Small molecule alpha4beta7 integrin inhibitor for use in the treatment of inflammatory bowel disease

Abstract

The present inventions relate to novel doses, and dose regimens of certain small molecule α4β7 integrin inhibitor compounds, and to related methods of treating α4β7 integrin-related conditions, such as inflammatory bowel disease (IBD), ulcerative colitis (UC), and Crohn's disease (CD). The present invention also relates to novel crystalline forms, and dispersions of certain small molecule α4β7 integrin inhibitor compounds.

Description

DOSING, DOSING REGIMENS, CRYSTALLINE FORMS, AND DISPERSIONS OF SMALL MOLECULE a4p7INTEGRIN INHIBITORFIELD OF THE INVENTION

[0001] The present invention relates to novel doses, and dose regimens of certain small molecule a4 7integrin inhibitor compounds, and to related methods of treating a4p7integrin-related conditions, such as inflammatory bowel disease (IBD), ulcerative colitis (UC), and Crohn’s disease (CD). The present invention also relates to novel crystalline forms, and dispersions of certain small molecule a4p7integrin inhibitor compounds.BACKGROUND OF THE INVENTION

[0002] Integrins are noncovalently associated a / p heterodimeric cell surface receptors involved in numerous cellular processes. Differential expression of integrins can regulate a cell’s adhesive properties, allowing different leukocyte populations to be recruited to specific organs in response to different inflammatory signals. The a4integrins, including a4p7, play a role in lymphocyte migration throughout the gastrointestinal tract. They are expressed on most leukocytes, including B and T lymphocytes, where they mediate cell adhesion via selective binding to its primary ligand, mucosal addressin cell adhesion molecule (MAdCAM). Memory T lymphocytes expressing the cup7integrin preferentially migrate into the gastrointestinal tract via firm adhesion to mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1).

[0003] Inhibitors of specific integrin-ligand interactions have been used for the treatment of various diseases. For example, monoclonal antibodies displaying high binding affinity for a4p7have displayed therapeutic benefits for gastrointestinal auto-inflammatory / autoimmune diseases, such as CD and UC. However, these therapies also have certain undesirable properties for the patient. Vedolizumab (Entyvio®) is a monoclonal antibody that blocks ouP?, which is approved by the FDA for the treatment of UC and CD. Despite Vedolizumab’s demonstrated efficacy and general safety profile, a small molecule oral drug directed at a4p7inhibition would present several clinical advantages, including:• A flexible dosing regimen;• Lower safety concerns related to immunogenicity and infusion-related reactions; and• The requirement for fewer clinical visits, reducing patient and healthcare provider burden.

[0004] The compound (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid (hereinafter referred to as “Compound I”) is disclosed in WO 2021 / 076890 Al as a selective 014P7 integrin inhibitor.

[0005] There remains a need for stable forms and formulations of Compound I that can be orally administered in efficacious, safe doses, and easily manageable dosing regimens.SUMMARY OF THE INVENTION

[0006] The potency and selectivity of Compound I-mediated 014P7 inhibition has been demonstrated in a series of in vitro and in vivo assays. In vitro assays have shown the ability of Compound I to potently and specifically disrupt MAdCAM-1 interaction across multiple conditions, with selectivity against other integrins ranging from over 100-fold to over 143,000-fold. In vivo, mechanistically relevant mouse and non-human primate (NHP) animal models demonstrated that Compound I inhibited o^-mediated lymphocyte trafficking to the mucosal tissues to an extent comparable to treatment with an 014P7 antibody. Selectivity for 014P7 was monitored using an ex vivo method for measuring receptor occupancy (RO) in human whole blood for cuP? and 014P1. Notably, Compound I was shown to be a highly selective inhibitor for 014P7 over (X4P1, with a >600-fold selectivity ratio.

[0007] In a first aspect, the present invention relates to novel doses and dose regimens of small molecule 014P7 integrin inhibitor compounds, and to related methods of treating inflammatory bowel disease. The compounds of the present invention are potent inhibitors of C / .4P7 integrin and display high selectivity for C / .4P7 integrin over other integrins, especially cuP 1 integrin. These finely tuned properties allow the compounds of the present invention to be orally dosed to patients in need thereof in efficacious, safe doses, and easily manageable dosing regimens.

[0008] Accordingly, the invention provides a method of treating inflammatory bowel disease in a patient in need thereof comprising administering to the patient a compound which is (5)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid or a pharmaceuticallyacceptable salt or cocrystal thereof, wherein the compound is administered in a dose of about 10 mg to about 850 mg free form equivalent.

[0009] In an embodiment, the compound or pharmaceutically acceptable salt or cocrystal thereof is administered in a dose of about 25 mg to about 400 mg free form equivalent. In another embodiment, the compound or pharmaceutically acceptable salt or cocrystal thereof is administered in a dose of 50 mg to about 350 mg free form equivalent. In a yet another embodiment, the compound or pharmaceutically acceptable salt or cocrystal thereof is administered in a dose of about 100 mg to about 300 mg free form equivalent. In a further embodiment, the compound or pharmaceutically acceptable salt or cocrystal thereof is administered in a dose selected from about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, and about 400 mg free form equivalent. Preferentially, the compound or pharmaceutically acceptable salt or cocrystal thereof is administered in a dose selected from about 25mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, about 200 mg, about 300 mg, and about 400 mg free form equivalent. Even more preferentially, the compound or pharmaceutically acceptable salt or cocrystal thereof is administered in a dose selected from about 100 mg, about 150 mg, about 200 mg, about 300 mg, and about 400 mg free form equivalent.

[0010] In an embodiment, the compound or pharmaceutically acceptable salt or cocrystal thereof is administered in a dose of about 100 mg to about 800 mg free form equivalent. In another embodiment, the compound or pharmaceutically acceptable salt or cocrystal thereof is administered in a dose of about 100 mg to about 400 mg free form equivalent. In a further embodiment, the compound or pharmaceutically acceptable salt or cocrystal thereof is administered in a dose of about 200 mg to about 400 mg free form equivalent. In another embodiment the compound or pharmaceutically acceptable salt or cocrystal thereof is administered in a dose selected from about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg free form equivalent. In an embodiment, the compound or pharmaceutically acceptable salt orcocrystal thereof is administered in a dose selected from about 100 mg, about 150 mg, about 200 mg, about 300 mg, and about 400 mg free form equivalent. In another embodiment, the compound or pharmaceutically acceptable salt or cocrystal thereof is administered in a dose of about 200 mg free form equivalent. In another embodiment, the compound or pharmaceutically acceptable salt or cocrystal thereof is administered in a dose of about 400 mg free form equivalent.

[0011] In an embodiment, the compound or pharmaceutically acceptable salt or cocrystal thereof is administered once, or twice daily. In an embodiment, the compound or pharmaceutically acceptable salt or cocrystal thereof is administered twice daily. In another embodiment, the compound or pharmaceutically acceptable salt or cocrystal thereof is administered once daily. In a further embodiment, the compound or pharmaceutically acceptable salt or cocrystal thereof is administered once daily in the morning. In a separate embodiment, the compound or pharmaceutically acceptable salt or cocrystal thereof is administered once daily in the evening.

[0012] The present invention also provides a method of treating inflammatory bowel disease in a patient in need thereof comprising administering to the patient a compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is administered to the patient according to the following dosing regimen:a. initial doses of about 10 mg to about 850 mg free form equivalent for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 10 mg to about 850 mg free form equivalent.

[0013] In an embodiment the subsequent dose is lower than the initial dose. In another embodiment the subsequent dose is higher than the initial dose.

[0014] In an embodiment, the initial doses and subsequent doses are independently of about 100 mg to about 800 mg free form equivalent. In another embodiment, the initial doses and subsequent doses are independently of about 100 mg to about 400 mg free form equivalent. In a further embodiment, the initial doses and subsequent doses are independently of about 200 mg to about 400 mg free form equivalent. In an embodiment, the initial doses and subsequent doses are independently selected from about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg free form equivalent. Preferentially, the initial doses and subsequent doses are independently selected from about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 300 mg, and about 400 mg free form equivalent. Even more preferentially, the initial doses and subsequent doses are independently selected from about 100 mg, about 150 mg, about 200 mg, about 300 mg, and about 400 mg free form equivalent.

[0015] In an embodiment of the second invention, the initial doses and subsequent doses are independently administered twice daily, or once daily. In an embodiment, the initial doses and subsequent doses are independently administered twice daily, once daily in the morning, or once daily in the evening.

[0016] In another embodiment, the initial doses are administered for a period selected from about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, and about 12 weeks. Preferentially, the initial doses are administered for a period selected from about 10 weeks, about 11 weeks, and 12 weeks.

[0017] In yet another embodiment, the IBD is UC, and the initial doses are administered until achievement of clinical remission. In a further embodiment, the IBD is UC, and the subsequent doses are administered until achievement of clinical remission. In another embodiment, the IBD is UC, and the initial doses are administered until achievement of clinical response. In another embodiment, the IBD is UC, and the subsequent doses are administered until achievement of clinical response. In another embodiment, the IBD is UC, and the initial doses are administered until achievement of MCS remission. In a further embodiment, the IBD is UC, and the subsequent doses are administered until achievement of MCS remission. In another embodiment, the IBD is UC, and the initial doses are administered until achievement of MCS response. In a further embodiment, the IBD is UC, and the subsequent doses are administered until achievement of MCS response. In another embodiment, the IBD is UC, and the initial doses are administered until achievement of histologic remission by RHI. In another embodiment, the IBD is UC, and the subsequent doses are administered until achievement of histologic remission by RHI. Inanother embodiment, the IBD is UC, and the initial doses are administered until achievement of histologic improvement. In another embodiment, the IBD is UC, and the subsequent doses are administered until achievement of histologic improvement. In another embodiment, the IBD is UC, and the initial doses are administered until achievement of endoscopic improvement. In another embodiment, the IBD is UC, and the subsequent doses are administered until achievement of endoscopic improvement. In another embodiment, the IBD is UC, and the initial doses are administered until achievement of endoscopic remission. In another embodiment, the IBD is UC, and the subsequent doses are administered until achievement of endoscopic remission. In a further embodiment, the IBD is UC, and the initial doses are administered until achievement of mucosal healing. In another embodiment, the IBD is UC, and the subsequent doses are administered until achievement of mucosal healing. In a further embodiment, the IBD is UC, and the initial doses are administered until achievement of mucosal improvement. In another embodiment, the IBD is UC, and the subsequent doses are administered until achievement of mucosal improvement. In a further embodiment, the IBD is UC, and the initial doses are administered until achievement of symptomatic response. In another embodiment, the IBD is UC, and the subsequent doses are administered until achievement of symptomatic response.

[0018] In yet another embodiment, the IBD is CD, and the initial doses are administered until achievement of endoscopic response. In another embodiment, the IBD is CD, and the subsequent doses are administered until achievement of endoscopic response. In an embodiment, the IBD is CD, and the initial doses are administered until achievement of endoscopic remission. In another embodiment, the IBD is CD, and the subsequent doses are administered until achievement of endoscopic remission. In an embodiment, the IBD is CD, and the initial doses are administered until achievement of CD Al clinical response. In another embodiment, the IBD is CD, and the subsequent doses are administered until achievement of CD Al clinical response. In an embodiment, the IBD is CD, and the initial doses are administered until achievement of CD Al clinical remission. In another embodiment, the IBD is CD, and the subsequent doses are administered until achievement of CD Al clinical remission. In an embodiment, the IBD is CD, and the initial doses are administered until achievement of PRO2 clinical response. In another embodiment, the IBD is CD, and the subsequent doses are administered until achievement of PRO2 clinical response. In an embodiment, the IBD is CD, and the initial doses are administered until achievement of PRO2 clinical remission. In another embodiment, the IBD is CD, and thesubsequent doses are administered until achievement of PR02 clinical remission. In an embodiment, the IBD is CD, and the initial doses are administered until the patient is corticosteroid-free. In another embodiment, the IBD is CD, and the subsequent doses are administered until the patient is corticosteroid-free.

[0019] In an embodiment of both the above inventions, the compound or pharmaceutically acceptable salt or cocrystal thereof is administered to the patient orally, or parenterally.Preferentially, the compound or pharmaceutically acceptable salt or cocrystal thereof is administered to the patient orally.

[0020] In an embodiment of both the above inventions, the compound is administered as part of a pharmaceutical composition which further comprises at least one pharmaceutically acceptable carrier, diluent, or excipient. In a further embodiment, the pharmaceutical composition is for oral administration. In another embodiment, the pharmaceutical composition further comprises microcrystalline cellulose, lactose, pregelatinized starch, hydroxypropyl methylcellulose, croscarmellose sodium, poloxamer, colloidal silicon dioxide, and magnesium stearate. In a further embodiment, the pharmaceutical composition is administered in a capsule, or a tablet. In yet another embodiment, each capsule or tablet comprise about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 300 mg, and about 400 mg free form equivalent of the compound.

[0021] In an embodiment of both the above inventions, the patient is advanced therapy naive. In another embodiment, the patient is advanced therapy experienced. In an embodiment the advanced therapy comprises one or more agents selected from ouP? integrin antibodies, anti-TNF-a antibodies, IL-12 antibodies, IL-23 antibodies, JAK inhibitors, and SIP receptor modulators. In a further embodiment the advanced therapy comprises one or more agents selected from vedolizumab, infliximab, adalimumab, golimumab, ustekinumab, mirikizumab, tofacitinib, filgotinib, upadacitinib, estrasimod, ozanimod, and amiselimod.

[0022] In an embodiment of both the above inventions, the IBD is UC. In some embodiments, the UC is mildly to moderately active UC. In another embodiment, the UC is moderately to severely active UC. In an embodiment of both inventions, the IBD is CD. In an embodiment, the CD is mildly to moderately active CD. In another embodiment, CD is moderately to severely active CD.

[0023] In an embodiment of both the above inventions, the patient has a baseline level of CPa9-HNE of lower than about 200 ng / ml. In another embodiment, the patient has a baseline level of C1M of lower than about 100 ng / ml. In a separate embodiment, the patient has a baseline level of C7M of lower than about 10 ng / ml.

[0024] In an embodiment of both the above inventions, the compound is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid. In an embodiment, the compound is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid Free Form D. In another embodiment, the compound is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid adipic acid. In an embodiment, the compound is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid adipic acid Form A. In another embodiment, the compound is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid adipic acid Form B.

[0025] Early form and stability work on Compound I as obtained through the synthetic methods disclosed in WO 2021 / 076890 Al revealed that the material is subject to the formation of a variety of polymorphs, several of which possess undesirable physical, and chemical stability profiles. One particular form, initially selected for further development due to its high crystallinity and apparent stability, was later found to be susceptible to processing-induced phase transformation (PIPT) to the amorphous form on compression into tablet form. This undesirable property renders the particular form unsuitable for development as a tablet for oral administration. As such, there remains a need to develop new stable forms of Compound I that can be appropriately formulated in a convenient dosing form, especially as a tablet for oral administration, without undergoing PIPT.

[0026] As such, in another aspect, the present invention relates to novel cocrystalline forms of Compound I. These forms are highly crystalline, and possesses superior physical and chemical stability, making them suitable for formulating in tablet form.

[0027] Accordingly, the invention also provides a cocrystalline form comprising (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid.

[0028] In an embodiment, the cocrystalline form comprises (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid and a dicarboxylic acid. In an embodiment, the dicarboxylic acid is selected from adipic acid, azelaic acid, suberic acid, and pimelic acid. In a preferred embodiment, the dicarboxylic acid is from adipic acid.

[0029] In an embodiment, the cocrystalline form is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid adipic acid.

[0030] In an embodiment, the cocrystalline form is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid adipic acid, and is characterized by an X-ray powder diffraction pattern using CuKa radiation comprising a peak at diffraction angle 29 of 6.3°, and one or more peaks at 16.6°, and 18.9° (±0.2° respectively).

