Prolyl hydroxylase domain-containing protein (PHD) inhibitors, their combinations, and use

Abstract

A method for treating inflammatory bowel disease using prolyl hydroxylase domain-containing protein (PHD) inhibitors and additional agents is described herein.

Description

[Technical Field]

[0001] [Cross reference] This application claims the interests of International Application PCT / CN2023 / 091788, filed on 28 April 2023, which in whole constitutes part of this specification by reference. [Background technology]

[0002] Hypoxia-inducible factors (HIFs) mediate gene expression in response to changes in cellular oxygen concentration. HIFs are heterodimers containing an oxygen-regulating subunit (HIF-α) and a constitutively expressed subunit (HIF-β). HIF prolyl hydroxylase, also known as prolyl hydroxylase domain-containing protein (PHD), exists in humans as three isoforms (PHD1, PHD2, and PHD3). PHDs function as oxygen sensors that regulate the hypoxia-inducible factor ("HIF") degradation pathway. Briefly, PHDs are responsible for the hydroxylation of HIFα, a subunit of HIF, which ultimately initiates a pathway leading to proteasome degradation of HIFα. There are three subtypes of PHDs, including PHD1, PHD2, and PHD3. Inhibition of PHDs has been shown as a promising treatment for HIFα-related diseases, such as inflammatory epithelial diseases, including inflammatory bowel disease (IBD).

[0003] The features of the present invention are described in detail in the appended claims. A better understanding of the features of the present invention can be obtained by referring to the following detailed description and accompanying drawings illustrating exemplary embodiments utilizing the principles of the present invention. [Brief explanation of the drawing]

[0004] [Figure 1] This figure shows the disease activity index (DAI) scores for compound 29 and mesalamine alone and in combination in an IBD mouse model. [Figure 2]This figure shows the colon index for compound 29 and mesalamine alone and in combination in an IBD mouse model. [Figure 3] This figure shows the DAI scores for compound 29 and cyclosporine A (CsA) individually and in combination in an IBD mouse model. [Figure 4] This figure shows the colon index for compound 29 and cyclosporine A (CsA) individually and in combination in an IBD mouse model. [Figure 5] This figure shows the DAI scores for compound 29 and the anti-TNFα antibody, both individually and in combination, in an IBD mouse model. [Figure 6] This figure shows the colon index for compound 29 and anti-TNFα antibody, both individually and in combination, in an IBD mouse model. [Overview of the project]

[0005] Disclosed herein is a method for treating an inflammatory epithelial disease in a subject requiring treatment, the method comprising: (a) a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject: [ka] (b) administering an additional drug or a pharmaceutically acceptable salt thereof, The method involves determining that the combined amount of (a) and (b) is the therapeutically effective dose for treating inflammatory epithelial diseases.

[0006] In some embodiments, the compound of formula (I) is one of the compounds in Table 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer. In some embodiments, the compound of formula (I) is [ka] (Compound 29), or a pharmaceutically acceptable salt or stereoisomer thereof.

[0007] In some embodiments, inflammatory epithelial disease is a disease affecting the airways, mucous membranes, skin, gastrointestinal tract, the inner lining of major organs and endocrine glands, vascular tissue, or any combination thereof. In some embodiments, inflammatory epithelial disease is inflammatory bowel disease. In some embodiments, inflammatory epithelial disease is ulcerative colitis, Crohn's disease, collagenous colitis, lymphocytic colitis, ischemic colitis, fecal-diverting colitis, Behçet's syndrome, or unclassifiable colitis.

[0008] In some embodiments, additional agents include 5-aminosalicylic acid (5-ASA), anti-inflammatory agents, ASK1 inhibitors, α-fetoprotein modulators, adenosine A3 receptor antagonists, adrenomedullin ligands, AKT1 gene inhibitors, anti-CD28 inhibitors, antibiotics, antifungal agents, ATPase inhibitors, β-adrenergic receptor antagonists, BTK inhibitors, β-glucuronidase inhibitors, bradykinin receptor modulators, calcineurin inhibitors, chaperonin-binding immunoglobulin proteins, calcium channel inhibitors, cathepsin S inhibitors, CCR3 chemokine antagonists, CD40 ligand receptor antagonists, chemokine CXC ligand inhibitors, CHST15 gene inhibitors, collagen modulators, CSF-1 antagonists, cyclooxygenase inhibitors, and cytochrome P450. 3A4 inhibitors, carbohydrate metabolism modulators, CCR9 chemokine antagonists, CD233 modulators, CD29 modulators, CD3 antagonists, CD4 antagonists, CD40 ligand inhibitors, CD40 gene inhibitors, CX3CR1 chemokine modulators, COT protein kinase inhibitors, eotaxin ligand inhibitors, EP4 prostanoid receptor agonists, erythropoietin receptor agonists, ecobiotics, F1F0 ATP synthase modulators, farnesoid X receptor (FXR and NR1H4) agonists or modulators, fecal microbiota transplantation (FMT), fractalkine ligand inhibitors, free fatty acid receptor 2 antagonists, GATA3 transcription factor inhibitors, glucagon-like peptide-2 agonists, glucocorticoid receptor modulators, glucocorticoid receptor agonists, guanylate cyclase receptor agonists, histone deacetylase inhibitors, histone deacetylase-6 inhibitors, HLA class II antigen modulators, immunosuppressants, IL-12 antagonists, IL-13 antagonists, IL-23 antagonists, IL-6 antagonists, IL-6 receptor modulators, IL-7 receptor modulators, IL-7 antagonists, IL-8 antagonists, integrin α4 / β1 antagonists, integrin α4 / β7 antagonists, integrin αE antagonists, integrin antagonists, integrin β7 antagonists, interleukin ligand inhibitors, interleukin-2 ligands, interleukin receptor 17A antagonists, interleukin-1β ligands Interleukin-1β ligand modulator, IRAK4 inhibitor, ICAM1 gene inhibitor, IL-1β ligand modulator, IL-18 antagonist, IL-22 agonist, IL-23A inhibitor, interleukin-1-like receptor 2 inhibitor, JAK inhibitor, JAK tyrosine kinase inhibitor, Jak1 tyrosine kinase inhibitor, Jak3 tyrosine kinase inhibitor, LanC-like protein 2 modulator, lipoxygenase modulator, lactoferrin stimulant, leukocyte elastase inhibitor, leukocyte proteinase-3 inhibitor, MAdCAM inhibitor, matrix metalloproteinase inhibitor, melanocortin agonist, melanocortin MC1 agonist, metalloproteinase-9 inhibitor, melanin-concentrating hormone (MCH-1) antagonist, microbiome modulator, natriuretic peptide receptor C agonist, neureglin-4 ligand, NKG2 D-activated NK receptor antagonists, NLRP3 inhibitors, neuregulin-4 ligands, nuclear factor κB inhibitors, opioid receptor antagonists, opioid receptor δ antagonists, oxidoreductase inhibitors, OX40 ligand inhibitors, Pellino homolog 1 inhibitors, P2X7 prenoceptor agonists, PDE4 inhibitors, phagocytic peptide modulators, potassium channel inhibitors, PPARα agonists, PPARδ agonists, PPARγ agonists, protein fimH inhibitors, P-selectin glycoprotein ligand-1 inhibitors, Ret tyrosine kinase receptor inhibitors, RNA polymerase inhibitors, RIP-1 kinase inhibitors, RIP-2 kinase inhibitors, tissue transglutaminase inhibitors, sphingosine-1-phosphate phosphatase-1 stimulants, sphingosine-1-phosphate phosphatase modulators, sphingosine-1-phosphate receptor-1 agonists, sphingosine Sphingosine-1-phosphate receptor-1 antagonist, sphingosine-1-phosphate receptor-1 modulator, sphingosine-1-phosphate receptor-5 modulator, STAT3 gene inhibitor, stem cell antigen-1 inhibitor, superoxide dismutase modulator, superoxide dismutase stimulant, SYK inhibitor, TGFβ1 ligand inhibitor, thymrine agonist, TLR antagonist, TLR agonist, TNFα ligand inhibitor, TNF antagonist, tumor necrosis factor superfamily member 14 modulator, type II TNF receptor modulator, Tpl These include TLR-2 inhibitors, TLR-3 antagonists, TLR-4 antagonists, TLR-8 inhibitors, TLR-9 agonists, TNF ligand inhibitors, TNFα ligand modulators, TPL-2 inhibitors, tumor necrosis factor superfamily member 15 inhibitors, Tyk2 tyrosine kinase inhibitors, type I IL-1 receptor antagonists, TrkA receptor antagonists, vanilloid VR1 agonists, zonulin inhibitors, or pharmaceutically acceptable salts thereof.

[0009] [References] All publications, patents, and patent applications referenced herein are incorporated herein by reference to the same extent as each individual publication, patent, or patent application is specifically and individually indicated to be incorporated by reference. [Modes for carrying out the invention]

[0010] definition The following description includes certain details to provide a complete understanding of the various embodiments. However, those skilled in the art will understand that the invention may be carried out without these details. In other examples, known structures are not shown or described in detail to avoid unnecessarily obscuring the description of embodiments. Unless otherwise specified in the context, the word “comprise” and its variations such as “comprises” and “comprising” throughout this specification and the appended claims should be interpreted in an open and comprehensive sense as “including, but not limited to.” Furthermore, the headings presented herein are for convenience only and do not constitute an interpretation of the scope or meaning of the claimed invention.

[0011] Throughout this specification, any reference to “several embodiments” or “an embodiment” means that any particular feature, structure, or characteristic described in relation to that embodiment is included in at least one embodiment. Therefore, the phrases “in one embodiment” or “in an embodiment” appearing in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, any particular feature, structure, or characteristic can be combined in any suitable way in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms ("a", "an", and "the") include multiple references unless explicitly indicated otherwise. It should also be noted that the term “or” is generally used in its meaning including “and / or” unless explicitly indicated otherwise.

[0012] As used herein, the following terms have the meanings set forth below, unless otherwise indicated.

[0013] "Oxo" refers to =O.

[0014] "Carboxyl" refers to the -COOH group.

[0015] "Cyano" refers to -CN.

[0016] "Alkyl" refers to a linear or branched saturated hydrocarbon monovalent group having 1 to about 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl and octyl. Where applicable in this specification, "C1-C6 alkyl" or "C 1~6 Numerical ranges such as "alkyl" mean that an alkyl group can consist of one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, or six carbon atoms, but the definition here also includes the appearance of the term "alkyl" without a specified numerical range. In some embodiments, alkyl is C 1~10 It is alkyl. In some embodiments, alkyl is C 1~6 It is alkyl. In some embodiments, alkyl is C 1~5 It is alkyl. In some embodiments, alkyl is C 1~4 It is alkyl. In some embodiments, alkyl is C 1~3It is alkyl. Unless otherwise specified herein, alkyl groups may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkyl is optionally substituted with halogen.

