Adipic acid salt crystalline form of CCR6 antagonist

Abstract

The present invention relates to crystalline forms of 2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol adipate and its use in the treatment or prevention of various diseases or disorders, such as cancer or inflammatory / autoimmune diseases or disorders.

Description

[Technical Field]

[0001] The present invention relates to novel crystalline forms of 2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol adipic acid salt, methods for preparing the same, pharmaceutical compositions containing the crystalline forms, and uses thereof in the treatment or prevention of various diseases or disorders ameliorated by modulating chemokine receptor 6 (CCR6). Such diseases or disorders include cancer and inflammatory / autoimmune diseases or disorders such as psoriasis. [Background technology]

[0002] The synthesis of 2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol (hereinafter also referred to as "compound") represented by formula (I), its biological activity as a CCR6 antagonist and its medical use are disclosed in WO2021219849.

[0003] [ka]

[0004] Despite numerous experiments, it has been difficult to find a crystalline form of the compound or a crystalline salt of the compound suitable as an active pharmaceutical ingredient (API). According to the present invention, a novel crystalline form of 2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol adipate (hereinafter also referred to as "compound" adipate) has been discovered, which is believed to have advantageous properties in terms of the potential use of the compound as an API. Such properties include improved water solubility, better pharmacological and / or pharmacokinetic properties (e.g., bioavailability), less hygroscopicity, improved chemical and / or physical (e.g., thermal) stability, better reproducibility in manufacturing, more consistent particle size and / or morphology, and / or better bulk properties such as density or flowability. [Brief explanation of the drawings]

[0005] [Figure 1]FIG. 1 shows the powder X-ray diffractograms of the crystalline form A of "Compound" adipic acid salt obtained in Examples 1a to 1d. Powder X-ray diffractograms measured by the methods disclosed herein show peaks with the following percentage relative intensities (relative peak intensities are given in parentheses) compared to the most intense peak in the diagram at the indicated refraction angles 2-theta (peaks with a relative intensity greater than 7% from the 5-40° 2-theta range are reported): 6.9° (24%), 12.2° (7%), 15.0° (9%), 16.4° (8%), 17.8° (15%), 19.2° (68%), 20.3° (100%), 20.9° (8%), 21.5° (12%), 22.6° (44%), 24.7° (9%), 26.8° (16%), 27.7° (10%), 30.3° (8%), and 35.3° (9%). In contrast to the peak list above, it should be understood that only selected characteristic peaks are necessary to completely and unambiguously characterize crystalline Form A of Compound adipic acid salt. It should also be understood that relative peak intensities may vary as a result of, among other things, preferred orientation or particle size. In the powder X-ray diffractogram of Figure 1, the refraction angle 2-theta (2θ) is plotted on the horizontal axis and counts on the vertical axis. [Figure 2] FIG. 2 shows the thermogravimetric analysis (TGA) of crystalline form A of Compound adipate, plotting relative mass (% of the total mass of the sample) on the vertical axis versus temperature (° C.). [Figure 3] FIG. 3 shows a differential scanning calorimetry (DSC) analysis of crystalline form A of Compound adipate salt, plotting heat flow (mW) on the vertical axis against temperature (° C.). [Figure 4] FIG. 4 shows the gravimetric vapor sorption analysis (GVS) of crystalline form A of Compound adipate salt, plotting the relative change in mass (%) against relative humidity (%) on the vertical axis. [Figure 5]5 shows the powder X-ray diffractogram of crystalline form B of "Compound" adipic acid salt obtained in Reference Example 1. The powder X-ray diffractogram measured by the method disclosed herein shows peaks with the following percentage relative intensities (relative peak intensities are given in parentheses) compared to the most intense peak in the diagram at the indicated refraction angles 2-theta (peaks with a relative intensity of 19% or greater from the 5-40° 2-theta range are reported): 6.2° (63%), 7.0° (45%), 8.8° (27%), 12.4° (23%), 12.9° (34%), 14.8° (30%), 15.8° (29%), 16.7° (30%), 18.3° (47%), 19.6° (100%), 21.3° (30%), 27.6° (19%), 29.5° (19%). It should be understood that, in contrast to the peak list above, only selected characteristic peaks are necessary to completely and unambiguously characterize Compound adipic acid salt of crystalline form B. In the powder X-ray diffractogram of Figure 5, refraction angle 2 theta (2θ) is plotted on the horizontal axis and counts on the vertical axis. [Figure 6] FIG. 6 shows the thermogravimetric analysis (TGA) of crystalline form B of Compound adipate, plotting relative mass (% of the total mass of the sample) on the vertical axis versus temperature (° C.). [Figure 7] FIG. 7 shows a differential scanning calorimetry (DSC) analysis of crystalline form B of Compound adipate salt, plotting heat flow (mW) on the vertical axis against temperature (° C.). Summary of the Invention

[0006] Detailed Description of the Invention 1) One aspect of the present invention relates to a crystalline form of the Compound, 2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol adipate, characterized by the presence of peaks at the following refraction angles 2θ: 6.9°, 17.8°, and 19.2° in a powder X-ray diffractogram.

[0007] 2) One embodiment relates to a crystalline form of Compound adipate according to embodiment 1), characterized by the presence of peaks at the following refraction angles 2θ in a powder X-ray diffractogram: 6.9°, 12.2°, 16.8°, 17.8° and 19.2°.

[0008] 3) Another embodiment relates to a crystalline form of Compound adipate according to embodiment 1), characterized by the presence of peaks at the following refraction angles 2θ in an X-ray powder diffractogram: 6.9°, 12.2°, 15.6°, 16.4°, 16.8°, 17.8°, 19.2°, 20.3°, 21.5° and 22.6°.

[0009] 4) Another embodiment relates to a crystalline form of the Compound adipate according to any one of embodiments 1) to 3), which exhibits an X-ray powder diffraction pattern essentially as depicted in FIG.

[0010] 5) Another embodiment relates to a crystalline form of Compound Adipic Acid Salt, specifically according to any one of embodiments 1) to 4), characterized by the presence of an endothermic peak at 163.5±5°C (particularly 163.5±2°C) in a Differential Scanning Calorimetry (DSC) thermogram [measured by the DSC method described herein].

[0011] Salts of adipic acid may be described as adipates. Thus, the terms "compound adipate" or "2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol adipate" may be described as "compound adipate" or "2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol adipate," respectively.

[0012] Form A of Compound adipate may have 0.9 to 1.1 (particularly 0.95 to 1.05; particularly 1) equivalents of adipic acid and may be described as Form A of Compound monoadipate or Form A of Compound adipate (1:1).

[0013] When the plural is used for compounds, solids, crystalline forms, hydrates, compositions, diseases, etc., it is intended to refer also to a singular compound, solid, crystalline form, hydrate, composition, disease, etc.

[0014] It is understood that the crystalline salts of the present invention may have non-coordinating solvents (e.g., water) and / or coordinating solvents (e.g., water). Non-coordinating solvents are used herein as a term for physically adsorbed or physically trapped solvents (see Polymorphism in the Pharmaceutical Industry (Ed. R. Hilfiker, VCH, 2006), Chapter 8: U.J. Griesser: The Importance of Solvates). The crystalline salts of the present invention are particularly essentially free of coordinating solvents (e.g., water).

[0015] For the avoidance of any doubt, whenever one of the above embodiments refers to "a peak in a powder X-ray diffractogram at the following refraction angle 2θ", the powder X-ray diffractogram is α The present invention is based on a 2θ value obtained using combined Cu Kα1 and Kα2 radiation without removing Cu Kα1 and Kα2; and it should be understood that the accuracy of the 2θ values ​​provided herein is within the range of + / −0.1 to 0.2°. In particular, when specifying the refraction angle 2θ for a peak in the embodiments and claims of the present invention, the 2θ value recited is between −0.2° and +0.2° (2θ + / −0.2°); and preferably between −0.1° and to the value in question + / -0.1° (2θ+ / -0.1°).

[0016] The definitions set forth herein apply uniformly to the subject matter defined in any one of the embodiments disclosed herein and apply mutatis mutandis throughout the specification and claims, unless a broader or narrower definition is given by a specific definition. It should be understood that any definition or preferred definition of a term or expression may independently (and together with) define and replace the respective term or expression in any or preferred definition of any or all other terms or expressions defined herein.

[0017] For example, when defining the presence of a peak in an X-ray powder diffractogram, a common way is to do this in terms of the signal-to-noise ratio (S=signal, N=noise). According to this definition, when stating that a peak must be present in an X-ray powder diffractogram, it is understood that a peak in an X-ray powder diffractogram is defined by having an S / N ratio (S=signal, N=noise) greater than x (where x is a number greater than 1), usually greater than 2, and especially greater than 3.