[0031] In an embodiment, the cocrystalline form is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid adipic acid, and is characterized by an X-ray powder diffraction pattern using CuKa radiation comprising a peak at diffraction angle 29 of 5.5°, and one or more peaks at 6.8°, and 8.8° (±0.2° respectively).

[0032] In an embodiment, the cocrystalline form is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid adipic acid, and is characterized by a13C solid state NMR spectrum which comprises peaks referenced to the methyl peak of 3 -methylglutaric acid (18.8 ppm) at 16.5, 160.9, 179.3, and 20.0 ppm, with a tolerance of ±0.4 ppm.

[0033] In an embodiment, the cocrystalline form is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid adipic acid, and is characterized by a13C solidstate NMR spectrum which comprises peaks referenced to the methyl peak of 3 -methylglutaric acid (18.8 ppm) at 11.2, 163.5, 21.2, and 21.4 ppm, with a tolerance of ±0.4 ppm.

[0034] In an embodiment, the cocrystalline form is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid adipic acid, and is characterized by a19F solid state NMR spectrum which comprises peaks referenced to niflumic acid (-122 ppm) at -128.7, and -62.6 ppm, with a tolerance of ±1.0 ppm.

[0035] In an embodiment, the cocrystalline form is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid adipic acid, and is characterized by a19F solid state NMR spectrum which comprises peaks referenced to niflumic acid (-122 ppm) at -133.3, and -62.3 ppm, with a tolerance of ±1.0 ppm.

[0036] In a further aspect, the present invention relates to dispersions of Compound I. These dispersions are amorphous, stable and allow for a high loading of active compound, making them highly suitable for formulation in tablet form.

[0037] Accordingly, the invention further provides a dispersion comprising (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid and a pharmaceutically acceptable polymer. In an embodiment, the dispersion is a spray dried dispersion.

[0038] In an embodiment, the pharmaceutically acceptable polymer is selected from an HPMC polymer, and an HPMC-AS polymer. In an embodiment, the HMPC polymer is HPMC E3, while in another embodiment, the HPMC-AS polymer is HPMC-AS 716.

[0039] In a further embodiment, (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid is present in a quantity between about 30% w / w to about 95% w / w of the total weight of the dispersion. In another embodiment, (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid is present in a quantity selected from about 30% w / w, about 40% w / w, about 50% w / w, about 60% w / w, about 70% w / w, about 80% w / w, about 90% w / w, and about 95% w / w of the total weight of the dispersion.

[0040] The invention further provides a pharmaceutical composition comprising the dispersion according to previous embodiments and a pharmaceutical acceptable carrier, diluent, or excipient.BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 depicts the1HNMR spectrum of (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid Form D.

[0042] Figure 2 depicts the13C NMR spectrum of (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid Form D.

[0043] Figure 3 depicts the XRPD pattern of (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid Form D.

[0044] Figure 4 depicts the DSC graph of (5 -3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid Form D.

[0045] Figure 5 depicts the TGA graph of (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid Form D.

[0046] Figure 6 depicts the XRPD pattern of (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid Form C.

[0047] Figure 7 depicts the XRPD pattern of (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid adipic acid Form A.

[0048] Figure 8 depicts the13C SSNMR spectrum of (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid adipic acid Form A.

[0049] Figure 9 depicts the19F SSNMR spectrum of (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid adipic acid Form A.

[0050] Figure 10 depicts the XRPD pattern of (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid adipic acid Form B.

[0051] Figure 11 depicts the13C SSNMR spectrum of (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid adipic acid Form B.

[0052] Figure 12 depicts the19F SSNMR spectrum of (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid adipic acid Form B.

[0053] Figure 13 depicts the TGA graph for the spray dried dispersion consisting of 30% w / w (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l, l'-biphenyl]-3-yl)propanoic acid, and 70% w / wHPMC E3.

[0054] Figure 14 depicts the DSC graph for the spray dried dispersion consisting of 30% w / w (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l, l'-biphenyl]-3-yl)propanoic acid, and 70% w / wHPMC E3.

[0055] Figure 15 depicts the TGA graph for the spray dried dispersion consisting of 90% w / w (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l, l'-biphenyl]-3-yl)propanoic acid, and 10% w / wHPMC E3.

[0056] Figure 16 depicts the DSC graph for the spray dried dispersion consisting of 90% w / w (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l, l'-biphenyl]-3-yl)propanoic acid, and 10% w / wHPMC E3.

[0057] Figure 17 depicts the TGA graph for the spray dried dispersion consisting of 50% w / w (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l, l'-biphenyl]-3-yl)propanoic acid, and 50% w / w HPMC-AS 716.

[0058] Figure 18 depicts the DSC graph for the spray dried dispersion consisting of 50% w / w (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l, l'-biphenyl]-3-yl)propanoic acid, and 50% w / w HPMC-AS 716.

[0059] Figure 19 depicts (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid a4[37 integrin receptor occupancy in healthy volunteers following administration of different doses during the multiple ascending doses study.DETAILED DESCRIPTION OF THE INVENTION

[0060] IBD is a term used to describe two idiopathic conditions characterized by chronic inflammation of the gastrointestinal tract: UC and CD. In patients with UC, mucosal inflammation and ulceration occurs in the rectum and can extend proximally to a portion of or to the full colon, resulting in symptoms and signs such as urgency to defecate, fatigue, bloody stool, diarrhea, nausea or loss of appetite, weight loss, fever, and anemia. While UC affects only the colon, CD is characterized by transmural inflammation involving any portion of luminal gastrointestinal tract, from the oral cavity to the perianal area.

[0061] There are a number of methods for assessing the severity of UC, including the Mayo Clinic Score (MCS), the modified Mayo Clinic Score (mMCS, or mMS), the Robarts Histological Scale (RHI), the Nancy Histopathology Index (NI), and the continuous Geboes Score (cGS). The MCS is a composite instrument comprised of the following 4 subscores:Stool Frequency (SF): The SF subscore is a patient-reported measure. This item reports the number of stools in a 24-hour period, relative to the normal number of stools for that patient in the same period, on a 4-point scale. A stool is defined as a trip to the toilet when the patient has either a bowel movement, or passes blood alone, blood and mucus, or mucus only. The total number of stools passed in a 24-hour period is recorded by the patient. The reference “normal” SF for that patient is typically recorded at the outset of a study or period of observation. NormalSF for that patient is on the reported SF when the patient was in remission or, if the patient has never achieved remission, the reported SF before initial onset of signs and symptoms of UC.Rectal Bleeding (RB): The RB subscore is a patient-reported measure. This item reports the most severe amount of blood passed per rectum for a given day, on a 4-point scale.Mayo Endoscopic Subscore (MES): The MES is a physician-reported measure that reports the worst appearance of the mucosa on flexible sigmoidoscopy or colonoscopy, on a 4-point scale. Consistent with current clinical practice, friability is excluded from the definition of an MES of 1.Physician’s Global Assessment (PGA): The PGA is a physician-reported measure that summarizes the assessment of the patient’s disease activity on a 4-point scale.Each subscore is scored on a 4-point scale, ranging from 0 to 3, to give a maximum Mayo score of 12. The mMCS is a modification made to the original Mayo Index reference (Schroeder et al., New Eng J Med, 317(26): 1625-1629, 1987) and includes 3 of the 4 subscores of the Mayo Score. It does not include the Physician’s Global Assessment. The mMCS evaluates three subscores, each on a scale of 0 to 3 with a maximum total score of 9. The following table summarizes the respective mMCS subscales for scoring.Partial mMCS is a composite of the MCS stool frequency subscore, and the MCS rectal bleeding sub score.

[0062] The RHI is a validated index derived from the Geboes Score (GS) (Geboes et al., Gut, 47(3):404-409, 2000) that was designed to be reproducible and responsive to clinically meaningful change in disease activity in UC and CD over time. It is calculated by evaluating 4 histologic items, each on a scale from 0 to 3. The included items are 1: lamina propria chronic inflammation; 2: lamina propria neutrophils; 3: epithelial neutrophils; 4: surface epithelial injury. Each item is individually weighted in the RHI formula. The formula is as follows: RHI = (1 x chronic inflammatory infiltrate score) + (2 x lamina propria neutrophils score) + (3 x neutrophils in epithelium score) + (5 x erosion or ulceration score). Thus, the total RHI Score ranges from 0 (no disease activity) to 33 (severe disease activity).

[0063] The NI is validated index for assessing histological disease activity in UC. It is determined by evaluating 3 histological items: ulceration, acute inflammatory cells infiltrate, and chronic inflammatory infiltrate. These items are used to define 5 grades of disease activity (Grades 0 to 4). The presence of ulceration on the biopsy specimen corresponds to severely active disease (Grade 4). If there is no ulceration, acute inflammatory cells infiltrate (presence of neutrophils) is assessed. Moderate or severe acute inflammatory cells infiltrate corresponds to moderately active disease (Grade 3), whereas mild acute inflammatory cells infiltrate correspond to mildly active disease (Grade 2). If there is no acute inflammatory cells infiltrate, an assessment of chronic inflammatory infiltrate (presence of lymphocytes and / or plasmacytes and / or eosinophils) is made. A biopsy specimen showing moderate or marked chronic inflammatory infiltrate corresponds to moderate or marked chronic acute inflammatory infiltrate (Grade 1). A biopsy specimen showing mild or no chronic inflammatory infiltrate corresponds to absence of significant histological disease (Grade 0).

[0064] The cGS is a stepwise grading system used for the evaluation of microscopic inflammation and histopathologic disease activity in UC. The microscopic appearance of the mucosa is categorized into 6 grades: structural change only (Grade 0); chronic inflammation (Grade 1); lamina propria neutrophils (Grade 2); neutrophils in epithelium (Grade 3); crypt destruction (Grade 4); and erosions or ulcers (Grade 5) (Geboes etal., Gut, 47(3):404-409, 2000). Each of these grades has 4 to 5 sub-grades. This scoring system has been converted into a continuous scale that is calculated by adding up the numerical values of the different subscores, yielding a final value between 0 and 22.

[0065] The Simple Endoscopic Score for CD (SES-CD) assesses four variables in five predefined ileocolonic segment. The variables are size of ulcers, proportion of the surface covered by ulcers, proportion of the surface with any other lesions, and presence of narrowings (stenosis). The variables and their scorings are summarized in the table below (Daperno, M. et al., Gastrointest. Endosc., 60(4):505-512, 2004).>< >< >o = Diameter

[0066] The Crohn’s Disease Activity Index (CD Al) (Best, W.R. et al., Gastroenterology, 70(3):439-444, 1976) is a research tool used to quantify the symptoms of patients with Crohn’s disease. It measures the severity of disease symptoms based on diary entries kept by the patient for 7 days, along with other measurements such as weight and hematocrit. The individual variables, and their individual weightings are as follows:

[0067] The Patient-Reported Outcome 2 (PRO2) is a composite of the subscores for abdominal pain and total number of liquid or very soft stools in the last 7 days. The total number of liquid or very soft stools has a weighting of x 2, while the abdominal pain (0 = none, 1 = mild, 2 = moderate, 3 = severe) has a weighting ofx 5 (Kanna, R. et al., Aliment. Pharmacol. Then, 41(l):77-86, 2015).

[0068] As used herein, the terms “treating,” “treat,” or “treatment,” refer to restraining, slowing, lessening, reducing, or reversing the progression or severity of an existing symptom, disorder, condition, or disease, or ameliorating clinical symptoms and / or signs of a condition. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of the extent of a disease or disorder, stabilization of a disease or disorder (i.e., where the disease or disorder does not worsen), delay or slowing of the progression of a disease or disorder, amelioration or palliation of the disease or disorder, and remission (whether partial or total) of the disease or disorder, whether detectable or undetectable.

[0069] As used herein, the term “patient” refers to a human.

[0070] As used herein, the term “excipient” refers to any substance needed to formulate the composition to a desired form. For example, suitable excipients include but are not limited to, diluents and fillers, binders or granulating agents or adhesives, disintegrants, lubricants, antiadherants, glidants, dispersing or wetting agents, dissolution retardants or enhancers, adsorbents, buffers, chelating agents, preservatives, colors, flavors, and sweeteners. A “pharmaceutically acceptable carrier, diluent, or excipient” is a medium generally accepted in the art for the delivery of biologically active agents to humans. The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, co-solvents, complexing agents, dispersion media, coatings, films, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, which are not biologically or otherwise undesirable.The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic formulations is contemplated. Supplementary active ingredients can also be incorporated into the formulations. In addition, various excipients, such as are commonly used in the art, can be included. These and other such compounds are described in the literature, e.g., in the Merck Index, Merck & Company, Rahway, N.J. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (2010); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 12thEd., The McGraw-Hill Companies.

[0071] As used herein, the term “room temperature” or “RT” refers to the ambient temperature of a typical laboratory, which is typically around 25°C.

[0072] As used herein, the term “pharmaceutically acceptable salt thereof’ refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemi sulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, -toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. In some embodiments, pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.

[0073] As used herein, the term “cocrystal” refers to solids that are crystalline materials composed of two or more different molecular compounds, generally in a stoichiometric ratio.

[0074] As used herein, the term “dose” or “dosing” refers to the administration of a substance, for example a small molecule 014P7 integrin inhibitor, to achieve a therapeutic objective, for example, the treatment of UC or CD.

[0075] As used herein, the term “free form” refers to the neutral, non-ionic, form of a compound.

[0076] As used herein, the term “free form equivalent” refers to the weight of an equimolar amount of the free form. The molecular weight of Compound I free form is 645.74 g / mol.

[0077] As used herein, the term “parenterally” refers to administration of a substance to the human body by a route other than the digestive tract. Parenterally may refer to administration by injection or infusion, for example via subcutaneous or intravenous injection.

[0078] As used herein, the term “orally” refers to administration of a substance to the human body through the mouth. Oral administration can be of a liquid or a solid, for example through a tablet or a capsule.

[0079] As used herein, the term “advanced therapy” or “AT” refers to approved therapies for the treatment of moderate-to-severe UC and CD. Examples of such therapies include ouP? integrin antibodies, anti-TNF-a antibodies, IL-12 antibodies, IL-23 antibodies, JAK inhibitors, and SIP receptor modulators. Examples of specific advanced therapy agents are vedolizumab, infliximab, adalimumab, golimumab, ustekinumab, mirikizumab, tofacitinib, filgotinib, upadacitinib, estrasimod, ozanimod, and amiselimod.

[0080] As used herein, the term “advanced therapy naive” refers to a patient that has not previously received an advanced therapy.

[0081] As used herein, the term “advanced therapy experienced” refers to a patient that has previously received an advanced therapy.

[0082] As used herein, the term “mildly to moderately active ulcerative colitis” refers to a score of at least 4 on the mMCS, including an endoscopy subscore of at least 2 and a rectal bleeding sub score of at least 1.

[0083] As used herein, the term “moderately to severely active ulcerative colitis” refers to an mMCS of 5 to 9 (inclusive), with an MES >2 (confirmed by central reader).

[0084] As used herein, the term “mildly to moderately active Crohn’s disease” refers to a CD Al score of 15-220 inclusive with an SES-CD score of 3-6.

[0085] As used herein, the term “moderately to severely active Crohn’s disease” refers to a CD Al score of 220 to 450 inclusive with an SES-CD score of >6.

[0086] As used herein, the term “clinical remission” as determined using the mMCS and in the context of UC refers to an RB subscore of 0, and SF subscore of <1, and an MES of <1 without friability.

[0087] As used herein, the term “clinical response” as determined using the mMCS and in the context of UC refers to a decrease from baseline in the mMCS >2 points and >30% from baseline, plus a decrease in RB subscore >1 or an absolute RB subscore <1.

[0088] As used herein, the term “MCS remission” in the context of UC refers to an MCS <2 and no subscore higher than 1.

[0089] As used herein, the term “MCS response” in the context of UC refers to a decrease in MCS >3 points and >30% from baseline, plus a decrease in rectal bleeding score >1 or an absolute rectal bleeding score <1.

