Interleukin-23 receptor antagonists for the treatment of ulcerative colitis

Abstract

The present disclosure relates to methods of administering a cyclic peptide inhibitor of interleukin-23 receptor (IL-23R), or a pharmaceutically acceptable salt or solvate form thereof, corresponding compositions, assays, methods, and / or uses for the treatment of ulcerative colitis.

Description

Cross-references to related applications

[0001] This application claims priority to U.S. Patent Application No. 63 / 584,295, filed September 21, 2023, the disclosure of which is incorporated herein by reference in its entirety.

[0002] sequence list

[0003] This application includes a sequence list that has been submitted electronically, and which is hereby incorporated in its entirety by reference. The XML copy was created on August 11, 2024, named PRD4284WOPCT1_SL, and is 5,758 bytes in size. Background Technology

[0004] Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology that affects the surface mucosa, crypt epithelium, and submucosa of the colon. Ulcerative colitis is characterized by a lifelong alternating course of remission and exacerbation, with 15% of patients experiencing an acute exacerbation requiring hospitalization at some point during the course of the disease (Willert RP, Lawrance IC. Use of infliximab in the prevention and delay of colectomy in severe steroid dependent and refractory ulcerative colitis. World J Gastroenterol. 2008; 14(16):2544-2549).

[0005] IL-23 is a heterodimer composed of a unique p19 subunit and a p40 subunit shared with IL-12. IL-12 is a helper T cell (T1) cell involved in the production of interferon-γ (IFN-γ). H 1) Developmental cytokines. Although both IL-23 and IL-12 contain p40 subunits, they have different phenotypic properties. For example, animals lacking IL-12 are susceptible to inflammatory autoimmune diseases, while animals lacking IL-23 are resistant to such diseases. This may be because IL-23-deficient animals produce CD4+ IL-6, IL-17, and TNF in the CNS. +This is due to a decrease in the number of T cells. IL-23 binds to IL-23R. The binding of IL-23 to IL-23R activates the Jak-Stat signaling molecules Jak2, Tyk2, and Stat1, Stat3, Stat4, and Stat5, although the activation of Stat4 is significantly weaker. Furthermore, a different DNA-binding Stat complex is formed in response to IL-23 compared to IL-12. IL-23R constitutively associates with Jak2 and with Stat3 in a ligand-dependent manner. While IL-12 primarily acts on naive CD4(+) T cells, IL-23 preferentially acts on memory CD4(+) T cells.

[0006] Monoclonal antibodies (mAbs) targeting IL-23 have been shown to be effective in treating ulcerative colitis. However, patients with ulcerative colitis still require effective treatment, especially oral therapy. Summary of the Invention

[0007] This disclosure particularly provides a method for treating ulcerative colitis in a subject of need, the method comprising administering a compound of formula (I) to the subject:

[0008]

[0009] (I),

[0010] Or its pharmaceutically acceptable salts or solvates.

[0011] In some implementations, after treatment with a compound of formula (I) or its pharmaceutically acceptable salts or solvates, a subject is considered responsive to treatment on at least one of the following indicators of treatment response, selected from groups comprising: (i) clinical response, as determined by: a modified Mayo score that is ≥30% lower than baseline and a reduction of ≥2 points, and a Mayo rectal bleeding sub-score that is ≥1 point lower than baseline, or a Mayo rectal bleeding sub-score of 0 or 1; (ii) clinical remission, as determined by: a Mayo defecation frequency sub-score of 0 or 1, wherein the Mayo defecation frequency sub-score has not increased from baseline, a Mayo rectal bleeding sub-score of 0, and a Mayo endoscopy score of 0 or 1; (iii) symptom remission, as determined by: a Mayo defecation frequency sub-score of 0 or 1, wherein the Mayo defecation frequency sub-score has not increased from baseline. (iv) Endoscopic improvement, as determined by a Mayo endoscopic score of 0 or 1; (v) Histological remission, as determined by the absence of neutrophils, crypt destruction, erosions, ulcers, or granulation tissue in the mucosa (lamina propria and epithelium) according to the Geboes grading system; (vi) Histological-endoscopic mucosal improvement, as determined by the absence of neutrophils, crypt destruction, erosions, ulcers, or granulation tissue in the mucosa (lamina propria and epithelium) according to the Geboes grading system, and a Mayo endoscopic score of 0 or 1; (vii) Deep symptom remission, as determined by a Mayo defecation frequency sub-score of 0 and a rectal bleeding sub-score of 0; (viii) Modified Mayo score <5; and (ix) Partial Mayo score <5.

[0012] In some implementations, the method includes administering a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in an amount of about 100 mg.

[0013] In some implementations, the method includes administering a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in an amount of about 200 mg.

[0014] In some implementations, the method includes administering a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in an amount of about 400 mg. Attached Figure Description

[0015] Figure 1A This provides a schematic overview of the main study phases of the protocol described in Example 1. Safety follow-up was conducted only at weeks 28–30 for participants who did not proceed to the long-term extension.

[0016] Figure 1BThis provides a schematic overview of the long-term extension of the protocol described in Example 1. Participants who met the clinical response criteria at week 28 continued to receive the same study intervention as before week 28 during the long-term extension. The long-term extended 400 mg qd group included participants initially randomized to the 400 mg qd regimen and participants randomized to the placebo group who began receiving the study intervention at week 16.

[0017] Figure 2 The XRPD spectrum of the crystalline form of the hydrochloride salt of compound (I) is shown. Detailed Implementation

[0018] This disclosure provides an effective treatment for ulcerative colitis using oral IL-23 receptor antagonists. As described below, IL-23 receptor antagonists offer a novel and effective therapy for patients with ulcerative colitis.

[0019] The discussions of documents, actions, materials, devices, articles, etc., included in this specification are intended to provide background for the disclosed methods. Such discussions are not an admission that any or all of these matters constitute prior art with respect to any disclosed or claimed method or pharmaceutical product.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Otherwise, certain terms used herein have the meanings set forth in this specification.

[0021] "A" or "a" are indefinite articles that, when used to refer to a group of substituents or "substituent groups," mean at least one or at least one.

[0022] When referring to a value, “about” includes a specified value plus or minus 10% of that specified value. For example, about 50% includes a range of 45% to 55%, while about 20 molar equivalents includes a range of 18 molar equivalents to 22 molar equivalents. Therefore, when referring to a range, “about” means each of the specified values ​​at each end of the range plus or minus 10% of that specified value. For example, a ratio of about 1 to about 3 (weight / weight) includes a range of 0.9 to 3.3.

[0023] Unless otherwise stated, naturally occurring L-amino acids and D-amino acids are represented by the conventional three-letter or uppercase single-letter amino acid names in Table 1. In some embodiments, naturally occurring L-amino acids are represented by the conventional three-letter or uppercase single-letter amino acid names in Table 1. In some embodiments, D-amino acids are represented by lowercase single-letter amino acid names corresponding to the single-letter names in Table 1, namely, g, a, l, m, f, w, k, q, e, s, p, v, i, c, y, h, r, n, d, and t.

[0024] Table 1: Naturally occurring amino acids

[0025]

[0026] "Administration" means applying the composition of this disclosure to a subject.

[0027] As used in this article, the terms “qd” and “QD” mean once daily.

[0028] As used herein, unless otherwise stated, the term “baseline” refers to the initial condition of a subject as determined by observation or measurement at the start of treatment or just before the start of treatment.

[0029] As used herein, “composition” is intended to cover products that contain a specified active product ingredient (API) (i.e., a compound of formula (I) as defined herein or a pharmaceutically acceptable salt or solvate thereof) and a pharmaceutically acceptable excipient, carrier, or diluent as described herein, the product being produced from a combination of specific components.

[0030] Improvement can be indicated by improvements in disease activity indices, relief of clinical symptoms, or any other disease activity indicators. One such disease index is the Mayo Criterion for Ulcerative Colitis (UC). The Mayo Criterion is an empirically validated and mature disease activity index for mild, moderate, and severe ulcerative colitis (UC). It is calculated as the sum of four sub-scores: defecation frequency, rectal bleeding, endoscopic findings, and physician overall assessment (PGA), and ranges from 0 to 12. Other disease activity indices for UC include, for example, the Ulcerative Colitis Endoscopic Severity Index (UCEIS) score. The UCEIS score provides an overall assessment of the endoscopic severity of UC based on mucosal vascular texture, bleeding, and ulceration (Travis et al., Gut. 61:535-542 (2012)). The score ranges from 3 to 11, with higher scores indicating more severe endoscopic disease. Histological indices used to assess histopathological disease activity in patients with ulcerative colitis include the Geboes score (GS), the Robarts histopathological index (RHI), and the Nancy index (NI).

[0031] As used herein, the “Mayo Clinical Score” or “Mayo Score” refers to an index system used to assess the severity of ulcerative colitis. See Table 2 and Schoeder et al., N Engl J Med 1987; 317:1625-9. The Mayo Clinical Score is calculated as the sum of four sub-scores: defecation frequency, rectal bleeding, endoscopic findings, and physician overall assessment (PGA), ranging from 0 to 12, with sub-scores ranging from 0 to 3. Higher scores indicate more severe disease. Scores of 3 to 5 indicate mild active disease, 6 to 10 indicate moderate active disease, and 11 to 12 indicate severe disease. A partial Mayo score is a Mayo score without endoscopic assessment, calculated as the sum of the defecation frequency, rectal bleeding, and physician overall assessment sub-scores, ranging from 0 to 9. The modified Mayo score is a Mayo score without the PGA sub-score, calculated as the sum of defecation frequency, rectal bleeding, and endoscopic scores, and ranges from 0 to 9.

[0032] Table 2. Mayo Criterion System for Assessing Ulcerative Colitis Activity

[0033]

[0034] As used herein, the “Geboes score” or “Geboes grading system” refers to a histological scoring system that incorporates the infiltration of immune cells (lymphocytes and neutrophils) into the lamina propria and epithelium, as well as crypt structure and destruction, and the presence of ulcers and erosions. The score is divided into six grades: structural changes [Grade 0], chronic inflammatory infiltration [Grade 1], lamina propria neutrophils and eosinophils [Grade 2], intraepithelial neutrophils [Grade 3], crypt destruction [Grade 4], and erosion or ulceration [Grade 5], and each grade is further divided into four subcategories (Geboes K, Riddel R, Ost A et al. A Reproducible Grading Scale for Histological Assessment of Inflammation in Ulcerative Colitis. Gut 2000.4; 404-409). When the individual subcategories are summed, the total score ranges from 0 (normal) to 22 (severe inflammation and tissue destruction) (Table 3).

[0035] Table 3. Geboes Ratings

[0036]

[0037] As used in this article, the Robarts Histopathological Index (RHI) is a tool commonly used to assess the histopathological disease activity in subjects with ulcerative colitis (Mosli MH, Feagan BG, Zou G. Development and Validation of a Histological Index for UC.Gut.2017; 66:50-58). The RHI includes an assessment of four mucosal activity features: inflammatory infiltration, lamina propria neutrophils, intraepithelial neutrophils, and erosion or ulceration. Each of these features is rated on a scale of 0 to 3 and weighted using multiplicative weights of 1, 2, 3, and 5, respectively, to arrive at a total score ranging from 0 (no disease activity) to 33 (most severe disease activity).

[0038] "Patient" or "subject" means a living organism, including but not limited to human subjects who have or are susceptible to a disease or condition that can be treated by administration of the pharmaceutical compositions provided herein. Further non-limiting examples may include, but are not limited to, humans or other mammals. In some embodiments, the subject or patient is a human.

[0039] "Pharmaceutical acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for use in humans or domestic animals, or that are generally recognized by a skilled person in the field of formulation technology.

[0040] Pharmaceutically acceptable salts of the compounds disclosed herein are salts formed with acids such as mineral acids, organic carboxylic acids and organic sulfonic acids, hydrochloric acid, methanesulfonic acid, and maleic acid; salts may also be formed if a basic group (such as an amine) forms part of the structure.

[0041] As used herein, "salt" refers to the acidic or basic salt of a compound used in the methods of this disclosure. Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, and quaternary ammonium (iodomethane, iodoethane, etc.) salts. It should be understood that pharmaceutically acceptable salts are non-toxic.

[0042] The compounds of this disclosure can form solvates, such as solvates with water (i.e., hydrates) or solvates with common organic solvents. As used herein, the term "solvate" means the physical association of a compound of this disclosure with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be separated when, for example, one or more solvent molecules are incorporated into the lattice of a crystalline solid. The term "solvate" is intended to cover both solution-phase solvates and separable solvates. Non-limiting examples of suitable solvates include combinations of the compounds of this disclosure with water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, or ethanolamine, etc. The compounds of this disclosure can exert their biological effects when in solution. Solvates are well known in the pharmaceutical industry. They can be important for the preparation process of substances (e.g., relating to their purification, storage (e.g., their stability), and ease of handling), and are often formed as part of the separation or purification stage of chemical synthesis. Those skilled in the art can determine whether hydrates or other solvates have formed by using techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray crystallography (e.g., single-crystal X-ray diffraction or X-ray powder diffraction), and solid-state NMR (SS-NMR, also known as magic angle rotation NMR or MAS-NMR), depending on the separation or purification conditions used to prepare a given compound.

[0043] “Treatment” refers to any indicator of success in treating or improving an injury, pathology, or condition, including any objective or subjective parameters such as: symptom relief; remission; symptom resolution or increased patient tolerance to the injury, pathology, or condition; slowing the rate of degeneration or decline; reducing the degree of attenuation of degenerative endpoints; or improving the patient’s physical or mental health. Treatment or improvement of symptoms may be based on objective or subjective parameters, including the results of physical examination, neuropsychiatric examination, and / or psychiatric evaluation.

[0044] The term "pharmaceutical product" refers to a product containing an active pharmaceutical ingredient that has been proven to be a safe and effective treatment for one or more indications, based on the results of clinical trials regulated by government agencies (such as the U.S. Food and Drug Administration or similar agencies in other countries).