[0017] "Alkenyl" refers to a linear or branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and containing 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The group may be in either a cis or trans configuration with respect to the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Where used herein, "C2-C6 alkenyl" or "C 2~6The numerical ranges for "alkenyl," etc., mean that the alkenyl group may consist of 2, 3, 4, 5, or 6 carbon atoms, but the definition herein also includes the appearance of the term "alkenyl" without a specified numerical range. Unless otherwise specified herein, the alkenyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0018] "Alkynyl" refers to a linear or branched hydrocarbon monovalent group having one or more carbon-carbon triple bonds and containing 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiinyl. Where used herein, it is referred to as "C2-C6 alkynyl" or "C 2~6The numerical range such as "alkynyl" means that an alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. However, the definition here also includes the occurrence of the term "alkynyl" for which no numerical range is specified. Unless otherwise specifically stated herein, an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0019] "Alkylene" refers to a straight-chain or branched-chain divalent hydrocarbon chain. Unless otherwise specifically stated herein, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkylene is optionally substituted with halogen.

[0020] "Alkoxy" refers to a radical of the formula -OR a where R ais an alkyl radical as defined. Unless otherwise specified herein, the alkoxy group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0021] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. Aryl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, including fused ring systems (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded via an aromatic ring atom) or bridging ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl(phenyl). Examples of aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluorantene, fluorene, as-indacene, s-indacene, indan, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specified herein, aryls may be optionally substituted with, for example, halogens, aminos, nitriles, nitros, hydroxyls, alkyls, alkenyls, alkynyls, haloalkyls, alkoxys, carboxyls, carboxylates, aryls, cycloalkyls, heterocycloalkyls, heteroaryls, etc. In some embodiments, aryls are optionally substituted with halogens, methyls, ethyls, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, aryls are optionally substituted with halogens, methyls, ethyls, -CN, -CF3, -OH, or -OMe. In some embodiments, aryls are optionally substituted with halogens.

[0022] "Cycloalkyl" refers to a partially or completely saturated monocyclic or polycyclic carbon ring, which may include fused ring systems (when fused with an aryl or heteroaryl ring, the cycloalkyl is bonded via a non-aromatic ring atom), spiro ring systems, or bridging ring systems. In some embodiments, the cycloalkyl is completely saturated. Typical cycloalkyls include cycloalkyls having 3 to 15 carbon atoms (e.g., C3-C3). 15 Fully saturated cycloalkyl or C3-C15 Cycloalkenyls, cycloalkyls having 3 to 10 carbon atoms (e.g., C3-C3) 10 Fully saturated cycloalkyl or C3-C 10Examples include, but are not limited to, cycloalkenyls, cycloalkyls having 3 to 8 carbon atoms (e.g., C3-C8 fully saturated cycloalkyls or C3-C8 cycloalkenyls), cycloalkyls having 3 to 6 carbon atoms (e.g., C3-C6 fully saturated cycloalkyls or C3-C6 cycloalkenyls), cycloalkyls having 3 to 5 carbon atoms (e.g., C3-C5 fully saturated cycloalkyls or C3-C5 cycloalkenyls), or cycloalkyls having 3 or 4 carbon atoms (e.g., C3 or C4 fully saturated cycloalkyls or C3 or C4 cycloalkenyls). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- or 6-membered fully saturated cycloalkyl or a 5- or 6-membered cycloalkenyl. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyls include adamantyl, norbornyl, dekalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, as well as 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specified herein, cycloalkyls may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.In some embodiments, the cycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group is optionally substituted with halogen.

[0023] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodine. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0024] "Haloalkyl" refers to an alkyl radical as defined above, which is substituted with one or more halo radicals as defined above. Examples include trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0025] "Hydroxyalkyl" refers to an alkyl radical as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Examples of hydroxyalkyls include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0026] "Aminoalkyl" refers to an alkyl radical as defined above, which is substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Examples of aminoalkyls include aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0027] A "heteroalkyl" refers to an alkyl group in which one or more of the alkyl backbone atoms are atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof. In a heteroalkyl group, the carbon atoms of the heteroalkyl group are bonded to the rest of the molecule. In one embodiment, a heteroalkyl group is a C1-C6 heteroalkyl group, which consists of one to six carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof, and the carbon atoms of the heteroalkyl group are bonded to the rest of the molecule. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specified herein, heteroalkyls are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyls are optionally substituted with halogens.

[0028] A "heterocycloalkyl" refers to a 3- to 24-membered, partially or fully saturated ring radical containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl contains 1 to 3 nitrogen atoms. In some embodiments, the heterocycloalkyl contains 1 or 2 nitrogen atoms. In some embodiments, the heterocycloalkyl contains 1 nitrogen atom. In some embodiments, the heterocycloalkyl contains 1 nitrogen atom and 1 oxygen atom. Unless otherwise specified herein, heterocycloalkyl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, including fused ring systems (when fused with an aryl ring or heteroaryl ring, the heterocycloalkyl is bonded via a non-aromatic ring atom), spirocyclic ring systems, or bridging ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may optionally be oxidized, and the nitrogen atom may optionally be quaternized. Typical heterocycloalkyls include heterocycloalkyls having 2 to 15 carbon atoms (e.g., C2-C2). 15 Fully saturated heterocycloalkyl or C2-C 15 Heterocycloalkenyls, heterocycloalkyls having 2 to 10 carbon atoms (e.g., C2-C2) 10 Fully saturated heterocycloalkyl or C2-C 10Examples include, but are not limited to, heterocycloalkenyls, heterocycloalkyls having 2 to 8 carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyls or C2-C8 heterocycloalkenyls), heterocycloalkyls having 2 to 7 carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyls or C2-C7 heterocycloalkenyls), heterocycloalkyls having 2 to 6 carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyls or C2-C6 heterocycloalkenyls), heterocycloalkyls having 2 to 5 carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyls or C2-C5 heterocycloalkenyls), or heterocycloalkyls having 2 to 4 carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyls or C2-C4 heterocycloalkenyls). Examples of such heterocycloalkyl radicals include azilidinyl, azetidinyl, oxetanyl, dioxolanil, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperadinyl, 4-piperidonyl, and pylori. Examples include, but are not limited to, dinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianil, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, heterocycloalkyls have 2 to 10 carbon atoms in the ring.When referring to the number of carbon atoms in a heterocycloalkyl, it should be understood that the number of carbon atoms in a heterocycloalkyl is not the same as the total number of atoms constituting the heterocycloalkyl (including heteroatoms) (i.e., the skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- or 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-membered or 6-membered heterocycloalkenyl. Unless otherwise specified herein, the heterocycloalkyl may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc., as described below. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0029] A "heteroaryl" refers to a 5- to 14-membered cyclic radical comprising 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains 1 to 3 nitrogen atoms. In some embodiments, the heteroaryl contains 1 or 2 nitrogen atoms. In some embodiments, the heteroaryl contains 1 nitrogen atom. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a condensed ring system (when condensed with a cycloalkyl ring or heterocycloalkyl ring, the heteroaryl is bonded via an aromatic ring atom) or a bridging ring system, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may optionally be oxidized, and the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranil, benzoxazolyl, benzothiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, sinnolinil, dibenzofuranil, dibenzothiophenyl, furanil, furanonil, isothiazolyl, imidazolyl, indazolyl, indolyl, isoin Examples include, but are not limited to, drill, indolinyl, isoindolinyl, isoquinolyl, indolidinyl, isoxazolyl, naphthilidinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified herein, heteroaryls may be optionally substituted with, for example, halogens, aminos, nitriles, nitros, hydroxyls, alkyls, alkenyls, alkynyls, haloalkyls, alkoxys, carboxyls, carboxylates, aryls, cycloalkyls, heterocycloalkyls, heteroaryls, etc. In some embodiments, heteroaryls are optionally substituted with halogens, methyls, ethyls, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, the heteroaryl is optionally substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.

[0030] The terms “optional” or “optionally” mean that the events or situations described thereafter may or may not occur, and such descriptions include both cases in which such events or situations occur and cases in which they do not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Furthermore, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at a level between fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). With respect to any group containing one or more substituents, it will be understood by those skilled in the art that such a group is not intended to introduce any substitution or substitution pattern that is sterically impractical and / or synthetically unfeasible (e.g., a substituted alkyl is defined as containing an optionally substituted cycloalkyl group, which further contains an optionally substituted alkyl group, and so on, indefinitely). Therefore, any substituent described should be understood to have a maximum molecular weight of approximately 1000 daltons, and more typically, up to approximately 500 daltons.

[0031] When referring to any substituent, the term "one or more" means that the group in question may be optionally substituted with one, two, three, four, or more substituents. In some embodiments, the group in question may be optionally substituted with one, two, three, or four substituents. In some embodiments, the group in question may be optionally substituted with one, two, or three substituents. In some embodiments, the group in question may be optionally substituted with one or two substituents. In some embodiments, the group in question may be optionally substituted with one substituent. In some embodiments, the group in question may be optionally substituted with two substituents.

[0032] "Effective dose" or "therapeutic dose" refers to the amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, that is effective in producing the desired therapeutic effect.

[0033] "Therapy" of an individual (e.g., a mammal such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, therapy includes the administration of a pharmaceutical composition after the onset of a pathological event or after contact with a pathogen, and includes stabilization of the condition (e.g., preventing deterioration of the condition) or alleviation of the condition.

[0034] compound This specification describes compounds of formula (I), or pharmaceutically acceptable salts thereof, or stereoisomers, which are useful for the treatment of inflammatory epithelial diseases such as inflammatory bowel disease (IBD).