[0090] As used herein, the term “histologic remission by RHI” in the context of UC refers to an RHI score of <2 (with 0 for lamina propria neutrophils score and neutrophils in the epithelium score and without ulcers or erosions).

[0091] As used herein, the term “histologic remission by NT’ in the context of UC refers to an NI score of 0.

[0092] As used herein, the term “histologic remission by cGS” in the context of UC refers to a cGS score of <3.

[0093] As used herein, the term “histologic improvement” in the context of UC refers to a >7 point reduction in RHI score.

[0094] As used herein, the term “endoscopic improvement” in the context of UC refers to an MES <1.

[0095] As used herein, the term “endoscopic remission” in the context of UC refers to and an MES ofO.

[0096] As used herein, the term “mucosal healing” in the context of UC refers to an MES of 0 and an RHI score of <3 (with 0 for lamina propria neutrophils score and neutrophils in the epithelium score and without ulcers or erosions).

[0097] As used herein, the term “mucosal improvement” in the context of UC refers to an MES of <1 and a >7 point reduction in RHI score.

[0098] As used herein, the term “symptomatic response” in the context of UC refers to decrease in Partial mMCS >1 point and >30% from baseline, plus a decrease in rectal bleeding subscore >1 or an absolute rectal bleeding subscore <1.

[0099] As used herein, the term “endoscopic response” in the context of CD refers to an SES-CD decrease from baseline of >50%.

[0100] As used herein, the term “endoscopic remission” in the context of CD refers to an SES-CD of <4 points and a SES-CD decrease from baseline >2 points with no SES-CD subscore >1 point.

[0101] As used herein, the term “CD Al clinical response” in the context of CD refers to a CD Al reduction from baseline of >100 points or a CD Al score of <150 points.

[0102] As used herein, the term “CD Al clinical remission” in the context of CD refers to a CD Al score of <150 points.

[0103] As used herein, the term “PRO2 clinical response” in the context of CD refers to a decrease of >50% from baseline in the weighted sum of the average daily stool frequency and abdominal pain scores using the original CD Al multiplication factors.

[0104] As used herein, the term “PRO2 clinical response” in the context of CD refers to an average daily stool frequency score of <3 points and an average daily abdominal pain score of <1 point, with abdominal pain and stool frequency scores no greater than baseline.

[0105] As used herein, the term “corticosteroid-free” in the context of CD refers to cessation of corticosteroid use for at least 12 weeks before the applicable timepoint.

[0106] As used herein, the term “initial doses” in the context of UC refers to first doses of a small molecule 014P7 integrin inhibitor administered to a patient in order to induce clinical remission, clinical response, endoscopic remission, MCS remission, MCS response, histologic remission by RHI, histologic remission by NI, histologic remission by cGS, histologic improvement, endoscopic improvement, endoscopic remission, mucosal healing, mucosal improvement, and / or symptomatic response, each of these terms as defined above.

[0107] As used herein, the term “subsequent doses” in the context of UC refers to subsequent doses of a small molecule 014P7 integrin inhibitor administered to maintain or continue a desired therapeutic effect, namely clinical remission, clinical response, endoscopic remission, MCS remission, MCS response, histologic remission by RHI, histologic remission by NI, histologic remission by cGS, histologic improvement, endoscopic improvement, endoscopic remission, mucosal healing, mucosal improvement, and / or symptomatic response, each of these terms as defined above.

[0108] As used herein, the term “initial doses” in the context of CD refers to first doses of a small molecule ouP? integrin inhibitor administered to a patient in order to induce endoscopic response, endoscopic remission, CD Al clinical response, CD Al clinical remission, PRO2 clinical response, PRO2 clinical remission, and achievement of corticosteroid-free status.

[0109] As used herein, the term “subsequent doses” in the context of CD refers to subsequent doses of a small molecule 014P7 integrin inhibitor administered to maintain or continue a desired therapeutic effect, namely endoscopic response, endoscopic remission, CD Al clinical response, CD Al clinical remission, PRO2 clinical response, PRO2 clinical remission, and achievement of corticosteroid-free status.

[0110] As used herein, the term “XRPD” refers to X-ray powder diffraction analysis.

[0111] As used herein, the term “IBD” refers to inflammatory bowel disease.

[0112] As used herein, the term “UC” refers to ulcerative colitis.

[0113] As used herein, the term “CD” refers to Crohn’s disease.

[0114] As used herein, the term “PIPT” refers to processing-induced phase transformation.

[0115] As used herein, the term “NMR” refers to nuclear magnetic resonance.

[0116] As used herein, the term “ppm” refers to parts per million.

[0117] As used herein, the term “CuKa” refers to radiation with a wavelength of 1.5406 A.

[0118] As used herein, the term “29” refers to the diffracted angle between the X-ray source and the detector.

[0119] As used herein, the term “HPMC” refers to hydroxypropyl methylcellulose.

[0120] As used herein, the term “w / w” refers to weight by weight.

[0121] As used herein, the term “mucosal improvement” refers to partial resolution of mucosal inflammation as seen on endoscopy. Involves a reduction from baseline in the Mayo Endoscopic Score (MES), often achieving a score of 1 (mild erythema, decreased vascular pattern, no ulcers).

[0122] As used herein, the term “mucosal healing” refers to complete resolution of visible mucosal inflammation, often combined with histologic remission. It is associated with an MES score of 0 (normal mucosa, no friability, granularity, erosions, or ulcers), and absence of neutrophils and minimal chronic inflammation in biopsies (e.g. Geboes score <2.0 or Nancy Index = 0).CLINICAL STUDIESPhase la study in healthy volunteers

[0123] The first-in-human (FIH) study was a Phase la, randomized, double-blind, placebo-controlled study conducted to evaluate the safety, tolerability, and PK of single and multiple ascending doses of oral Compound I for up to 14 days in healthy subjects. This study was comprised of the following 3 parts:i) Part 1 - Single Ascending Dose (SAD): Cohorts of healthy subjects received placebo or single escalating oral doses of Compound I, as follows: 25 mg, 50 mg, 100 mg, 150 mg, and 400 mg.ii) Part 2 - Food Effect (FE): Cohorts of healthy subjects received placebo or single oral doses of 100 mg Compound I in a 2-treatment (fed versus fasting), 2-period, 2- sequence crossover phase.iii) Part 3 - Multiple Ascending Dose (MAD): Cohorts of healthy subjects received placebo or escalating B.I.D. P.O. administrations of Compound I, as follows. MAD 25 mg B.I.D. (50 mg total daily dose), 50 mg B.I.D. (100 mg total daily dose), and 100 mg B.I.D. (200 mg total daily dose) for 14 days.Following single doses between 25 mg and 400 mg and multiple doses between 25 mg and 100 mg B.I.D., Compound I was rapidly absorbed and displayed generally linear dose-proportional exposures and low interpatient variability. No clinically relevant food effect was demonstrated, and no adverse events related to single, multiple dosing, or food administration were observed. In Part 3, maximum 014P7 receptor occupancy was observed for doses of 100 mg B.I.D. and above, while ouPi receptor occupancy remained below quantification limit at all doses. This data supported the selection of 100 mg, and 200 mg doses of Compound I.The pharmacokinetic data for Part 1 is shown in the table below.Abbreviations: AUC0-12 = area under the concentration-time curve from time 0 to 12 hours; AUCo-inf = area under the concentration-time curve from time extrapolated to infinity; AUCo-t = area under the concentration-time curve from time 0 to the last measurable non-zero concentration; C12 = plasma concentration at 12 hours post-dose; CL / F = apparent clearance; Cmax= maximum observed plasma concentration; N = number of participants; N / A = not applicable; t> / 2= terminal phase half-life; t- / 2,f = apparent first-order functional half-life determined up to 12 hours post-dose; Vd / p = apparent volume of distribution; Tmax= time to achieve maximum observed plasma concentration.aN = 5,bN = 3,CN = 4.Note: All PK parameters are presented as geometric mean (geometric %CV) except Tmax, which is presented as median (minimum, maximum), and t> / 2which is presented as arithmetic mean (%CV). The pharmacokinetic data for Part 3 is shown in the table below.Abbreviations: AIAUC = accumulation index based upon AUCtau; AIcmax= accumulation index based upon Cmax; AUCtau = area under the concentration-time curve across the dosing interval; C12 = plasma concentration at 12 hours postdose; Cmax= maximum observed plasma concentration; N = number of patients; ty2f = apparent first-order functional half-life determined up to 12 hours post-dose; Tmax= time to achieve maximum observed plasma concentrationaN = 5;bti / 2f was derived using I z,f determined up to 12 hours post-dose.Note: All PK parameters are presented as geometric mean (geometric CV%) except Tmax, which is presented as median (minimum, maximum), and ti / 2.f, which is presented as arithmetic mean (%CV). All PK parameters were calculated up to 12 hours following A.M. dosing.Further Phase 1 study in healthy volunteers

[0124] This study was a randomized, placebo-controlled, fixed sequence study to evaluate the PK and cuP? receptor occupancy following single dose oral administration of 200 mg, 400 mg, 600 mg, and 800 mg Compound I. Participants were healthy volunteers aged between 18 and 65 years. The study was divided into four treatment periods, with approximately ten days between treatments. During each treatment period, patients received either a single dose of Compound I or placebo. The pharmacokinetic data is shown in the table below.AUCo-t = area under the concentration-time curve from time 0 to the last measurable non-zero concentration; CL / F = apparent clearance; Cmax = maximum observed plasma concentration; N = number of participants; t> / 2= terminal phase half-life; t- / 2,f = apparent first-order functional half-life determined up to 12 hours post-dose; VZ / F = apparent volume of distribution during the terminal phase after extra-vascular administration;Note: All PK parameters are presented as geometric mean (geometric %CV)The 014P7 receptor occupancy data for the tested doses of Compound I is shown in the table belowAbbreviations: CV = coefficient of variation (%); N = number of participants; SD = standard deviation

[0125] The above data shows that Compound I administration in 200 mg, 400 mg, 600 mg, and 800 mg doses achieves full, or near full ouP? receptor occupancy. The previous Phla data also showed full, or near full ouP? receptor occupancy for the 100 mg dose. This data supports the clinical investigation of the tested doses of Compound I in the treatment of patients with IBDPhase 2a study in patients with moderately to severely active UC

[0126] This study was an open-label, single-arm, multicenter study to evaluate the efficacy, PK, PD, safety, and tolerability of Compound I in patients with moderately to severely active UC. The main cohort of the study included approximately 35patients with moderately to severely active UC who have or have not been exposed to advanced therapies (ATs), including vedolizumab. In addition, an exploratory cohort was comprised of a maximum of 10 additional patients with moderately to severely active UC who are secondary non-responders to vedolizumab. The study consisted of 3 study periods, namely a screening period of up to 6 weeks, a treatment period of 52 weeks, split into a 12-week induction period and a 40-weel maintenance period, and a safety follow-up period of 4 weeks. Patients received a dose of 100 mg of Compound I twice a day for the full 52-week treatment period. The mean PK parameter values following administration of Compound I at 100 mg BID for 12 weeks are shown in the table below.Abbreviations: AUCo-6 = area under the concentration-time curve from time 0 to 6 hours; Cmax= maximum observed plasma concentration; C12 = maximum concentration at 12 hours; Ctrough = maximum concentration before administration of subsequent dose; N = number of participants; CV% = coefficient of variation; t> / 2= terminal phase half-life; ty2,f = apparent first-order functional half-life determined up to 12 hours post-dose; Tmax= time to achieve maximum observed plasma concentration.Note: AUC, Cmax, and Ctrough are reported as geometric mean. Tmaxand ti / 2 are reported as median (min, max).Overall, the PK parameters were consistent with those observed in the previously reported Phi study in healthy volunteers. Similar to previous observations for multiple dose administration, the exposure of Compound I reached steady state by day 15 and remained similar constant from day 15 through day 85. Compound I trough concentrations provided cuP? receptor occupancy (RO) close to the saturating level, which was in line with expectations for the 100 mg BID dose based on results from healthy volunteers.

[0127] After the 12-week induction period, no safety signals were identified. Among 35 subjects, no deaths or serious treatment-emergent adverse events (TEAEs) were recorded, 2 subjects (5.7%) experienced treatment-related adverse events (AEs), 2 subjects (5.7%) experienced a TEAE with a severity of Grade 3 or higher, and 1 subject (2.9%) subject discontinued due to an AE. The most common (.5%) AEs reported were ulcerative colitis (11.4%) and anemia (8.6%).

[0128] In this trial, Compound I achieved the primary endpoint, demonstrating a statistically significant reduction in the histological remission (RHI) score of 6.4 points (p = 0.002) from baseline to week 12. In the prespecified secondary endpoint of change in mMCS, patients had a 2.3 -point reduction from baseline. In the study, patients receiving Compound I experienced a 25.7% remission rate, according to mMCS.Phase 2b study in patients with moderately to severely active UC

[0129] This clinical study is a randomized, double-blind, placebo-controlled, multicenter, Phase 2b study to evaluate the efficacy and safety of 3 active dose regimens of Compound I versus matching placebo in patients with moderately to severely active UC. For this study, Compound I is administered as the free form, in capsule form, for oral administration. Approximately 280 participants are randomized into the treatment groups in a 1 : 1 : 1 : 1 ratio (70 participants pergroup). The study enrols participants who are advanced therapy-naive (i.e., have no previous exposure to an advanced therapy treatment for UC) and advanced therapy-experienced (excluding vedolizumab), with at least 30% but no more than 40% of advanced therapy-experienced participants. Randomization stratification factors include baseline MES (<3 vs 3) and previous use of advanced therapy treatment (advanced therapy -naive vs advanced therapy-experienced). All participants are enrolled from approximately 150 centers worldwide. For this study, moderately to severely active UC is defined as having an mMCS of 5 to 9 (inclusive), with an MES >2 (confirmed by central reader). The main part of this Phase 2b study consists of a Screening Period (up to 6 weeks, consisting of Stage 1 and Stage 2 testing), a Treatment Period (52 weeks, including a 12-week Induction Period and a 40-week Maintenance Period), and a Safety Follow-up (SFU) Period (4 weeks). During the main part of this study, there are approximately 11 scheduled study visits: Screening Visit(s) (Visit 1 at Weeks -6 to -1), multiple Treatment Visits (Visits 2-10 at Weeks 0, 2, 6, 12, 18, 24, 32, 42, and 52 [End of Treatment (EOT)]), and an SFU Visit (visit to occur 4 weeks after the last dose of study drug is received, which will be at Week 56 if the full Treatment Period is completed or earlier if treatment is discontinued early). Study Day 1 represents the first day of the Treatment Period (i.e., when the participant will receive the first dose of study drug). All participants who complete the 52-week Treatment Period have the opportunity to continue their treatment in a 52-week Maintenance Extension Period. During the optional Maintenance Extension, there are 5 scheduled visits: 4 Treatment Visits (Visits 11-14 at Weeks 65, 78, 91, and 104 [EOT]) and an SFU Visit (visit to occur 4 weeks after the last dose of study drug is received, which is at Week 108 if the full Maintenance Extension is completed or earlier if treatment is discontinued early). Participants who do not enrol into the Maintenance Extension must complete the final SFU Period for the main part of the study, including the Week 56 Visit (4 weeks after receiving the last dose of Compound I), for a maximum time on-study of 62 weeks. Participants who choose to continue in the Maintenance Extension do not complete the SFU Period for the main part of the study; instead, they directly enter the Maintenance Extension and complete a separate SFU Period, including the Week 108 Visit (4 weeks after receiving the last dose of Compound I), for a maximum time on-study of 114 weeks. An independent DSMB reviews participant safety data and monitor scientific integrity throughout the study. Details related to the DSMB are clearly delineated in the DSMB Charter. Enrolled participants are randomized to a treatment group to receive active Compound I or placebo. Participants initially randomized into an activeCompound I treatment group receive an active treatment (according to study period and group assignment) for the full 52-week Treatment Period. Participants initially randomized into the placebo group are switched to an active Compound I regimen (200 mg once a day - evening [Q.D.-E]) after they complete the Induction Period and the Week 12 assessments. After participants complete the full 52-week Treatment Period, they have the option to enter an additional 52-week Maintenance Extension Period. All participants who choose to continue in the Maintenance Extension continue receiving the same Compound I regimen they had during the Maintenance Period for up to an additional 52 weeks. The dosing regimens for the 4 treatment groups during the study are shown below.Abbreviations: B.I.D.: twice a day; Q.D.-M: once a day in the morning; Q.D.-E: once a day in the evening.The following study objectives are completed by assessing the associated endpoints in participants with moderately to severely active UC.Phase 2b study in patients with moderately to severely active CD