[0045] compound

[0046] This disclosure relates to an IL-23 receptor antagonist that can be used to treat ulcerative colitis. In some embodiments, the IL-23 receptor antagonist is a peptide. In some embodiments, the IL-23 receptor antagonist is a cyclic peptide.

[0047] This disclosure relates to a compound of formula (I), Ac-[Pen]*-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]*-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2 (*[Pen]-[Pen]* forms a disulfide bond) (SEQ ID No: 1):

[0048]

[0049] (I),

[0050] Or in pharmaceutically acceptable salt or solvate form. The compounds of formula (I) have an amino acid chain Ac-[Pen]*-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]*-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2 (*[Pen]-[Pen]* forms a disulfide bond) (SEQ ID No: 1), and the structures of the non-naturally occurring amino acids present in the compounds of formula (I) are provided in Table 4.

[0051] Table 4 :

[0052]

[0053] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvation may be present in any form, such as a pharmaceutically acceptable salt, hydrate, or other solvation. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvation may be provided in crystalline, amorphous, or semi-crystalline form.

[0054] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvation is a salt. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvation is a hydrochloride salt. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvation is an acetate. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvation is a diacetate. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvation is an acetate. In some embodiments, the acetate of the compound of formula (I) or its pharmaceutically acceptable salt or solvation is an amorphous form. In some embodiments, the acetate of the compound of formula (I) or its pharmaceutically acceptable salt or solvation is an acetate. In some embodiments, the acetate of the compositions disclosed herein is an amorphous form. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is a solvate. In some embodiments, the acetate form of the compound of formula (I) is an acetate solvate.

[0055] This disclosure also provides the crystalline form of the peptide of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Pharmaceutically acceptable salts of the peptide of SEQ ID NO: 1 provided herein include hydrochloride, dihydrochloride, acetate, fumarate, glutarate, glycolate, methanesulfonate, sulfate, and citrate, as described in PCT application PCT / US2023 / 06165, which is incorporated herein by reference in its entirety.

[0056] This disclosure also provides crystalline forms of compounds of formula (I), or pharmaceutically acceptable salts thereof, or the aforementioned solvates. Pharmaceutically acceptable salts of compounds of formula (I) provided herein include hydrochloride, dihydrochloride, acetate, fumarate, glutarate, glycolate, methanesulfonate, sulfate, and citrate.

[0057] In some embodiments, this disclosure provides the crystalline hydrochloride form of the compound of formula (I):

[0058]

[0059] (I),

[0060] Or its solvates.

[0061] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvate form is a hydrochloride salt of the compound of formula (I) or its solvate.

[0062] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is the hydrochloride salt form of the peptide of SEQ ID NO: 1. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is the hydrochloride salt form of the peptide of SEQ ID NO: 1, characterized by having a basic... Figure 2 The XRPD map shown.

[0063] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvation is a crystalline form and is in solvation form.

[0064] In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvation is characterized by having an XRPD pattern with two or more diffraction peaks at a 2θ angle selected from 4.2, 6.9, 7.6, and 9.2 ± 0.2 degrees 2θ. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvation is characterized by having an XRPD pattern with two or more diffraction peaks at a 2θ angle selected from 4.2, 6.9, 7.6, and 9.2 ± 0.3 degrees 2θ. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvation is characterized by having an XRPD pattern with two or more diffraction peaks at a 2θ angle selected from 4.2, 6.9, 7.6, and 9.2 ± 0.4 degrees 2θ.

[0065] In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvation is characterized by having an XRPD pattern with two or more diffraction peaks at a 2θ angle selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 10.0, 10.7, 12.2, 13.9, 15.7, or 17.1 ± 0.2 degrees 2θ. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvation is characterized by having an XRPD pattern with two or more diffraction peaks at a 2θ angle selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 10.0, 10.7, 12.2, 13.9, 15.8, or 17.1 ± 0.3 degrees 2θ. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern with two or more diffraction peaks at a 2θ angle selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8 or 17.1 + / - 0.4 degrees 2θ.

[0066] In other embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvation is characterized by having an XRPD pattern with two or more diffraction peaks at a 2θ angle selected from 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7 or 21.8 + / - 0.2 degrees 2θ. In other embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern with two or more diffraction peaks at a 2θ angle selected from 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7 or 21.8 + / - 0.3 degrees 2θ. In other embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvation is characterized by having an XRPD pattern with two or more diffraction peaks at a 2θ angle selected from 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7 or 21.8 + / - 0.4 degrees 2θ.

[0067] In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern with diffraction peaks at at least 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7 or 21.8 + / - 0.2 degrees 2θ. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern with diffraction peaks at at least 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7 or 21.8 + / - 0.3 degrees 2θ. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern with diffraction peaks at at least 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7 or 21.8 + / - 0.4 degrees 2θ.

[0068] In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvation is characterized by having an XRPD pattern with two or more diffraction peaks at a 2θ angle selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.2 degrees 2θ. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvation is characterized by having an XRPD pattern with two or more diffraction peaks at a 2θ angle selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.6, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.3 degrees 2θ. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvation is characterized by having an XRPD pattern with two or more diffraction peaks at a 2θ angle selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.4 degrees 2θ.

[0069] In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern with diffraction peaks at at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.2 degrees 2θ. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern with diffraction peaks at at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.3 degrees 2θ. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern with diffraction peaks at at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.4 degrees 2θ.

[0070] In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvation is characterized by having an endothermic peak at about 81.4 °C, as determined by differential scanning calorimetry (DSC). In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvation is characterized by having a weight loss of about 5.6% from about 26.5 °C to about 160.0 °C, as determined by thermogravimetric analysis (TGA).

[0071] In one aspect, the hydrochloride salt or solvation thereof of the compound of formula (I) is a hemihydrochloride salt. In some embodiments, the hemihydrochloride salt has about 0.1 molar equivalent to about 0.9 molar equivalents, such as about 0.2 molar equivalents to about 0.8 molar equivalents, or about 0.3 molar equivalents to about 0.7 molar equivalents of hydrogen chloride compared to the compound of formula (I). In some embodiments, the hemihydrochloride salt has about 0.1 molar equivalents, 0.2 molar equivalents, 0.3 molar equivalents, 0.4 molar equivalents, 0.5 molar equivalents, 0.6 molar equivalents, 0.7 molar equivalents, 0.8 molar equivalents, or about 0.9 molar equivalents of hydrogen chloride compared to the compound of formula (I). In some embodiments, the hemihydrochloride salt has about 0.5 molar equivalents of hydrogen chloride compared to the compound of formula (I).

[0072] In some embodiments, the molar equivalent of the chloride anion in the crystalline hydrochloride salt of formula (I) is about 0.2 to about 2.0 relative to one mole of the compound (I). In some embodiments, the molar equivalent of the chloride anion in the crystalline hydrochloride salt of formula (I) is about 0.4 to about 1.5 relative to one mole of the compound (I). In other embodiments, the molar equivalent of the chloride anion in the crystalline hydrochloride salt of formula (I) is about 0.5 to about 1.0 relative to one mole of the compound (I). In some embodiments, the molar equivalent of the chloride anion in the crystalline hydrochloride salt of formula (I) is about 0.6 to about 0.7 relative to one mole of the compound (I).

[0073] In some embodiments, the hydrochloride salt of the compound of formula (I) or a solvation thereof may be a hydrate. In some embodiments, the hydrate of the hydrochloride salt of the compound of formula (I) has about 0.2 molar equivalents to about 10 molar equivalents of water compared to the compound of formula (I).

[0074] Alternatively, those skilled in the art can intentionally form solvates by using crystallization conditions with a solvent that includes the amount required for the specific solvate.

[0075] Composition

[0076] This disclosure also relates to compositions of compounds of formula (I). Suitable compositions of this disclosure may be in various forms, including but not limited to liquid compositions (such as solution compositions) or tablet compositions. When the composition is a tablet, the tablet may comprise two or more distinct phases, including an inner phase and an outer phase that may contain a core. The tablet composition may also comprise one or more coatings.

[0077] Therefore, in some embodiments of the method described herein, the compound of formula (I) is administered as a pharmaceutical composition comprising the compound of formula (I) and one or more pharmaceutically acceptable excipients.

[0078] Compositions intended for oral use may contain one or more excipients, including sweeteners, flavoring agents, colorants, and preservatives, to provide a palatable formulation. Acceptable tablets contain an active ingredient blended with a non-toxic, pharmaceutically acceptable excipient suitable for tablet manufacturing. These excipients may be, for example: inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binding agents such as cellulose, microcrystalline cellulose, starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc.

[0079] In some embodiments, the composition comprises a compound of formula (I) in an amount of about 5 mg to about 600 mg, or in a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises a compound of formula (I) in an amount of about 5 mg to about 500 mg, or in a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises a compound of formula (I) in an amount of about 10 mg to about 500 mg, or in a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises a compound of formula (I) in an amount of about 10 mg to about 300 mg, or in a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises a compound of formula (I) in an amount of about 10 mg to about 250 mg, or in a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises a compound of formula (I) in an amount of about 50 mg to about 250 mg, or in a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises a compound of formula (I) in an amount of about 150 mg to about 450 mg, or in a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises a compound of formula (I) in an amount of about 100 mg to about 250 mg, or in a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises a compound of formula (I) in an amount of about 50 mg to about 150 mg, or in a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises a compound of formula (I) in an amount of about 150 mg to about 250 mg, or in a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises a compound of formula (I) in an amount of about 350 mg to about 450 mg, or in a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients.

[0080] In some embodiments, the composition is an oral tablet comprising 100 mg of a compound of formula (I), or in a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients.

[0081] In some embodiments, the composition comprises 200 mg of a compound of formula (I), or in a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition is a tablet.

[0082] In some embodiments, the composition comprises 400 mg of a compound of formula (I), or in a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition is a tablet.

[0083] Method of application, treatment, assay and / or use

[0084] In some embodiments, this disclosure relates to a method and / or use for administering a compound of formula (I) to a subject in need:

[0085]

[0086] (I),

[0087] Or in its pharmaceutically acceptable salt or solvate form.

[0088] In some embodiments, this disclosure relates to a method for treating ulcerative colitis in a subject of need, the method comprising administering a compound of formula (I) to the subject:

[0089]

[0090] (I),

[0091] Or its pharmaceutically acceptable salts or solvates.

[0092] In some embodiments, this disclosure relates to a method for treating ulcerative colitis in a subject of need, the method comprising administering a compound of formula (I) to the subject:

[0093]

[0094] (I),

[0095] Or its pharmaceutically acceptable salts or solvates;

[0096] Among those who have been treated with a compound of formula (I) or its pharmaceutically acceptable salts or solvates, a subject who is responsive to treatment on at least one of the following indicators of treatment response, selected from groups comprising: (i) clinical response, as determined by: a modified Mayo score that is ≥30% lower than baseline and a reduction of ≥2 points, and a Mayo rectal bleeding sub-score that is ≥1 point lower than baseline, or a Mayo rectal bleeding sub-score of 0 or 1; (ii) clinical remission, as determined by: a Mayo defecation frequency sub-score of 0 or 1, wherein the Mayo defecation frequency sub-score has not increased from baseline, a Mayo rectal bleeding sub-score of 0, and a Mayo endoscopy score of 0 or 1; (iii) symptom remission, as determined by: a Mayo defecation frequency sub-score of 0 or 1, wherein the Mayo defecation frequency sub-score has not increased from baseline, and (iv) Mayo score for rectal bleeding < 0; (v) endoscopic improvement, as determined by a Mayo score of 0 or 1; (vi) histological remission, as determined by the absence of neutrophils, crypt destruction, erosions, ulcers, or granulation tissue in the mucosa (lamina propria and epithelium) according to the Geboes grading system; (vi) histological-endoscopic mucosal improvement, as determined by the absence of neutrophils, crypt destruction, erosions, ulcers, or granulation tissue in the mucosa (lamina propria and epithelium) according to the Geboes grading system, and a Mayo score of 0 or 1; (vii) deep symptom remission, as determined by a Mayo score for bowel frequency < 0 and a Mayo score for rectal bleeding < 0; (viii) modified Mayo score < 5; and (ix) partial Mayo score < 5.

[0097] In some embodiments, this disclosure relates to a method for treating ulcerative colitis in a subject in need, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein, following treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, the subject is deemed to be responsive to treatment on indicators of clinical response to treatment, such as by: a modified Mayo score that is ≥30% lower than baseline and a reduction of ≥2 points, and a Mayo rectal bleeding score that is ≥1 point lower than baseline, or a Mayo rectal bleeding score of 0 or 1.

[0098] In some embodiments, this disclosure relates to a method for treating ulcerative colitis in a subject in need, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein, following treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, the subject is deemed responsive to treatment in terms of clinical remission of treatment response, such as by: a Mayo defecation frequency subscore of 0 or 1, wherein the Mayo defecation frequency subscore has not increased from baseline, a Mayo rectal bleeding subscore of 0, and a Mayo endoscopy score of 0 or 1.

[0099] In some embodiments, this disclosure relates to a method for treating ulcerative colitis in a subject in need, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein, following treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, the subject is deemed responsive to treatment in terms of symptom relief, such as by: a Mayo defecation frequency subscore of 0 or 1, wherein the Mayo defecation frequency subscore has not increased from baseline, and a Mayo rectal bleeding subscore of 0.

[0100] In some embodiments, this disclosure relates to a method for treating ulcerative colitis in a subject in need, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein, following treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, the subject is deemed responsive to treatment on an indicator of improved endoscopic response to treatment, such as by a Mayo endoscopy score of 0 or 1.

