitative composition of 5 mg crystalline form A-containing tablets

[0239]

[0240] Granulation:

[0241] To improve the content uniformity of the tablet core formulation, 5 mg strength tablets were manufactured using a high-shear wet granulation process.

[0242] First, the drug substance was screened through a 30 mesh screen. Subsequently, hydroxypropyl cellulose, sodium lauryl sulfate, lactose monohydrate, microcrystalline cellulose, and croscarmellose sodium were screened through a 20 mesh screen. Then, these six substances were granulated in a 25 L bowl while adding purified water. Water was added at a rate of 350 to 450 g / min to a granulator operated at an impeller speed of 290 RPM and a chopper speed of 1760. After reaching the endpoint, the wet granules were exfoliated in a standard grinder equipped with a 375Q screen. Subsequently, the broken granules were dried in an oven operated at 40 °C until the amount of water in the granules was less than 4 wt%. Subsequently, the dried granules were ground in a standard grinder (canonical mill) equipped with a 40 G or 75 R screen.

[0243] Lubrication and Compression:

[0244] Next, the crushed granules were added to an 8-quart V mixer along with magnesium stearate and separated using a 30 mesh screen. These two components were mixed for 4 minutes until a uniform mixture was obtained.

[0245] The tablet cores were compressed using a Korsch XL 100 rotary tablet press equipped with 0.2188-inch circular tooling. The tablet press was operated at 70 RPM with a compressive force of approximately 10 kN. The average weight of the tablets was 64.2 mg, the average thickness was 1.93 mm, and the average hardness was 3.1 kP.

[0246] Example 9. Immediate-release oral formulation (strength 50 mg)

[0247] The composition of the 50 mg dosage strength oral tablet is shown in Table 5.

[0248] Table 5. Quantitative composition of 50 mg crystalline form A-containing tablets

[0249]

[0250] Granulation:

[0251] A similar granulation procedure as described in Example 8 was followed.

[0252] Lubrication and Compression:

[0253] Next, the crushed granules were added to a 16-quart V mixer along with magnesium stearate and exfoliated using a 30-mesh screen. These two components were blended for 4 minutes until a uniform mixture was obtained. The tablet cores were compressed using a Korsch XL 100 rotary tablet press equipped with 0.6496 x 0.3504-inch caplet tooling. The tablet press was operated at 30 RPM with a compressive force of approximately 29.5 kN. The average weight of the tablets was 647.5 mg, the average thickness was 4.84 mm, and the average hardness was 12.3 kP.

[0254] Example 10. Immediate-release oral formulation (strength 25 mg)

[0255] The composition of the 25 mg dosage strength oral tablet is shown in Table 6.

[0256] Table 6. Quantitative composition of 25 mg crystalline form A-containing tablets

[0257]

[0258] Granulation and Lubrication:

[0259] First, the drug substance was screened through a 30 mesh screen. Subsequently, hydroxypropyl cellulose, sodium lauryl sulfate, lactose monohydrate, microcrystalline cellulose, and croscarmellose sodium were screened through a 20 mesh screen. Then, these six substances were granulated in a 25 L bowl while adding purified water. Water was added at a rate of 350 to 450 g / min to a granulator operated at an impeller speed of 290 RPM and a chopper speed of 1760. After reaching the endpoint, the wet granules were exfoliated in a standard grinder equipped with a 375Q screen. Subsequently, the broken granules were dried in an oven operated at 40°C until the amount of water in the granules was less than 4% by weight. Afterward, the dried granules were ground in a standard grinder equipped with a 75R screen. Next, the crushed granules were added to a 1 cubic foot V mixer along with magnesium stearate and separated using a 30 mesh screen. These two components were mixed for 4 minutes until a uniform mixture was obtained.

[0260] compression:

[0261] The tablet core was compressed using a Korsch XL 100 rotary tablet press equipped with 7.5 mm circular tooling. The tablet press was operated at 40 RPM with a compressive force of approximately 15 kN. The average weight of the tablet 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 ½ gallon container and mixed until a homogeneous suspension was observed. Subsequently, uncoated tablets were 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 to 60 °C. The suspension was sprayed onto the tablets until a weight increase of at least 3% was reached. The coated tablets had an average weight of 171.8 mg.

[0264] Example 11. Immediate-release oral tablet (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 75 mg crystalline form A-containing tablets

[0267]

[0268] Granulation and Lubrication:

[0269] For the granulation and lubrication steps, a procedure similar to that described in Example 10 was followed.

[0270] compression:

[0271] The 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 with a compressive force of approximately 9.3 kN. The average weight of the tablets was 494.2 mg, the average thickness was 5.46 mm, and the average hardness was 15.2 kP.