[0130] This clinical study is a randomized, double-blind, placebo-controlled, multicentre, Phase 2 study to evaluate the efficacy and safety of 2 active dose regimens of Compound I versus matching placebo in adult study participants with moderately to severely active CD. For this study, Compound I is administered as the free form, in capsule form, for oral administration. Approximately 210 participants are randomized into the 3 treatment groups in a 1:1:1 ratio (i.e., 70 participants per group). The study enrols participants who are advanced therapy-naive (i.e., have no previous exposure to an advanced therapy treatment for CD, including investigational treatment) and advanced therapy-experienced (excluding vedolizumab or any other a4p7 / a4pi integrin antagonist), with approximately 30% of advanced therapy-experienced participants. Participants who previously received a blinded treatment in an advanced therapy trial are considered as advanced therapy experienced. Randomization stratification factors include previous use of advanced therapy treatment (advanced therapy -naive vs advanced therapy-experienced) and baseline SES-CD score (>15 vs <15). Participants are enrolled from approximately 150 centers worldwide. For this study, moderately to severely active CD aredefined as having a CD Al score of 220 to 450 inclusive with an SES-CD score of >6. If disease is isolated to the ileum, the requirement is an SES-CD score >4. The main part of this Phase 2 study consists of a Screening Period (up to 6 weeks, consisting of Stage 1 and Stage 2 testing), a Treatment Period (52 weeks, including a 14-week Induction Period and a 38-week Maintenance Period), and a Safety Follow-up (SFU) Period (4 weeks). All participants are encouraged to remain on study for at least 28 weeks of study drug treatment, which corresponds to 14 weeks of active Compound I treatment for participants who are randomized to Group 3 and receive Placebo during the Induction Period. Any participant who has not shown clinical improvement (as determined by the Investigator) by Week 28 is discontinued from the study following an End of Treatment (EOT) Visit and a Safety Follow-up (SFU) Visit. All participants who complete the 52-week Treatment Period have the opportunity to continue treatment in a 52-week Maintenance Extension. All participants complete an SFU Visit 4 weeks after their last dose of study drug. During the main part of this study, there are approximately 11 scheduled study visits: Screening Visit(s) (Visit 1 at Weeks -6 to -1), 4 study visits during the Induction Period (Visits 2-5 at Weeks 0, 2, 7, and 14), 5 study visits during the Maintenance Period (Visits 6-10 at Weeks 21, 28, 36, 44, and 52), and an SFU visit for participants who complete the Maintenance Period and do not enter the Maintenance Extension or for participants who discontinue study treatment before the end of the Maintenance Period (the SFU visit will be 4 weeks after the last dose of study drug is received). Study Day 1 represents the first day of the Treatment Period (i.e., when the participant receives the first dose of study drug). During the optional Maintenance Extension, there are 5 scheduled visits: 4 Treatment Visits (Visits 11-14 at Weeks 65, 78, 91, and 104 [End of Treatment]) and an SFU Visit (visit to occur 4 weeks after the last dose of study drug is received, which will be at Week 108 if the full Maintenance Extension is completed or earlier if treatment is discontinued early). Participants who do not enrol into the Maintenance Extension may remain on study for a maximum of 62 weeks. Participants who choose to continue in the Maintenance Extension may remain on study for a maximum of 114 weeks. An independent DSMB reviews participant safety data and monitor scientific integrity throughout the study. Details related to the DSMB are clearly delineated in the DSMB Charter. Enrolled participants are randomized to a treatment group to receive active Compound I or placebo. Participants initially randomized into an active Compound I treatment group (i.e., Groups 1 and 2) receive an active treatment for the full 52-week Treatment Period as outlined in the table below. Participants initially randomized into the placebo group (i.e., Group 3) are switched to an active Compound Iregimen (100 mg twice a day [B.I.D.]) after they complete the Induction Period and the Week 14 assessments. All participants who choose to continue in the Maintenance Extension continue receiving 100 mg B.I.D. of Compound I for up to an additional 52 weeks. The dosing regimens for the 3 treatment groups during the study are shown below.Abbreviations: B.I.D.: twice a day.The following study objectives will be completed by assessing the associated endpoints in participants with moderately to severely active CD.Phase 2b / 3 study in patients with moderately to severely active UC

[0131] This clinical study is a multicenter, randomized, double-blind, parallel, placebo-controlled, Phase 2b / 3 study to evaluate the safety and efficacy of Compound I in adults with moderately to severely active UC.

[0132] Up to 1431 participants are enrolled with 369 and 1062 participants randomized to Ph3b and Ph3, respectively. The Ph2b study has an interim analysis to potentially declare success early with group sequential testing. If the Ph2b is declared successful early, then all participants randomized after the participants included in the interim analysis are included in the Ph3 study.In the Ph2b induction stage, participants are randomized into three treatment groups in a 1:1:1 ratio, the treatment groups receiving 400 mg BID Compound I, 200 mg BID Compound I, or placebo for 10 weeks. In the Ph3 induction stage, participants are randomized into three treatment groups in a 1 : 1 : 1 ratio, the treatment groups receiving 400 mg BID Compound I, 200 mg BID Compound I, or placebo. Following the Ph3 induction stage, responders are rerandomized into a 200 mg BID Compound I treatment group, or a placebo group in a 2: 1 ratio. All non-responders receive 400 mg BID Compound I for 10 weeks, followed by 200 mg BID Compound I.

[0133] The following are the objectives for the Ph2b and Ph3 induction phases.< >

[0134] The following are the objectives for the Ph3 maintenance phase.< >COCRYSTALLINE FORMS OF COMPOUND I

[0135] Compound I in the amorphous form obtained using the synthetic methods described in WO 2021 / 076890 Al was used to investigate the compound’s solid-state behavior. The following experiments were carried out during the initial polymorph screening project: short term slurries, evaporative crystallization, antisolvent crystallization, cooling crystallization, dry and solvent milling, amorphous slurries, thermal treatment of select forms, and seeding experiments. A total of 21 unique free form patterns were observed throughout the screening work. Of the 21 unique patterns observed, several were of low crystallinity, or unstable to drying, and were not considered as viable for further investigation. After further work, only one unique pattern (“Compound I Free Form D”) was deemed suitable for further investigation.Example 1(5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid “Compound I Free Form D”

[0136] Amorphous (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoicacid (1.2 g, 1.9 mmol) was stirred in ACN (7.5 volumes) for 3 days at room temperature, resulting in a flowable white slurry. XRPD analysis (Figure 1) of the wet slurry revealed that the amorphous starting material had fully converted to a crystalline ACN solvate (“Compound I Free Form C”). The slurry was filtered and dried at 50°C under vacuum. XRPD (see Figure 1) revealed partial conversion of Free Form C to a second crystalline form (“Compound I Free Form D”). Further drying resulted into full conversion of Compound I Free Form C to Compound I Free Form D. The solid was a white flowable powder and the yield was 64%.

[0137] The XRPD patterns of crystalline Compound I Free Form C and Compound I Free Form D were obtained on a Rigaku MiniFlex 600 X-ray powder diffractometer, equipped with a Cu Kai (1.540598 A) source and a detector operating at 40 kV and 15 mA. The samples were scanned between 4 and 3029°, with a step size of 0.05 29° and a scan rate of 5° / min. The dry powders were packed on a silicon sample holder and smooth surfaces were obtained using a glass slide. The crystal form diffraction patterns were collected at ambient temperature and relative humidity. It is well known in the crystallographic art that, for any given crystal form, the relative intensities of the diffraction peaks may vary due to preferred orientation resulting from factors such as crystal morphology and habit. Where the effects of preferred orientation are present, peak intensities are altered, but the characteristic peak positions of the polymorph are unchanged. See for example The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. Furthermore, it is also well known in the crystallography art that for any given crystal form the angular peak position may vary slightly. For example, peak positions can shift due to a variation in the temperature at which the sample is analyzed, sample displacement, or the presence or absence of an internal standard. In the present case, a peak position variability of 9.2 29° is presumed to take into account these potential variations without hindering the unequivocal identification of the indicated crystal form. Confirmation of a crystal form may be made based on any unique combination of distinguishing peaks.

[9138] A prepared sample of Compound I Free Form C was characterized by an XRPD pattern using CuKa radiation as having diffraction peaks (2 -theta values) as described in the table below, and in particular having a peak at 6.69 in combination with one or more of the peaks selected from the group consisting of 7.79 and 15.26, with a tolerance for the diffraction angles of 9.2 degrees.

[0139] A prepared sample of Compound I Free Form D was characterized by an XRPD pattern using CuKa radiation as having diffraction peaks (2 -theta values) as described in the table below, and in particular having a peak at 6.88 in combination with one or more of the peaks selected from the group consisting of 7.60 and 5.42, with a tolerance for the diffraction angles of 0.2 degrees.

[0140] Following multiple polymorph, salt, and cocrystal screens and the discovery of Compound I Free Form D, the ability of Compound I to generate cocrystalline forms using a variety of organic acids was re-investigated. Surprisingly, while monocarboxylic acids failed to provide positive results, Compound I successfully formed cocrystals with a small number of dicarboxylic acids, namely azelaic acid, suberic acid, pimelic acid, and adipic acid (structures shown below).azelaic acid pimelic acidAfter additional characterization and stability work, (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid adipic acid (“Compound I adipic acid”) was selected for further investigation. Two stable forms of this cocrystals were then discovered, Compound I adipic acid Form A, and Compound I adipic acid Form B. The chemical structure of these cocrystalline forms is shown below.(5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid adipic acidThe synthetic procedures for each of the cocrystals were as follows.Example 2(5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid azelaic acid

[0141] (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l, l'-biphenyl]-3-yl)propanoic acid (302mg, 0.47 mmol) was placed in a vial. EtOAc (7.5 ml) saturated with azelaic acid was then added. The resultant slurry for stirred at 500 rpm at room temperature for 30 minutes. Vacuum filtration and drying under a nitrogen stream for 15 minutes afforded the title compound.Example 3(5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid suberic acid

[0142] (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l, l'-biphenyl]-3-yl)propanoic acid (998 mg, 1.55 mmol) was placed in a vial. EtOAc (20 ml) saturated with suberic acid was then added. The resultant slurry for stirred at 500 rpm at room temperature over the weekend. Vacuum filtration and drying under a nitrogen stream for 30 minutes afforded the title compound as a bright white solid.Example 4(5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid pimelic acid

[0143] (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid (1.04g mg, 1.61 mmol) was placed in a vial. EtOAc (20 ml) saturated with pimelic acid was then added. The resultant slurry for stirred at 500 rpm at room temperature over the weekend. Vacuum filtration and drying under a nitrogen stream for 30 minutes afforded the title compound as a bright white solid.Example 5(5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid adipic acid Form A (“Compound I adipic acid Form A”)

[0144] (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid (10.00g mg, 15.49 mmol) was placed into a 100 ml round bottom flask. EtOAc (50 ml) was added, and the mixture heated to 53°C to obtain a clear, light-yellow solution. Adipic acid (2.36 g, 16.15 mmol) was then added, and the mixture was stirred until a light golden solution was obtained. The solution was filtered through a 0.45 pm syringe filter. The solution was cooled to room temperature and the resulting slurry was stirred at 900 rpm for 2 hours. Vacuum filtration and drying under nitrogen stream for 45 minutes afforded a solid, which was further dried in a vacuum oven at 55°C over the weekend to afford the title compound as a bright white solid.Example 6(5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid adipic acid Form B (“Compound I adipic acid Form B”)

[0145] (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l, l'-biphenyl]-3-yl)propanoic acid (4.20 g mg, 6.50 mmol) was placed into a 100 ml EasyMax™ reactor. THF / heptane (1:1 v / v, 70 ml) containing adipic acid (1.39 g, 9.51 mmol) was added and the mixture heated to 55°C, and stirred for 30 minutes. The solution was cooled to 50°C and then stirred at this temperature for 30 minutes. Added heptane (30 ml) over 240 minutes, cooled to 25°C over 120 minutes and stirred at this temperature for 20 hours. The resulting solid was filtered under vacuum and then washed with 6 volumes of fresh 1 : 1 THF -heptane. Drying under vacuum at 60°C afforded the title product.

[0146] The XRPD patterns of crystalline Compound I adipic acid Form A, and crystalline Compound I adipic acid Form B were obtained on a Bruker D8 Endeavor X-ray powder diffractometer, equipped with a CuKa (1.5418 A) source and a Linxeye detector, operating at 40 kV and 40 mA. The samples were scanned between 4 and 4229°, with a step size of 0.00929° and a scan rate of 0.5 seconds / step, and using 0.3° primary slit opening, and 3.9° PSD opening. The dry powders were packed on a quartz or silicon sample holder and smooth surfaces were obtained using a glass slide. The crystal form diffraction patterns were collected at ambient temperature and relative humidity. Crystal peak positions were determined in MDI-Jade after whole pattern shifting based on an internal NIST 675 standard with peaks at 8.853 and 26.774 29°. It is well known in the crystallographic art that, for any given crystal form, the relative intensities of the diffraction peaks may vary due to preferred orientation resulting from factorssuch as crystal morphology and habit. Where the effects of preferred orientation are present, peak intensities are altered, but the characteristic peak positions of the polymorph are unchanged. See, for example The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. Furthermore, it is also well known in the crystallography art that for any given crystal form the angular peak positions may vary slightly. For example, peak positions can shift due to a variation in the temperature at which a sample is analyzed, sample displacement, or the presence or absence of an internal standard. In the present case, a peak position variability of ± 0.229° is presumed to take into account these potential variations without hindering the unequivocal identification of the indicated crystal form. Confirmation of a crystal form may be made based on any unique combination of distinguishing peaks.

[0147] A prepared sample of crystalline Compound I adipic acid Form A is characterized by an XRPD pattern using CuKa radiation as having diffraction peaks (2 -theta values) as described in the table below, and in particular having a peak at 6.3 in combination with one or more of the peaks selected from the group consisting of 16.6 and 18.9; with a tolerance for the diffraction angles of 0.2 degrees.

[0148] A prepared sample of crystalline Compound I adipic acid Form B is characterized by an XRPD pattern using CuKa radiation as having diffraction peaks (2 -theta values) as described in the table below, and in particular having a peak at 5.5 in combination with one or more of the peaks selected from the group consisting of 6.8 and 8.8; with a tolerance for the diffraction angles of 0.2 degrees.