[0035] Disclosed herein are compounds of formula (I), or pharmaceutically acceptable salts thereof, or stereoisomers: [ka] (In the formula, R 1 These are monocyclic heterocycloalkyl compounds that are arbitrarily and independently substituted. X is N or CR 2 And, R 2 These are hydrogen, fluoro, chloro, bromo, -CN, -NO2, -OH, -OR a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, R 3 These are hydrogen, halogen, -CN, -NO2, -OH, -OR a -C(=O)R a, -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, R 4 These are hydrogen, halogen, -CN, -NO2, -OH, -OR a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, R 5 These are hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. Y is -O-, -S-, or NR 6 -and, R 6 These are hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. L is -(CR 7 R 8 ) p -and, Each R 7 and R 8 These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. Alternatively, R on the same carbon 7 and R 8 However, together they form a cycloalkyl or heterocycloalkyl group, each containing one or more R 7a It is arbitrarily replaced with, Each R 7a These are, independently, halogen, -CN, -NO2, -OH, -OR a , -NR c R d-C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, p is between 0 and 4. Ring A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring. Each R 9 These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl elements are optionally and independently substituted. n is between 0 and 4. Each R aThese are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl can be independently and optionally substituted. Each R b These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl can be independently and optionally substituted. Each R c and R d These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl can be independently and optionally substituted. Or, R c and R d However, together with the atoms to which they are bonded, they form arbitrarily substituted heterocycloalkyl groups.

[0036] Disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof:

Chemical Structure

[0037] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, X is N. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, X is CR. 2 That is the case.

[0038] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 2 is hydrogen, fluoro, or C1-C6 alkyl. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 2 R is hydrogen or a C1-C6 alkyl group. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 2 It is hydrogen.

[0039] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 3 R is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salt, or stereoisomer, R 3 is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 3 R is hydrogen or a C1-C6 alkyl group. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 3 It is hydrogen.

[0040] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 4 R is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salt, or stereoisomer, R 4 is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 4 R is hydrogen or a C1-C6 alkyl group. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 4 It is hydrogen.

[0041] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 5 R is hydrogen or a C1-C6 alkyl group. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 5 is a C1-C6 alkyl group. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 5 It is hydrogen.

[0042] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, [ka] teeth, [ka] That is the case.

[0043] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, [ka] teeth, [ka] That is the case.

[0044] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, Y is -O- or NR 6 -In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, Y is -NR 6 -. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, Y is -O-. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, Y is -S-.

[0045] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 6 R is hydrogen or a C1-C6 alkyl group. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 6 is a C1-C6 alkyl group. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 6 It is hydrogen.

[0046] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salt, or stereoisomer, p is 1 to 4. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salt, or stereoisomer, p is 1 to 3. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salt, or stereoisomer, p is 1 or 2. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salt, or stereoisomer, p is 1. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salt, or stereoisomer, p is 2. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salt, or stereoisomer, p is 3.

[0047] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R 7 and R 8 These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl, or R on the same carbon. 7 and R 8 However, together they form a cycloalkyl or heterocycloalkyl group. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R 7 and R 8 R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R on the same carbon 7 and R 8 These combine to form a cycloalkyl or heterocycloalkyl group. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R 7 and R 8 R is independently hydrogen or a C1-C6 alkyl group. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R 7 and R8 is hydrogen.

[0048] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, each R 7a is independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, each R 7a is independently halogen, -OH, -OR a , C1-C6 alkyl.

[0049] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, ring A is aryl or heteroaryl. In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, ring A is phenyl. In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, ring A is a 5- or 6-membered heteroaryl. In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, ring A is a 6-membered heteroaryl. In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, ring A is 6-membered pyridyl.

[0050] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, n is from 1 to 3. In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, n is from 2 to 4. In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, n is 2 or 3. In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, n is 1 or 2. In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, n is 0. In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, n is 1. In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, n is 2. In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, n is 3.

[0051] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, each R 9 is independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0052] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, each R 9 [[ID=二十六]]is independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)OR b , C1-C6 alkyl, or C1-C6 haloalkyl.

[0053] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R 9 These are, independently, halogen or -CN.

[0054] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R 9 is -CN.

[0055] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 1 is one or more R 1a It is a monocyclic heterocycloalkyl independently substituted with R. In some embodiments, R 1 is one, two, three, or four R 1a It is independently replaced by R. In some embodiments, 1 is one or two R 1a It is independently replaced by R. In some embodiments, 1 It is a substituted monocyclic heterocycloalkyl compound.

[0056] In some embodiments, R 1 R is an optionally substituted four-membered monocyclic heterocycloalkyl. In some embodiments, R 1 R is an optionally substituted five-membered monocyclic heterocycloalkyl. In some embodiments, R 1 is an optionally substituted six-membered monocyclic heterocycloalkyl. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 1 R 1 It is bonded to the rest of the fragment of formula (I) via the nitrogen atom. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 1 teeth, [ka] Each of these is one or more R1a It is optionally replaced by R. In some embodiments, 1 teeth, [ka] This is because it involves one or two R 1a It is optionally replaced by R. In some embodiments, 1 teeth, [ka] This is because it involves one or two R 1a It is optionally replaced by R. In some embodiments, 1 teeth, [ka] This is because it involves one or two R 1a It is optionally replaced by R. In some embodiments, 1 teeth, [ka] This is because it involves one or two R 1a It can be arbitrarily replaced with.

[0057] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 1 These are azetidinil, pyrrolidinil, piperidinil, piperazinil, or morpholinil, each containing one or more R 1a It is replaced arbitrarily and independently.

[0058] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 1 is one or more R 1a It is piperidinyl that has been arbitrarily substituted with [the specified compound].

[0059] In some embodiments, R 1 is one or two R 1aIt is a monocyclic heterocycloalkyl that is optionally and independently substituted with R. In some embodiments, 1 is one or two R 1a A 5- to 7-membered (e.g., 6-membered) monocyclic heterocycloalkyl group is optionally and independently substituted, wherein the monocyclic heterocycloalkyl group contains 1 to 3 ring nitrogen atoms.

[0060] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 1 This is a non-substitution.

[0061] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R 1a These are, independently, halogen, -CN, -OH, and -OR a , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or two R on the same atom 1a However, they come together to form an oxoplasm.

[0062] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R 1a These are, independently, halogen, -CN, -OH, and -OR a , -NR c R d , -NR b C(=O)R a , -NRb C(=O)OR b -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, or two R on the same atom 1a However, they come together to form an oxoplasm.

[0063] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R 1a These are, independently, halogen, -CN, -OH, and -OR a , -NR c R d , -NR b C(=O)R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, or two R on the same atom 1a However, they come together to form an oxoplasm.

[0064] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R 1a These are, independently, halogen, -OH, and -OR a , -NR b C(=O)R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, or cycloalkyl, or two R on the same atom 1acombine to form an oxo group.

[0065] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, each R 1a is independently C1-C6 alkyl (e.g., methyl), C1-C6 haloalkyl, or C(=O)OR b (e.g., -C(=O)O(C1-C6 alkyl)).

[0066] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, R 1a is -C(=O)NR c R d is. In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, R 1a is -C(=O)NH2. In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, R 1a is

Chemical Structure

[0067] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, R 1 is

Chemical Structure

[0068] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, R 1 is

Chemical Structure

[0069] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, R1 teeth, [ka] That is the case.

[0070] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 1 teeth, [ka] That is the case.

[0071] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 1 teeth, [ka] That is the case.

[0072] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R 1 teeth, [ka] That is the case.

[0073] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R aR is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R a R is independently a C1-C6 alkyl, a C1-C6 haloalkyl, or a cycloalkyl or heterocycloalkyl, where each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R a R is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl). In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R a R is independently a C1-C6 alkyl, a C1-C6 haloalkyl, or a cycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R a R is independently a C1-C6 alkyl or a C1-C6 haloalkyl. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R a These are independently C1-C6 alkyl groups.

[0074] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R b R is independently hydrogen, a C1-C6 alkyl, a C1-C6 haloalkyl, or a cycloalkyl or heterocycloalkyl, where each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl). In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R bR is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R b R is independently hydrogen or a C1-C6 alkyl group. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R b R is hydrogen. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R b These are independently C1-C6 alkyl groups.

[0075] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R c and R d R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R c and R d R is independently hydrogen, a C1-C6 alkyl, a C1-C6 haloalkyl, or a cycloalkyl or heterocycloalkyl, where each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R c and R dR is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl). In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R c and R d R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R c and R d R is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R c and R d R is independently hydrogen or a C1-C6 alkyl group. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R c and R d R is hydrogen. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R c and R d R is independently a C1-C6 alkyl group. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R c R is hydrogen, C1-C6 hydroxyalkyl, C1-C6 alkyl, C1-C6 aminoalkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salt, or stereoisomer, R dR is hydrogen, C1-C6 hydroxyalkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene (cycloalkyl), or C1-C6 alkylene (heterocycloalkyl). In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R d These are -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2CH2OH, or -CH2CH2NHC(=O)Ot-butyl.

[0076] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, R c and R d These atoms, together with the atoms to which they are bonded, form heterocycloalkyl groups optionally substituted with one or more R atoms.

[0077] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R is independently a halogen, -CN, -OH, -OC1~C6 alkyl, -NH2, -NHC1~C6 alkyl, -N(C1~C6 alkyl)2, -NHC(=O)OC1~C6 alkyl, -C(=O)C1~C6 alkyl, -C(=O)OH, -C(=O)OC1~C6 alkyl, -C(=O)NH2, -C(=O)N(C1~C6 alkyl)2, -C(=O)NHC1~C6 alkyl, C1~C6 alkyl, or C1~C6 haloalkyl. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts, or stereoisomers, each R is independently a halogen, -CN, -OH, -OC1~C6 alkyl, -NH2, -C(=O)C1~C6 alkyl, -C(=O)OH, -C(=O)OC1~C6 alkyl, -C(=O)NH2, C1~C6 alkyl, or C1~C6 haloalkyl.

[0078] In some embodiments of the compounds disclosed herein, each R 1 , R 9 , R a , R b , R c , R d , R 7 and R 8 A heterocycloalkyl group is formed by the combination of these, and R c and R d The heterocycloalkyl groups formed together are optionally and independently substituted with one, two, three, or four substituents as defined herein. In some embodiments of the compounds disclosed herein, each R 1 , R 9 , R a , R b , R c , R d , R 7 and R 8A heterocycloalkyl group is formed by the combination of these, and R c and R d The heterocycloalkyl groups formed together are optionally and independently substituted with one, two, or three substituents as defined herein. In some embodiments of the compounds disclosed herein, each R 1 , R 9 , R a , R b , R c , R d , R 7 and R 8 A heterocycloalkyl group is formed by the combination of these, and R c and R d The heterocycloalkyl groups formed together are optionally and independently substituted with one or two substituents as defined herein. In some embodiments of the compounds disclosed herein, each R 1 , R 9 , R a , R b , R c , R d , R 7 and R 8 A heterocycloalkyl group is formed by the combination of these, and R c and R d The heterocycloalkyl group formed by these elements together may be optionally and independently substituted with one substituent as defined herein.

