DHODH inhibitor polymorphism

Abstract

The present disclosure relates to physical forms, such as stable crystalline forms, of DHODH inhibitors and compositions comprising the same. Use of the physical forms (such as polymorphs) or compositions thereof in therapy, such as the treatment of viral or autoimmune diseases or disorders, is also provided.

Description

[Technical field]

[0001] The present disclosure relates to physical forms, such as stable crystalline forms, of DHODH inhibitors and compositions comprising the same. Use of the physical forms (such as polymorphs) or compositions in therapy, such as in the treatment of viral or autoimmune diseases or disorders, is also provided. [Background technology]

[0002] 2-(3,5-Difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid (faldodstat, formerly known as ASLAN003) is a next-generation DHODH inhibitor. Dihydroorotate dehydrogenase (DHODH) is the enzyme that catalyzes the fourth step of the pyrimidine biosynthetic pathway, i.e., the conversion of dihydroorotate to orotate with concomitant electron transfer via a flavin mononucleotide intermediate to ubiquinone (cofactor Q) (Loffler MoI Cell Biochem, 1997). In contrast to parasites (Plasmodium falciparum) and bacteria (Escherichia coli) that have only this de novo pathway as a pyrimidine source (McRobert et al MoI Biochem Parasitol 2002), mammalian cells have an additional salvage pathway. During homeostatic proliferation, the salvage pathway independent of DHODH appears to be sufficient for the cell's supply of pyrimidine bases. However, cells with high turnover require a novel pathway to proliferate. In these cells, DHODH inhibition halts cell cycle progression by suppressing DNA and RNA synthesis and ultimately cell proliferation (Breedveld FCAnn Rheum Dis 2000).

[0003] There are some indications that inhibition of mitochondrial cytochrome bc1, a component of complex III of the electron transport chain, leads to activation of p53 and subsequent induction of apoptosis.The mitochondrial respiratory chain is coupled to the de novo pyrimidine biosynthetic pathway via the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). Thus, administration of Fardoostat to cells with high metabolic load can inhibit the normal function of the cells and promote apoptosis / removal of these cells by the body's natural mechanisms. The latter is useful in virally infected cells and cancer cells. In addition, Fardoostat has activity against the underlying causes of autoimmune diseases, i.e. abnormal T cells and / or B cells, which surprisingly translates in vivo into broad spectrum activity against autoimmune diseases with minimal off-target effects, especially liver toxicity.

[0004] Compared with other existing DHDOH inhibitors, faldodstat has high affinity for DHODH, is well tolerated, and provides excellent results for patients. It has the ability to control the disease state, halt its progression, and put the disease into remission, positively impacting the patient's quality of life. Advantageously, healthy cells with a lower metabolic burden are usually not affected by the treatment. The well-balanced therapeutic profile is highly beneficial for patients.

[0005] Polymorphs are crystals of the same molecule that have different physical properties as a result of different arrangements of the molecules within the crystal lattice. Ostwarld stated in 1899 that "Nearly every substance can exist in two or more solid phases, given the right experimental conditions." Different spatial structures result in differences in physical properties that can affect various parameters: e.g., compressibility and density, manufacturability, storage, physical stability, chemical stability, thermal stability, melting point, grindability, powder rheological properties, hygroscopicity, solubility, dissolution rate, in vivo pharmacological action, etc. These properties, in turn, can affect pharmaceutical-related parameters such as ease of formulation and / or good pharmacokinetics. Therefore, it is crucial to select a suitable polymorph in drug development. In particular, it is important to identify the dominant stable pharmaceutical polymorph (DSP polymorph). For example, in ranitidine, this was form 4. The present inventors have identified a Faldodstat DSP polymorphism that has superior stability as well as good pharmacological function. Summary of the Invention

[0006] The present disclosure is summarized in the following sections: 1. A polymorph, such as a crystalline polymorph, of the DHODH inhibitor 2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid, characterized by an X-ray powder diffraction pattern including peaks at the following approximate degrees 2θ: 9.129±0.1, 17.375±0.1, 20.708±0.1, 25.274±0.1, 26.488±0.1, and 29.041±0.1. 2. The polymorph of claim 1, wherein the X-ray powder diffraction pattern further comprises one or more peaks selected from the group comprising: 13.686±0.1, 14.159±0.1, 19.900±0.1, 21.431±0.1, 22.750±0.1, 25.607±0.1 and 30.893±0.1. 3. The polymorphism of item 2, wherein the pattern comprises a peak at 13.686±0.1, e.g., of about 14% relative intensity. 4. The polymorphism according to item 2 or 3, wherein the pattern comprises a peak at 14.159±0.1, e.g., of about 16% relative intensity. 5. The polymorphism according to any one of items 2 to 4, wherein the pattern comprises a peak at 19.900±0.1, e.g., of a relative intensity of about 11.5%. 6. The polymorphism according to any one of items 2 to 5, wherein the pattern comprises a peak at 21.431±0.1, e.g., of a relative intensity of about 14%. 7. The polymorphism according to any one of items 2 to 6, wherein the pattern comprises a peak at 22.750±0.1, e.g., of a relative intensity of about 16.5%. 8. The polymorphism according to any one of items 2 to 7, wherein the pattern comprises a peak at 25.607±0.1, e.g., of about 12% relative intensity. 9. The polymorphism according to any one of items 2 to 8, wherein the pattern comprises a peak at 30.893±0.1, e.g., of about 15% relative intensity. 10. The polymorphism of any one of items 1 or 9, wherein the X-ray powder diffraction pattern further comprises one or more peaks selected from the group comprising: 12.313±0.1, 13.223±0.1, 16.477±0.1, 18.167±0.1, 22.146±0.1, 23.418±0.1, 23.828±0.1, 25.885±0.1, 27.219±0.1 and 30.612±0.1. 11. The polymorph according to item 10, wherein the X-ray powder diffraction pattern further comprises a peak at 12.313±0.1, e.g., at a relative intensity of about 10.5%. 12. The polymorph according to item 10 or 11, wherein the X-ray powder diffraction pattern further comprises a peak at 13.223±0.1, e.g., of about 7% relative intensity. 13. The polymorph according to any one of items 10 to 12, wherein the X-ray powder diffraction pattern further comprises a peak at 16.477±0.1, e.g., of a relative intensity of about 10.5%. 14. The polymorph according to any one of items 10 to 13, wherein the X-ray powder diffraction pattern further comprises a peak at 18.167±0.1, e.g., of a relative intensity of about 7.0%. 15. The polymorph according to any one of items 10 to 14, wherein the X-ray powder diffraction pattern further comprises a peak at 22.146±0.1, e.g., of about 8% relative intensity. 16. The polymorph according to any one of items 10 to 15, wherein the X-ray powder diffraction pattern further comprises a peak at 23.418±0.1, e.g., of about 10% relative intensity. 17. The polymorph according to any one of items 10 to 16, wherein the X-ray powder diffraction pattern further comprises a peak at 25.885±0.1, e.g., of a relative intensity of about 7.5%. 18. The polymorph according to any one of items 10 to 17, wherein the X-ray powder diffraction pattern further comprises a peak at 27.219±0.1, e.g., of a relative intensity of about 9.5%. 19. The polymorph according to any one of items 10 to 18, wherein the X-ray powder diffraction pattern further comprises a peak at 30.612±0.1, e.g., of a relative intensity of about 7.5%. 20. The polymorph according to any one of the preceding claims, wherein the X-ray powder diffraction pattern further comprises one or more peaks selected from the group comprising: 10.645±0.1, 27.453±0.1, 29.762±0.1, 31.743±0.1 and 39.115±0.1. 21. The polymorph according to item 20, wherein the X-ray powder diffraction pattern further comprises a peak at 10.645±0.1, e.g., of a relative intensity of about 4.5%. 22. The polymorph according to item 20 or 21, wherein the X-ray powder diffraction pattern further comprises a peak at 27.453±0.1, e.g., of a relative intensity of about 5.6%. 23. The polymorph according to any one of items 20 to 22, wherein the X-ray powder diffraction pattern further comprises a peak at 29.762±0.1, e.g., of a relative intensity of about 4.5%. 24. The polymorph according to any one of items 20 to 23, wherein the X-ray powder diffraction pattern further comprises a peak at 31.743±0.1, e.g., of about 5% relative intensity. 25. The polymorph according to any one of items 20 to 23, wherein the X-ray powder diffraction pattern further comprises a peak at 39.115±0.1, e.g., of about 6% relative intensity. 26. The polymorph according to any one of items 1 to 25, characterized by the X-ray powder diffraction pattern shown in FIG. 2. 27. The polymorph according to any one of items 1 to 26, wherein the average diameter of the particles in the polymorph is in the range of 5 to 15 microns, such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 microns. 28. The polymorph according to item 27, wherein ten percent (D10) of the particles in the polymorph are in the range of 0.5 to 5 microns in diameter, for example 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5 microns in diameter. 29. The polymorph according to item 27 or 28, wherein 50 percent of the particles in the polymorph are in the range of 1 to 10 microns in diameter, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 microns in diameter. 30. The polymorph according to any one of items 27 to 29, wherein 90 percent of the particles in the polymorph are in the range of 5 to 50 microns in diameter, for example 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 microns in diameter. 31. The polymorph according to any one of items 1 to 26, wherein the average diameter of the particles in the polymorph is 147 to 157 microns, such as 147, 148, 149, 150, 151, 152, 153, 154, 155, 156 or 157 microns. 32. The polymorph according to item 31, wherein 10 percent of the particles in the polymorph are in the range of 20 to 40 microns in diameter, e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 microns in diameter, e.g., 32 microns in diameter. 33. The polymorph according to item 31 or 32, wherein 50 percent of the particles in the polymorph are in the range of 150 to 170 microns in diameter, e.g., 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169 or 170 microns in diameter, e.g., 161 microns in diameter. 34. The polymorph according to any one of items 31 to 33, wherein 90 percent of the particles in the polymorph are in the range of 230 to 245 microns in diameter, e.g., 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242 microns in diameter, e.g., 238 microns in diameter. 35. A composition comprising a polymorph according to any one of items 1 to 34 and a pharma- ceutically acceptable excipient, diluent or carrier. 36. A polymorphism according to any one of items 1 to 34 or a composition according to item 35 for use in the treatment of cancer, such as, for example, a blood cancer. 37. The polymorphism or composition for use according to item 36, wherein the treatment is for a viral disease or an autoimmune disease. 38. The polymorphism or composition for use according to item 37, wherein the virus is selected from the group comprising dengue (e.g. serotype 1, 2, 3 or 4), Zika, chikungunya and SARS-CoV-2. 39. The polymorphism or composition for use according to item 37, wherein the autoimmune disease is selected from the group comprising multiple sclerosis, rheumatoid arthritis and inflammatory bowel disease (such as ulcerative colitis and Crohn's disease). 40. The polymorphism or composition for use according to item 37, wherein the autoimmune disease is an autoimmune skin disease selected from the group comprising, for example, vitiligo, alopecia, atopic dermatitis, Behcet's disease, dermatitis herpetiformis, dermatomyositis, lichen planus, linear IgA disease, cutaneous lupus, morphea / scleroderma, ocular cicatricial pemphigoid, pemphigoid such as bullous pemphigoid or gestational pemphigoid, pemphigus (pemphigus vulgaris, pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, IgA pemphigus, pemphigus vegetans, or paraneoplastic pemphigus), vasculitis, epidermolysis bullosa acquisita, psoriasis, and vesicular bullous dermatoses. 41. The polymorphism or composition for use according to item 40, wherein the autoimmune skin disease is selected from the group comprising vitiligo, such as vitiligo divided or non-divided, and alopecia, such as alopecia universalis, alopecia areata, alopecia areata, alopecia areata, alopecia totalis or alopecia universalis. 42. Use of a polymorphism according to any one of items 1 to 34 or a composition according to item 35 in the manufacture of a medicament for the treatment of a viral infection or an autoimmune disease. 43. The use according to item 42, wherein the virus is selected from the group including dengue (e.g. serotype 1, 2, 3 or 4), Zika, chikungunya and SARS-CoV-2. 44. The use according to item 42, wherein the autoimmune disease is selected from the group comprising multiple sclerosis, rheumatoid arthritis and inflammatory bowel disease (such as ulcerative colitis and Crohn's disease). 45. The use according to item 42, wherein the autoimmune disease is an autoimmune skin disease selected from the group comprising, for example, vitiligo, alopecia, atopic dermatitis, Behcet's disease, dermatitis herpetiformis, dermatomyositis, lichen planus, linear IgA disease, cutaneous lupus, morphea / scleroderma, ocular cicatricial pemphigoid, pemphigoid such as bullous pemphigoid or gestational pemphigoid, pemphigus (pemphigus vulgaris, pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, IgA pemphigus, pemphigus vegetans, or paraneoplastic pemphigus), vasculitis, epidermolysis bullosa acquisita, psoriasis, and vesicular bullous dermatoses. 46. ​​The use according to item 45, wherein the autoimmune skin disease is selected from the group comprising vitiligo, such as vitiligo segmented or non-segmented, and alopecia, such as alopecia universalis, alopecia areata, alopecia areata, alopecia areata, alopecia totalis or alopecia universalis. 47. A method for treating a viral infection or an autoimmune disease comprising administering to a subject in need thereof a therapeutically effective amount of a polymorphism according to any one of items 1 to 34 or a composition according to item 35. 48. The method according to item 47, wherein the virus is selected from the group including dengue (e.g., serotype 1, 2, 3 or 4), Zika, chikungunya and SARS-CoV-2. 49. The method according to item 47, wherein the autoimmune disease is selected from the group comprising multiple sclerosis, rheumatoid arthritis and inflammatory bowel disease (such as ulcerative colitis and Crohn's disease). 50. The method according to item 47, wherein the autoimmune disease is an autoimmune skin disease selected from the group comprising, for example, vitiligo, alopecia, atopic dermatitis, Behcet's disease, dermatitis herpetiformis, dermatomyositis, lichen planus, linear IgA disease, cutaneous lupus, morphea / scleroderma, ocular cicatricial pemphigoid, pemphigoid such as bullous pemphigoid or gestational pemphigoid, pemphigus (pemphigus vulgaris, pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, IgA pemphigus, pemphigus vegetans, or paraneoplastic pemphigus), vasculitis, epidermolysis bullosa acquisita, psoriasis, and vesicular bullous dermatoses. 51. The method according to item 50, wherein the autoimmune skin disease is selected from the group comprising vitiligo, such as vitiligo segmented or non-segmented, and alopecia, such as alopecia universalis, alopecia areata, alopecia areata, alopecia areata, alopecia totalis or alopecia universalis.