[0149] 13C solid-state NMR (SSNMR) experiments on Compound I adipic acid Form A, and Compound I adipic acid Form B were performed on a Bruker Avance NEO spectrometer (Bruker, Billerica, MA) operating at 100.52 MHz for13C and 399.71 MHz forXH. A RevNMR HX probe, fitted with a 7 mm magic angle spinning module (Revolution NMR, Fort Collins, CO) was used to acquire the data. Saturation recovery with13C observation was used to measure1H I relaxation times. The1H Tuho values were determined by13C observation. The pulse sequence details are noted in the KAS1724-0SI report. A pulse delay of 1 second was used between successive acquisitions for the 'H I\ measurement, and a 5.1 second pulse delay was used between successive acquisitions for the 'H Tuho measurement. High quality13C spectra were signal averaged for 12 hours using the Cross Polarization Total Sideband Suppression (CPTOSS) sequence, and a MAS frequency of 5 kHz with a 1.5 ms contact time. One dummy scan prior to acquisition was used, with a ~50 ms of acquisition time, a 5.1 second pulse delay, and 8384 acquisitions were used to acquire the data. 3 -methylglutaric acid was used as a tune-up standard to ensure the spectrometer was operating properly.13C chemical shifts are reported relative to the methyl peak of 3 -methylglutaric acid at 18.84 ppm with an accuracy of ±0.4 ppm. 3-methylglutaric acid was purchased from Sigma Aldrich and used as is without further purification. The data was processed using Topspin® 4.0.8® software package from Bruker Biospin. The data was Fourier transformed using the full FID (3960 points) and applying exponential multiplication line broadening (10 Hz for13C CPTOSS spectra, 'H 7i, and 'H Tirho experiments), phased (apk), and baseline corrected (abs). Manual phasing was performed as needed. The 1112 function in the Topspin® software package was used for the exportation of the 'H Zi and 'H Tirho integrated areas in the region of 0 - 200 ppm. Semi-automatic peak picking was used for determining the chemical shifts of the spectrum. For the relaxation data fitting, the13C NMR integrated areas for the relaxation measurements were exported from the Topspin® software and imported into KaleidaGraph (Synergy Software) to determine the relaxation values and associated errors for the fit. The sample was received as a powdered like material and packed into a 7 mm rotor with Kel-F® spacers, as is without modification. Sample was received, stored, and prepared under ambient conditions. When the sample was stored, the sample was covered in aluminum foil to prevent sample exposure to light.

[0150] 19F solid-state NMR (SSNMR) experiments on Compound I adipic acid Form A were performed on a Bruker Avance NEO spectrometer (Bruker, Billerica, MA) operating at 375.88 MHz for19F and 399.50 MHz forXH. A RevNMR HF probe, fitted with a 4 mm magic angle spinning module (Revolution NMR, Fort Collins, CO) was used to acquire the data. Saturation recovery with19F observation was used to measure both the1H I\ and19F I relaxation times. The1H Zirho values were determined by19F observation. The pulse sequence details are noted in the KAS1724-0SI report. A pulse delay of 1 second was used between successive acquisitions for the 'H Zi and19F I\ measurements, and a 5.1 second pulse delay was used between successive acquisitions for the1H ZIAO measurement. One dummy scan was used prior to the1H Zi,19F Zi, and1H ZIAO measurements. High quality19F spectra were signal averaged for a total of 12 hours using CP sequence, with an MAS frequency of 15 kHz. Due to the shorter 'H Zi compared to the19F ZI, the single pulse (HPDEC) experiment was not used. One dummy scan prior to acquisition was used, a 1 ms contact time, and ~10 ms of acquisition time, a 5.1 second pulse delay, and 8,488 acquisitions were used to acquire the data. To identify spinning sidebands (SSB) versus the isotropic chemical shifts19F CP spectra were acquired at spinning frequencies of 10 kHz, 13 kHz, and 15 kHz. Niflumic acid and Flutamide were used as a tune-up standard to ensure the spectrometer was operating properly for single pulse experiments (KAS-RS-012) and cross polarization experiments (KAS-RS-013).19F chemical shifts are reported relative to Teflon™ at -122 ppm via a secondary reference of niflumic acid at -60.5 ppm with an accuracy of ±1.0 ppm. KAS-RS-012 was purchased from Alfa Aesar chemicals and used as is without additional purification. Flutamide was purchased from Sigma Aldrich and used as is without additional purification. The data was processed using Topspin® 4.0.8® software package from Bruker Biospin. The data was Fourier transformed using the full FID (2924 points) and applying exponential multiplication line broadening (10 Hz for19F CP spectra, and 0 Hz for the 'H Zi,19F Zi, and1H ZIAO experiments), phased (apk), and baseline corrected (spline for the HQ spectrum and abs the spinning sideband vs. isotropic chemical shift comparison). Manual phasing was performed as needed. The 1112 function in the Topspin® software package was used for the exportation of the 'H Zi,19F Zi, and 'H ZIAO integrated areas for the19F isotropic chemical shifts. Semi-automatic peak picking was used for determining the chemical shifts of the spectrum. For the relaxation data fitting, the19F NMR integrated areas for the relaxation measurements were exported from the Topspin® software and imported into KaleidaGraph (Synergy Software) to determine the relaxation values and associated errors for the fit. The sample was received as apowdered like material and packed into a 4 mm rotor with Vespel® spacers, as is without modification. Sample was received, stored, and prepared under ambient conditions. When the sample was stored, the sample was covered in aluminum foil to prevent sample exposure to light.

[0151] A prepared sample of crystalline Compound I adipic acid Form A is characterized by a13C SSNMR spectrum displaying peaks as shown in the table below, and in particular by peaks at 16.5, 160.9, 179.3, and 20.0 ppm with a tolerance of ±0.4 ppm.

[0152] A prepared sample of crystalline Compound I adipic acid Form A is characterized by a19F SSNMR spectrum displaying peaks as shown in the table below, and in particular by peaks at -128.7, -62.6 ppm with a tolerance of ±1.0 ppm.

[0153] A prepared sample of crystalline Compound I adipic acid Form B is characterized by a13C SSNMR spectrum displaying peaks as shown in the table below, and in particular by peaks at 11.2, 163.5, 21.2, and 21.4 ppm with a tolerance of ±0.4 ppm.

[0154] A prepared sample of crystalline Compound I adipic acid Form B is characterized by a19F SSNMR spectrum displaying peaks as shown in the table below, and in particular by peaks at -133.3, -62.3 ppm with a tolerance of ±1.0 ppm.

[0155] The solid-state stability of the following forms was then investigated: Compound I Free Form D, Compound I adipic acid Form A, and Compound I adipic acid Form B. Approximately 2 mg of each of the three forms were weighed by difference into 20 ml scintillation vials.Additionally, 10 mg of samples were weighed by difference into 20 ml vials specifically for XRPD after 14 days. All samples were subjected to multiple stress conditions, including light, 40°C, 40°C / 75% RH, 50°C / 30% RH, 50°C / 50% RH, 70°C, and 70°C / 75% RH. Samples under RH conditions were stored with the cap removed. At 7-day, and 14-day timepoints samples were dissolved in 1 : 1 v / v ACN:H20 and analyzed by HPLC for potency and relative substance analysis. XRPD analyses were performed only on 14-day samples. When not analyzed immediately after removed form stress conditions, visual observations were recorded, and samples were kept at -20°C until analysis. The results of the stability screen are presented in the tables below.C

[0156] The stability study results clearly demonstrate that Compound I adipic acid Form A, and Compound I adipic acid Form B are overall more stable when exposed to light, increased temperatures, and increased relative humidities than Compound I Form D. These results suggest that Compound I adipic acid, especially Compound I adipic acid Form B, is an ideal candidate for further development into a commercial drug product.SPRAY DRIED DISPERSIONS OF COMPOUND I

[0157] A spray dried dispersion screen was performed for Compound I. The two best performing polymers were determined to be HMPC E3, and HMPC-AS 716. Various spray dried dispersions using these polymers were prepared using a conventional spray drier with a water bath temperature of 80°C, an oil bath temperature of 200°C, and a nitrogen pressure of 10 psi. The table below summarizes the synthesis of the various spray dried dispersions of Compound I.

[0158] The solid-state stability of the spray dried dispersions was then tested. Approximately 2 mg of each of the three dispersions were weighed by difference into 20 ml scintillation vials. Additional samples were weighed by difference into 20 ml vials specifically for XRPD after 1, and 4 weeks. All samples were subjected to multiple stress conditions, including 40°C / 20% RH, 40°C / 75% RH, 50°C / 30% RH, 50°C / 50% RH, and 70°C / 20% RH. Samples under RH conditions were stored with the cap removed. At 7-day, and 14-day timepoints samples were dissolved in 1 : 1 v / v ACN:H20 and analyzed by HPLC for potency and relative substance analysis. When not analyzed immediately after removed form stress conditions, visual observations were recorded, and samples were kept at -20°C until analysis. The results of the stability screen are presented in the table below.

[0159] The stability results show that all three spray dried dispersions display good stability under standard storage conditions, and also under accelerated high temperature and high humidity conditions.

[0160] To test potential PIPT susceptibility, the three spray dried dispersions were subjected to a test comprising the following steps:a. A small sample of one of the spray dried dispersions was applied to a glass microscope slide, and a cover slide was added.b. An initial photomicrograph at 200x was taken.c. Pressure was applied to the slide with a finger, and the top slide was swirled over the bottom slide 10 times.d. A final photomicrograph at 200x was taken.

[0161] The photomicrographs obtained from these experiments revealed no visual change, or increase in birefringent material had occurred, suggesting that none of the investigated spray dried formulations had undergone PIPT. As such, all the investigated spray dried dispersions, namely Compound I HPMC E3 (30%), Compound I HPMC E3 (90%), and Compound I HPMC - AS 716 (50%), are suitable for further development into a commercial drug product.EMBODIMENTS