[0079] In some embodiments of the compounds disclosed herein, R, R 1 , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 7a , R 8 , R 9 , R 9a , R a , R b , R c , and / or R dThe amount of deuterium present in each of these is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of the total amount of hydrogen and deuterium.

[0080] In some embodiments of the compounds disclosed herein, R, R 1 , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 7a , R 8 , R 9 , R 9a , R a , R b , R c , and / or R d One or more of the groups contain deuterium at a higher percentage than the natural abundance of deuterium.

[0081] In some embodiments of the compounds disclosed herein, one or more hydrogen atoms are R, R 1 , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 7a , R 8 , R 9 , R 9a , R a , R b , R c , and / or R d One or more of the groups are replaced by one or more deuterium atoms.

[0082] In some embodiments of the compounds disclosed herein, one or more hydrogen atoms of ring A are replaced by one or more deuterium atoms.

[0083] In this specification, any combination of the groups described above is considered for various variables. Throughout this specification, the groups and their substituents are selected by those skilled in the art to provide stable moieties and compounds.

[0084] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, is one of the compounds in Table 1.

[0085] [Table 1] TIFF2026516849000023.tif252170TIFF2026516849000024.tif254170TIFF202 6516849000025.tif243170TIFF2026516849000026.tif252170TIFF20265168490 00027.tif254170TIFF2026516849000028.tif238170TIFF2026516849000029.t if238170TIFF2026516849000030.tif250170TIFF2026516849000031.tif196170

[0086] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis isomers, trans isomers, syn isomers, anti isomers, entgegen(E) isomers, and zusammen(Z) isomers, as well as their corresponding mixtures. In some situations, the compounds described herein have one or more chiral centers, each center existing in either an R or S configuration. The compounds described herein include all diastereomers, enantiomers, and epimers, as well as their corresponding mixtures. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers resulting from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomer compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these dissimilarity. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably by separation / resolving techniques based on differences in solubility. Then, in some embodiments, the optically pure enantiomers are recovered together with the resolving agent by any practical means that do not result in racemization.

[0087] labeled compound In some embodiments, the compounds described herein exist in their isotopically labeled forms. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such isotopically labeled compounds as a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those described herein, except that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, for example, respectively. 2 H(D), 3 H(T), 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl is an example. Compounds described herein containing the aforementioned isotopes and / or other isotopes of other atoms, and their pharmaceutically acceptable salts or stereoisomers, are within the scope of the present invention. Certain isotope-labeled compounds, for example, 3 H and 14 Products incorporating radioactive isotopes such as 13C are useful in tissue distribution assays of drugs and / or substrates. Tritiation, i.e. 3 H, and carbon 14, that is 14 13C isotopes are particularly preferred due to their ease of preparation and detectability.

[0088] In some embodiments, the amount of deuterium present in each substituent disclosed herein is, independently, at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of the total amount of hydrogen and deuterium. In some embodiments, one or more substituents disclosed herein contain deuterium at a higher percentage than the natural abundance of deuterium. In some embodiments, one or more hydrogen atoms are replaced by one or more deuterium atoms in one or more substituents disclosed herein.

[0089] In some embodiments, the compounds described herein are labeled by means of other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0090] Pharmaceutically acceptable salts In some embodiments, the compounds described herein exist as pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0091] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with a number of inorganic or organic bases, as well as either inorganic or organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or their stereoisomers, or by reacting the purified compounds separately in their free form with suitable acids or bases and then isolating the salts thus formed.

[0092] Examples of pharmaceutically acceptable salts include salts prepared by reacting the compounds described herein with mineral acids, organic acids, or inorganic bases, such as acetates, acrylates, adipicates, alginates, aspartates, benzoates, benzenesulfons, bisulfates, bisulfites, bromides, butyrates, butyn-1,4-dioate, camphorates, camphorsulfons, capronates, caprylates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, diglucons, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfons, formates, fumarates, glucoheptanoates, glycerophosphates, glycolates, hemisulfates, heptanoates, hexanoates, hexyn-1,6-dioate, hydroxybenzoates, γ-hydroxybutyrates, hydrochlorides, and bromine. Examples include hydrochlorides, hydroiodides, 2-hydroxyethanesulfonates, iodides, isobutyrates, lactates, maleates, malons, methanesulfonates, mandelates, metaphosphates, methanesulfonates, methoxybenzoates, methylbenzoates, monohydrogen phosphates, 1-naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, palmoate, pectinates, persulfates, 3-phenylpropionates, phosphates, picrinates, pivalates, propions, pyrosulfates, pyrophosphates, propiolates, phthalates, phenylacetates, phenylbutyrates, propanesulfonates, salicylates, succinates, sulfates, sulfites, succinates, suberinates, sebacinates, sulfonates, tartrates, thiocyanates, tosylates, undecanoates, and xylenesulfonates.

[0093] Furthermore, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, such as inorganic acids including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, as well as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, and manic acid. Examples of organic acids include, but are not limited to, delicates, aryl sulfonic acids, methanesulfonic acids, ethanesulfonic acids, 1,2-ethanedisulfonic acids, 2-hydroxyethanesulfonic acids, benzenesulfonic acids, 2-naphthalenesulfonic acids, 4-methylbicyclo-[2.2.2]octa-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids such as oxalic acid are used in the preparation of salts that are useful as intermediates in obtaining the compounds disclosed herein, or their stereoisomers, and their pharmaceutically acceptable acid addition salts, although they are not pharmaceutically acceptable in themselves.

[0094] In some embodiments, the compounds described herein containing a free acid group react with a suitable base such as a pharmaceutically acceptable metal cation hydroxide, carbonate, bicarbonate, or sulfate, ammonia, or a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Typical salts include alkali metal salts or alkaline earth metal salts such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Exemplary examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2. + (C 1~4 Examples include alkyl(4) and others.

[0095] Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine. It should be understood that the compounds described herein also include those in which any basic nitrogen-containing group contained in the compound has been quaternized. In some embodiments, such quaternization yields water-soluble or oil-soluble or water-dispersible or oil-dispersible products.

[0096] Tautomers In some circumstances, compounds exist as tautomers. The compounds described herein include all possible tautomers in the formulas described herein. A tautomer is a compound that can be interconverted by the movement of hydrogen atoms, involving the switching of a single bond with an adjacent double bond. In bond configurations where tautomerization is possible, a chemical equilibrium of tautomers will exist. All tautomers of the compounds disclosed herein are intended. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0097] combination This specification describes a method for treating an inflammatory epithelial disease in a subject requiring treatment, comprising administering to the subject a compound disclosed herein and an additional agent or a pharmaceutically acceptable salt thereof.

[0098] This specification describes a method for treating an inflammatory epithelial disease in a subject requiring treatment, the method comprising: (a) Compounds of formula (I), or pharmaceutically acceptable salts or stereoisomers thereof: [ka] (In the formula, R 1 is one or more R 1a It is a monocyclic heterocycloalkyl that is arbitrarily and independently substituted, Each R 1aThese are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, Alternatively, two R atoms on the same atom 1a However, together they form an oxo, X is N or CR 2 And, R 2 These are hydrogen, fluoro, chloro, bromo, -CN, -NO2, -OH, -OR a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, R 3 These are hydrogen, halogen, -CN, -NO2, -OH, -OR a-C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, R 4 These are hydrogen, halogen, -CN, -NO2, -OH, -OR a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, R 5 These are hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. Y is -O-, -S-, or NR 6 -and, R 6 These are hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. L is -(CR 7 R 8 ) p -and, Each R 7 and R 8 These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. Alternatively, R on the same carbon 7 and R 8 However, together they form a cycloalkyl or heterocycloalkyl group, each containing one or more R 7a It is arbitrarily replaced with, Each R 7a These are, independently, halogen, -CN, -NO2, -OH, -OR a , -NR cR d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, p is between 0 and 4. Ring A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring. Each R 9 These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more R 9a It can be replaced arbitrarily and independently, Alternatively, two R atoms on the same atom 9 However, together they form an oxo, Each R 9a These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, Alternatively, two R atoms on the same atom 9a However, together they form an oxo, n is between 0 and 4. Each R aThese are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. Each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. Each R c and R d These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. Or, R c and R dHowever, together with the atoms to which they are bonded, they form heterocycloalkyl groups optionally substituted with one or more R atoms. Each R independently corresponds to halogen, -CN, -OH, -OC1~C6 alkyl, -S(=O)C1~C6 alkyl, -S(=O)2C1~C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1~C6 alkyl, -S(=O)2N(C1~C6 alkyl)2, -NH2, -NHC1~C6 alkyl, -N(C1~C6 alkyl)2, -NHC(=O)OC1~C6 alkyl Kill, -C(=O)C1~C6 alkyl, -C(=O)OH, -C(=O)OC1~C6 alkyl, -C(=O)NH2, -C(=O)N(C1~C6 alkyl)2, -C(=O)NHC1~C6 alkyl, C1~C6 alkyl, C1~C6 haloalkyl, C1~C6 hydroxyalkyl, C1~C6 aminoalkyl, or C1~C6 heteroalkyl, or Two R atoms on the same atom combine to form an oxo. (b) Additional drugs or pharmaceutically acceptable salts thereof This includes administering, The method involves determining that the combined amount of (a) and (b) is the therapeutically effective dose for treating inflammatory epithelial diseases.

[0099] This specification describes a method for treating an inflammatory epithelial disease in a subject requiring treatment, comprising administering to the subject a compound of Table 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and an additional agent or a pharmaceutically acceptable salt thereof.

[0100] This specification describes a method for treating an inflammatory epithelial disease in a subject requiring treatment, comprising administering to the subject compound 29 or a pharmaceutically acceptable salt or stereoisomer thereof, and an additional agent or a pharmaceutically acceptable salt thereof.