[0007] In one embodiment, the relative intensity of peak 17.375 is about 100%. In one embodiment, the relative intensity of peak 9.129 is about 66%. In one embodiment, the relative intensity of peak 20.708 is about 76%. In one embodiment, the relative intensity of peak 26.488 is about 43%. In one embodiment, the relative intensity of peak 29.041 is about 29%. Thus, in one aspect, there is provided a stable crystalline polymorph of the DHODH inhibitor 2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid, characterized by an X-ray powder diffraction pattern comprising peaks at approximately the following degrees 2θ: 9.129±0.1, 17.375±0.1, 20.708±0.1, 25.274±0.1, 26.488±0.1, and 29.041±0.1. Advantageously, the inventors have established that the crystalline polymorph of 2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid (Faldodstat), characterized by the X-ray powder diffraction pattern described above, has an extremely high degree of stability. In one embodiment, the X-ray powder diffraction pattern further comprises one or more peaks selected from the group comprising: 13.686±0.1, 14.159±0.1, 19.900±0.1, 21.431±0.1, 22.750±0.1, 25.607±0.1 and 30.893±0.1. In one embodiment, the X-ray powder diffraction pattern further comprises one or more peaks selected from the group comprising: 12.313±0.1, 13.223±0.1, 18.167±0.1, 22.146±0.1, 23.418±0.1, 23.828±0.1, 25.885±0.1, 27.219±0.1 and 30.612±0.1. In one embodiment, the X-ray powder diffraction pattern further comprises one or more peaks selected from the group comprising: 10.645±0.1, 27.453±0.1, 29.762±0.1, 31.743±0.1, and 39.115±0.1. In one embodiment, the X-ray powder diffraction pattern further comprises one or more peaks selected from the group comprising: 14.580±0.1, 28.368±0.1, 32.950±0.1, 33.445±0.1, 33.800±0.1, 34.936±0.1, 35.497±0.1, 35.981±0.1, 37.678±0.1, 38.099±0.1 and 38.520±0.1. In one embodiment, the X-ray powder diffraction pattern comprises (or further comprises) one or more peaks selected from the group comprising: 13.686±0.1, 14.159±0.1, 19.900±0.1, 21.431±0.1, 22.750±0.1, 25.607±0.1, 30.893±0.1, 12.313±0.1, 13.223±0.1, 18.167±0.1, 22.146±0.1, 23.418±0.1, 23.828±0.1, 25.885±0.1, 27.219±0.1 and 30.612±0.1. In one embodiment, the X-ray powder diffraction pattern is: 13.686±0.1, 14.159±0.1, 19.900±0.1, 21.431±0.1, 22.750±0.1, 25.607±0.1, 30.893±0.1, 12.313±0.1, 13.223±0.1, 18.167±0.1, 22.146±0.1, 2 3.418±0.1, 23.828±0.1, 25.885±0.1, 27.219±0.1, 30.612±0.1, 10.645±0.1, 27.453±0.1, 29.762±0.1, 31.743±0.1 and 39.115±0.1. In one embodiment, the X-ray powder diffraction pattern is: 13.686±0.1, 14.159±0.1, 19.900±0.1, 21.431±0.1, 22.750±0.1, 25.607±0.1, 30.893±0.1, 12.313±0.1, 13.223±0.1, 18.167±0.1, 22.146±0.1, 23.418±0.1, 23.828±0.1, 25.885±0.1, 27.219±0.1, 30.612±0.1, 10. 645±0.1, 27.453±0.1, 29.762±0.1, 31.743±0.1, 39.115±0.1, 14.580±0.1, 28.368±0.1, 32.950±0.1, 33.445±0.1, 33.800±0.1, 34.936±0.1, 35.497±0.1, 35.981±0.1, 37.678±0.1, 38.099±0.1 and 38.520±0.1. In one embodiment, the X-ray powder diffraction pattern further comprises the following peaks: 13.686±0.1, 14.159±0.1, 19.900±0.1, 21.431±0.1, 22.750±0.1, 25.607±0.1, 30.893±0.1, 12.313±0.1, 13.223±0.1, 18.167±0.1, 22.146±0.1, 23.418±0.1, 23.828±0.1, 25.885±0.1, 27.219±0.1, and 30.612±0.1. In one embodiment, the X-ray powder diffraction pattern has the following peaks: 13.686±0.1, 14.159±0.1, 19.900±0.1, 21.431±0.1, 22.750±0.1, 25.607±0.1, 30.893±0.1, 12.313±0.1, 13.223±0.1, 18.167 ... 0.1, 22.146±0.1, 23.418±0.1, 23.828±0.1, 25.885±0.1, 27.219±0.1, 30.612±0.1, 10.645±0.1, 27.453±0.1, 29.762±0.1, 31.743±0.1 and 39.115±0.1. In one embodiment, the X-ray powder diffraction pattern has the following peaks: 13.686±0.1, 14.159±0.1, 19.900±0.1, 21.431±0.1, 22.750±0.1, 25.607±0.1, 30.893±0.1, 12.313±0.1, 13.223±0.1, 18.167±0.1, 22.146±0.1, 23.418±0.1, 23.828±0.1, 25.885±0.1, 27.219 ...31.04±0.1, 32.02±0.1, 33.01±0.1, 34.01±0.1, 35.01±0.1, 36.01±0.1, 37.01±0.1, 38.01±0.1, 39.01±0.1, 40.01±0.1, 41.01±0.1, 42.01±0.1, 43.01±0.1, 44.01±0.1, 45.01±0.1, 46.01±0.1, 47.01±0.1, 48.01± 0.612±0.1, 10.645±0.1, 27.453±0.1, 29.762±0.1, 31.743±0.1, 39.115±0.1, 14.580±0.1, 28.368±0.1, 32.950±0.1, 33.445±0.1, 33.800±0.1, 34.936±0.1, 35.497±0.1, 35.981±0.1, 37.678±0.1, 38.099±0.1 and 38.520±0.1. In one embodiment, the X-ray powder diffraction pattern has the following peaks: 9.129±0.1, 10.645±0.1, 12.313±0.1, 13.223±0.1, 13.686±0.1, 14.159±0.1, 14.580±0.1, 16.477±0.1, 17.375±0.1, 18.167±0.1, 19.900±0.1, 20.708±0.1, 21.431±0.1, 22.146±0.1, 22.750±0.1, 23.418±0.1, 23.828±0.1, 25.274±0.1, 25.607±0.1, 26.707±0.1, 27.707±0.1, 28.707±0.1, 29.707±0.1, 30.707±0.1, 31.707±0.1, 32.707±0.1, 33.707±0.1, 34.707±0.1, 35.707±0.1, 36.707±0.1, 37.707±0.1, 38.707±0.1, 39.707±0.1, 40.707±0.1, 41.707±0.1, 42.707±0.1, 43.707±0.1, 44.707±0.1, 45.707±0.1, 46.707±0.1, 47.707±0.1, 48 0.1, 25.885±0.1, 26.488±0.1, 27.219±0.1, 27.453±0.1, 28.368±0.1, 29.041±0.1, 29.762±0.1, 30.612±0.1, 30.893±0.1, 31.743±0.1, 32.950±0.1, 33.445±0.1, 33.800±0.1, 34.936±0.1, 35.497±0.1, 35.981±0.1, 37.678±0.1, 38.099±0.1, 38.520±0.1 and 39.115±0.1. In one embodiment, the polymorph is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 2. In one embodiment, the polymorph is characterized by the XRPD pattern shown in Figure 26 as Pattern 1. In one embodiment, the polymorphism is characterized by an XRPD pattern that includes one or more (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, or all) of the peaks listed in Figure 3 (which shows peaks 1-39). In one embodiment, the polymorphism is characterized by an XRPD pattern that includes all of the peaks listed in Figure 3. In one embodiment, the peaks are approximately in degrees 2θ: 8.9072±0.1, 10.464±0.1, 12.132±0.1, 13.5505±0.1, 13.9897±0.1, 16.3257±0.1, 17.0936±0.1, 17.2922±0.1, 19.6989±0.1, 20.4996±0.1, 21.225±0.1, 22.0126±0.1, 22.5466±0.1, 22.7501±0.1, 25.121±0.1, 26.121±0.1, 27.121±0.1, 28.121±0.1, 29.121±0.1, 30.121±0.1, 31.121±0.1, 32.121±0.1, 33.121±0.1, 34.121±0.1, 35.121±0.1, 36.121±0.1, 37.121±0.1, 38.121±0.1, 39.121±0.1, 40.121±0.1, 41.121±0.1, 42.121±0.1, 43.121±0.1, 44.121±0.1, 45.121±0.1, 46.121±0.1, 47.121±0.1, 48.121±0.1, 49.121±0.1, 50.121±0.1, 51.12 In one embodiment, polymorphs are provided, such as crystalline polymorphs of the DHODH inhibitor 2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamino) nicotinic acid, characterized by X-ray powder diffraction patterns including one or more of: 26.3694±0.1, 27.2907±0.1, 28.7305±0.1, 29.3309±0.1, 30.7531±0.1, 31.7095±0.1, 32.9909±0.1, and 34.266±0.1. In one embodiment, the polymorphism includes one or more of the following peaks: 8.9072±0.1, 17.0936±0.1, 20.4996±0.1, 25.121±0.1, and 26.3694±0.1. In one embodiment, the polymorphism includes at least the following peaks: 8.9072±0.1, 17.0936±0.1, 20.4996±0.1, 25.121±0.1, and 26.3694±0.1. In one embodiment, the polymorphism is represented by the following peaks: 8.9072±0.1, 10.464±0.1, 12.132±0.1, 13.5505±0.1, 13.9897±0.1, 16.3257±0.1, 17.0936±0.1, 17.2922±0.1, 19.6989±0.1, 20.4996±0.1, 21.225±0.1, 22.0126±0.1, 23.0126±0.1, 24.0126±0.1, 25.0126±0.1, 26.0126±0.1, 27.0126±0.1, 28.0126±0.1, 29.0126±0.1, 30.0126±0.1, 31.0126±0.1, 32.0126±0.1, 33.0126±0.1, 34.0126±0.1, 35.0126±0.1, 36.0126±0.1, 37.0126±0.1, 38.0126±0.1, 39.0126±0.1, 40.0126±0.1, 41.0126±0.1, 42.0126±0.1, 43.0126±0.1, 44.0126±0.1, 45.0126±0.1, 46.0126±0.1, 47.0126±0.1, 48.0126±0.1, 49.0 The samples were characterized by XRPD patterns including: 0.1, 22.5466±0.1, 22.7501±0.1, 25.121±0.1, 26.3694±0.1, 27.2907±0.1, 28.7305±0.1, 29.3309±0.1, 30.7531±0.1, 31.7095±0.1, 32.9909±0.1, and 34.266±0.1. In one embodiment, the polymorphism is characterized by the XRPD pattern shown as Pattern 1 in FIG. In one embodiment, the polymorphism is characterized by an XRPD pattern that includes one or more (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or all) of the peaks listed in Figure 43 (which shows peaks 1-30). In one embodiment, the polymorphism is characterized by an XRPD pattern that includes all of the peaks listed in Figure 43. In one embodiment, the polymorphism is characterized by an XRPD pattern that includes one or more of the peaks listed in Figure 43: 1, 2, 3, 4, 5, 6, 7, 8, 12, 13, 14, 15, 16, 17, 20, 22, 23, 24, 25, 27, 28, 29, and 30. In one embodiment, the polymorphism is characterized by an XRPD pattern that includes the peaks listed in Figure 43: 1, 2, 3, 4, 5, 6, 7, 8, 12, 13, 14, 15, 16, 17, 20, 22, 23, 24, 25, 27, 28, 29, and 30. In another embodiment, the peaks are in the following approximate degrees 2θ: 9.3112±0.1, 10.2275±0.1, 11.2939±0.1, 11.9453±0.1, 14.3786±0.1, 14.7466±0.1, 16.1054±0.1, 16.561±0.1, 17.0456±0.1, 17.6267±0.1, 18.2131±0.1, 18.6757±0.1, 20.5363±0.1, 22.7337±0.1, 23.5524±0.1, 24.07±0.1, 25.04±0.1, 26.07±0.1, 27.07±0.1, 28.07±0.1, 29.07±0.1, 30.07±0.1, 31.07±0.1, 32.07±0.1, 33.07±0.1, 34.07±0.1, 35.07±0.1, 36.07±0.1, 37.07±0.1, 38.07±0.1, 39.07±0.1, 40.07±0.1, 41.07±0.1, 42.07±0.1, 43.07±0.1, 44.07±0.1, 45.07±0.1, 46.07±0.1, 47.07±0.1, 48.07±0.1, 49.07±0.1, 50.07±0.1, 51. Polymorphs, such as crystalline polymorphs of the DHODH inhibitor 2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid, are provided, characterized by X-ray powder diffraction patterns including one or more of: 4.0002±0.1, 24.4047±0.1, 24.8923±0.1, 25.2252±0.1, 25.8169±0.1, 27.3981±0.1, 28.1985±0.1, 30.8567±0.1, and 32.9406±0.1. In one embodiment, the peaks are approximately in degrees 2θ: 9.3112±0.1, 10.2275±0.1, 11.2939±0.1, 11.9453±0.1, 14.3786±0.1, 14.7466±0.1, 16.1054±0.1, 16.561±0.1, 17.0456±0.1, 17.6267±0.1, 18.2131±0.1, 18.6757±0.1, 20.5363±0.1, 22.7337±0.1, 23.5524±0.1, 24.07±0.1, 25.04±0.1, 26.07±0.1, 27.07±0.1, 28.07±0.1, 29.07±0.1, 30.07±0.1, 31.07±0.1, 32.07±0.1, 33.07±0.1, 34.07±0.1, 35.07±0.1, 36.07±0.1, 37.07±0.1, 38.07±0.1, 39.07±0.1, 40.07±0.1, 41.07±0.1, 42.07±0.1, 43.07±0.1, 44.07±0.1, 45.07±0.1, 46.07±0.1, 47.07±0.1, 48.07±0.1, 49.07±0.1, 50.07±0.1, 51.07 Polymorphs such as crystalline polymorphs of the DHODH inhibitor 2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid are provided, characterized by X-ray powder diffraction patterns including: 24.0002±0.1, 24.4047±0.1, 24.8923±0.1, 25.2252±0.1, 25.8169±0.1, 27.3981±0.1, 28.1985±0.1, 30.8567±0.1, and 32.9406±0.1. In another embodiment, there is provided a polymorph, such as a crystalline polymorph, of the DHODH inhibitor 2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid, characterized by the X-ray powder diffraction pattern shown as pattern 2 in FIG. In one embodiment, the polymorphism is characterized by an XRPD pattern that includes one or more (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or all) of the peaks listed in Figure 38. In one embodiment, the polymorphism is characterized by an XRPD pattern that includes all of the peaks listed in Figure 38. In one embodiment, the solid form of the disclosure is a solvate, for example a hydrate or hemihydrate. In one embodiment, the polymorph is a crystalline polymorph. In one embodiment, the particles are irregularly shaped. In one embodiment, the particles are regularly shaped, spherical. In one embodiment, the compound (API) is milled. Examples of milling include cone milling and hammer mill milling. In one embodiment, the compound (API) is micronized, for example to provide a uniform particle size, such as a D90 of 10 microns or less. The primary particle size is affected by temperature. In one embodiment, the primary particle size is formed at 15-65°C, e.g., 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or 65°C. In one embodiment, the primary particle size is formed at 20-60°C, e.g., 20, 25, 30, 35, 40, 45, 50, 55, or 60°C. In one embodiment, the primary particle size is formed at 20-35°C, e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35°C. The solvent also affects the primary particle size, hi one embodiment, the solvent is one described in the examples herein, or a combination thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] As used herein, a predominant stable pharmaceutical polymorph means a polymorphic form that, upon preparation, becomes a predominant form (e.g., replaces other, earlier forms) and is suitable for use as a pharmaceutical API (active ingredient of a product), particularly the polymorphs described in the Examples and Figures herein. 2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid (referred to herein as Faldodstat or ASLAN003) has the following structure: [ka]