[0101] In some embodiments, this disclosure relates to a method for treating ulcerative colitis in a subject in need, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein, following treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, the subject is a responder to treatment in terms of histological remission, such as by means of the absence of neutrophils, crypt destruction, and erosions, ulcers, or granulation tissue in the mucosa (both lamina propria and epithelium) according to the Geboes grading system.

[0102] In some embodiments, this disclosure relates to a method for treating ulcerative colitis in a subject in need, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein, following treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, the subject is deemed responsive to treatment on histological-endoscopic mucosal improvement indicators of treatment response, as determined by the following criteria: the absence of neutrophils in the mucosa (both lamina propria and epithelium) according to the Geboes grading system, the absence of crypt destruction, and the absence of erosions, ulcers, or granulation tissue, and a Mayo endoscopic score of 0 or 1.

[0103] In some embodiments, this disclosure relates to a method for treating ulcerative colitis in a subject of need, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein, following treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, the subject is deemed responsive to treatment on indicators of deep symptom relief, such as by means of a Mayo defecation frequency subscore of 0 and a rectal bleeding subscore of 0.

[0104] In some embodiments, this disclosure relates to a method for treating ulcerative colitis in a subject in need, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein, after treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, the subject is a responder on a modified Mayo score <5 as an indicator of treatment response.

[0105] In some embodiments, this disclosure relates to a method for treating ulcerative colitis in a subject of need, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein, following treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, the subject demonstrates a response to treatment on a partial Mayo score <5.

[0106] In some implementations, as part of the treatment response, the subject achieved a modified Mayo score reduction of ≥35% from baseline. In some implementations, as part of the treatment response, the subject achieved a modified Mayo score reduction of ≥40% from baseline. In some implementations, as part of the treatment response, the subject achieved a modified Mayo score reduction of ≥45% from baseline. In some implementations, as part of the treatment response, the subject achieved a modified Mayo score reduction of ≥50% from baseline. In some implementations, as part of the treatment response, the subject achieved a modified Mayo score reduction of ≥55% from baseline. In some implementations, as part of the treatment response, the subject achieved a modified Mayo score reduction of ≥60% from baseline. In some implementations, as part of the treatment response, the subject achieved a modified Mayo score reduction of ≥65% from baseline. In some implementations, as part of the treatment response, the subject achieved a modified Mayo score reduction of ≥70% from baseline. In some implementations, as part of the treatment response, the subject achieved a modified Mayo score reduction of ≥75% from baseline.

[0107] In some implementations, as part of a treatment response, the subject achieved a modified Mayo score reduction of ≥3 points from baseline. In some implementations, as part of a treatment response, the subject achieved a modified Mayo score reduction of ≥4 points from baseline. In some implementations, as part of a treatment response, the subject achieved a modified Mayo score reduction of ≥5 points from baseline. In some implementations, as part of a treatment response, the subject achieved a modified Mayo score reduction of ≥6 points from baseline. In some implementations, as part of a treatment response, the subject achieved a modified Mayo score reduction of ≥7 points from baseline. In some implementations, as part of a treatment response, the subject achieved a modified Mayo score reduction of ≥8 points from baseline.

[0108] In some implementations, as part of a treatment response, the subject achieved a modified Mayo score of less than 5 (i.e., a modified Mayo score of 0, 1, 2, 3, or 4). In some implementations, as part of a treatment response, the subject achieved a modified Mayo score of less than 4 (i.e., a modified Mayo score of 0, 1, 2, or 3). In some implementations, as part of a treatment response, the subject achieved a modified Mayo score of less than 3 (i.e., a modified Mayo score of 0, 1, or 2). In some implementations, as part of a treatment response, the subject achieved a modified Mayo score of 0 or 1. In some implementations, the subject did not experience an increase in modified Mayo score from baseline during treatment.

[0109] In some implementations, as part of a treatment response, the subject achieved a partial Mayo score of less than 5 (i.e., a partial Mayo score of 0, 1, 2, 3, or 4). In some implementations, as part of a treatment response, the subject achieved a partial Mayo score of less than 4 (i.e., a partial Mayo score of 0, 1, 2, or 3). In some implementations, as part of a treatment response, the subject achieved a partial Mayo score of less than 3 (i.e., a partial Mayo score of 0, 1, or 2). In some implementations, as part of a treatment response, the subject achieved a partial Mayo score of 0 or 1. In some implementations, the subject did not experience an increase in their partial Mayo score from baseline during treatment.

[0110] In some implementations, as part of a treatment response, the subject achieved a Mayo defecation frequency sub-score reduction of ≥1 point from baseline. In some implementations, as part of a treatment response, the subject achieved a Mayo defecation frequency sub-score of 0 or 1. In some implementations, as part of a treatment response, the subject achieved a Mayo defecation frequency sub-score of 0. In some implementations, as part of a treatment response, the subject achieved a Mayo defecation frequency sub-score of 1. In some implementations, the subject did not experience an increase in the Mayo defecation frequency sub-score from baseline during treatment. In some implementations, as part of a treatment response, the subject achieved a Mayo defecation frequency sub-score of 0 or 1, and the subject did not experience an increase in the Mayo defecation frequency sub-score from baseline during treatment.

[0111] In some implementations, as part of the treatment response, the subject achieved a Mayo endoscopy score reduction of ≥1 point from baseline. In some implementations, as part of the treatment response, the subject achieved a Mayo endoscopy score of 0 or 1. In some implementations, as part of the treatment response, the subject achieved a Mayo endoscopy score of 0. In some implementations, as part of the treatment response, the subject achieved a Mayo endoscopy score of 1. In some implementations, the subject did not experience an increase in Mayo endoscopy score from baseline during treatment. In some implementations, as part of the treatment response, the subject achieved a Mayo endoscopy score of 0 or 1, and the subject did not experience an increase in Mayo endoscopy score from baseline during treatment.

[0112] In some implementations, as part of a treatment response, the subject achieved a Mayo rectal bleeding score reduction of ≥1 point from baseline. In some implementations, as part of a treatment response, the subject achieved a Mayo rectal bleeding score of 0 or 1. In some implementations, as part of a treatment response, the subject achieved a Mayo rectal bleeding score of 0. In some implementations, as part of a treatment response, the subject achieved a Mayo rectal bleeding score of 1. In some implementations, the subject did not experience an increase in the Mayo rectal bleeding score from baseline during treatment. In some implementations, as part of a treatment response, the subject achieved a Mayo rectal bleeding score of 0 or 1, and the subject did not experience an increase in the Mayo rectal bleeding score from baseline during treatment.

[0113] In some implementations, as part of the treatment response, the subject achieved a Mayo Physician Global Assessment (PGA) sub-score reduction of ≥1 point from baseline. In some implementations, as part of the treatment response, the subject achieved a Mayo PGA sub-score of 0 or 1. In some implementations, as part of the treatment response, the subject achieved a Mayo PGA sub-score of 0. In some implementations, as part of the treatment response, the subject achieved a Mayo PGA sub-score of 1. In some implementations, the subject did not experience an increase in Mayo PGA sub-score from baseline during treatment. In some implementations, as part of the treatment response, the subject achieved a Mayo PGA sub-score of 0 or 1, and the subject did not experience an increase in Mayo PGA sub-score from baseline during treatment.

[0114] In some implementations, as part of the treatment response, the subject achieved a Mayo defecation frequency sub-score of 0 or 1, wherein the Mayo defecation frequency sub-score did not increase from baseline, and the Mayo rectal bleeding sub-score was 0. In some implementations, as part of the treatment response, the subject achieved a Mayo defecation frequency sub-score of 0 or 1, wherein the Mayo defecation frequency sub-score did not increase from baseline, the Mayo rectal bleeding sub-score was 0, and the Mayo endoscopy score was 0 or 1. In some implementations, as part of the treatment response, the subject achieved a Mayo defecation frequency sub-score of 0 or 1, wherein the Mayo defecation frequency sub-score did not increase from baseline, and the Mayo rectal bleeding sub-score was 0.

[0115] In some implementations, as part of the treatment response, the subject achieved a Mayo defecation frequency subscale score of 0 or 1, a Mayo endoscopy score of 0 or 1, and a Mayo rectal bleeding subscale score of 0 or 1. In some implementations, as part of the treatment response, the subject achieved a Mayo defecation frequency subscale score of 0 and a Mayo endoscopy score of 0. In some implementations, as part of the treatment response, the subject achieved a Mayo defecation frequency subscale score of 0 and a Mayo rectal bleeding subscale score of 0. In some implementations, as part of the treatment response, the subject achieved a Mayo endoscopy score of 0 and a Mayo rectal bleeding subscale score of 0.

[0116] In some implementations, as part of the treatment response, the subject achieved a reduction in Geboes score relative to baseline Geboes score. In some implementations, the baseline Geboes score is the initial Geboes score prior to administration. In some implementations, as part of the treatment response, the subject achieved a reduction in Geboes score relative to baseline of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 units.

[0117] In some embodiments, after treatment with a compound of formula (I) or its pharmaceutically acceptable salts or solvates, the subject exhibits the absence of neutrophils in the subject's mucosal lamina propria. In some embodiments, after treatment with a compound of formula (I) or its pharmaceutically acceptable salts or solvates, the subject exhibits a decrease in the concentration of neutrophils in the subject's mucosal lamina propria relative to baseline.

[0118] In some embodiments, after treatment with a compound of formula (I) or its pharmaceutically acceptable salts or solvates, the subject exhibits the absence of neutrophils in the subject's mucosal epithelium. In some embodiments, after treatment with a compound of formula (I) or its pharmaceutically acceptable salts or solvates, the subject exhibits a decrease in the concentration of neutrophils in the subject's mucosal epithelium relative to baseline.

[0119] In some embodiments, after treatment with a compound of formula (I) or its pharmaceutically acceptable salts or solvates, the subject exhibits no crypt destruction relative to baseline.

[0120] In some embodiments, after treatment with a compound of formula (I) or its pharmaceutically acceptable salts or solvates, the subject exhibits no erosion, ulceration, or granulation tissue relative to baseline.

[0121] In some implementations, after treatment with a compound of formula (I) or its pharmaceutically acceptable salt or solvate, the subject exhibits, according to the Geboes classification system, the absence of neutrophils in the mucosa (both the lamina propria and the epithelium); no crypt destruction; and no erosions, ulcers, or granulation tissue.

[0122] In some implementations, as part of the treatment response, the subject achieves a Mayo endoscopy score of 0 or 1; and after treatment with a compound of formula (I) or its pharmaceutically acceptable salt or solvate, the subject demonstrates, according to the Geboes grading system, the absence of neutrophils in the mucosa (both the lamina propria and the epithelium); no crypt destruction; and no erosions, ulcers, or granulation tissue.

[0123] In some implementations, as part of a treatment response, subjects achieved a reduction in their Ulcerative Colitis Endoscopic Severity Index (UCEIS) score relative to baseline. The UCEIS score provides an overall assessment of endoscopic severity of ulcerative colitis based on mucosal vascular texture, bleeding, and ulceration. The score ranges from 3 to 11, with higher scores indicating more severe endoscopic disease. In some implementations, subjects achieved a UCEIS score ≤4 as part of a treatment response.

[0124] In some embodiments, as part of a treatment response, the subject achieves a reduction in C-reactive protein (CRP) concentration relative to baseline CRP. CRP is used as an inflammatory marker in subjects with IBD. In UC, elevated CRP is associated with severe clinical activity, accelerated sedimentation rate, and disease activity detected by colonoscopy. CRP concentration can be determined from a blood sample. CRP concentration may be serum CRP concentration. CRP concentration can be determined by immunoassay or turbidimetric assay. Immunoassay may be enzyme-linked immunosorbent assay (ELISA). In some embodiments, the CRP concentration is the systemic concentration of CRP. In some embodiments, the reduction in CRP concentration is a reduction of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, or 99% relative to baseline CRP. In some embodiments, the CRP concentration is reduced by at least 10% relative to baseline CRP. In some embodiments, the CRP concentration is reduced by at least 40% relative to baseline CRP. In some embodiments, the initial CRP concentration is higher than 5 mg / L. In some embodiments, the concentration of CRP is reduced to below 5 mg / L. In some embodiments, the concentration of CRP is reduced to below 3 mg / L.

[0125] In some embodiments, as part of a treatment response, the subject achieved a reduction in fecal lactoferrin concentration relative to baseline fecal lactoferrin. In some embodiments, the reduction in fecal lactoferrin concentration is a reduction of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, or 99% relative to baseline fecal lactoferrin concentration. In some embodiments, the initial concentration of fecal lactoferrin is higher than 7.24 µg / g. In some embodiments, the concentration of fecal lactoferrin is reduced to below 7.24 µg / g. In some embodiments, as part of a treatment response, the subject achieved a reduction in fecal calprotectin (FCP) concentration relative to baseline FCP. Fecal calprotectin is a biomarker of enteritis. The concentration of FCP can be determined from a stool sample or from a colonic biopsy. The concentration of FCP can be determined by an immunoassay. The immunoassay can be an enzyme-linked immunosorbent assay (ELISA). In some embodiments, the FCP concentration is expressed as mg calprotectin / kg feces or mg calprotectin / g feces. In some embodiments, the reduction in FCP concentration is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, or 99% relative to the FCP baseline. In some embodiments, the reduction in FCP concentration is at least 20% relative to the FCP baseline. In some embodiments, the reduction in FCP concentration is at least 50% relative to the FCP baseline. In some embodiments, the initial FCP concentration is higher than 250 mg / kg. In some embodiments, the FCP concentration is reduced to 250 mg / kg or lower.

[0126] In some implementations, as part of the treatment response, participants achieved improvement on the Inflammatory Bowel Disease Questionnaire (IBDQ) from baseline. The IBDQ is an empirical 32-item self-report questionnaire for participants with IBD that assesses disease-specific health-related quality of life (HRQoL) across four dimensions: bowel symptoms (loose stools, abdominal pain), systemic symptoms (fatigue, altered sleep patterns), social functioning (attendance, need to cancel social activities), and emotional functioning (anger, depression, irritability) (Irvine EJ, Feagan B, Rochon J et al. Quality of life: a valid and reliable measure of therapeutic efficacy in the treatment of inflammatory bowel disease. Canadian Crohn's Relapse Prevention Trial Study Group. Gastroenterology. 1994; 106(2):287-296). Scores ranged from 32 to 224, with higher scores indicating better outcomes. All items were reviewed over the past two weeks and were typically completed within 15 minutes.

