Use of biphenyl-containing compound for treating inflammatory bowel disease

Abstract

The present disclosure relates to the field of medicinal chemistry, and in particular, use of a biphenyl-containing compound (a compound of formula I or a pharmaceutically acceptable salt thereof) for treating inflammatory bowel disease.

Description

Use of compounds containing bicyclic rings in the treatment of inflammatory bowel disease

[0001] Citation of relevant applications

[0002] This application claims priority and benefits to Chinese Patent Application No. 202411638664.0, filed on November 15, 2024 with the State Intellectual Property Office of the People's Republic of China, the entire contents of which are hereby incorporated herein by reference. Technical Field

[0003] This disclosure belongs to the field of medicinal chemistry and provides the use of ring-containing compounds for the treatment of inflammatory bowel disease. Background Technology

[0004] The immune mechanism plays a crucial role in the development of inflammatory bowel disease (IBD). The interaction between innate and adaptive immunity leads to the production of inflammatory mediators, thereby inducing inflammation and causing excessive proliferation of keratinocytes. Janus kinases (JAKs) are a family of intracellular non-receptor tyrosine kinases, with four members: JAK1, JAK2, JAK3, and TYK2. Different JAK family subtypes share 40%–70% homology. The downstream pathway of JAKs is the signal transducers and activators of transcription (STAT) family. The JAK-STAT signaling pathway participates in the development, differentiation, maturation, apoptosis, and functional expression of various immune and hematopoietic cells, significantly influencing the regulation of the body's immune response, immune cell differentiation and development, and inflammatory responses. Inhibitors of tyrosine kinase 2 (TYK2) have potential therapeutic effects for inflammatory bowel disease. TYK2 inhibition is expected to affect a variety of immune-mediated diseases through its influence on the IL-23 / Th17 / Th22 axis, IL-12-mediated Th1 function, and the regulation of various immune pathways and cell types driven by type I interferon. Summary of the Invention

[0005] This disclosure provides a method for treating inflammatory bowel disease in a subject, comprising administering the compound of formula I or a pharmaceutically acceptable salt thereof to the subject.

[0006] Among them, T 7 T 8 T 9 T 10 T 11 T 12Each is independently selected from CH, C, NH, N, O or bonds, with one or two selected from NH or N;

[0007] Each R 3 Each group is independently selected from halogen, hydroxyl, amino, cyano, nitro, and C groups. 1-3 Alkyl or C 3-6 cycloalkyl, the C 1-3 Alkyl or C 3-6 The cycloalkyl group may optionally be substituted with one or more halogens, hydroxyl groups, amino groups, or cyano groups;

[0008] m is selected from 1 or 2.

[0009] In some implementations, X is selected from CH or X.

[0010] In some embodiments, this disclosure provides a method of treating a subject with inflammatory bowel disease, comprising administering to the subject a compound of formula I or a pharmaceutically acceptable salt thereof.

[0011] Among them, T 7 T 8 T 9 T 10 T 11 and T 12 Each is independently selected from CH, C, NH, N, O or bonds, with at least one or two of them selected from NH or N;

[0012] Each R 3 Each group is independently selected from halogen, hydroxyl, amino, cyano, nitro, and C groups. 1-3 Alkyl or C 3-6 cycloalkyl, the C 1-3 Alkyl or C 3-6 The cycloalkyl group may optionally be substituted with one or more halogens, hydroxyl groups, amino groups, or cyano groups;

[0013] m is selected from 1 or 2.

[0014] X is N.

[0015] In some embodiments, the method of treating a subject with inflammatory bowel disease includes administering to the subject an effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating a subject with inflammatory bowel disease includes administering to the subject a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof.

[0016] In some implementations, the T 7 T 8 T 9 T 10 T 11 T12 Each is independently selected from CH, C, NH, N, O or bonds, with one, two or three of them selected from NH or N.

[0017] In some implementation schemes, each R 3 Each is independently selected from F, or from methyl or cyclopropyl groups optionally substituted with F.

[0018] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from compound A, compound B, compound C, compound D, compound E, or compound F, or a pharmaceutically acceptable salt thereof:

[0019] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from compound A or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from compound B or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from compound C or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from compound D or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from compound E or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from compound F or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in a single dose or multiple doses.

[0026] On the other hand, this disclosure provides compounds of formula I (e.g., compounds A to F) or pharmaceutically acceptable salts thereof for the treatment of inflammatory bowel disease.

[0027] On the other hand, this disclosure provides the use of compounds of formula I (e.g., compounds A to F) or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating inflammatory bowel disease.

[0028] On the other hand, this disclosure provides the use of compounds of formula I (e.g., compounds A to F) or pharmaceutically acceptable salts thereof in the treatment of inflammatory bowel disease.

[0029] On the other hand, this disclosure provides a kit comprising a compound of formula I (e.g., compounds A-F) or a pharmaceutically acceptable salt thereof, and instructions for treating or preventing inflammatory bowel disease with the compound of formula I (e.g., compounds A-F) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula I (e.g., compounds A-F) or a pharmaceutically acceptable salt thereof is present in the kit in single-dose or multi-dose form.

[0030] On the other hand, this disclosure provides the use of the kit disclosed herein in the preparation of medicaments for the treatment or prevention of inflammatory bowel disease.

[0031] On the other hand, this disclosure provides a method for treating or preventing inflammatory bowel disease, which includes administering an effective amount of the kit of this disclosure to an individual in need.

[0032] In some embodiments, the compound of formula I (e.g., compounds A to F) or a pharmaceutically acceptable salt thereof may be in the form of a pharmaceutical composition.

[0033] On the other hand, this disclosure provides the use of the kit disclosed herein in the treatment or prevention of inflammatory bowel disease.

[0034] On the other hand, this disclosure provides a kit for the treatment or prevention of inflammatory bowel disease.

[0035] On the other hand, this disclosure provides pharmaceutical compositions for treating inflammatory bowel disease, comprising compounds of formula I (e.g., compounds A-F) or pharmaceutically acceptable salts thereof. In some embodiments of this disclosure, the pharmaceutical compositions further comprise pharmaceutically acceptable excipients.

[0036] On the other hand, this disclosure provides the use of the kit of this disclosure in the preparation of a medicament for the treatment or prevention of inflammatory bowel disease, the kit comprising a pharmaceutical composition of a compound of formula I (e.g., compounds A to F) or a pharmaceutically acceptable salt thereof.

[0037] On the other hand, this disclosure provides a method for treating inflammatory bowel disease in a subject, comprising administering to the subject a pharmaceutical composition of a compound of formula I (e.g., compounds A-F) or a pharmaceutically acceptable salt thereof. In some embodiments, the method for treating inflammatory bowel disease in a subject comprises administering to the subject an effective or therapeutically effective amount of a pharmaceutical composition of a compound of formula I (e.g., compounds A-F) or a pharmaceutically acceptable salt thereof.

[0038] On the other hand, this disclosure provides the use of pharmaceutical compositions of compounds of formula I (e.g., compounds A to F) or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating inflammatory bowel disease.

[0039] On the other hand, this disclosure provides the use of pharmaceutical compositions of compounds of formula I (e.g., compounds A to F) or pharmaceutically acceptable salts thereof in the treatment of inflammatory bowel disease.

[0040] In some embodiments of this disclosure, the pharmaceutical composition is packaged in a kit that also includes instructions for using a compound of formula (I) (e.g., compounds A-F) or a pharmaceutically acceptable salt thereof to treat inflammatory bowel disease. In some embodiments of this disclosure, the pharmaceutical composition also contains pharmaceutically acceptable excipients.

[0041] In another aspect, this disclosure provides a method for treating inflammatory bowel disease in a subject, comprising administering to the subject compound A, compound B, compound C, compound D, compound E, or compound F, or a pharmaceutically acceptable salt thereof:

[0042] In some embodiments, this disclosure relates to a method of treating a subject with inflammatory bowel disease, comprising administering to the subject an effective amount of compound A, compound B, compound C, compound D, compound E, or compound F, or a pharmaceutically acceptable salt thereof.

[0043] In another aspect, this disclosure provides said compound A, compound B, compound C, compound D, compound E or compound F, or a pharmaceutically acceptable salt thereof, for the treatment of inflammatory bowel disease.

[0044] In another aspect, this disclosure provides the use of said compound A, compound B, compound C, compound D, compound E or compound F, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating inflammatory bowel disease.