[0009] As used herein, the term "polymorph" refers to a particular crystalline form of a chemical compound that can exist in more than one crystalline form in the solid state. A crystalline form of a compound contains constituent molecules arranged in an orderly and repeating pattern that extends to all three spatial dimensions (in contrast, amorphous solids have no long-range order of the positions of the molecules). Different polymorphs of a compound have different arrangements of atoms and / or molecules in their crystalline structures. If the compound is a biologically active compound, differences in the crystalline structure can result in different polymorphs with different chemical, physical and biological properties. Properties that may be affected include crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspendability, dissolution rate and bioavailability. Thus, a particular polymorph may have properties that make it more advantageous than another polymorph of the same compound. It is not possible to predict whether the solid state of a compound can exist as more than one polymorph, nor is it possible to predict the properties of any of these crystalline forms.

[0010] X-ray powder diffraction (XRPD) is a rapid analytical technique primarily used to identify the phases of crystalline materials and can provide information about the dimensions of the unit cell. The material being analyzed is finely ground and homogenized, and the average bulk composition is measured. An X-ray diffractometer generates X-rays in an X-ray tube and directs the X-rays at the sample. As the sample and detector are rotated, the intensity of the reflected X-rays is recorded. If the geometry of the incident X-rays striking the sample satisfies the Bragg equation, constructive interference occurs and a peak in intensity occurs. The detector records this X-ray signal, processes it, and converts the signal into a count rate, which is then output to a device such as a printer or computer monitor. The geometry of the X-ray diffractometer is such that the sample rotates through an angle θ in the path of the collimated X-ray beam while the X-ray detector is mounted on an arm that collects the diffracted X-rays and rotates through an angle of 2θ (two theta). The collected data is used to generate an X-ray powder diffraction pattern.

[0011] As used herein, the term "X-ray powder diffraction pattern" refers to a plot of intensity on the y-axis versus the detector angle 2θ (2 theta) on the x-axis. Peak positions in an X-ray powder diffraction pattern are typically reported in units of angular position (2 theta) with an allowable variation of ±0.1 for polymorphs, as specified by the United States Pharmacopeia, pages 1843-1844 (1995).

[0012] The ±0.1 variation is intended to be used when comparing two powder X-ray diffraction patterns: in effect, if a diffraction pattern peak from one pattern is assigned to a range of angular positions (2 theta) at ±0.1 of the measured peak position, and a diffraction pattern peak from the other pattern is assigned to a range of angular positions (2 theta) at ±0.1 of the measured peak position, and these peak position ranges overlap, then the two peaks are considered to have the same angular position (2 theta).

[0013] Those skilled in the art are aware that a particular polymorphism analyzed by different instruments, laboratories, different temperatures, etc. may produce spectra with a certain amount of variation. However, the spectral profiles and ratios for the same polymorphism are identifiable. Thus, shifts or drifts in the spectrum will not usually prevent one skilled in the art from positively identifying the presence of a particular polymorphism. Thus, in one embodiment, the X-ray diffusion pattern is shifted along the X-axis by less than or equal to 10%, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10%.

[0014] Drift is a measurement error caused by a gradual shift in an instrument's measurements over time. Almost all measuring devices experience drift during their lifetime, although imprecise handling can accelerate it.

[0015] In one embodiment, the Faldhodstat polymorph of the present disclosure is produced using the following manufacturing process (also shown in FIG. 1A): [ka]

[0016] formulation A DHODH inhibitor is a moiety (eg, a compound) that inhibits, eg, reduces or blocks, the activity of the DHODH enzyme (see background for definition).

[0017] In one embodiment, the DHODH inhibitor is provided in a pharmaceutical formulation. The pharmaceutical compositions of the present invention may be administered by several routes, including, but not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracerebroventricular, transdermal, transdermal (e.g., WO98 / 20734), subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, vaginal or rectal routes.

[0018] In one embodiment, the pharmaceutical formulations are for oral administration, e.g., are formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, and suspensions, for ingestion by the patient. Excipients may include lactose, dextrin, glucose, sucrose, sorbitol, starch, sugars, sugar alcohols and cellulose. Other suitable forms for administration include parenteral administration, eg, by injection or infusion, eg, by bolus injection or continuous infusion.

[0019] If the product is for injection or infusion, it may be in the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, which may contain formulatory agents such as suspending agents, preservatives, stabilizing and / or dispersing agents. Alternatively, the molecule may be in a dry form for reconstitution with an appropriate sterile liquid before use. Pharmaceutically acceptable carriers in therapeutic compositions may additionally contain liquid agents such as water, saline, glycerol, and ethanol. In addition, auxiliary substances such as wetting agents, emulsifying agents, lubricants, or pH buffering agents may be present in such compositions. A complete discussion of pharma-ceutically acceptable carriers is provided in Remington's Pharmaceutical Sciences (Mack Publishing Company, NJ 1991).

[0020] treatment As used herein, treatment means that when a patient has a disease or disorder, such as an autoimmune disease (particularly those disclosed herein), a drug according to the present disclosure is administered to stabilize the disease, delay the disease, reverse the disease, remit the disease, maintain the disease in remission, or cure the disease. As used herein, treatment includes administration of a drug according to the present disclosure for treatment or prevention. The treatment or therapy may be used prophylactically. As used herein, a therapeutically effective amount is a range that produces a desired physiological effect while minimizing side effects. As used herein, disease modifying treatment refers to treatment that allows the immune system to reset itself and regain balance, thereby functioning more normally following treatment. The DHODH inhibitor of the present disclosure or a formulation containing same may be administered at a dosage in the range of 1 mg to 400 mg / day, for example, 10 mg to 400 mg / day, 50 mg to 400 mg / day, 100 mg to 400 mg / day, 150 mg to 400 mg / day, 200 mg to 400 mg / day, 250 mg to 400 mg / day, 300 mg to 400 mg / day, or 350 mg to 400 mg / day. In particular, a dosage in the range of 100mg to 400mg per day is administered. Thus, the daily dosage can be, for example, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg or 400mg.

[0021] In one embodiment, the treatment is administered daily, for example, once or twice daily. In one embodiment, the treatment is administered once daily. In one embodiment, fardodstat is administered orally, for example as a tablet or capsule or caplet. As used herein, comorbidity means when a patient has a second or underlying health condition.

[0022] Combination therapy (including further therapy) as used herein means that two or more therapeutic regimens are used, especially when used simultaneously. The therapeutic agents may be in separate formulations or co-formulated formulations. They may be administered at the same time or at different times. However, the pharmacological effects of the therapeutic agents are present in the patient at the same time.

[0023] As used herein, additional therapy refers to a therapy in addition to a DHODH inhibitor. Such additional therapy may be an anti-inflammatory agent, including but not limited to a nonsteroidal anti-inflammatory drug (NSAID), a disease-modifying antirheumatic drug (DMARD), a statin drug (including an HMG-CoA reductase inhibitor such as simvastatin), a biological agent (biologicals), a steroid, an immunosuppressant, a salicylic acid, and / or a fungicide.

[0024] Nonsteroidal anti-inflammatory agents include antimetabolites (e.g., methotrexate) and anti-inflammatory gold agents (gold salts such as gold sodium thiomalate, gold thiomalic acid, or auranofin). Biological agents include anti-TNF agents (including adalimumab, etanercept, infliximab, anti-IL-1 agents, anti-IL-6 agents, anti-CD20 agents, anti-B cell agents (such as rituximab), anti-T cell agents (anti-CD4 antibodies), anti-IL-15 agents, anti-CLTA4 agents, anti-RAGE agents), antibodies, soluble receptors, receptor-binding proteins, cytokine-binding proteins, mutant proteins with altered or attenuated function, RNAi, polynucleotide aptamers, antisense oligonucleotides, or omega-3 fatty acids. Steroids (also known as corticosteroids) include cortisone, prednisolone, or dexamethasone, which may also be used in combination therapy.

[0025] Immunosuppressants for use in the combination therapy according to the present disclosure include cyclosporine, FK506, rapamycin, mycophenolic acid.Salicylates for use in the combination therapy include aspirin, sodium salicylate, choline salicylate, and magnesium salicylate.Antimicrobial agents include quinine and chloroquine. Anti-inflammatory agents, as used herein, refer to moieties that reduce inflammation, instead of nonsteroidal anti-inflammatory agents, steroids, and the like.

[0026] In one embodiment, the combination therapy includes an anti-CD20 agent or a biosimilar thereof, such as Rituxan (rituximab), rituximab biosimilar, Gazyva, Kesimpta, Ocrevus (ocrelizumab), Ruxience, Truxima, Zevalin, Arzerra, AcellBia, HLX01, Reditux, Ritucad, or Zytux. In one embodiment, the combination therapy includes therapeutic agents independently selected from corticosteroids (e.g., oral prednisone and intravenous methylprednisolone), plasma exchange (plasma exchange therapy), interferon beta drugs, glatiramer acetate, fingolimod, dimethyl fumarate, diroximel fumarate, teriflunomide, siponimod, cladribine, ocrelizumab, natalizumab, and alemtuzumab. In one embodiment, the combination therapy includes a therapeutic agent that relieves or reduces the symptoms of multiple sclerosis, such as a muscle relaxant (e.g., baclofen, tizanidine and cyclobenzaprine), a drug that reduces fatigue (e.g., amantadine, modafinil, methylphenidate) or a drug that increases walking speed (e.g., dalfampridine). In one embodiment, the combination therapy includes cannabis or a derivative thereof, for example cannabis oil. In one embodiment, the combination therapy includes a second DHODH inhibitor. In one embodiment, the additional therapy includes teriflunomide. In one embodiment, the additional therapy includes bidoflumidmus. In one embodiment, the combination therapy does not include a second DHODH inhibitor. In an embodiment, the combination therapy does not include teriflunomide and / or bidoflumidmus. In one embodiment, the combination therapy includes a disease modifying therapy selected from, for example, alemtuzumab, avonex, betaferon, cladribine, daclizumab, dimethyl fumarate, extavia, fingolimod, glatiramer acetate, natalizumab, ocrelizumab, plegridy, rebif, siponimod, and combinations of two or more thereof. In one embodiment, the additional therapy comprises interferon beta (IFNβ), such as interferon beta-1a or interferon beta-1b. Thus, in one embodiment, the additional therapy comprises interferon beta-1a. In an alternative embodiment, the additional therapy comprises interferon beta-1b. In one embodiment, the combination therapy includes a Bruton's tyrosine kinase (BTK) inhibitor, such as ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ABBV-105, fenebrutinib, GS-4059, spebrutinib and / or HM71224.

[0027] In one embodiment, the additional therapy includes glatiramer acetate. In one embodiment, the additional therapy includes natalizumab. In one embodiment, the additional therapy includes mitoxantrone. In one embodiment, the additional therapy includes fingolimod. In one embodiment, the additional therapy includes siponimod. In one embodiment, the additional therapy includes dimethyl fumarate. In one embodiment, the additional therapy includes alemtuzumab. In one embodiment, the additional therapy includes cyclophosphamide. In one embodiment, the additional therapy includes cladribine. In one embodiment, the additional therapy includes ocrelizumab. In one embodiment, the additional therapy includes dimethyl fumarate. In one embodiment, the additional therapy includes daclizumab. In one embodiment, the additional therapy includes azathioprine. In one embodiment, the additional therapy includes methotrexate. In an alternative embodiment, the additional therapy does not include methotrexate. In one embodiment, the additional therapy includes laquinimod.

[0028] autoimmune disease As used herein, autoimmune disease means any disease or condition in which an individual's immune system mistakenly targets an individual's own "healthy" cells, particularly characterized by aberrant T cell and / or B cell activation. Aberrant T cell and / or B cell activation, as used herein, refers in particular to aberrant T cell and / or B cell activation where the aberrant cells recognize self or self antigens. A serious autoimmune disease is when the disease is not controlled by standard treatment drugs / treatments. A flare is a period of disease worsening.

[0029] "Inadequate control" as used herein means that standard treatment drugs fail to reduce or control symptoms, particularly when the patient's quality of life is adversely affected.

[0030] As used herein, a "defined endpoint" means a clinically defined point, such as remission or stable disease.

[0031] In one embodiment, fardostat is used for maintenance therapy, for example, at low doses. Maintenance therapy as used herein refers to continuous therapy to stabilize disease or keep disease in remission, for example, when the dose is low and especially when it is frequent. For example, a dose of 100-200 mg given once or twice a day can be used as maintenance therapy.