[0127] In some implementations, as part of the treatment response, subjects achieved improvement from baseline using the Patient-Reported Outcomes Measurement Information System 29 Short Form v2.1 (PROMIS-29). PROMIS-29 is a non-disease-specific, empirically-based, universal health assessment tool. It is a series of short forms covering seven domains (depression, anxiety, physical functioning, pain disturbance, fatigue, sleep disturbance, and ability to participate in social roles and activities), with four items in each domain. PROMIS-29 also includes the overall mean pain intensity of 0-10 NRS. The review period for all items was the past 7 days. Raw domain scores were converted to standardized T-scores with a mean of 50 and a standard deviation of 10. Additionally, PCS and MCS can be calculated by combining the seven PROMIS-29 v2.0 domain scores and a single pain intensity item (Hays RD, Spritzer KL, Schalet BD, et al., PROMIS). ®-29 v2.0 profile physical and mental health summary scores. Qual Life Res. 2018; 27(7):1885-1891). Higher scores for anxiety, depression, fatigue, sleep disturbances, and pain interference indicate more severe symptoms. Higher scores for physical function and social participation indicate better health outcomes. The PROMIS-29 questionnaire can usually be completed within 10 minutes.

[0128] In some implementations, as part of the treatment response, subjects achieved improvement from baseline in patient-reported outcomes signs and symptoms (UC-pro / SS) for ulcerative colitis. The UC-PRO / SS measurement has been approved through the FDA COA Qualification Program process and was developed to standardize the quantification of GI signs and symptoms of UC through direct reporting of patient ratings (Higgins PDR, Harding G, Revicki DA et al. Development and validation of the Ulcerative Colitis patient-reported outcomes signs and symptoms (UC-pro / SS) diary. J Patient Rep Outcomes. 2017; 2(1):26). The UC-PRO tool is designed to comprehensively assess the signs, symptoms, and impact of UC.

[0129] In some implementations, as part of the treatment response, participants achieved improvement in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) from baseline. The BASDAI consists of a visual analog scale, with "None" on the left, indicating no symptoms, and "Extremely Severe" on the right, indicating the most severe symptom severity. Participants are asked to draw a vertical line on the visual analog scale at the location that best reflects their experience of the symptom. The BASDAI presents six questions covering five major symptoms of IBD-related axial and peripheral spondyloarthritis: fatigue, spinal pain, joint pain / swelling, localized tenderness (also known as enthesitis, or inflammation of tendons and ligaments), duration of morning stiffness, and severity of morning stiffness. To assign equal weight to each symptom, the average (mean) of the two scores associated with morning stiffness is taken. The resulting score (0-50) is divided by 5 to obtain a final BASDAI score of 0-10. A score of 4 or higher indicates poor disease control.

[0130] In some implementations, as part of the treatment response assessment, subjects achieved improvement from baseline on the Treatment Satisfaction Questionnaire-9 (TSQM-9). The TSQM-9 is a self-administered 9-item questionnaire used to measure patient satisfaction with treatment. The review period for all items is 2 to 3 weeks, or since the last medication administration. The TSQM-9 comprises three domains: effectiveness (3 items), convenience (3 items), and overall satisfaction (3 items). Responses to all items are rated using a 5-point or 7-point Likert scale. The three domains are scored from 0 to 100, with higher scores indicating higher satisfaction. The TSQM-9 can typically be completed in 5 to 10 minutes.

[0131] Compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof may be administered to a subject or patient in any manner consistent with therapeutic administration to achieve the intended purpose or therapeutic effect. Examples include administration via oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, local, oral, or ocular routes. In some embodiments, administration of compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof is suitable for oral administration.

[0132] In some implementations, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is administered orally.

[0133] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvation is administered orally on an empty stomach. In some embodiments, the subject has fasted for at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours prior to administration of the compound of formula (I) or its pharmaceutically acceptable salt or solvation. In some embodiments, the subject has fasted for at least 2 hours prior to administration of the compound of formula (I) or its pharmaceutically acceptable salt or solvation. In some embodiments, the subject has fasted for at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, or 3 hours after administration of the compound of formula (I) or its pharmaceutically acceptable salt or solvation. In some embodiments, the subject has fasted for at least 30 minutes after administration of the compound of formula (I) or its pharmaceutically acceptable salt or solvation. In some implementations, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is administered orally while ingested.

[0134] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is in tablet form. In some embodiments, the method includes administering a tablet to a subject, the tablet comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one or more pharmaceutically acceptable excipients.

[0135] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvation is administered daily. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvation is administered once daily.

[0136] In some implementations, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is administered orally once daily.

[0137] In some implementations, the subject had moderate to severe ulcerative colitis prior to treatment. In some implementations, the subject's modified Mayo score was 5 to 9 prior to treatment. In some implementations, the subject's modified Mayo score was 5 to 7 prior to treatment. In some implementations, the subject's modified Mayo score was 7 to 9 prior to treatment. In some implementations, the subject's modified Mayo score was 5, 6, 7, 8, or 9 prior to treatment.

[0138] In some implementations, the subject's Mayo defecation frequency subscale score was 1, 2, or 3 prior to treatment. In some implementations, the subject's Mayo defecation frequency subscale score was 2 or 3 prior to treatment. In some implementations, the subject's Mayo defecation frequency subscale score was 1 prior to treatment. In some implementations, the subject's Mayo defecation frequency subscale score was 2 prior to treatment. In some implementations, the subject's Mayo defecation frequency subscale score was 3 prior to treatment.

[0139] In some implementations, the subject's Mayo Cognitive Assessment (MCA) score was 1, 2, or 3 prior to treatment. In some implementations, the subject's MCA score was 2 or 3 prior to treatment. In some implementations, the subject's MCA score was 2 prior to treatment. In some implementations, the subject's MCA score was 3 prior to treatment.

[0140] In some embodiments, the subject's Mayo Cervical Bleeding Spontaneous Scale (MCS) score was 1, 2, or 3 prior to treatment. In some embodiments, the subject's MCS score was 2 or 3 prior to treatment. In some embodiments, the subject's MCS score was 1 prior to treatment. In some embodiments, the subject's MCS score was 2 prior to treatment. In some embodiments, the subject's MCS score was 3 prior to treatment.

[0141] In some implementations, the subject's Mayo Physician Global Assessment (PGA) sub-score was 1, 2, or 3 prior to treatment. In some implementations, the subject's Mayo PGA sub-score was 2 or 3 prior to treatment. In some implementations, the subject's Mayo PGA sub-score was 1 prior to treatment. In some implementations, the subject's Mayo PGA sub-score was 2 prior to treatment. In some implementations, the subject's Mayo PGA sub-score was 3 prior to treatment.

[0142] In some implementations, the subject is administered a compound of formula (I) or a pharmaceutically acceptable salt or solvation thereof for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 weeks. In some implementations, the subject is administered a compound of formula (I) or a pharmaceutically acceptable salt or solvation thereof for at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 weeks. In some embodiments, the subject is administered a compound of formula (I) or a pharmaceutically acceptable salt or solvation thereof for at least 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, the subject is administered a compound of formula (I) or a pharmaceutically acceptable salt or solvation thereof for at least 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks.

[0143] In some embodiments, the subject is administered a compound of formula (I) or a pharmaceutically acceptable salt or solvation thereof for about 8 to 30 weeks, about 12 to 28 weeks, about 14 to 26 weeks, or about 16 to 24 weeks. In some embodiments, the subject is administered a compound of formula (I) or a pharmaceutically acceptable salt or solvation thereof for about 12 to 28 weeks. In some embodiments, the subject is administered a compound of formula (I) or a pharmaceutically acceptable salt or solvation thereof for about 16 to 76 weeks, about 18 to 68 weeks, about 20 to 60 weeks, about 22 to 52 weeks, or about 24 to 44 weeks.

[0144] In some embodiments, the subject is administered a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for at least 2 weeks. In some embodiments, the subject is administered a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for at least 4 weeks. In some embodiments, the subject is administered a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for at least 8 weeks. In some embodiments, the subject is administered a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for at least 12 weeks. In some embodiments, the subject is administered a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for at least 16 weeks. In some embodiments, the subject is administered a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for at least 20 weeks. In some embodiments, the subject is administered a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for at least 28 weeks.

[0145] In some embodiments, the subject is administered a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for at least 36 weeks. In some embodiments, the subject is administered a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for at least 44 weeks. In some embodiments, the subject is administered a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for at least 52 weeks. In some embodiments, the subject is administered a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for at least 60 weeks. In some embodiments, the subject is administered a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for at least 68 weeks. In some embodiments, the subject is administered a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for at least 76 weeks.

[0146] In some implementations, a treatment response is achieved at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 weeks after treatment initiation. In other implementations, a treatment response is achieved at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 weeks after treatment initiation. In some implementations, a treatment response is achieved at least 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks after treatment initiation. In other implementations, a treatment response is achieved at least 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks after treatment initiation.

[0147] In some embodiments, a response to treatment is achieved at least 2 weeks after treatment initiation. In some embodiments, a response to treatment is achieved at least 4 weeks after treatment initiation. In some embodiments, a response to treatment is achieved at least 8 weeks after treatment initiation. In some embodiments, a response to treatment is achieved at least 12 weeks after treatment initiation. In some embodiments, a response to treatment is achieved at least 16 weeks after treatment initiation. In some embodiments, a response to treatment is achieved at least 20 weeks after treatment initiation. In some embodiments, a response to treatment is achieved at least 28 weeks after treatment initiation.

[0148] In some embodiments, a response to treatment is achieved at least 36 weeks after treatment initiation. In some embodiments, a response to treatment is achieved at least 44 weeks after treatment initiation. In some embodiments, a response to treatment is achieved at least 52 weeks after treatment initiation. In some embodiments, a response to treatment is achieved at least 60 weeks after treatment initiation. In some embodiments, a response to treatment is achieved at least 68 weeks after treatment initiation. In some embodiments, a response to treatment is achieved at least 76 weeks after treatment initiation.

[0149] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvation is administered to the subject in an amount of about 5 mg to about 600 mg. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvation is administered to the subject in an amount of about 100 mg to about 400 mg. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvation is administered to the subject in an amount of at least 100 mg. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvation is administered to the subject in an amount of about 50 mg to about 150 mg. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvation is administered to the subject in an amount of about 150 mg to about 250 mg. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvation is administered to the subject in an amount of about 350 mg to about 450 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvation thereof is administered to the subject in an amount of at least 100 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvation thereof is administered to the subject in an amount of about 100 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvation thereof is administered to the subject in an amount of about 200 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvation thereof is administered to the subject in an amount of about 400 mg.

[0150] In some embodiments, this document discloses a method for treating ulcerative colitis in a subject of need, the method comprising administering a compound of formula (I) to the subject:

[0151]

[0152] (I),

[0153] Or its pharmaceutically acceptable salt or solvate, in amounts from about 50 mg to about 500 mg.

[0154] In some embodiments, this document discloses a method for treating ulcerative colitis in a subject of need, the method comprising administering a compound of formula (I) to the subject in an amount of about 100 mg:

[0155]

[0156] (I),

[0157] Or its pharmaceutically acceptable salts or solvates. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salts or solvates are administered once daily in an amount of about 100 mg. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salts or solvates are administered orally once daily in an amount of about 100 mg. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salts or solvates are administered to the subject for about 12 to about 28 weeks. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salts or solvates are administered to the subject for about 16 weeks.

[0158] In some embodiments, this document discloses a method for treating ulcerative colitis in a subject of need, the method comprising administering a compound of formula (I) to the subject in an amount of about 200 mg:

[0159]

[0160] (I),

[0161] Or its pharmaceutically acceptable salts or solvates. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salts or solvates are administered once daily in an amount of about 200 mg. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salts or solvates are administered orally once daily in an amount of about 200 mg. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salts or solvates are administered to the subject for about 12 to about 28 weeks. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salts or solvates are administered to the subject for about 16 weeks.

[0162] In some embodiments, this document discloses a method for treating ulcerative colitis in a subject of need, the method comprising administering a compound of formula (I) to the subject in an amount of about 400 mg:

[0163]

[0164] (I),

[0165] Or its pharmaceutically acceptable salts or solvates. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salts or solvates are administered once daily in an amount of about 400 mg. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salts or solvates are administered orally once daily in an amount of about 400 mg. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salts or solvates are administered to the subject for about 12 to about 28 weeks. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salts or solvates are administered to the subject for about 16 weeks.

[0166] In some embodiments of the methods disclosed herein, the subject had not been treated with a biological agent for ulcerative colitis prior to treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvation thereof. In some embodiments of the methods disclosed herein, the subject had not responded to or tolerated treatment with a biological agent for ulcerative colitis prior to treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvation thereof.

[0167] In some embodiments of the methods disclosed herein, the subject has been administered an oral corticosteroid or immunomodulatory agent to treat ulcerative colitis prior to treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvation thereof. In some embodiments of the methods disclosed herein, the subject has not responded to or tolerated treatment with an oral corticosteroid or immunomodulatory agent for ulcerative colitis prior to treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, the subject has a history of corticosteroid dependence. A history of corticosteroid dependence is defined as the inability to successfully reduce the dose of corticosteroids without recurrence of symptoms of ulcerative colitis.

