Therapeutic agents that enhance epithelial and / or endothelial barrier function

Abstract

The present invention relates to novel compounds and compositions thereof that are useful for treating epithelial or endothelial barrier dysfunction in a subject.

Description

[Technical Field]

[0001] Priority This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 419,015, filed October 25, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Barrier dysfunction (epithelial or endothelial) is observed in a variety of medical disorders and pathologies. For example, disruption of normal epithelial or endothelial barrier function is a common feature of many chronic autoimmune and inflammatory diseases, as well as other metabolic and neuronal disorders. In epithelial layers, such as the intestinal epithelium, the intercellular barrier consists of tight junction complexes formed by tight junction proteins such as claudins and occludin. In endothelial cell layers, such as those in blood vessels and the heart, the intercellular barrier consists of both tight junctions and adherens junctions formed by tight junction proteins and vascular endothelial (VE) cadherin, respectively. Maintaining a strong physical barrier in epithelial and endothelial layers is important for maintaining immune homeostasis.

[0003] Impaired intestinal barrier function allows microorganisms and microbial antigens to enter the systemic circulation, resulting in excessive inflammation and organ-specific immune dysfunction. Intestinal barrier dysfunction is associated with various diseases, including but not limited to inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and celiac disease (CeD). Intestinal barrier dysfunction is also strongly correlated with other autoimmune, inflammatory, and metabolic diseases, including but not limited to obesity, alcoholic and nonalcoholic liver disease, atherosclerosis, heart failure, hypertension, food allergies, and cancer. Various external factors, such as alcohol, nonsteroidal anti-inflammatory drugs (NSAIDs), and certain pathogens, have been reported to directly alter intestinal barrier function and may be involved in the pathogenesis of various diseases. Intestinal microbial imbalance (dysbiosis) is also associated with intestinal barrier dysfunction and an immature immune system, leading to widespread disorders of the intestine, liver, and nervous system.

[0004] Furthermore, the physical barrier of blood vessels comprises a monolayer of endothelial cells interconnected by tight junction protein complexes and VE-cadherin.1 Acute respiratory distress syndrome (ARDS), an example of an endothelial dysfunction disorder, is characterized by the breakdown of the paracellular barrier between endothelial cells and alveolar epithelial cells in the alveolar capillaries, allowing fluid and immune cell infiltration into the lungs.

[0005] Ulcerative colitis (UC) and Crohn's disease (CD), collectively known as inflammatory bowel disease (IBD), affect 3 million Americans. Increased intestinal barrier permeability is a key factor in the pathogenesis and progression of IBD in patients. Increased permeability is caused, in part, by altered expression and / or distribution of intercellular tight junction proteins (TJPs). Altered TJP expression and distribution have been demonstrated in clinically active IBD patients, and enhancing barrier integrity is associated with clinical remission and improved patient outcomes. More broadly, increased intestinal permeability is associated with an increased risk of relapse, which has been reported in both clinically active and remitted IBD patients and correlates with disease severity. Furthermore, treatments that improve barrier integrity prevent IBD progression in animal models. Furthermore, patients with Crohn's disease or UC who exhibit high levels of intestinal permeability have a poorer prognosis than those with relatively low levels. Similarly, healthy relatives of Crohn's disease patients with increased intestinal permeability are at higher risk of disease.

[0006] Despite growing evidence indicating that barrier dysfunction plays a key role in IBD, most currently FDA-approved IBD medications and those under development target intestinal inflammation rather than directly affecting (i.e., targeting) barrier dysfunction. The primary goals of IBD therapy are to prevent progression from mild to severe disease, induce remission of acute exacerbations, and / or maintain remission. Unfortunately, mesalamine (5-aminosalicylic acid, 5ASA), the first-line treatment for patients with mild to moderate UC, is ineffective in up to 50%–60% of patients. For the approximately 50% of UC patients who do not respond to mesalamine, the next treatment option is corticosteroids, followed by off-label use of immunosuppressants such as 6-mercaptopurine. Corticosteroids are usually the first-line therapy for patients with CD. Biologics targeting TNF-α and integrin α4β7 have become the standard of care for patients with moderate to severe UC and CD who do not respond to "traditional" immunosuppressive therapy. Anti-integrin biologics may be less toxic than TNF-α mAbs; however, TNF-α mAbs and integrin α4β7 mAbs have drawbacks, including the inability to administer orally, relatively low response rates (45%-60%), the development of resistance, and irreversibility.

[0007] There is a need for therapeutic agents that directly target barrier dysfunction and improve barrier integrity to promote mucosal or tissue healing. What is particularly needed are orally available, non-toxic, non-immunosuppressive therapeutic agents that directly promote the re-establishment of epithelial integrity and maintain long-term remission in IBD. The present invention meets these and other needs. Summary of the Invention

[0008] In various aspects and embodiments, the present disclosure provides compounds (i.e., active agents) useful for improving epithelial and / or endothelial barrier dysfunction and, therefore, treating various diseases and conditions involving tissue barrier dysfunction. Exemplary conditions include those involving gastrointestinal inflammation and / or permeability, including inflammatory bowel disease (IBD) (i.e., ulcerative colitis or Crohn's disease), as well as other diseases of the gastrointestinal tract and diseases involving inflammation or tissue permeability in other tissues and organs. The present disclosure further provides pharmaceutical compositions comprising the compounds, as well as methods of treatment and use in therapy.

[0009] In various aspects and embodiments, the present invention provides novel compounds of Formula (I), Formula (II), and Formula (III), and compositions thereof, as described in detail herein. In some embodiments, the compounds described herein exhibit gastric and / or intestinal stability, thereby enhancing their effectiveness as oral therapeutic agents and their use in treatments using other routes of administration. In some embodiments, the compounds described herein have a low risk of toxicity with long-term use (e.g., a low risk of genotoxicity or toxicity associated with quinone formation).

[0010] In various embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] According to formula (I): each R1 is independently selected from the group consisting of OH, NO2, halo, CF3, NR3R4, (C1-C6)alkoxy, -C(O)(C1-C6)alkyl, and -C(O)O(C1-C6)alkyl; each R2 is a substituent other than OH; R3 and R4 are each independently selected from the group consisting of H, alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclo, aryl, and heteroaryl, and R3 and R4 together with the carbon to which they are attached form a (C3-C8)cycloalkyl or a (C3-C8)heterocyclo; X1 and X2 are each independently C or N, with the proviso that X1 and X2 are not both C; X3 is O or S; m is an integer ranging from 1 to 4; n is an integer ranging from 1 to 4.

[0011] In various embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof: [ka] According to formula (II): each R1 is independently selected from the group consisting of OH, NO2, halo, CF3, NR3R4, (C1-C6)alkoxy, -C(O)(C1-C6)alkyl, and -C(O)O(C1-C6)alkyl; each R2 is a substituent other than OH; R3 and R4 are each independently selected from the group consisting of H, alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclo, aryl, and heteroaryl, and R3 and R4 together with the carbon to which they are attached form a (C3-C8)cycloalkyl or a (C3-C8)heterocyclo; X1 and X2 are independently C or N; X4 and X5 are either both bonds, or X4 is CR5R6 and X5 is S, O, or CR7R8; R5, R6, R7, and R8 are each independently selected from the group consisting of H, halo, alkyl, alkenyl, and alkoxy; m is an integer ranging from 1 to 4; n is an integer ranging from 1 to 4.

[0012] In various embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof: [ka] According to formula (III): each R1 is independently selected from the group consisting of OH, NO2, halo, CF3, NR3R4, (C1-C6)alkoxy, -C(O)(C1-C6)alkyl, and -C(O)O(C1-C6)alkyl; each R2 is a substituent other than OH; R3 and R4 are each independently selected from the group consisting of H, alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclo, aryl, and heteroaryl, and R3 and R4 together with the carbon to which they are attached form a (C3-C8)cycloalkyl or a (C3-C8)heterocyclo; with the proviso that R3 and R4 are not both H; X6 and X7 are each independently C or N; X3 is O or S; m is an integer ranging from 1 to 4; n is an integer ranging from 1 to 4.

[0013] In various embodiments, the compounds of Formula (I), (II), or (III) are activators / ligands of the aryl hydrocarbon receptor (AhR). In various embodiments, the compounds of Formula (I), (II), or (III) are non-genotoxic, even with long-term use. In various embodiments, the compounds of Formula (I), (II), or (III) do not exhibit significant or substantial quinone formation. In various embodiments, the compounds of Formula (I), (II), or (III) are effective in enhancing the barrier integrity of epithelial and endothelial tissues, and in some embodiments, also have the effect of enhancing barrier function in the gastrointestinal tract (e.g., small intestine and / or large intestine).

[0014] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of Formula (I), (II), or (III) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient and / or carrier.

[0015] In various embodiments, the compositions are formulated for oral delivery to the gastrointestinal tract. Alternatively, the compositions are formulated for direct delivery to the lungs or for parenteral delivery, including, for example, by a route selected from intravenous, intraarterial, intramuscular, intradermal, intrathecal, and subcutaneous administration. Other modes of administration are contemplated in the present disclosure, including topical or local administration to a target tissue (including, for example, the eye, ear, or any mucosal surface, or skin).

[0016] In another aspect, the present disclosure provides a method for treating epithelial or endothelial dysfunction in a subject. The method comprises administering to the subject a compound of Formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In an embodiment, the method induces expression of tight junction proteins in the tissue. In an exemplary embodiment, the subject has inflammation to be treated in one or more organs or tissues selected from the liver, kidney, pancreas, heart, lung, skin, muscle, fat, brain, eye, bone, bone marrow, intestine, cartilage, and skin. Such inflammation can be alleviated through systemic or local treatment with the compounds and compositions, or by treating intestinal barrier function.

[0017] Other aspects and embodiments of the present disclosure will become apparent from the following figures and detailed description. The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings. [Brief explanation of the drawings]

[0018] [Figure 1] The chemical structures of urolithin A (UroA) and UAS03 are shown. [Figure 2]Panels A–D show that UAS03 is effective in a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced mouse model when administered either before or after TNBS treatment. Pretreatment: Mice (n=10 per group) were orally administered UAS03 (20 mg / kg) once daily for 7 days, followed by TNBS administration. Mice were euthanized 72 hours after TNBS administration. Posttreatment: Mice (n=10 per group) were administered UAS03 (20 mg / kg) once daily at 24, 48, and 72 hours after TNBS administration. A) Colon weight / length ratio. B) Intestinal permeability assessed using a FITC-dextran leakage assay. C) Serum levels of TNF-α measured using a standard ELISA method. D) Claudin-4 (Cldn4) expression in mouse colon. Panel D shows data from a separate experiment. Error bars, ±SEM, ***p<0.001. [Figure 3] A and B show the potential tendency of UAS03 to form reactive quinones. A. Formation of quinones by UAS03. B. Quinones can generate toxic reactive oxygen radicals or conjugate with proteins containing reactive thiols, causing potential long-term toxicity. [Figure 4] The structures of exemplary compounds are shown with reference to UAS03. [Figure 5]Results are shown for compounds tested in a human EpiIntestinal 3D in vitro tissue model. This model system incorporates intestinal epithelial cells, Paneth cells, M cells, tufted cells, and intestinal stem cells, forming a highly differentiated and polarized epithelial structure. The EpiIntestinal tissue model resembles native human intestinal tissue and recapitulates many aspects of normal intestinal function, including barrier function, metabolism, and inflammatory and toxic responses. Key features of EpiIntestinal tissue include functional tight junctions and brush borders at the apical tissue surface (EpiIntestinal 3D in vitro Microtissues, purchased from MatTek Life Sciences). EpiIntestinal 3D tissues in 96-well transwell plates were treated with 500 ng / mL LPS for 24 hours to disrupt barrier function, followed by treatment with test compounds (25 μM) in the presence of 250 ng / mL LPS for an additional 24 hours. FITC-dextran permeability assay was performed by adding FITC-dextran (1 mg / mL) to the upper chamber and measuring the amount of FITC-dextran leaking into the lower chamber 2 hours after each treatment. **** indicates p<0.0001, *** indicates p<0.001, and * indicates p≤0.05. [Figure 6]Figures A–F show the efficacy of ARTX-339, ARTX-405A, ARTX-413, and ARTX-425P1 in a mouse model of DSS-induced ulcerative colitis. A. C57BL / 6 mice (7–8 weeks old) were fed 2.5% DSS in their drinking water for 7 days. Starting on day 4 of DSS treatment, mice were orally administered 100 μL of vehicle (ARTX compound formulations in 0.25% sodium carboxymethylcellulose) or 100 μL of ARTX-339, ARTX-405A, ARTX-413, or ARTX-425P1 at a dose of 20 mg / kg body weight every other day (days 4, 6, 8, and 10). Mice were euthanized on day 12. Four hours before euthanasia, mice were orally administered FITC-dextran. After euthanasia, the colon was dissected and its length was measured. A. Colon length measurement. C. Photograph of the dissected colon. D. Measurement of serum FITC-dextran after euthanasia. FITC-dextran is a high-molecular-weight fluorescent molecule that is normally blocked, at least in part, from permeating into the bloodstream by the intestinal epithelial layer. Elevated serum FITC-dextran levels after DSS treatment indicate a loss of barrier function. E. Body weight was measured every other day starting on the day DSS treatment began (day 0). F. Disease Activity Index (DAI) scores were assigned every other day. The higher the DAI score, the worse the symptoms. **** indicates p<0.0001, *** indicates p<0.001, and ** indicates p<0.01. [Figure 7] A and B show the ability of ARTX-413 to activate the AhR signaling pathway. [Figure 8] The hERG inhibition of ARTX-413 is demonstrated, indicating that ARTX-413 has a very low risk of cardiotoxicity. [Figure 9] 1 shows a synthetic scheme for the synthesis of ARTX-413. [Figure 10] 1 shows a synthetic scheme for the synthesis of ARTX-405A. [Figure 11] 1 shows a synthetic scheme for the synthesis of ARTX-425P1. DETAILED DESCRIPTION OF THE INVENTION