[0032] In one embodiment, the autoimmune disease is an autoimmune skin disease, i.e. an autoimmune disease manifested or present in the skin, in particular the dermis and / or epidermis, such as, for example, lupus. In one embodiment, the autoimmune skin disease is selected from the group comprising vitiligo, alopecia, Behcet's disease, dermatitis herpetiformis, dermatomyositis, lichen planus, linear IgA dermatosis, cutaneous lupus, morphea / scleroderma, ocular cicatricial pemphigoid, pemphigoid such as bullous pemphigoid or gestational pemphigoid, pemphigus (pemphigus vulgaris, pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, IgA pemphigus, pemphigus vegetans, or paraneoplastic pemphigus), vasculitis, epidermolysis bullosa acquisita, psoriasis, vesicular bullous dermatosis, and atopic dermatitis. In one embodiment, the autoimmune skin disease is selected from the group comprising vitiligo and alopecia. In one embodiment, the autoimmune skin disease is vitiligo and alopecia.

[0033] In one embodiment, the autoimmune skin disease is vitiligo. In one embodiment, the autoimmune skin disease is vitiligo selected from the group including segmental vitiligo or non-segmental vitiligo. In one embodiment, the vitiligo is segmental vitiligo. In one embodiment, the vitiligo is non-segmental vitiligo (e.g., focal vitiligo, generalized vitiligo, or acrofacial vitiligo). In one embodiment, the autoimmune skin disease is alopecia. In one embodiment, the alopecia is selected from the group comprising alopecia universalis, alopecia areata, alopecia areata, alopecia areata, alopecia areata, alopecia areata totalis, or alopecia areata universalis. In one embodiment, the alopecia is alopecia areata universalis. In one embodiment, the alopecia is alopecia areata, alopecia areata, alopecia areata totalis. In one embodiment, the alopecia is alopecia areata, alopecia areata totalis. In one embodiment, the alopecia is alopecia areata universalis.

[0034] Thus, in one embodiment, the autoimmune disease is selected from the following: acute disseminated encephalomyelitis (adem), acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, adrenal insufficiency, hypocortisolism, amyloidosis, ankylosing spondylitis, spondyloarthritis, Strümpel-Marie disease, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome (aps), autoimmune angioedema, autoimmune aplastic anemia, autoimmune autonomic neuropathy, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED), autoimmune lymphoproliferative syndrome (ALPS), Canel- Smith syndrome, autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis (AIP), autoimmune polyglandular syndromes (types I, II, and III), autoimmune retinopathy (AR), autoimmune thrombocytopenic purpura (ATP), autoimmune thyroid disease, autoimmune urticaria, neuronal axonal neuropathy, Baro's disease, Behçet's disease, bullous pemphigoid, cardiomyopathy, Castleman's disease, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome, cicatricial pemphigoid / benign mucous membrane pemphigoid pulmonary tuberculosis (CP), Crohn's disease, inflammatory bowel disease, colitis (including ulcerative colitis), enteritis, ileitis, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, Crest's disease, cryoglobulinemia, demyelinating neuropathy, dermatitis herpetiformis, Duhring's disease, dermatomyositis, type I diabetes mellitus, discoid lupus erythematosus (DLE), Dressler's syndrome, endometriosis, epidermolysis bullosa (EB) and epidermolysis bullosa acquisita (EBA), eosinophilic gastroenteritis, esophagitis, eosinophilic fasciitis, Shulman's syndrome, erythema nodosum, experimental allergic encephalomyelitis, Evans' syndrome, fibrosing alveolitis , giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis (non-proliferative: focal segmental glomerulosclerosis and membranous nephropathy. Proliferative: IgA nephropathy), Goodpasture's syndrome, granulomatosis with polyangiitis (GPA) (previously called Wegener's granulomatosis), Graves' disease, Guillain-Barré syndrome, Miller-Fisher syndrome, acute motor axonal neuropathy, acute motor and sensory axonal neuropathy, acute autonomic neuropathy, Bickerstaff brainstem encephalitis, Hashimoto's encephalopathy, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpes gestationis,Hypogammaglobulinemia, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy (IGAN), Berger syndrome, pharyngeal glomerulonephritis, IgA pemphigus, IgG4-related sclerosing disease, immunomodulatory infertility, inclusion body myositis, insulin-dependent diabetes mellitus, interstitial cystitis, Isaacs syndrome, neuromyotonia, juvenile arthritis, juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, linear IgA dermatosis (LAD), pemphigoid, lupus (SLE), Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), monoclonal gammopathy, Mooren's ulcer, Mucha-Habermann disease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica (Devic's disease), neuromyotonia, Isaacs syndrome (acquired, paraneoplastic, hereditary), neutropenia, ocular cicatricial pemphigoid, optic neuritis, oophoritis, opsoclonus-myoclonus syndrome, orchitis, relapsing rheumatism, pandas (pediatric autoimmune streptococcal neuropsychiatric disorder), paraneoplastic Autoimmune multisystem syndrome (PAMS), paraneoplastic cerebellar degeneration, paraneoplastic pemphigus (PNP), paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, Parsonage-Turner syndrome, pars planitis (peripheral uveitis), gestational pemphigoid (PG), pemphigus vulgaris (PV), pemphigus foliaceus (PF), peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa (PAN), polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, progesterone dermatitis, primary biliary ulcerative cirrhosis, Hanot's syndrome, primary sclerosing cholangitis (PSC), sclerosing cholangitis, psoriasis, psoriatic arthritis, pyoderma gangrenosum, pure red cell aplasia, Rasmussen's encephalitis, chronic focal encephalitis (CFE), Raynaud's phenomenon, reactive arthritis, Reiter's syndrome, recovery-associated retinopathy (RAR), reflex sympathetic dystrophy, Reiter's syndrome, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, systemic sclerosis, Sjogren's syndrome, spermatozoon autoimmunity, stiff-person syndrome / stiff-person syndrome, subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia, Takayasu's arteritis,Temporal arteritis / giant cell arteritis, thromboangiitis obliterans, Buerger's disease, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, transverse myelitis, undifferentiated connective tissue disease (UCTD), uveitis, Takayasu's arteritis, temporal arteritis, Buerger's disease, cutaneous vasculitis, Kawasaki disease, polyarteritis nodosa, Behçet's syndrome, Churg-Strauss syndrome, cutaneous vasculitis, Henoch-Schönlein purpura, microscopic polyangiitis, Wegener's granulomatosis, golfer's vasculitis, vesicular bullous dermatosis, and Wegener's granulomatosis (today called granulomatosis with polyangiitis (GPA)).

[0035] In one embodiment, the autoimmune disease comprises or is selected from the group consisting of: ANCA vasculitis, IgA nephropathy (Buerger's disease), pemphigus vulgaris / bullous pemphigoid, ITP, primary biliary cirrhosis, autoimmune thyroiditis (Graves' disease), Hashimoto's disease, lupus nephritis, membranous glomerulonephritis (or membranous nephropathy), APS, myasthenia gravis, neuromyelitis optica, primary Sjogren's syndrome, autoimmune neutropenia, autoimmune pancreatitis, dermatomyositis, autoimmune uveitis, autoimmune retinopathy, Behcet's disease, IPF, systemic sclerosis, hepatic fibrosis, autoimmune hepatitis, primary sclerosing cholangitis, Goodpasture's syndrome, pulmonary alveolar proteinosis, chronic autoimmune urticaria, psoriasis, rheumatoid arthritis, chronic pulmonary fibrosis ... Arthritis, psoriatic arthritis, axial spondyloarthritis, transplant (including GvHD), asthma, COPD, giant cell arteritis, refractory autoimmune cytopenias, Evans syndrome (autoimmune hemolytic anemia), type I diabetes mellitus, sarcoidosis, polymyositis, ulcerative colitis, Crohn's disease, celiac disease, Waldenström's macroglobulinemia, focal segmental glomerulosclerosis, chronic Lyme disease (Lyme borreliosis), lichen planus, stiff-body syndrome, dilated cardiomyopathy, autoimmune (lymphocytic) oophoritis, epidermolysis bullosa acquisita, autoimmune atrophic gastritis, pernicious anemia, atopic dermatitis, atherosclerosis, multiple sclerosis, Rasmussen's encephalitis, Guillain-Barré syndrome, acquired neuromyotonia, and stroke.

[0036] In one embodiment, the autoimmune disease comprises or is selected from the group consisting of: hidradenitis suppurativa, scleroderma (generalized scleritis), lichen planus, morphea, psoriasis, type 1 diabetes, autoimmune thyroiditis, Graves' disease, endometriosis, celiac disease, Crohn's disease, ulcerative colitis, axial spondyloarthritis, juvenile arthritis, relapsing rheumatism, psoriatic arthritis, rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus (SLE), undifferentiated connective tissue disease (UCTD), multiple sclerosis, pattern II, restless legs syndrome, optic neuritis, uveitis, scleritis, Mooren's ulcer, Meniere's disease, Graves' ophthalmopathy, neuromyelitis optica, Susac syndrome, and lupus erythematosus.

[0037] As used herein, autoimmune skin disease or disorder refers to any disease or condition in which an individual's immune system, such as an individual's T cells and / or B cells, mistakenly targets an individual's skin tissue or the cells therein, including hair follicles.Fardodstat can block the biosynthesis of pyrimidines, which are believed to stop cell cycle arrest, resulting in reduced pro-inflammatory cytokine production and / or apoptosis of T cells and / or B cells.Therefore, it is believed that Fardodstat has the potential to treat various autoimmune skin diseases, such as vitiligo and alopecia.

[0038] As used herein, vitiligo refers to an autoimmune skin disease characterized by a decrease in skin pigmentation patches. Vitiligo occurs when melanocytes die or stop functioning. This results in a decrease in melanin, which is responsible for skin pigmentation. Pale areas of the skin are more susceptible to sunburn, making it important that proper precautions are taken by vitiligo patients. The condition can affect any part of the body, but more typically manifests itself on the face, neck, hands, and skin creases. Vitiligo can also affect hair, or the inside of the mouth. There are two main types of vitiligo: non-segmental and segmental. Non-segmental vitiligo is much more common than segmental vitiligo, with approximately 90% of patients having this form of the disease. Patients with non-segmental vitiligo usually have symptoms on both sides of the body, i.e., the white patches tend to be present as symmetrical patches. In contrast, segmental vitiligo usually presents as white patches in only one area of ​​the body. There is no currently available treatment that can stop the vitiligo process. Therefore, the white patches caused by vitiligo are usually permanent. Available treatments, such as steroid creams, phototherapy or camouflage creams, are therefore focused on reducing the appearance of the white patches.

[0039] As used herein, Alopecia areata, alopecia or spot baldness refers to an autoimmune skin disorder in which hair follicles are targeted by the immune system. This results in the inhibition of hair growth and hair loss. Hair loss usually occurs in clumps and may grow back, but the hair may fall out again. Alopecia can be further subdivided into: · Alopecia areata universalis: This hair loss is widely distributed over the entire scalp; · Single-site alopecia areata: This is when hair loss occurs in only one area; · Alopecia Areata: This is when hair loss occurs in multiple areas; · Alopecia areata: This is when there is a sudden thinning of hair rather than hair loss in patches; · Alopecia areata: This is when the hair loss is limited to the beard area; Alopecia totalis: This is the presence of total hair loss over the scalp; and Alopecia universalis: This is the loss of all body hair, including pubic hair.

[0040] There is no known cure for alopecia. Treatment options usually include corticosteroids such as clobetasol or fluocinonide, and immunosuppressants such as minoxidil, cyclosporine, and diphenylcyclopropenone. Wigs or hairpieces can be used to hide bald areas, but some patients may find these uncomfortable to wear.

[0041] Vitiligo and alopecia areata are not life-threatening conditions and are not contagious, but the symptoms of both diseases are highly visible and therefore can have a negative impact on the emotional and mental health of patients suffering from one or both diseases. In this regard, studies have shown that vitiligo and alopecia are more likely to occur together in patients than pure chance. In addition, both diseases are characterized by uneven distribution and minimal symptomatology compared to other more inflammatory skin diseases such as atopic dermatitis or psoriasis. The similarities between the two autoimmune skin diseases extend beyond the common clinical symptoms - they share similarities in pathogenesis. For example, increased reactive oxygen species (ROS) and high cellular stress levels are thought to act as triggers to initiate the innate immune system in both conditions. In addition, studies in mouse models have implicated IFNγ-promoted immune responses and cytotoxic CD8+ T cells as key pathogenic factors in both diseases. See review by Rork et al., Curr Opin Pediatr 2016 Aug;28(4):463-469. Given the implication of the IFNγ signaling pathway in both diseases, ruxolitinib, an inhibitor that targets JAK, a downstream effector of IFNγ signaling, is currently in clinical trials for both vitiligo and alopecia. Thus, without wishing to be bound by theory, the inventors believe that faldodstat has the potential to treat both vitiligo and alopecia due to their various similarities, in particular the important role of cytotoxic CD8+ T cells in both diseases.

[0042] In one embodiment, the autoimmune disease is selected from the group including or consisting of lichen planus, hidradenitis suppurativa, celiac disease, ulcerative colitis, Crohn's disease, Graves' disease, autoimmune thyroiditis, endometriosis, multiple sclerosis, and optic neuritis.

[0043] Multiple sclerosis (MS) is a disease in which the myelin sheath that insulates nerve cells in the brain and spinal cord is damaged. As a result of this damage, the nervous system's ability to transmit signals properly is disrupted. This in turn causes a series of severe physical and mental problems, such as double vision, blindness in one eye, muscle weakness, problems related to sensation or coordination, problems related to speech, acute or chronic pain, bladder and bowel disorders, depression, and mood swings. In most cases, the condition begins as a syndrome consisting of an initial episode lasting several days, with most suffering from motor or sensory impairment. The course of symptoms occurs in two patterns, either initially as an improvement in most cases followed by an episode of sudden worsening lasting several days to several months, known as a relapse, or as a gradual worsening over a long period of time with no period of recovery. Relapses are usually unpredictable and occur without warning. The cause of multiple sclerosis is currently unknown, but the underlying mechanism is thought to be the destruction of the myelin sheath by an individual's own immune system, i.e., multiple sclerosis is thought to be, at least in part, an autoimmune disease. It is the most common immune-mediated disorder affecting the central nervous system, affecting approximately 2.3 million people worldwide. However, there are numerous autoimmune diseases that have a serious and detrimental impact on the lives of many sufferers.