[0168] This disclosure also relates to a pharmaceutical product for treating a subject suffering from ulcerative colitis, the pharmaceutical product comprising a compound of formula (I):

[0169]

[0170] (I),

[0171] Or its pharmaceutically acceptable salts or solvates, when administered to the subject in an amount of at least 100 mg, the compound of formula (I) or its pharmaceutically acceptable salts or solvates induce at least one of the following indicators of treatment response selected from the group consisting of: (i) clinical response, as determined by: a reduction of ≥30% and ≥2 points in the modified Mayo score from baseline, and a reduction of ≥1 point in the Mayo rectal bleeding sub-score from baseline, or a Mayo rectal bleeding sub-score of 0 or 1; (ii) clinical remission, as determined by: a Mayo defecation frequency sub-score of 0 or 1, wherein the Mayo defecation frequency sub-score has not increased from baseline, a Mayo rectal bleeding sub-score of 0, and a Mayo endoscopy score of 0 or 1; (iii) symptom remission, as determined by: a Mayo defecation frequency sub-score of 0 or 1, wherein the Mayo defecation frequency sub-score has not increased from baseline, a Mayo rectal bleeding sub-score of 0, and a Mayo endoscopy score of 0 or 1; (iv) No increase in baseline and a Mayo score of 0 for rectal bleeding; (ix) Endoscopic improvement, as determined by a Mayo score of 0 or 1; (v) Histological remission, as determined by the absence of neutrophils, crypt destruction, erosions, ulcers, or granulation tissue in the mucosa (lamina propria and epithelium) according to the Geboes grading system; (vi) Histological-endoscopic mucosal improvement, as determined by the absence of neutrophils, crypt destruction, erosions, ulcers, or granulation tissue in the mucosa (lamina propria and epithelium) according to the Geboes grading system, and a Mayo score of 0 or 1; (vii) Deep symptom remission, as determined by a Mayo score of 0 for defecation frequency and a rectal bleeding score of 0; (viii) Modified Mayo score <5; and (ix) Partial Mayo score <5f=.

[0172] In some implementations, the drug product induces a clinical response, such as by: a modified Mayo score that decreases by ≥30% from baseline and by ≥2 points, and a Mayo rectal bleeding sub-score that decreases by ≥1 point from baseline, or a Mayo rectal bleeding sub-score of 0 or 1.

[0173] In some implementations, the drug product induces clinical remission, as determined by the following criteria: a Mayo defecation frequency subscore of 0 or 1, wherein the Mayo defecation frequency subscore has not increased from baseline, a Mayo rectal bleeding subscore of 0, and a Mayo endoscopy score of 0 or 1.

[0174] In some implementations, the drug product induces symptom relief, as determined by the following criteria: a Mayo bowel frequency subscore of 0 or 1, wherein the Mayo bowel frequency subscore has not increased from baseline, and the Mayo rectal bleeding subscore is 0.

[0175] In some implementations, the pharmaceutical product induces endoscopic improvement, as determined by a Mayo endoscopy score of 0 or 1.

[0176] In some implementations, the drug product induces histological remission, as determined by the following criteria: the absence of neutrophils, crypt destruction, and erosion, ulceration, or granulation tissue in the mucosa (both lamina propria and epithelium) according to the Geboes grading system.

[0177] In some implementations, the drug product induces histological-endoscopic mucosal improvement, as determined by the following criteria: the absence of neutrophils, crypt destruction, erosion, ulceration, or granulation tissue in the mucosa (both lamina propria and epithelium) according to the Geboes grading system, and a Mayo endoscopy score of 0 or 1.

[0178] In some implementations, the drug product induces deep symptom relief, as determined by the following criteria: a Mayo bowel frequency subscore of 0 and a rectal bleeding subscore of 0.

[0179] In some implementations, the drug product induces a modified Mayo score of <5.

[0180] In some implementations, the drug product induces a Mayo score of <5.

[0181] In some embodiments, the amount of the compound of formula (I) or its pharmaceutically acceptable salt or solvation is from about 100 mg to about 600 mg. In some embodiments, the amount of the compound of formula (I) or its pharmaceutically acceptable salt or solvation is about 100 mg. In some embodiments, the amount of the compound of formula (I) or its pharmaceutically acceptable salt or solvation is about 200 mg. In some embodiments, the amount of the compound of formula (I) or its pharmaceutically acceptable salt or solvation is about 400 mg.

[0182] This disclosure also relates to an assay method for evaluating the dose response of a compound of formula (I) or its pharmaceutically acceptable salt or solvation to placebo in the treatment of moderate to severe ulcerative colitis.

[0183] Example

[0184] Example 1. A period of time was conducted in adult human subjects with moderate to severe active ulcerative colitis. Daily application for 28 weeks

[0185] As used in this embodiment, the IL-23 receptor antagonist peptide refers to a compound of formula (I) or its pharmaceutically acceptable salt or solvate.

[0186] The following describes a randomized, double-blind, placebo-controlled, parallel-group, multicenter study to evaluate the efficacy and safety of induction and maintenance therapy of the compound of formula (I) in adult participants with moderate to severe active ulcerative colitis.

[0187] Compound (I) directly binds to the IL-23R subunit and prevents IL-23p19 from binding to its receptor, thereby inhibiting proximal IL-23R signaling and downstream effector functions, such as the secretion of pro-inflammatory cytokines. The IL-23 pathway is a clinically validated pathway in the pathogenesis of ulcerative colitis. Although the oral bioavailability of compound (I) is low (<1%), its systemic activity and high colonic exposure due to unabsorbed drug may contribute to its overall efficacy in the treatment of ulcerative colitis.

[0188] Goals and End Points

[0189] Definitions of point in time and endpoint:

[0190] • Clinical response: Modified Mayo score decreased by ≥30% from baseline and by ≥2 points, while rectal bleeding sub-score decreased by ≥1 point from baseline, or rectal bleeding sub-score was 0 or 1.

[0191] - Modified Mayo score: 3-point Mayo score (defecation frequency score, rectal bleeding score, and endoscopy score).

[0192] • Clinical remission: Defecation frequency subscore is 0 or 1, with no increase in defecation frequency subscore from baseline, rectal bleeding subscore is 0, and endoscopy score is 0 or 1.

[0193] Symptom relief: Defecation frequency sub-score is 0 or 1, with no increase in defecation frequency sub-score from baseline and rectal bleeding sub-score is 0.

[0194] • Endoscopic improvement: Endoscopic score is 0 or 1.

[0195] Endoscopic relief: Endoscopic score was 0.

[0196] • Histological remission: According to the Geboes grading system, there are no neutrophils in the mucosa (both the lamina propria and the epithelium), no crypt destruction, and no erosions, ulcers, or granulation tissue.

[0197] • Histological-endoscopic mucosal improvement: A combination of histological remission and endoscopic improvement, as defined above.

[0198] • Deep symptom relief: Defecation frequency sub-score is 0, and rectal bleeding sub-score is 0.

[0199]

[0200]

[0201] Overall design and intervention group

[0202] This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter interventional study in subjects with moderate to severe active ulcerative colitis. The study aims to enroll 240 subjects, with 60 subjects planned for each intervention group. A schematic diagram of the study is shown below. Figure 1A and Figure 1B middle.

[0203] Based on a computer-generated randomization plan developed by the sponsor prior to the study or under its supervision, eligible participants were randomly assigned to one of four intervention groups (in a 1:1:1:1 ratio). Randomization was balanced using a randomized block designation and stratified according to advanced treatment inadequacy (ADT-IR) status (yes or no) and endoscopic scores obtained during central review of video endoscopy during the screening period (moderate[2] or severe[3]). The four intervention groups are as follows:

[0204] · Group 1: 100mg once daily From week 0 to week 28, subjects received an IL-23 receptor antagonist peptide as an oral tablet administered once daily (QD) at a dose of 100 mg.

[0205] · Group 2: 200mg once daily From week 0 to week 28, subjects received an IL-23 receptor antagonist peptide as a 200 mg QD oral tablet.

[0206] · Group 3: 400mg once daily From week 0 to week 28, subjects received an IL-23 receptor antagonist peptide as a 400 mg QD oral tablet.

[0207] · Group 4: Placebo From week 0 to week 28, subjects received a placebo QD, administered as an oral tablet.

[0208] The total study duration was 84 weeks and included the following phases:

[0209] • Screening period: up to 6 weeks;

[0210] • Main treatment period: 28 weeks (daily administration from week 0 to week 28);

[0211] • Long-Term Extension (LTE) Period: 48 weeks (daily dosing from week 28 to week 76); and

[0212] • Safety follow-up period: 2 weeks after the last intervention administration.

[0213] Participants will be instructed to take the study intervention with 240 mL of water at approximately the same time each day (preferably upon waking in the morning). Participants must fast for at least 2 hours before taking the study intervention and for at least 30 minutes after taking it.

[0214] Inadequate response will be assessed in all participants at week 16. Inadequate response is defined as meeting all three of the following criteria:

[0215] 1. Unable to achieve an improved Mayo score of <5 in week 12, and

[0216] 2. In week 16, some Mayo scores were less than 5.

[0217] 3. Failure to achieve a clinical response by week 12 (defined as a modified Mayo score that decreases by ≥30% from baseline and by ≥2 points, and a rectal bleeding sub-score that decreases by ≥1 point from baseline, or a rectal bleeding sub-score of 0 or 1).

[0218] Participants who met the criteria for inadequate response at week 16 and were treated with placebo will receive a treatment adjustment to 400 mg of the IL-23 receptor antagonist peptide daily.

[0219] Participants treated with IL-23 receptor antagonist peptides who met the criteria for inadequate response at week 16 will continue their assigned treatment regimen (pseudo-treatment adjustment).

[0220] If any of the three criteria for inadequate response cannot be calculated due to missing data, the subject will not be considered to meet the criteria for inadequate response, and the treatment will not be adjusted.

[0221] Participants who complete the assessment at week 28 and achieve a clinical response at week 28 will be eligible to participate in the 48-week long-term extension (LTE) phase of the study.

[0222] The efficacy, pharmacokinetics, immunogenicity, pharmacodynamics, biomarkers, and safety will be evaluated. Additionally, pharmacogenomic blood samples will be collected from consenting participants and where permitted by local regulations.

[0223] Selection criteria

[0224] Each participant is ≥18 years old and meets all of the following criteria:

[0225] (a) Diagnosed with UC at least 12 weeks prior to screening, and confirmed to have colitis by radiological, histological and / or endoscopic examination at any previous time;

[0226] (b) Having moderate to severe active UC, defined as using the endoscopic score obtained during central review of video endoscopy during the screening period, with a baseline (week 0) modified Mayo score of 5 to 9 (inclusive).

[0227] (c) An endoscopy score ≥2 obtained during the central review of video endoscopy during the screening period;

[0228] (d) Laboratory test results during the screening period meet the following limits, and if one or more laboratory parameters exceed the range, a single retest of the out-of-range laboratory value is permitted during the screening period:

[0229] (i) Hemoglobin ≥ 8.0 g / dL (SI: ≥ 80.0 g / L);

[0230] (ii)WBC ≥3.0×103 / μL (SI: ≥3.0×109 / L);

[0231] (iii) Neutrophils ≥ 1.5 × 10³ / μL (SI: ≥ 1.5 × 10⁹ / L);

[0232] (iv) Platelet count ≥100×103 / μL (SI: ≥100×109 / L);

[0233] (v) Using the CKD-EPI formula, eGFR ≥45mL / min / 1.73m2;

[0234] (vi)AST ≤ 2 times ULN;

[0235] (vii)ALT ≤ 2 times ULN; and

[0236] (viii) Direct (conjugated) bilirubin ≤ 1.5 times ULN;

[0237] (e) Medications previously or currently used for UC include at least one of the following:

[0238] (i) Currently receiving oral corticosteroids (including budesonide and beclomethasone dipropionate) and / or immunomodulators (AZA, 6-MP);

[0239] (ii) History of non-response or intolerance to at least one of the following therapies: oral corticosteroids (including budesonide and beclomethasone dipropionate) or immunomodulators (AZA, 6-MP).

[0240] (iii) A history of corticosteroid dependence (i.e., inability to successfully tape off corticosteroids without recurrence of UC symptoms); or

[0241] (iv) Prior lack of initial response (primary non-response), initial response followed by loss of response with continued treatment (secondary non-response), or intolerance to one or more advanced therapies (at least the locally approved dose for UC treatment); these advanced therapies are infliximab, adalimumab, golimumab, vedozizumab, or ustekinumab (or an approved biosimilar), an approved S1P modulator (i.e., ozamod), or an approved JAK inhibitor (i.e., tofacitinib, utpatinib, or filogrinib).

[0242] (f) Comply with all requirements for the medications used to treat UC. The following medications are permitted if the dosing requirements listed below were met and the medications were used consistently before baseline (week 0) or discontinued within the timeframes specified below:

[0243] (i) A stable dose of an oral 5-ASA compound has been maintained for at least 2 weeks; or if recently discontinued, it must have been discontinued for at least 2 weeks.

[0244] (ii) Oral corticosteroids at or below the prednisone equivalent dose of 20 mg / day, or budesonide 9 mg / day, or beclomethasone dipropionate 5 mg / day, and maintained stable administration for at least 2 weeks; or if recently discontinued, must have been discontinued for at least 2 weeks.

[0245] (iii) A conventional immunomodulatory agent (i.e., AZA, 6-MP or MTX) has been used for >12 weeks and has been at a stable dose for at least 4 weeks; or if recently discontinued, it must have been discontinued for at least 4 weeks.

[0246] For subjects with extensive UC for ≥8 years or disease limited to the left colon for ≥10 years, the subject must meet the following criteria:

[0247] (a) Underwent a complete colonoscopy within one year prior to the first administration of the study intervention to assess for the presence of dysplasia; or

[0248] (b) During baseline endoscopy at the screening period, a complete colonoscopy and biopsy should be performed to monitor for dysplasia. These monitoring biopsies must be negative for dysplasia (low-grade or high-grade) prior to the first administration of the study intervention.