[0019] In various aspects and embodiments, the present disclosure provides compounds that reduce epithelial and / or endothelial barrier dysfunction and are therefore useful for treating various diseases and conditions involving tissue barrier dysfunction. Exemplary conditions include those involving gastrointestinal inflammation and / or permeability, including inflammatory bowel disease (IBD) (i.e., ulcerative colitis or Crohn's disease), as well as other diseases of the gastrointestinal tract and diseases involving other tissues and organs. Accordingly, the active ingredients described herein are useful for treating, alleviating, or preventing symptoms such as alcohol-related liver disease (AALD), alcoholic fatty liver disease, non-alcoholic fatty liver disease, chronic kidney disease, sepsis and other systemic inflammatory diseases, autoimmune diseases, metabolic diseases, neuroinflammatory diseases, and neurodegenerative diseases, among others. The present disclosure further provides pharmaceutical compositions comprising the compounds, as well as methods of treatment or use in therapy.

[0020] In various aspects and embodiments, the present invention provides novel compounds of Formula (I), Formula (II), and Formula (III), and compositions thereof, as described in detail herein. In some embodiments, the compounds described herein exhibit gastric and / or intestinal stability, thereby enhancing their effectiveness as oral therapeutics. In some embodiments, the compounds described herein have a low risk of toxicity with long-term use (e.g., a low risk of genotoxicity or toxicity associated with quinone formation).

[0021] In various embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] According to formula (I): each R1 is independently selected from the group consisting of OH, NO2, halo, CF3, NR3R4, (C1-C6)alkoxy, -C(O)(C1-C6)alkyl, and -C(O)O(C1-C6)alkyl; each R2 is a substituent other than OH; R3 and R4 are each independently selected from the group consisting of H, alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclo, aryl, and heteroaryl, and R3 and R4 together with the carbon to which they are attached form a (C3-C8)cycloalkyl or a (C3-C8)heterocyclo; X1 and X2 are each independently C or N, with the proviso that X1 and X2 are not both C; X3 is O or S; m is an integer ranging from 1 to 4; n is an integer ranging from 1 to 4.

[0022] Without intending to be bound by theory, it is believed that by not introducing a hydroxyl group into R2 and substituting at least one of X1 and X2 with N, the compound can have the effect of reducing the overall reactivity at R1 and R2. In some embodiments, X1 and X2 are each N.

[0023] In various embodiments, each R2 is independently selected from the group consisting of halo, NO2, CF3, NR3R4, (C1-C6)alkoxy, —C(O)(C1-C6)alkyl, (C3-C8)cycloalkyl, and —C(O)O(C1-C6)alkyl. In some embodiments, R2 is halo and m is 1 or 2. For example, R2 can be selected from F, Cl, Br, and I. In some embodiments, one or more of R2 is methyl, ethyl, methoxy, or isopropyl.

[0024] In some embodiments, X3 is O.

[0025] In some embodiments, R 1 is OH and n is 1 or 2.

[0026] In certain embodiments, R3 and R4 are each H or C1-C3 alkyl, optionally methyl, ethyl, or isopropyl. In some embodiments, the substituents of R3 and / or R4 are sufficiently bulky to reduce interaction of the compound with DNA (e.g., reduce DNA intercalation). In certain embodiments, one of R3 and R4 is (C1-C6) alkyl or (C1-C6) alkenyl, and the other is H. In certain embodiments, R3 and R4 are each H. In still other embodiments, R3 and R4, together with the carbons to which they are attached, form a (C3-C8) cycloalkyl or (C3-C8) heterocyclo.

[0027] In various embodiments of formula (I), R1 is OH and n is 1; R2 is halo and m is 1; X1 and X2 are both N; X3 is O; and R3 and R4 are each H.

[0028] In one embodiment, the compound of formula (I) has the structure [ka] and is also referred to herein as ARTX-413.

[0029] Thus, in one embodiment, the compound of formula (I) is 8-fluoro-6H-isochromeno[3,4-d]pyrimidin-3-ol.

[0030] In one embodiment, the compound of formula (I) has the structure [ka] and is also referred to herein as ARTX-436. Thus, in one embodiment, the compound of formula (I) is 8-fluoro-6-isopropyl-6H-isochromeno[3,4-d]pyrimidin-3-ol.

[0031] In one embodiment, the compound of formula (I) has the structure [ka] Thus, in one embodiment, the compound of formula (I) is (S)-8-fluoro-6-isopropyl-6H-isochromeno[3,4-d]pyrimidin-3-ol.

[0032] In one embodiment, the compound of formula (I) has the structure [ka] It has.

[0033] Thus, the compound of formula (I) can be (R)-8-fluoro-6-isopropyl-6H-isochromeno[3,4-d]pyrimidin-3-ol.

[0034] In various embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof: [ka] According to formula (II): each R1 is independently selected from the group consisting of OH, NO2, halo, CF3, NR3R4, (C1-C6)alkoxy, -C(O)(C1-C6)alkyl, and -C(O)O(C1-C6)alkyl; each R2 is a substituent other than OH; R3 and R4 are each independently selected from the group consisting of H, alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclo, aryl, and heteroaryl, and R3 and R4 together with the carbon to which they are attached form a (C3-C8)cycloalkyl or a (C3-C8)heterocyclo; X1 and X2 are independently C or N; X4 and X5 are either both bonds, or X4 is CR5R6 and X5 is S, O, or CR7R8; R5, R6, R7, and R8 are each independently selected from the group consisting of H, halo, alkyl, alkenyl, and alkoxy; m is an integer ranging from 1 to 4; n is an integer ranging from 1 to 4.

[0035] Without intending to be bound by theory, it is believed that by incorporating a five- or seven-membered ring as shown in formula (II), the molecule becomes substantially non-planar, avoiding genotoxicity due to DNA intercalation.

[0036] In some embodiments, each R 1 is OH and n is 1 or 2.

[0037] In some embodiments, X4 and X5 are both bonds.

[0038] In some embodiments, X4 is CH2.

[0039] In some embodiments, X4 is CH2; and X5 is O.

[0040] In some embodiments, X1 and X2 are each C. In some embodiments, n is 1 and one or both of X1 and X2 are N.

[0041] In some embodiments, each R2 is a substituent selected from halo, NO2, CF3, NR3R4, (C1-C6)alkoxy, —C(O)(C1-C6)alkyl, (C3-C8)cycloalkyl, and —C(O)O(C1-C6)alkyl. In some embodiments, R2 is methyl, ethyl, methoxy, or isopropyl. In some embodiments, R2 is halo (e.g., F, Cl, Br, I). In some embodiments, m is 1. In an exemplary embodiment, R2 (or each R2) is F.

[0042] In some embodiments, R3 and R4, together with the carbons to which they are attached, form a (C3-C8)cycloalkyl or (C3-C8)heterocyclo. In some embodiments, the substituents of R3 and / or R4 are sufficiently bulky to reduce interaction of the compound with DNA (e.g., reduce DNA intercalation). In some embodiments, R3 and R4, together with the carbons to which they are attached, form a 5-, 6-, or 7-membered carbocyclic ring. In some embodiments, one of R3 and R4 is (C1-C6)alkyl or (C2-C6)alkenyl, and the other is H. In some embodiments, one of R3 and R4 is H. In some embodiments, R3 is methyl, ethyl, methoxy, or isopropyl. In some embodiments, R4 is methyl, ethyl, methoxy, or isopropyl.

[0043] In certain other embodiments, both R3 and R4 can be H.

[0044] In some embodiments of Formula (II), each R1 is OH and n is 1 or 2; each R2 is halo (e.g., F or Cl) and m is 1 or 2; and R3 and R4, together with the carbons to which they are attached, form a 5- or 7-membered carbocyclic ring.

[0045] In one embodiment, the compound of formula (II) has the structure [ka] and is also referred to herein as ARTX-405A. Thus, in one embodiment, the compound of formula (II) is 7'-fluorospiro[cyclopentane-1,9'-fluorene]-2',4'-diol.

[0046] In other embodiments, the compound of formula (II) has the following structure, also referred to herein as ARTX-437: [ka]

[0047] In some embodiments, the compound of formula (II) has the following structure, also referred to herein as ARTX-438: [ka]

[0048] In some embodiments, the compound of formula (II) has the following structure, also referred to herein as ARTX-439: [ka]

[0049] In some embodiments, the compound of formula (II) has the following structure, also referred to herein as ARTX-440: [ka]

[0050] In various embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof: [ka] According to formula (III): each R1 is independently selected from the group consisting of OH, NO2, halo, CF3, NR3R4, (C1-C6)alkoxy, -C(O)(C1-C6)alkyl, and -C(O)O(C1-C6)alkyl; each R2 is a substituent other than OH; R3 and R4 are each independently selected from the group consisting of H, alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclo, aryl, and heteroaryl, and R3 and R4 together with the carbon to which they are attached form a (C3-C8)cycloalkyl or a (C3-C8)heterocyclo; with the proviso that R3 and R4 are not both H; X6 and X7 are each independently C or N; X3 is O or S; m is an integer ranging from 1 to 4; n is an integer ranging from 1 to 4.

[0051] In some embodiments, X3 is O.

[0052] In some embodiments, R1 is OH.

[0053] In some embodiments, X6 is N and X7 is N. In some embodiments, X6 is N and X7 is C. In some embodiments, X6 is C and X7 is N. In some embodiments, X6 is C and X7 is C.

[0054] In some embodiments, each R2 is selected from halo, CN, NO2, —C(O)(C1-C6)alkyl, (C1-C6)alkoxy, C(O)O(C1-C6)alkyl, aryl, heteroaryl, NR3R4, and CF3. In some embodiments, R2 is methyl, ethyl, methoxy, or isopropyl. In some embodiments, R2 is halo (e.g., independently selected from F, Cl, Br, or I). In some embodiments, each R2 is halo and m is 1 or 2. For example, each R2 can be F and m is 1 or 2.

[0055] In some embodiments, R3 and R4 are each selected from alkyl, alkenyl, and cycloalkyl. For example, one of R3 and R4 can be isopropyl.

[0056] Alternatively, R3 and R4 together with the carbon to which they are attached can form a (C3-C8)cycloalkyl or a (C3-C8)heterocyclo.