[0018] In the context of the statement that a crystalline form essentially exhibits the powder X-ray diffraction pattern shown in a figure, the term "essentially" means that at least the main peaks of the diagrams shown in the respective figures, i.e., peaks having a relative intensity of more than 20%, in particular more than 10%, compared to the most intense peak in the diagram, must be present. However, those skilled in the art of powder X-ray diffraction will recognize that the relative intensities in powder X-ray diffractograms can be subject to strong variations due to preferred orientation effects, which result, for example, in the loss of peaks or in the intensity variations of single peaks.

[0019] When not used in reference to temperature, the term "about" placed before a numerical value "X" in this application means between 10% of XX and 10% of X+X, preferably between 5% of XX and 5% of X+X, most preferably X. In the specific case of temperature, the term "about" placed before a temperature "Y" in this application means between Y-10°C and Y+10°C, preferably between Y-5°C and Y+5°C. Room temperature means a temperature of about 25°C.

[0020] Whenever terms such as "between X and Y," "X to Y," "X to Y," or "X to Y" are used to describe a numerical range, the endpoints "X" and "Y" of the stated range are expressly included in the range. For example, when a temperature range is described as being between 40°C and 80°C (or 40°C to 80°C), the endpoints 40°C and 80°C are meant to be included in the range.

[0021] 6) Another aspect relates to a crystalline form of the Compound adipic acid salt according to any one of embodiments 1) to 5), for example an essentially pure crystalline form, obtainable by a process comprising the steps of: a) providing a first solution / suspension of about 1 eq. adipic acid in acetone (particularly about 4 to about 10 vol.; more particularly about 7 vol.); b) providing a second solution having about 1 eq. of Compound in acetone (particularly about 4 to about 10 vol.; more particularly about 7 vol.); c) mixing the first solution / suspension with the second solution under heating (particularly at about 25°C to about 56°C; more particularly at about 40°C to about 50°C); d) cooling the resulting mixture (particularly to a temperature below about 25°C; more particularly to about 5 to about 10°C); e) optionally stirring the resulting mixture (particularly for at least about 30 min); f) isolating the solid residue by solid-liquid separation; and g) drying (especially under vacuum) the solid residue.

[0022] 7) An embodiment relates to a crystalline form, e.g., an essentially pure crystalline form, of Compound Adipic Acid Salt according to embodiment 6), wherein said mixing of said first solution / suspension and said second solution is carried out by adding said second solution to said first solution / suspension under heating.

[0023] For the avoidance of doubt, in embodiment 7), mixing of said first solution / suspension and said second solution is performed by adding said second solution to said first solution / suspension; rather than adding said first solution / suspension to said second solution.

[0024] The above step of isolating the solid residue by solid-liquid separation is understood to mean separating the solid phase of the suspension from its liquid phase, which may be carried out by any method for solid-liquid separation, such as filtration (e.g., gravity filtration or vacuum filtration).

[0025] After isolation, the solid residue is optionally washed with a solvent such as acetone.

[0026] 8) Another aspect relates to a method for preparing a crystalline form, e.g., an essentially pure crystalline form, of Compound adipic acid salt according to any one of embodiments 1) to 7), comprising the steps defined in embodiment 6) or 7).

[0027] 9) Another aspect relates to a pharmaceutical composition comprising a crystalline form of Compound adipic acid salt according to any one of embodiments 1) to 7), further comprising at least one pharmaceutically acceptable carrier material; in particular, such carrier material is selected from the group comprising alpha-lactose monohydrate, beta-lactose, mannitol, starch, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, sodium starch glycolate, croscarmellose sodium, magnesium stearate, compritol, aerosil, talc, sodium dodecyl sulfate, ascorbic acid, sodium bicarbonate, calcium hydrogen phosphate, or mixtures thereof.

[0028] Pharmaceutical compositions can be produced in a manner well known to any person skilled in the art (see, for example, Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]) by combining the crystalline form of the present invention, optionally with other therapeutically valuable substances, with suitable non-toxic, inert, pharmaceutically acceptable solid or liquid carrier materials and, if necessary, conventional pharmaceutical adjuvants to form a pharmaceutical dosage form.

[0029] The crystalline forms of the present invention may be used as medicaments, for example in the form of pharmaceutical compositions for enteral or parenteral administration, especially oral administration in the form of solid pharmaceutical compositions such as capsules or tablets.

[0030] The crystalline forms of the present invention may be used as the sole crystalline form or as a mixture with other crystalline forms and / or amorphous Compound adipate.

[0031] 10) Another aspect relates to a crystalline form of the Compound adipic acid salt according to any one of embodiments 1) to 7) for use as a pharmaceutical.

[0032] 11) In one embodiment, chemokine receptor 6 (CCR6) is ameliorated (at least in part) The present invention relates to a crystalline form according to any one of aspects 1) to 7) for use in the prevention or treatment of a disease or disorder.

[0033] 12) Another embodiment relates to a crystalline form according to any one of embodiments 1) to 7) for use in the prevention or treatment of cancer or inflammatory / autoimmune diseases or disorders.

[0034] For the avoidance of any doubt, where a crystalline form of the present invention is described as being useful for the prevention or treatment of a disease or disorder, such crystalline form is likewise suitable for use in the manufacture of a medicament for the prevention or treatment of that disease or disorder.

[0035] 13) Another aspect relates to a method for preventing or treating cancer; or an inflammatory / autoimmune disease or disorder, comprising administering to a subject in need of such prevention or treatment an effective amount of a crystalline form according to any one of aspects 1) to 7).

[0036] The term "inflammatory / autoimmune disease or disorder" as used herein means a disease or disorder selected from the group consisting of: rheumatoid arthritis; ankylosing spondylitis; spondyloarthritis; psoriasis; psoriatic arthritis; inflammatory skin disorders such as rosacea and hidradenitis suppurativa; Crohn's disease; ulcerative colitis; inflammatory bowel disease; irritable bowel syndrome; dry eye disease; multiple sclerosis; systemic lupus erythematosus; Sjogren's syndrome; autoimmune hepatitis; primary sclerosing cholangitis (primary sclerosing cirrhosis) primary biliary cholangitis (primary biliary cirrhosis); posterior uveitis; allergic conjunctivitis; allergic diseases of the gastrointestinal tract; endometriosis; ocular surface diseases in which elevated IL-17A levels have been documented, such as meibomian gland dysfunction; graft-versus-host disease (GvHD); autoimmune keratitis; filamentous keratitis; dry eye syndrome associated with rheumatoid arthritis; dry eye syndrome without systemic disease; Stevens-Johnson syndrome; psoriasis vulgaris, guttate psoriasis, and inverse psoriasis Psoriasis, including pustular psoriasis and erythrodermic psoriasis; autoimmune keratitis; autoimmune bullous disease; filamentous keratitis; pityriasis rubra pilaris; autoimmune uveitis; allergic conjunctivitis; asthma; allergic diseases of the gastrointestinal tract; type 1 diabetes; meibomian gland dysfunction; juvenile arthritis; juvenile rheumatoid arthritis; systemic-onset rheumatoid arthritis; oligoarticular rheumatoid arthritis; oligoarticular juvenile rheumatoid arthritis; polyarticular rheumatoid arthritis; enteropathic arthritis; juvenile Reiter's syndrome; juvenile ankylosing spondylitis; seronegative enthesopathy and arthropathy (SEA) syndrome arthropathy (SEA) syndrome); reactive arthritis, reactive arthropathy; psoriatic arthropathy; juvenile enteropathic arthritis; polymyalgia rheumatica; enteropathic spondylitis; juvenile idiopathic arthritis; juvenile psoriatic arthritis; juvenile rheumatoid arthritis; acute pancreatitis; chronic pancreatitis; giant cell arteritis; and osteoarthritis secondary to inflammatory diseases.

[0037] The term "inflammatory / autoimmune disease or disorder" as used herein particularly refers to a disease or disorder selected from the group consisting of: rheumatoid arthritis; ankylosing spondylitis; spondyloarthritis; psoriasis; psoriatic arthritis; inflammatory skin disorders such as rosacea; Crohn's disease; ulcerative colitis; irritable bowel syndrome; inflammatory bowel disease; dry eye disease; multiple sclerosis; systemic lupus erythematosus; hidradenitis suppurativa; Sjogren's syndrome; autoimmune hepatitis; primary sclerosing cholangitis; primary biliary cholangitis; psoriasis, including plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, and erythrodermic psoriasis; autoimmune keratitis; filamentous keratitis; pityriasis rubra pilaris; autoimmune bullous diseases; autoimmune uveitis; allergic conjunctivitis; asthma; allergic diseases of the gastrointestinal tract; type 1 diabetes; endometriosis; meibomian gland dysfunction; and graft-versus-host disease.