[0101] Additional medications In some embodiments, additional agents include 5-aminosalicylic acid (5-ASA), anti-inflammatory agents, ASK1 inhibitors, α-fetoprotein modulators, adenosine A3 receptor antagonists, adrenomedullin ligands, AKT1 gene inhibitors, anti-CD28 inhibitors, antibiotics, antifungal agents, ATPase inhibitors, β-adrenergic receptor antagonists, BTK inhibitors, β-glucuronidase inhibitors, bradykinin receptor modulators, calcineurin inhibitors, chaperonin-binding immunoglobulin proteins, calcium channel inhibitors, cathepsin S inhibitors, CCR3 chemokine antagonists, CD40 ligand receptor antagonists, chemokine CXC ligand inhibitors, CHST15 gene inhibitors, collagen modulators, CSF-1 antagonists, cyclooxygenase inhibitors, and cytochrome P450. 3A4 inhibitors, carbohydrate metabolism modulators, CCR9 chemokine antagonists, CD233 modulators, CD29 modulators, CD3 antagonists, CD4 antagonists, CD40 ligand inhibitors, CD40 gene inhibitors, CX3CR1 chemokine modulators, COT protein kinase inhibitors, eotaxin ligand inhibitors, EP4 prostanoid receptor agonists, erythropoietin receptor agonists, ecobiotics, F1F0 ATP synthase modulators, farnesoid X receptor (FXR and NR1H4) agonists or modulators, fecal microbiota transplantation (FMT), fractalkine ligand inhibitors, free fatty acid receptor 2 antagonists, GATA3 transcription factor inhibitors, glucagon-like peptide-2 agonists, glucocorticoid receptor modulators, glucocorticoid receptor agonists, guanylate cyclase receptor agonists, histone deacetylase inhibitors, histone deacetylase-6 inhibitors, HLA class II antigen modulators, immunosuppressants, IL-12 antagonists, IL-13 antagonists, IL-23 antagonists, IL-6 antagonists, IL-6 receptor modulators, IL-7 receptor modulators, IL-7 antagonists, IL-8 antagonists, integrin α4 / β1 antagonists, integrin α4 / β7 antagonists, integrin αE antagonists, integrin antagonists, integrin β7 antagonists, interleukin ligand inhibitors, interleukin-2 ligands, interleukin receptor 17A antagonists, interleukin-1β ligands Interleukin-1β ligand modulator, IRAK4 inhibitor, ICAM1 gene inhibitor, IL-1β ligand modulator, IL-18 antagonist, IL-22 agonist, IL-23A inhibitor, interleukin-1-like receptor 2 inhibitor, JAK inhibitor, JAK tyrosine kinase inhibitor, Jak1 tyrosine kinase inhibitor, Jak3 tyrosine kinase inhibitor, LanC-like protein 2 modulator, lipoxygenase modulator, lactoferrin stimulant, leukocyte elastase inhibitor, leukocyte proteinase-3 inhibitor, MAdCAM inhibitor, matrix metalloproteinase inhibitor, melanocortin agonist, melanocortin MC1 agonist, metalloproteinase-9 inhibitor, melanin-concentrating hormone (MCH-1) antagonist, microbiome modulator, natriuretic peptide receptor C agonist, neureglin-4 ligand, NKG2 D-activated NK receptor antagonists, NLRP3 inhibitors, neuregulin-4 ligands, nuclear factor κB inhibitors, opioid receptor antagonists, opioid receptor δ antagonists, oxidoreductase inhibitors, OX40 ligand inhibitors, Pellino homolog 1 inhibitors, P2X7 prenoceptor agonists, PDE4 inhibitors, phagocytic peptide modulators, potassium channel inhibitors, PPARα agonists, PPARδ agonists, PPARγ agonists, protein fimH inhibitors, P-selectin glycoprotein ligand-1 inhibitors, Ret tyrosine kinase receptor inhibitors, RNA polymerase inhibitors, RIP-1 kinase inhibitors, RIP-2 kinase inhibitors, tissue transglutaminase inhibitors, sphingosine-1-phosphate phosphatase-1 stimulants, sphingosine-1-phosphate phosphatase modulators, sphingosine-1-phosphate receptor-1 agonists, sphingosine Sphingosine-1-phosphate receptor-1 antagonist, sphingosine-1-phosphate receptor-1 modulator, sphingosine-1-phosphate receptor-5 modulator, STAT3 gene inhibitor, stem cell antigen-1 inhibitor, superoxide dismutase modulator, superoxide dismutase stimulant, SYK inhibitor, TGFβ1 ligand inhibitor, thymrine agonist, TLR antagonist, TLR agonist, TNFα ligand inhibitor, TNF antagonist, tumor necrosis factor superfamily member 14 modulator, type II TNF receptor modulator, Tpl These include TLR-2 inhibitors, TLR-3 antagonists, TLR-4 antagonists, TLR-8 inhibitors, TLR-9 agonists, TNF ligand inhibitors, TNFα ligand modulators, TPL-2 inhibitors, tumor necrosis factor superfamily member 15 inhibitors, Tyk2 tyrosine kinase inhibitors, type I IL-1 receptor antagonists, TrkA receptor antagonists, vanilloid VR1 agonists, zonulin inhibitors, or pharmaceutically acceptable salts thereof.

[0102] In some embodiments, the additional agent is 5-aminosalicylic acid (5-ASA) or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an anti-inflammatory agent or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an ASK1 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an α-fetoprotein modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an adenosine A3 receptor antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an adrenomedullin ligand or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an AKT1 gene inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an anti-CD28 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an antibiotic or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an antifungal agent or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an ATPase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a β-adrenergic receptor antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a BTK inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a β-glucuronidase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a bradykinin receptor modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a calcineurin inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a chaperonin-binding immunoglobulin protein or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a calcium channel inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a cathepsin S inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a CCR3 chemokine antagonist or a pharmaceutically acceptable salt thereof.In some embodiments, the additional agent is a CD40 ligand receptor antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a chemokine CXC ligand inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a CHST15 gene inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a collagen modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a CSF-1 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a cyclooxygenase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a cytochrome P450 3A4 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a carbohydrate metabolism modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a CCR9 chemokine antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a CD233 modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a CD29 modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a CD3 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a CD4 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a CD40 ligand inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a CD40 gene inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a CX3CR1 chemokine modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a COT protein kinase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an eotaxin ligand inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an EP4 prostanoid receptor agonist or a pharmaceutically acceptable salt thereof.In some embodiments, the additional agent is an erythropoietin receptor agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an ecobiotic or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an F1F0 ATP synthase modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a farnesoid X receptor (FXR and NR1H4) agonist or modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a fecal microbiota transplant (FMT) or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a fractalkine ligand inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a free fatty acid receptor 2 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a GATA 3 transcription factor inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a glucagon-like peptide 2 agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a glucocorticoid receptor modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a glucocorticoid receptor agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a guanylate cyclase receptor agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a histone deacetylase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a histone deacetylase-6 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an HLA class II antigen modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an immunosuppressant or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an IL-12 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an IL-13 antagonist or a pharmaceutically acceptable salt thereof.In some embodiments, the additional agent is an IL-23 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an IL-6 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an IL-6 receptor modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an IL-7 receptor modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an IL-7 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an IL-8 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an integrin α4 / β1 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an integrin α4 / β7 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an integrin αE antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an integrin antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an integrin β7 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an interleukin ligand inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an interleukin-2 ligand or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an interleukin receptor 17A antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an interleukin-1β ligand or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an interleukin-1β ligand modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an IRAK4 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an ICAM1 gene inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an IL-1β ligand modulator or a pharmaceutically acceptable salt thereof.In some embodiments, the additional agent is an IL-18 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an IL-22 agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an IL-23A inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an interleukin-1-like receptor 2 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a JAK inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a JAK tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a Jak1 tyrosine kinase inhibitor. In some embodiments, the additional agent is a Jak3 tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a LanC-like protein 2 modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a lipoxygenase modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a lactoferrin stimulant or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a leukocyte elastase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a leukocyte proteinase-3 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a MAdCAM inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a matrix metalloproteinase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a melanocortin agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a melanocortin MC1 agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a metalloproteinase-9 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a melanin-concentrating hormone (MCH-1) antagonist or a pharmaceutically acceptable salt thereof.In some embodiments, the additional agent is a microbiome modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a natriuretic peptide receptor C agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a neuregulin-4 ligand or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an NKG2 D-activated NK receptor antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an NLRP3 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a neuregulin-4 ligand or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a nuclear factor κB inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an opioid receptor antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an opioid receptor δ antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an oxidoreductase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an OX40 ligand inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a Pellino homolog 1 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a P2X7 prenoceptor agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a PDE 4 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a phagocytic-stimulating peptide modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a potassium channel inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a PPARα agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a PPARδ agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a PPARγ agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a protein fimH inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a P-selectin glycoprotein ligand-1 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a Ret tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an RNA polymerase inhibitor or a pharmaceutically acceptable salt thereof.In some embodiments, the additional agent is a RIP-1 kinase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a RIP-2 kinase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a tissue transglutaminase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a sphingosine-1-phosphate phosphatase-1 stimulant or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a sphingosine-1-phosphate phosphatase modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a sphingosine-1-phosphate receptor-1 agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a sphingosine-1-phosphate receptor-1 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a sphingosine-1-phosphate receptor-1 modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a sphingosine-1-phosphate receptor-5 modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a STAT3 gene inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a stem cell antigen-1 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a superoxide dismutase modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a superoxide dismutase stimulant or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a SYK inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a TGFβ1 ligand inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a thymrine agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a TLR antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a TLR agonist or a pharmaceutically acceptable salt thereof.In some embodiments, the additional agent is a TNFα ligand inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a TNF antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a tumor necrosis factor superfamily member 14 modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a type II TNF receptor modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a Tpl 2 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a TLR-3 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a TLR-4 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a TLR-8 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a TLR-9 agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a TNF ligand inhibitor. In some embodiments, the additional agent is a TNFα ligand modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a TPL-2 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a tumor necrosis factor superfamily member 15 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a Tyk2 tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a type I IL-1 receptor antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a TrkA receptor antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a vanilloid VR1 agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is a zonulin inhibitor or a pharmaceutically acceptable salt thereof.