[0057] In some embodiments, X3 is O; each R1 is independently selected from OH and halo; X6 and X7 are CH; n is 1; each R2 is halo and m is 1, 2, or 3; R3 is alkyl or H, and R4 is H.

[0058] In one embodiment, the compound of formula (III) has the structure [ka] It has.

[0059] In one embodiment, the compound of formula (III) has the structure [ka] and is also referred to herein as ATRX-425P1.

[0060] In one embodiment, the compound of formula (III) has the structure [ka] and is also referred to herein as ARTX-425P2.

[0061] In one embodiment, the compound of formula (III) has the structure [ka] and is also referred to herein as ARTX-408.

[0062] In some embodiments, the compounds of the present disclosure have any one of the structures shown in FIG.

[0063] In various embodiments, the compounds of Formula (I), (II), or (III) are agonists of the aryl hydrocarbon receptor (AhR) and activate the AhR signaling pathway. In various embodiments, the compounds of Formula (I), (II), or (III) are non-genotoxic, even with long-term use. In various embodiments, the compounds of Formula (I), (II), or (III) do not exhibit significant or substantial quinone formation. In various embodiments, the compounds of Formula (I), (II), or (III) are effective in enhancing the barrier integrity of epithelial and endothelial tissues, and in some embodiments, also have the effect of enhancing barrier function in the gastrointestinal tract.

[0064] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of Formula (I), (II), or (III) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or carrier.

[0065] The pharmaceutical compositions may contain pharmaceutically acceptable salts of the compounds of formula (I), (II), or (III). Any pharmaceutically acceptable salt can be used, including those listed in Journal of Pharmaceutical Science, 66, 2-19 (1977) and The Handbook of Pharmaceutical Salts: Properties, Selection, and Use, P.H. Stahl and C.G. Wermuth (eds.), Verlag, Zurich (Switzerland), 2002. Exemplary pharmaceutically acceptable salts may be selected from acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, and toluenesulfonate.

[0066] In some embodiments, the composition is formulated for oral delivery to the gastrointestinal tract. Exemplary forms for oral delivery include tablets, capsules, solutions, and suspensions. In some embodiments, the composition is formulated for delivery to, for example, the small intestine and / or large intestine. For example, the formulation may include a pH-dependent enteric coating (e.g., EUDRAGIT) that prevents release of the active ingredient in the low pH environment of the stomach and dissolves in the small intestine and / or large intestine. Various enteric coatings can be selected to target portions of the small intestine and / or large intestine, such as the duodenum, jejunum, ileum, or colon. In some embodiments, the composition is formulated without an enteric coating.

[0067] In some embodiments, the composition is formulated for delivery to the lung. In such embodiments, the active ingredient enhances the integrity of the epithelium and / or endothelium of the lung. In some embodiments, the pharmaceutical composition is formulated as a solution or powder aerosol. In some embodiments, the composition is delivered locally to the lung by use of a nebulizer or inhaler.

[0068] In some embodiments, the composition is formulated for parenteral delivery, including, for example, by a route selected from intravenous, intraarterial, intramuscular, intradermal, intrathecal, and subcutaneous administration.

[0069] Other modes of administration are contemplated in this disclosure, including local or topical administration to target tissues. Examples of pharmaceutical compositions are described elsewhere herein.

[0070] In another aspect, the present disclosure provides a method for treating epithelial or endothelial dysfunction in a subject. The method comprises administering to the subject a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In an embodiment, the method induces expression of tight junction proteins in a tissue. In an exemplary embodiment, the subject has inflammation to be treated in one or more organs or tissues selected from the intestine, liver, kidney, pancreas, heart, lung, skin, muscle, fat, brain, eye, ear, mucosa(s), bone, joint, bone marrow, and cartilage. Such inflammation can be alleviated through systemic or local treatment with the compounds and compositions, or by treating intestinal barrier function.

[0071] In various embodiments, the subject is an animal, such as a mammal, and may be a human subject, hi some embodiments, the subject is a veterinary subject, such as a cat, dog, horse, cow, sheep, bird, or the like.

[0072] In some embodiments, the subject has an inflammatory or metabolic disorder associated with epithelial or endothelial barrier dysfunction. In some embodiments, the inflammatory or metabolic disorder is an epithelial disorder of the gastrointestinal tract, such as inflammatory bowel disease or irritable bowel syndrome. If the subject has inflammatory bowel disease, the subject may have ulcerative colitis or Crohn's disease. In other embodiments, the subject has a disorder selected from celiac disease, Whipple's disease, tropical sprue, colonic inflammation, and MIS-C / MIS / A. For example, the subject may exhibit symptoms of gastrointestinal permeability or inflammation, and the composition is administered to the small intestine and / or large intestine (e.g., enterally).

[0073] In some embodiments, the subject has mucositis, such as oral mucositis or intestinal mucositis. In some embodiments, the subject has radiation-induced mucositis or intestinal permeability, or drug-induced mucositis or intestinal permeability. In some embodiments, the subject has undergone radiation therapy or chemotherapy for cancer that results in mucositis, which can be prevented or ameliorated by the present disclosure.

[0074] Other indications potentially related to gastrointestinal permeability include colon cancer, diverticular disease, colitis, immune checkpoint inhibitor-induced colitis, esophagitis (e.g., eosinophilic esophagitis), environmental enteropathy (EED), HIV-associated gastrointestinal conditions, gastric ulcers, ischemic bowel disease, fatty liver disease and / or kidney disease, obesity, cardiovascular disease (CVD), and metabolic syndrome. In some embodiments, the subject has or is at risk of having nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), alcohol-associated liver disease (AALD) (also known as alcoholic liver disease (ALD)), nonalcoholic fatty liver disease (NAFLD), or primary sclerosing cholangitis. In these or other embodiments, the subject has chronic kidney disease. In some embodiments, the subject has hepatitis or cirrhosis. In some embodiments, the subject has an inflammatory skin disease, such as atopic dermatitis, pemphigus, or psoriasis.

[0075] In some embodiments, the subject has organ fibrosis, which is optionally fibrosis of the liver, kidney, heart, pancreas, or lung, and in some embodiments is associated with gastrointestinal permeability, hi some embodiments, the subject has pancreatitis or idiopathic pulmonary fibrosis.

[0076] In some embodiments, the present invention provides methods for enhancing the integrity of the airway barrier in the lung. In these embodiments, the methods comprise administering an effective amount of a composition described herein to a subject in need thereof. In various embodiments, the composition is administered systemically (e.g., enterally or parenterally) or locally to the lung (e.g., by inhalation). According to these embodiments, the active ingredient can reduce vascular permeability in the lung and, in addition, can reduce the permeability of the epithelial barrier. In some embodiments, the compound or composition reduces fibrosis. In some embodiments, the subject has pulmonary fibrosis (e.g., IPF), chronic obstructive pulmonary disease (COPD), acute lung injury, acute respiratory distress syndrome, or asthma.

[0077] In some embodiments, the subject has or is at risk of having sepsis or septic shock, hi these embodiments, the subject may exhibit gastrointestinal permeability and / or vascular permeability.

[0078] In some embodiments, the subject has an immune or autoimmune condition that may be associated with gastrointestinal permeability. For example, the subject may have a condition selected from food allergies, diabetes mellitus, scleroderma, celiac disease, herpes dermatitis, atopic dermatitis, psoriasis, vasculitis, Sjögren's syndrome, rheumatoid arthritis, and multiple sclerosis. The active ingredients described herein may be administered to the gastrointestinal tract or directly to the affected tissue.

[0079] In some embodiments, the subject has a neuroinflammatory disorder, which in some embodiments may be associated with gastroenteritis. For example, the neuroinflammatory disorder may be Alzheimer's disease, Parkinson's disease, dementia, or multiple sclerosis. Other CNS disorders that may be treated according to the present disclosure include panic disorder, social phobia, atypical depression, bipolar disorder, mixed anxiety and depression, bulimia, post-traumatic stress disorder, borderline personality disorder, and migraine. Still other conditions include chronic fatigue syndrome, post-COVID-19 syndrome, and fibromyalgia.

[0080] In some embodiments, the neuroinflammatory disorder is Alzheimer's disease or Parkinson's disease, and the subject has early-stage disease in which the course of the disease is modifiable. In some embodiments, the neuroinflammatory disorder is a neurodegenerative disease such as multiple sclerosis. In some embodiments, the compound or composition is administered directly to the CNS, such as by intrathecal or intranasal administration. In other embodiments, the administration is systemic (either parenterally or enterally).

[0081] In some embodiments, the disorder is a pulmonary epithelial or endothelial disorder, for example, acute respiratory distress syndrome (ARDS) or acute lung injury (ALI).

[0082] In some embodiments, the disorder is a cardiovascular disease (CVD) in which increased endothelial permeability is observed, including hypertension, coronary artery disease, atherosclerosis, heart failure, or myocardial infarction.

[0083] In some embodiments, the subject has a condition related to endothelial barrier dysfunction or organ damage or inflammation. In some embodiments, the condition is vasculitis, sepsis, scleroderma, drug-induced internal bleeding, vascular permeability, capillary leak syndrome, diabetic retinopathy, diabetic macular edema, age-related macular degeneration (e.g., wet AMD), hepatitis, cirrhosis, primary sclerosing cholangitis, and pancreatitis. In some embodiments for treating conditions such as diabetic retinopathy, diabetic macular edema, and age-related macular degeneration (e.g., wet AMD), the composition can be applied locally as eye drops or by intraocular injection.

[0084] In various embodiments, the subject has a disease or condition selected from metabolic stress, cardiovascular disease, sarcopenia, muscle degenerative disease, Duchenne muscular dystrophy, drug-induced liver injury, chronic kidney disease, alpha-antitrypsin deficiency, ischemia / reperfusion injury, metabolic syndrome, type II diabetes mellitus, hyperlipidemia, osteoarthritis, neurodegenerative disease, amyotrophic lateral sclerosis (ALS), cognitive impairment, and mood disorder. The compound or composition, which may be in a chronic administration regimen, treats or ameliorates the disease or condition.

[0085] In some embodiments, the subject has cancer and is optionally receiving chemotherapy, radiation therapy, or immunotherapy (such as immune checkpoint inhibitor therapy, e.g., PD-1 blockade therapy or anti-CTLA4 therapy). In some embodiments, the cancer is a sarcoma, carcinoma, or solid tumor, or a cancer selected from germline tumors, tumors of the central nervous system, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, head and neck cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, glioma, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma, kidney cancer, bladder cancer, esophageal cancer, laryngeal cancer, parotid cancer, biliary tract cancer, rectal cancer, endometrial cancer, squamous cell carcinoma, adenocarcinoma, small cell carcinoma, neuroblastoma, mesothelioma, adrenocortical carcinoma, epithelial carcinoma, desmoid tumor, desmoplastic small round cell tumor, endocrine tumor, Ewing's sarcoma family of tumors, germ cell tumor, hepatoblastoma, hepatocellular carcinoma, lymphoma, melanoma, non-rhabdomyosarcoma soft tissue sarcoma, osteosarcoma, peripheral primitive neuroectodermal tumor, retinoblastoma, rhabdomyosarcoma, and Wilms' tumor. In some embodiments, the cancer is colon cancer.

[0086] Exemplary chemotherapeutic agents include aminoglutethimide, amsacrine, anastrozole, asparaginase, bicalutamide, bleomycin, buserelin, busulfan, camptothecin, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, estradiol, estramustine, etoposide, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide, among others. , imatinib, interferon, irinotecan, ironotecan, letrozole, leucovorin, leuprorelin, levamisole, lomustine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, octreotide, oxaliplatin, paclitaxel , pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, suramin, tamoxifen, temozolomide, teniposide, testosterone, thioguanine, thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin, vinblastine, vincristine, vindesine, and vinorelbine.

[0087] In various embodiments, the composition is administered systemically or locally to the target tissue by parenteral administration. The pharmaceutical composition can be formulated for administration by any suitable route, including oral administration, transdermal administration, inhalation administration, nasal administration, topical administration, intravaginal administration, ocular administration, intraaural administration, intracerebral administration, rectal administration, and parenteral administration. Some preferred routes include enteral, parenteral, inhalation, intranasal, rectal, and topical administration. In some embodiments, the compound of Formula (I), (II), or (III) is administered orally, acts locally to improve intestinal barrier function, and is partially absorbed systemically for systemic benefit.