[0038] The term "inflammatory / autoimmune disease or disorder" as used herein means, inter alia, a disease or disorder selected from the group comprising: psoriasis; psoriatic arthritis; rheumatoid arthritis; ankylosing spondylitis; spondyloarthritis; inflammatory skin disorders, such as rosacea; autoimmune bullous diseases; suppurative sweat glands. adenitis; Crohn's disease; ulcerative colitis; irritable bowel syndrome; dry eye disease; multiple sclerosis; systemic lupus erythematosus; Sjogren's syndrome; autoimmune hepatitis; and primary sclerosing cholangitis.

[0039] The term "inflammatory / autoimmune disease or disorder" as used herein particularly means a disease or disorder selected from the group consisting of: psoriasis, including plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis (preferred); psoriatic arthritis; hidradenitis suppurativa; ankylosing spondylitis; and primary sclerosing cholangitis.

[0040] The term "cancer" as used herein means a cancer selected from the group consisting of: skin cancer, e.g., melanoma (superficial spreading, nodular, lentigo maligna, and acral lentigo melanoma); advanced melanoma; metastatic melanoma; Merkel cell carcinoma; Kaposi's sarcoma; basal cell carcinoma; squamous cell carcinoma; and precancerous skin lesions such as actinic keratosis; lung cancer, including small cell lung cancer and non-small cell lung cancer (SCLC, NSCLC), such as squamous and non-squamous NSCLC; pleuropulmonary blastoma and tracheobronchial tumor; bladder cancer, including urinary bladder cancer; urothelial cell carcinoma; mesothelioma; clear cell RCC; papillary RCC; chromophobe RCC; non-clear cell RCC; unclassified RCC; metastatic renal cell carcinoma; metastatic renal clear cell carcinoma; renal parenchymal carcinoma Gastrointestinal cancers, including renal cell carcinoma (RCC), such as ovarian carcinoma; colorectal cancer; metastatic colorectal cancer; familial adenomatous polyposis (FAP); rectal cancer; colon carcinoma; colorectal adenoma; colorectal adenocarcinoma; colorectal liver metastasis; hereditary non-polyposis colorectal cancer; esophageal cancer; gastric cancer; advanced gastric cancer; gallbladder cancer; bile duct cancer; hepatocellular carcinoma; pancreatic cancer, such as pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma; pancreatic endocrine tumors; endometrial cancer; ovarian cancer; prostate cancer, including castration-resistant prostate cancer; brain metastasis, malignant glioma, glioblastoma multiforme Brain tumors, including multiforme, medulloblastoma, meningioma, and astrocytoma; peripheral neuroectodermal tumors; oligoastrocytic tumors; oligodendroglioma; ependymal tumors; anaplastic astrocytoma; pilocytic astrocytoma; craniopharyngioma; spinal cord tumors; brain stem gliomas; central nervous system atypical teratoid / rhabdomyosarcoma-like tumors; medulloblastoma; central nervous system germ cell tumors; craniopharyngioma; ependymoma; head and neck cancers, including neuroblastoma and esthesioneuroblastoma; cervical cancer Advanced cervical cancer; normal-like, basal-like, claudin-low, HER2-positive, luminal-A, luminal-B, and triple-negative breast cancer carcinoma; breast cancer, including pregnancy breast cancer and male breast cancer; oral tumors; nasopharyngeal tumors; cardiac tumors; thoracic cancer cancer); Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma; primary intraocular B-cell lymphoma; diffuse large B-cell lymphoma; primary mediastinal large B-cell lymphoma; mucosa-associated lymphoid tissue (MALT) lymphoma; gastric MALT lymphoma; cutaneous T-cell lymphoma; primary central nervous system lymphoma; Sézary syndrome and Waldenstroem's macroglobulinemia; lymphomas such as acute lymphocytic leukemia; acute myeloid leukemia; chronic lymphocytic leukemia; chronic myeloid leukemia; hairy cell leukemia; chronic myeloid leukemia; adult T-cell leukemia; carcinoma; adenocarcinoma; thyroid cancer, including papillary and medullary thyroid carcinoma; choriocarcinoma; Ewing's sarcoma; bone cancer, including osteosarcoma; high-grade osteosarcoma; rhabdomyosarcoma; Ewing's sarcoma sarcoma; malignant fibrous histiocytoma of bone; chordoma; sarcoma including soft tissue sarcoma; myeloma; multiple myeloma; labial cancer; laryngeal cancer; hypopharyngeal carcinoma; tongue cancer; salivary gland cancer gland carcinoma; cervical cancer; uterine cancer; endometrium carcinoma; choriocarcinoma; testicular cancer; urinary carcinoma; bronchial carcinoma; basal cell tumor; teratoma; retinoblastoma; choroidal melanoma; seminoma; chondrosarcoma; myosarcoma; liposarcoma; fibrosarcoma; plasma cell neoplasm; hepatocellular carcinoma; advanced liver cancer; gastrointestinal stromal tumor; neuroendocrine tumor; bile duct cancer; appendix cancer; gastrointestinal carcinoid tumor; carcinoid tumor; pancreatic islet tumor; small intestine cancer; gastric cancer pheochromocytoma; pituitary tumor; penile cancer; renal pelvic and ureteral cancer; testicular cancer; urethral cancer; Wilms tumor; extracranial germ cell tumor; extragonadal germ cell tumor; cancer); laryngeal cancer; papillomatosis cancer; lip and oral cavity cancer; metastatic squamous cell carcinoma of the neck; mouth cancer; nasopharyngeal cancer; oropharyngeal cancer; neoplasm); myelodysplastic syndrome; myeloproliferative disease; midline cancer Cancers such as tract carcinoma; virus-induced tumors; and diseases involving CCR6 and / or CCL20 mediated metastasis, chemotaxis, cell adhesion, transendothelial migration, cell proliferation and / or survival.

[0041] The term "cancer" as used herein particularly refers to cancer selected from the group comprising: lymphoma, including T-cell lymphoma and primary mediastinal large B-cell lymphoma; brain cancer, including glioma and glioblastoma; breast cancer, including triple-negative breast cancer; colorectal cancer; hepatocellular carcinoma; renal cell carcinoma; lung cancer, including non-small cell lung cancer and small cell lung cancer; gastric cancer; melanoma, including Merkel cell carcinoma, cutaneous squamous cell carcinoma, and malignant melanoma; bladder cancer; head and neck cancer, including squamous cell head and neck cancer; Hodgkin's lymphoma; cervical cancer; endometrial cancer; colon cancer; gastrointestinal stromal tumor; pancreatic cancer; prostatic cancer; leukemia, including acute myeloid leukemia; ovarian cancer; esophageal cancer carcinomas); mesothelioma; neuroblastoma; sarcoma, such as high-grade osteosarcoma; astrocytoma; myeloma; urothelial carcinoma, including locally advanced and metastatic urothelial carcinoma; MSI-H or dMMR cancer; rectal cancer; laryngeal cancer; salivary gland cancer; multiple myeloma; bile duct cancer; oral squamous cell carcinoma; thyroid cancer; and esophagogastric junction cancer.

[0042] The term "cancer" as used herein refers inter alia to cancers selected from the group consisting of lymphomas (e.g., T-cell lymphoma); brain cancers (e.g., glioma or glioblastoma); breast cancer; colorectal cancer; hepatocarcinomas; renal cell carcinoma; lung cancer; and gastric cancer.

[0043] When used for the prevention or treatment of cancer, such uses include the use of the Compound, 2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol, particularly the adipic acid salt of the Compound, in crystalline form A, as a monotherapy and in combination with one or more chemotherapeutic agents and / or radiotherapy and / or targeted therapy (particularly in combination with targeted therapy; especially in combination with immune checkpoint inhibitors such as those targeting the programmed death receptor 1 (PD-1 receptor) or its ligand PD-L1 (Feig C et al., PNAS 2013)).

[0044] "Radiotherapy" (or "radiation therapy") The term "radiation oncology" or "radiation therapy" refers to the medical use of ionizing radiation in the prevention (adjuvant therapy) and / or treatment of cancer; it includes external and internal radiation therapy.

[0045] The term "targeted therapy" refers to the prevention (adjuvant therapy) and / or treatment of cancer using one or more anti-neoplastic agents, such as small molecules or antibodies, that act on specific types of cancer cells or stromal cells. Some targeted therapies block the action of certain enzymes, proteins, or other molecules involved in the growth and spread of cancer cells. Other types of targeted therapies help the immune system kill cancer cells (immunotherapy); or deliver toxic substances directly to cancer cells, killing them. An example of a targeted therapy particularly suitable for combination with The Compound, 2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol, particularly the crystalline form A of The Compound adipic acid salt, is immunotherapy, particularly immunotherapy targeting the programmed cell death 1 (PD-1) receptor or its ligand PD-L1 (Feig C et al., PNAS 2013).