[0044] In one embodiment, the autoimmune disease is multiple sclerosis (MS). Multiple sclerosis is usually further classified into one of four variants: first episode syndrome (CIS), relapsing remitting MS (RRMS), primary progressive MS (PPMS) and secondary progressive MS (SPMS). Thus, in one embodiment, the autoimmune disease is selected from the group including CIS, RRMS, PPMS and SPMS. Relapsing-remitting MS (RRMS) is characterized by unpredictable relapses followed by months to years of relatively calm periods (remissions) without signs of new disease activity. The condition is characterized by progressive, persistent demyelination, and associated axonal loss. In one embodiment, the autoimmune disease is RRMS.

[0045] Attacks - also called relapses or exacerbations (herein also called flares) - are followed by periods of partial or complete recovery (remission). During remission, all symptoms may disappear, or some symptoms may continue and become permanent. However, during periods of remission, there is no obvious disease progression. RRMS can be further characterized as active (with relapses and / or evidence of new MRI activity over a period of time) or inactive, and exacerbations (established increase in disability followed by relapses) or no exacerbations.

[0046] The relapsing-remitting subtype usually begins with a first episode syndrome (CIS). In CIS, a person experiences attacks suggestive of demyelination but does not meet the criteria for multiple sclerosis. 30-70% of people who experience CIS subsequently develop MS. In one embodiment, the autoimmune disease is CIS.

[0047] Primary progressive MS (PPMS) occurs in approximately 10-20% of individuals and has no remissions after initial symptoms. It is characterized by a progression of disability from onset, with no remissions or only sporadic and mild remissions and improvements. In one embodiment, the autoimmune disease is PPMS.

[0048] Secondary progressive MS (SPMS) occurs in about 65% of patients with initial relapsing-remitting MS, and there is eventually progressive neurological decline between acute attacks without any clear remission. Occasional relapses and mild remissions may occur. SPMS can be further characterized as active (with evidence of relapses and / or new MRI activity over a period of time) or inactive, and progressive (with or without evidence of accumulation of disability over time, relapses or new MRI activity) or non-progressive. In one embodiment, the autoimmune disease is SPMS.

[0049] In one embodiment, the disease is chronic inflammatory demyelinating polyneuropathy. In one embodiment, the disease is transverse myelitis. In one embodiment, the disease is neuromyelitis optica.

[0050] In one embodiment, the autoimmune disease is one or more of the following: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, Wegener's granulomatosis, systemic lupus erythematosus, psoriasis, sarcoidosis, polyarticular juvenile idiopathic arthritis, inflammatory bowel disease such as ulcerative colitis and Crohn's disease, Reiter's syndrome, fibromyalgia, and diabetes mellitus type 1. In one embodiment, it is not any one of the foregoing.

[0051] In one embodiment, the autoimmune disease is psoriatic arthritis. In one embodiment, it is not psoriatic arthritis. In one embodiment, the autoimmune disease is ankylosing spondylitis. In one embodiment, it is not ankylosing spondylitis. In one embodiment, the autoimmune disease is multiple sclerosis. In one embodiment, it is not multiple sclerosis. In one embodiment, the autoimmune disease is Wegener's granulomatosis. In one embodiment, it is not Wegener's granulomatosis. In one embodiment, the autoimmune disease is systemic lupus erythematosus. In one embodiment, it is not systemic lupus erythematosus. In one embodiment, the autoimmune disease is psoriasis. In one embodiment, it is not psoriasis. In one embodiment, the autoimmune disease is sarcoidosis. In one embodiment, it is not sarcoidosis. In one embodiment, the autoimmune disease is polyarticular juvenile idiopathic arthritis. In one embodiment, it is not polyarticular juvenile idiopathic arthritis. In one embodiment, the autoimmune disease is inflammatory bowel disease, such as ulcerative colitis or Crohn's disease. In one embodiment, it is not inflammatory bowel disease, such as ulcerative colitis or Crohn's disease. In one embodiment, the autoimmune disease is Reiter's syndrome. In one embodiment, it is not Reiter's syndrome. In one embodiment, the autoimmune disease is fibromyalgia. In one embodiment, it is not fibromyalgia. In one embodiment, the autoimmune disease is type 1 diabetes. In one embodiment, it is not type 1 diabetes. In one embodiment, the autoimmune disease is arthritis, such as rheumatoid arthritis. In one embodiment, it is not arthritis, such as rheumatoid arthritis.

[0052] In one embodiment, the autoimmune skin disease is not atopic dermatitis. In one embodiment, the autoimmune skin disease is not erythema. In one embodiment, the autoimmune skin disease is not scleroderma. In one embodiment, the autoimmune skin disease is not lupus. In one embodiment, the autoimmune skin disease is not Behcet's disease. In one embodiment, the autoimmune skin disease is not bullous pemphigoid. In one embodiment, the autoimmune skin disease is not IgA pemphigus. In one embodiment, the autoimmune skin disease is not pemphigoid. In one embodiment, the autoimmune skin disease is not ocular cicatricial pemphigoid. In one embodiment, the autoimmune skin disease is not gestational pemphigoid (PG), pemphigus vulgaris (PV), or pemphigus foliaceus (PF). In one embodiment, the autoimmune skin disease is not vesicular bullous dermatosis. In one embodiment, the autoimmune skin disease is not dermatomyositis. In one embodiment, the autoimmune skin disease is not lichen planus. In one embodiment, the autoimmune skin disease is not dermatitis herpetiformis. In one embodiment, the autoimmune skin disease is not vesicular bullous dermatosis. In one embodiment, the autoimmune skin disease is not linear IgA dermatosis. In one embodiment, the autoimmune skin disease is not vasculitis.

[0053] Viral infections As used herein, a virus refers to a virus that is involved in a viral infection or disease. Thus, in the context of this disclosure, a virus generally refers to a pathogenic virus. It is not intended to refer to a virus that is used as a viral vector or therapeutic agent. Viral infection or viral disease, used interchangeably herein, means an infection or disease caused by the presence of a virus in the body. In one embodiment, the virus involved in the viral infection is an RNA virus. RNA viruses are usually classified as the Ribovirus and Orthornavirus kingdoms. There are also single-stranded and double-stranded forms of RNA viruses (Group III of the Baltimore Classification). Single-stranded viruses are classified as positive-sense single-stranded RNA viruses (Group IV Baltimore Classification); negative-sense single-stranded RNA viruses (Group V Baltimore Classification) and single-stranded RNA viruses with DNA intermediates (Group VI Baltimore Classification). Thus, in one embodiment, the virus is a single-stranded RNA virus, e.g., a positive-sense single-stranded RNA virus or a negative-sense single-stranded RNA virus.

[0054] In one embodiment, the virus involved in the viral infection is a sarbecovirus. Sarbecovirus is a subgenus of viruses that cause severe acute respiratory syndrome. Examples of sarbecovirus include SARS-CoV, SARS-CoV2, Bat SARS-like coronavirus WIV1 and Bat coronavirus RaTG13. The genus is betacoronavirus and the family is Coronaviridae. Thus, in one embodiment, the virus is Coronaviridae.

[0055] Merbecovirus is a subgenus of the virus responsible for Middle East Respiratory Syndrome-associated coronavirus. The genus is Betacoronavirus and the family is Coronaviridae. Thus, in one embodiment, the virus is a Merbecovirus. The present disclosure also extends to the treatment of Embecoviruses (known as Group 2a coronaviruses), such as the human coronavirus HKU1. Thus, in one embodiment, the virus is Embecovirus. The present disclosure also includes Novecoviruses (known as Group 2d coronaviruses).

[0056] In one embodiment, the virus involved in the viral infection is SARS-CoV. SARS-CoV is also called SARS-CoV1 or SARS. In one embodiment, the virus is SARS-CoV2. SARS-CoV2 is also called coronavirus or COVID-19. In one embodiment, the virus is MERS-CoV, also known as Middle East Respiratory Syndrome coronavirus.

[0057] The viral infection may be a mosquito-borne viral disease or may be caused by a mosquito-borne virus. Common examples of mosquito-borne diseases include malaria, chikungunya, dengue, Zika, West Nile virus, and yellow fever. Yellow fever, dengue, and chikungunya are primarily transmitted by the Aedes aegypti mosquito. Other mosquito-borne diseases, such as epizootic polyarthritis, Rift Valley fever, Ross River fever, St. Louis encephalitis, West Nile fever, Japanese encephalitis, and La Crosse encephalitis, are carried by several different mosquitoes. Thus, in one embodiment, the viral infection is a mosquito-borne viral disease, in other words, in one embodiment, the virus is transmitted by mosquitoes. In one embodiment, the virus is a Flavivirus. Flavivirus is a genus of viruses that includes West Nile virus, Dengue virus, Tick-borne encephalitis virus, Yellow fever virus, Zika virus, etc. Flaviviridae is a family. Thus, in one embodiment, the virus is a Flaviviridae.

[0058] The present disclosure extends to the treatment of dengue virus. There are five serotypes of the virus, all of which are capable of causing a full spectrum of disease. In one embodiment, the dengue virus is any one of serotypes 1-5, in particular serotypes 1, 2, 3 or 4. Thus, in one embodiment, the virus is dengue serotype 1, 2, 3 or 4. In one embodiment, the virus is dengue serotype 1. In one embodiment, the virus is dengue serotype 2. In one embodiment, the virus is dengue serotype 3. In one embodiment, the virus is dengue serotype 4. In one embodiment, the virus is dengue serotype 5.

[0059] In one embodiment, the virus is an alphavirus. Alphaviruses are a genus of viruses that are the only genus in the Togaviridae family. There are 31 alphaviruses, including Chikungunya virus, Bebaru virus, Getah virus, Mayaro virus, O'nyong-nyong virus, Ross River virus, and Semliki Forest virus. In one embodiment, the virus is selected from the group comprising sarbecoviruses and mosquito-borne viruses. In one embodiment, the sarbecovirus is SARS-CoV or SARS-CoV2, in particular SARS-CoV2. In one embodiment, the mosquito-borne viral disease or infection is selected from the group comprising dengue, chikungunya and Zika. In one embodiment, the dengue is dengue serotype 1, 2, 3 or 4. Thus, in one embodiment, the virus is selected from the group comprising SARS-CoV-2, dengue, chikungunya and Zika.

[0060] In the context of this specification, comprising is intended to mean "including". Where technically appropriate, embodiments of the invention may be combined. Embodiments are described herein as comprising certain features / elements. The disclosure also extends to separate embodiments consisting of or consisting essentially of said features / elements. Technical references such as patents and applications are incorporated herein by reference. Any embodiment detailed and expressly described herein may form the basis of a disclaimer either alone or in combination with one or more further embodiments.

[0061] The background contains technical information and can be used as a basis for correction. The invention will now be described with reference to the following examples, which are merely illustrative and should not be construed as limiting the scope of the invention. This application claims priority from SG10202201038X, which is incorporated by reference. The priority document may be used as a basis for corrections. [Brief description of the drawings]