[0088] In some embodiments, the pharmaceutical composition is formulated for intravenous administration (i.e., suitable for intravenous administration), e.g., as an aqueous or non-aqueous solution or suspension. Systemic administration of the pharmaceutical composition provides the advantage of reducing systemic inflammation as well as improving the integrity of endothelial tight junctions.

[0089] In some embodiments, the composition is an aerosol (including powder or solution aerosol) or mist (eg, optionally may be delivered using a nebulizer) formulated for pulmonary administration.

[0090] In some embodiments, the composition is formulated for topical administration to the skin, eye, ear, nose, throat, rectum, or mucous membranes.

[0091] In some embodiments, the composition is formulated for administration to the gastrointestinal tract. For example, in some embodiments, the composition is formulated to deliver an effective amount of a compound of Formula (I), (II), or (III) to the mouth, esophagus, stomach, small intestine, large intestine, colon, and / or rectum. The composition can be administered orally or topically to the rectum using a suppository or enema.

[0092] In some embodiments, the composition is formulated for systemic administration, including enteral or parenteral routes.

[0093] In some embodiments, the composition is administered to the central nervous system (CNS) of a subject. For example, the composition can be formulated for intranasal or intrathecal administration.

[0094] Exemplary doses (e.g., unit doses) of the active ingredient (a compound of Formula (I), (II), or (III), such as ARTX-413, ARTX-405A, ARTX-425P1, or ARTX-339) are in the range of about 10 mg to about 1000 mg. For example, suitable doses may range from about 25 mg to about 1000 mg, or from about 100 mg to about 1000 mg, or from about 100 mg to about 500 mg, or from about 100 mg to about 250 mg. In some embodiments, the dose (e.g., unit dose) may range from 200 mg to about 1000 mg, or from about 200 mg to about 750 mg, or from about 200 mg to about 500 mg. Such doses are administered, for example, once to three times daily. Exemplary daily doses may range from 20 mg to about 3000 mg, e.g., from 100 mg to about 2000 mg, or from about 150 mg to about 2000 mg, or from about 150 mg to about 1000 mg, or from about 150 mg to about 750 mg. In some embodiments, the unit dose according to this paragraph is an oral dosage formulation for delivery to the gastrointestinal tract or is an aerosol delivered by inhalation.

[0095] In some embodiments, the dosage is determined based on the patient's size, i.e., the active ingredient (a compound of Formula (I), (II), or (III), e.g., ARTX-413, ARTX-405A, ARTX-425P1, or ARTX-339) is administered at a dose ranging from about 1 mg / kg to about 25 mg / kg, or from 1 mg / kg to about 10 mg / kg. In some embodiments, the composition is administered parenterally (e.g., by i.v.).

[0096] Exemplary pharmaceutically acceptable carriers include sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for dissolving into sterile injectable solutions or dispersions immediately prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethylcellulose, suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. The compositions may also contain preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. To prolong absorption of injectable pharmaceutical forms, agents delaying absorption, such as aluminum monostearate and gelatin, may be included. Injectable depot forms are made by forming microencapsulated matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters), and poly(anhydrides). The rate of drug release can be controlled depending on the ratio of drug to polymer and the properties of the particular polymer used. Depot injectable formulations are also prepared by entrapping the drug in liposomes, lipid nanoparticles, or microemulsions that are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use. Suitable inert carriers include sugars such as lactose.

[0097] In some embodiments, the active ingredient is formulated as a tablet or capsule or other solid dosage form for enteral administration.In some embodiments, the solid dosage form for enteral administration not only produces local effects in the gastrointestinal tract, but also acts systemically through systemic absorption.In some embodiments, the pharmaceutical composition is formulated to deliver the active ingredient to one or more areas of the gastrointestinal tract that show inflammatory symptoms or loss of tight junction integrity, such as the esophagus, stomach, duodenum, jejunum, ileum, transverse colon, descending colon, ascending colon, sigmoid colon, cecum, rectum, etc.

[0098] In some embodiments, the active ingredient may be administered to the patient's colon as an orally administered modified-release composition. For example, the formulation may use a colon-specific drug delivery system (CODES), as described, for example, in Li et al., AAPS PharmSciTech (2002), 3(4):1-9 (the entire contents of which are incorporated herein by reference). In such a system, drug release is triggered by the colonic microflora in combination with a pH-sensitive polymer coating. For example, the formulation may be designed as a core tablet with three polymer layers: the first coating is an acid-soluble polymer (e.g., EUDRAGIT E), the outer coating is enteric, and a hydroxypropyl methylcellulose barrier layer is interposed between them. In other embodiments, colonic delivery may be achieved by formulating the active ingredient with a specific polymer, such as pectin, that degrades in the colon. The pectin may be further gelled or crosslinked with cations, such as zinc cations. Additional colon-specific formulations include, but are not limited to, pressure-controlled drug delivery systems (eg, prepared with ethylcellulose) and osmotic pressure-controlled drug delivery systems (ie, ORDS-CT).

[0099] In one embodiment, the composition may remain essentially intact or may be essentially insoluble in gastric juice. In some embodiments, the stability of the coating may be pH-dependent. A pH-dependent delayed-release coating is substantially stable in an acidic environment (a pH of about 5 or less) and substantially unstable in a near-neutral to alkaline environment (a pH of above about 5). For example, the delayed-release coating may substantially disintegrate or dissolve in a near-neutral to alkaline environment such as that found in the small intestine (e.g., one or more of the duodenum, jejunum, and ileum) and / or the large intestine (e.g., one or more of the cecum, ascending colon, transverse colon, descending colon, and sigmoid colon).

[0100] In some embodiments, the delayed-release coating comprises an enteric agent that is substantially stable in an acidic environment and substantially unstable in a near-neutral to alkaline environment. In one embodiment, the delayed-release coating contains an enteric agent that is substantially stable in gastric fluids. The enteric agent can be selected from, for example, a solution or dispersion of methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethyl ethyl cellulose, and EUDRAGIT® type polymers (poly(methacrylic acid), methyl methacrylate), hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimetate, shellac, or other suitable enteric coating polymers. EUDRAGIT® type polymers include, for example, EUDRAGIT® FS30D, L30D-55, L100-55, L100, L12,5, L12,5P, RL30D, RLPO, RL100, RL12,5, RS30D, RSPO, RS100, RS12,5, NE30D, NE40D, NM30D, S100, S12,5, and S12,5P. In some embodiments, one or more of EUDRAGIT® FS30D, L30D-55, L100-55, L100, L12,5, L12,5P RL30D, RLPO, RL100, RL12,5, RS30D, RSPO, RS100, RS12,5, NE30D, NE40D, NM30D, S100, S12,5, and S12,5P are used. The enteric coating may also be a combination of the foregoing solutions or dispersions.

[0101] In other embodiments, the delayed-release coating can degrade over time in aqueous solution, regardless of pH and / or the presence of enzymes in the solution. Such a coating can include a water-insoluble polymer. Therefore, the solubility of the coating in aqueous solution is pH-independent. As used herein, the term "pH-independent" means that the polymer's water permeability and ability to release the pharmaceutical ingredient are not a function of pH and / or only slightly dependent on pH. Such a coating can be used, for example, in the preparation of sustained-release formulations. Suitable water-insoluble polymers include pharmaceutically acceptable, non-toxic polymers that are substantially insoluble in aqueous media, such as water, regardless of the pH of the solution. Suitable polymers include, but are not limited to, cellulose ethers, cellulose esters, or cellulose ether-esters, i.e., cellulose derivatives in which some hydroxy groups on the cellulose backbone are substituted with alkyl groups and some hydroxy groups are modified with alkanoyl groups. Examples include ethyl cellulose, acetyl cellulose, nitrocellulose, etc. Other examples of insoluble polymers include, but are not limited to, lacquers, acrylic and / or methacrylic acid ester polymers, acrylate or methacrylate polymers or copolymers with low quaternary ammonium content, or combinations thereof, etc. Other examples of insoluble polymers include EUDRAGIT RS®, EUDRAGIT RL®, EUDRAGIT NE®, polyvinyl esters, polyvinyl acetals, polyacrylic esters, butadiene styrene copolymers, etc.

[0102] In some embodiments, the active ingredient is formulated as a suppository for local rectal or systemic effect. Exemplary ingredients that form the suppository base include, but are not limited to, cocoa butter or similar substitutes, polyethylene glycols, hydrogels, and glycerinated gelatin.

[0103] Topical compositions may be formulated as aqueous or non-aqueous solutions or suspensions, creams, gels (e.g., hydrogels), ointments, foams, etc. Exemplary excipients in topical compositions include, but are not limited to, emulsifiers and surfactants, including CREMOPHOR EL, lauramine oxide, myristyl dimethylamine oxide, polyoxyl 20 cetostearyl ether, polyoxyl 40 hydrogenated castor oil, polyoxyl 23 lauryl ether, poloxamer 407, carboxymethylcellulose, and the like.

[0104] In various embodiments, the compound or composition can be administered using a dosing schedule or regimen suitable for alleviating disease symptoms and / or for reducing or ameliorating disease activity or progression or for enhancing overall well-being. For example, the composition can be administered daily or 1-3 times per week. In some embodiments, the composition is administered at least about daily or at least about weekly. The dosing regimen can be for at least about one week, at least about one month, or at least about six months, or can be continued to reduce disease activity or enhance overall well-being.

[0105] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to "a functional group," "an alkyl," or "a residue" includes two or more of such functional groups, alkyls, or residues, etc.

[0106] As used herein, the terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where the event or circumstance does not occur.

[0107] As used herein, the term "subject" or "patient" refers to the target of administration, and these terms are used interchangeably.

[0108] As used herein, the term "treatment" refers to the medical management of a patient with the intent to cure, ameliorate, or stabilize a pathological condition or disorder. This term includes active treatment, the direct goal of which is to ameliorate the disease, pathological condition, or disorder, and also includes causal treatment, the goal of which is to eliminate the cause of the associated disease, pathological condition, or disorder. This term also includes palliative treatment (i.e., treatment aimed at alleviating symptoms rather than curing the disease, pathological condition, or disorder) and supportive treatment (i.e., treatment given to complement other specific treatments aimed at ameliorating the associated disease, pathological condition, or disorder).

[0109] As used herein, the terms "prevent" or "preventing" refer to preventing, avoiding, eliminating, forestalling, deterring, or impeding an event from occurring, especially by proactive action.

[0110] As used herein, the terms "administering" and "administration" refer to any method of providing a pharmaceutical preparation to a subject. Such methods of administration are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, intranasal administration, topical administration, intravaginal administration, ocular administration, intraaural administration, intracerebral administration, intrarectal administration, and parenteral administration, including injection administration (intravenous administration, intraarterial administration, intramuscular administration, subcutaneous administration, etc.). Administration can be continuous or intermittent. In various embodiments, the preparation can be administered therapeutically, i.e., administered to treat an existing disease or condition. In further various embodiments, the preparation can be administered prophylactically, i.e., administered to prevent a disease or condition.

[0111] As used herein, the term "effective amount" refers to an amount sufficient to achieve a desired result or affect an undesired condition. For example, a "therapeutically effective amount" refers to an amount sufficient to achieve a desired therapeutic result or affect an undesired condition, but generally insufficient to cause significant adverse side effects. The specific therapeutically effective dose level for a particular patient will depend on the disorder being treated and the severity of the disorder; the specific composition used; the patient's age, weight, general health, sex, and diet; the timing of administration; the route of administration; the excretion rate of the specific compound used; the duration of treatment; drugs used in combination or concomitantly with the specific compound used, and similar factors well known in the medical field. If desired, the effective daily dose can be divided into multiple doses for administration purposes. Consequently, a single dose of the composition may contain that amount or a fraction thereof to make up the daily dose. If there are any contraindications, the dosage can be adjusted by the individual physician. In further various embodiments, the preparation can be administered in a "prophylactically effective amount," i.e., an amount effective for the prevention of a disease or condition.