[0046] Immunotherapy further refers to (i) agonists of stimulatory receptors (including costimulatory) or (ii) antagonists of inhibitory signals (including costimulatory) to T cells, both of which lead to the amplification of antigen-specific T cell responses (often referred to as immune checkpoint regulators). Some of the stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or costimulatory receptors is the B7 family, which includes B7-1, B7-2, B7-HI (PD-LI), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members: CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-IBBL, CD137 (4-IBB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTpR, LIGHT, DcR3, HVEM, VEGi / TLIA, TRAMP / DR3, EDAR, EDAI, XEDAR, EDA2, TNFRI, lymphotoxin a / TNFp, TNFR2, TNFa, LTPR, lymphotoxin a These include 1p2, FAS, FASL, RELT, DR6, TROY, and NGFR.

[0047] When used in combination with the Compound, 2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol, particularly the Compound adipic acid salt in crystalline form A, the term "targeted therapy" refers in particular to agents such as:

[0048] a) Epidermal growth factor receptor (EGFR) inhibitors or blocking antibodies (e.g., Gefitinib, Erlotinib, Afatinib, Icotinib, Lapatinib, Panitumumab, Neratinib, Osimertinib, Dacomitinib, Almonertinib, Tucatinib, Zalutumumab, Nimotuzumab) , Matuzumab, Cetuximab) and trastuzumab (HERCEPTIN);

[0049] b) RAS / RAF / MEK pathway inhibitors (e.g., vemurafenib, sorafenib, dabrafenib, GDC-0879, PLX-4720, encorafenib LGX818, RG7304, trametinib (GSK1120212), cobimetinib (GDC-0973 / XL518), binimetinib (MEK162, ARRY-162), selumetinib (AZD6244), sotorasib, adagrasib, and various mutant KRAS-specific, pan RAS, SOS1, and SHP2 inhibitors (Punekar et al., Nature Rev Clin Oncology, 19(10):637–655));

[0050] c) Janus kinase (JAK) inhibitors (e.g., Ruxolitinib, Itacitinib, Momelotinib, Fedratinib);

[0051] d) Aromatase inhibitors (e.g., Exemestane, Letrozole, Anastrozole, Vorozole, Formestane, Fadrozole);

[0052] e) Signal transduction inhibitors (STIs) that induce apoptosis by selectively inhibiting one or more key steps in signal pathways in the normal function of cancer cells, in particular: (i) bcr / abl kinase inhibitors (e.g., STI571 (GLEEVEC®), dasatinib, ponatinib, imatinib, nilotinib, radotinib); (ii) inhibitors of Akt family kinases or Akt pathways (e.g., sirolimus, everolimus, temsirolimus); (iii) cell cycle kinase inhibitors (e.g., palbociclib, ribociclib, abemaciclib); (iv) Phosphatidylinositol kinase inhibitors (e.g., Copanlisib, Duvelisib, Idelalisib, Leniolisib, Alpelisib, Umbralisib); (v) ALK inhibitors (e.g., Crizotinib, Ceritinib, Alectinib, Lorlatinib); (vi) BTK inhibitors (e.g., Ibrutinib, Acalabrutinib, Zanubrutinib); (vii) IDH inhibitors (e.g., Enasidenib, Ivosidenib); (viii) RET inhibitors (e.g., selpercatinib); (ix) BCL-2 inhibitors (e.g., venetoclax); or (x) c-MET inhibitors (e.g., capmatinib, tepotinib);

[0053] f) Angiogenesis inhibitors, particularly VEGF signaling inhibitors (e.g., Bevacizumab (Avastin), Ramucirumab, Sorafenib, Axitinib);

[0054] g) Poly-ADP-ribose-polymerase (PARP) inhibitors (e.g., Olaparib, Niraparib, Rucaparib, Talazoparib);

[0055] h) Proteasome inhibitors (e.g., Bortezomib, Carfilzomib, Ixazomib);

[0056] i) HDAC inhibitors (e.g., Vorinostat, Romidepsin, Belinostat, Panobinostat, Tucidinostat);

[0057] j) EZH2 inhibitors (e.g., tazemetostat);

[0058] k) immune checkpoint inhibitors (e.g., pembrolizumab (lambrolizumab, MK-3475), nivolumab, pidilizumab (CT-011), AMP-514 / MEDI0680, PDR001, SHR-1210, REGN2810, BGBA317, PF-06801591, MGA-012, TSR042, JS-001, BCD100, IBI-308, BI-754091, anti-PD1 antibodies such as toripalimab; fusion proteins targeting PD-1 (e.g., AMP-224); small molecule anti-PD1 agents (e.g., WO2015 / 03 3299, compounds disclosed in WO2015 / 044900 and WO2015 / 034820); anti-PD1L antibodies (e.g., BMS-936559, Atezolizumab (MPDL3280A, RG7446), Avelumab (MSB0010718C), Durvalumab (MEDI4736)); anti-PDL2 antibodies (e.g., AMP224); anti-CTLA-4 antibodies (e.g., Ipilimumab, Tremilmumab); anti-lymphocyte activation gene 3 (LAG-3) antibodies (e.g., Relatlimab (BMS-986016), IMP701, IMP731, MK-4280, ImmuFact IMP321; anti-T cell immunoglobulin mucin-3 (TIM-3) antibodies (e.g., MBG453, TSR-022); anti-Ig and T cell immunoreceptor (TIGIT) antibodies with ITIM domains (e.g., RG6058 (anti-TIGIT, MTIG7192A)); anti-killer cell immunoglobulin-like receptor (KIR) antibodies (e.g., lirilumab (IPH2102 / BMS-986015)); galectin antagonists (e.g., galectin-1, galectin-9); anti-B and T lymphocyte attenuators attenuator) (BTLA) antibodies (e.g., JS004);

[0059] l) vaccine therapy approaches (e.g., dendritic cell vaccine therapy, DNA, RNA, peptide or protein vaccine therapy (e.g., using gp100 peptides or MAGE-A3 peptides);

[0060] m) Reintroduction of patient-derived or allogenic (non-autologous) cancer cells genetically modified to secrete immunomodulatory factors such as granulocyte-monocyte colony-stimulating factor (GMCSF), gene-transfected tumor cell vaccine (GVAX), or Fms-related tyrosine kinase 3 (Flt-3) ligand gene-transfected tumor cell vaccine (FVAX), or Toll-like receptor-enhanced GM-CSF tumor-based vaccine (TEGVAX);

[0061] n) T cell-based immunotherapy, such as chimeric antigen receptor (CAR)-modified T cells (e.g., CTL019) Adoptive immunotherapy;

[0062] o) cytokine or immunocytokine-based therapy (e.g., interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 6, interleukin 10, interleukin 15, TGF-β);

[0063] p) Toll-like receptor (TLR) agonists (e.g., resiquimod, imiquimod, glucopyranosyl lipid A, CpG oligodeoxynucleotides);

[0064] q) Thalidomide analogues (e.g., lenalidomide, pomalidomide);

[0065] r) Indoleamine-2,3-dioxygenase (IDO) and / or tryptophan-2,3-dioxygenase (TDO) inhibitors (e.g., RG6078 / NLG919 / GDC-0919; indoximod / 1MT (1-methyltryptophan), INCB024360 / epacadostat, PF-06840003 (EOS200271), F001287);

[0066] s) activators of T cell costimulatory receptors (e.g., anti-CD137 / 4-1BB antibodies (e.g., BMS-663513 / Urelumab), Utomilumab (PF-05082566) and second-generation 4-1BB agonist drugs (Claus et al., MABS 2023, VOL.15(1), 2167189); anti-OX40 / CD134 (tumor necrosis factor receptor superfamily, member 4) antibodies (including agonist antibodies) and fusion proteins (e.g., RG7888 (MOXR0916), 9B12; MEDI6469, GSK3174998, MEDI6383, MEDI0562), anti-OX40-ligand / CD252; anti-glucocorticoid-induced TNFR family-related gene (GITR) antibodies and fusion proteins (e.g., TRX518, MEDI1873, MK-4166, BMS-986156, BMS-986153), anti-CD40 (TNF receptor superfamily member 5) antibodies (e.g., Dacetuzumab (SGN-40), HCD122, CP-870,893, RG7876, ADC-1013, APX005M, SEA-CD40); anti-CD40-ligand antibodies (e.g., BG9588); anti-CD27 antibodies (e.g., Varlilumab); anti-CD28 antibodies; anti-ICOS antibodies);

[0067] t) Molecules that bind to tumor-specific antigens and T-cell surface markers (e.g., bispecific antibodies (e.g., RG7802 targeting CEA and CD3) or antibody fragments; antibody mimetic proteins (e.g., designed ankyrin repeat proteins); bispecific T cell engagers (BITEs, e.g., blinatumomab, amivantanab, and tebentafusp, are in clinical development (Wei et al., Frontiers in Immunology, 2022, 13:1035276));