[0062] [Figure 1A] A synthetic route for producing a dominant stable pharmaceutical (DSP) polymorph of fardotstat is presented. [Figure 1B] 1 shows a flow diagram of the steps used to synthesize the Faldhodstad polymorph. [Figure 1C] 1 shows a table of the in-process control steps used during the synthesis of the Faldhodstad polymorph. [Diagram 2] 1 shows the XRPD pattern of the Faldhodstat DSP polymorph. [Diagram 3] 1 shows details of the peaks in the XRPD pattern of the Faldhodstat DSO polymorph. [Figure 4A] 1 shows the XRPD results of the anti-solvent method from the first experiment. [Figure 4B] 1 shows anti-solvent method XRPD results from a second experiment. [Figure 5A] 1 shows the XRPD results of the slurry from the first experiment (25° C.). [Figure 5B] 1 shows the XRPD results of the slurry from the second experiment (25° C.). [Figure 5C] 13 shows XRPD results of the slurry from the third experiment (25° C.). [Figure 5D] 13 shows XRPD results of the slurry from the fourth experiment (50° C.). [Figure 5E] 13 shows XRPD results of the slurry from the fifth experiment (50° C.). [Figure 5F] 13 shows XRPD results of the slurry from the sixth experiment (50° C.). [Figure 6A] 1 shows the XRPD results of the first solvent-heat / cool experiment. [Figure 6B] 1 shows the XRPD results of a second solvent-heat / cool experiment. [Figure 7]1 shows the XRPD results of the evaporation experiment. [Figure 8] 1 shows the XRPD results of the milling experiment. [Figure 9] 1 shows the XRPD results of the recrystallization experiment. [Figure 10] 1 shows XRPD results of reactive crystallization experiments. [Figure 11] 1 shows the XRPD result of the crystalline form of Faldhodstat from evaporation of the THF solution. [Figure 12] 1 shows the XRPD result of the crystalline form of Faldhodstat from anti-solvent in THF-water. [Figure 13] 1 shows the XRPD results of a spray dried Fardotstat sample. [Figure 14] 1 shows the Falddotstat XRPD results from a solvent evaporation experiment. [Figure 15] 1 shows the XRPD results of a freeze-dried Faldotstat sample. [Figure 16] 1 shows the XRPD result of a ground Faldotstat sample. [Figure 17] 1 shows the TGA and DSG profiles of the Faldodstat DSP polymorphism. [Figure 18] 1 shows the TGA and DSC profiles of the crystalline form of Faldodead from evaporation of the THF solution. [Figure 19] 4 shows the TGA and DSC profiles of the crystalline form of Faldodstat from anti-solvent in THF-water. [Figure 20A] Shown is a polarized light microscopy (PLM) image at 200x magnification of the Faldo Dotstat after 27 hours of milling. [Figure 20B] Shown is a PLM image at 500x magnification of the Faldo Dotstat after 27 hours of milling. [Figure 21A] Shown is a PLM image at 200x magnification from a recrystallization experiment. [Figure 21B] Shown is a PLM image at 500x magnification from a recrystallization experiment. [Figure 22A] 1 shows a PLM image at 200x magnification from a reactive recrystallization experiment using HCl-NaOH. [Figure 22B] 1 shows a PLM image at 500x magnification from a reactive recrystallization experiment using HCl-NaOH. [Figure 22C] Shown is a PLM image at 200x magnification from a reactive recrystallization experiment using NaOH-HCl. [Figure 22D] Shown is a PLM image at 500x magnification from a reactive recrystallization experiment using NaOH-HCl. [Figure 23A] Shown is a PLM image at 200x magnification of the crystalline form of Faldodeadstat from evaporation of the THF solution. [Figure 23B] Shown is a PLM image at 500x magnification of the crystalline form of Faldodeadstat from evaporation of the THF solution. [Figure 24A] Shown is a PLM image at 200x magnification of the crystalline form of Faldodstat from antisolvent in THF-water. [Figure 24B] Shown is a PLM image at 500x magnification of the crystalline form of Faldodstat from antisolvent in THF-water. [Figure 25A] 1 shows XRPD results from a solvent solubility evaluation experiment. [Figure 25B] A summary table of the results of the solubility evaluation experiments is shown. * = Few solids available to perform XRPD. Pattern 1 = XRPD pattern of the Faldo Dotstat DSP polymorph. [Figure 26] 1 shows XRPD results from bead milling of the Faldhodstat DSP polymorph. [Figure 27A] 1 shows XRPD results from a solvent drop milling experiment. [Figure 27B] A summary table of results from the solvent drop milling experiments is shown. *WP = white powder, Pattern 1 = XRPD pattern of the Faldhodstat DSP polymorph. [Figure 28A] 1 shows XRPD results from a thermal cycling experiment. [Figure 28B] A summary table of the results from the thermal cycling experiments is shown, where WS = wet slurry, CS = clear solution, Pattern 1 = XRPD pattern of the Faldhodstat DSP polymorph. [Figure 29A] 1 shows XRPD results from a room temperature evaporation experiment. [Figure 29B] A summary table of results from room temperature evaporation experiments is shown: Pattern 1 = XRPD pattern of the Faldhodstat DSP polymorph. [Figure 30A] 1 shows XRPD results from a fast evaporation experiment of 1,3-dioxolane at 50° C. [Figure 30B] 1 shows XRPD results from a 1,4-dioxane fast evaporation experiment at 50° C. [Figure 30C] 1 shows XRPD results from a fast evaporation experiment of 2-propanol and 1,1-dimethoxymethane at 50° C. [Figure 30D] 1 shows XRPD results from a fast evaporation experiment with THP, THF, 2-methylTHF and 1,1,1,3,3,3-hexafluoro-2-propanol at 50° C. [Figure 30E] 1 shows XRPD results from a fast evaporation experiment of 2-ethoxyethanol at 50° C. [Figure 30F] 1 shows XRPD results from a DMF fast evaporation experiment at 50° C. [Figure 30G] A summary table of results from the fast evaporation experiment at 50° C. is shown. WS=wet slurry, **=few solids, Pattern 1=XRPD pattern of the Faldhodstat DSP polymorph. [Figure 31A] 1 shows XRPD results from a DMA fast evaporation experiment at 100° C. [Figure 31B] 1 shows XRPD results from a DMF flash evaporation experiment at 100° C. [Figure 32A] 1 shows XRPD results from a fast evaporation experiment of 1,3-dioxolane. [Figure 32B] A summary table of the results from the rapid cooling experiments is shown: Pattern 1 = XRPD pattern of the Faldhodstat DSP polymorph, WS = wet slurry, CS = clear solution. [Figure 33A] 1 shows XRPD results from a two week slurry experiment. [Figure 33B] 1 shows XRPD results from a 2 week slurry experiment after flash evaporation at 100° C. [Figure 33C]A summary table of results from a two week slurry experiment is shown: Pattern 1 = XRPD pattern of the Faldodstat DSP polymorph, Pattern 1+ = Pattern 1 with additional peaks, WS = wet solid, CS = clear solution. [Figure 34A] 4 shows XRPD results from anti-solvent addition (water) experiments. [Figure 34B] A summary table of results from antisolvent addition (water) experiments is shown: Pattern 1 = XRPD pattern of the Faldhodstat DSP polymorph. [Figure 34C] 4 shows XRPD results from an anti-solvent addition (acetone) experiment. [Fig. 34D] A summary table of results from antisolvent addition (acetone) experiments is shown. Pattern 1+=Pattern 1+additional peaks. [Figure 34E] 1 shows a summary table of results from anti-solvent addition (heptane) experiments. [Fig. 34F] 1 shows a summary table of results from antisolvent addition (MEK) experiments. [Diagram 35] 1 shows XRPD results from an anti-solvent addition + rapid cooling experiment using 1,4-dioxane with MEK as the anti-solvent. [Figure 36A] 1 shows XRPD results from an anti-solvent addition experiment at 50° C. [Figure 36B] A summary table of XRPD results from anti-solvent addition experiments at 50° C. is shown. Pattern 1 = XRPD pattern of the Faldhodstat DSP polymorph. [Figure 37] 1 shows the XRPD diffractogram of the Faldodstat DSP polymorph (CS-276-22 Pattern 1) compared to the XRPD diffractograms of the 1,1,1,3,3,3-hexafluoro-2-propanol polymorph before (Pattern 2) and after drying (Post-Drying Pattern 1). [Figure 38] 1 shows the XRPD peak list of 1,1,1,3,3,3-hexafluoro-2-propanol polymorph (pattern 2). [Figure 39A] 1 shows thermogravimetry (TG) / differential scanning calorimetry (DSC) thermograms of HIFP polymorphs before drying (wet). [Figure 39B]TG / DSC thermograms of 1,1,1,3,3,3-hexafluoro-2-propanol polymorphs after drying. [Figure 40A] 1 shows the 1H NMR spectrum of 1,1,1,3,3,3-hexafluoro-2-propanol polymorph before drying (wet). [Figure 40B] 1H NMR spectrum of 1,1,1,3,3,3-hexafluoro-2-propanol polymorphs after drying. [Figure 41A] FIG. 1 shows the Fourier transform infrared spectroscopy (FT-IR) spectra of 1,1,1,3,3,3-hexafluoro-2-propanol polymorphs. [Figure 41B] 1 shows the Fourier transform infrared spectroscopy (FT-IR) spectrum of the Faldhodstat DSP polymorph. [Diagram 42] 1 shows the XRPD diffractogram of the Faldodstat DSP polymorph (CS-276-22 Pattern 1) compared to the XRPD diffractograms of the 1NMP polymorph before (NMP Pattern 3) and after drying (NMP Dry Pattern 1). [Diagram 43] The XRPD peak list of NMP polymorphism (pattern 3) is shown. [Diagram 44] TG / DSC thermograms of NMP polymorphs. [Diagram 45] 1 shows the 1H NMR spectra of NMP polymorphs. [Diagram 46] A summary diagram of the identified Faldodstat polymorphisms is shown.

[0063] Working Example Example 1 - Synthesis of the dominant stable pharmaceutical (DSP) polymorph of Faldodostat A flow diagram of the synthetic pathway and manufacturing process for the production of the Faldhodstat DSP polymorph is shown in Figures 1A and 1B, respectively. Figure 1C is a table describing the in-process control steps used during the synthesis of the Faldhodstat polymorph.

[0064] Stage 1 Process Description A mixture of 2-chloronicotinic acid, 4-bromo-2,6-difluoroaniline and p-toluenesulfonic acid monohydrate in 2-propanol was heated to completion (>90% conversion). The mixture was cooled, filtered and the filter cake was washed. The product was dried under reduced pressure to give crude intermediate 1, which was dissolved in water and the pH was adjusted using sodium hydroxide. The resulting slurry was filtered and the filter cake was washed with HCl (aq) followed by acetone. The product was dried under reduced pressure to give intermediate 1 (C 12 H7BrF2N2O2) was obtained in 70-80% yield.

[0065] Stage 2 Process Description Intermediate 1 (C 12 A mixture of 1,3-dimethylphenylboronic acid (H7BrF2N2O2), 3-methoxyphenylboronic acid, potassium carbonate, triphenylphosphine and palladium acetate in ethanol and water was heated until reaction completion (Intermediate 1≦0.3%). Hydrochloric acid was added, the resulting slurry was filtered and the cake was washed with water. The product was dried under reduced pressure to obtain crude Faldodstat. The crude product was dissolved in tetrahydrofuran and treated with a metal removal agent before filtering with activated charcoal. The resulting solution was tested for residual palladium levels (<50 ppm). If the in-process test for residual palladium does not meet the criteria, the scavenging procedure may be repeated until the criteria are met to ensure effective removal of residual palladium.

[0066] Example 2 - Materials and Methods 1. Reagents [Table 1]

[0067] 2. Equipment Milli-Q Direct 8 water purification system, Sartorius CP 225D balance, Mettler Toledo XP6 balance, Eppendorf Thermomixer Comfort, Bruker D8 Advance X-ray powder diffractometer (XRPD), Nikon LV100 polarizing microscope (PLM), TA Q2000 differential scanning calorimeter (DSC), TA Q5000IR thermogravimetric analyzer (TGA), Crystal 16, AVANTIUM, Rotavapor R-114, Planetary Peach Mill (pulverisette-6), Freeze dryer (Free zoon-6).

[0068] 3. Instrument parameters X-ray powder diffractometer (XRPD) Approximately 5-10 mg of sample was measured by XRPD using the following parameters: Tube: Cu:K-alpha (λ=1.54179 Å); Generator: Voltage: 40 kV; Current: 40 mA; Scan range: 4-40 degrees; Sample rotation speed: 15 rpm; Scan rate: 10 degrees / min. Differential Scanning Calorimetry (DSC) and Modulated DSC Using a crimped aluminum balance dish, the sample (approximately 1 mg) was heated from 25°C to 280°C at a rate of 10°C per minute and measured. Thermogravimetric analysis (TGA) method Samples (2–5 mg) were placed in an open platinum dish and heated from room temperature to 300 °C at a rate of 10 °C / min. Polarized Light Microscope (PLM) The samples were dispersed in silicone oil and observed under crossed polarizers with an objective lens (10X) and physical lenses (20X and 50X), resulting in total magnifications of 200X and 500X.

[0069] Example 3 - Characterization of the physicochemical properties of the Faldhodstat DSP polymorphism The Faldodstat DSP polymorph was characterized using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and polarized light microscopy (PLM), and was subsequently subjected to various recrystallization and analysis procedures to confirm that it is the DSP polymorph. Crushing experiment 30 mg of DSP polymorphs were ground with a mortar and pestle for 15 minutes and subsequently examined by XRPD. A few drops of THF were added to the sample during the grinding process. If new forms are identified, they will be further characterized by DSC and TGA. The XRPD results are shown in Figure 8. Recrystallization experiments Approximately 3 mg of the Faldotstat raw material was dissolved in acetic acid to obtain a clear solution at room temperature. The sample was heated to 55° C. and further material was added until no more material dissolved. After this, the samples were filtered and stored at room temperature and allowed to recrystallize for approximately 20 hours before they were analyzed by XRPD and PLM. In cases where new forms were identified, they were further characterized by DSC and TGA. The XRPD results are shown in FIG. 9. The PLM images are shown in FIG. 20A and 20B. Reactive crystallization experiments Approximately 100 mg of the DSP polymorph was dissolved in a basic solvent (1N NaOH) to produce a clear solution. After filtering the solution, an acid solution (1N HCl) was mixed to precipitate the drug substance, which was then isolated and analyzed by XRPD and PLM. If a new form was identified, it was further characterized by DSC and TGA. The XRPD results are shown in Figure 10. The PLM images are shown in Figures 22A-22D. Preparation of amorphous samples Spray drying Approximately 1.2 g of the DSP polymorph was dissolved in THF solvent to produce a clear solution. This solution was then spray dried to produce an amorphous solid dispersion. The parameters used for spray drying are as follows: [Table 2] The spray dried sample was analyzed by XRPD and the results are shown in FIG. Solvent evaporation Approximately 260 mg of the Faldodstat raw material was dissolved in THF solvent to produce a clear solution. The solution was then concentrated to dryness using a rotary evaporator at a temperature of approximately 40° C. The residual solid was analyzed by XRPD. The XRPD results are shown in FIG. 14. The PLM results are shown in FIG. 23A and 23B. ·Lyophilization Approximately 30 mg of the Faldodstat raw material was dissolved in DMSO to produce a clear solution, which was then cooled with dry ice in acetone. Water was then added to the sample, after which it was cooled again. Finally, the frozen solution was freeze-dried and the remaining solid was analyzed by XRPD. The XRPD results are shown in Figure 15. Crushing experiment Approximately 1.2 g of Faldostat raw material was placed in the ball mill. The sample was ground for approximately 24 cycles of grinding followed by a 30 minute pause. The sample was then analyzed by XRPD and PLM. The XRPD results are shown in Figure 16. The PLM results are shown in Figures 20A and 20B. Characterization of DSP polymorphisms FIG. 2 shows the XRPD of the Faldhodstat DSP polymorph. FIG. 3 shows the detailed positions of the peaks in FIG. FIG. 17 shows the TGA and DSG profiles of the DSP polymorphism.

[0070] Example 4 - Approximate solubility of DSP in different solvents and solvent mixtures Approximate solubility was tested at room temperature using a combination of manual dilution and visual observation. The solubility of the materials in different single and mixed solvents was measured once the solvent had reached a concentration at which no particles of the Fauldhoddath particles could be visually observed. The results of solubility testing of the Faldhodstadt DSP polymorphs in 43 solvent systems are shown in Table 3 below. High solubilities (greater than 100 mg / ml) were observed in several solvents, particularly THF, 2-MeTHF, THF-MeOH (3:1), THF-CAN (3:1), THF-dichloromethane (3:1), THF-heptane (3:1), THF-water (3:1) and THF-MeOH (1:1) at room temperature. Conversely, 11 organic solvents / solvent mixtures had relatively low solubility (less than 10 mg / ml). [Table 3] Suspension equilibrium (slurry) of DSP polymorphs Suspensions of the DSP polymorphs were prepared in different single and mixed solvents (see Table 4 below). After this, the samples were kept under shaking at 25°C and 50°C for 72 hours, and then centrifuged at 14,000 rpm for 10 minutes until solid material was separated from the supernatant. The centrifuged samples were investigated by XRPD. The samples were dried overnight at 40°C under vacuum conditions and new XRPD patterns were found and investigated by XRPD, DSC and TGA. The XRPD results are shown in Figures 5A-5F.