[0112] Chemical structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds in which one or more hydrogen atoms are replaced by deuterium or tritium, or compounds in which one or more carbon atoms are replaced by 13 C- or 14 Compounds with C-enriched carbons substituted are within the scope of the present invention.

[0113] The compounds of the present invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compound(s) and mixtures thereof, including racemic mixtures, are contemplated as part of the present invention. Furthermore, the present invention contemplates all geometric and positional isomers. For example, if a compound contains a double bond, both cis and trans forms (referred to as Z and E, respectively) and mixtures thereof are contemplated.

[0114] Mixtures of stereoisomers, e.g., mixtures of diastereomers, can be separated into their individual stereochemical components on the basis of their physical chemical differences by known methods, such as, for example, chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., alcohol), separating the resulting diastereomers, and then converting the individual diastereomers into their corresponding pure enantiomers (e.g., by hydrolysis).

[0115] The term "H" represents a single hydrogen atom and is not a substituent.

[0116] The term "alkyl," when used alone or within other terms such as "haloalkyl" or "alkylamino," encompasses straight-chain or branched hydrocarbon radicals. Exemplary alkyls have 1 to about 30 carbon atoms (or in some embodiments, 1 to 8 carbon atoms, or 1 to 4 carbon atoms). Examples of alkyls include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, and the like. The terms "alkenyl" or "alkylene" encompass bridged divalent alkyl radicals such as methylenyl or ethylenyl.

[0117] The term "alkenyl" embraces straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon double bond. Exemplary alkenyl groups have from 1 to about 30 carbon atoms (or in some embodiments, from 1 to 8 carbon atoms, or from 1 to 4 carbon atoms). Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" embraces radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations.

[0118] The term "alkynyl" refers to a straight- or branched-chain radical having at least one carbon-carbon triple bond. Exemplary alkynyl groups have from 2 to about 30 carbon atoms (or in some embodiments, from 1 to 8 carbon atoms, or from 1 to 4 carbon atoms). Examples of such radicals include propargyl and butynyl.

[0119] The alkyl, alkylenyl, alkenyl, and alkynyl substituents (including those described for compounds of Formula (I), (II), or (III)) may optionally be substituted with one or more functional groups such as halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, and heterocyclo.

[0120] The term "halo" means halogens such as fluorine, chlorine, bromine, or iodine atoms.

[0121] The term "haloalkyl" embraces radicals in which any one or more of the alkyl carbon atoms is substituted with halo, as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl, and polyhaloalkyl radicals, including perhaloalkyl. For example, monohaloalkyl radicals may have either iodo, bromo, chloro, or fluoro atoms within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl.

[0122] The term "hydroxyalkyl" embraces straight- or branched-chain alkyl radicals, e.g., having 1 to about 30 carbon atoms (or 1 to 8 or 1 to 4 carbon atoms), any one of which may be substituted with one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, and hydroxyhexyl.

[0123] The term "alkoxy" embraces straight- or branched-chain oxy-containing radicals, each having an alkyl portion of, for example, 1 to about 30 carbon atoms (or 1 to 8 or 1 to 4 carbon atoms). Examples of such radicals include methoxy, ethoxy, propoxy, butoxy, and tert-butoxy. Alkoxy radicals can be further substituted with one or more halo atoms, such as fluoro, chloro, or bromo, to provide "haloalkoxy" radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, and fluoropropoxy.

[0124] The term "aryl," alone or in combination, means a carbocyclic aromatic system containing one or more rings, and such rings may be joined together in a fused fashion. The term "aryl" encompasses aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. An "aryl" group may have one or more substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, and lower alkylamino.

[0125] The term "heterocyclyl" (or "heterocyclo") encompasses saturated, partially saturated, and unsaturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur, and oxygen. It does not include rings containing -OO-, -OS-, or -SS- moieties. "Heterocyclyl" groups may have 1 to 4 substituents such as hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy, amino, and lower alkylamino.

[0126] Examples of saturated heterocyclic radicals include saturated 3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl), saturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g., morpholinyl), and saturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl). Examples of partially saturated heterocyclyl radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.

[0127] Examples of unsaturated heterocyclic radicals, also referred to as "heteroaryl" radicals, include unsaturated 5- to 6-membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyranidyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic groups containing an oxygen atom, such as pyranyl, 2-furyl, 3-furyl, etc.; and unsaturated 5- to 6-membered heteromonocyclic groups containing a sulfur atom. Monocyclic groups include, for example, 2-thienyl, 3-thienyl, etc., unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl], and unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

[0128] The term heterocyclyl, (or heterocyclo) also encompasses radicals in which a heterocyclic radical is fused / condensed with an aryl radical: unsaturated fused heterocyclic groups containing 1-5 nitrogen atoms, e.g., indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo[1,5-b]pyridazinyl]; unsaturated fused heterocyclic groups containing 1-2 oxygen atoms and 1-3 unsaturated fused heterocyclic groups containing nitrogen atoms (e.g., benzoxazolyl, benzoxadiazolyl); unsaturated fused heterocyclic groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms (e.g., benzothiazolyl, benzothiadiazolyl); and saturated, partially unsaturated, and unsaturated fused heterocyclic groups containing 1-2 oxygen or sulfur atoms (e.g., benzofuryl, benzothienyl, 2,3-dihydro-benzo[1,4]dioxinyl, and dihydrobenzofuryl). Examples of heteroaryl radicals include quinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl, and pyrazinyl. Other heteroaryl radicals are 5- or 6-membered heteroaryl containing one or two heteroatoms selected from sulfur, nitrogen, and oxygen, and are selected from thienyl, furyl, pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl, and pyrazinyl.

[0129] Particular examples of non-nitrogen-containing heteroaryls include pyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzofuryl, and benzothienyl.

[0130] Specific examples of partially saturated and saturated heterocyclyl include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindonyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isobenzo ... quinolyl, 1,2,3,4-tetrahydroquinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.

[0131] Thus, the term "heterocyclo" encompasses the following ring systems: [ka] [ka] [ka] etc.

[0132] The terms "carboxy" or "carboxyl," whether used alone or with other terms such as "carboxyalkyl," refer to -CO2H.

[0133] The term "carbonyl," whether used alone or with other terms, such as "aminocarbonyl," refers to --(C.dbd.O)--.

[0134] The term "cycloalkyl" embraces saturated carbocyclic groups. Examples of such radicals include cyclopentyl, cyclopropyl, and cyclohexyl.

[0135] The term "cycloalkenyl" includes carbocyclic groups having one or more carbon-carbon double bonds, including "cycloalkyldienyl" compounds.

[0136] For purposes of describing and claiming the present invention, the open-ended term "comprising" is used herein as synonymous with terms such as including, containing, or having, although the invention, or embodiments thereof, may alternatively be described using alternative terms, for example, "consisting of" or "consisting essentially of."

[0137] The symbol "-" represents a covalent bond and can also be used in radical groups to indicate a point of attachment to another group. In chemical structures, this symbol is commonly used to represent a methyl group in a molecule.

[0138] The term "excipient" means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API), that is normally included in a formulation and / or administration to a patient.

[0139] The term "therapeutically effective amount" means an amount of a compound that ameliorates, attenuates, or eliminates one or more symptoms of a particular disease or condition, or prevents or delays the onset of one or more symptoms of a particular disease or condition.

[0140] The term "pharmaceutically acceptable" means that the referenced substance, such as a compound or composition described herein, or a salt thereof, or a formulation containing a compound described herein or a particular excipient, is suitable for administration to a patient.

[0141] As used herein, the term "about" means ±10% of the relevant numerical value.

[0142] All patents, patent applications, and other publications cited herein are hereby incorporated by reference.

[0143] Those skilled in the art may make modifications and variations in the embodiments described herein without departing from the scope and spirit of the present disclosure.

[0144] 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 invention belongs.

[0145] Other aspects and embodiments of the present invention will become apparent from the following examples. [Example]

[0146] The present teachings having been generally described will be more readily understood with reference to the following examples. Example 1: UroA and UAS03 enhance intestinal epithelial barrier function via the aryl hydrocarbon (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways.

[0147] The lactone ring of Urolithin A (UroA) is acid-labile and sensitive to hydrolytic enzymes (see Figure 1). The UroA cyclic ester was converted to an ether to produce a compound designated UAS03, which is stable in the presence of gastric enzymes at pH 2.0 for at least 12 hours (while UroA is rapidly hydrolyzed under the same conditions). 44 UroA 36~43 Similarly, UAS03 also inhibits bone marrow-derived macrophages and LPS-induced mouse peritonitis model. 44It significantly reduced lipopolysaccharide (LPS)-induced TNF-α, IL-6, CXCL-1, and IL-1β levels in HT-29 and Caco-2 intestinal epithelial cell lines. RNA-seq and qRT-PCR analysis revealed that UAS03 was involved in the regulation of the tight junction proteins (TJPs) claudin-4, ZO-1, and occludin-1. 44 UAS03 was shown to upregulate the expression of Caco2 or HT-29 in Transwell assays. 44 UAS03 also upregulated the cytochrome P450 1A1 (Cyp1A1) and heme oxynase 1 (HMOX1 or HO1) genes. 44 (AhR, respectively) 62 and Nrf2 63 Importantly, the barrier-protective activity of UAS03 was mediated by the AhR and Nrf2 pathways. 44 It depends on the expression of UroA, which indicates that UroA regulates the AhR signaling pathway. 64 This is consistent with published data showing that Nrf2 is an AhR ligand that activates AhR. - / - or AhR - / - Experiments using mice have shown that UroA and UAS03 activate the AhR pathway, which in turn activates the Nrf2 pathway and TJP expression. 44 This model supports the idea that

[0148] AhR is a ligand-dependent transcription factor that is sensitive to diet and the gut microbiota. 65~67 Accumulating evidence suggests that AhR mediates intestinal epithelial barrier function. 50~52 and that the absence of AhR or its ligands compromises the integrity of the intestinal barrier. 53、54、68、69 The discovery of endogenous AhR ligands has led to the discovery that AhR acts as a receptor for xenotoxins. 65~67、46 Finally, natural microbial tryptophan metabolites, which are AhR ligands, are also involved in the regulation of ulcerative colitis in animal models.51 restores intestinal barrier dysfunction in IBD, suggesting that AhR-based therapeutics may restore barrier function in IBD.

[0149] Example 2: UAS03 in the murine TNBS and DSS models of ulcerative colitis Intrarectal administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS) inhibited CD4 proliferation in mice. + Induces dependent colitis, increasing intestinal permeability, shortening of the colon, and increased inflammation 70 Oral administration of 20 mg / kg UAS03 QD or BID for 3 days after TNBS treatment dramatically improved the symptoms of UC (Figure 2, A-D). 44 UAS03 also blocked the development of TNBS-induced symptoms when mice were pretreated with 20 mg / kg UAS03 QD for 7 days. Ameliorated symptoms included weight loss, colon weight / length ratio (Figure 2A), increased intestinal permeability (Figure 2B), and elevated levels of proinflammatory cytokines (Figure 2C). 44 UAS03 treatment induced the expression of the tight junction protein, claudin 4 (cldn4). Importantly, UAS03 also ameliorated the dramatic decrease in claudin 4 (Cldn4) protein levels in TNBS-treated mice (Figure 2D). The beneficial effects of UAS03 in TNBS-treated mice were due to the AhR - / - Nrf2 in mutant mice - / - was not observed in mutant mice 44 UAS03 was approximately 10-fold more effective than UroA in the TNBS model, likely due to its improved stability. 44 UAS03 inhibits acute and chronic dextran sulfate sodium (DSS)-induced 71、72 It was also effective in both colitis models. 44In the chronic model, mice received 2% DSS in drinking water for 7 days, followed by a 14-day washout period with regular water for four cycles (total 90-day experiment). Mice were administered 20 mg / kg UAS03 QD on days 4 and 6 of the DSS treatment cycle and on day 7 of the water cycle. UAS03 treatment protected against DSS-induced chronic colitis. Published UAS03 data from TNBS and DSS experiments are summarized in Table 1. 44 . [Table 1]

[0150] Although UAS03 has biological activity, it is not considered a viable candidate for therapeutic development. UAS03 (and UroA) are predicted to form highly reactive quinones, which are associated with "false-positive" hits in chemical library screening and long-term toxicity due to their reactivity (see Figure 3B). Another concern with the UAS03 and UroA scaffolds is that they are planar molecules that may intercalate into the DNA helix, potentially forming reactive metabolites that covalently bind to DNA bases and result in genotoxicity. While UroA is not known to be genotoxic, some UroA analogs with the same planar structure have tested positive in the Ames test, suggesting that these structures may be genotoxic (especially when stabilized with ether bonds). Therefore, careful compound design is considered necessary to avoid planarity and / or reactive hydroxyl groups, e.g., those that can be metabolized to highly reactive species.