[0045] In another aspect, this disclosure provides the use of said compound A, compound B, compound C, compound D, compound E or compound F, or a pharmaceutically acceptable salt thereof, in the treatment of inflammatory bowel disease.

[0046] In another aspect, this disclosure provides a kit comprising compound A, compound B, compound C, compound D, compound E, or compound F, or a pharmaceutically acceptable salt thereof, and instructions for treating or preventing inflammatory bowel disease with compound A, compound B, compound C, compound D, compound E, or compound F, or a pharmaceutically acceptable salt thereof. In some embodiments, in the kit, compound A, compound B, compound C, compound D, compound E, or compound F, or a pharmaceutically acceptable salt thereof, is present in a single-dose or multiple-dose form.

[0047] In some embodiments, compound A, compound B, compound C, compound D, compound E, or compound F, or a pharmaceutically acceptable salt thereof, may be in the form of a pharmaceutical composition.

[0048] In another aspect, this disclosure provides pharmaceutical compositions for treating inflammatory bowel disease, comprising compound A, compound B, compound C, compound D, compound E, or compound F, or pharmaceutically acceptable salts thereof. In some embodiments of this disclosure, the pharmaceutical compositions further comprise pharmaceutically acceptable excipients.

[0049] In another aspect, this disclosure provides a method for treating inflammatory bowel disease in a subject, comprising administering to the subject a pharmaceutical composition of said compound A, compound B, compound C, compound D, compound E, or compound F, or a pharmaceutically acceptable salt thereof. In some embodiments, the method for treating inflammatory bowel disease in a subject comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition of said compound A, compound B, compound C, compound D, compound E, or compound F, or a pharmaceutically acceptable salt thereof.

[0050] In another aspect, this disclosure provides the use of pharmaceutical compositions of said compounds A, B, C, D, E, or F, or pharmaceutically acceptable salts thereof, in the preparation of medicaments for treating inflammatory bowel disease.

[0051] Furthermore, this disclosure provides the use of pharmaceutical compositions of compounds A, B, C, D, E, or F, or pharmaceutically acceptable salts thereof, in the treatment of inflammatory bowel disease. In some embodiments of this disclosure, the pharmaceutical compositions are packaged in a kit that further includes instructions for using compounds A, B, C, D, E, or F, or pharmaceutically acceptable salts thereof, to treat inflammatory bowel disease. In some embodiments of this disclosure, the pharmaceutical compositions also contain pharmaceutically acceptable excipients.

[0052] In some embodiments, compound A, compound B, compound C, compound D, compound E, or compound F, or a pharmaceutically acceptable salt thereof, is administered in a single dose or multiple doses.

[0053] Inflammatory bowel disease

[0054] In some embodiments, the inflammatory bowel disease is selected from ulcerative colitis (UC) or Crohn's disease (CD). In some embodiments, the subject of the inflammatory bowel disease is an adult.

[0055] In some implementations, the inflammatory bowel disease is selected from moderate to severe inflammatory bowel disease.

[0056] In some implementations, the inflammatory bowel disease is selected from moderate to severe inflammatory bowel disease.

[0057] In some implementations, the inflammatory bowel disease is selected from ulcerative colitis (UC).

[0058] In some implementations, the inflammatory bowel disease is selected from moderate to severe ulcerative colitis (UC).

[0059] In some implementations, the inflammatory bowel disease is selected from Crohn's disease (CD).

[0060] In some implementations, the inflammatory bowel disease is selected from moderate to severe Crohn's disease (CD).

[0061] In some implementations, the inflammatory bowel disease is selected from moderate to severe active ulcerative colitis or Crohn's disease.

[0062] In some implementations, the inflammatory bowel disease is selected from moderate to severe active ulcerative colitis or Crohn's disease in adults.

[0063] In some implementations, the inflammatory bowel disease is selected from those diagnosed as ulcerative colitis or Crohn's disease by histopathological or endoscopic examination.

[0064] In some embodiments, the inflammatory bowel disease may or may not be accompanied by complications. In some embodiments, the inflammatory bowel disease may or may not be accompanied by complications selected from intestinal obstruction, abdominal abscess, intestinal perforation, intestinal fistula, or massive hemorrhage.

[0065] In some embodiments, the inflammatory bowel disease is not accompanied by complications. In other embodiments, the inflammatory bowel disease is not accompanied by complications selected from intestinal obstruction, abdominal abscess, intestinal perforation, intestinal fistula, or massive hemorrhage.

[0066] In some embodiments, the subject of the inflammatory bowel disease may or may not exhibit complications. These complications may be selected from intestinal obstruction, abdominal abscess, intestinal perforation, intestinal fistula, or massive hemorrhage.

[0067] In some implementations, the subjects with the inflammatory bowel disease do not exhibit complications. In some implementations, the subjects with the inflammatory bowel disease do not exhibit complications selected from intestinal obstruction, abdominal abscess, intestinal perforation, intestinal fistula, or massive hemorrhage.

[0068] In some implementations, the inflammatory bowel disease is selected from those diagnosed as ulcerative colitis or Crohn's disease for ≥3 months by histopathological or endoscopic evaluation.

[0069] In some embodiments, the inflammatory bowel disease is an inflammatory bowel disease for which the patient has previously received at least one drug treatment for ulcerative colitis or Crohn's disease (e.g., treatment failure or intolerance). In some embodiments, the "drug for ulcerative colitis or Crohn's disease" is selected from one or more of conventional treatments, biologics (e.g., anti-TNF-α agents), JAK1 inhibitors, SIPR modulators, or NLRP3 inhibitors.

[0070] In some implementations, the subject of the inflammatory bowel disease is a subject who has failed or is intolerant to at least one drug treatment for ulcerative colitis or Crohn's disease.

[0071] In some implementations, the subjects with inflammatory bowel disease are selected from those who have failed previous treatment regimens.

[0072] In some embodiments, the subjects with inflammatory bowel disease are selected from those who have failed or are contraindicated to previous treatment regimens. In some embodiments, the subjects with inflammatory bowel disease are selected from those who have poor response to, are intolerant of, or are contraindicated to previous treatment regimens.

[0073] In some implementations, the subjects with inflammatory bowel disease are selected from subjects who have received one or more of the following treatments: conventional treatment, biologic treatment (e.g., anti-TNF-α agents), JAK1 inhibitor treatment, SIPR modulator treatment, or NLRP3 inhibitor treatment.

[0074] In some implementations, the conventional treatment includes, but is not limited to, aminosalicylic acid preparations (sulfasalazine, mesalazine, etc.), hormones (e.g. glucocorticoids, such as methylprednisolone, prednisone, etc.), and immunosuppressants (azathioprine, methotrexate, etc.).

[0075] In some implementations, the subjects with inflammatory bowel disease are selected from those who have received conventional treatment (e.g., treatment failure).

[0076] In some implementations, the subjects with inflammatory bowel disease are selected from those who have received biologic therapy (e.g., treatment failure).

[0077] In some implementations, the subjects with inflammatory bowel disease are selected from those who have received treatment with anti-TNF-α agents (e.g., treatment failure).

[0078] In some implementations, the subjects with inflammatory bowel disease are selected from those who have received JAK1 inhibitor treatment (e.g., treatment failure).

[0079] In some implementations, the subjects with inflammatory bowel disease are selected from those who have received SIPR modulator treatment (e.g., treatment failure).

[0080] In some implementations, the subjects with inflammatory bowel disease are selected from those who have received NLRP3 inhibitor treatment (e.g., treatment failure).

[0081] In some implementations, the subjects with inflammatory bowel disease are selected from those who have received treatment with anti-TNF-α agents (e.g., treatment failure).

[0082] In some implementations, the subjects with inflammatory bowel disease are selected from those who have failed or are contraindicated to conventional treatment or anti-TNF-α therapy.

[0083] In some implementations, the subjects with inflammatory bowel disease are selected from those who have poor response to, are intolerant of, or have contraindications to conventional treatment or anti-TNF-α agents.

[0084] In some implementations, the subjects with inflammatory bowel disease are selected from those who have failed or are contraindicated to treatment with one or more anti-TNF-α agents.

[0085] In some implementations, the subjects with inflammatory bowel disease are selected from those who have a poor response to, are intolerant of, or have contraindications to one or more anti-TNF-α agents.