[0071] Example 5 - Testing the Ability to Form DSP Polymorphisms After Processing / Treatment The Faldhodstat DSP polymorph was subjected to processing or treatment to test the physical stability of the form. Anti-solvent precipitation (anti-solvent) 50 mg of DSP polymorphs were dissolved in the selected solvent (see Table 4) according to the solubility results to form a saturated solution. Then, under stirring, anti-solvent was slowly added into the solution until a precipitate formed. In the absence of a solid precipitate at room temperature, the sample was transferred to a freezer and stored at -20°C. After this, the sample was stirred for 24 hours and then centrifuged at 14,000 rpm for 10 minutes until solid material was separated from the supernatant. The centrifuged sample was investigated by XRPD. The sample was then dried overnight at 40°C under vacuum conditions. Once a crystalline XRPD pattern was found, the sample was further investigated by XRPD, DSC and TGA. The XRPD results are shown in Figure 4A and Figure 3B. The test parameters are shown in Table 4. [Table 4] All experiments confirmed that the DSP polymorph was the predominant form. No precipitation was obtained for the poor solvents DMSO, NMP and evaporated NMP. Spontaneous precipitation (evaporation) from a saturated solution Due to the high solubility of DSP polymorphs in some of the solvents (see Table 4), these solvents were selected for the evaporation study. Solutions were prepared according to the solubility of the compounds and kept open at room temperature to allow the solvent to evaporate and form crystals. After evaporation was complete, the dry solids were collected and investigated by XRPD. When new XRPD patterns were found, further investigations were carried out by DSC and TGA. The XRPD results are shown in Figure 7. Solvent-heating / cooling experiments 10-30 mg of ASLAN003 in its original form was filled into glass vials and placed in a thermomixer at 60°C or 50°C. After this, the solvent of choice (see Table 4) was slowly added to the sample until the compound was completely dissolved. The sample was then transferred to a Crystal 16 crystallizer and cooled to 0°C at a rate of 0.5°C / min, followed by holding at 0°C for 24 hours. In the absence of solid precipitation at 0°C, the sample was transferred to a -20°C freezer. Once the cooling process was complete, the sample was centrifuged at 14,000 rpm for 10 minutes until the solid material was separated from the supernatant. The centrifuged wet sample was examined by XRPD. The sample was then dried overnight at 40° C. under vacuum conditions. Once a crystalline XRPD pattern was found, the sample was further examined by XRPD, DSC and TGA. The XRPD results are shown in Figures 6A and 6B.

[0072] Example 6 - Further characterization of the Faldhodstat DSP polymorphism Two samples from Example 4: 1. THF solvent by evaporation: and 2. Water-containing THF as a poor solvent was dried overnight at 40° C. under reduced pressure and then further characterized and evaluated. The PLM results are shown in Figures 23 and 24. The XRPD results are shown in Figures 11 and 12. The TGA and DSC results of the mixed sample are shown in Figures 18 and 19. The results of the sample in THF solvent by the evaporation method and in a mixture of THF and water by the antisolvent method confirm that the polymorph is stable. conclusion Experiments show that the Faldhodstat DSP polymorph exhibits good crystallinity and a high melting point with minimal weight loss after heating to 200°C. The Faldodstat DSP polymorph was recrystallized from multiple solvents and was stable and reproducible, suggesting that it is the dominant and stable pharmaceutical polymorph (DSP).

[0073] Example 7 - Faldostat DSP Polymorphic Particle Size Distribution (PSD) [Table 5]

[0074] Example 8 - Faldodstat polymorphism screening experiment A solvent solubility screen was performed on the Faldhodstat DSP polymorph (also referred to as CS-276-22 in the following examples) to measure its solubility in various solvents and to obtain an initial assessment of the polymorphic status. Aliquots (2x50μL and then 100μL) of the selected solvent were added to approximately 20mg samples of predominantly amorphous Faldhodstat until dissolution was observed or until the addition of 2mL was complete. The samples were manually stirred and heated to approximately 40°C on a block attached to a water bath between each aliquot. The clear solution was uncapped and allowed to evaporate at room temperature. The slurries and all solids obtained from the evaporation were analyzed by X-ray powder diffraction (XRPD). The results of the solvent solubility evaluation are shown in Figure 25A and summarized in Figure 25B. The results show that all solids isolated from 2-propanol, 48% methanol:52% water (% v / v), 93% ethanol:7% water (% v / v), 98.5% ethanol:1.5% water (% v / v), methanol and tert-butyl methyl ether reverted to pattern 1 (except for 1,1-dimethoxymethane, 1,4-dioxane, 2-ethoxyethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, 2-methylTHF and benzyl alcohol, all of which remained amorphous). The high boiling solvents, DMSO, DMA, DMP and NMP, were evaporated successively. The solids isolated from the evaporation of clear solutions of THF and THP showed preferred orientation but later reverted to pattern 1 after grinding. Preferred orientation is a problem often observed in XRPD experiments that can occur depending on the size / morphology of the crystals being analyzed. In a normal experiment, a crystalline powder has a distribution that, as each face of the crystal is analyzed, ultimately gives an accurate diffractogram with peak intensities corresponding to the atoms (electrons) on each crystal face. However, when preferred orientation occurs, only certain faces of the crystal are observed. For example, needles tend to align like cigarette packets rather than in a random distribution. Thus, certain crystal faces are exposed to more X-ray radiation than other faces. Preferred orientation therefore sometimes results in diffractograms where only one peak is observed, or the appearance of peaks that would not normally be observed. Gentle grinding of the sample can therefore be used to minimize the possibility of these confusing effects. Based on the solvent solubility evaluation results, 16 solvent systems shown in Table 6 were selected for polymorphism screening experiments. [Table 6] The following experiments: solvent drop milling, rapid cooling, rapid evaporation at 50°C and 100°C (thermal cycling), addition of anti-solvent at ambient (room) and elevated temperature (50°C), and a two-week slurry experiment at 40°C were performed to identify additional Faldhodstadt polymorphs. Solvent Droplet Grinding 16x20mg of Faldodstat DSP polymorph samples were weighed into 2mL bead mill vials and milled for 1.5 hours for amorphization. 5μL of the appropriate solvent (see Table 6) was then added to each sample. The samples were then bead milled using the following procedure: 1.2 stainless steel beads were added to each vial. 2.4500rpm 3.10X90s cycle 4. Hold for 10 seconds between each cycle 5. Repeat 4x to get 1 hour of grind time The post-milling solids were first analyzed by XRPD to examine the amorphous pattern in comparison to the Faldhodstat DSP polymorph. This investigation step was performed for other experiments whenever bead milling was performed. Representative XRPD results are shown in FIG. 26. The XRPD results suggest that Faldhodstat bead milling typically gives less crystalline material. Similar XRPD patterns were observed for post-bead milling examinations performed in other experiments. FIG. 27A shows the XRPD patterns from the solvent drop crushing experiments for the 16 solvent systems tested, and FIG. 27B summarizes the results. The results show that the solids returned from the solvent drop milling from all 16 solvent systems reverted to pattern 1. Thermal cycle experiment First, 16x20mg of Faldodstat sample was weighed into a 2mL bead mill vial and milled for amorphous material preparation. For all 20 bead milled samples, 100μL aliquots of the appropriate solvent (see Table 6) were added until a flowable slurry was obtained without any appreciable dissolution. Samples were stirred at 40°C during addition. Samples were then stirred and temperature cycled between 5 and 40°C for approximately 72 hours (0.1°C / min heating / cooling rate, 1 hour hold at each temperature). After 48 hours, the samples were inspected. Additional solids were added if necessary. Non-flowable solids in the solution samples were stirred with a spatula until a flowable slurry was obtained. The slurry was separated by centrifugation (0.22 μm nylon filter) and the solids were analyzed by XRPD. After XRPD analysis, the XRPD plate was dried under vacuum at 40° C. for 48 hours and the solids were reanalyzed by XRPD to provide an indication of morphological stability. FIG. 28A shows the XRPD results from the thermal cycling experiment, and FIG. 28B shows a summary of the results. High boiling point solvents such as DMSO, DMA, DMF and NMP were clear solutions and were allowed to evaporate. After isolation of the solids, the saturates were allowed to evaporate for 72 hours and all the returned solids were further analyzed by XRPD. The results show that the solids returning from the thermal cycling experiment reverted to pattern 1, with the exception of 1,4-dioxane, THP and THF, which remained semi-crystalline. Room temperature evaporation experiment The saturates isolated from the previous thermal cycling experiment were allowed to evaporate at room temperature. All solids returned from the evaporation were analyzed by XRPD. Figure 29A shows the XRPD results from the thermal cycling experiment, and Figure 29B shows a summary of the results. The results show that solids obtained from room temperature evaporation of 1,1,1,3,3,3-hexafluoro-2-propanol, 2-methylTHF, DMF, and THF and THP reverted to pattern 1. Solids returned from 1,1-dimethoxymethane, 1,3-dioxolane, and 1,4-dioxane showed the preferred orientation of pattern 1, but reverted to pattern 1 after grinding. Rapid evaporation experiment at 50℃ 16x20mg of Faldodstat sample was weighed into a 2mL bead mill vial and then milled for amorphous material preparation. The appropriate solvent was added in 100μL aliquots to the bead milled sample until a flowable slurry was obtained without any appreciable dissolution. During the addition, the sample was stirred at 50°C and 100°C depending on the boiling point of the solvent that dissolves the API in that solvent system. The sample was inspected, the slurry was separated by centrifugation (0.22μm nylon filter) and the saturates were placed in an HPLC vial. The vial was then uncapped and evaporated using a water bath at 50°C. Finally, after the solvent evaporation was complete, the remaining solid was analyzed by XRPD to check for the appearance of any new patterns. 30A-F show the XRPD results from the thermal cycling experiments, and FIG. 30G shows a summary of the results. Solids returned after flash evaporation of saturates in 1,3-dioxolane, 1,4-dioxane at 50° C. showed preferred orientation. See Figures 30A and B. Solids returned after flash evaporation of saturates in 1,1-dimethoxymethane and 2-propanol at 50° C. showed amorphous patterns. Very little solid was obtained from the 2-propanol sample. See Figure 30C. Solids returned after flash evaporation of saturates in THP, THF, 2-methylTHF and 1,1,1,3,3,3-hexafluoro-2-propanol at 50° C. returned to pattern 1. See Figure 30D. A possible new pattern was observed in 2-ethoxyethanol, where a new peak at 21.1° 2θ appeared. See Figure 30E. Solids returned after flash evaporation of saturates in DMF at 50° C. showed pattern 1 with pronounced preferred orientation. See Figure 30F. The DMA, NMP and DMSO are still in solution. Rapid evaporation experiments at 100°C for high boiling point solvents (DMSO, DMA, DMP and NMP) Five 20mg Faldodstat samples were weighed into 2ml bead mill vials and milled to prepare the amorphous material. To the bead milled samples, 100μL aliquots of the appropriate solvent were added until a flowable slurry was obtained without any appreciable dissolution. During the addition, the samples were stirred at 100°C to dissolve the API in the solvent system. The samples were inspected, the slurry was separated by centrifugation (0.22μm nylon filter) and the saturates were placed in an HPLC vial. The vials were then uncapped and evaporated at 100°C using a water bath. After complete evaporation of the solvent, the remaining solids were analyzed by XRPD to check for the appearance of any new patterns. Figures 31A and B show the XRPD results from the fast evaporation experiments and Table 7 below shows a summary of the results. [Table 7] The solid returned from the flash evaporation of DMA showed a preferred orientation which, after grinding, reverted to pattern 1. See Figure 31A. The solid returned from the flash evaporation of DMF showed a preferred orientation which, after grinding, reverted to pattern 1. See Figure 31B. The DMSO, NMP saturates were subsequently evaporated. Rapid cooling experiment 20mg x 16 Faldotstat samples were weighed into 2ml bead mill vials and milled to prepare amorphous material. The appropriate solvent was added in 100μL aliquots until a flowable slurry was obtained without any appreciable dissolution. During addition, the samples were stirred at 50°C and 100°C depending on the boiling point of the solvent that dissolves the API in that solvent system. The samples were inspected, the slurry was separated by centrifugation (0.22μm nylon filter) and the saturates were placed in a freezer for 72 hours. The vials were inspected for any solid precipitate. The solids were then separated by centrifugation (0.22μm nylon filter) and analyzed by XRPD. FIG. 32A shows the XRPD results from the rapid cooling experiment, and FIG. 32B shows a summary of the results. The solid recovered from the rapid cooling of 1,3-dioxolane showed a preferred orientation of pattern 1. No solids were obtained from rapid cooling of the other 15 saturates. Two-week slurry experiment 16x20mg of Faldodstat sample was weighed into a 2mL bead mill vial and bead milled for preparation of amorphous material. Milling followed the following protocol: ·Two stainless steel beads were added to each vial. 5000rpm 10X90s cycle -10s hold between each cycle -6 iterations to get 1.5 hours of grinding time The ground sample was analyzed by XRPD to check for amorphous patterns as usual. The desired amount of an appropriate solvent was then added to the ground sample to create a white slurry. The vial was sealed with paraffin and stirred isothermally at 40° C. for 2 weeks. After 2 weeks, the slurry was observed and the separated solids were characterized by XRPD. All clear solutions were evaporated at 100° C. and all returned solids were further analyzed by XRPD. Figure 33A shows the XRPD results from the two week slurry experiment. Figure 33B shows the XRPD results from the two week slurry experiment for a sample that was subjected to flash evaporation at 100° C. Figure 33C shows a summary table of the results from the entire two week slurry experiment. Results show that solids returned from 2-week slurry experiments in 93% ethanol:7% water (% v / v), 48% methanol:52% water (% v / v), 2-propanol, and 2-methylTHF reverted to Pattern 1. Solids returned from THF and THP showed an additional peak of Pattern 1 at 8.1° 2θ (Pattern 1+). After flash evaporation at 100 °C, the solids obtained from 1,1-dimethoxymethane, 1,3-dioxolane, 2-ethoxyethanol and 1,1,1,3,3,3-hexafluoro-2-propanol, DMA, DMF and NMP showed preferred orientation. However, after grinding, they reverted to pattern 1. Antisolvent addition experiments (acetone, heptane, MEK and water) 20mg x 16 Faldotstat samples were weighed into 2ml bead mill vials and milled to prepare amorphous material. Appropriate solvent was added in 100μL aliquots until a flowable slurry was obtained without any observed dissolution. Samples were stirred at elevated temperature (40°C). Samples were inspected, the slurry was separated by centrifugation (0.22μm nylon filter) and the saturates were split into 4 different vials. Anti-solvents water, MEK, acetone and heptane were added to each vial at room temperature and any solid precipitate was inspected. The solids were then separated by centrifugation (0.22μm nylon filter) and analyzed by XRPD. The results are shown in Figures 34A and C and summarized in Figures 34B and 34D-F. Solids returning from water as anti-solvent addition reverted to pattern 1, with the exception of 2-methyl THF, 2-propanol, 48% methanol:52% water (% v / v), 93% ethanol:7% water (% v / v) and benzyl alcohol, which remained as clear solutions. See Figure 34A. Solids returned from acetone as anti-solvent addition to 1,1,1,3,3,3-hexafluoro-2-propanol returned to pattern 1 with additional peaks likely due to splitting of the peaks due to preferred orientation. See Figure 34C. A cloudy solution was observed for the addition of heptane in 1,1-dimethoxymethane and 1,2-dioxolane. No precipitation of solids was observed upon addition of heptane to any of the other 14 solvent systems. No solid precipitation was observed upon addition of MEK to any of the 16 solvent systems tested. Antisolvent addition + rapid cooling experiment All clear solutions from previous antisolvent addition experiments were placed in a freezer for rapid cooling. After 72 hours, samples were inspected and the solid precipitate was separated by centrifugation (0.22 μm nylon filter) and then reanalyzed by XRPD. Only the sample using MEK as the anti-solvent in 1,4-dioxane produced a white solid after flash cooling and was analyzed by XRPD. The XRPD results are shown in Figure 35 and show that the sample has an XRPD pattern consistent with Pattern 1. All other flash-cooled samples remained as clear solutions. Addition of antisolvent at high temperature (50℃) 20mg x 16 Faldotstat samples were weighed into 2ml bead mill vials and milled to prepare amorphous material. The appropriate solvent was added in 100μL aliquots until a flowable slurry was obtained without any appreciable dissolution. The samples were stirred at elevated temperature (40°C). The samples were then inspected, the slurry was separated by centrifugation (0.22μm nylon filter) and the saturates were transferred to HPLC vials. Water as anti-solvent was added to each vial at 50°C and any solid precipitate was inspected. The solids were then separated by centrifugation (0.22μm nylon filter) and analyzed by XRPD. The results are shown in Figure 36A and summarized in Figure 36B. The results show that for all 16 saturates, the solids obtained from water addition at 50°C reverted to Pattern 1. conclusion Most of the solids recovered from the solvent systems tested produced XRPD patterns consistent with the Faldhodstat DSP polymorph (Pattern 1). Thus, the above experiments provide further evidence that the Faldhodstat DSP polymorph disclosed herein is highly stable.