[0151] Example 3: Compound screening process Compounds with structures derived from UroA and UAS03 but that are likely to be non-genotoxic due to their inability to form quinones and / or their lack of a non-planar and / or reactive hydroxyl moiety were designed (Figure 4) and synthesized according to the general scheme shown in Example 9.

[0152] The following steps show the procedure used to screen compounds with reference to UroA and UAS03.

[0153] Step 1: Test compounds at 25 μM in an EpiIntestinal tissue model using TEER and / or FITC-dextran assays to identify structures with activity comparable to UAS03 and UroA in restoring barrier function disrupted by LPS. This "EpiIntestinal" transwell model incorporates enterocytes, Paneth cells, M cells, tufted cells, intestinal stem cells, and the basal lamina propria into a differentiated, polarized epithelium. 73 This model exhibits functional tight junctions and brush borders at the apical tissue surface, which mimics many aspects of normal intestinal function, including intestinal barrier function and inflammatory responses. 73 The rationale for testing compounds first in the EpiIntestinal Permeability Model is that this model allows for relatively high throughput in 96-well plates, allowing a direct test of efficacy in enhancing barrier function.

[0154] Step 2: Compounds selected in Step 1 were tested at various concentrations for activation of Cyp1A1 mRNA levels by qRT-PCR, activation of Cyp1A1 enzymatic activity (ethoxyresorufin-O-deethylase (EROD) assay), or activation of an AhR reporter gene driven by a so-called dioxin-responsive element (DRE) using a commercially available kit. Activation of Cyp1A1 mRNA levels, activation of Cyp1A1 enzymatic activity, or activation of a DRE-driven AhR reporter gene construct is generally considered to be an indication of the compound's ability to function as an AhR ligand. Upon ligand activation, cytoplasmic AhR translocates to the nucleus and dimerizes with the AhR nuclear transport protein ARNT. The AhR / ARNT complex then binds to the DRE and activates gene transcription.

[0155] Step 3: A limited number of compounds selected in Step 2 were tested in a mouse DSS-induced ulcerative colitis model to identify compounds with efficacy equivalent to UAS03 / UroA at 10 and / or 20 mg / kg.

[0156] Step 4: Compounds are subjected to toxicity testing, including hERG and Ames tests.

[0157] Example 4: Efficacy and efficacy of ARTX-86 ARTX-86 has the following chemical structure: [ka] It has.

[0158] Following the procedures described in Example 3, ARTX-86, a compound designed to be unable to form quinones, was found to be comparable in potency and efficacy to UAS03 in enhancing intestinal epithelial barrier function in a 3D EpiIntestinal tissue model. ARTX-86 was also as effective as UAS03 in the DSS and TNBS mouse models of UC. ARTX-86 also demonstrated activity comparable to UroA and UAS03 in activating Cyp1A1 expression. Furthermore, ARTX-86 did not exhibit any observable acute toxicity in rats (MTD > 2000 mg / kg, NOAEL = 1000 mg / kg / day), did not exhibit cardiac toxicity up to 60-fold the effective dose in the hERG assay, and demonstrated favorable pharmacokinetic properties in preliminary rat studies (C when administered at 20 mg / kg). max = 92 ± 15 ng / mL, T 1 / 2= 2.22 ± 0.5 hours). However, when ARTX-86 was subjected to the Ames test, one Salmonella strain tested positive in the presence of liver-derived S9 enzyme but negative in its absence, suggesting that ARTX-86 may be metabolized to a potentially genotoxic compound. This was unexpected, as UroA has been extensively tested for genotoxicity and no genotoxic indications have been reported. However, the genotoxic potential of ARTX-86 is consistent with its planar structure, which allows ARTX-86 to intercalate into the DNA double helix. Reactive metabolites of ARTX-86 may be formed by the S9 fraction, and ARTX-86 intercalating into the DNA helix may deliver radicals and other toxic metabolites directly to DNA.

[0159] Example 5: ARTX-405A, ARTX-413, and ARTX-425P1 are effective in reducing LPS-induced intestinal permeability in an EpiIntestinal tissue model. After ARTX-86 was found to be genotoxicity-positive in the Ames test (Example 4), only compounds designed to be non-genotoxic (e.g., by not containing a non-planar structure and / or a reactive hydroxyl moiety) were subjected to the screening step described in Example 3. As a result, as shown in Figure 5, several compounds, including ARTX-405A, ARTX-413, and ARTX-425P1, were found to be as effective as or more effective than ARTX-86 in reducing intestinal permeability in the EpiIntestinal tissue model.

[0160] Example 6: ARTX-339, ARTX-405A, ARTX-413, and ARTX-425P1 are effective in a mouse DSS UC model. The efficacy of compounds in vivo was measured using a mouse dextran sulfate sodium (DSS)-induced ulcerative colitis model. Oral administration of DSS, a chemical colitis inducer with anticoagulant properties, in drinking water damages the intestinal epithelium, leading to increased intestinal permeability, inflammation, and severe impairment of the intestinal barrier function. 71、72 DSS model in mice 71、72 The reason for using UC as a model is that this model, which disrupts the intestinal epithelial barrier, is well established and can model both acute and chronic UC. 70,71 Using an acute DSS-induced model, we tested the efficacy of ARTX-339, ARTX-405A, ARTX-413, and ARTX-425P1 in reducing LPS-induced permeability in a human-derived in vitro EpiIntestinal organoid tissue model. Most of these compounds were designed to be non-genotoxic because, in addition to being unable to form quinones, they are non-planar and / or do not contain reactive hydroxyl moieties.

[0161] As shown in Figure 6A, C57BL / 6 mice (7–8 weeks old) were fed 2.5% DSS in their drinking water for 7 days. Starting on day 4 of DSS treatment (day 4), mice were orally administered 100 μL of vehicle (0.25% sodium carboxymethylcellulose, used in the formulation of ARTX compounds) or 100 μL of ARTX-339, ARTX-405A, ARTX-413, or ARTX-425P1 at a dose of 20 mg / kg body weight every other day (days 4, 6, 8, and 10). Mice were euthanized on day 12. Four hours before euthanasia, mice were orally administered FITC-dextran. After euthanasia, the colons were dissected and their lengths were measured.

[0162] A total of five mice were used in each experimental group (Figures 6A-6F). ARTX-339, ARTX-405A, ARTX-413, and ARTX-425P1 each demonstrated efficacy in the DSS-induced colitis mouse model. Figures 6A-6F show that ARTX-405A and ARTX-413 demonstrated significant efficacy in this model, as measured by their ability to increase colon length (Figures 6B and 6C), reduce intestinal permeability (Figure 6D), protect against DSS-induced weight loss (Figure 6E), and reduce the disease activity index (DAI) (Figure 6F). Although no statistically significant increase in colon length was observed with ARTX-339 and ARTX-425P1, each of ARTX-339 and ARTX-425P1 showed highly statistically significant data regarding the reduction of intestinal permeability (FIG. 6D), as well as the suppression of body weight loss (FIG. 6E) and the reduction of DAI (FIG. 6F), as follows: **** indicates p<0.0001, *** indicates p<0.001, and ** indicates p<0.01.

[0163] Example 7. ARTX-413 activates the AhR signaling pathway. Figures 7A and 7B show the ability of ARTX-413 to activate the AhR signaling pathway. In these experiments, human hepatocytes (Figure 7A) or human intestinal epithelial cells (Figure 7B) containing a luciferase AhR reporter gene construct driven by a so-called dioxin response element (DRE) were treated with various concentrations of ARTX-413 or the well-studied AhR ligand β-naphthoflavone (BNF) using commercially available kits. Activation of Cyp1A1 mRNA levels, Cyp1A1 enzyme activity, or the DRE-driven AhR reporter gene construct is generally considered to indicate the compound's ability to function as an AhR ligand.

[0164] Example 8. Toxicity Testing of ARTX-413 The Ames test demonstrated that ARTX-413 was non-genotoxic, even at concentrations as high as 1.0 mg / mL. Figure 8 shows the results of ARTX-413 in the hERG assay, suggesting that ARTX-413 poses a low risk of cardiac toxicity. Furthermore, in vitro safety pharmacology assays did not identify any significant off-target effects.

[0165] Example 9: Synthetic Scheme The synthetic scheme for the synthesis of ARTX-413 is shown in FIG. Preparation of 2-bromo-5-fluorobenzyl acetate (compound 2 in Figure 9) To a solution of (2-bromo-5-fluorophenyl)methanol (100 g, 487.75 mmol, 1.00 equiv) and AcO (74.69 g, 731.62 mmol, 68.52 mL, 1.50 equiv) in DCM (500 mL) was added pyridine (3.86 g, 48.77 mmol, 3.94 mL, 0.1 equiv) dropwise at 25 °C, and the resulting mixture was stirred at 25 °C for 16 h. The mixture was quenched with saturated aqueous sodium bicarbonate (200 mL) and stirred at 20 °C for 1 h. The organic phase was washed with saturated aqueous sodium bicarbonate (200 mL x 2), 1 N aqueous HCl (200 mL), water (500 mL), and brine (500 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The crude product was used directly without further purification. 2-Bromo-5-fluorobenzyl acetate (105 g, 425.00 mmol, 87.13% yield) was obtained as a colorless crystalline solid.

[0166] Preparation of 5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (Compound 3 in Figure 9) To a solution of 2-bromo-5-fluorobenzyl acetate (50 g, 202.38 mmol, 1.00 equiv.) in dioxane (600 mL) was added AcOK (56.00 g, 570.60 mmol, 2.82 equiv.) and bis(pinacolato)diboron (56.00 g, 220.53 mmol, 1.09 equiv.). The resulting mixture was degassed and purged with nitrogen three times, then Pd(dppf)Cl (2.50 g, 3.42 mmol, 1.69 × 10 -2 Equivalents) were added, and the mixture was heated to 80°C and stirred at 80°C for 16 hours. The reaction mixture was cooled and quenched with water (500 mL) and extracted with ethyl acetate (3 x 500 mL). The combined layers were washed with water (1000 mL) and brine (1000 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The crude product was used directly without further purification. 5-Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (65 g, 194.47 mmol, 96.09% yield, 88% purity) was obtained as a yellow oil.

[0167] Preparation of (4-fluoro-2-(hydroxymethyl)phenyl)boronic acid (compound 4 in Figure 9) To a solution of 5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (140 g, 475.99 mmol, 1 equiv.) in MeOH (40 mL) was added NaOH (38.08 g, 951.97 mmol, 2 equiv.) and the mixture was stirred at 20° C. for 4 h. The mixture was concentrated in vacuo to give a residue. The crude product was used directly without further purification. (4-Fluoro-2-(hydroxymethyl)phenyl)boronic acid (81 g, crude) was obtained as a white solid.

[0168] Preparation of 5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol (Compound 5 in Figure 9) To a solution of (4-fluoro-2-(hydroxymethyl)phenyl)boronic acid (81 g, 476.62 mmol, 1 equiv.) in THF (480 mL) and water (240 mL), HCl (12 M, 210.21 mL, 5.29 equiv.) was added dropwise over 5 minutes at 25° C., and the resulting mixture was stirred at 25° C. for 16 hours. The mixture was extracted with ethyl acetate (5×20 mL), and the combined layers were concentrated in vacuo to give a residue that was then redissolved in a solution of NaOH (19.06 g, 476.62 mmol, 1 equiv.) in water (480 mL), followed by the addition of ethyl acetate (50 mL). The aqueous solution was separated, washed with ethyl acetate (50 mL), and acidified with 1N aqueous HCl (5 mL). A white solid precipitated and was filtered to give the crude product. The crude product was used directly without further purification. 5-Fluorobenzo[c][1,2]oxaborol-1(3H)-ol (42 g, 276.44 mmol, 58.00% yield) was obtained as a white solid.