[0103] In some embodiments, the additional agent is 5-ASA or a pharmaceutically acceptable salt thereof. In some embodiments, 5-ASA is valsalazide, sulfasalazine, mesalazine, olsalazine, mesalamine, or a pharmaceutically acceptable salt thereof. In some embodiments, 5-ASA is valsalazide or a pharmaceutically acceptable salt thereof. In some embodiments, 5-ASA is sulfasalazine or a pharmaceutically acceptable salt thereof. In some embodiments, 5-ASA is mesalazine or a pharmaceutically acceptable salt thereof. In some embodiments, 5-ASA is olsalazine or a pharmaceutically acceptable salt thereof. In some embodiments, 5-ASA is mesalamine or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the additional agent is an anti-inflammatory agent or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-inflammatory agent is a corticosteroid, a non-steroidal anti-inflammatory drug (NSAID), a nonspecific cyclooxygenase enzyme inhibitor, or a COX-2 specific cyclooxygenase enzyme inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-inflammatory agent is a corticosteroid. In some embodiments, the corticosteroid is cortisone or a pharmaceutically acceptable salt thereof. In some embodiments, the corticosteroid is dexamethasone or a pharmaceutically acceptable salt thereof. In some embodiments, the corticosteroid is prednisolone or a pharmaceutically acceptable salt thereof. In some embodiments, the corticosteroid is prednisolone sodium phosphate. In some embodiments, the anti-inflammatory agent is a non-steroidal anti-inflammatory drug (NSAID) or a pharmaceutically acceptable salt thereof. In some embodiments, the NSAID is ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, a combination of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, nabumeton sodium, sulfasalazine, tolmetin sodium, hydroxychloroquine, or a pharmaceutically acceptable salt thereof. In some embodiments, the NSAID is ibuprofen or a pharmaceutically acceptable salt thereof. In some embodiments, the NSAID is flurbiprofen or a pharmaceutically acceptable salt thereof. In some embodiments, the NSAID is naproxen or a pharmaceutically acceptable salt thereof. In some embodiments, the NSAID is naproxen sodium. In some embodiments, the NSAID is diclofenac or a pharmaceutically acceptable salt thereof. In some embodiments, the NSAID is a combination of diclofenac sodium and misoprostol or a pharmaceutically acceptable salt thereof. In some embodiments, the NSAID is sulindac or a pharmaceutically acceptable salt thereof.In some embodiments, the NSAID is oxaprozin or a pharmaceutically acceptable salt thereof. In some embodiments, the NSAID is diflunisal or a pharmaceutically acceptable salt thereof. In some embodiments, the NSAID is piroxicam or a pharmaceutically acceptable salt thereof. In some embodiments, the NSAID is indomethacin or a pharmaceutically acceptable salt thereof. In some embodiments, the NSAID is etodolac or a pharmaceutically acceptable salt thereof. In some embodiments, the NSAID is fenoprofen calcium. In some embodiments, the NSAID is ketoprofen or a pharmaceutically acceptable salt thereof. In some embodiments, the NSAID is nabumetone sodium. In some embodiments, the NSAID is sulfasalazine or a pharmaceutically acceptable salt thereof. In some embodiments, the NSAID is tolmetin sodium. In some embodiments, the NSAID is hydroxychloroquine or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-inflammatory agent is a COX-2 specific cyclooxygenase enzyme inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the COX-2 specific cyclooxygenase enzyme inhibitor is celecoxib, valdecoxib, lumiracoxib, etoricoxib, rofecoxib, or a pharmaceutically acceptable salt thereof. In some embodiments, the COX-2 specific cyclooxygenase enzyme inhibitor is celecoxib or a pharmaceutically acceptable salt thereof. In some embodiments, the COX-2 specific cyclooxygenase enzyme inhibitor is valdecoxib or a pharmaceutically acceptable salt thereof. In some embodiments, the COX-2 specific cyclooxygenase enzyme inhibitor is lumiracoxib or a pharmaceutically acceptable salt thereof. In some embodiments, the COX-2 specific cyclooxygenase enzyme inhibitor is etoricoxib or a pharmaceutically acceptable salt thereof. In some embodiments, the COX-2 specific cyclooxygenase enzyme inhibitor is rofecoxib or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-inflammatory agent is sodium aurthiomalate, auranofin, or a pharmaceutically acceptable salt thereof.In some embodiments, the anti-inflammatory agent is sodium aurthiomalate or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-inflammatory agent is auranofin or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments, the anti-inflammatory agent is an immunosuppressant or a pharmaceutically acceptable salt thereof. In some embodiments, the immunosuppressant is mercaptopurine, methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, or a pharmaceutically acceptable salt thereof. In some embodiments, the immunosuppressant is mercaptopurine or a pharmaceutically acceptable salt thereof. In some embodiments, the immunosuppressant is methotrexate or a pharmaceutically acceptable salt thereof. In some embodiments, the immunosuppressant is leflunomide or a pharmaceutically acceptable salt thereof. In some embodiments, the immunosuppressant is cyclosporine or a pharmaceutically acceptable salt thereof. In some embodiments, the immunosuppressant is cyclosporine or a pharmaceutically acceptable salt thereof. In some embodiments, the immunosuppressant is tacrolimus or a pharmaceutically acceptable salt thereof. In some embodiments, the immunosuppressant is azathioprine or a pharmaceutically acceptable salt thereof. In some embodiments, the immunosuppressant is mycophenolate mofetil or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the additional agent is an ASK1 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the ASK1 inhibitor is GS-4997 or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, the additional agent is a BTK inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the BTK inhibitor is GS-4059 or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, the additional agent is a β-adrenergic receptor antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the β-adrenergic receptor antagonist is NM-001 or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments, the additional agent is a calcineurin inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the calcineurin inhibitor is tacrolimus, cyclosporine, or a pharmaceutically acceptable salt thereof. In some embodiments, the calcineurin inhibitor is tacrolimus or a pharmaceutically acceptable salt thereof. In some embodiments, the calcineurin inhibitor is cyclosporine or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments, the additional agent is a CD40 ligand receptor antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the CD40 ligand receptor antagonist is FFP-104, BI-655064, or a pharmaceutically acceptable salt thereof. In some embodiments, the CD40 ligand receptor antagonist is FFP-104 or a pharmaceutically acceptable salt thereof. In some embodiments, the CD40 ligand receptor antagonist is BI-655064 or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, the additional agent is a cathepsin S inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the cathepsin S inhibitor is VBY-129 or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, the additional agent is a chemokine CXC ligand inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the chemokine CXC ligand inhibitor is LY-3041658 or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the additional agent is a CHST15 gene inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the CHST15 gene inhibitor is STNM-01 or a pharmaceutically acceptable salt thereof.

[0114] In some embodiments, the additional agent is a collagen modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the collagen modulator is ECCS-50 (DCCT-10) or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments, the additional agent is a CSF-1 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the CSF-1 antagonist is JNJ-40346527 (PRV-6527), SNDX-6352, or a pharmaceutically acceptable salt thereof. In some embodiments, the CSF-1 antagonist is JNJ-40346527 (PRV-6527) or a pharmaceutically acceptable salt thereof. In some embodiments, the CSF-1 antagonist is SNDX-6352 or a pharmaceutically acceptable salt thereof.

[0116] In some embodiments, the additional agent is an eotaxin ligand inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the eotaxin ligand inhibitor is vertilimumab or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, the additional agent is an EP4 prostanoid receptor agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the EP4 prostanoid receptor agonist is KAG-308 or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments, the additional agent is a free fatty acid receptor 2 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the free fatty acid receptor 2 antagonist is GLPG-0974 or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, the additional agent is a GATA 3 transcription factor inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the GATA 3 transcription factor inhibitor is SB-012 or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, the additional agent is a GATA 3 transcription factor inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the GATA 3 transcription factor inhibitor is SB-012 or a pharmaceutically acceptable salt thereof.

[0121] In some embodiments, the additional agent is a fractalkine ligand inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the fractalkine ligand inhibitor is quetomolimab (E-6011) or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, the additional agent is a glucagon-like peptide 2-agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the glucagon-like peptide 2-agonist is teduglutide, appraglutide, or a pharmaceutically acceptable salt thereof. In some embodiments, the glucagon-like peptide 2-agonist is teduglutide or a pharmaceutically acceptable salt thereof. In some embodiments, the glucagon-like peptide 2-agonist is appraglutide or a pharmaceutically acceptable salt thereof.

[0123] In some embodiments, the additional agent is a guanylate cyclase receptor agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the guanylate cyclase receptor agonist is dolucanatide or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments, the additional agent is a histone deacetylase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the histone deacetylase inhibitor is gibinostat or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, the additional agent is an HLA class II antigen modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the HLA class II antigen modulator is an HLA class II protein modulator or a pharmaceutically acceptable salt thereof.

[0126] In some embodiments, the additional agent is an IL-12 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the IL-12 antagonist is ustekinumab (IL12 / IL23), MEDI2070, or a pharmaceutically acceptable salt thereof. In some embodiments, the IL-12 antagonist is ustekinumab (IL12 / IL23) or a pharmaceutically acceptable salt thereof. In some embodiments, the IL-12 antagonist is MEDI2070 or a pharmaceutically acceptable salt thereof.

[0127] In some embodiments, the additional agent is an IL-13 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the IL-13 antagonist is tralokinumab or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the additional agent is an IL-23 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the IL-23 antagonist is tildrakizumab, risankizumab (BI-655066), myrikizumab (LY-3074828), brazicumab (AMG-139), PTG-200, or a pharmaceutically acceptable salt thereof. In some embodiments, the IL-23 antagonist is tildrakizumab or a pharmaceutically acceptable salt thereof. In some embodiments, the IL-23 antagonist is risankizumab (BI-655066) or a pharmaceutically acceptable salt thereof. In some embodiments, the IL-23 antagonist is myrikizumab (LY-3074828) or a pharmaceutically acceptable salt thereof. In some embodiments, the IL-23 antagonist is brazicumab (AMG-139) or a pharmaceutically acceptable salt thereof. In some embodiments, the IL-23 antagonist is PTG-200 or a pharmaceutically acceptable salt thereof.

[0129] In some embodiments, the additional agent is an IL-6 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the IL-6 antagonist is olokizumab or a pharmaceutically acceptable salt thereof.

[0130] In some embodiments, the additional agent is an IL-6 receptor modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the IL-6 receptor modulator is oramxept or a pharmaceutically acceptable salt thereof.

[0131] In some embodiments, the additional agent is an IL-7 receptor antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the IL-7 receptor antagonist is OSE-127 or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, the additional agent is an IL-8 receptor antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the IL-8 receptor antagonist is clotrimazole or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, the additional agent is an integrin α4 / β7 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the integrin α4 / β7 antagonist is etrolizumab (a4b7 / aEb7), vedolizumab, carotegastmethyl, TRK-170 (a4b7 / a4b1), PN-10943, PTG-100, or a pharmaceutically acceptable salt thereof. In some embodiments, the integrin α4 / β7 antagonist is etrolizumab (a4b7 / aEb7) or a pharmaceutically acceptable salt thereof. In some embodiments, the integrin α4 / β7 antagonist is vedolizumab or a pharmaceutically acceptable salt thereof. In some embodiments, the integrin α4 / β7 antagonist is carotegastmethyl or a pharmaceutically acceptable salt thereof. In some embodiments, the integrin α4 / β7 antagonist is TRK-170(a4b7 / a4b1) or a pharmaceutically acceptable salt thereof. In some embodiments, the integrin α4 / β7 antagonist is PN-10943 or a pharmaceutically acceptable salt thereof. In some embodiments, the integrin α4 / β7 antagonist is PTG-100 or a pharmaceutically acceptable salt thereof.