[0086] In some implementations, the subjects with ulcerative colitis are selected from subjects who have received one or more of the following treatments: conventional treatment, biologic treatment, JAK1 inhibitor treatment, SIPR modulator treatment, and NLRP3 inhibitor treatment.

[0087] In some implementations, the subjects with ulcerative colitis are selected from those who have received conventional treatment (e.g., treatment failure).

[0088] In some implementations, the subjects with ulcerative colitis are selected from those who have received biologic therapy (e.g., treatment failure).

[0089] In some implementations, the subjects with ulcerative colitis are selected from those who have received SIPR modulator treatment (e.g., treatment failure).

[0090] In some implementations, the subjects with ulcerative colitis are selected from those who have received NLRP3 inhibitor treatment (e.g., treatment failure).

[0091] In some implementations, the subjects with ulcerative colitis are selected from those who have received JAK1 inhibitor treatment (e.g., treatment failure).

[0092] In some implementations, the subjects with ulcerative colitis are selected from subjects who have received treatment with anti-TNF-α agents (e.g., treatment failure).

[0093] In some implementations, the subjects with ulcerative colitis are selected from those who have failed or are contraindicated to conventional treatment or anti-TNF-α therapy.

[0094] In some implementations, the subjects with ulcerative colitis are selected from those who have poor response to, are intolerant of, or are contraindicated to conventional treatment or anti-TNF-α agents.

[0095] In some embodiments, the subjects with ulcerative colitis are selected from those who have failed or are contraindicated to treatment with one or more anti-TNF-α agents.

[0096] In some embodiments, the subjects with ulcerative colitis are selected from those who have a poor response to, are intolerant of, or are contraindicated to one or more anti-TNF-α agents.

[0097] In some implementations, the subjects with inflammatory bowel disease are selected from (adult) subjects with moderate to severe active ulcerative colitis / Crohn's disease who have failed or are contraindicated for conventional treatment or anti-TNF-α agents.

[0098] In some implementations, the subjects for the inflammatory bowel disease are selected from (adult) subjects with moderate to severe active ulcerative colitis / Crohn's disease who have poor response to, are intolerant of, or are contraindicated to conventional treatment or anti-TNF-α agents.

[0099] In some embodiments, the subjects with inflammatory bowel disease are selected from (adult) subjects with moderate to severe active ulcerative colitis / Crohn's disease who have failed or are contraindicated in treatment with one or more anti-TNF-α agents.

[0100] In some embodiments, the subjects with inflammatory bowel disease are selected from (adult) subjects with moderate to severe active ulcerative colitis / Crohn's disease who have poor response to, are intolerant of, or have contraindications to one or more anti-TNF-α agents.

[0101] In some implementations, the “treatment failure” includes, but is not limited to, poor response or intolerance.

[0102] In some specific embodiments, the "medication for ulcerative colitis or Crohn's disease" is selected from conventional treatments or biologics. In some specific embodiments, the "medication for ulcerative colitis or Crohn's disease" is selected from aminosalicylic acid, hormones, immunosuppressants, or biologics.

[0103] In some implementations, the "medication for ulcerative colitis or Crohn's disease" is an oral medication.

[0104] In some implementations, the JAK1 inhibitor is selected from utpatinib or filogrinib, etc.

[0105] In some embodiments, the biological agent is selected from anti-IL-12 monoclonal antibodies, anti-IL-23 monoclonal antibodies, anti-TNF-α agents, or anti-α4β7 integrin agents.

[0106] In some embodiments, the biological agent is selected from anti-IL-12 monoclonal antibodies or anti-IL-23 monoclonal antibodies.

[0107] In some embodiments, the biological agent is selected from anti-TNF-α agents and anti-α4β7 integrin agents.

[0108] In some implementations, the anti-IL-12 monoclonal antibody is selected from ustekinumab.

[0109] In some implementations, the anti-IL-23 monoclonal antibody is selected from glucocorticoid, levosciutto, or migelizumab.

[0110] In some embodiments, the anti-TNF-α agent is selected from infliximab or adalimumab, etc.

[0111] In some embodiments, the anti-α4β7 integrin agent is selected from vedelizumab.

[0112] In some embodiments, the biological agent is selected from ustekinumab, gusejinumab, levosinizumab, migelizumab, infliximab, adalimumab, or vedelizumab.

[0113] In some embodiments, the "aminosalicylic acid" is selected from mesalazine (e.g., mesalazine ≥ 2.4 g / d or equivalent dose).

[0114] In some embodiments, the hormone is selected from oral hormones (e.g., oral systemic hormones). In some embodiments, the hormone is selected from prednisone (e.g., prednisone ≤20 mg / day or equivalent dose).

[0115] In some embodiments, the immunosuppressant is selected from oral immunosuppressants. In some embodiments, the immunosuppressant is selected from azathioprine and methotrexate.

[0116] In some implementations, intolerance refers to the discontinuation of drug use as determined by an adverse reaction.

[0117] In some embodiments, the subject may be a subject currently receiving treatment with aminosalicylic acid or a hormone. In some embodiments, the subject may be selected from a subject who has been receiving treatment with aminosalicylic acid and has been stably treated for at least 3 weeks (e.g., 3, 4, or 5 weeks or more), preferably an oral aminosalicylic acid (e.g., mesalazine ≥ 2.4 g / day or equivalent dose); or, the subject may be selected from a subject who has been receiving treatment with a hormone and has been stably treated for at least 2 weeks (e.g., 2, 3, 4, or 5 weeks or more), preferably an oral systemic hormone (e.g., prednisone ≤ 20 mg / day or equivalent dose). In some embodiments, when the subject is selected from a subject currently receiving treatment with aminosalicylic acid or a hormone, the subject may maintain a stable dose of the aminosalicylic acid or hormone during treatment with the compound of formula I described herein (e.g., compounds A-F) or a pharmaceutically acceptable salt thereof (i.e., the subject may maintain a stable dose of aminosalicylic acid or hormone as background treatment). In some embodiments, the subject is using the following medications for treating UC or CD, and prior to the first use of the compound of this application or its pharmaceutically acceptable salt, is taking aminosalicylic acid (e.g., mesalazine ≥2.4 g / day or equivalent dose) orally for at least 3 weeks, or prior to the first use of the compound of this application or its pharmaceutically acceptable salt, is taking systemic steroids (e.g., prednisone ≤20 mg / day or equivalent dose) orally for at least 2 weeks, and maintaining a stable dose during the trial.

[0118] In some implementations, the subjects are selected from those who are being treated with aminosalicylic acid or hormones.

[0119] In some implementations, the subjects showed improvement in their Inflammatory Bowel Disease Quality of Life Questionnaire (IBDQ) scores relative to baseline at the end of week 8 or longer (e.g., 12 to 52 weeks) of treatment.

[0120] In some embodiments, the subject achieves improvement in one or more of the following indicators after treatment with the compound of Formula I (e.g., compounds A-F) or its pharmaceutically acceptable salt: modified Mayo score; Mayo endoscopic score; Best CDAI score (Crohn's disease activity index score); SES-CD score (Simplified Crohn's disease endoscopic score); IBDQ; and inflammatory markers such as C-reactive protein (CRP), fecal calprotectin (FC), and erythrocyte sedimentation rate (ESR).

[0121] In some implementations, the moderate to severe active ulcerative colitis is defined as follows: a modified Mayo score (MMS) total score ≥6 and ≤12, of which the Mayo endoscopic score is ≥2.

[0122] In some embodiments, a reduction in the modified Mayo score was observed in the ulcerative colitis subjects. Specifically, a reduction was observed after 4 weeks of treatment with a compound of formula I (e.g., compounds A-F) or a pharmaceutically acceptable saline thereof. Specifically, a reduction was observed after 8 weeks of treatment with a compound of formula I (e.g., compounds A-F) or a pharmaceutically acceptable saline thereof. Specifically, a reduction was observed after 12 weeks of treatment. Specifically, a reduction was observed after 16 weeks of treatment. Specifically, a reduction was observed after 20 weeks of treatment. Specifically, a reduction was observed after 24 weeks of treatment.

[0123] In some implementations, the ulcerative colitis subjects were observed to have a modified Mayo score reduction of at least 2 points. In particular, a reduction of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 points could be observed.