[0169] Preparation of 3-chloro-8-fluoro-6H-isochromeno[3,4-d]pyrimidine (Compound 7 in Figure 9) A mixture of 5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol (26.53 g, 174.63 mmol, 1.2 equiv.), 2,4-dichloro-5-iodopyrimidine (40 g, 145.52 mmol, 1 equiv.), Pd(dppf)Cl (10.65 g, 14.55 mmol, 0.1 equiv.), and sodium carbonate (46.27 g, 436.56 mmol, 3 equiv.) in dioxane (400 mL) and water (100 mL) was stirred at 80° C. under nitrogen for 2 h. The mixture was cooled to 20° C. and poured into a mixture of water (500 mL) and ethyl acetate (1000 mL). The aqueous solution was washed with ethyl acetate (2×1000 mL). The combined layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The crude product was triturated in dichloromethane (100 mL) at 20° C. for 30 minutes to give 3-chloro-8-fluoro-6H-isochromeno[3,4-d]pyrimidine (25 g, 105.65 mmol, 72.60% yield) as an off-white solid.

[0170] Preparation of ARTX-413—8-fluoro-6H-isochromeno[3,4-d]pyrimidin-3-ol (Figure 9) To a solution of 3-chloro-8-fluoro-6H-isochromeno[3,4-d]pyrimidine (23 g, 97.20 mmol, 1 equiv.) in dioxane (600 mL) and water (600 mL) was added potassium carbonate (24.18 g, 174.96 mmol, 1.8 equiv.) and 1,4-diazabicyclo[2.2.2]octane (5.45 g, 48.60 mmol, 5.34 mL, 0.5 equiv.) at 20° C., and the resulting mixture was stirred at 70° C. for 2 hours. The mixture was cooled, acidified to pH 5 with 1 N HCl at 10° C., filtered, and the filter cake was collected. The crude product was triturated with methanol (50 mL) at 25° C. for 1 hour and then filtered to obtain the filter cake. 8-Fluoro-6H-isochromeno[3,4-d]pyrimidin-3-ol (11.38 g, 50.30 mmol, 51.75% yield, 96.403% purity) was obtained as an off-white solid.

[0171] The synthetic scheme of ARTX-405A is shown in Figure 10. Preparation of 2-bromo-4-fluoro-2',4'-dimethoxy-1,1'-biphenyl (Compound 2 in Figure 10) A mixture of 2-bromo-4-fluoro-1-iodo-benzene (25.0 g, 83.1 mmol, 1.00 equiv.), (2,4-dimethoxyphenyl)boronic acid (15.1 g, 83.1 mmol, 1.00 equiv.), potassium carbonate (34.5 g, 249.26 mmol, 3.00 equiv.), and bis(triphenylphosphine)palladium(II) chloride (5.83 g, 8.31 mmol, 0.100 equiv.) in dioxane (250 mL) and water (50.0 mL) was degassed and purged with nitrogen three times, and then stirred at 80° C. under a nitrogen atmosphere for 3 hours. The reaction mixture was diluted with water (1000 mL) and extracted with ethyl acetate (2×1000 mL). The combined organic layers were washed with brine (1000 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1 to 20 / 1) to give 1-(2-bromo-4-fluoro-phenyl)-2,4-dimethoxy-benzene (48 g, 146.6 mmol, yield 88.2%, purity 95.0%) as a yellow solid.

[0172] Preparation of 1-(4-fluoro-2',4'-dimethoxy-[1,1'-biphenyl]-2-yl)cyclopentanol (Compound 3 in Figure 10) To a solution of 1-(2-bromo-4-fluoro-phenyl)-2,4-dimethoxy-benzene (12.0 g, 38.6 mmol, 1.00 equiv.) in tetrahydrofuran (200 mL), n-butyllithium (2.50 M, 18.5 mL, 1.20 equiv.) was added dropwise at −78° C. under a nitrogen atmosphere. After the addition, the mixture was stirred at that temperature for 1 hour, and then cyclopentanone (9.73 g, 116 mmol, 10.2 mL, 3.00 equiv.) was added dropwise at −78° C. The resulting mixture was stirred at 20° C. for 2 hours. The reaction mixture was quenched at 0° C. by adding saturated aqueous ammonium chloride solution (100 mL), then diluted with water (50.0 mL), and extracted with ethyl acetate (150 mL×3). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 330 g SepaFlash® silica flash column, elution with a 0-20% ethyl acetate / petroleum ether gradient at a flow rate of 100 mL / min) to give 1-[2-(2,4-dimethoxyphenyl)-5-fluoro-phenyl]cyclopentanol (16.0 g, 47.5 mmol, 30.8% yield, 94.0% purity) as a yellow oil. Preparation of 7'-fluorospiro[cyclopentane-1,9'-fluorene]-2',4'-diol (ARTX-405A in Figure 10) To a solution of 1-[2-(2,4-dimethoxyphenyl)-5-fluoro-phenyl]cyclopentanol (8.00 g, 25.3 mmol, 1.00 equiv) in dichloromethane (80.0 mL) was added boron tribromide (31.7 g, 126 mmol, 12.2 mL, 5.00 equiv) at 0° C. The mixture was stirred at 25° C. for 12 hours. The mixture was added dropwise to water (500 mL), and the organic phase was separated from the aqueous phase and extracted with dichloromethane (500×3 mL). The organic layers were combined, washed with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 330 g SepaFlash® silica flash column, eluting with a 0-20% ethyl acetate / petroleum ether gradient at a flow rate of 100 mL / min) to give 7'-fluorospiro[cyclopentane-1,9'-fluorene]-2',4'-diol (10.32 g, 37.7 mmol, 74.5% yield, 98.7% purity) as an off-white solid.

[0173] The synthetic scheme for ARTX-425-P1 is shown in Figure 11.

[0174] Preparation of 8-fluoro-3-hydroxy-6H-benzo[c]chromen-6-one (Compound 3 in Figure 11) 2-Bromo-5-fluorobenzoic acid (100 g, 456.60 mmol, 1 equiv.), resorcinol (100.55 g, 913.21 mmol, 152.35 mL, 2 equiv.), and sodium hydroxide (36.53 g, 913.21 mmol, 2 equiv.) were dissolved in water (1 L), followed by the addition of copper sulfate pentahydrate (11.40 g, 45.66 mmol, 0.1 equiv.). The mixture was stirred under nitrogen at 80° C. for 2 hours. The mixture was filtered, and the filter cake was collected. The solid was mixed with methanol (100 mL) and then concentrated in vacuo to give a residue. The crude product was used directly without further purification. 8-Fluoro-3-hydroxy-6H-benzo[c]chromen-6-one (57.6 g, 248.73 mmol, 54.47% yield, 99.4% purity) was obtained as a red solid.

[0175] Preparation of 8-fluoro-6-isopropyl-6H-benzo[c]chromene-3,6-diol (Compound 4 in Figure 11) To a solution of 8-fluoro-3-hydroxy-6H-benzo[c]chromen-6-one (25 g, 108.61 mmol, 1 equiv.) in dry tetrahydrofuran (1.5 L) at −25°C under a nitrogen atmosphere was added i-PrMgCl ·LiCl (1.3 M, 501.26 mL, 6 equiv.) dropwise. The mixture was stirred at −25°C for 2 hours and at −10°C for an additional 2 hours. The mixture was quenched with saturated NH Cl (aqueous, 500 mL), diluted with water (500 mL), and extracted with ethyl acetate (2 L × 3). The combined layers were washed with brine (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The crude product was used directly without further purification. 8-Fluoro-6-isopropyl-6H-benzo[c]chromene-3,6-diol (40 g, 145.83 mmol, 67.14% yield) was obtained as a white solid.

[0176] Preparation of 8-fluoro-6-isopropyl-6H-benzo[c]chromen-3-ol (Compound 5 in Figure 11) To a solution of 8-fluoro-6-isopropyl-6H-benzo[c]chromene-3,6-diol (40 g, 145.83 mmol, 1 equiv) in dichloromethane (1.6 L) was added EtSiH (254.36 g, 2.19 mol, 349.39 mL, 15 equiv) and BF·EtO (82.79 g, 583.33 mmol, 71.99 mL, 4 equiv) dropwise at −70° C., and the resulting mixture was stirred at 25° C. for an additional 16 h. The mixture was concentrated in vacuo to give a residue.

[0177] Preparation of ARTX-425 (peak 1) and ARTX-425 (peak 2)-(S)-8-fluoro-6-isopropyl-6H-benzo[c]chromen-3-ol and (R)-8-fluoro-6-isopropyl-6H-benzo[c]chromen-3-ol (Figure 11).

[0178] The crude product was purified by preparative SFC (column: DAICEL CHIRALPAK AD (250 mm × 50 mm, 10 μm); mobile phase: [0.1% NH₃·HO EtOH]; B%: 45% to 45%, B%: 5.7; 150 min). (S)-8-Fluoro-6-isopropyl-6H-benzo[c]chromen-3-ol (15.73 g, 60.58 mmol, 41.54% yield, 99.48% purity) was obtained as a white solid. References 1 Loftus, EV, Jr. Update on the Incidence and Prevalence of Inflammatory Bowel Disease in the United States. Gastroenterol Hepatol (NY) 12, 704-707 (2016). 2 Buhner, S. et al. Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation? Gut 55, 342-347, doi:10.1136 / gut.2005.065557 (2006). 3 Gecse, K. et al. Leaky gut in patients with diarrhea-predominant irritable bowel syndrome and inactive ulcerative colitis. Digestion 85, 40-46, doi:10.1159 / 000333083 (2012). 4 Turpin, W. et al. Increased Intestinal Permeability Is Associated With Later Development of Crohn's Disease. 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Claims

1. A compound of formula (I), 【Chemistry 1】 or a pharmaceutically acceptable salt or solvate thereof, wherein: Each R １ are independently OH, NO ２ , Haro, CF ３ , N.R. ３ R ４ , (C １ -C ６ ) alkoxy, —C(O)(C １ -C ６ ) alkyl, and —C(O)O(C １ -C ６ ) alkyl; Each R ２ is a substituent other than OH; R ３ and R ４ are each independently selected from the group consisting of H, alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclo, aryl, and heteroaryl; R ３ and R ４ together with the carbon to which they are attached (C ３ -C ８ ) cycloalkyl or (C ３ -C ８ ) forming a heterocycle; X １ and X ２ are each independently C or N, provided that X １ and X ２ are not both C; X ３ is O or S; m is an integer ranging from 1 to 4; The compound, or a pharmaceutically acceptable salt or solvate thereof, wherein n is an integer ranging from 1 to 4.

2. Each R ２ are independently halo, NO ２ , C.F. ３ , N.R. ３ R ４ , (C １ -C ６ ) alkoxy, —C(O)(C １ -C ６ ) alkyl, (C ３ -C ８ ) cycloalkyl, and —C(O)O(C １ -C ６ 2. The compound of claim 1, wherein the alkyl is selected from the group consisting of:

3. R １ 3. The compound of claim 1, wherein is OH and n is 1 or 2.

4. 4. The compound of claim 3, wherein n is 1.

5. R ２ The compound of any one of claims 1 to 4, wherein is halo and m is 1 or 2.

6. 6. The compound of claim 5, wherein m is 1.

7. R ２ The compound according to claim 5 or 6, wherein is F.

8. X １ and X ２ The compound according to any one of claims 1 to 7, wherein each is N.

9. X ３ The compound according to any one of claims 1 to 8, wherein is O.

10. R ３ and R ４ The compound according to any one of claims 1 to 9, wherein each is H.

11. R ３ and R ４ One of them is (C １ -C ６ ) alkyl or (C ２ -C ６ 10. The compound of claim 1, wherein one of the groups is 1-3, and the other is H.

12. R ３ and R ４ together with the carbon to which they are attached (C ３ -C ８ ) cycloalkyl or (C ３ -C ８ ) forming a heterocycle.