[0162] The present invention is embodied as follows:1. A method of treating an inflammatory bowel disease in a patient in need thereof comprising administering to the patient a compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)- 2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'- tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is administered to the patient in a dose of about 10 mg to about 850 mg free form equivalent.2. The method according to embodiment 1, wherein the compound is administered to the patient orally, or parenterally.3. The method according to embodiment 1 or embodiment 2, wherein the compound is administered orally.4. The method according to any one of embodiments 1 to 3, wherein the patient is advanced therapy naive.5. The method according to any one of embodiments 1 to 3, wherein the patient is advanced therapy experienced.6. The method according to embodiment 4 or embodiment 5, wherein the advanced therapy comprises one or more agents selected from 014P7 integrin antibodies, anti-TNF-a antibodies, IL-12 antibodies, IL-23 antibodies, JAK inhibitors, and SIP receptor modulators.7. The method according to embodiment 6, wherein the agents are selected from vedolizumab, infliximab, adalimumab, golimumab, ustekinumab, mirikizumab, tofacitinib, filgotinib, upadacitinib, estrasimod, ozanimod, and amiselimod.8. The method according to any one of embodiments 1 to 7, wherein the inflammatory bowel disease is ulcerative colitis.The method according to embodiment 8, wherein the ulcerative colitis is mildly to moderately active ulcerative colitis.The method according to embodiment 8, wherein the ulcerative colitis is moderately to severely active ulcerative colitis.The method according to any one of embodiments 1 to 7, wherein the inflammatory bowel disease is Crohn’s disease.The method according to embodiment 11, wherein the Crohn’s disease is mildly to moderately active Crohn’s disease.The method according to embodiment 11, wherein the Crohn’s disease is moderately to severely active Crohn’s disease.The method according to any one of embodiments 1 to 13, wherein the compound is («S)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid. The method according to any one of embodiments 1 to 13, wherein the compound is (S)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid adipic acid.The method according to any one of embodiments 1 to 15, wherein the compound is administered in a dose of about 100 mg to about 800 mg free form equivalent.The method according to any one of embodiments 1 to 15, wherein the compound is administered in a dose of about 100 mg to about 400 mg free form equivalent.The method according to any one of embodiments 1 to 15, wherein the compound is administered in a dose of about 200 mg to about 400 mg free form equivalent.The method according to any one of embodiments 1 to 15, wherein the compound is administered in a dose selected from about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, and about 850 mg free form equivalent.The method according to any one of embodiments 1 to 15, wherein the compound is administered in a dose selected from about 100 mg, about 150 mg, about 200 mg, about 300 mg, and about 400 mg free form equivalent.The method according to any one of embodiments 1 to 20 wherein the compound is administered twice daily.The method according to any one of embodiments 1 to 20, wherein the compound is administered once daily.The method according to any one of embodiments 1 to 20, wherein the compound is administered once daily in the morning.The method according to any one of embodiments 1 to 20, wherein the compound is administered once daily in the evening.The method according to any one of embodiments 1 to 24, wherein the patient has a baseline level of CPa9-HNE of lower than about 200 ng / ml.The method according to any one of embodiments 1 to 25, wherein the patient has a baseline level of C1M of lower than about 100 ng / ml.The method according to any one of embodiments 1 to 26, wherein the patient has a baseline level of C7M of lower than about 10 ng / ml.The method according to any one of embodiments 1 to 27, wherein the compound is administered as part of a pharmaceutical composition which further comprises at least one pharmaceutically acceptable carrier, diluent, or excipient.The method according to embodiment 28, wherein the pharmaceutical composition is for oral administration.The method according to embodiment 28 or embodiment 29, wherein the pharmaceutical composition further comprises microcrystalline cellulose, lactose, pregelatinized starch, hydroxypropyl methylcellulose, croscarmellose sodium, poloxamer, colloidal silicon dioxide, and magnesium stearate.The method according to any one of embodiments 28 to 30, wherein the pharmaceutical composition is administered in a capsule, or a tablet.The method according to embodiment 31, wherein each capsule or tablet comprises about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 300 mg, or about 400 mg free form equivalent of the compound.A method of treating an inflammatory bowel disease in a patient in need thereof comprising administering to the patient a compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is administered to the patient according to the following dosing regimen:a. initial doses of about 10 mg to about 850 mg free form equivalent for a period of about 5 weeks and about 20 weeks, followed byb. subsequent doses of about 10 mg to about 850 mg free form equivalent.The method according to embodiment 33, wherein the compound is administered to the patient orally, or parenterally.The method according to embodiment 33 or embodiment 34, wherein the compound is administered to the patient orally.The method according to any one of embodiments 33 to 35, wherein the patient is advanced therapy naive.The method according to any one of embodiments 33 to 35, wherein the patient is advanced therapy experienced.The method according to embodiment 36 or embodiment 37, wherein the advanced therapy comprises one or more agents selected from ouP? integrin antibodies, anti-TNF-a antibodies, IL-12 antibodies, IL-23 antibodies, JAK inhibitors, and SIP receptor modulators.The method according to embodiment 38, wherein the agents are selected from vedolizumab, infliximab, adalimumab, golimumab, ustekinumab, mirikizumab, tofacitinib, filgotinib, upadacitinib, estrasimod, ozanimod, and amiselimod.The method according to any one of embodiments 33 to 39, wherein the compound is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid. The method according to any one of embodiments 33 to 39, wherein the compound is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid adipic acid.The method according to any one of embodiments 33 to 41, wherein the initial doses and subsequent doses are of about 100 mg to about 800 mg free form equivalent.The method according to any one of embodiments 33 to 41, wherein the initial doses and subsequent doses are of about 100 mg to about 400 mg free form equivalent.The method according to any one of embodiments 33 to 41, wherein the initial doses and subsequent doses are of about 200 mg to about 400 mg free form equivalent.The method according to any one of embodiments 33 to 41, wherein the initial doses and subsequent doses are independently selected from about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, and about 850 mg free form equivalent. The method according to any one of embodiments 33 to 41, wherein the initial doses and subsequent doses are independently selected from about 100 mg, about 150 mg, about 200 mg, about 300 mg, and about 400 mg free form equivalent.The method according to any one of embodiments 33 to 46, wherein the initial doses and subsequent doses are independently administered twice daily, or once daily.The method according to any one of embodiments 33 to 46, wherein the initial doses and subsequent doses are independently administered twice daily, once daily in the morning, or once daily in the evening.The method according to any one of embodiments 33 to 41, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 100 mg free form equivalent twice daily for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 100 mg free form equivalent twice daily.The method according to any one of embodiments 33 to 41, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 100 mg free form equivalent twice daily for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 200 mg free form equivalent twice daily.The method according to any one of embodiments 33 to 41, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 200 mg free form equivalent twice daily for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 100 mg free form equivalent twice daily.The method according to any one of embodiments 33 to 41, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 200 mg free form equivalent twice daily for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 200 mg free form equivalent twice daily.The method according to any one of embodiments 33 to 41, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 100 mg free form equivalent once daily in the morning for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 100 mg free form equivalent once daily in the morning. The method according to any one of embodiments 33 to 41, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 100 mg free form equivalent once daily in the morning for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 200 mg free form equivalent once daily in the morning. The method according to any one of embodiments 33 to 41, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 200 mg free form equivalent once daily in the morning for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 100 mg free form equivalent once daily in the morning. The method according to any one of embodiments 33 to 41, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 200 mg free form equivalent once daily in the morning for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 200 mg free form equivalent once daily in the morning. The method according to any one of embodiments 33 to 41, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 100 mg free form equivalent once daily in the evening for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 100 mg free form equivalent once daily in the evening.The method according to any one of embodiments 33 to 41, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 100 mg free form equivalent once daily in the evening for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 200 mg free form equivalent once daily in the evening.The method according to any one of embodiments 33 to 41, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 200 mg free form equivalent once daily in the evening for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 100 mg free form equivalent once daily in the evening.The method according to any one of embodiments 33 to 41, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 200 mg free form equivalent once daily in the evening for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 200 mg free form equivalent once daily in the evening.The method according to any one of embodiments 33 to 41, wherein the initial doses are administered for a period selected from about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, and about 12 weeks.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is ulcerative colitis.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of clinical remission.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of clinical remission.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of clinical response.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of clinical response.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of MCS remission.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of MCS remission.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of MCS response.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of MCS response.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of histologic remission by RHI.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of histologic remission by RHI.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of histologic improvement.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of histologic improvement.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of endoscopic improvement.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of endoscopic improvement.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of endoscopic remission.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of endoscopic remission.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of mucosal healing.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of mucosal healing.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of mucosal improvement.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of mucosal improvement.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of symptomatic response.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of symptomatic response.The method according to any one of embodiments 62 to 84, wherein the ulcerative colitis is mildly to moderately active ulcerative colitis.The method according to any one of embodiments 62 to 84, wherein the ulcerative colitis is moderately to severely active ulcerative colitis.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is Crohn’s disease.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is Crohn’s disease, and the initial doses are administered until achievement of endoscopic response.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is Crohn’s disease, and the subsequent doses are administered until achievement of endoscopic response.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is Crohn’s disease, and the initial doses are administered until achievement of endoscopic remission.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is Crohn’s disease, and the subsequent doses are administered until achievement of endoscopic remission.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is Crohn’s disease, and the initial doses are administered until achievement of CD Al clinical response.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is Crohn’s disease, and the subsequent doses are administered until achievement of CD Al clinical response.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is Crohn’s disease, and the initial doses are administered until achievement of CD Al clinical remission.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is Crohn’s disease, and the subsequent doses are administered until achievement of CD Al clinical remission.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is Crohn’s disease, and the initial doses are administered until achievement of PRO2 clinical response.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is Crohn’s disease, and the subsequent doses are administered until achievement of PRO2 clinical response.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is Crohn’s disease, and the initial doses are administered until achievement of PR02 clinical remission.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is Crohn’s disease, and the subsequent doses are administered until achievement of PR02 clinical remission.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is Crohn’s disease, and the initial doses are administered until the patient is corticosteroid-free.The method according to any one of embodiments 33 to 61, wherein the inflammatory bowel disease is Crohn’s disease, and the subsequent doses are administered until the patient is corticosteroid-free.The method according to any one of embodiments 87 to 101, wherein the Crohn’s disease is mildly to moderately active Crohn’s disease.The method according to any one of embodiments 87 to 101, wherein the Crohn’s disease is moderately to severely active Crohn’s disease.The method according to any one of embodiments 33 to 103, wherein the patient has a baseline level of CPa9-HNE of lower than about 200 ng / ml.The method according to any one of embodiments 33 to 104, wherein the patient has a baseline level of C1M of lower than about 100 ng / ml.The method according to any one of embodiments 33 to 105, wherein the patient has a baseline level of C7M of lower than about 10 ng / ml.The method according to any one of embodiments 33 to 106, wherein the compound is administered as part of a pharmaceutical composition which further comprises at least one pharmaceutically acceptable carrier, diluent, or excipient.The method according to embodiment 107, wherein the pharmaceutical composition is for oral administration.The method according to embodiment 107 or embodiment 108, wherein the pharmaceutical composition further comprises microcrystalline cellulose, lactose, pregelatinized starch, hydroxypropyl methylcellulose, croscarmellose sodium, poloxamer, colloidal silicon dioxide, and magnesium stearate.0. The method according to any one of embodiments 107 to 109, wherein the pharmaceutical composition is administered in a capsule, or a tablet.l.The method according to embodiment 110, wherein each capsule or tablet comprises about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 300 mg, or about 400 mg free form equivalent of the compound. . A compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl- [l,l'-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt or cocrystal thereof for use in the treatment of an inflammatory bowel disease in a patient, wherein the compound is administered to the patient in a dose of about 10 mg to about 850 mg free form equivalent.3. The compound for use according to embodiment 112, wherein the compound is administered to the patient orally, or parenterally.. The compound for use according to embodiment 113, wherein the compound is administered orally.5. The compound for use according to any one of embodiments 112 to 114, wherein the patient is advanced therapy naive.6. The compound for use according to any one of embodiments 112 to 114, wherein the patient is advanced therapy experienced.7. The compound for use according to embodiment 115 or embodiment 116, wherein the advanced therapy comprises one or more agents selected from 014P7 integrin antibodies, anti- TNF-a antibodies, IL-12 antibodies, IL-23 antibodies, JAK inhibitors, and SIP receptor modulators.8. The compound for use according to embodiment 117, wherein the agents are selected from vedolizumab, infliximab, adalimumab, golimumab, ustekinumab, mirikizumab, tofacitinib, filgotinib, upadacitinib, estrasimod, ozanimod, and amiselimod.9. The compound for use according to any one of embodiments 112 to 118, wherein the inflammatory bowel disease is ulcerative colitis.0. The compound for use according to embodiment 119, wherein the ulcerative colitis is mildly to moderately active ulcerative colitis.1. The compound for use according to embodiment 119, wherein the ulcerative colitis is moderately to severely active ulcerative colitis.-n-The compound for use according to any one of embodiments 112 to 118, wherein the inflammatory bowel disease is Crohn’s disease.The compound for use according to embodiment 122, wherein the Crohn’s disease is mildly to moderately active Crohn’s disease.The compound for use according to embodiment 122, wherein the Crohn’s disease is moderately to severely active Crohn’s disease.The compound for use according to any one of embodiments 112 to 124, wherein the compound is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid.The compound for use according to any one of embodiments 112 to 124, wherein the compound is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid adipic acid.The compound for use according to any one of embodiments 112 to 126, wherein the compound is administered in a dose of about 100 mg to about 800 mg free form equivalent. The compound for use according to embodiment 127, wherein the compound is administered in a dose of about 100 mg to about 400 mg free form equivalent.The compound for use according to embodiment 128, wherein the compound is administered in a dose of about 200 mg to about 400 mg free form equivalent.The compound for use according to embodiment 127, wherein the compound is administered in a dose selected from about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, and about 850 mg free form equivalent.The compound for use according to embodiment 130, wherein the compound is administered in a dose selected from about 100 mg, about 150 mg, about 200 mg, about 300 mg, and about 400 mg free form equivalent.The compound for use according to any one of embodiments 112 to 131, wherein the compound is administered twice daily.The compound for use according to any one of embodiments 112 to 131, wherein the compound is administered once daily.The compound for use according to embodiment 133, wherein the compound is administered once daily in the morning.The compound for use according to embodiment 133, wherein the compound is administered once daily in the evening.The compound for use according to any one of embodiments 112 to 135, wherein the patient has a baseline level of CPa9-HNE of lower than about 200 ng / ml.The compound for use according to any one of embodiments 112 to 136, wherein the patient has a baseline level of C1M of lower than about 100 ng / ml.The compound for use according to any one of embodiments 112 to 137, wherein the patient has a baseline level of C7M of lower than about 10 ng / ml.The compound for use according to any one of embodiments 112 to 138, wherein the compound is administered as part of a pharmaceutical composition which further comprises at least one pharmaceutically acceptable carrier, diluent, or excipient.The compound for use according to embodiment 139, wherein the pharmaceutical composition is for oral administration.The compound for use according to embodiment 140 or embodiment 139, wherein the pharmaceutical composition further comprises microcrystalline cellulose, lactose, pregelatinized starch, hydroxypropyl methylcellulose, croscarmellose sodium, poloxamer, colloidal silicon dioxide, and magnesium stearate.The compound for use according to any one of embodiments 139 to 141, wherein the pharmaceutical composition is administered in a capsule, or a tablet.The compound for use according to embodiment 142, wherein each capsule or tablet comprises about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 300 mg, or about 40 mg free form equivalent of the compound.A compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt or cocrystal thereof for use in the treatment of an inflammatory bowel disease in a patient, wherein the compound is administered to the patient according to the following dosing regimen:a. initial doses of about 10 mg to about 850 mg free form equivalent for a period of about 5 weeks and about 20 weeks, followed byb. subsequent doses of about 10 mg to about 850 mg free form equivalent.The compound for use according to embodiment 144, wherein the compound is administered to the patient orally, or parenterally.The compound for use according to embodiment 145, wherein the compound is administered to the patient orally.The compound for use according to any one of embodiments 144 to 146, wherein the patient is advanced therapy naive.The compound for use according to any one of embodiments 144 to 146, wherein the patient is advanced therapy experienced.The compound for use according to embodiment 147 or embodiment 148, wherein the advanced therapy comprises one or more agents selected from 014P7 integrin antibodies, anti-TNF-a antibodies, IL-12 antibodies, IL-23 antibodies, JAK inhibitors, and SIP receptor modulators.The compound for use according to embodiment 149, wherein the agents are selected from vedolizumab, infliximab, adalimumab, golimumab, ustekinumab, mirikizumab, tofacitinib, filgotinib, upadacitinib, estrasimod, ozanimod, and amiselimod.The compound for use according to any one of embodiments 144 to 150, wherein the compound is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid.The compound for use according to any one of embodiments 144 to 150, wherein the compound is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid adipic acid.The compound for use according to any one of embodiments 144 to 152, wherein the initial doses and subsequent doses are of about 100 mg to about 800 mg free form equivalent. The compound for use according to embodiment 153, wherein the initial doses and subsequent doses are of about 100 mg to about 400 mg free form equivalent.The compound for use according to embodiment 154, wherein the initial doses and subsequent doses are of about 200 mg to about 400 mg free form equivalent.The compound for use according to embodiment 153, wherein the initial doses and subsequent doses are independently selected from about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, and about 850 mg free form equivalent. The compound for use according to embodiment 156, wherein the initial doses and subsequent doses are independently selected from about 100 mg, about 150 mg, about 200 mg, about 300 mg, and about 400 mg free form equivalent.The compound for use according to any one of embodiments 144 to 157, wherein the initial doses and subsequent doses are independently administered twice daily, or once daily. The compound for use according to embodiment 158, wherein the initial doses and subsequent doses are independently administered twice daily, once daily in the morning, or once daily in the evening.The compound for use according to any one of embodiments 144 to 152, wherein the compound is administered orally to the patient according to the following dosing regimen: a. initial doses of about 100 mg free form equivalent twice daily for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 100 mg free form equivalent twice daily.The compound for use according to any one of embodiments 144 to 152, wherein the compound is administered orally to the patient according to the following dosing regimen: a. initial doses of about 100 mg free form equivalent twice daily for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 200 mg free form equivalent twice daily.The compound for use according to any one of embodiments 144 to 152, wherein the compound is administered orally to the patient according to the following dosing regimen: a. initial doses of about 200 mg free form equivalent twice daily for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 100 mg free form equivalent twice daily.The compound for use according to any one of embodiments 144 to 152, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 200 mg free form equivalent twice daily for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 200 mg free form equivalent twice daily.The compound for use according to any one of embodiments 144 to 152, wherein the compound is administered orally to the patient according to the following dosing regimen: a. initial doses of about 100 mg free form equivalent once daily in the morning for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 100 mg free form equivalent once daily in the morning. The compound for use according to any one of embodiments 144 to 152, wherein the compound is administered orally to the patient according to the following dosing regimen: a. initial doses of about 100 mg free form equivalent once daily in the morning for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 200 mg free form equivalent once daily in the morning. The compound for use according to any one of embodiments 144 to 152, wherein the compound is administered orally to the patient according to the following dosing regimen: a. initial doses of about 200 mg free form equivalent once daily in the morning for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 100 mg free form equivalent once daily in the morning. The compound for use according to any one of embodiments 144 to 152, wherein the compound is administered orally to the patient according to the following dosing regimen: a. initial doses of about 200 mg free form equivalent once daily in the morning for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 200 mg free form equivalent once daily in the morning. The compound for use according to any one of embodiments 144 to 152, wherein the compound is administered orally to the patient according to the following dosing regimen: a. initial doses of about 100 mg free form equivalent once daily in the evening for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 100 mg free form equivalent once daily in the evening.The compound for use according to any one of embodiments 144 to 152, wherein the compound is administered orally to the patient according to the following dosing regimen: a. initial doses of about 100 mg free form equivalent once daily in the evening for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 200 mg free form equivalent once daily in the evening.The compound for use according to any one of embodiments 144 to 152, wherein the compound is administered orally to the patient according to the following dosing regimen: a. initial doses of about 200 mg free form equivalent once daily in the evening for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 100 mg free form equivalent once daily in the evening.The compound for use according to any one of embodiments 144 to 152, wherein the compound is administered orally to the patient according to the following dosing regimen: a. initial doses of about 200 mg free form equivalent once daily in the evening for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 200 mg free form equivalent once daily in the evening.The compound for use according to any one of embodiments 144 to 171, wherein the initial doses are administered for a period selected from about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, and about 12 weeks. The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is ulcerative colitis.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of clinical remission.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of clinical remission.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of clinical response.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of clinical response.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of MCS remission.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of MCS remission.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of MCS response.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of MCS response.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of histologic remission by RHI.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of histologic remission by RHI.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of histologic improvement.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of histologic improvement.