[0075] Example 9 - Characterization of the Faldhodstat Polymorphism The solids returned from the 2-week slurry experiment in THF and THP showed an additional peak of Pattern 1 at 8.1° 2θ (Pattern 1+). In light of this interesting observation, the 2-week slurry experiment was repeated. As a result of the experiment, two novel Faldhodstat polymorphs were identified: Faldhodstadt polymorph obtained by crystallization from 1,1,1,3,3,3-hexafluoro-2-propanol (HIFP) 500 μL of 1,1,1,3,3,3-hexafluoro-2-propanol was added to 20 mg of amorphous Faldhodstadt DSP polymorph in a 1.5 mL HPLC vial equipped with a magnetic stir bar to form a fluid slurry. The slurry was stirred isothermally at 40° C. for 2 weeks. After 1 week, a clear solution was obtained and an additional 20 mg of material was added to the slurry. The solids were separated by centrifugation using a 0.22 μm nylon filter and analyzed without further drying by XRPD, TGA and HPLC. 1 The sample was analyzed by H NMR (proton nuclear magnetic resonance). Finally, the sample was dried at 40° C. for 4 hours and then reanalyzed by XRPD. The XRPD results are shown in Figure 37. As can be seen from Figure 37, a distinct new XRPD pattern was observed for 1,1,1,3,3,3-hexafluoro-2-propanol, which we call pattern 2. However, gentle drying at 40°C for 4 hours reverted the XRPD pattern back to the Faldhodstat DSP polymorph (pattern 1). Figure 38 shows the XRPD peak list for pattern 2. Figures 39A and B show the results of the TG analysis. The TG analysis showed a mass loss of 0.118 mg (5.59%), which corresponds to 0.13 equivalents of hexafluoro-2-propanol. Concurrent DSC analysis showed an endothermic event, consistent with the melting of pattern 1. This suggests that the new 1,1,1,3,3,3-hexafluoro-2-propanol polymorph is a metastable form that readily reverts to the Faldhodstat DSP polymorph after drying at 40°C for 4 hours. 40A and B show the 1,1,1,3,3,3-hexafluoro-2-propanol polymorph before (wet) and after drying, respectively. 1 1 H NMR spectrum is shown. The NMR spectrum in Figure 40A shows the presence of an additional peak at 5.15 ppm (methine protons of HFIP). The overall data also suggests that the 1,1,1,3,3,3-hexafluoro-2-propanol polymorph appears to be a monosolvate. 41A and B show the FR-IR spectrum of the 1,1,1,3,3,3-hexafluoro-2-propanol polymorph and the FR-IR spectrum of the Faldhodstat DSP polymorph, respectively. As can be seen, the FR-IR spectra are clearly different between the two samples. The difference in solvent content between TGA and NMR analysis can be explained at least in part by the nature of the analysis. In this regard, TGA uses a stream of nitrogen gas that covers the sample during the analysis. This appears to be sufficient to partially desolvate the 1,1,1,3,3,3-hexafluoro-2-propanol polymorph. In contrast, in NMR, the entire sample is dissolved in the NMR solvent and added to the NMR tube. Thus, the entire sample as well as the 1,1,1,3,3,3-hexafluoro-2-propanol solvent will be included in the subsequent analysis. Taken together, the data provide evidence that the polymorph derived from 1,1,1,3,3,3-hexafluoro-2-propanol is a novel, but unstable polymorphic form of Faldodstat. Faldodstadt polymorphs obtained by crystallization from N-methylpyrrolidone (NMP) 350 μL of N-methylpyrrolidone (NMP) was added to 20 mg of amorphous Faldodato DSP polymorph in a 1.5 mL HPLC vial equipped with a magnetic stir bar to prepare a flowable slurry. The resulting slurry was thermally cycled between 5 and 40 °C for 3 days (ramp rate: 0.1 °C / min, 1 h isothermal holds at 40 °C and 5 °C). The solid was then analyzed by XRPD after evaporation of the saturated solution at 100 °C. The XRPD results are shown in Figure 42. The XRPD diffractogram of the evaporated solid, which we call Pattern 3, showed additional peaks at 15.28°2θ, 17.73°2θ, 18.48°2θ, 23.13°2θ, 24.60°2θ, 25.96°2θ, and 29.90°2θ along with Pattern 1, suggesting the presence of a mixture of the Faldhodstat DSP polymorph and another novel polymorphic form. Gentle grinding did not change the observed pattern. However, drying at 40°C for 4 hours converted Pattern 3 to Pattern 1 (i.e., the XRPD pattern of the Faldhodstat DSP polymorph). Figure 43 shows the peak list for Pattern 3. Enhanced peaks are additional peaks observed in addition to the peaks in Pattern 1. The results of the TG analysis are shown in Figure 44. The analysis showed a mass loss of 0.048 mg from the start of heating, which corresponds to 0.07 equivalents of NMP. The results of the NMR analysis are shown in FIG. 1 The 1 H NMR spectrum showed multiplets at 2.06 ppm and 1.96 ppm, corresponding to 0.2 equivalents of NMP solvent present in the test sample. Taken together, the above data indicate that a new Faldhodstadt polymorph may be obtained by crystallization from NMP. At this stage, this new polymorph has not been isolated in pure form, but instead was obtained as a mixture with the Faldhodstadt DSP polymorph. However, given that gentle heating at 40°C for 4 hours was sufficient to revert from pattern 3 back to pattern 1, this new polymorph (like the 1,1,1,3,3,3-hexafluoro-2-propanol polymorph) may be unstable / metastable. conclusion These experiments indicate that the novel Faldhodstat polymorphs may be obtained by crystallization from the solvents 1,1,1,3,3,3-hexafluoro-2-propanol and NMP (see schematic diagram in Figure 46). However, the data suggest that these novel polymorphs have a high tendency to revert to the Faldhodstat DSP polymorph, thus further indicating the high stability of the Faldhodstat DSP polymorph successfully produced and identified.

Claims

1. 1. A polymorph, such as a crystalline polymorph, of the DHODH inhibitor 2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid, characterized by an X-ray powder diffraction pattern including peaks at the following approximate degrees 2θ: 9.129±0.1, 17.375±0.1, 20.708±0.1, 25.274±0.1, 26.488±0.1, and 29.041±0.

1.

2. 2. The polymorph of claim 1, wherein the X-ray powder diffraction pattern further comprises one or more peaks selected from the group comprising: 13.686±0.1, 14.159±0.1, 19.900±0.1, 21.431±0.1, 22.750±0.1, 25.607±0.1 and 30.893±0.

1.

3. 3. The polymorphism of claim 1 or 2, wherein the X-ray powder diffraction pattern further comprises one or more peaks selected from the group comprising: 12.313±0.1, 13.223±0.1, 18.167±0.1, 22.146±0.1, 23.418±0.1, 23.828±0.1, 25.885±0.1, 27.219±0.1 and 30.612±0.

1.

4. 4. The polymorph of any one of claims 1 to 3, wherein the X-ray powder diffraction pattern further comprises one or more peaks selected from the group comprising: 10.645±0.1, 27.453±0.1, 29.762±0.1, 31.743±0.1 and 39.115±0.

1.

5. 5. The polymorph of any one of claims 1 to 4, wherein the X-ray powder diffraction pattern further comprises one or more peaks selected from the group comprising: 14.580±0.1, 28.368±0.1, 32.950±0.1, 33.445±0.1, 33.800±0.1, 34.936±0.1, 35.497±0.1, 35.981±0.1, 37.678±0.1, 38.099±0.1 and 38.520±0.

1.

6. 6. The polymorphism of any one of claims 1 to 5, wherein the X-ray powder diffraction pattern further comprises one or more peaks selected from the group comprising: 12.313±0.1, 13.223±0.1, 13.686±0.1, 14.159±0.1, 16.477±0.1, 18.167±0.1, 19.900±0.1, 21.431±0.1, 22.146±0.1, 22.750±0.1, 23.418±0.1, 23.828±0.1, 25.607±0.1, 25.885±0.1, 27.219±0.1, 30.612±0.1 and 30.893±0.

1.

7. 7. The polymorphism of any one of claims 1 to 6, wherein the X-ray powder diffraction pattern further comprises one or more peaks selected from the group comprising: 10.645±0.1, 14.580±0.1, 27.453±0.1, 28.368±0.1, 29.762±0.1, 31.743±0.1, 32.950±0.1, 33.445±0.1, 33.800±0.1, 34.936±0.1, 35.497±0.1, 35.981±0.1, 37.678±0.1, 38.099±0.1, 38.520±0.1 and 39.115±0.

1.

8. The X-ray powder diffraction pattern shows peaks: 9.129±0.1, 10.645±0.1, 12.313±0.1, 13.223±0.1, 13.686±0.1, 14.159±0.1, 14.580±0.1, 16.477±0.1, 17.375±0.1, 18.167±0.1, 19.900±0.1, 20.708±0.1, 21.431±0.1, 22.146±0.1, 22.750±0.1, 23.418±0.1, 23.828±0.1, 25.274±0.1, 25.607±0.1, 25.885±0.1, 8. The polymorphism of any one of claims 1 to 7, further comprising: 26.488±0.1, 27.219±0.1, 27.453±0.1, 28.368±0.1, 29.041±0.1, 29.762±0.1, 30.612±0.1, 30.893±0.1, 31.743±0.1, 32.950±0.1, 33.445±0.1, 33.800±0.1, 34.936±0.1, 35.497±0.1, 35.981±0.1, 37.678±0.1, 38.099±0.1, 38.520±0.1 and 39.115±0.

1.

9. 9. The polymorph according to any one of claims 1 to 8, characterized by the X-ray powder diffraction pattern shown in Figure 2.

10. A composition comprising the polymorph of any one of claims 1 to 9 and a pharma- ceutically acceptable excipient, diluent or carrier.

11. A polymorphism according to any one of claims 1 to 9 or a composition according to claim 10 for use in therapy.

12. 12. The polymorphism or composition for use according to claim 11, wherein the treatment is for a viral disease or an autoimmune disease.

13. The polymorphism or composition for use according to any one of claims 11 to 12, wherein the virus is selected from the group comprising Dengue (e.g. serotype 1, 2, 3 or 4), Zika, Chikungunya and SARS-CoV-2.

14. 14. The polymorphism or composition for use according to any one of claims 12 to 13, wherein the autoimmune disease is selected from the group comprising multiple sclerosis, rheumatoid arthritis and inflammatory bowel disease (such as ulcerative colitis and Crohn's disease).

15. 13. The polymorphism or composition for use according to claim 12, wherein the autoimmune disease is an autoimmune skin disease selected from the group comprising, for example, vitiligo, alopecia, atopic dermatitis, Behcet's disease, dermatitis herpetiformis, dermatomyositis, lichen planus, linear IgA disease, cutaneous lupus, morphea / scleroderma, ocular cicatricial pemphigoid, pemphigoid such as bullous pemphigoid or pemphigoid of gestation, pemphigus (pemphigus vulgaris, pemphigus vulgaris, pemphigus foliaceus, erythematous pemphigus, IgA pemphigus, pemphigus vegetans, or paraneoplastic pemphigus), vasculitis, epidermolysis bullosa acquisita, psoriasis, and vesicular bullous dermatoses.

16. 16. The polymorphism or composition for use according to claim 15, wherein the autoimmune skin disease is selected from the group comprising vitiligo, such as vitiligo divided or non-divided, and alopecia, such as alopecia universalis, alopecia areata, alopecia areata, alopecia areata beard, alopecia areata totalis or alopecia universalis.

17. Use of a polymorphism according to any one of claims 1 to 9 or a composition according to claim 10 in the manufacture of a medicament for the treatment of a viral infection or an autoimmune disease.

18. A method of treating a viral infection or an autoimmune disease comprising administering to a subject in need thereof a therapeutically effective amount of a polymorphism according to any one of claims 1 to 9 or a composition according to claim 10.

Images