[0068] u) Antibodies or low molecular weight inhibitors targeting colony-stimulating factor-1 receptor (CSF-1R) (e.g., Emactuzumab (RG7155), Cabiralizumab (FPA-008), PLX3397);

[0069] v) Agents that target immune cell checkpoints on natural killer cells (e.g., antibodies against killer cell immunoglobulin-like receptors (KIRs) (e.g., Lirilumab) (IPH2102 / BMS-986015));

[0070] w) Drugs that target adenosine receptors or the ectonucleotidases CD39 and CD73 that convert ATP to adenosine (e.g., MEDI9447 (anti-CD73 antibody), PBF-509, CPI-444 (adenosine A2a receptor antagonist);

[0071] x) antagonists of chemokine receptors such as CCR2 or CCR4;

[0072] y) agents that deplete or inhibit regulatory T cells (e.g., by anti-CD25 monoclonal antibodies (e.g., Daclizumab) or ex vivo anti-CD25 bead depletion) or that reverse or prevent T cell anergy or exhaustion;

[0073] z) Antibodies or biologic-based disease-modifying antirheumatic drugs (DMARDS) useful in the treatment of autoimmune diseases (e.g., antibodies (including engineered antibodies); CD20 (e.g., Rituximab), CD3 (e.g., Teplizumab), TNF-alpha (e.g., Etanercept), IFN-alpha (e.g., Anifrolumab), CD80 or CD86 (e.g., Abatacept), VLA-4 (e.g., Natalizumab), IL-1 (e.g., Anakinra), Biologics targeting IL-6 (e.g., sarilumab), IL-17 (e.g., secukinumab), IL-23 (e.g., guselkumab), or IL12 / 23 (e.g., ustekinumab); small molecule DMARDS (e.g., methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, or Janus kinase (JAK) inhibitors);

[0074] bb) glucocorticoids;

[0075] cc) Antibody-drug conjugates (e.g., mirvetuximab soravtansine, tisotumab vedotin) vedotin-tftv, loncastuximab tesirine-lpyl, belantamab mafodotin-blmf, sacituzumab govitecan, trastuzumab deruxtecan, enfortumab vedotin, polatuzumab vedotin-piiq, moxetumomab pasudotox, inotuzumab ozogamicin, trastuzumab emtansine, brentuximab vedotin vedotin or gemtuzumab ozogamicin);

[0076] dd) Radioligand therapies (e.g., 177Lu-Lutathera or 177Lu-PSMA-617).

[0077] The term "chemotherapy" refers to the use of one or more cytotoxic anti-neoplastic agents ("cytotoxic chemotherapy"). Chemotherapy refers to the treatment of cancer with chemotherapy (or other chemotherapy agents). Chemotherapy is often combined with other cancer treatments, such as radiation therapy or surgery. The term specifically refers to traditional chemotherapy agents that work by killing rapidly dividing cells, which is one of the main characteristics of most cancer cells. Chemotherapy can use one drug at a time (single-agent chemotherapy) or several drugs at a time (combination or polychemotherapy). Chemotherapy that uses drugs that are converted to cytotoxic activity only by exposure to light is called photochemotherapy or photodynamic therapy.

[0078] As used herein, the term "cytotoxic chemotherapeutic agent" or "chemotherapeutic agent" refers to an active anti-neoplastic agent that causes apoptosis or cell necrosis. When used in combination with the Compound, 2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol, particularly the Compound adipic acid salt in crystalline form A, this term refers specifically to conventional cytotoxic chemotherapeutic agents, such as:

[0079] a) alkylating agents (e.g., mechlorethamine, chlorambucil, cyclophosphamide, ifosfamido, streptozocin, carmustine, lomustine, melphalan, busulfan, dacarbazine, temozolomide, thiotepa or altretamine); especially temozolomide;

[0080] b) platinum agents (e.g., cisplatin, carboplatin, or oxaliplatin);

[0081] c) antimetabolites (e.g., 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, or pemetrexed);

[0082] d) antitumor antibiotics (e.g., daunorubicin, doxorubicin, epirubicin, idarubicin, actinomycin-D, bleomycin, mitomycin-C, or mitoxantrone);

[0083] e) a mitotic inhibitor (e.g., paclitaxel, docetaxel, ixabepilone, vinblastine, vincristine, vinorelbine, vindesine, or estramustine); or

[0084] f) Topoisomerase inhibitors (e.g., etoposide, teniposide, topotecan, irinotecan, diflomotecan or elomotecan).

[0085] "Compound", 2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl) When used in combination with Compound adipic acid salt, particularly crystalline form A, the preferred cytotoxic chemotherapeutic agents are the alkylating agents mentioned above (particularly mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, streptozocin, carmustine, lomustine, melphalan, busulfan, dacarbazine, 3-methyl-( triazene-1-yl)imidazole-4-carboxamide (MTIC) and its prodrugs (e.g., particularly temozolomide), thiotepa, altretamine; or pharmaceutically acceptable salts of these compounds; particularly temozolomide); and mitotic inhibitors (especially paclitaxel, docetaxel, ixabepilone, vinblastine, vincristine, vinorelbine, vindesine, estramustine; or pharmaceutically acceptable salts of these compounds; particularly paclitaxel). The most preferred cytotoxic chemotherapeutic agents to be used in combination with the Compound, 2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol, particularly crystalline form A of the Compound adipic acid salt, are those routinely used to treat glioblastoma multiforme, particularly temozolomide. Equally preferred is radiation therapy.

[0086] Chemotherapy may be administered with curative intent or with the aim of prolonging life or ameliorating symptoms.

[0087] a) Combined modality chemotherapy is the use of drugs in conjunction with other cancer treatments such as radiation therapy or surgery.

[0088] b) Induction chemotherapy is the first-line treatment of cancer with chemotherapy drugs. This type of chemotherapy is used for curative purposes.

[0089] c) Consolidation chemotherapy is administered after remission with the goal of prolonging overall disease-free interval and improving overall survival. The drugs administered are the same as those that produced remission.

[0090] d) Intensification chemotherapy is the same as consolidation chemotherapy, but different drugs are used than induction chemotherapy.

[0091] e) Combination chemotherapy involves treating patients with many different drugs at the same time. These drugs have different mechanisms and side effects. The biggest advantage is that it minimizes the chance of developing resistance to any one drug. Also, lower doses of drugs are often used, reducing toxicity.

[0092] f) Neoadjuvant chemotherapy is administered prior to local treatment such as surgery with the aim of shrinking the primary tumor. It is also administered for cancers at high risk of micrometastatic disease.

[0093] g) Adjuvant chemotherapy is given after local treatment (radiation or surgery). It can be used when there is little evidence of cancer, but there is a risk of recurrence. It is also useful for killing any cancerous cells that have spread to other parts of the body. These micrometastases can be treated with adjuvant chemotherapy, reducing the chance of recurrence from these disseminated cells.

[0094] h) Maintenance chemotherapy is repeated to prolong remission. It is a low-dose treatment.

[0095] i) Salvage or palliative chemotherapy is not intended to cure, but is given solely to reduce tumor burden and increase life expectancy. A better toxicity profile is generally required for such treatment regimens.

[0096] When used in combination with the Compound 2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol, particularly the adipic acid salt of the Compound in crystalline form A, prophylactic or therapeutic forms of chemotherapy (or mutatis mutandis: radiotherapy) such as those described above in a), b), c), d), e) and especially g) and / or h) are preferred.

[0097] When used in combination with the Compound, 2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol, particularly crystalline form A of the Compound adipic acid salt, chemotherapy, radiotherapy, EGFR inhibitors, aromatase inhibitors, and immunotherapy are preferred. Particularly preferred are immunotherapies or other targeted therapies, such as those targeting the programmed death receptor 1 (PD-1 receptor) or its ligand PD-L1, i.e., PD1 and / or PDL1 blockade; and / or CTLA4 blockade; and / or TIGIT blockade and / or LAG3 blockade. The most preferred immunotherapy used in combination with the Compound, 2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol, particularly crystalline form A of the Compound adipic acid salt, is blockade of PD1 and / or PDL1.

[0098] In some embodiments, the crystalline forms of the present invention are administered in an amount between about 1 mg and about 1000 mg per day, e.g., between about 5 mg and about 500 mg per day, between about 25 mg and about 400 mg per day, or between about 50 mg and about 200 mg per day.

[0099] As used herein, the term "prevention" means prophylaxis.

[0100] The present application provides deuterated forms of the Compounds, their pharmaceutically acceptable salts, and their uses in the treatment or prevention of various diseases or disorders ameliorated by modulation of chemokine receptor 6 (CCR6).