[0249] For participants aged ≥45 years, participants must meet the following criteria: they must have undergone a complete colonoscopy within 5 years prior to the first administration of the study intervention to assess for the presence of adenomatous polyps, or they must have undergone a complete colonoscopy at the screening visit to assess for the presence of adenomatous polyps. Adenomatous polyps must be removed before the first administration of the study intervention.

[0250] Exclusion criteria

[0251] Potential participants are excluded if they meet any of the following criteria:

[0252] (a) Current or previous diagnosis of fulminant colitis and / or toxic megacolon;

[0253] (b) UC is limited to the rectum or colon <15cm;

[0254] (c) An ostomy is present;

[0255] (d) The presence of a fistula or a history of fistula;

[0256] (e) Within 8 weeks prior to screening, surgery has been required or will be required due to active gastrointestinal bleeding, peritonitis, intestinal obstruction, or intra-abdominal abscess requiring surgical drainage, or other conditions that may confound the evaluation of the benefits of the study intervention.

[0257] (f) There is symptomatic colonic or small bowel obstruction, with objective radiological or endoscopic evidence confirming the presence of stenosis leading to obstruction (barium meal radiography showing bowel dilatation proximal to the stenosis, or the endoscope being unable to pass through the stenosis).

[0258] (g) History of extensive colectomy (e.g., residual colon <30cm);

[0259] (h) Had a colectomy within 24 weeks prior to baseline, or any other intra-abdominal surgery within 12 weeks prior to the first administration of the study intervention;

[0260] (i) History of colonic mucosal dysplasia (participants will not be excluded from the study due to the pathological finding of “indeterminate dysplasia with reactive atypical changes”).

[0261] (j) Endoscopic examination during the screening period revealed colonic adenomatous polyps (if not removed before randomization), or a history of unremoved adenomatous colonic polyps.

[0262] (k) Diagnosis of undifferentiated colitis, microscopic colitis, ischemic colitis, Crohn's colitis, or clinical findings suggestive of Crohn's disease;

[0263] (l) Within 4 months prior to the first administration of the study intervention, a stool culture or other examination showed a positive result for intestinal pathogens (including Clostridium dificile toxin), unless a repeat test was negative and there was no indication of persistent infection with the pathogen;

[0264] (m) A history of, or signs of, a serious, progressive or uncontrolled disorder of the kidney, genitourinary, liver, gallbladder, blood, endocrine, heart, blood vessels, lungs, rheumatism, nervous system, mental or metabolic system.

[0265] (n) Currently have a malignant tumor, or have a history of a malignant tumor within 5 years prior to screening (except for non-melanoma skin cancer that has been adequately treated and has no evidence of recurrence within 12 months prior to the first study intervention; or cervical carcinoma in situ that has been treated and has no evidence of recurrence within ≥12 months prior to the first study intervention).

[0266] (o) A history of known lymphoproliferative disorders (including lymphoma), a history of monoclonal immunoglobulinosis of unknown significance; or signs and symptoms suggesting the possible presence of lymphoproliferative disorders;

[0267] (p) Known hypersensitivity, hypersensitivity or intolerance to IL-23 receptor antagonist peptides or excipients thereof;

[0268] (q) Meets any of the following tuberculosis (TB) screening criteria:

[0269] (i) A history of active TB, or signs or symptoms suggestive of active TB as shown by medical history and / or physical examination during screening;

[0270] (ii) History of untreated latent TB prior to screening;

[0271] (iii) Recent close contact with patients with active TB;

[0272] (iv) IGRA testing (IGRA testing includes QuantiFERON-TB) within 2 months prior to the administration of the first study intervention. ® Or T-SPOT ® The TB test result was positive; or

[0273] (v) Chest X-ray or chest computed tomography showed abnormalities suggestive of active or inactive TB within 12 weeks prior to the first study intervention.

[0274] (r) Has received an organ transplant (except for corneal transplants >12 weeks prior to screening);

[0275] (s) Poor tolerance to venipuncture, or lack of adequate venous access for the required blood sample collection during the study;

[0276] (t) Has had suicidal thoughts or attempted suicide within the past 6 months;

[0277] (u) A history of drug or alcohol abuse according to DSM-5 criteria within one year prior to screening;

[0278] (v) Have received or plan to receive any live attenuated vaccine within 12 weeks before the first administration of the study drug or within 4 weeks after the last administration of the study drug;

[0279] (w) Received BCG vaccine within 1 year prior to the first study intervention, or are scheduled to receive BCG vaccine or any other live bacteria or live virus vaccine during the study period;

[0280] (x) Received any of the following medications or treatments within the period specified from baseline (week 0):

[0281] (i) Any prior exposure to any other biologic agent targeting IL-23, including but not limited to gusecurumab, migilizumab, resalizumab, or brecurumab;

[0282] (ii) 5-ASA compound for rectal use (5-ASA administered rectally via foam, enema, or suppository): 2 weeks;

[0283] (iii) Rectal corticosteroids (corticosteroids administered rectally via foam, enema, or suppository): 2 weeks;

[0284] (iv) JAK inhibitors (e.g., tofacitinib, utpatinib, or fegastinib) for at least 2 weeks;

[0285] (v) Parenteral nutrition: 2 weeks;

[0286] (vi) Antibiotics used as the primary treatment for UC (e.g., ciprofloxacin, metronidazole, or rifaximin): 2 weeks;

[0287] (vii) IV. Corticosteroids: 3 weeks;

[0288] (viii) Treat with apheresis (e.g., Adacolumn apheresis): 3 weeks;

[0289] (ix) Receive cyclosporine, tacrolimus, sirolimus or mycophenolate mofetil: 4 weeks;

[0290] (x)6-thioguanine: 4 weeks;

[0291] (xi) Ozamod or other S1P modulators: 4 weeks (lymphocyte count must be >400 / L at screening);

[0292] (xii) Any investigational intervention: 4 weeks or 5 half-lives (whichever is longer);

[0293] (xiii) Biologics (including approved biosimilars of these therapies) (4 half-lives) (e.g., infliximab: 4 weeks; adalimumab: 8 weeks; golimumab: 7 weeks; vedolizumab: 12 weeks; ustekinumab: 12 weeks)

[0294] (xiv) Fecal microbiota transplantation or any live bacterial therapy: 12 weeks;

[0295] (xv) Other immunomodulatory biologics, including approved and investigational biologics: 12 weeks or 5 half-lives (whichever is longer).

[0296] (xvi) Drugs that deplete B cells or T cells (e.g., rituximab, alemtuzumab): 24 weeks;

[0297] (xvii) Non-autologous stem cell therapy (e.g., Prochymal): 1 year; and

[0298] (xviii) Natazacillinab: 1 year;

[0299] (y) There are any circumstances where the researcher believes that participation in the study is not in the best interests of the participants (e.g., may harm their health) or may prevent, limit or obscure the assessment specified in the protocol;

[0300] (z) Positive results for hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) during screening;

[0301] (aa) History of latent or active granulomatous infection prior to screening, including histoplasmosis or coccidioidomycosis;

[0302] (bb) A history of or current presence of chronic or recurrent infectious diseases, including but not limited to sinus lung infection, bronchiectasis, recurrent kidney / urinary tract infection (e.g., pyelonephritis, cystitis), open, draining or infected skin wounds or ulcers.

[0303] (cc) Has or has had a nontuberculous mycobacterial infection or a clinically significant opportunistic infection (e.g., cytomegalovirus colitis, Pneumocystis infection, invasive aspergillosis, PML);

[0304] (dd) Had a clinically significant infection (e.g., hepatitis, sepsis, pneumonia, or pyelonephritis) within 8 weeks prior to the first administration of the study intervention, had been hospitalized for the infection, or had been treated for the infection with parenteral antibiotics;

[0305] (ee) Evidence of herpes zoster infection within 8 weeks prior to the first study intervention administration;

[0306] (ff) Those who tested positive for COVID-19 or had been exposed to COVID-19 within 4 weeks prior to the first study intervention.

[0307] Research Evaluation

[0308] During the primary treatment period of 28 weeks (weeks 0, 2, 4, 8, 12, 16, 20, and 28), efficacy, pharmacokinetics, immunogenicity, pharmacodynamics and biomarkers, pharmacogenomics, and safety criteria will be measured. For subjects participating in the subsequent 48-week LTE period, additional measurements will be performed at weeks 36, 44, 52, 60, 68, and 76.

[0309] The efficacy evaluation will include the following:

[0310] • Full Mayo rating, modified Mayo rating, and partial Mayo rating

[0311] • Histological assessment (Geboes score and Robarts histopathological index)

[0312] • Inflammatory pharmacodynamic (PD) markers, including C-reactive protein (CRP) and fecal calprotectin.

[0313] • Patient-reported outcomes (PRO) measures used to assess symptom severity, function, health-related quality of life (HRQoL), and treatment satisfaction include: Inflammatory Bowel Disease Questionnaire (IBDQ), Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29), Patient-Reported Outcomes Signs and Symptoms of Ulcerative Colitis (UC-PRO / SS), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and Treatment Satisfaction Questionnaire-9 (TSQM-9).

[0314] • Intestinal ultrasound (IUS) assessment (sub-study)

[0315] Pharmacokinetic evaluation: Plasma, tissue, and fecal samples will be collected and used to evaluate the pharmacokinetics of the IL-23 receptor antagonist peptide.

[0316] Immunogenicity assessment: Antibodies that bind to the IL-23 receptor antagonist peptide will be screened in serum samples. Further analyses may be performed to verify the stability of the antibodies against the IL-23 receptor antagonist peptide.

[0317] Pharmacodynamic and Biomarker Evaluation: Inflammatory pharmacodynamic biomarkers (CRP and fecal calprotectin) will be evaluated using blood and stool samples collected during visits. Biomarker assessment will be used to define and identify pharmacodynamic biomarkers of treatment response to better understand the mechanism of action of IL-23 receptor antagonist peptides in participants with UC and to help evaluate the study intervention-clinical response relationship and the pathophysiology of UC. This will include, as per protocol and where permitted by local regulations, the evaluation of relevant disease and pathway involvement biomarkers in serum, stool, whole blood, and tissue biopsies.

[0318] Pharmacogenomic (DNA) evaluation: Participation in pharmacogenomics research is optional. Where permitted by local regulations, pharmacogenomics (DNA) blood samples will be collected from participants who have separately consented to this part of the study, preferably at baseline, to allow for pharmacogenomics research.

[0319] Safety assessment: Safety assessment includes physical examination, vital signs, electrocardiogram (ECG), clinical safety laboratory assessment, pregnancy testing, suicidal ideation and behavioral risk monitoring, concomitant medication review, tuberculosis (TB) evaluation, and other infection assessments.

[0320] Primary endpoint analysis

[0321] The primary endpoint was clinical response at week 12 (defined as a modified Mayo score reduction of ≥30% from baseline and a reduction of ≥2 points, along with a reduction of ≥1 point in the rectal bleeding sub-score from baseline, or a rectal bleeding sub-score of 0 or 1). Analysis of the primary endpoint will be based on the full analysis set, defined as all randomly assigned participants who received at least one dose of the study intervention. Participants will be analyzed according to their intervention group, regardless of the specific study intervention they received.

[0322] Clinical responses at week 12 will be analyzed based on the primary estimation objectives, taking into account treatment groups, populations, variables, comorbidity events (ICE) strategies, and population-level summaries.

[0323] After taking the ICE strategy into account, any participant missing a primary endpoint response status will be considered a non-responder.

[0324] To control the Type I error rate at 0.05 (two-tailed), the primary endpoint will be tested using a fixed-order test method. For the clinical response endpoint at week 12, the test will first be performed between the IL-23 receptor antagonist peptide 400 mg qd group and the placebo group, followed by the IL-23 receptor antagonist peptide 200 mg qd group and the placebo group, and then the IL-23 receptor antagonist peptide 100 mg qd group and the placebo group. If the test between the 400 mg qd group and the placebo group is positive, the study will be considered positive.

[0325] The primary endpoint was compared between the IL-23 receptor antagonist peptide treatment groups and the placebo group using the Cochran-Mantel-Haenszel (CMH) test (two-sided), stratified by baseline ADT-IR status (yes or no) and endoscopic scores obtained during central review of video endoscopy during the screening period (moderate[2] or severe[3]).

[0326] Secondary endpoint analysis

[0327] The secondary endpoint is:

[0328] • Achieving clinical remission at week 12 (defined as a defecation frequency subscore of 0 or 1, with no increase in defecation frequency subscore from baseline, a rectal bleeding subscore of 0, and an endoscopy score of 0 or 1).

[0329] • Symptom relief was achieved by week 12 (defined as a bowel frequency sub-score of 0 or 1, where the bowel frequency sub-score did not increase from baseline and the rectal bleeding sub-score was 0).

[0330] • Achieve endoscopic improvement by week 12 (defined as an endoscopic score of 0 or 1).

[0331] • Achieve histological-endoscopic mucosal improvement by week 12 (defined as an endoscopy score of 0 or 1, and the absence of neutrophils, crypt destruction, erosions, ulcers, or granulation tissue in the mucosa (lamina propria and epithelium) according to the Geboes grading system).

[0332] The analysis will be based on the full analysis set. Participants will be analyzed according to the intervention group they were randomly assigned to, regardless of the research intervention they received.

[0333] After considering the ICE strategy, participants missing any item in the Mayo sub-score that includes the secondary endpoint will be considered non-responders for that secondary endpoint. Additionally, participants missing any or all items in the Geboes grading system will be considered non-responders for histological-endoscopic mucosal improvement.

[0334] Secondary endpoints will be tested regardless of the significance of the comparison of the primary endpoints.

[0335] The order of testing for secondary endpoints was as follows: each secondary endpoint was tested between the IL-23 receptor antagonist peptide 400 mg qd group and the placebo group, then each secondary endpoint was tested between the IL-23 receptor antagonist peptide 200 mg qd group and the placebo group, and then each secondary endpoint was tested between the IL-23 receptor antagonist peptide 100 mg qd group and the placebo group, in the order listed above.