[0272] It should be noted that alternative ways of carrying out the present invention exist. Accordingly, the embodiments shall be considered exemplary and not limited, and the present invention is not limited to the details given herein but may be modified within the scope and equivalents of any claim(s) issued therefrom. All publications and patents cited herein are incorporated by reference in their entirety.

Claims

Claim 1 A compound in crystalline form 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate, wherein the compound has characteristic absorption peaks (2θ) at 18.4°±0.3°, 22.9°±0.3°, 21.2°±0.3° and 15.9°±0.3° in X-ray powder diffraction using Cu Kα radiation. Claim 2 A compound according to claim 1, having characteristic absorption peaks (2θ) at 12.2°±0.3°, 23.8°±0.3° and 25.6°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation. Claim 3 A compound according to claim 2, having characteristic absorption peaks (2θ) at 23.1°±0.3°, 20.0°±0.3° and 16.2°±0.3° in an X-ray powder diffraction pattern using Cu Kα radiation. Claim 4 In claim 1, in the X-ray powder diffraction pattern using Cu Kα radiation, 4.6°±0.3°, 9.2°±0.3°, 9.3°±0.3°, 12.2°±0.3°, 13.7°±0.3°, 14.6°±0.3°, 16.2°±0.3°, 16.5°±0.3°, 16.8°±0.3°, 20.0°±0.3°, 20.2°±0.3°, 21.5°±0.3°, 23.1°±0.3°, 23.8°±0.3°, 24.3°±0.3°, 24.4°±0.3°, 24.7°±0.3°, 25.1°±0.3°, 25.6°±0.3°, 26.0°±0.3°, 26.8°±0.3°, 27.2°±0.3°, 27.6°±0.3°, 27.9°±0.3°, 28.1°±0.3°, 28.9°±0.3°, 29.1°±0.3°, 30.5°±0.3°, 31.5°±0.3°, 32.1°±0.3°, 33.2°±0.3°, 33.8°±0.3°, 34.2°±0.3°, 34.8°±0.3°, 35.4°±0.3°, 36.2°±0.3°, 36.9°±0.3°, 37.8°±0.3°, 38.8°±0.3°, Compound having characteristic absorption peaks (2θ) at 40.2°±0.3°, 40.6°±0.3°, 41.2°±0.3°, 41.7°±0.3°, 42.0°±0.3°, 42.5°±0.3°, and 44.4°±0.3°. Claim 5 A compound according to claim 1, having a melting point of 170 ℃ to 173 ℃ when measured by differential scanning calorimetry at a scanning rate of 5 ℃ / min. Claim 6 A compound in crystalline form 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)azetidine-3-yl)piperidine-1-yl)ethanol-1-olbenzenesulfonate, wherein the compound has characteristic absorption peaks (2θ) at 12.5°±0.3°, 14.6°±0.3°, 22.3°±0.3°, and 13.3°±0.3° in X-ray powder diffraction using Cu Kα radiation. Claim 7 In claim 6, the compound having characteristic absorption peaks (2θ) at 15.8°±0.3°, 24.5°±0.3°, and 4.5°±0.3° in the X-ray powder diffraction pattern using Cu Kα radiation. Claim 8 In claim 7, the compound having characteristic absorption peaks (2θ) at 22.8°±0.3°, 10.6°±0.3°, and 18.6°±0.3° in the X-ray powder diffraction pattern using Cu Kα radiation. Claim 9 In claim 6, in the X-ray powder diffraction pattern using Cu Kα radiation, 4.5°±0.3°, 5.2°±0.3°, 7.8°±0.3°, 8.9°±0.3°, 9.4°±0.3°, 10.6°±0.3°, 10.8°±0.3°, 11.1°±0.3°, 11.3°±0.3°, 11.9°±0.3°, 14.9°±0.3°, 15.8°±0.3°, 16.2°±0.3°, 16.6°±0.3°, 17.0°±0.3°, 17.8°±0.3°, 18.6°±0.3°, 18.8°±0.3°, 19.3°±0.3°, 19.7°±0.3°, 20.4°±0.3°, 21.1°±0.3°, 21.3°±0.3°, 21.7°±0.3°, 22.8°±0.3°, 23.3°±0.3°, 23.8°±0.3°, 24.5°±0.3°, 25.0°±0.3°, 26.0°±0.3°, 26.8°±0.3°, 27.1°±0.3°, 29.1°±0.3°, 31.0°±0.3°, 31.4°±0.3°, 32.7°±0.3°, 33.3°±0.3°, 34.9°±0.3°, 36.8°±0.3°, Compound having characteristic absorption peaks (2θ) at 38.8°±0.3°, 40.7°±0.3°, and 42.4°±0.3°. Claim 10 A compound according to claim 6, having a melting point of 116 ℃ to 119 ℃ when measured by differential scanning calorimetry at a scanning rate of 5 ℃ / min. Claim 11 A pharmaceutical composition comprising a crystalline compound of any one of claims 1 to 10 and a pharmaceutically acceptable vehicle for treating immune, inflammatory, or cancer-related diseases or disorders, wherein said disease or disorder is an allergy-related disorder, hypersensitivity, anaphylactic reaction, gastrointestinal disorder, respiratory allergic disease, hypersensitivity lung disease, autoimmune disease, inflammatory skin disease, graft rejection, allogeneic graft rejection, transplant rejection, cancer, metastatic cancer, neurodegenerative disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, ileitis, enteritis, psoriasis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria, pruritus, vasculitis, scleroderma, asthma, COPD, allergic rhinitis, arthritis (rheumatic and psoriatic), multiple sclerosis, systemic lupus erythematosus, type I diabetes