[0124] In some embodiments, the ulcerative colitis may be observed as relief of rectal bleeding and normal defecation frequency, or a modified Mayo score <2 with no individual sub-score >1. In some embodiments, the ulcerative colitis may be observed as normalization of inflammatory markers. Specifically, normalization of inflammatory markers includes normal CRP or a decrease in fecal calprotectin (FC) to an acceptable range (100–250 μg / g). Specifically, inflammatory markers include CRP, FC, or ESR.

[0125] In some implementations, improvements in Mayo endoscopic scores were observed in the ulcerative colitis subjects, for example, Mayo endoscopic scores improved to <2 points.

[0126] In some implementations, the moderate to severe active Crohn's disease is defined as follows: a Best CDAI score of ≥220 and ≤450, with an average of ≥4 bowel movements per day and / or an average abdominal pain score of ≥2 per day, and a SES-CD score >6 (or an SE S-CD score ≥4 for subjects with isolated ileal disease).

[0127] In some embodiments, the Crohn's disease subject exhibits a Best CDAI score of at least 220, at least 250, at least 300, at least 350, or at least 400 before treatment. In one particular embodiment, the Crohn's disease subject exhibits a Best CDAI score of at least 250, at least 300, or at least 350 before treatment. In a more particular embodiment, the Crohn's disease subject exhibits a Best CDAI score of at least 250, at least 260, at least 270, at least 280, at least 290, or at least 300 before treatment.

[0128] In some embodiments, the Crohn's disease subjects were observed to have a Best CDAI score that decreased after 4 weeks of treatment with compounds of formula I described herein (e.g., compounds A-F) or their pharmaceutically acceptable saline. Specifically, a decrease was observed after 8 weeks of treatment. Specifically, a decrease was observed after 12 weeks of treatment. Specifically, a decrease was observed after 16 weeks of treatment. Specifically, a decrease was observed after 20 weeks of treatment. Specifically, a decrease was observed after 24 weeks of treatment.

[0129] In some embodiments, the Crohn's disease subject, after administration of the compound of Formula I or a pharmaceutically acceptable salt thereof, is observed to have a Best CDAI score reduction of at least 70, at least 80, at least 90, at least 100, at least 110, at least 120, at least 130, at least 140, at least 150, at least 200, or at least 250 after 8 or more weeks of treatment. In a more specific aspect, the subject achieves clinical remission (Best CDAI score <150) after 2, 4, 6, 8, or 12 weeks. In another specific aspect, the subject achieves clinical remission (Best CDAI score <150) after 8 weeks.

[0130] In some implementations, a reduction in SES-CD scores to at least 0 to 6 was observed in the Crohn's disease subjects.

[0131] In some embodiments, the Formula I compound described in this application (e.g., compounds A to F) or a pharmaceutically acceptable salt thereof can effectively alleviate the symptoms of Crohn's disease in a subject, induce a clinical response, induce or maintain clinical remission, inhibit disease progression, or inhibit disease complications in a subject.

[0132] In some embodiments, the Formula I compounds described herein (e.g., compounds A to F) or their pharmaceutically acceptable salts can effectively reduce the subject's Crohn's Disease Activity Index (Best CDAI score), reduce the subject's CRP level, reduce the subject's fecal calpain level, or reduce the number of open drainage fistulas in the subject.

[0133] In some implementations, following the treatment described herein, improvements in symptoms such as abdominal pain, diarrhea, and abdominal mass can be observed in Crohn's disease patients. In some implementations, following the treatment described herein, a Best CDAI score <150 is considered a remission period for Crohn's disease subjects.

[0134] Dosing regimen

[0135] In some embodiments, the daily dose of the compound of formula I (e.g., compounds A to F) or a pharmaceutically acceptable salt thereof is selected from 2-32 mg or 12-48 mg; or the daily dose is selected from 4-28 mg; or the daily dose is selected from 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 32 mg, 48 mg or any range formed by the above values; or the daily dose is selected from 6 mg, 12 mg, or 18 mg; or the daily dose is selected from 12 mg, 24 mg, 32 mg, or 48 mg; or the daily dose is selected from 32 mg; or the daily dose is selected from 48 mg.

[0136] In some embodiments, the daily dose of the compound of formula I (e.g., compounds A to F) or a pharmaceutically acceptable salt thereof is selected from 12 mg, preferably 24 mg, and more preferably 32 mg.

[0137] In some embodiments, the administration (or application) of the compound of formula I (e.g., compounds A to F) or a pharmaceutically acceptable salt thereof in a single or multiple dose is selected from 2-32 mg or 12-48 mg; or the single or multiple dose is selected from 4-28 mg; or the single or multiple dose is selected from 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 32 mg, 48 mg, or any range formed by the above values; or the single or multiple dose is selected from 6 mg, 12 mg, or 18 mg; or the single or multiple dose is selected from 12 mg, 24 mg, 32 mg, or 48 mg; or the single or multiple dose is selected from 32 mg; or the single or multiple dose is selected from 48 mg.

[0138] The specific dose for any particular subject will depend on a variety of factors, including age, weight, general health condition, sex, diet, timing of administration, excretion rate, combination of drugs, the judgment of the treating physician, and the severity of the specific disease being treated.

[0139] In some embodiments, the compound of formula I (e.g., compounds A to F) or a pharmaceutically acceptable salt thereof is administered to the subject in a single daily dose or multiple daily doses.

[0140] In some implementations, a compound of formula I (e.g., compounds A to F) or a pharmaceutically acceptable salt thereof is administered to the subject daily for, for example, for 1, 2, 3, 4, 5, 6, 7, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks or longer, or any range of the above values.

[0141] In some implementations, a compound of formula I (e.g., compounds A to F) or a pharmaceutically acceptable salt thereof is administered to the subject daily for 2 to 52 weeks or longer; or for 8, 12, 16, 24, 48, or 52 weeks, or any range of the above values; or for 8 weeks.

[0142] In some embodiments, the compound of formula I (e.g., compounds A to F) or a pharmaceutically acceptable salt thereof is administered daily for approximately 1 to 7 days, approximately 1 to 14 days, approximately 1 to 28 days, approximately 1 to 56 days, approximately 1 to 3 weeks, approximately 3 to 6 weeks, approximately 6 to 9 weeks, approximately 12 weeks, or any range of the above values; or for approximately 8 weeks, 12 weeks, approximately 12 to 15 weeks, or approximately 15 to 18 weeks, or approximately 15 to 52 weeks, or any range of the above values; or for approximately 8 weeks.

[0143] In some implementations, the subject is given a compound of formula I (e.g., compounds A to F) or a pharmaceutically acceptable salt thereof orally every day.

[0144] In some embodiments, a compound of form I (e.g., compounds A-F) or a pharmaceutically acceptable salt thereof is taken orally daily at the same time (±2 hours) on an empty stomach. In some embodiments, the compound is administered once daily. In some embodiments, the compound is administered continuously for 12-52 weeks or longer. In some embodiments, the compound is administered continuously for 8, 12, 16, 24, 52 weeks or longer. In some embodiments, the compound is administered continuously for 8 weeks or longer (e.g., 12 weeks). In some embodiments, a compound of form I (e.g., compounds A-F) or a pharmaceutically acceptable salt thereof (e.g., compound C) is taken orally daily at the same time (±2 hours) on an empty stomach, at a dose of 32 mg or 48 mg.

[0145] Compound of Formula I or its pharmaceutically acceptable salt

[0146] The compounds of Formula I disclosed herein (e.g., compounds A to F) may be administered in their free base form, or in the form of pharmaceutically acceptable salts, hydrates, and prodrugs, wherein the prodrugs may be converted in vivo into the free base form of the compounds of Formula I.

[0147] The compounds of formula I disclosed herein (e.g., compounds A to F) or their pharmaceutically acceptable salts may also be administered in the form of pharmaceutical compositions. These pharmaceutical compositions may also contain pharmaceutically acceptable excipients.

[0148] In some embodiments, the daily (or dose) of the Formula I compound (e.g., compounds A-F) or its pharmaceutically acceptable salt, or its pharmaceutical composition thereof, disclosed herein is selected from 2-32 mg or 4-28 mg; or from 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 32 mg, or any range of the above values. Alternatively, the daily (or dose) of the Formula I compound (e.g., compounds A-F) or its pharmaceutically acceptable salt, or its pharmaceutical composition thereof, is selected from 6 mg, 12 mg, or 18 mg. Alternatively, the daily (or dose) of the Formula I compound (e.g., compounds A-F) or its pharmaceutically acceptable salt, or its pharmaceutical composition thereof, disclosed herein is selected from 12 mg, 24 mg, or 32 mg of the Formula I compound (e.g., compounds A-F) or its pharmaceutically acceptable salt, or its pharmaceutical composition thereof.