[0336] In this sequence, if any test (including the test for the primary endpoint that will be performed before the secondary endpoint) does not reach significance at the two-sided 0.05 level, then all p-values ​​of subsequent tests will be treated as nominal values.

[0337] Secondary endpoints will be analyzed by the CMH test (two-tailed), stratified by baseline ADT-IR status (yes or no) and endoscopic scores (moderate[2] or severe[3]) obtained during central review of video endoscopy during the screening period.

[0338] Security Analysis

[0339] All safety analyses will be based on the full analysis set, which is defined as all randomly assigned participants who received at least one dose of the study intervention.

[0340] Safety data will be compiled, including but not limited to adverse events (AEs), serious adverse events (SAEs), infections, changes in clinical laboratory parameters (hematology and chemistry), and suicidal ideation and behavior. All reported AEs occurring during treatment will be included in the analysis.

[0341] Example 2. Preparation of the crystalline form of the hydrochloride salt of the peptide of SEQ ID NO: 1

[0342] Ac-[Pen]*-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]*-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2

[0343] (where [Pen]*-[Pen]* forms a disulfide bond) (SEQ ID NO: 1):

[0344] .

[0345] 18.9 kg of Rink amide AM resin (degree of substitution: 0.95 mmol / g) was loaded into a 1000 L SPPS reactor and subjected to SPPS. Each SPPS cycle consisted of Fmoc cleavage, coupling with the corresponding building block, and necessary end-capping. For Fmoc cleavage, the resin was treated with a 20% piperidine DM solution (10 ml / g resin each time) at 25 °C for 5 ± 2 min and 10 ± 2 min. Coupling was performed using DMF as solvent (10 ml / g resin) with the building blocks, coupling reagents, and conditions described in Table 5. For end-capping, the resin was treated with a DMF solution of anhydride and pyridine (V / V ratio DMF / Ac2O / pyridine 50:1:1; DMF: 10 ml / g resin) for 20 min. Diisopropyl carbonate (DIC) was added in two portions, with the second portion added approximately 20 to 30 minutes after the first portion.

[0346] Table 5 :

[0347]

[0348] The final acetylation of the peptide resin was carried out for 20 min using a DMF solution of acid anhydride and pyridine (volume ratio DMF / Ac2O / pyridine 10:1:1; DMF: 10 ml / g resin). After drying at 25℃-35℃, 72.8 kg of linear peptide-Rink amide AM resin was obtained.

[0349] TFA pyrolysis

[0350] In a jacketed reactor, 100 g of the above-mentioned resin was added to 700 mL of pyrolysis mixture at 18°C. This mixture consisted of 630 mL TFA, 35 mL TIS, 17.5 mL EDT, and 17.5 mL water. After adding the resin, the temperature was raised to 30°C, and the mixture was stirred at 30°C for another 35 min. The mixture was cooled to 20°C, the resin was filtered off, and the mixture was washed twice with 100 mL of TFA each time. The filtrates were combined and cooled to -15°C. To induce precipitation, 4.0 L of diisopropyl ether was added over 20 min, while maintaining the solution / suspension temperature at 7°C. After the diisopropyl ether was completely added, the temperature was raised to 22°C, and the suspension was stirred for 2.5 h.

[0351] The suspension was then transferred to a filter dryer, and the crude precipitate was filtered off at ambient temperature. The filter cake was then washed three times with 300 mL of diisopropyl ether each time and dried under vacuum at 30 °C overnight to obtain 52.87 g of linear peptide in the form of TFA salt.

[0352] Oxidation and purification by preparative HPLC

[0353] 28 g of the linear peptide in TFA salt form was dissolved in 280 mL of 30% AcOH aqueous solution at ambient temperature. 3.71 g of iodine and 7.17 g of potassium iodide were dissolved in 280 mL of water. At ambient temperature, the peptide and iodine / iodide solutions were added in parallel to a vigorously stirred mixture of 2.2 L of 30% AcOH aqueous solution over 60 min. After complete addition of both solutions, a brown oxidized mixture was obtained. After stirring at ambient temperature for 30 min, IPC indicated almost complete conversion of the starting material. 1.5 h after complete addition of the peptide and iodine solutions, 3.5 g of vitamin C was added. The resulting yellow solution was stirred for 10 min. The oxidized mixture was filtered through a sintered glass funnel before application to a preparative RP-HPLC column. Chromatographic conditions were the same as those used in Example 4. All fractions were adjusted to pH 7 with an aqueous solution of 18% HCl. Fractions collected during preparative RP-HPLC were analyzed by UHPLC. Fractions containing >98% product were combined for subsequent separation.

[0354] Separation

[0355] Following oxidation and preparative HPLC purification, a product pool of 420 mL was obtained. The product concentration in this solution was determined to be approximately 29 g / L by experimental lyophilization, corresponding to a theoretical yield of approximately 12.2 g.

[0356] From the total combined volume, 120 mL was transferred to a round-bottom flask, and the initial pH of 7.51 was adjusted to pH 3.00 with 4.5 mL of 1M HCl aqueous solution. Acetonitrile was evaporated from the product solution under vacuum at 40 °C until water began to evaporate. After evaporation, the remaining 80 mL of the product aqueous solution (pH 2.54) was transferred, with 40 mL transferred to a reactor connected to the heating / cooling system for subsequent separation.

[0357] The pH of the solution was then adjusted to pH 3.75 by adding 1.0 mL of 0.5 M NH4HCO3 over 65 min. 1% (w / w) of the compound of formula (I) was added to the clear yellow solution as a seed material, and the resulting dilute suspension was stirred at 25 °C for 60 min. The pH of the suspension was then adjusted to pH 4.50 by adding 2.9 mL of 0.5 M NH4HCO3 over 125 min. After stirring the suspension at 25 °C for 30 min, the pH dropped to pH 4.12. The pH was then readjusted to 4.50 by adding 0.2 mL of 0.5 M NH4HCO3. After stirring at 25 °C for 16 h, a thick suspension was formed, which was filtered through a glass Knoop filter (G4) (1 min filtration time) and washed with 1.59 mL of water (1 volume equivalent; 1 min filtration time) without stirring. The washed filter cake was vacuum dried in a vacuum oven at 25 °C for 16 h. Finally, the dried product is discharged from the filter.

[0358] A total of 1.77 g of compound (I) (partially HCl salt) was isolated from 60 mL of the product pool, which is equivalent to the isolation of 12.4 g of compound (I) from the total 420 mL of the product pool. The purity (HPLC) of the separated material was 99.4%, the chlorine content (titration) was 1.6%, and the water content (KF) was 3.6%.

[0359] X-ray powder diffraction (XRPD) patterns of partial hydrochloride salts of the compound of formula (I) confirmed its crystallinity. The following 2θ peaks were observed: 4.2920, 6.9201, 7.6600, 8.5693, 9.2667, 9.9817, 10.7256, 11.5429, 11.9937, 13.0633, 13.3317, 13.9650, 14.7879, 15.8430, 17.1481, 17.6468, 18.1402, 18.6158, 19.3291, 20.4899, 20.7090, or 21.7813 + / - 0.2 degrees 2θ.

[0360] Example 3. Synthesis procedure for the crystalline hydrochloride of the peptide of SEQ ID NO: 1

[0361] 30 g of crystalline hydrochloride of the compound of formula (I) prepared according to Example 2 was dissolved in 120 mL of methanol and 51.4 mL of water. Dissolution was carried out in an EasyMax 402 reactor at 40 °C with stirring. 57.1 mL of 1M sodium chloride was added to the EasyMax reactor over 1 h. The solution was then seeded with 300 mg of the hydrochloride of the compound of formula (I) prepared according to Example 3. The slurry was then aged at 40 °C with stirring for 8 h. The slurry was cooled to 5 °C at a cooling rate of 0.1 K / min. An additional 114.31 mL of 1M sodium chloride was added to the EasyMax reactor over 4 h, and the slurry was aged for an additional 5 h. The solid was separated by vacuum filtration and washed twice with 30 mL of water and twice with 30 mL of isopropanol. The solid was dried at atmospheric pressure.

[0362] The purity (UPLC) of the isolated solid in the crystalline hydrochloride form of compound (I) was 99.3% by area and the water content (KF) was 6.33 w / w. The chlorine content of the isolated crystalline hydrochloride form of compound (I) was determined by ion chromatography and found to be 0.64 molar equivalents of the compound (I). XRPD spectra of the crystalline hydrochloride form of compound (I) confirmed its crystallinity. Figure 2 The following 2θ peaks were observed: 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.6, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 degrees 2θ + / - 0.2 degrees 2θ.

[0363] Although the foregoing disclosure has been described in considerable detail by way of illustration and examples for purposes of clarity, those skilled in the art will understand that certain changes and modifications may be made within the scope of the appended claims. In the event of any conflict between this application and the references provided herein, this application shall prevail.

Claims

1. A method for treating ulcerative colitis in a subject of need, the method comprising administering a compound of formula (I) to the subject: (I)， Or its pharmaceutically acceptable salts or solvates; Upon treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, the subject is deemed responsive to treatment on at least one of the following indicators of treatment response, selected from the group consisting of: (i) clinical response, as determined by: a modified Mayo score that is ≥30% lower than baseline and a decrease of ≥2 points, and a Mayo rectal bleeding sub-score that is ≥1 point lower than baseline, or a Mayo rectal bleeding sub-score of 0 or 1; (ii) clinical remission, as determined by: a Mayo defecation frequency sub-score of 0 or 1, wherein the Mayo defecation frequency sub-score has not increased from baseline, a Mayo rectal bleeding sub-score of 0, and a Mayo endoscopy score of 0 or 1; (iii) symptom remission, as determined by: a Mayo defecation frequency sub-score of 0 or 1, wherein the Mayo defecation frequency sub-score has not increased from baseline. (iv) Endoscopic improvement, as determined by a Mayo endoscopic score of 0 or 1; (v) Histological remission, as determined by the absence of neutrophils, crypt destruction, erosions, ulcers, or granulation tissue in the mucosa (lamina propria and epithelium) according to the Geboes grading system; (vi) Histological-endoscopic mucosal improvement, as determined by the absence of neutrophils, crypt destruction, erosions, ulcers, or granulation tissue in the mucosa (lamina propria and epithelium) according to the Geboes grading system, and a Mayo endoscopic score of 0 or 1; (vii) Deep symptom remission, as determined by a Mayo defecation frequency sub-score of 0 and a rectal bleeding sub-score of 0; and (viii) Modified Mayo score <5; (ix) Partial Mayo score <5.

2. The method of claim 1, wherein the treatment response is a clinical response, such as determined by: a modified Mayo score that is ≥30% lower than baseline and a decrease of ≥2 points, and a Mayo rectal bleeding sub-score that is ≥1 point lower than baseline, or a Mayo rectal bleeding sub-score of 0 or 1.

3. The method of claim 1 or claim 2, wherein, as part of the treatment response, the subject achieved a modified Mayo score reduction of ≥40% from baseline.

4. The method of claim 3, wherein, as part of the treatment response, the subject achieved a modified Mayo score reduction of ≥50% from baseline.

5. The method according to any one of claims 1-4, wherein, as part of the treatment response, the subject achieved a reduction of ≥3 points in the modified Mayo score from baseline.

6. The method according to any one of claims 1-5, wherein, as part of the treatment response, the subject achieves a modified Mayo score of less than 4.

7. The method of claim 6, wherein, as part of the treatment response, the subject achieves a modified Mayo score of less than 3.

8. The method according to any one of claims 1-7, wherein, as part of the treatment response, the subject achieves a partial Mayo score of less than 4.

9. The method of claim 8, wherein, as part of the treatment response, the subject achieves a partial Mayo score of less than 3.

10. The method according to any one of claims 1-9, wherein, as part of the treatment response, the subject achieves a Mayo defecation frequency sub-score of 0 or 1.

11. The method of claim 10, wherein, as part of the treatment response, the subject achieved a Mayo defecation frequency sub-score of 1.

12. The method of claim 10, wherein, as part of the treatment response, the subject achieved a Mayo defecation frequency sub-score of 0.

13. The method according to any one of claims 1-12, wherein the Mayo defecation frequency sub-score has not increased from baseline.

14. The method according to any one of claims 1-13, wherein the response to treatment is a Mayo endoscopic score of 0 or 1.

15. The method according to any one of claims 1-14, wherein, as part of the treatment response, the subject achieves a Mayo endoscopy score of 1.

16. The method according to any one of claims 1-14, wherein, as part of the treatment response, the subject achieves a Mayo endoscopy score of 0.

17. The method according to any one of claims 1-16, wherein the Mayo endoscopic score does not increase from the baseline.

18. The method according to any one of claims 1-17, wherein, as part of the treatment response, the subject achieved a Mayo rectal bleeding subscale score that decreased by ≥1 point from baseline.

19. The method according to any one of claims 1-18, wherein, as part of the treatment response, the subject achieves a Mayo rectal bleeding score of 0 or 1.

20. The method according to any one of claims 1-19, wherein, as part of the treatment response, the subject achieved a Mayo rectal bleeding score of 1.

21. The method according to any one of claims 1-19, wherein, as part of the treatment response, the subject achieved a Mayo rectal bleeding score of 0.

22. The method according to any one of claims 1-21, wherein the Mayo rectal bleeding score has not increased from baseline.

23. The method according to any one of claims 1-19, 21 or 22, wherein the treatment response is symptom relief, as determined by: a Mayo defecation frequency sub-score of 0 or 1, wherein the Mayo defecation frequency sub-score has not increased from baseline and the Mayo rectal bleeding sub-score is 0.

24. The method according to any one of claims 1-19, 21 or 22, wherein the treatment response is a clinical remission, as determined by: a Mayo defecation frequency sub-score of 0 or 1, wherein the Mayo defecation frequency sub-score has not increased from baseline, a Mayo rectal bleeding sub-score of 0, and a Mayo endoscopy score of 0 or 1.