[0101] 14) Another aspect of the present invention is a deuterated form of the "compound" which is also a compound of formula (II):

[0102] [ka]

[0103] or a pharmaceutically acceptable salt thereof: (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 and R 32 are each independently selected from hydrogen and deuterium; At least one R 1 , R 2 , R 3, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 and R 32 represents deuterium.

[0104] With respect to compounds of formula (II), when a particular atomic position is described as representing deuterium or "D" or "d", it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%. Positions designated as having deuterium typically have a minimum isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium position, in certain embodiments.

[0105] The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the subject compound and exhibits minimal undesired toxicological effects. Such salts include inorganic or organic acid and / or base addition salts, depending on the presence of basic and / or acidic groups in the subject compound. References include, for example, "Handbook of Pharmaceutical Salts. Properties, Selection and Use.", P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008; and "Pharmaceutical Salts 's and Co-crystals', Johan Wouters and Luc See Quere (Eds.), RSC Publishing, 2012.

[0106] The metabolism of the Compound may be achieved by the use of a 14C-labeled analog of the Compound: (R)-2-(3-(5-((1,3-dimethyl-azetidin-3-yl)(hydroxy)(4-isopropylphenyl)methyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl-3- 14 C) Using propan-2-ol, the metabolites were investigated in liver microsomes and hepatocytes from humans and a set of animal species (mouse, rat, dog, rabbit, and cynomolgus monkey). As a result, several metabolites of the Compound were observed, and their chemical structures were proposed. It was revealed that certain positions of the Compound molecule are important for metabolism. In particular, such positions are the isopropyl substituent on the phenyl ring, and in particular the two methyl substituents on the azetidinyl ring and the 2-hydroxy-propan-2-yl substituent on the oxadiazoyl ring. Therefore, substitution of one or more metabolically important positions of the Compound with one or more deuterium atoms will likely result in at least one therapeutic advantage resulting from increased metabolic stability, such as increased in vivo half-life or reduced dose requirements, or an improved safety profile. Therefore, deuterated analogs of the Compounds described in Aspects 15) to 19) are particularly preferred.

[0107] 15) In one embodiment, R 1 , R 2 and R 3 At least one, especially all, of the R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 and R 32 represents hydrogen;

[0108] 16) Another aspect is R 8 , R 9 and R 10 At least one, especially all, of the R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R26 , R 27 , R 28 , R 29 , R 30 , R 31 and R 32 represents hydrogen;

[0109] 17) Another aspect is R 25 , R 26 , R 27 , R 28 , R 29 and R 30 At least one, especially all, of the R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 31 and R 32 represents hydrogen;

[0110] 18) Another aspect is R 18 , R 19 , R 20 , R 21 , R 22 , R 23 and R 24 At least one, especially all, of the R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 and R 32 represents hydrogen;

[0111] 19) Another aspect is (R)-2-(3-(5-(hydroxy(4-isopropylphenyl)(3-methyl-1-(methyl-d)azetidin-3-yl)methyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)propan-2-ol; (R)-2-(3-(5-(hydroxy(4-isopropylphenyl)(3-methyl-1-(methyl-d2)azetidin-3-yl)methyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)propan-2-ol; (R)-2-(3-(5-hydroxy(4-isopropylphenyl)(3-methyl-1 -(methyl-d3)azetidin-3-yl)methyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)propan-2-ol; (R)-2-(3-(5-(hydroxy(4-isopropylphenyl)(1-methyl-3-(methyl-d)azetidin-3-yl)methyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)propan-2-ol; (R)-2-(3-(5-(hydroxy(4-isopropylphenyl)(1-methyl-3-(methyl-d2)azetidin-3-yl)methyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)propan-2-ol; (R)-2-(3-(5-(hydroxy(4-isopropylphenyl)(1-methyl-3-(methyl-d3)azetidin-3-yl)methyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)propan-2-ol; 2-(3-(5-((R)-(1,3-dimethylazetidin-3-yl)(hydroxy)(4-isopropylphenyl)methyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)propan-1-d-2-ol; 2-(3-(5-((R)-(1,3-dimethylazetidin-3-yl)(hydroxy)(4-isopropylphenyl)methyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)propan-1,1-d2-2-ol; 2-(3-(5-((R)-(1,3-dimethylazetidin-3-yl)(hydroxy)(4-isopropylphenyl)methyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)propan-1,1,1-d3-2-ol; 2-(3-(5-((R)-(1,3-dimethylazetidin-3-yl)(hydroxy)(4-isopropylphenyl)methyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)propan-1,1,1,3-d4-2-ol; 2-(3-(5-((R)-(1,3-dimethylazetidin-3-yl)(hydroxy)(4-isopropylphenyl)methyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)propan-1,1,1,3,3-d5-2-ol; (R)-2-(3-(5-((1,3-dimethylazetidin-3-yl)(hydroxy)(4-isopropylphenyl)methyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)propan-1,1,1,3,3,3-d6-2-ol; 2-(3-(5-((1R)-(1,3-dimethylazetidin-3-yl)(hydroxy)(4-(propan-2-yl-1-d)phenyl)methyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)propan-2-ol; 2-(3-(5-((1R)-(1,3-dimethylazetidin-3-yl)(hydroxy)(4-(propan-2-yl-1,1-d2)phenyl)methyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)propan-2-ol; 2-(3-(5-((1R)-(1,3-dimethylazetidin-3-yl)(hydroxy)(4-(propan-2-yl-1,1,1-d3)phenyl)methyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)propan-2-ol; 2-(3-(5-((1R)-(1,3-dimethylazetidin-3-yl)(hydroxy)(4-(propan-2-yl-1,1,1,3-d4)phenyl)methyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)propan-2-ol; 2-(3-(5-((1R)-(1,3-dimethylazetidin-3-yl)(hydroxy)(4-(propan-2-yl-1,1,1,3,3-d5)phenyl)methyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)propan-2-ol; 2-(3-(5-((1R)-(1,3-dimethylazetidin-3-yl)(hydroxy)(4-(propan-2-yl-1,1,1,3,3,3-d6)phenyl)methyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)propan-2-ol; or 2-(3-(5-((1R)-(1,3-dimethylazetidin-3-yl)(hydroxy)(4-(propan-2-yl-d7)phenyl)methyl)pyridin-3-yl)-1, 2,4-Oxadiazol-5-yl)propan-2-ol; or a pharmaceutically acceptable salt thereof, according to embodiment 14).

[0112] The present disclosure discloses synthetic methods for incorporating deuterium into "compounds." Synthetic methods for incorporating radioisotopes into organic compounds are well known (Alan F. Thomas et al., Deuterium Labeling in Organic Chemistry, 1971; Jens Atzrodt et al., The Renaissance of H / D Exchange, Angew. Chem. Int. Ed. 2007, 7744-7765; James R. et al., The Organic Chemistry of Isotopic Labelling, 2011), and those skilled in the art will readily recognize methods applicable to "compounds." In particular, deuterated compounds of formula (II) may be prepared similarly to the methods described in WO2021219849, except for using appropriate isotopic versions of the appropriate reagents or starting materials. In particular, compounds of formula (II) may be prepared according to Scheme 1:

[0113] [ka]

[0114] In the above scheme, substitution of the azetidine nitrogen of intermediate 1 (described in WO2021219849) can give rise to two possible deuterated forms (2 or 3): To this end, the CD3 group can be introduced by reductive amination using paraformaldehyde-d2 in the presence of NaBHD4 in 2,2,2-trifluoroethanol-d3 according to the conditions described in [M. Tajbakhsh et al., Synthesis, 2011, 3, 490]. Alternatively, the CDH2 group can be similarly introduced by reductive amination of 1 using non-deuterated formaldehyde solution and NaBHD4, as described in the examples of this application.

[0115] As previously reported in the patent literature (WO2006073361 or WO2021102314) using CH3I, alkylation of methyl 1-Boc-azetidine-3-carboxylate (4) with CD3I can lead to intermediate 5, which can be converted to final compound 6 using the procedure described in WO2021219849. PyBOP-mediated oxadiazole formation of intermediate 7 with xy-2-methyl-d3-propanoic-3,3,3-d3 acid (8) (described in WO2021219849) leads to intermediate 9, which undergoes Boc cleavage and reductive amination to give the hexadeuterated compound 10. Acid 8 is obtained in two steps from acetone-d6 as described in published procedures [D. Passarella et al., J. Labelled Cpd. Radiopharm. 1999, 42, 275 and US4286105].