[0149] In some embodiments, the pharmaceutical composition of the Formula I compound (e.g., compounds A to F) or its pharmaceutically acceptable salts is selected from solid pharmaceutical compositions, including but not limited to tablets or capsules.

[0150] In some embodiments, the pharmaceutical composition containing the Formula I compound (e.g., compounds A-F) or its pharmaceutically acceptable salt is a single or multiple dose of 2-32 mg or 4-28 mg. Specifically, the pharmaceutical composition is selected from pharmaceutical compositions with single or multiple doses of 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 32 mg, or any value within the range formed by any of the above values. In some embodiments, the single or multiple doses of the pharmaceutical composition containing the Formula I compound (e.g., compounds A-F) or its pharmaceutically acceptable salt are selected from 6 mg, 12 mg, or 18 mg. In some embodiments, the single or multiple doses of the pharmaceutical composition containing the Formula I compound (e.g., compounds A-F) or its pharmaceutically acceptable salt are selected from 12 mg, 24 mg, or 32 mg.

[0151] In some embodiments, the pharmaceutical composition containing a compound of formula I (e.g., compounds A-F) or a pharmaceutically acceptable salt thereof is a multi-dose pharmaceutical composition, wherein the multi-dose composition may consist of multiple single-dose pharmaceutical compositions containing compounds of formula I (e.g., compounds A-F) or pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition containing a compound of formula I (e.g., compounds A-F) or a pharmaceutically acceptable salt thereof is a multi-dose pharmaceutical composition, wherein the multi-dose composition may consist of a single dose of 2 mg or 8 mg of a pharmaceutical composition containing a compound of formula I (e.g., compounds A-F) or pharmaceutically acceptable salt thereof.

[0152] In some embodiments, the pharmaceutical composition containing a compound of formula I (e.g., compounds A to F) or a pharmaceutically acceptable salt thereof is specified as containing 2 mg or 8 mg of a compound of formula I (e.g., compounds A to F) or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from compound B or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from compound C or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from compound D or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from compound F or a pharmaceutically acceptable salt thereof.

[0154] In one embodiment, the pharmaceutical combination of this disclosure can be formulated into a pharmaceutical composition suitable for single or multiple administration. In one embodiment, the pharmaceutical combination of this disclosure can be a single-dose or multi-dose pharmaceutical composition.

[0155] Definitions and Explanations

[0156] Unless otherwise stated, the following terms as used in this disclosure shall have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art.

[0157] The word “comprise” or “comprise” and its English variants such as comprises or comprising, and their equivalents, should be understood in an open, non-exclusive sense, meaning “including but not limited to”, implying that in addition to the listed elements, components, and steps, other unspecified elements, components, and steps may also be included.

[0158] The term "substituted" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on aromatic groups.

[0159] The terms “optional” or “optionally” mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, the ethyl group “optionally” being halogenated means that the ethyl group can be unsubstituted (-CH2CH3), monosubstituted (e.g., -CH2CH2F), polysubstituted (e.g., -CHFCH2F, -CH2CHF2, etc.), or fully substituted (-CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0160] C in this article m-n This means that the part has an integer number of carbon atoms within a given range. For example, "C 1-6 "" means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms; for example, "C 1-3 "" means that the group can have 1 carbon atom, 2 carbon atoms or 3 carbon atoms.

[0161] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0162] The term "alkyl" refers to a compound with the general formula C1. n H 2n+1 The alkyl group. This alkyl group can be straight-chain or branched. For example, the term "C 1-6 "Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Another example is the term "C..." 1-4 "Alkyl" refers to an alkyl group containing 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.). Another example is the term "C1-3 alkyl," which refers to an alkyl group containing 1 to 3 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, etc.).

[0163] The term "cycloalkyl" refers to a fully saturated carbon ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered ring, preferably a 4- to 6-membered ring or a 3- to 6-membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0164] The term "bond" can be a single bond or a double bond.

[0165] Unless otherwise stated, the dosages and ranges of compounds of formula I (e.g., compounds A to F) or their pharmaceutically acceptable salts provided in this disclosure are calculated based on the molecular weight of the free base of the compounds of formula I (e.g., compounds A to F).

[0166] The terms “application,” “giving,” or “administering” mean the introduction of a therapeutic agent or a composition containing a therapeutic agent into a host body using any of a variety of methods and delivery systems known to those skilled in the art. The terms “application,” “giving,” or “administering” are used interchangeably herein.

[0167] The term "treatment" generally refers to achieving the desired pharmacological and / or physiological effect. This effect can be therapeutic, depending on whether it partially or completely stabilizes or cures the disease and / or causes side effects due to the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., preventing its progression; or (b) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress.

[0168] The terms “effective amount” or “therapeutic effective amount” mean (i) the amount of the disclosed compound used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the disclosed compound constituting a “therapeutic effective amount” varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the content of this disclosure.

[0169] The terms “subject,” “patient,” or “subject” are used interchangeably herein and refer to an animal, preferably a mammal, preferably a primate, which has become the subject of treatment, observation, or experimentation, including human and non-human primates (such as apes, monkeys, orangutans, and chimpanzees, such as cynomolgus monkeys, spider monkeys, and macaques, such as rhesus monkeys), with humans being the most preferred. In some embodiments, the subject has experienced and / or exhibited at least one symptom of a disease or condition to be treated and / or prevented.

[0170] As used in this disclosure, the compound of formula I (e.g., compounds A to F) or pharmaceutically acceptable salts thereof may be administered by any applicable route and method, such as by oral or parenteral (e.g., intravenous) administration.

[0171] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or pharmaceutical combinations thereof, or salts thereof, with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the disclosed compounds or pharmaceutical combinations thereof to a subject.

[0172] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0173] The pharmaceutical compositions disclosed herein can be prepared by combining the compounds of the disclosed invention with suitable pharmaceutically acceptable excipients, for example, by formulating them into solid dosage forms such as tablets, pills, capsules, etc.

[0174] The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0175] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0176] Solid oral pharmaceutical compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet, capsule, or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0177] The terms "pharmaceutically acceptable salt" or "medicinal salt" refer to salts of compounds of this disclosure that fall within the definition of "pharmaceutically acceptable." In this document, the terms "pharmaceutically acceptable salt" or "medicinal salt" are used interchangeably.

[0178] Unless otherwise specified, singular terms encompass plural terms, and plural terms encompass singular terms. Unless otherwise specified, the words "a" or "an" mean "at least one" or "at least one". Unless otherwise specified, the use of "or" means "and / or".

[0179] In this document, unless otherwise stated, the terms “comprising, including, and containing” or equivalents are open-ended expressions, meaning that they may cover other unspecified elements, components, and steps in addition to those listed.

[0180] The term "single dose" refers to the smallest packaged unit containing a certain amount of medicine. For example, if a box of medicine contains seven capsules, then each capsule is a single dose; or each vial of injection is a single dose; or each tablet in a box of medicine is a single dose.

[0181] The term "multiple doses" consists of multiple single doses.

[0182] Unless otherwise stated, all dosages described in this disclosure are calculated based on compounds of Formula I.

[0183] When referring to dosing regimens, terms such as "day" or "daily" refer to the time within a calendar day, beginning at midnight and ending at the next midnight.

[0184] The term "daily dose" or "daily dose" refers to the dose administered to a patient each day.

[0185] In this document, unless the context clearly indicates otherwise, singular terms encompass plural referents, and vice versa. Similarly, unless the context clearly indicates otherwise, the word "or" is intended to include "and," and vice versa.

[0186] Unless otherwise stated, in this document, parameter values ​​representing the amount of an ingredient, its physicochemical properties, or reaction conditions, etc., should be understood to be modified by the term "about" in all cases. When the present disclosure is described using the term "about," the term "about" indicates an existing error value, such as a variation within ±5%, for example ±1%, or ±0.1% of a particular value.

[0187] For purposes of description and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their publications predate the filing date of this disclosure. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publications are part of the general knowledge in the art.