[0134] In some embodiments, the additional agent is an integrin antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the integrin antagonist is E-6007 or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, the additional agent is an interleukin ligand inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the interleukin ligand inhibitor is bimekizumab (IL-17A / IL-17F) or a pharmaceutically acceptable salt thereof.

[0136] In some embodiments, the additional agent is an interleukin receptor 17A antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the interleukin receptor 17A antagonist is brodalumab or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments, the additional agent is an interleukin-1β ligand or a pharmaceutically acceptable salt thereof. In some embodiments, the interleukin-1β ligand is K(D)PT or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments, the additional agent is a JAK tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK tyrosine kinase inhibitor is tofacitinib, peficitinib, TD-3504, TD-1473, or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK tyrosine kinase inhibitor is tofacitinib or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK tyrosine kinase inhibitor is tofacitinib, peficitinib, TD-3504, TD-1473, or a pharmaceutically acceptable salt thereof.

[0139] In some embodiments, the additional agent is a Jak3 tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the Jak3 tyrosine kinase inhibitor is PF-06651600 or a pharmaceutically acceptable salt thereof.

[0140] In some embodiments, the additional agent is a LanC-like protein 2 modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the LanC-like protein 2 modulator is BT-11 or a pharmaceutically acceptable salt thereof.

[0141] In some embodiments, the additional agent is a MAdCAM inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the MAdCAM inhibitor is SHP-647 (PF-547659) or a pharmaceutically acceptable salt thereof.

[0142] In some embodiments, the additional agent is a melanocortin MC1 receptor agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the melanocortin MC1 receptor agonist is ASP-3291, PL-8177, or a pharmaceutically acceptable salt thereof. In some embodiments, the melanocortin MC1 receptor agonist is ASP-3291 or a pharmaceutically acceptable salt thereof. In some embodiments, the melanocortin MC1 receptor agonist is PL-8177 or a pharmaceutically acceptable salt thereof.

[0143] In some embodiments, the additional agent is a natriuretic peptide receptor C agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the natriuretic peptide receptor C agonist is precanatide or a pharmaceutically acceptable salt thereof.

[0144] In some embodiments, the additional agent is an opioid receptor antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the opioid receptor antagonist is naltrexone, IRT-103, or a pharmaceutically acceptable salt thereof. In some embodiments, the opioid receptor antagonist is naltrexone or a pharmaceutically acceptable salt thereof. In some embodiments, the opioid receptor antagonist is IRT-103 or a pharmaceutically acceptable salt thereof.

[0145] In some embodiments, the additional agent is an oxidoreductase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the oxidoreductase inhibitor is orsalazine or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, the additional agent is a P2X7 prenoceptor modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the P2X7 prenoceptor modulator is SGM-1019 or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments, the additional agent is a PDE 4 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the PDE 4 inhibitor is apremilast or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments, the additional agent is a PPARα agonist or a PPARδ agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the PPARα agonist or PPARδ agonist is ellafibranol (GFT-1007) or a pharmaceutically acceptable salt thereof.

[0149] In some embodiments, the additional agent is a PPARγ agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the PPARγ agonist is GED-0507-34-Levo or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the additional agent is a protein fimH inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the protein fimH inhibitor is cibofimloc (EB-8018) or a pharmaceutically acceptable salt thereof.

[0151] In some embodiments, the additional agent is a P-selectin glycoprotein ligand-1 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the P-selectin glycoprotein ligand-1 inhibitor is SEL-K2, AbGn-168H, neihulizumab, or a pharmaceutically acceptable salt thereof. In some embodiments, the P-selectin glycoprotein ligand-1 inhibitor is SEL-K2 or a pharmaceutically acceptable salt thereof. In some embodiments, the P-selectin glycoprotein ligand-1 inhibitor is AbGn-168H or a pharmaceutically acceptable salt thereof. In some embodiments, the P-selectin glycoprotein ligand-1 inhibitor is neihulizumab or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, the additional agent is a sphingosine-1-phosphate phosphatase-1 stimulant or a pharmaceutically acceptable salt thereof. In some embodiments, the sphingosine-1-phosphate phosphatase-1 stimulant is etrasimodo or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments, the additional agent is a sphingosine-1-phosphate receptor-1 agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the sphingosine-1-phosphate receptor-1 agonist is ozanimod, moclavin (KRP-203), BMS-986166, or a pharmaceutically acceptable salt thereof. In some embodiments, the sphingosine-1-phosphate receptor-1 agonist is ozanimod or a pharmaceutically acceptable salt thereof. In some embodiments, the sphingosine-1-phosphate receptor-1 agonist is moclavin (KRP-203) or a pharmaceutically acceptable salt thereof. In some embodiments, the sphingosine-1-phosphate receptor-1 agonist is BMS-986166 or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, the additional agent is a sphingosine-1-phosphate receptor-5 agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the sphingosine-1-phosphate receptor-5 agonist is ozanimod or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments, the additional agent is a sphingosine-1-phosphate receptor-1 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the sphingosine-1-phosphate receptor-1 antagonist is amicelimod (MT-1303) or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, the additional agent is a sphingosine-1-phosphate receptor-1 modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the sphingosine-1-phosphate receptor-1 modulator is OPL-002 or a pharmaceutically acceptable salt thereof.

[0157] In some embodiments, the additional agent is a stem cell antigen-1 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the stem cell antigen-1 inhibitor is ampon(DMI-9523) or a pharmaceutically acceptable salt thereof.

[0158] In some embodiments, the additional agent is a superoxide dismutase modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the superoxide dismutase modulator is a midismase or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, the additional agent is a SYK inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the SYK inhibitor is GS-9876 or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments, the additional agent is a TNFα ligand inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the TNFα ligand inhibitor is adalimumab, certolizumab pegol, infliximab, golimumab, DLX-105, Debio-0512, HMPL-004, CYT-020-TNFQb, Hemay-007, V-565, an anti-TNFα antibody, or a pharmaceutically acceptable salt thereof. In some embodiments, the TNFα ligand inhibitor is adalimumab or a pharmaceutically acceptable salt thereof. In some embodiments, the TNFα ligand inhibitor is certolizumab pegol or a pharmaceutically acceptable salt thereof. In some embodiments, the TNFα ligand inhibitor is infliximab or a pharmaceutically acceptable salt thereof. In some embodiments, the TNFα ligand inhibitor is golimumab or a pharmaceutically acceptable salt thereof. In some embodiments, the TNFα ligand inhibitor is DLX-105 or a pharmaceutically acceptable salt thereof. In some embodiments, the TNFα ligand inhibitor is Debio-0512 or a pharmaceutically acceptable salt thereof. In some embodiments, the TNFα ligand inhibitor is HMPL-004 or a pharmaceutically acceptable salt thereof. In some embodiments, the TNFα ligand inhibitor is CYT-020-TNFQb or a pharmaceutically acceptable salt thereof. In some embodiments, the TNFα ligand inhibitor is Hemay-007 or a pharmaceutically acceptable salt thereof. In some embodiments, the TNFα ligand inhibitor is V-565 or a pharmaceutically acceptable salt thereof. In some embodiments, the TNFα ligand inhibitor is an anti-TNFα antibody or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, the additional agent is a tumor necrosis factor superfamily member 14 modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the tumor necrosis factor superfamily member 14 modulator is AEVI-002 or a pharmaceutically acceptable salt thereof.

[0162] In some embodiments, the additional agent is a TNF antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the TNF antagonist is AVX-470, tournercept, etanercept, or a pharmaceutically acceptable salt thereof. In some embodiments, the TNF antagonist is AVX-470 or a pharmaceutically acceptable salt thereof. In some embodiments, the TNF antagonist is tournercept or a pharmaceutically acceptable salt thereof. In some embodiments, the TNF antagonist is etanercept or a pharmaceutically acceptable salt thereof.

[0163] In some embodiments, the additional agent is a zonulin inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the zonulin inhibitor is larazotide acetate or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, the additional agent is a CD40 ligand inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the CD40 ligand inhibitor is SAR-441344, letrizumab, or a pharmaceutically acceptable salt thereof. In some embodiments, the CD40 ligand inhibitor is SAR-441344 or a pharmaceutically acceptable salt thereof. In some embodiments, the CD40 ligand inhibitor is letrizumab or a pharmaceutically acceptable salt thereof.

[0165] In some embodiments, the additional agent is an adenosine A3 receptor antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the adenosine A3 receptor antagonist is PBF-677 or a pharmaceutically acceptable salt thereof.

[0166] In some embodiments, the additional agent is an adremedullin ligand or a pharmaceutically acceptable salt thereof. In some embodiments, the adremedullin ligand is adremedullin or a pharmaceutically acceptable salt thereof.

[0167] In some embodiments, the additional agent is an antibiotic or a pharmaceutically acceptable salt thereof. In some embodiments, the antibiotic is ciprofloxacin, clarithromycin, metronidazole, vancomycin, rifamycin, rifaximin, tosufloxacin, or a pharmaceutically acceptable salt thereof. In some embodiments, the antibiotic is ciprofloxacin or a pharmaceutically acceptable salt thereof. In some embodiments, the antibiotic is clarithromycin or a pharmaceutically acceptable salt thereof. In some embodiments, the antibiotic is metronidazole or a pharmaceutically acceptable salt thereof. In some embodiments, the antibiotic is vancomycin or a pharmaceutically acceptable salt thereof. In some embodiments, the antibiotic is rifamycin or a pharmaceutically acceptable salt thereof. In some embodiments, the antibiotic is rifaximin or a pharmaceutically acceptable salt thereof. In some embodiments, the antibiotic is tosufloxacin or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the additional agent is an α-fetoprotein modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the α-fetoprotein modulator is ACT-101 or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, the additional agent is a carbohydrate metabolism modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the carbohydrate metabolism modulator is ASD-003 or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the additional agent is a CCR9 chemokine antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the CCR9 chemokine antagonist is CCX-507 or a pharmaceutically acceptable salt thereof.

[0171] In some embodiments, the additional agent is a CD233 modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the CD233 modulator is GSK-2831781 or a pharmaceutically acceptable salt thereof.

[0172] In some embodiments, the additional agent is a CD29 modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the CD29 modulator is PF-06687234 or a pharmaceutically acceptable salt thereof.

[0173] In some embodiments, the additional agent is a CX3CR1 chemokine modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the CX3CR1 chemokine modulator is E-6130 or a pharmaceutically acceptable salt thereof.