[0116] Preparation of deuterated analogs of Compound: (R)-2-(3-(5-(hydroxy(4-isopropylphenyl)(3-methyl-1-(methyl-d)azetidin-3-yl)methyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)propan-2-ol To a solution of secondary amine 1 (Scheme 1 above) (20 mg, 0.04 mmol, 1 eq) as the HCl salt described in WO2021219849 in trifluoroethanol (200 μL, 0.2 M) was added EtN (40 μL, 0.285 mmol, 7.1 eq) and a 37% solution of formaldehyde in HO (12 μL, 0.161 mmol, 4 eq) sequentially at RT. The mixture was stirred at RT for 2 min, and NaBD (4 mg, 0.086 mmol, 2.1 eq) was added at RT. The reaction mixture was stirred at RT for 2 h to complete the reaction, diluted with CHCl, and quenched with saturated NaHCO solution. The aqueous phase was extracted twice with CHCl, and the combined organic phases were dried over MgSO and concentrated in vacuo. The crude material was purified by prep LC-MS (basic conditions) to give (R)-2-(3-(5-(hydroxy(4-isopropylphenyl)(3-methyl-1-(methyl-d)azetidin-3-yl)methyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)propan-2-ol as a white foam (12 mg, 69% yield). LC-MS(I):t R =0.70min; [M+H + ]:438.16. 1 H NMR (400MHz, d6-DMSO) δ:9.05(s, 1H), 8.50(s, 1H), 8.24(s, 1H), 7.23(d, 2H), 7.11(d, J=7.9Hz, 2H), 6.13(s, 2H), 3.41-3.49(m, 2H), 3.0 2(dd, J1=72.5Hz, J2=6.4Hz, 2H), 2.85-2.90(m, 1H), 2.10(s, 2H), 1.61(s, 6H), 1.38(s, 3H), 1.20(d, J=6.9Hz, 6H).

[0117] (R)-2-(3-(5-((1,3-dimethylazetidin-3-yl)(hydroxy)(4-isopropylphenyl)methyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)propan-1,1,1,3,3,3-d6-2-ol Tert-butyl (R)-3-(hydroxy(5-(5-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)(4-isopropylphenyl)methyl)-3-methylazetidine-1-carboxylate (intermediate 9) was prepared as follows: intermediate 7 (1267 mg, 2.79 mmol) as described in WO2021219849 To a suspension of 8 (614 mg, 5.57 mmol, 2 eq), 2-hydroxy-2-methyl-d-propane-3,3,3-d acid 8 (614 mg, 5.57 mmol, 2 eq), DIPEA (1.43 mL, 8.36 mmol, 3 eq), and KPO (2415 mg, 11.1 mmol, 4 eq) in DMF (10 mL) was added PyBOP (3191 mg, 6.13 mmol, 2.2 eq), and the mixture was stirred at 90 °C for 3 h. Additional 8 (130 mg, 1.11 mmol, 0.4 eq) and PyBOP (638.2 mg, 1.23 mmol, 0.44 eq) of 2-hydroxy-2-methyl-d-propane-3,3,3-d acid 8 were added, and stirring was continued at 90 °C for another 3 h. The reaction mixture was filtered to remove solid particles, and the filtrate was injected directly into a Prep LC-MS (acidic) to give 725 mg of 9 as a white solid. LC-MS (I): R =1.04 min, [M+H + ]:529.21.

[0118] To a solution of intermediate 9 (725 mg, 1.37 mmol, 1 eq) in dioxane (5 mL), 4 M HCl in dioxane (3.5 mL, 14 mmol, 10.2 eq) was added dropwise and the reaction mixture was stirred at RT for 6 h. The solvent was evaporated under reduced pressure and the crude product was dried overnight under high vacuum (685 mg, white solid). LC-MS analysis (I): R =0.68min, [M+H + ]429.29.

[0119] To a suspension of the crude product (637 mg, 1.37 mmol, 1 eq) from the previous step in THF (5 mL) was added DIPEA (0.704 mL, 4.11 mmol, 3 eq) dropwise, followed by formaldehyde 37 wt% in HO (0.204 mL, 2.74 mmol, 2 eq) and sodium triacetoxyborohydride (581 mg, 2.6 mmol, 1.9 eq). The reaction mixture was stirred at RT for 15 min. Solid particles were filtered off and THF was evaporated under reduced pressure. Purification by prep LC-MS (acidic, then basic) gave (R)-2-(3-(5-((1,3-dimethylazetidin-3-yl)(hydroxy)(4-isopropylphenyl)methyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)propan-1,1,1,3,3,3-d6-2-ol (10) as a white solid (494 mg). LC-MS (I):t R =0.70min, [M+H + ]:443.24.

[0120] 20) Another embodiment relates to a pharmaceutical composition comprising a compound according to any one of embodiments 14) to 19) and at least one pharmaceutically acceptable carrier material; in particular a carrier material selected from embodiment 9).

[0121] The preparation of pharmaceutical compositions can be carried out in a manner well known to any person skilled in the art (see, for example, Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]) by combining the compounds of formula (II) described above or pharmaceutically acceptable salts thereof, optionally with other therapeutically valuable substances, with suitable non-toxic, inert, pharmaceutically compatible solid or liquid carrier materials and, if necessary, conventional pharmaceutical adjuvants, to form a pharmaceutical dosage form.

[0122] The compounds of formula (II) are useful as pharmaceuticals; particularly in the treatment of cancer; and inflammatory / autoimmune diseases or disorders, such as those disclosed for the Compound and / or crystalline forms of the Compound adipic acid salt herein.

[0123] For the avoidance of any doubt, where a compound of formula (II) or a pharmaceutically acceptable salt thereof is described as being useful for the prevention or treatment of a disease or disorder, such compound of formula (II) or a pharmaceutically acceptable salt thereof is likewise suitable for use in the manufacture of a medicament for the prevention or treatment of that disease.

[0124] For the avoidance of any doubt, where a compound of formula (II) or a pharmaceutically acceptable salt thereof is described as being useful for the prevention or treatment of a disease, such compound of formula (II) or a pharmaceutically acceptable salt thereof is likewise suitable for use in a method of prevention or treatment of a disease or disorder, which method comprises administering an effective amount of the deuterated form of the Compound or a pharmaceutically acceptable salt thereof to a subject in need of such prevention or treatment.

[0125] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered at a dose of between about 1 mg and about 1000 mg per day, e.g., between about 5 mg and about 500 mg per day, between about 25 mg and about 400 mg per day, or between about 50 mg and about 20 mg per day. It is administered in amounts between 0 mg.

[0126] Experimental section All temperatures are given in °C.

[0127] Abbreviations (used above and below): Ac Acetyl aq. aqueous solution Boc tert.-butyloxycarbonyl DIPEA N-Ethyldiisopropylamine DMF Dimethylformamide DMSO dimethyl sulfoxide eq. equivalent amount g grams h time HV high vacuum HPLC High Performance Liquid Chromatography 1 H-NMR Proton Nuclear Magnetic Resonance LC liquid chromatography K Kelvin kV kilovolts M Molar concentration [mol / L] mA milliampere mbar millibar Me methyl mg milligram min mL milliliter mm millimeters mmol millimole NMR nuclear magnetic resonance spectroscopy MS mass spectrometry NEt3 Triethylamine org.organic Prep preparative PyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate RH Relative Humidity rt or RT room temperature rpm revolutions per minute s seconds sat. saturation tBME (or TBME) tertiary-butyl methyl ether THF tetrahydrofuran t R retention time w / w Weight per unit weight

[0128] Purification and Characterization Liquid chromatography-mass spectrometry (LC-MS) LC-MS retention times were obtained using the following elution conditions: LC-MS(I): 40 The column was a Zorbax RRHD SB-Aq, 1.8 μm, 2.1×50 mm column, thermostated at ° C. The two elution solvents were as follows: Solvent A = water + 0.04% TFA; Solvent B = MeCN. The eluent flow rate was 0.8 mL / min and the characteristics of the elution mixture proportions as a function of time t (min) from the start of elution are summarized below (a linear gradient is used between two consecutive time points):

[0129] [Table 1]

[0130] Preparative Liquid Chromatography-Mass Spectrometry (Prep LC-MS) Purification by preparative LC-MS was performed using the following conditions: an X-Bridge column (Waters C18, 30x75 mm or 50x150 mm, 10 μm) or an Agilent Zorbax (SB-Aq 30x75 mm 5 μm) column was used with a linear gradient of water / formic acid 0.5% (A) and MeCN (B) (acidic conditions) or water / 0.5% ammonium hydroxide solution (25%) (A) and MeCN (B) (basic conditions).

[0131] X-ray powder diffraction (XRPD) A Bruker D8 Advance diffractometer (Bruker AXS GmbH) equipped with a FlipStick stage, CuKα radiation (40 kV, 40 mA), and a 1D-linear LynxEye detector was used. The sample was prepared on a silicon single-crystal sample holder with a cavity 25 mm in diameter and 0.5 mm deep. It was spread with a microscope slide to obtain a flat surface. Diffractograms were collected in reflectance mode with a combined 2θ / θ angle ranging from 3 to 50° 2θ, an increment of 0.02° per step, and an accumulation time of 0.4 s. The divergence slit was set to variable slit size, and the antiscatter slit was set to 0.3°. The sample was continuously rotated at 30 rpm during the measurements.