[0188] Technical effect

[0189] For compound C, a Phase I clinical trial has been initiated in healthy adult subjects with a dose escalation design of 2 mg, 6 mg, 12 mg, 18 mg, 24 mg, and 32 mg (Groups 1, 2, 3, 4, 5, and 6). Group 1 enrolled subjects (all orally administered compound C capsules); Groups 2, 3, and 4 will complete single-dose and multiple-dose dose escalation studies, with each group randomly assigned to receive either compound C capsules or a placebo; Groups 5 and 6 each randomly assigned either compound C capsules or a placebo for a single-dose study, with subsequent groups adding more subjects and randomly assigned either compound C capsules or a placebo for multiple-dose studies. This study also evaluated the effects of fasting and postprandial administration on the pharmacokinetic parameters of compound C, employing a randomized, single-dose, two-period, crossover design, with participants divided into two groups, A and B, receiving 12 mg of compound C capsules orally.

[0190] Results showed that, with a single dose ranging from 2 mg to 32 mg, the level of exposure in vivo increased proportionally with increasing dose. No significant accumulation was observed after 7 days of continuous administration at doses ranging from 6 mg to 18 mg. Overall safety was good, with no SAEs or grade 3 or higher TEAEs occurring. Most AEs returned to normal during the study period, indicating manageable safety. In the multiple-dose studies of the 6 mg and 32 mg groups, one subject discontinued the drug due to an upper respiratory tract infection. Common adverse events (≥5%) included hypertriglyceridemia, elevated ALT, hypercholesterolemia, hyponatremia, and folliculitis. Other relatively common adverse events (≥3%) included elevated low-density lipoprotein, hyperuricemia, T-wave changes on electrocardiogram, and oral ulcers.

[0191] The compound of Formula I disclosed herein, or a pharmaceutically acceptable salt thereof, exhibits good efficacy, safety, pharmacokinetic properties, and pharmacodynamic properties in the treatment of inflammatory bowel diseases such as moderate to severe active ulcerative colitis or Crohn's disease. It shows particularly better efficacy in the treatment of ulcerative colitis.

[0192] Safety: All adverse events will be graded according to NCI-CTCAE version 5.0, and the incidence, correlation between adverse events and the investigational drug, and severity will be statistically described for each subject. Descriptive statistics will be performed on changes in laboratory tests, vital signs, 12-lead electrocardiograms, and other data relative to baseline. Furthermore, if applicable, changes in clinical significance after baseline will be analyzed using pre- and post-treatment cross-tabulations for applicable safety indicators. According to the methods disclosed herein, the incidence and severity of all adverse events (AEs), serious adverse events (SAEs), and treatment-related adverse events (TEAEs) are low. Moreover, the overall safety profile of the methods disclosed herein is good, with adverse events primarily related to laboratory tests, most of which recovered to normal, and no serious adverse events or grade 3 or higher adverse events occurred.

[0193] Pharmacokinetics: AUC was calculated using a non-compartmental analysis (NCA) model based on the actual sampling time. 0-24 T max,ss C min,ss C max,ss C av，ss AUC 0-t,ss AUC 0-∞,ss CL t,ss R ac Based on PKPS, the analysis results of the main pharmacokinetic parameters were summarized and displayed according to the dose group, using sample size, arithmetic mean, standard deviation, coefficient of variation, median, minimum, maximum, geometric mean, and geometric coefficient of variation.

[0194] Pharmacodynamics: Based on PDS, the mean values ​​and changes from baseline of IL-17A, IL-19, β-defensin, etc. at different detection time points in each group were described using mean, standard deviation, median, quartiles, minimum and maximum values. Analysis of variance or nonparametric tests were used to compare the changes from baseline of IL-17A, IL-19, β-defensin, etc. at different detection time points in each group with the placebo group.

[0195] Validity analysis: For the categorical indicators, the calculated rate and 95% CI were used. The 95% CI was calculated based on the exact binomial method of the F-distribution. Descriptive statistics were performed on the change in IBDQ scores relative to baseline at the end of week 8, listing the number of cases, mean, standard deviation, median, minimum, and maximum.

[0196] The compounds of this application have one or more of the following effects in the DSS-induced C57BL / 6UC model: improving the H-score, DAI score, pathological score, spleen index, and colon length of epithelial tissue MUC2, and have a therapeutic effect on ulcerative colitis.

[0197] The compounds of this application have one or more of the following effects in the TNBS-induced C57BL / 6CD model or the SAMP1 / Yit intestinal inflammation mouse model: inhibiting the release of pro-inflammatory mediators tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and IL-1β; improving colitis symptoms in mice (decreased body weight, increased disease activity index, and increased inflammation score); inhibiting intestinal epithelial cell inflammation; and protecting against intestinal barrier damage, thereby achieving the therapeutic effect on Crohn's disease.

[0198] In some implementation schemes, the TNBS-induced C57BL / 6CD model and experiment can refer to the experimental method disclosed in Li Jing et al., Chin J Cell Mol Immunol 2024, 40(3), which describes how safflower extract inhibits the TLR4 / MyD88 pathway to reduce intestinal epithelial inflammation and improve Crohn's disease-like colitis in mice.

[0199] In some implementation schemes, the DSS-induced C57BL / 6UC model and experiments can refer to the experimental methods disclosed in the comparison of two methods for inducing animal models of ulcerative colitis, Zheng Xiaoxia et al., Chinese Journal of Veterinary Medicine, 2024, 60(8):32-37.

[0200] Terminology Explanation

[0201] The Mayo Score is a clinical scoring method for determining the severity of inflammatory bowel disease (IBD) such as Crohn's disease and ulcerative colitis. It consists of four categories (bleeding, bowel frequency, physician assessment, and endoscopic findings), each graded from 0 to 3. The scores of the four categories are then summed to obtain a total score from 0 to 12.

[0202] The modified Mayo Criterion (MCC) score is a tool for assessing the severity of ulcerative colitis. The weighted total score ranges from 0 to 12 points. It is the most commonly used scoring system in clinical research and is a recommended endpoint for clinical trials of ulcerative colitis in many countries. Typically, a MCC score of 3–5 indicates mild activity, 6–10 indicates moderate activity, and 11–12 indicates severe activity.

[0203] Treatment goals for UC: Clinical remission is defined as relief of rectal bleeding and normal bowel frequency or a modified Mayo score <2 with no individual sub-score >1.

[0204] Normalization of inflammatory markers includes normal CRP or a decrease in FC to an acceptable range (100–250 μg / g).

[0205] The Mayo Cognitive Score (MCS) has a clear correlation with the activity level of ulcerative colitis and can be used for monitoring treatment efficacy and assessing mid- to long-term prognosis. It is the most widely used scoring system in clinical practice. Typically, 1 indicates mild activity; 2 indicates moderate activity; and 3 indicates severe activity. A Mayo COS score of 0 indicates mucosal healing.

[0206] Best CDAI (Crohn's Disease Activity Index) Score: Crohn's disease activity is mainly divided into clinical disease activity and endoscopic disease activity. Currently, there is no gold standard for evaluating disease activity. The scoring system widely used in clinical practice and research is Best CDAI (Crohn's disease activity index). It calculates scores based on eight variables, including abdominal pain, diarrhea, and abdominal mass, over a one-week observation period. These scores are multiplied by prescribed weights, and the sum of the eight scores is the total score. A Best CDAI score <150 indicates remission, ≥150 indicates active disease (150–220 indicates mild, 221–450 indicates moderate, and >450 indicates severe).

[0207] The Simplified Endoscopic Score (SES-CD) for Crohn's Disease: The severity of endoscopic lesions is an important reference indicator for assessing disease activity. Endoscopic lesion severity can be assessed by the depth, size, extent, and accompanying stenosis of the ulcer. A more precise assessment uses a scoring system. The SES-CD is commonly used in research. Currently, a total score of 0-2 indicates remission, 3-6 indicates mild activity, 7-15 indicates moderate activity, and ≥16 indicates severe activity.

[0208] The IBDQ (Inflammatory Bowel Disease Questionnaire) is a widely used indicator for assessing the quality of life of patients with inflammatory bowel disease. It contains 32 questions covering four dimensions: intestinal symptoms, systemic symptoms, emotional function, and systemic function. Each question is answered on a 7-point scale, with a total score ranging from 32 to 224 points. Higher scores indicate better health.