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of endoscopic improvement.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of endoscopic improvement.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of endoscopic remission.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of endoscopic remission.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of mucosal healing.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of mucosal healing.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of mucosal improvement.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of mucosal improvement.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of symptomatic response.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of symptomatic response.The compound for use according to any one of embodiments 173 to 195, wherein the ulcerative colitis is mildly to moderately active ulcerative colitis.The compound for use according to any one of embodiments 173 to 195, wherein the ulcerative colitis is moderately to severely active ulcerative colitis.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is Crohn’s disease.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is Crohn’s disease, and the initial doses are administered until achievement of endoscopic response.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is Crohn’s disease, and the subsequent doses are administered until achievement of endoscopic response.The compound for use according to any one of embodiments 144 to 172wherein the inflammatory bowel disease is Crohn’s disease, and the initial doses are administered until achievement of endoscopic remission.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is Crohn’s disease, and the subsequent doses are administered until achievement of endoscopic remission.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is Crohn’s disease, and the initial doses are administered until achievement of CD Al clinical response.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is Crohn’s disease, and the subsequent doses are administered until achievement of CD Al clinical response.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is Crohn’s disease, and the initial doses are administered until achievement of CD Al clinical remission.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is Crohn’s disease, and the subsequent doses are administered until achievement of CD Al clinical remission.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is Crohn’s disease, and the initial doses are administered until achievement of PRO2 clinical response.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is Crohn’s disease, and the subsequent doses are administered until achievement of PRO2 clinical response.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is Crohn’s disease, and the initial doses are administered until achievement of PRO2 clinical remission.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is Crohn’s disease, and the subsequent doses are administered until achievement of PRO2 clinical remission.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is Crohn’s disease, and the initial doses are administered until the patient is corticosteroid-free.The compound for use according to any one of embodiments 144 to 172, wherein the inflammatory bowel disease is Crohn’s disease, and the subsequent doses are administered until the patient is corticosteroid-free.The compound for use according to any one of embodiments 198 to 212 wherein the Crohn’s disease is mildly to moderately active Crohn’s disease.The compound for use according to any one of embodiments 198 to 212, wherein the Crohn’s disease is moderately to severely active Crohn’s disease.The compound for use according to any one of embodiments 144 to 214, wherein the patient has a baseline level of CPa9-HNE of lower than about 200 ng / ml.The compound for use according to any one of embodiments 144 to 215, wherein the patient has a baseline level of C1M of lower than about 100 ng / ml.The compound for use according to any one of embodiments 144 to 216, wherein the patient has a baseline level of C7M of lower than about 10 ng / ml.The compound for use according to any one of embodiments 144 to 217, wherein the compound is administered as part of a pharmaceutical composition which further comprises at least one pharmaceutically acceptable carrier, diluent, or excipient.The compound for use according to embodiment 218, wherein the pharmaceutical composition is for oral administration.The compound for use according to embodiment 218 or embodiment 219, wherein the pharmaceutical composition further comprises microcrystalline cellulose, lactose, pregelatinized starch, hydroxypropyl methylcellulose, croscarmellose sodium, poloxamer, colloidal silicon dioxide, and magnesium stearate.The compound for use according to any one of embodiments 218 to 220, wherein the pharmaceutical composition is administered in a capsule, or a tablet.The compound for use according to embodiment 221, wherein each capsule or tablet comprise about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150mg, about 175 mg, about 200 mg, about 300 mg, or about 400 mg free form equivalent of the compound.Use of a compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt or cocrystal thereof for the manufacture of a medicament for the treatment of an inflammatory bowel disease in a patient, wherein the compound is administered to the patient in a dose of about 10 mg to about 850 mg free form equivalent.The use according to embodiment 223, wherein the compound is administered to the patient orally, or parenterally.The use according to embodiment 224, wherein the compound is administered orally.The use according to any one of embodiments 223 to 225, wherein the patient is advanced therapy naive.The use according to any one of embodiments 223 to 225, wherein the patient is advanced therapy experienced.The use according to embodiment 226 or embodiment 227, wherein the advanced therapy comprises one or more agents selected from ouP? integrin antibodies, anti-TNF-a antibodies, IL-12 antibodies, IL-23 antibodies, JAK inhibitors, and SIP receptor modulators.The use according to embodiment 228, wherein the agents are selected from vedolizumab, infliximab, adalimumab, golimumab, ustekinumab, mirikizumab, tofacitinib, filgotinib, upadacitinib, estrasimod, ozanimod, and amiselimod.The use according to any one of embodiments 223 to 229, wherein the inflammatory bowel disease is ulcerative colitis.The use according to embodiment 230, wherein the ulcerative colitis is mildly to moderately active ulcerative colitis.The use according to embodiment 230, wherein the ulcerative colitis is moderately to severely active ulcerative colitis.The use according to any one of embodiments 223 to 229, wherein the inflammatory bowel disease is Crohn’s disease.The use according to embodiment 233, wherein the Crohn’s disease is mildly to moderately active Crohn’s disease.The use according to embodiment 233, wherein the Crohn’s disease is moderately to severely active Crohn’s disease.The use according to any one of embodiments 223 to 235, wherein the compound is (5)-3- (fS')-2-(5-(2-(di methyl ami no)ethyl )-2-oxo-4-(trifl uoromethyl )pyri di n- l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid. The use according to any one of embodiments 223 to 235, wherein the compound is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid adipic acid.The use according to any one of embodiments 223 to 237, wherein the compound is administered in a dose of about 25 mg to about 400 mg free form equivalent.The use according to embodiment 238, wherein the compound is administered in a dose of about 50 mg to about 350 mg free form equivalent.The use according to embodiment 238, wherein the compound is administered in a dose of about 100 mg to about 300 mg free form equivalent.The use according to embodiment 238, wherein the compound is administered in a dose selected from about 25 mg, about 50 mg, 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, and about 850 mg free form equivalent. The use according to embodiment 241, wherein the compound is administered in a dose selected from about 100 mg, about 150 mg, about 200 mg, about 300 mg, and about 400 mg free form equivalent.The use according to any one of embodiments 223 to 242, wherein the compound is administered twice daily.The use according to embodiment 243, wherein the compound is administered once daily. The use according to embodiment 244, wherein the compound is administered once daily in the morning.The use according to embodiment 244, wherein the compound is administered once daily in the evening.The use according to any one of embodiments 223 to 246, wherein the patient has a baseline level of CPa9-HNE of lower than about 200 ng / ml.The use according to any one of embodiments 223 to 247, wherein the patient has a baseline level of C1M of lower than about 100 ng / ml.The use according to any one of embodiments 223 to 248, wherein the patient has a baseline level of C7M of lower than about 10 ng / ml.The use according to any one of embodiments 223 to 249, wherein the compound is administered as part of a pharmaceutical composition which further comprises at least one pharmaceutically acceptable carrier, diluent, or excipient.The use according to embodiment 250, wherein the pharmaceutical composition is for oral administration.The use according to embodiment 250 or embodiment 251, wherein the pharmaceutical composition further comprises microcrystalline cellulose, lactose, pregelatinized starch, hydroxypropyl methylcellulose, croscarmellose sodium, poloxamer, colloidal silicon dioxide, and magnesium stearate.The use according to any one of embodiments 250 to 252, wherein the pharmaceutical composition is administered in a capsule, or a tablet.The use according to embodiment 253, wherein each capsule or tablet comprise about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 300 mg, or about 400 mg free form equivalent of the compound.Use of a compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt or cocrystal thereof for the manufacture of a medicament for the treatment of an inflammatory bowel disease in a patient, wherein the compound is administered to the patient according to the following dosing regimen:a. initial doses of about 10 mg to about 850 mg free form equivalent for a period of about 5 weeks and about 20 weeks, followed byb. subsequent doses of about 10 mg to about 850 mg free form equivalent.The use according to embodiment 255, wherein the compound is administered to the patient orally, or parenterally.The use according to embodiment 256, wherein the compound is administered to the patient orally.The use according to any one of embodiments 255 to 257, wherein the patient is advanced therapy naive.The use according to any one of embodiments 255 to 257, wherein the patient is advanced therapy experienced.The use according to embodiment 258 or embodiment 259, wherein the advanced therapy comprises one or more agents selected from ouP? integrin antibodies, anti-TNF-a antibodies, IL-12 antibodies, IL-23 antibodies, JAK inhibitors, and SIP receptor modulators.The method according to embodiment 38, wherein the agents are selected from vedolizumab, infliximab, adalimumab, golimumab, ustekinumab, mirikizumab, tofacitinib, filgotinib, upadacitinib, estrasimod, ozanimod, and amiselimod.The use according to any one of embodiments 255 to 261, wherein the compound is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid. The use according to any one of embodiments 255 to 261, wherein the compound is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid adipic acid.The use according to any one of embodiments 255 to 263, wherein the initial doses and subsequent doses are of about 100 mg to about 800 mg free form equivalent.The use according to embodiment 264, wherein the initial doses and subsequent doses are of about 100 mg to about 400 mg free form equivalent.The use according to embodiment 265, wherein the initial doses and subsequent doses are of about 200 mg to about 400 mg free form equivalent.The use according to embodiment 264, wherein the initial doses and subsequent doses are independently selected from about about 25 mg, about 50 mg, about 75 mg, about 100 mg about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg,about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, and about 850 mg free form equivalent.The use according to embodiment 267, wherein the initial doses and subsequent doses are independently selected from about 100 mg, about 150 mg, about 200 mg, about 300 mg, and about 400 mg free form equivalent.The use according to any one of embodiments 255 to 268, wherein the initial doses and subsequent doses are independently administered twice daily, or once daily.The use according to embodiment 269, wherein the initial doses and subsequent doses are independently administered twice daily, once daily in the morning, or once daily in the evening.The use according to any one of embodiments 255 to 263, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 100 mg free form equivalent twice daily for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 100 mg free form equivalent twice daily.The use according to any one of embodiments 255 to 263, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 100 mg free form equivalent twice daily for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 200 mg free form equivalent twice daily.The use according to any one of embodiments 255 to 263, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 200 mg free form equivalent twice daily for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 100 mg free form equivalent twice daily.The use according to any one of embodiments 255 to 263, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 200 mg free form equivalent twice daily for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 200 mg free form equivalent twice daily.The use according to any one of embodiments 255 to 263, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 100 mg free form equivalent once daily in the morning for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 100 mg free form equivalent once daily in the morning. The use according to any one of embodiments 255 to 263, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 100 mg free form equivalent once daily in the morning for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 200 mg free form equivalent once daily in the morning. The use according to any one of embodiments 255 to 263, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 200 mg free form equivalent once daily in the morning for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 100 mg free form equivalent once daily in the morning. The use according to any one of embodiments 255 to 263, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 200 mg free form equivalent once daily in the morning for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 200 mg free form equivalent once daily in the morning. The use according to any one of embodiments 255 to 263, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 100 mg free form equivalent once daily in the evening for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 100 mg free form equivalent once daily in the evening.The use according to any one of embodiments 255 to 263, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 100 mg free form equivalent once daily in the evening for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 200 mg free form equivalent once daily in the evening.The use according to any one of embodiments 255 to 263, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 200 mg free form equivalent once daily in the evening for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 100 mg free form equivalent once daily in the evening.The use according to any one of embodiments 255 to 263, wherein the compound is administered orally to the patient according to the following dosing regimen:a. initial doses of about 200 mg free form equivalent once daily in the evening for a period of about 5 weeks to about 20 weeks, followed byb. subsequent doses of about 200 mg free form equivalent once daily in the evening.The use according to any one of embodiments 255 to 263, wherein the initial doses are administered for a period selected from about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, and about 12 weeks.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is ulcerative colitis.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of clinical remission.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of clinical remission.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of clinical response.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of clinical response.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of MCS remission.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of MCS remission.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of MCS response.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of MCS response.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of histologic remission by RHI.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of histologic remission by RHI.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of histologic improvement.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of histologic improvement.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of endoscopic improvement.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of endoscopic improvement.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of endoscopic remission.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of endoscopic remission.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of mucosal healing.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of mucosal healing.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of mucosal improvement.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of mucosal improvement.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is ulcerative colitis, and the initial doses are administered until achievement of symptomatic response.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is ulcerative colitis, and the subsequent doses are administered until achievement of symptomatic response.The use according to any one of embodiments 284 to 306, wherein the ulcerative colitis is mildly to moderately active ulcerative colitis.The use according to any one of embodiments 284 to 306, wherein the ulcerative colitis is moderately to severely active ulcerative colitis.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is Crohn’s disease.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is Crohn’s disease, and the initial doses are administered until achievement of endoscopic response.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is Crohn’s disease, and the subsequent doses are administered until achievement of endoscopic response.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is Crohn’s disease, and the initial doses are administered until achievement of endoscopic remission.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is Crohn’s disease, and the subsequent doses are administered until achievement of endoscopic remission.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is Crohn’s disease, and the initial doses are administered until achievement of CD Al clinical response.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is Crohn’s disease, and the subsequent doses are administered until achievement of CD Al clinical response.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is Crohn’s disease, and the initial doses are administered until achievement of CD Al clinical remission.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is Crohn’s disease, and the subsequent doses are administered until achievement of CD Al clinical remission.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is Crohn’s disease, and the initial doses are administered until achievement of PR02 clinical response.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is Crohn’s disease, and the subsequent doses are administered until achievement of PR02 clinical response.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is Crohn’s disease, and the initial doses are administered until achievement of PRO2 clinical remission.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is Crohn’s disease, and the subsequent doses are administered until achievement of PRO2 clinical remission.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is Crohn’s disease, and the initial doses are administered until the patient is corticosteroid-free.The use according to any one of embodiments 255 to 283, wherein the inflammatory bowel disease is Crohn’s disease, and the subsequent doses are administered until the patient is corticosteroid-free.The use according to any one of embodiments 309 to 323, wherein the Crohn’s disease is mildly to moderately active Crohn’s disease.The use according to any one of embodiments 309 to 323, wherein the Crohn’s disease is moderately to severely active Crohn’s disease.The use according to any one of embodiments 255 to 325, wherein the patient has a baseline level of CPa9-HNE of lower than about 200 ng / ml.The use according to any one of embodiments 255 to 326, wherein the patient has a baseline level of C1M of lower than about 100 ng / ml.The use according to any one of embodiments 255 to 327, wherein the patient has a baseline level of C7M of lower than about 10 ng / ml.The use according to any one of embodiments 255 to 328, wherein the compound is administered as part of a pharmaceutical composition which further comprises at least one pharmaceutically acceptable carrier, diluent, or excipient.The use according to embodiment 329, wherein the pharmaceutical composition is for oral administration.The use according to embodiment 329 or embodiment 330, wherein the pharmaceutical composition further comprises microcrystalline cellulose, lactose, pregelatinized starch, hydroxypropyl methylcellulose, croscarmellose sodium, poloxamer, colloidal silicon dioxide, and magnesium stearate.The use according to any one of embodiments 329 to 331, wherein the pharmaceutical composition is administered in a capsule, or a tablet.The use according to embodiment 332, wherein each capsule or tablet comprise about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 300 mg, or about 400 mg free form equivalent of the compound.A compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid which is crystalline, and which is characterized by an X-ray powder diffraction pattern using CuKa radiation comprising a peak at diffraction angle 29 of 6.9°, and one or more peaks at 7.6°, and 5.4° (±0.2° respectively)335. A cocrystalline form comprising (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl- [1,1 '-biphenyl]-3 -yl)propanoic acid.336. The cocrystalline form according to embodiment 335, further comprising a dicarboxylic acid.337. The cocrystalline form according to embodiment 336, wherein the dicarboxylic acid is selected from adipic acid, azelaic acid, suberic acid, and pimelic acid.338. The cocrystalline form according to any one of embodiments 335 to 337, which is (5)-3-((5)- 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid adipic acid.339. The cocrystalline form according to embodiment 338, which is characterized by an X-ray powder diffraction pattern using CuKa radiation comprising a peak at diffraction angle 29 of 6.3°, and one or more peaks at 16.6°, and 18.9° (±0.2° respectively).340. The cocrystalline form according to embodiment 338, which is characterized by an X-ray powder diffraction pattern using CuKa radiation comprising a peak at diffraction angle 29 of 5.5°, and one or more peaks at 6.8°, and 8.8° (±0.2° respectively).341. The cocrystalline form according to embodiment 338, which is characterized by a13C solid state NMR spectrum which comprises peaks referenced to the methyl peak of 3- methylglutaric acid (18.8 ppm) at 16.5, 160.9, 179.3, and 20.0 ppm, with a tolerance of ±0.4 ppm.342. The cocrystalline form according to embodiment 338, which is characterized by a13C solid state NMR spectrum which comprises peaks referenced to the methyl peak of 3- methylglutaric acid (18.8 ppm) at 11.2, 163.5, 21.2, and 21.4 ppm, with a tolerance of ±0.4 ppm.343. The cocrystalline form according to embodiment 338, which is characterized by:a. An X-ray powder diffraction pattern using CuKa radiation comprising a peak at diffraction angle 29 of 6.3°, and one or more peaks at 16.6°, and 18.9° (±0.2° respectively); and b. A13C solid state NMR spectrum which comprises peaks referenced to the methyl peak of 3- methylglutaric acid (18.8 ppm) at 16.5, 160.9, 179.3, and 20.0 ppm, with a tolerance of ±0.4 ppm.344. The cocrystalline form according to embodiment 338, which is characterized by:a. An X-ray powder diffraction pattern using CuKa radiation comprising a peak at diffraction angle 29 of 5.5°, and one or more peaks at 6.8°, and 8.8° (±0.2° respectively); andb. A13C solid state NMR spectrum which comprises peaks referenced to the methyl peak of 3- methylglutaric acid (18.8 ppm) at 11.2, 163.5, 21.2, and 21.4 ppm, with a tolerance of ±0.4 ppm.345. A pharmaceutical composition comprising the cocrystalline form according to any one of embodiments 335 to 344 and a pharmaceutical acceptable carrier, diluent, or excipient.346. A dispersion comprising (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl- [l,l'-biphenyl]-3-yl)propanoic acid and a pharmaceutically acceptable polymer.347. The dispersion according to embodiment 346, which is spray dried.348. The dispersion according to embodiment 346 or embodiment 347, wherein the pharmaceutically acceptable polymer is selected from an HPMC polymer, and an HPMC-AS polymer.349. The dispersion according to embodiment 348, wherein the HMPC polymer is HPMC E3. 350. The dispersion according to embodiment 348, wherein the HPMC-AS polymer is HPMC-AS 716.351. The dispersion according to any one of embodiments 346 to 350, wherein (5)-3-((5)-2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3- (4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid is present in a quantity between about 30% w / w to about 95% w / w of the total weight of the dispersion.352. The dispersion according to any one of embodiments 346 to 350, wherein (5)-3-((5)-2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3- (4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid is present in a quantity selected from about 30% w / w, about 40% w / w, about 50% w / w, about 60% w / w, about 70% w / w, about 80% w / w, about 90% w / w, and about 95% w / w of the total weight of the dispersion.353. A pharmaceutical composition comprising the dispersion according to any one of embodiments 346 to 352 and a pharmaceutical acceptable carrier, diluent, or excipient.354. A method of treating moderately to severely active ulcerative colitis in a patient in need thereof comprising administering to the patient a compound which is (5)-3-((5)-2-(5-(2-(di methyl ami no)ethyl)-2-oxo-4-(trifluoromethyl)pyri di n- l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid adipic acid Form B, wherein the compound is administered to the patient orally, in a dose of about 400 mg free form equivalent, twice daily.A method of treating moderately to severely active ulcerative colitis in a patient in need thereof comprising administering to the patient a compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid adipic acid Form B, wherein the compound is administered to the patient orally, in a dose of about 200 mg free form equivalent, twice daily.A method of treating moderately to severely active Crohn’s disease in a patient in need thereof comprising administering to the patient a compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid adipic acid Form B, wherein the compound is administered to the patient orally, in a dose of about 400 mg free form equivalent, twice daily.A method of treating moderately to severely active Crohn’s disease in a patient in need thereof comprising administering to the patient a compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid adipic acid Form B, wherein the compound is administered to the patient orally, in a dose of about 200 mg free form equivalent, twice daily.A compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid adipic acid Form B for use in the treatment of moderately to severely active ulcerative colitis in a patient, wherein the compound is administered to the patient orally, in a dose of about 400 mg free form equivalent, twice daily.A compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid adipic acid Form B for use in the treatment of moderately to severely active ulcerative colitis in a patient, wherein the compound isadministered to the patient orally, in a dose of about 200 mg free form equivalent, twice daily.A compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid adipic acid Form B for use in the treatment of moderately to severely active Crohn’s disease in a patient, wherein the compound is administered to the patient orally, in a dose of about 400 mg free form equivalent, twice daily.A compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid adipic acid Form B for use in the treatment of moderately to severely active Crohn’s disease in a patient, wherein the compound is administered to the patient orally, in a dose of about 200 mg free form equivalent, twice daily.Use of a compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid adipic acid Form B for the manufacture of a medicament for the treatment of moderately to severely active ulcerative colitis in a patient, wherein the compound is administered to the patient orally, in a dose of about 400 mg free form equivalent, twice daily.Use of a compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid adipic acid Form B for the manufacture of a medicament for the treatment of moderately to severely active ulcerative colitis in a patient, wherein the compound is administered to the patient orally, in a dose of about 200 mg free form equivalent, twice daily.Use of a compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid adipic acid Form B for the manufacture of a medicament for the treatment of moderately to severely active Crohn’s disease in a patient, wherein the compound is administered to the patient orally, in a dose of about 400 mg free form equivalent, twice daily.Use of a compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid adipic acid Form B for the manufacture of a medicament for the treatment of moderately to severely active Crohn’s disease in a patient, wherein the compound is administered to the patient orally, in a dose of about 200 mg free form equivalent, twice daily.