[0132] The measurement software used was DIFFRAC Measurement Center V7.5.0 (released in 2017, Bruker AXS GmbH), and the analysis software was DIFFRAC.Suite Eva V4.2.2.3 (released in 2016, Bruker AXS GmbH).

[0133] Thermogravimetric analysis (TGA) Thermogravimetric analysis was performed using a Mettler Toledo TGA / DSC 3+ STARe system. Samples were weighed into aluminum pans with automatically drilled lids and heated from 30 to 350 °C at a scan rate of 10 °C / min in a constant flow of nitrogen. Measurements and data evaluation were performed using the software Mettler Toledo STARe. This was performed using version 16.00b.

[0134] Gravimetric Vapor Sorption (GVS) Analysis Gravimetric vapor sorption analysis was performed using an SPS 100n (ProUmid GmbH & Co. KG). An appropriate amount of sample was placed in a tared aluminum pan without any pretreatment. The analysis was performed at a temperature of 25 °C using the following humidity program: 40%-0%-95%-40% (in steps of 5%, with a maximum equilibration time of 24 h at each step). The analytical software was the ProUmid Excel template #SPS_4_3_23_E2010_drycorr.xltm. Ta.

[0135] Differential scanning calorimetry (DSC) DSC data were collected on a Mettler Toledo DSC 3+ STARe system. Samples were prepared under ambient conditions. Mettler Toledo aluminum sample pans, part numbers ME-51119870 and ME-51119873 (automatically drilled by the instrument), were used. Scans were performed from -20 to 250 °C at 10 °C / min. Measurements and data evaluation were performed using the software Mettler Toledo This was performed using STARe version 16.00b.

[0136] Example The amorphous "compound" can be produced by the method disclosed in WO2021219849.

[0137] Example 1a A suspension of 20.67 mg of amorphous Compound in 200 μL of a saturated solution of adipic acid in isopropanol was stirred at room temperature. After 3 weeks, the solid was filtered and crystalline Form A of Compound adipic acid salt was obtained as confirmed by XRPD. Proton nuclear magnetic resonance spectroscopy revealed that the solid contained equimolar amounts of Compound and adipic acid.

[0138] Example 1b 102 mg of amorphous Compound and 35 mg (1 eq.) of adipic acid are suspended in 1 mL of tBME. The mixture is stirred at room temperature for 3 weeks. The solid is filtered and dried under vacuum to obtain 95 mg of a white substance of crystalline Form A of Compound adipic acid salt.

[0139] Example 1c 500 mg of amorphous Compound and 172 mg (1 eq.) adipic acid are suspended in 5 mL of acetone. The suspension is heated. After recooling to rt, more acetone is added to obtain a stirrable suspension again. After 5 days, the solid is filtered to give 569 mg (85%) of crystalline Form A of Compound adipic acid salt.

[0140] Example 1d A 30 L double-jacketed, glass-lined steel reactor was charged with adipic acid (277 g, 1.90 mol, 1.00 eq.) and acetone (6.7 L, 7 vol.). The reactor contents were warmed to 45-50°C, and the acetone solution containing Compound (1.00 eq. Compound, 7 vol. acetone) was added to the adipic acid solution at 45-50°C over 75-90 min. After addition was complete, the resulting suspension was cooled to 5-10°C over 1 h and finally aged at this temperature for at least 1 h. The product was filtered on a 30 L Büchi funnel with N2-overpressure, washed three times with cold acetone (3 x 1.5 L) and finally dried on a rotary evaporator (900-10 mbar, 65 °C) to give crystalline form A of "Compound" adipate (856 g, 1.47 mmol, >99% w / w).

[0141] [Table 2]

[0142] Example 2 Solid pharmaceutical compositions having crystalline Form A of Compound adipic acid salt in dosage strengths of 1 mg, 10 mg, and 50 mg API per 250 mg unit are shown in Table 2.

[0143] [Table 3]

[0144] The above API, glidant, filler, disintegrant, and lubricant are sieved and blended (e.g., in a Turbula T10B™). Optionally, the API is mixed with at least a portion of the lubricant in a separate step before adding the remainder of the excipients. The powder blend is then dry granulated (e.g., in a dry compression granulator, Gerteis Mini Pactor®), and the resulting granules are further blended before final encapsulation in hard gelatin capsules (e.g., ConiSnap® capsules, size 2) or enteric-coated capsules (e.g., BB6 / S equipment). The hard gelatin capsules may be further encapsulated in enteric-coated capsules (so-called over-encapsulation) to potentially improve gastric tolerability.

[0145] Reference Example 1 A solution of 51 mg of crystalline form A of Compound adipate in 5 mL of THF was evaporated at rt to give crystalline form B of Compound adipate.

[0146] [Table 4]

[0147] Reference Example 2 Several crystallization attempts were performed using various salt formers by reacting the Compound with ascorbic acid, benzoic acid, butyric acid, citric acid, fumaric acid, glutamic acid, 1 M HCl, DL-lactic acid, oxalic acid, 1 M aqueous H3PO4, succinic acid, 0.5 M aqueous H2SO4, or L-tartaric acid. Typically, a mixture of the Compound and the corresponding acid, optionally using isopropanol as a solvent, was stirred in a sealed vial at room temperature for about three months and then analyzed. No solid salt of the Compound was observed with any of the above salt formers.

Claims

1. A crystalline form of the compound 2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol adipate, characterized by the presence of peaks at the following refraction angles 2θ in an X-ray powder diffractogram: 6.9°, 17.8°, and 19.2°.

2. The crystalline form of the compound of claim 1, 2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol adipate, is characterized by the presence of peaks at the following refraction angles 2θ in a powder X-ray diffractogram: 6.9°, 12.2°, 16.8°, 17.8°, and 19.2°.

3. 2. The compound of claim 1, a crystalline form of 2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol adipate, characterized by the presence of peaks at the following refraction angles 2θ in a powder X-ray diffractogram: 6.9°, 12.2°, 15.6°, 16.4°, 16.8°, 17.8°, 19.2°, 20.3°, 21.5°, and 22.6°.

4. 4. A crystalline form of the compound of any one of claims 1 to 3, 2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol adipate, having essentially the powder X-ray diffraction pattern depicted in FIG.

5. The crystalline form of the compound of any one of claims 1 to 4, 2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol adipate, is characterized by the presence of an endothermic peak at 163.5±5°C in a differential scanning calorimetry thermogram.

6. A method for preparing the crystalline form of the compound of any one of claims 1 to 5, 2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol adipate, comprising the following steps: a) providing a first solution / suspension of about 1 eq. adipic acid in acetone; b) providing a second solution of about 1 eq. of the compound 2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol in acetone; c) mixing said first solution / suspension with said second solution under heating; d) cooling the resulting mixture; e) optionally stirring the resulting mixture; f) isolating the solid residue by solid-liquid separation; and g) drying the solid residue.

7. The mixing of the first solution / suspension with the second solution causes the second solution to be mixed with the first solution.

7. The process according to claim 6, wherein the process is carried out by adding the compound to the liquid / suspension under heating.

8. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 5 and at least one pharmaceutically acceptable carrier material.

9. The crystalline form of any one of claims 1 to 5 for use as a pharmaceutical.

10. 6. The crystalline form of any one of claims 1 to 5 for use in the prevention or treatment of an inflammatory / autoimmune disease or disorder.

11. 6. The crystalline form of any one of claims 1 to 5 for use in the prevention or treatment of an inflammatory / autoimmune disease or disorder selected from the group consisting of hidradenitis suppurativa; ankylosing spondylitis; and primary sclerosing cholangitis.

12. 6. The crystalline form of any one of claims 1 to 5 for use in the prevention or treatment of a disease or disorder selected from the group consisting of psoriasis.

13. 6. The crystalline form of any one of claims 1 to 5 for use in the prevention or treatment of cancer, wherein said crystalline form is used as a monotherapy or in combination with one or more chemotherapeutic agents and / or radiotherapy and / or targeted therapy.

14. 6. The crystalline form of any one of claims 1 to 5 for use in the prevention or treatment of cancer, wherein said crystalline form is used as a monotherapy or in combination with one or more chemotherapeutic agents and / or radiation therapy and / or targeted therapy; wherein the cancer is selected from the group consisting of lymphoma; brain cancer; breast cancer; colorectal cancer; hepatocellular carcinoma; renal cell carcinoma; lung cancer; and gastric cancer.

15. A method for the prevention or treatment of cancer or an inflammatory / autoimmune disease or disorder, comprising administering to a subject in need of such prevention or treatment an effective amount of the crystalline form of any one of claims 1 to 5.

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