25. The method according to any one of claims 1-10, 12-19, 21 or 22, wherein the therapeutic response is a Mayo defecation frequency subscore of 0 and a Mayo rectal bleeding subscore of 0.

26. The method according to any one of claims 1-25, wherein, as part of the treatment response, the subject achieves a Mayo Physician Global Assessment sub-score of 0 or 1.

27. The method according to any one of claims 1-26, wherein, as part of the treatment response, the subject achieved a Mayo Physician Global Assessment sub-score of 1.

28. The method according to any one of claims 1-26, wherein, as part of the treatment response, the subject achieves a Mayo Physician Global Assessment sub-score of 0.

29. The method according to any one of claims 1-28, wherein the Mayo Physician Overall Assessment Sub-score has not increased from baseline.

30. The method of any one of claims 1-29, wherein, as part of the treatment response, the subject achieves a reduction in Geboes score relative to baseline.

31. The method according to any one of claims 1-30, wherein after treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, the subject exhibits the absence of neutrophils in the subject's lamina propria.

32. The method according to any one of claims 1-31, wherein after treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, the subject exhibits the absence of neutrophils in the subject's epithelium.

33. The method according to any one of claims 1-32, wherein the subject exhibits no crypt destruction after treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

34. The method according to any one of claims 1-33, wherein after treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, the subject exhibits no erosion, ulceration or granulation tissue.

35. The method according to any one of claims 1-30, wherein the therapeutic response is a histological remission, as determined by the following: the mucosa (both the lamina propria and the epithelium) is free of neutrophils, crypt destruction, and erosion, ulceration, or granulation tissue, according to the Geboes grading system.

36. The method according to any one of claims 1-30, wherein the therapeutic response is histological endoscopic mucosal improvement, as determined by the following: the mucosa (both the lamina propria and the epithelium) is free of neutrophils, crypt destruction, and erosion, ulceration, or granulation tissue according to the Geboes grading system; and the Mayo endoscopic score is 0 or 1.

37. The method according to any one of claims 1-36, wherein, as part of the treatment response, the subject achieves a reduction in the concentration of C-reactive protein (CRP) relative to baseline.

38. The method according to any one of claims 1-37, wherein, as part of the treatment response, the subject achieves a decrease in the concentration of fecal calprotectin relative to baseline.

39. The method according to any one of claims 1-38, wherein a response to treatment is achieved at least 12 weeks after the start of treatment.

40. The method according to any one of claims 1-39, wherein a response to treatment is achieved at least 16 weeks after the start of treatment.

41. The method according to any one of claims 1-40, wherein a response to treatment is achieved at least 20 weeks after the start of treatment.

42. The method according to any one of claims 1-41, wherein a response to treatment is achieved at least 28 weeks after the start of treatment.

43. The method according to any one of claims 1-42, wherein the compound of formula (I) is a hydrochloride salt of the compound of formula (I) or a solvation thereof.

44. The method according to any one of claims 1-43, wherein the compound of formula (I) or its pharmaceutically acceptable salt or solvate is administered orally.

45. The method of claim 44, wherein the subject has fasted for at least 2 hours prior to administration of the compound of formula (I) or its pharmaceutically acceptable salt or solvate.

46. ​​The method according to claim 44 or claim 45, wherein the subject has fasted for at least 30 minutes after administration of the compound of formula (I) or its pharmaceutically acceptable salt or solvate.

47. The method according to any one of claims 1-46, wherein the compound of formula (I) or its pharmaceutically acceptable salt or solvate is administered daily.

48. The method according to claim 47, wherein the compound of formula (I) or its pharmaceutically acceptable salt or solvate is administered once daily.

49. The method according to any one of claims 1-48, wherein the compound of formula (I) or its pharmaceutically acceptable salt or solvate is administered to the subject in an amount of about 5 mg to about 600 mg.

50. The method according to any one of claims 1-49, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered to the subject in an amount of about 100 mg to about 400 mg.

51. The method according to any one of claims 1-49, wherein the compound of formula (I) or its pharmaceutically acceptable salt or solvate is administered to the subject in an amount of at least 100 mg.

52. The method according to any one of claims 1-51, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered to the subject in an amount of about 100 mg.

53. The method according to any one of claims 1-51, wherein the compound of formula (I) or its pharmaceutically acceptable salt or solvate is administered to the subject in an amount of about 200 mg.

54. The method according to any one of claims 1-51, wherein the compound of formula (I) or its pharmaceutically acceptable salt or solvate is administered to the subject in an amount of about 400 mg.

55. The method according to any one of claims 1-54, wherein the subject's modified Mayo score is 5 to 9 prior to treatment.

56. The method according to any one of claims 1-55, wherein the subject's modified Mayo score is 5 to 7 prior to treatment.

57. The method according to any one of claims 1-55, wherein the subject's modified Mayo score is 7 to 9 prior to treatment.

58. The method according to any one of claims 1-57, wherein prior to treatment, the subject's Mayo defecation frequency sub-score was 2 or 3.

59. The method according to any one of claims 1-58, wherein prior to treatment, the subject's Mayo endoscopic score is 2 or 3.

60. The method according to any one of claims 1-59, wherein prior to treatment, the subject's Mayo rectal bleeding score was 1, 2, or 3.

61. The method according to any one of claims 1-60, wherein prior to treatment, the subject's Mayo Physician Global Assessment sub-score is 2 or 3.

62. The method according to any one of claims 1-61, wherein the subject has not been treated with a biological agent for ulcerative colitis prior to treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

63. The method according to any one of claims 1-61, wherein the subject is unresponsive to or intolerant of treatment with a biological agent for ulcerative colitis prior to treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

64. The method according to any one of claims 1-61, wherein the subject has been given an oral corticosteroid or immunomodulator to treat ulcerative colitis prior to treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

65. The method of claim 64, wherein the subject is unresponsive to or intolerant of treatment with the oral corticosteroid or the immunomodulator.

66. The method of claim 64, wherein the subject has a history of corticosteroid dependence.

67. The method according to any one of claims 1-66, wherein the ulcerative colitis is moderate to severe active ulcerative colitis.

68. A method for treating ulcerative colitis in a subject of need, the method comprising administering a compound of formula (I) to the subject in an amount of about 100 mg: (I)， Or its pharmaceutically acceptable salts or solvates.

69. The method according to claim 68, wherein the compound of formula (I) or its pharmaceutically acceptable salt or solvate is administered once daily in an amount of about 100 mg.

70. A method for treating ulcerative colitis in a subject of need, the method comprising administering a compound of formula (I) to the subject in an amount of about 200 mg: (I)， Or its pharmaceutically acceptable salts or solvates.

71. The method according to claim 70, wherein the compound of formula (I) or its pharmaceutically acceptable salt or solvate is administered once daily in an amount of about 200 mg.

72. A method for treating ulcerative colitis in a subject of need, the method comprising administering a compound of formula (I) to the subject in an amount of about 400 mg: (I)， Or its pharmaceutically acceptable salts or solvates.

73. The method according to claim 72, wherein the compound of formula (I) or its pharmaceutically acceptable salt or solvate is administered once daily in an amount of about 400 mg.

74. The method according to any one of claims 68-73, wherein the compound of formula (I) or its pharmaceutically acceptable salt or solvate is administered orally.

75. The method of claim 74, wherein the subject has fasted for at least 2 hours prior to administration of the compound of formula (I) or its pharmaceutically acceptable salt or solvate.

76. The method according to claim 74 or claim 75, wherein the subject has fasted for at least 30 minutes after administration of the compound of formula (I) or its pharmaceutically acceptable salt or solvate.

77. The method according to any one of claims 68-76, wherein the compound of formula (I) is a hydrochloride salt of the compound of formula (I) or a solvation thereof.

78. The method according to any one of claims 68-77, wherein the subject's modified Mayo score is 5 to 9 prior to treatment.

79. The method according to any one of claims 68-78, wherein the subject's modified Mayo score is 5 to 7 prior to treatment.

80. The method according to any one of claims 68-78, wherein the subject's modified Mayo score is 7 to 9 prior to treatment.

81. The method according to any one of claims 68-80, wherein prior to treatment, the subject's Mayo defecation frequency sub-score is 1, 2, or 3.

82. The method according to any one of claims 68-81, wherein prior to treatment, the subject's Mayo endoscopic score is 2 or 3.

83. The method according to any one of claims 68-82, wherein prior to treatment, the subject's Mayo rectal bleeding score was 1, 2, or 3.

84. The method according to any one of claims 68-83, wherein prior to treatment, the subject's Mayo Certified General Assessment (MCO) sub-score is 2 or 3.

85. The method according to any one of claims 68-84, wherein the subject has not been treated with a biological agent for ulcerative colitis prior to treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

86. The method according to any one of claims 68-84, wherein the subject is unresponsive to or intolerant of treatment with a biological agent for ulcerative colitis prior to treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

87. The method according to any one of claims 68-84, wherein the subject has been given an oral corticosteroid or immunomodulator to treat ulcerative colitis prior to treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

88. The method of claim 87, wherein the subject is unresponsive to or intolerant of treatment with the oral corticosteroid or the immunomodulator.

89. The method of claim 87, wherein the subject has a history of corticosteroid dependence.

90. The method according to any one of claims 68-89, wherein the ulcerative colitis is moderate to severe active ulcerative colitis.

91. A pharmaceutical product for treating a subject suffering from ulcerative colitis, said pharmaceutical product comprising a compound of formula (I): (I)， Or a pharmaceutically acceptable salt or solvation thereof, wherein the compound of formula (I) or its pharmaceutically acceptable salt or solvation, when administered to the subject in an amount of at least 100 mg, induces at least one of the following indicators of treatment response selected from the group consisting of: (i) clinical response, as determined by: a modified Mayo score of ≥30% and ≥2 points lower than baseline, and a Mayo rectal bleeding sub-score of ≥1 point lower than baseline, or a Mayo rectal bleeding sub-score of 0 or 1; (ii) clinical remission, as determined by: a Mayo defecation frequency sub-score of 0 or 1, wherein the Mayo defecation frequency sub-score has not increased from baseline, a Mayo rectal bleeding sub-score of 0, and a Mayo endoscopy score of 0 or 1; (iii) symptom remission, as determined by: a Mayo defecation frequency sub-score of 0 or 1, wherein the Mayo defecation frequency sub-score has not increased from baseline, and a Mayo rectal bleeding sub-score of 0; (iv) Mayo endoscopic score of 0 or 1; (v) Histological remission, as determined by the following: absence of neutrophils, crypt destruction, and erosion, ulceration, or granulation tissue in the mucosa (lamina propria and epithelium) according to the Geboes grading system; (vi) Histological-endoscopic mucosal improvement, as determined by the following: absence of neutrophils, crypt destruction, and erosion, ulceration, or granulation tissue in the mucosa (lamina propria and epithelium) according to the Geboes grading system, and a Mayo endoscopic score of 0 or 1; and (vii) Mayo defecation frequency sub-score of 0 and rectal bleeding sub-score of 0.

92. The pharmaceutical product of claim 91, wherein the pharmaceutical product induces a clinical response, as determined by: a modified Mayo score that decreases by ≥30% from baseline and by ≥2 points, while the Mayo rectal bleeding score decreases by ≥1 point from baseline, or the Mayo rectal bleeding score is 0 or 1.

93. The pharmaceutical product of claim 91, wherein the pharmaceutical product induces clinical remission, as determined by: a Mayo defecation frequency subscore of 0 or 1, wherein the Mayo defecation frequency subscore has not increased from baseline, a Mayo rectal bleeding subscore of 0, and a Mayo endoscopy score of 0 or 1.

94. The pharmaceutical product of claim 91, wherein the pharmaceutical product induces symptom relief, as determined by: a Mayo defecation frequency sub-score of 0 or 1, wherein the Mayo defecation frequency sub-score has not increased from baseline, and the Mayo rectal bleeding sub-score is 0.

95. The pharmaceutical product of claim 91, wherein the pharmaceutical product induces a Mayo endoscopic score of 0 or 1.

96. The pharmaceutical product of claim 91, wherein the pharmaceutical product induces histological remission, as determined by the following criteria: the absence of neutrophils, crypt destruction, and erosion, ulceration, or granulation tissue in the mucosa (both lamina propria and epithelium) according to the Geboes grading system.

97. The pharmaceutical product of claim 91, wherein the pharmaceutical product induces histological-endoscopic mucosal improvement, as determined by the following criteria: the absence of neutrophils, crypt destruction, erosion, ulceration, or granulation tissue in the mucosa (both lamina propria and epithelium) according to the Geboes grading system, and a Mayo endoscopic score of 0 or 1.

98. The pharmaceutical product of claim 91, wherein the pharmaceutical product induces a Mayo defecation frequency sub-score of 0 and a rectal bleeding sub-score of 0.

99. The pharmaceutical product according to claim 91, wherein the pharmaceutical product induces a modified Mayo score <5.

100. The pharmaceutical product according to claim 91, wherein the pharmaceutical product induces a Mayo score <5.

101. The pharmaceutical product according to any one of claims 91-100, wherein the amount of the compound of formula (I) or its pharmaceutically acceptable salt or solvate is from about 5 mg to about 600 mg.

102. The pharmaceutical product according to any one of claims 91-100, wherein the amount of the compound of formula (I) or its pharmaceutically acceptable salt or solvate is about 100 mg.

103. The pharmaceutical product according to any one of claims 91-100, wherein the amount of the compound of formula (I) or its pharmaceutically acceptable salt or solvate is about 200 mg.

104. The pharmaceutical product according to any one of claims 91-100, wherein the amount of the compound of formula (I) or its pharmaceutically acceptable salt or solvate is about 400 mg.

105. The pharmaceutical product according to any one of claims 91-104, wherein the ulcerative colitis is moderate to severe active ulcerative colitis.

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