Claims

1. WE CLAIM:

1. A method of treating an inflammatory bowel disease in a patient in need thereof comprising administering to the patient a compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)- 2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'- tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is administered to the patient in a dose of about 100 mg to about 800 mg free form equivalent.

2. The method according to claim 1, wherein the compound is administered orally.

3. The method according to claim 1 or claim 2, wherein the inflammatory bowel disease is ulcerative colitis.

4. The method according to claim 3, wherein the ulcerative colitis is moderately to severely active ulcerative colitis.

5. The method according to claim 1 or claim 2, wherein the inflammatory bowel disease is Crohn’s disease.

6. The method according to claim 5, wherein the Crohn’s disease is moderately to severely active Crohn’s disease.

7. The method according to any one of claims 1 to 6, wherein the compound is (5)-3-((5)-2-(5- (2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid adipic acid.

8. The method according to claim 7, wherein the compound is (5)-3-((5)-2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3- (4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid adipic acid Form B.

9. The method according to any one of claims 1 to 8, wherein the compound is administered in a dose of about 100 mg to about 400 mg free form equivalent.

10. The method according to any one of claims 1 to 9, wherein the compound is administered in a dose of about 200 mg to about 400 mg free form equivalent.

11. The method according to any one of claims 1 to 10, wherein the compound is administered in a dose selected from about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, and about 800 mg free form equivalent.

12. The method according to any one of claims 1 to 11 wherein the compound is administered twice daily.

13. A method of treating moderately to severely active ulcerative colitis in a patient in need thereof comprising administering to the patient a compound which is (5)-3-((5)-2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3- (4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid adipic acid Form B, wherein the compound is administered to the patient orally, in a dose of about 400 mg free form equivalent, twice daily.

14. A method of treating moderately to severely active ulcerative colitis in a patient in need thereof comprising administering to the patient a compound which is (5)-3-((5)-2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3- (4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid adipic acid Form B, wherein the compound is administered to the patient orally, in a dose of about 200 mg free form equivalent, twice daily.

15. A method of treating moderately to severely active Crohn’s disease in a patient in need thereof comprising administering to the patient a compound which is (5)-3-((5)-2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3- (4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid adipic acid Form B, wherein the compound is administered to the patient orally, in a dose of about 400 mg free form equivalent, twice daily.

16. A method of treating moderately to severely active Crohn’s disease in a patient in need thereof comprising administering to the patient a compound which is (5)-3-((5)-2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3- (4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid adipic acid Form B, wherein the compound is administered to the patient orally, in a dose of about 200 mg free form equivalent, twice daily.

17. A compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl- [l,l'-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt or cocrystal thereof for use in the treatment of an inflammatory bowel disease in a patient, wherein thecompound is administered to the patient in a dose of about 100 mg to about 800 mg free form equivalent.

18. The compound for use according to claim 17, wherein the compound is administered orally.

19. The compound for use according to claim 17 or claim 18, wherein the inflammatory bowel disease is ulcerative colitis.

20. The compound for use according to claim 19, wherein the ulcerative colitis is moderately to severely active ulcerative colitis.

21. The compound for use according to claim 17 or claim 18, wherein the inflammatory bowel disease is, Crohn’s disease.

22. The compound for use according to claim 21, wherein the Crohn’s disease is moderately to severely active Crohn’s disease.

23. The compound for use according to any one of claims 17 to 22, wherein the compound is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid adipic acid.

24. The compound for use according to claim 23, wherein the compound is (5)-3-((5)-2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3- (4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid adipic acid Form B.

25. The compound for use according to any one of claims 17 to 24, wherein the compound is administered in a dose of about 100 mg to about 400 mg free form equivalent.

26. The compound for use according to any one of claims 17 to 25, wherein the compound is administered in a dose of about 200 mg to about 400 mg free form equivalent.

27. The compound for use according to any one of claims 17 to 26, wherein the compound is administered in a dose selected from about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, and about 800 mg free form equivalent.

28. The compound for use according to any one of claims 17 to 27, wherein the compound is administered twice daily.

29. A compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl- [l,l'-biphenyl]-3-yl)propanoic acid adipic acid Form B for use in the treatment of moderately to severely active ulcerative colitis in a patient, wherein the compound is administered to the patient orally, in a dose of about 400 mg free form equivalent, twice daily.

30. A compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl- [l,l'-biphenyl]-3-yl)propanoic acid adipic acid Form B for use in the treatment of moderately to severely active ulcerative colitis in a patient, wherein the compound is administered to the patient orally, in a dose of about 200 mg free form equivalent, twice daily.

31. A compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl- [l,l'-biphenyl]-3-yl)propanoic acid adipic acid Form B for use in the treatment of moderately to severely active Crohn’s disease in a patient, wherein the compound is administered to the patient orally, in a dose of about 400 mg free form equivalent, twice daily.

32. A compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl- [l,l'-biphenyl]-3-yl)propanoic acid adipic acid Form B for use in the treatment of moderately to severely active Crohn’s disease in a patient, wherein the compound is administered to the patient orally, in a dose of about 200 mg free form equivalent, twice daily.

33. Use of a compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl- [l,l'-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt or cocrystal thereof for the manufacture of a medicament for the treatment of an inflammatory bowel disease in a patient, wherein the compound is administered to the patient in a dose of about 100 mg to about 800 mg free form equivalent.

34. The use according to claim 33, wherein the compound is administered orally.

35. The use according to claim 33 or claim 34, wherein the inflammatory bowel disease is ulcerative colitis.

36. The use according to claim 35, wherein the ulcerative colitis is moderately to severely active ulcerative colitis.

37. The use according to claim 33 or claim 34, wherein the inflammatory bowel disease is, Crohn’s disease.

38. The use according to claim 37, wherein the Crohn’s disease is moderately to severely active Crohn’s disease.

39. The use according to any one of claims 33 to 38, wherein the compound is (5)-3-((5)-2-(5- (2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid adipic acid.

40. The use according to claim 39, wherein the compound is (5)-3-((5)-2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3- (4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid adipic acid Form B.

41. The use according to any one of claims 33 to 40, wherein the compound is administered in a dose of about 100 mg to about 400 mg free form equivalent.

42. The use according to any one of claims 33 to 41, wherein the compound is administered in a dose of about 200 mg to about 400 mg free form equivalent.

43. The use according to any one of claims 33 tc • 42, wherein the compound is administered in a dose selected from about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, and about 800 mg free form equivalent.

44. The use according to any one of claims 33 tc • 43, wherein the compound is administered twice daily.

45. Use of a compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl- [l,l'-biphenyl]-3-yl)propanoic acid adipic acid Form B for the manufacture of a medicament for the treatment of moderately to severely active ulcerative colitis in a patient, wherein thecompound is administered to the patient orally, in a dose of about 400 mg free form equivalent, twice daily.

46. Use of a compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl- [l,l'-biphenyl]-3-yl)propanoic acid adipic acid Form B for the manufacture of a medicament for the treatment of moderately to severely active ulcerative colitis in a patient, wherein the compound is administered to the patient orally, in a dose of about 200 mg free form equivalent, twice daily.

47. Use of a compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl- [l,l'-biphenyl]-3-yl)propanoic acid adipic acid Form B for the manufacture of a medicament for the treatment of moderately to severely active Crohn’s disease in a patient, wherein the compound is administered to the patient orally, in a dose of about 400 mg free form equivalent, twice daily.

48. Use of a compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl- [l,l'-biphenyl]-3-yl)propanoic acid adipic acid Form B for the manufacture of a medicament for the treatment of moderately to severely active Crohn’s disease in a patient, wherein the compound is administered to the patient orally, in a dose of about 200 mg free form equivalent, twice daily49. A compound which is (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl- [l,l'-biphenyl]-3-yl)propanoic acid which is crystalline, and which is characterized by an X- ray powder diffraction pattern using CuKa radiation comprising a peak at diffraction angle 29 of 6.9°, and one or more peaks at 7.6°, and 5.4° (±0.2° respectively).

50. A cocrystalline form comprising (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl- [1,1 '-biphenyl]-3 -yl)propanoic acid.

51. The cocrystalline form according to claim 50, further comprising a dicarboxylic acid.

52. The cocrystalline form according to claim 51, wherein the dicarboxylic acid is selected from adipic acid, azelaic acid, suberic acid, and pimelic acid.

53. The cocrystalline form according to any one of claims 50 to 52, which is (5)-3-((5)-2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3- (4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid adipic acid.

54. The cocrystalline form according to claim 53, which is characterized by an X-ray powder diffraction pattern using CuKa radiation comprising a peak at diffraction angle 29 of 6.3°, and one or more peaks at 16.6°, and 18.9° (±0.2° respectively).

55. The cocrystalline form according to claim 53, which is characterized by an X-ray powder diffraction pattern using CuKa radiation comprising a peak at diffraction angle 29 of 5.5°, and one or more peaks at 6.8°, and 8.8° (±9.2° respectively).

56. The cocrystalline form according to claim 53, which is characterized by a13C solid state NMR spectrum which comprises peaks referenced to the methyl peak of 3 -methylglutaric acid (18.8 ppm) at 16.5, 169.9, 179.3, and 29.9 ppm, with a tolerance of ±9.4 ppm.

57. The cocrystalline form according to claim 53, which is characterized by a13C solid state NMR spectrum which comprises peaks referenced to the methyl peak of 3 -methylglutaric acid (18.8 ppm) at 11.2, 163.5, 21.2, and 21.4 ppm, with a tolerance of ±9.4 ppm.

58. The cocrystalline form according to claim 53, which is characterized by:a. an X-ray powder diffraction pattern using CuKa radiation comprising a peak at diffraction angle 29 of 6.3°, and one or more peaks at 16.6°, and 18.9° (±9.2° respectively); and b. a13C solid state NMR spectrum which comprises peaks referenced to the methyl peak of 3- methylglutaric acid (18.8 ppm) at 16.5, 169.9, 179.3, and 29.9 ppm, with a tolerance of ±9.4 ppm.

59. The cocrystalline form according to claim 53, which is characterized by:a. an X-ray powder diffraction pattern using CuKa radiation comprising a peak at diffraction angle 29 of 5.5°, and one or more peaks at 6.8°, and 8.8° (±9.2° respectively); andb. a13C solid state NMR spectrum which comprises peaks referenced to the methyl peak of 3- methylglutaric acid (18.8 ppm) at 11.2, 163.5, 21.2, and 21.4 ppm, with a tolerance of ±9.4 PPm69. A pharmaceutical composition comprising the cocrystalline form according to any one of claims 59 to 59 and a pharmaceutical acceptable carrier, diluent, or excipient.

61. A dispersion comprising (5)-3-((5)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl- [l,l'-biphenyl]-3-yl)propanoic acid and a pharmaceutically acceptable polymer.-HO-62. The dispersion according to claim 61, which is spray dried.

63. The dispersion according to claim 61 or claim 62, wherein the pharmaceutically acceptable polymer is selected from an HPMC polymer, and an HPMC-AS polymer.

64. The dispersion according to claim 63, wherein the HMPC polymer is HPMC E3.

65. The dispersion according to claim 63, wherein the HPMC-AS polymer is HPMC-AS 716.

66. The dispersion according to any one of claims 61 to 65, wherein (5)-3-((5)-2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3- (4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid is present in a quantity between about 30% w / w to about 95% w / w of the total weight of the dispersion.

67. The dispersion according to any one of claims 61 to 65, wherein (5)-3-((5)-2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3- (4-fluoro-2',4',5,6'-tetramethyl-[l,T-biphenyl]-3-yl)propanoic acid is present in a quantity selected from about 30% w / w, about 40% w / w, about 50% w / w, about 60% w / w, about 70% w / w, about 80% w / w, about 90% w / w, and about 95% w / w of the total weight of the dispersion.

68. A pharmaceutical composition comprising the dispersion according to any one of claims 61 to 67 and a pharmaceutical acceptable carrier, diluent, or excipient.

Images