13. R １ is OH and n is 1; R ２ is halo and m is 1; X １ and X ２ are both N; X ３ is O; R ３ and R ４ 10. The compound of claim 1, wherein each is H.

14. R ２ The compound of claim 13, wherein is F.

15. 15. The compound of claim 14 having the structure: 【Chemistry 2】

16. R １ is OH and n is 1; R ２ is F and m is 1; X １ and X ２ are both N; X ３ is O; R ３ is H; The compound of claim 1, wherein R4 is isopropyl.

17. 17. The compound of claim 16 having the structure: 【Transformation 3】

18. A compound of formula (II), 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, wherein: Each R １ are independently OH, NO ２ , Haro, CF ３ , N.R. ３ R ４ , (C １ -C ６ ) alkoxy, —C(O)(C １ -C ６ ) alkyl, and —C(O)O(C １ -C ６ ) alkyl; Each R ２ is a substituent other than OH; R ３ and R ４ are each independently selected from the group consisting of H, alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclo, aryl, and heteroaryl; R ３ and R ４ together with the carbon to which they are attached (C ３ -C ８ ) cycloalkyl or (C ３ -C ８ ) forming a heterocycle; X １ and X ２ is independently C or N; X ４ and X ５ are both bonds or X ４ is CR ５ R ６ and X ５ is S, O, or CR ７ R ８ either R ５ , R ６ , R ７ , and R ８ are each independently selected from the group consisting of H, halo, alkyl, alkenyl, and alkoxy; m is an integer ranging from 1 to 4; The compound, or a pharmaceutically acceptable salt thereof, wherein n is an integer ranging from 1 to 4.

19. Each R １ 19. The compound of claim 18, wherein is OH and n is 1 or 2.

20. 20. The compound of claim 19, wherein n is 2.

21. X １ and X ２ and each is C.

22. n is 1 and X １ and X ２ 20. The compound of claim 19, wherein one or both of

23. Each R ２ Ha, hello, NO ２ , C.F. ３ , N.R. ３ R ４ , (C １ -C ６ ) alkoxy, —C(O)(C １ -C ６ ) alkyl, (C ３ -C ８ ) cycloalkyl, and —C(O)O(C １ -C ６ 23. The compound of any one of claims 18 to 22, wherein the aryl group is selected from the group consisting of aryl, aryl, aryl ...

24. R ２ 24. The compound of claim 23, wherein is halo.

25. R ２ is F.

26. 26. The compound of claim 24 or 25, wherein m is 1.

27. R ３ and R ４ together with the carbon to which they are attached (C ３ -C ８ ) cycloalkyl or (C ３ -C ８ ) forming a heterocycle.

28. R ３ and R ４ 28. The compound of claim 27, wherein, together with the carbons to which they are attached, form a 5- or 7-membered carbocyclic ring.

29. R ３ and R ４ One of them is (C １ -C ６ ) alkyl or (C ２ -C ６ 27. The compound of any one of claims 18 to 26, wherein one is alkenyl and the other is H.

30. R ３ and R ４ The compound according to any one of claims 18 to 26, wherein one of

31. R ３ and R ４ The compound of any one of claims 18 to 26, wherein both of are H.

32. Each R １ is OH and n is 1 or 2; Each R ２ is halo and m is 1 or 2; R ３ and R ４ 19. The compound of claim 18, wherein, together with the carbons to which they are attached, form a 5- or 7-membered carbocyclic ring.

33. n is 2; m is 1; R １ is F; R ３ and R ４ together with the carbon to which they are attached form a cyclopentyl.

34. 34. The compound of claim 33, wherein the compound has the structure: 【Transformation 5】

35. A compound of formula (III), 【Transformation 6】 or a pharmaceutically acceptable salt thereof, wherein: Each R １ are independently OH, NO ２ , Haro, CF ３ , N.R. ３ R ４ , (C １ -C ６ ) alkoxy, —C(O)(C １ —C(O)O(C1-C6)alkyl; Each R ２ is a substituent other than OH; R ３ and R ４ are each independently selected from the group consisting of H, alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclo, aryl, and heteroaryl; R ３ and R ４ together with the carbon to which they are attached (C ３ -C ８ ) cycloalkyl or (C ３ -C ８ ) form a heterocycle; provided that R ３ and R ４ are not both H; X ６ and X ７ are each independently C or N; X ３ is O or S; m is an integer ranging from 1 to 4; The compound, or a pharmaceutically acceptable salt thereof, wherein n is an integer ranging from 1 to 4.

36. X ３ is O.

37. R １ 37. The compound of claim 35 or 36, wherein is OH.

38. X ６ is N and X ７ The compound according to any one of claims 35 to 37, wherein is N.

39. X ６ is N and X ７ The compound according to any one of claims 35 to 37, wherein is C.

40. X ６ is CH, and X ７ The compound according to any one of claims 35 to 37, wherein is N.

41. X ６ is CH, and X ７ The compound according to any one of claims 35 to 37, wherein is C.

42. Each R ２ Ha, Halo, CN, NO ２ , -C(O)(C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, C(O)O(C １ -C ６ ) alkyl, aryl, heteroaryl, NR ３ R ４ , and CF ３ The compound according to any one of claims 35 to 41, selected from:

43. Each R ２ 43. The compound of claim 42, wherein is halo and m is 1 or 2.

44. R ２ is F.

45. 45. The compound of claim 43 or 44, wherein m is 1.

46. R ３ The compound of any one of claims 35 to 45, wherein is alkyl, alkenyl, or cycloalkyl.

47. R ３ is (C １ -C ６ ) alkyl.

48. R ３ 48. The compound of claim 47, wherein is isopropyl.

49. R ４ The compound of any one of claims 46 to 48, wherein is H.

50. R ４ The compound of any one of claims 46 to 48, wherein is alkyl, alkenyl, or cycloalkyl.

51. R ３ and R ４ together with the carbon to which they are attached (C ３ -C ８ ) cycloalkyl or (C ３ -C ８ ) forming a heterocycle.

52. X ３ is O; R １ is OH; n is 1; X ６ is CH; Each R ２ is halo and m is 1 or 2; R ３ is alkyl, and R ４ is H.

53. The R ２ 53. The compound of claim 52, wherein is F and m is 1.

54. R ３ 54. The compound of claim 52 or 53, wherein is isopropyl.

55. 36. The compound of claim 35 having the structure: 【Transformation 7】

56. 36. The compound of claim 35 having the structure: 【Transformation 8】

57. 36. The compound of claim 35 having the structure: 【Chemistry 9】

58. 58. A pharmaceutical composition comprising a compound according to any one of claims 1 to 57, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient and / or carrier.

59. 59. The pharmaceutical composition of claim 58, wherein the compound is a pharmaceutically acceptable salt, optionally selected from acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, and toluenesulfonate.

60. 60. The pharmaceutical composition of claim 58 or 59, wherein the composition is formulated for oral delivery to the gastrointestinal tract.

61. 61. The method of claim 60, wherein the pharmaceutical composition is a tablet, capsule, solution, or suspension.

62. 62. The pharmaceutical composition of claim 60 or 61, wherein the composition is formulated for delivery to the small intestine and / or large intestine.

63. 60. The pharmaceutical composition of any one of claims 58 to 59, wherein the composition is formulated for pulmonary delivery.

64. 64. The pharmaceutical composition of claim 63, wherein the pharmaceutical composition is a solution or an aerosol.

65. 60. The pharmaceutical composition of claim 58 or 59, wherein the composition is formulated for parenteral delivery.

66. 66. A method of treating epithelial or endothelial dysfunction in a subject, comprising administering to said subject a pharmaceutical composition according to any one of claims 58 to 65.

67. 67. The method of claim 66, wherein the subject has an inflammatory or metabolic disorder associated with epithelial or endothelial barrier dysfunction.

68. 68. The method of claim 66 or 67, wherein the disorder is an epithelial disorder of the gastrointestinal tract.

69. 69. The method of claim 68, wherein the disorder is inflammatory bowel disease or irritable bowel syndrome.

70. 70. The method of claim 69, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

71. 69. The method of claim 68, wherein the disorder is selected from celiac disease, Whipple's disease, tropical sprue, and MIS-C / MIS / A.

72. 67. The method of claim 66, wherein the disorder is radiation-induced mucositis or intestinal permeability, or drug-induced mucositis or intestinal permeability.

73. 73. The method of claim 72, wherein the subject has oral mucositis or intestinal mucositis.

74. 74. The method of claim 72 or 73, wherein the subject is undergoing radiation therapy or chemotherapy for cancer.

75. 75. The method of claim 68 or 74, wherein the disorder is colon cancer.

76. 69. The method of claim 68, wherein the disorder is diverticular disease.

77. 69. The method of claim 68, wherein the subject has immune checkpoint inhibitor-induced colitis.

78. 69. The method of claim 68, wherein the subject has esophagitis, which is optionally eosinophilic esophagitis.

79. 69. The method of claim 68, wherein the subject has an environmental enteropathy disorder (EED).

80. 69. The method of claim 68, wherein the subject has a gastrointestinal symptom associated with HIV.

81. 69. The method of claim 68, wherein the subject has ischemic bowel disease.

82. 69. The method of claim 68, wherein the subject has fatty liver disease and / or kidney disease.

83. 83. The method of claim 82, wherein the subject has non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), alcoholic fatty liver disease, or non-alcoholic fatty liver disease (NAFLD).

84. 84. The method of claim 82 or 83, wherein the subject has chronic kidney disease.

85. 85. The method of any one of claims 68 to 84, wherein the subject has organ fibrosis, optionally organ fibrosis being hepatic, renal, cardiac, pancreatic, or pulmonary fibrosis.

86. 69. The method of any one of claims 66 to 68, wherein the subject has pancreatitis.

87. 69. The method of any one of claims 66 to 68, wherein the subject is suffering from sepsis or septic shock or is at risk of suffering from sepsis or septic shock.

88. 70. The method of any one of claims 66 to 69, wherein the subject has cardiovascular disease.

89. 69. The method of claim 68, wherein the subject has an autoimmune disease.

90. 69. The method of claim 68, wherein the subject has a condition selected from food allergies, obesity, metabolic syndrome, diabetes mellitus, scleroderma, dermatitis herpeticum, vasculitis, Sjogren's syndrome, rheumatoid arthritis, and multiple sclerosis.

91. 67. The method of claim 66, wherein the subject has a neuroinflammatory disorder optionally selected from Alzheimer's disease, Alzheimer's disease, Parkinson's disease, dementia, multiple sclerosis, chronic fatigue syndrome, COVID-19 sequelae, and fibromyalgia.

92. 92. The method of any one of claims 66 to 91, wherein the pharmaceutical composition is administered to the gastrointestinal tract.

93. 68. The method of claim 66 or 67, wherein the disorder is a pulmonary epithelial or endothelial disorder.

94. 94. The method of claim 93, wherein the disorder is acute respiratory distress syndrome or acute lung injury.

95. 95. The method of claim 93 or 94, wherein the composition is delivered locally to the lung by solution or powder aerosol, or by use of a nebulizer.

96. 68. The method of claim 66 or 67, wherein the subject has a condition associated with endothelial barrier dysfunction or organ damage or inflammation.

97. 97. The method of claim 96, wherein the condition is alcohol-related liver disease (AALD), vasculitis, scleroderma, atopic dermatitis, pemphigus, psoriasis, drug-induced internal bleeding, vascular permeability, hepatitis, cirrhosis, primary sclerosing cholangitis, and pancreatitis.

98. 97. The method of claim 96, wherein the subject has sepsis or septic shock or is at risk of having sepsis or septic shock.

99. 97. The method of claim 96, wherein the subject has acute respiratory failure.

100. 97. The method of claim 96, wherein the subject has diabetic retinopathy, diabetic macular edema, or age-related macular degeneration (e.g., wet AMD).

101. 100. The method of claim 99, wherein the composition is administered topically to the eye, optionally as eye drops.

102. 101. The method of any one of claims 96 to 100, wherein the composition is administered parenterally, and optionally by a route selected from intravenous, intramuscular, intraocular, and subcutaneous administration.

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