[0209] Inflammatory markers (CRP, FC, ESR): These are superior to ESR and CRP, which are currently commonly used in clinical practice, in assessing the activity of inflammatory bowel disease (IBD). They are better indicators of intestinal mucosal inflammation, but are not specific diagnostic indicators. They are also important indicators for guiding treatment and monitoring efficacy. "CRP" refers to serum C-reactive protein, a marker of inflammation. "ESR" refers to erythrocyte sedimentation rate. "FC" refers to fecal calprotectin.

[0210] RB score (RBS): indicates the score of rectal bleeding. Detailed Implementation

[0211] For clarity, this disclosure is further illustrated by examples, but these examples are not intended to limit the scope of this disclosure. All reagents used in this disclosure are commercially available and can be used without further purification.

[0212] Compounds of Formula I (e.g., compounds A to F) can be prepared by referring to the method disclosed in WO2022166917.

[0213] Experimental Example 1

[0214] Only those who meet all of the following inclusion criteria can be enrolled as subjects:

[0215] 1) The patient was diagnosed with ulcerative colitis or Crohn's disease by histopathological or endoscopic examination before screening.

[0216] 2) Active moderate to severe UC or CD.

[0217] Active UC severity is moderate to severe, including but not limited to: Modified Mayo score (MMS) total score ≥6 and ≤12, of which Mayo endoscopic score ≥2;

[0218] Active CD severity is moderate to severe, including but not limited to: Best CDAI score ≥220 and ≤450, with an average of ≥4 bowel movements per day and / or an average abdominal pain score ≥2 per day, and a SES-CD score >6 (or SES-CD ≥4 for subjects with isolated ileal disease). Endoscopic examination results from our hospital within 14 days prior to the first dose of medication.

[0219] 3) Subjects must have experienced failure of at least one of the following drug treatments for UC or CD (treatment failure is defined as insufficient or no response in the investigator’s opinion) or intolerance (intolerance is defined as discontinuation of drug use due to adverse reactions in the investigator’s opinion): oral aminosalicylic acid preparations, oral hormones (prednisone (or equivalent)), immunosuppressants (such as azathioprine, methotrexate), biologics (anti-TNF-α preparations, anti-α4β7 integrin), etc.

[0220] 4) If a subject is currently using any of the following medications for the treatment of UC or CD at the time of screening, they should be treated with oral aminosalicylic acid (e.g., mesalazine ≥2.4 g / d or equivalent dose) for at least 3 weeks prior to the first dose of the investigational drug described in this article, or with oral systemic steroids (e.g., prednisone ≤20 mg / d or equivalent dose) for at least 2 weeks prior to the first dose of the investigational drug described in this article, and the stable dose should be maintained during the trial.

[0221] Test drug: Compound C capsules, manufactured and supplied by Nanjing Shunxin Pharmaceutical Co., Ltd., a subsidiary of Chia Tai Tianqing Pharmaceutical Group, in 2mg and 8mg strengths. Administration: Take on an empty stomach, once daily with a suitable amount of warm water, at a dose of 12mg-48mg, specifically 12mg, 24mg, 32mg, or 48mg.

[0222] Validity analysis:

[0223] Clinical remission, clinical response, endoscopic remission, etc., at the end of weeks 4, 6, 8, or longer (e.g., 12 or 52 weeks) of treatment; changes in IBDQ score relative to baseline at the end of weeks 4, 6, 8, or longer (e.g., 12 or 52 weeks) of treatment; pharmacokinetic characteristics. Examples include, but are not limited to, the following:

[0224] The proportion of subjects who achieved endoscopic remission after 12 weeks of treatment;

[0225] The proportion of subjects who achieved symptom relief after 6 and 12 weeks of treatment;

[0226] After 2, 6, and 12 weeks of treatment, the individual scores for Physician Overall Assessment (PGA), Rectal Bleeding (RB), and Frequency of Bowel Movements (SF) changed from baseline.

[0227] change;

[0228] Changes in modified Mayo score and Mayo endoscopic score from baseline after 12 weeks of treatment;

[0229] Changes in IBDQ score relative to baseline after 12 weeks of treatment;

[0230] PK parameters;

[0231] PD indicators: changes in fecal calprotectin (FC), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) relative to baseline.

[0232] Evaluation indicators include, but are not limited to: modified Mayo score, Mayo endoscopic score, Best CDAI score, SES-CD score, Inflammatory Bowel Disease Quality of Life Questionnaire (IBDQ), and inflammatory markers (CRP, FC, and ESR).

[0233] in,

[0234] UC effectiveness analysis

[0235] Based on the EAS (Efficacy Analysis Dataset), a modified Mayo Criterion system was used to assess efficacy. Assessment indicators included the proportions of clinical remission, clinical response, and endoscopic remission in each group at week 8, and the change in IBDQ score from baseline at week 8. At week 12, the following indicators were assessed: the proportions of clinical remission and endoscopic remission in each group; the proportions of symptom remission at weeks 6 and 12; the changes in individual scores for Physician Overall Assessment (PGA), Rectal Bleeding (RB), and SF frequency at weeks 2, 6, and 12 from baseline; and the changes in modified Mayo score, Mayo endoscopic score, and IBDQ score from baseline at week 12.

[0236] The calculation rate and 95% CI are calculated based on the exact binomial method of the F distribution.

[0237] Descriptive statistics were performed on the changes in scores relative to the baseline, listing the number of cases, mean, standard deviation, median, minimum, and maximum values.

[0238] Clinical remission is defined as the simultaneous achievement of symptom relief and endoscopic remission.

[0239] Endoscopic remission is defined as a score of 0 or 1 on the modified Mayo score for the endoscopy section, with no mucosal fragility.

[0240] Symptom relief was defined as a score of 0 for both the RB and SF scores; or a RB score of 0 and an SF score ≤1 with a decrease of at least 1 point from baseline.

[0241] Clinical response was defined as a reduction of ≥2 points in the modified Mayo score from baseline with a reduction of ≥30%, and a reduction of ≥1 point in the RB (hematochezia) score from baseline or an absolute RB value ≤1.

[0242] CD effectiveness analysis

[0243] Based on the EAS (Efficacy Analysis Dataset), the Best CDAI and SES-CD scoring systems were used to assess efficacy. The proportions of clinical remission, clinical response, and endoscopic remission in each group at week 8, and the proportions of clinical remission and clinical response in each group at the end of weeks 2 and 4, as well as the changes in IBDQ scores relative to baseline at week 8, were also included.

[0244] The specific analysis method is the same as that used in UC effectiveness analysis.

[0245] Clinical remission was defined as an average daily number of bowel movements ≤2.8 and an average daily abdominal pain score ≤1, both of which did not exceed the baseline score.

[0246] Clinical response is defined as a decrease of at least 100 points in Best CDAI relative to baseline.

[0247] Endoscopic remission was defined as a SES-CD score ≤4 and a decrease of at least 2 points from baseline, with no sub-score of any single variable greater than 1.

[0248] Security Analysis:

[0249] All adverse events will be classified according to NCI-CTCAE version 5.0, and statistical descriptions will be provided for adverse event incidence, correlation analysis between adverse events and investigational drugs, and severity analysis by treatment group.

[0250] Safety and tolerability, incidence and severity of all adverse events (AEs), serious adverse events (SAEs) and treatment-related adverse events (TEAEs), and abnormal clinical laboratory test results.

[0251] Experimental results:

[0252] An efficacy analysis was conducted on a subset of UC participants.

[0253] In the 12mg group, one subject had only received conventional treatment (mesalazine, hormones) and the treatment failed, achieving clinical remission;

[0254] In the 24mg group, two patients achieved clinical response after failing conventional treatment (mesalazine and sulfasalazine);

[0255] In the 32mg group, 4 out of 10 subjects failed conventional treatment (mesarazidine, sulfasalazine, hormones), and 6 failed one or more treatments including biologics (infliximab, vedelizumab), SIPR modulators, NLRP3 inhibitors, or JAK1 inhibitors. The overall clinical response rate was 40%, the clinical response rate was 90%, and the endoscopic response rate was 60%, achieving the efficacy of current anti-TNF-α agents after conventional treatment failure. Of the 2 subjects who failed biologic therapy, 1 achieved a clinical response and 1 achieved a clinical remission.

[0256] As the dosage of compound C increases, the therapeutic effect gradually improves, and the dose-response relationship becomes clear.

[0257] Efficacy analysis of some CD subjects:

[0258] One patient in the 12mg group had anal fistula and had previously received conventional treatment and anti-TNF-α therapy, achieving clinical remission.