mellitus, glomerulonephritis, leukemia, lymphoma, A pharmaceutical composition selected from gastric cancer, atherosclerosis, Alzheimer's disease, encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis media and sinusitis, idiopathic pulmonary fibrosis, contact dermatitis, pulmonary fibrosis, hepatic inflammation, asthma, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, cutaneous melanoma, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, nasopharyngeal carcinoma, Hodgkin lymphoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma and granuloma development. Claim 12 A pharmaceutical composition according to claim 11, wherein the composition is in the form of an oral tablet dosage. Claim 13 A pharmaceutical composition according to claim 12, wherein the composition comprises 75 mg of the crystal compound. Claim 14 A pharmaceutical composition according to claim 12, wherein the composition comprises 25 mg of the crystal compound. Claim 15 A pharmaceutical composition according to claim 11, wherein the composition comprises a wetting agent. Claim 16 A pharmaceutical composition according to claim 15, wherein the wetting agent is sodium lauryl sulfate. Claim 17 A pharmaceutical composition according to claim 12, wherein the composition comprises a water-soluble excipient. Claim 18 A pharmaceutical composition according to claim 17, wherein the water-soluble excipient is lactose monohydrate. Claim 19 A pharmaceutical composition according to claim 17, wherein the water-soluble excipient constitutes at least 50% by weight of the oral tablet formulation. Claim 20 A pharmaceutical composition according to claim 11, wherein the composition comprises a disintegrant. Claim 21 A pharmaceutical composition according to claim 20, wherein the disintegrant is cros-carmellose sodium. Claim 22 A pharmaceutical composition comprising a crystalline compound of any one of claims 1 to 10 for treating immune, inflammatory, or cancer-related diseases or disorders, wherein said disease or disorder is an allergy-related disorder, hypersensitivity, anaphylactic reaction, gastrointestinal disorder, respiratory allergic disease, hypersensitive lung disease, autoimmune disease, inflammatory skin disease, graft rejection, allogeneic graft rejection, transplant rejection, cancer, metastatic cancer, neurodegenerative disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, ileitis, enteritis, psoriasis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria, pruritus, vasculitis, scleroderma, asthma, COPD, allergic rhinitis, arthritis (rheumatoid and psoriasis), multiple sclerosis, systemic lupus erythematosus, type I diabetes mellitus, glomerulonephritis, leukemia, lymphoma, gastric cancer, atherosclerosis, A pharmaceutical composition selected from Alzheimer's disease, encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis media and sinusitis, idiopathic pulmonary fibrosis, contact dermatitis, pulmonary fibrosis, hepatic inflammation, asthma, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, cutaneous melanoma, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, nasopharyngeal carcinoma, Hodgkin lymphoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma and granuloma development. Claim 23 A pharmaceutical composition according to claim 22, wherein the crystal compound is administered in combination with another therapeutic agent. Claim 24 A pharmaceutical composition according to claim 23, wherein the therapeutic agent is pembrolizumab. Claim 25 A method for preparing a crystalline compound according to any one of claims 1 to 10, wherein methyl- t- A method of manufacturing comprising the step of crystallizing a crystalline compound of any one of claims 1 to 5 from a solvent mixture of butyl ether and ethanol, or crystallizing a crystalline compound of any one of claims 6 to 10 from a solvent mixture of isopropyl alcohol and methyl ethyl ketone. Claim 26 delete Claim 27 delete Claim 28 delete Claim 29 delete Claim 30 delete Claim 31 delete Claim 32 delete Claim 33 delete Claim 34 delete Claim 35 delete Claim 36 delete Claim 37 delete Claim 38 delete Claim 39 delete Claim 40 delete Claim 41 delete Claim 42 delete Claim 43 delete Claim 44 delete Claim 45 delete Claim 46 delete

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