[0259] Two patients were in the 24mg group. One patient had previously received only traditional treatment and failed, but achieved clinical remission. The other patient had previously received traditional treatment, multiple biologics, and JAK1 inhibitors but failed, but achieved endoscopic remission.

[0260] Traditional treatments include, but are not limited to, aminosalicylic acid preparations (sulfasalazine, mesalazine, etc.), glucocorticoids (methylprednisolone, prednisone, etc.) and immunosuppressants (azathioprine, methotrexate, etc.).

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammatory bowel disease, wherein, T 7 , T 8 , T 9 , T 10 , T 11 , T 12 are each independently selected from CH, C, NH, N, O or a bond, wherein one or two are selected from NH or N; Each R 3 Each group is independently selected from halogen, hydroxyl, amino, cyano, nitro, and C groups. 1-3 Alkyl or C 3-6 cycloalkyl, the C 1-3 Alkyl or C 3-6 The cycloalkyl group may optionally be substituted with one or more halogens, hydroxyl groups, amino groups, or cyano groups; m is selected from 1 or 2; Optionally, the inflammatory bowel disease is selected from ulcerative colitis (UC) or Crohn's disease (CD).

2. A compound of formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammatory bowel disease, wherein T 7 、T 8 、T 9 、T 10 、T 11 、T 12 are each independently selected from CH, C, NH, N, O or a bond, wherein one or two are selected from NH or N; Each R 3 Each group is independently selected from halogen, hydroxyl, amino, cyano, nitro, and C groups. 1-3 Alkyl or C 3-6 cycloalkyl, the C 1-3 Alkyl or C 3-6 The cycloalkyl group may optionally be substituted with one or more halogens, hydroxyl groups, amino groups, or cyano groups; m is selected from 1 or 2. X is N, Optionally, the inflammatory bowel disease is selected from ulcerative colitis (UC) or Crohn's disease (CD).

3. The compound of formula I or a pharmaceutically acceptable salt thereof for inflammatory bowel disease as described in claim 1 or 2. wherein T 7 , T 8 , T 9 , T 10 , T 11 , T 12 are each independently selected from CH, C, NH, N, O or a bond, wherein one, two or three are selected from NH or N; Or, each R 3 Each is independently selected from F, or from methyl or cyclopropyl groups optionally substituted with F.

4. The compound of formula I for use in inflammatory bowel disease according to any one of claims 1 to 3, wherein The compound of Formula I or a pharmaceutically acceptable salt thereof is selected from Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof:

5. The compound of formula I or a pharmaceutically acceptable salt thereof for inflammatory bowel disease as described in any one of claims 1-4, wherein, The inflammatory bowel disease is selected from moderate to severe active ulcerative colitis or Crohn's disease; Alternatively, the inflammatory bowel disease is selected from moderate to severe ulcerative colitis (UC); Alternatively, the inflammatory bowel disease is selected from moderate to severe Crohn's disease (CD); Alternatively, the inflammatory bowel disease is selected from adult active ulcerative colitis or Crohn's disease; Alternatively, the inflammatory bowel disease is selected from those diagnosed as ulcerative colitis or Crohn's disease by histopathological or endoscopic examination. Alternatively, the inflammatory bowel disease is an inflammatory bowel disease for which the patient has previously received at least one drug treatment for ulcerative colitis or Crohn's disease.

6. The compound of formula I for use in inflammatory bowel disease according to claim 5, wherein The drug for ulcerative colitis or Crohn's disease is selected from one or more of conventional treatment, biologic treatment, JAK1 inhibitor treatment, SIPR modulator treatment, and NLRP3 inhibitor treatment. Optionally, the drug for ulcerative colitis or Crohn's disease is an oral medication. Alternatively, the conventional treatment is selected from aminosalicylic acid preparations, hormones, and immunosuppressants; Alternatively, the aminosalicylic acid formulation is selected from sulfasalazine or mesalazine; Alternatively, the hormone may be selected from methylprednisolone or prednisone; Alternatively, the immunosuppressant is selected from azathioprine or methotrexate; Alternatively, the biological agent may be selected from one or more of ustekinumab, gusejinumab, levosinizumab, migelizumab, infliximab, adalimumab, or vedelizumab.

7. The compound of formula I for use in inflammatory bowel disease according to claim 5 or 6, or a pharmaceutically acceptable salt thereof, wherein, The subjects with inflammatory bowel disease were selected from those who had received conventional treatment; Alternatively, the subjects with inflammatory bowel disease may be selected from those who have received biologic therapy; Alternatively, the subjects with inflammatory bowel disease may be selected from those who have a poor response to, are intolerant of, or have contraindications to one or more anti-TNF-α agents.

8. The compound of formula I or a pharmaceutically acceptable salt thereof for use in inflammatory bowel disease according to any one of claims 1 to 7, wherein The daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from 2-32 mg or 12-48 mg; Alternatively, the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from 4-28 mg; Alternatively, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 32 mg or 48 mg; Alternatively, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from 6 mg, 12 mg, or 18 mg; Alternatively, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from 12 mg, 24 mg, 32 mg, or 48 mg; Alternatively, the single or multiple doses of the compound of Formula I or a pharmaceutically acceptable salt thereof are selected from 2-32 mg or 12-48 mg; Alternatively, the single or multiple doses of the compound of Formula I or a pharmaceutically acceptable salt thereof may be selected from 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 32 mg or 48 mg. Alternatively, the single or multiple doses of the compound of Formula I or a pharmaceutically acceptable salt thereof may be selected from 12 mg, 24 mg, 32 mg or 48 mg.

9. The compound of formula I or a pharmaceutically acceptable salt thereof for inflammatory bowel disease as described in any one of claims 1-8, wherein, Subjects were administered a compound of formula I or a pharmaceutically acceptable salt thereof daily, optionally for 2 to 52 weeks. Alternatively, the compound of Formula I or a pharmaceutically acceptable salt thereof may be administered daily, optionally for about 1 to 7 days, about 1 to 14 days, about 1 to 28 days, about 1 to 56 days, about 1 to 3 weeks, about 3 to 6 weeks, about 6 to 9 weeks, or about 12 weeks; or for about 8 weeks, 12 weeks, about 12 to 15 weeks, or about 15 to 18 weeks, or about 15 to 52 weeks; or for about 8 weeks.

10. A pharmaceutical composition for inflammatory bowel disease, comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein, T 7 , T 8 , T 9 , T 10 , T 11 , T 12 are each independently selected from CH, C, NH, N, O or a bond, wherein one or two are selected from NH or N; Each R 3 Each group is independently selected from halogen, hydroxyl, amino, cyano, nitro, and C groups. 1-3 Alkyl or C 3-6 cycloalkyl, the C 1-3 Alkyl or C 3-6 The cycloalkyl group may optionally be substituted with one or more halogens, hydroxyl groups, amino groups, or cyano groups; m is selected from 1 or 2. X is N, Optionally, the inflammatory bowel disease is selected from ulcerative colitis (UC) or Crohn's disease (CD).

11. The pharmaceutical composition for inflammatory bowel disease as claimed in claim 10, wherein, T 7 , T 8 , T 9 , T 10 , T 11 , T 12 are each independently selected from CH, C, NH, N, O or a bond, wherein one, two or three are selected from NH or N; Or, each R 3 Each is independently selected from F, or from methyl or cyclopropyl groups optionally substituted with F.

12. The pharmaceutical composition for inflammatory bowel disease according to claim 10 or 11, wherein, The compound of Formula I or a pharmaceutically acceptable salt thereof is selected from Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof:

13. A kit comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and instructions for treating or preventing inflammatory bowel disease with a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein T 7 、T 8 、T 9 、T 10 、T 11 、T 12 each independently is selected from CH, C, NH, N, O or a bond, wherein one or two are selected from NH or N; Each R 3 Each group is independently selected from halogen, hydroxyl, amino, cyano, nitro, and C groups. 1-3 Alkyl or C 3-6 cycloalkyl, the C 1-3 Alkyl or C 3-6 The cycloalkyl group may optionally be substituted with one or more halogens, hydroxyl groups, amino groups, or cyano groups; m is selected from 1 or 2. X is N, Optionally, the inflammatory bowel disease is selected from ulcerative colitis (UC) or Crohn's disease (CD).

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