[0174] In some embodiments, the additional agent is ecobiotic or a pharmaceutically acceptable salt thereof. In some embodiments, the ecobiotic is SER-287 or a pharmaceutically acceptable salt thereof.

[0175] In some embodiments, the additional agent is a CD3 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the CD3 antagonist is NI-0401 or a pharmaceutically acceptable salt thereof.

[0176] In some embodiments, the additional agent is F1F0 ATP synthase modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the F1F0 ATP synthase modulator is LYC-30937 EC or a pharmaceutically acceptable salt thereof.

[0177] In some embodiments, the additional agent is a glucocorticoid receptor modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid receptor modulator is ABBV-3373 or a pharmaceutically acceptable salt thereof.

[0178] In some embodiments, the additional agent is a TNF ligand inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the TNF ligand inhibitor is ABBV-3373 or a pharmaceutically acceptable salt thereof.

[0179] In some embodiments, the additional agent is an ICAM1 gene inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the ICAM1 gene inhibitor is aricahorsen or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, the additional agent is an IL-18 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the IL-18 antagonist is GSK-1070806 or a pharmaceutically acceptable salt thereof.

[0181] In some embodiments, the additional agent is an IL-22 agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the IL-22 agonist is RG-7880 or a pharmaceutically acceptable salt thereof.

[0182] In some embodiments, the additional agent is an IL-22 agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the IL-23A inhibitor is guselkumab or a pharmaceutically acceptable salt thereof.

[0183] In some embodiments, the additional agent is an interleukin-1-like receptor 2 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the interleukin-1-like receptor 2 inhibitor is BI-655130 or a pharmaceutically acceptable salt thereof.

[0184] In some embodiments, the additional agent is a lactoferrin stimulant or a pharmaceutically acceptable salt thereof. In some embodiments, the lactoferrin stimulant is recombinant human lactoferrin (VEN-100) or a pharmaceutically acceptable salt thereof.

[0185] In some embodiments, the additional agent is a leukocyte elastase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the leukocyte elastase inhibitor is tiprelestat or a pharmaceutically acceptable salt thereof.

[0186] In some embodiments, the additional agent is a leukocyte proteinase-3 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the leukocyte proteinase-3 inhibitor is ticplerestat or a pharmaceutically acceptable salt thereof.

[0187] In some embodiments, the additional agent is a melanin-concentrating hormone (MCH-1) antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the melanin-concentrating hormone (MCH-1) antagonist is CSTI-100 or a pharmaceutically acceptable salt thereof.

[0188] In some embodiments, the additional agent is a metalloproteinase-9 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the metalloproteinase-9 inhibitor is GS-5745 or a pharmaceutically acceptable salt thereof.

[0189] In some embodiments, the additional agent is an NLRP3 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the NLRP3 inhibitor is dapanstril, BMS-986299, SB-414, MCC-950, IFM-514, JT-194, PELA-167, NBC-6, or a pharmaceutically acceptable salt thereof. In some embodiments, the NLRP3 inhibitor is dapanstril or a pharmaceutically acceptable salt thereof. In some embodiments, the NLRP3 inhibitor is BMS-986299 or a pharmaceutically acceptable salt thereof. In some embodiments, the NLRP3 inhibitor is SB-414 or a pharmaceutically acceptable salt thereof. In some embodiments, the NLRP3 inhibitor is MCC-950 or a pharmaceutically acceptable salt thereof. In some embodiments, the NLRP3 inhibitor is IFM-514 or a pharmaceutically acceptable salt thereof. In some embodiments, the NLRP3 inhibitor is JT-194 or a pharmaceutically acceptable salt thereof. In some embodiments, the NLRP3 inhibitor is PELA-167 or a pharmaceutically acceptable salt thereof. In some embodiments, the NLRP3 inhibitor is NBC-6 or a pharmaceutically acceptable salt thereof.

[0190] In some embodiments, the additional agent is a farnesoid X receptor (FXR and NR1H4) agonist or modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the farnesoid X receptor (FXR and NR1H4) agonist or modulator is AGN-242266 or a pharmaceutically acceptable salt thereof. In some embodiments, the farnesoid X receptor (FXR and NR1H4) agonist or modulator is cilofexol tromethamine (GS-9674) or a pharmaceutically acceptable salt thereof. In some embodiments, the farnesoid X receptor (FXR and NR1H4) agonist or modulator is EDP-305 or a pharmaceutically acceptable salt thereof. In some embodiments, the farnesoid X receptor (FXR and NR1H4) agonist or modulator is EYP-001 or a pharmaceutically acceptable salt thereof. In some embodiments, the farnesoid X receptor (FXR and NR1H4) agonist or modulator is EYP-001 or a pharmaceutically acceptable salt thereof. In some embodiments, the farnesoid X receptor (FXR and NR1H4) agonist or modulator is GNF-5120 or a pharmaceutically acceptable salt thereof. In some embodiments, the farnesoid X receptor (FXR and NR1H4) agonist or modulator is MET-409 or a pharmaceutically acceptable salt thereof. In some embodiments, the farnesoid X receptor (FXR and NR1H4) agonist or modulator is nidufexor (LMB-763) or a pharmaceutically acceptable salt thereof. In some embodiments, the farnesoid X receptor (FXR and NR1H4) agonist or modulator is obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the farnesoid X receptor (FXR and NR1H4) agonist or modulator is TERN-101 or a pharmaceutically acceptable salt thereof. In some embodiments, the farnesoid X receptor (FXR and NR1H4) agonist or modulator is tropifexol or a pharmaceutically acceptable salt thereof.

[0191] In some embodiments, the additional agent is a nuclear factor-κB inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the nuclear factor-κB inhibitor is Thetanix or a pharmaceutically acceptable salt thereof.

[0192] In some embodiments, the additional agent is an OX40 ligand inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the OX40 ligand inhibitor is KHK-4083 or a pharmaceutically acceptable salt thereof.

[0193] In some embodiments, the additional agent is a Pellino homolog 1 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the Pellino homolog 1 inhibitor is BBT-401 or a pharmaceutically acceptable salt thereof.

[0194] In some embodiments, the additional agent is a Ret tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the Ret tyrosine kinase receptor inhibitor is GSK-3179106 or a pharmaceutically acceptable salt thereof.

[0195] In some embodiments, the additional agent is a RIP-1 kinase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the RIP-1 kinase inhibitor is GSK-2982772 or a pharmaceutically acceptable salt thereof.

[0196] In some embodiments, the additional agent is a RIP-2 kinase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the RIP-2 kinase inhibitor is GSK-2983559 or a pharmaceutically acceptable salt thereof.

[0197] In some embodiments, the additional agent is a tissue transglutaminase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the tissue transglutaminase inhibitor is zampilimab or a pharmaceutically acceptable salt thereof.

[0198] In some embodiments, the additional agent is a TLR-3 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the TLR-3 antagonist is PRV-300 or a pharmaceutically acceptable salt thereof.

[0199] In some embodiments, the additional agent is a TLR-4 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the TLR-4 antagonist is JKB-122 or a pharmaceutically acceptable salt thereof.

[0200] In some embodiments, the additional agent is a TLR8 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the TLR8 inhibitor is E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motlimod, reximod, VTX-1463, VTX-763, or a pharmaceutically acceptable salt thereof. In some embodiments, the TLR8 inhibitor is E-6887 or a pharmaceutically acceptable salt thereof. In some embodiments, the TLR8 inhibitor is IMO-4200 or a pharmaceutically acceptable salt thereof. In some embodiments, the TLR8 inhibitor is IMO-8400 or a pharmaceutically acceptable salt thereof. In some embodiments, the TLR8 inhibitor is IMO-9200 or a pharmaceutically acceptable salt thereof. In some embodiments, the TLR8 inhibitor is MCT-465 or a pharmaceutically acceptable salt thereof. In some embodiments, the TLR8 inhibitor is MEDI-9197 or a pharmaceutically acceptable salt thereof. In some embodiments, the TLR8 inhibitor is motlimod or a pharmaceutically acceptable salt thereof. In some embodiments, the TLR8 inhibitor is reximod or a pharmaceutically acceptable salt thereof. In some embodiments, the TLR8 inhibitor is VTX-1463 or a pharmaceutically acceptable salt thereof. In some embodiments, the TLR8 inhibitor is VTX-763 or a pharmaceutically acceptable salt thereof.

[0201] In some embodiments, the additional agent is a TLR-9 agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the TLR-9 agonist is covitrimod, IMO-2055, IMO-2125, lephyrimod, ritenimod, MGN-1601, PUL-042, or a pharmaceutically acceptable salt thereof. In some embodiments, the TLR-9 agonist is covitrimod or a pharmaceutically acceptable salt thereof. In some embodiments, the TLR-9 agonist is IMO-2055 or a pharmaceutically acceptable salt thereof. In some embodiments, the TLR-9 agonist is IMO-2125 or a pharmaceutically acceptable salt thereof. In some embodiments, the TLR-9 agonist is lephyrimod or a pharmaceutically acceptable salt thereof. In some embodiments, the TLR-9 agonist is ritenimod or a pharmaceutically acceptable salt thereof. In some embodiments, the TLR-9 agonist is MGN-1601 or a pharmaceutically acceptable salt thereof. In some embodiments, the TLR-9 agonist is PUL-042 or a pharmaceutically acceptable salt thereof.

[0202] In some embodiments, the additional agent is a TPL-2 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the TPL-2 inhibitor is GS-4875 or a pharmaceutically acceptable salt thereof.

[0203] In some embodiments, the additional agent is a tumor necrosis factor superfamily member 15 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the tumor necrosis factor superfamily member 15 inhibitor is PF-06480605, PRA023, or a pharmaceutically acceptable salt thereof. In some embodiments, the tumor necrosis factor superfamily member 15 inhibitor is PF-06480605 or a pharmaceutically acceptable salt thereof. In some embodiments, the tumor necrosis factor superfamily member 15 inhibitor is PRA023 or a pharmaceutically acceptable salt thereof.

[0204] In some embodiments, the additional agent is a Tyk2 tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the Tyk2 tyrosine kinase inhibitor is PF-06826647, BMS-986165, or a pharmaceutically acceptable salt thereof. In some embodiments, the Tyk2 tyrosine kinase inhibitor is PF-06826647 or a pharmaceutically acceptable salt thereof. In some embodiments, the Tyk2 tyrosine kinase inhibitor is BMS-986165 or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments, the additional agent is a type I IL-1 receptor antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the type I IL-1 receptor antagonist is anakinra or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments, the additional agent is an anti-CD28 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-CD28 inhibitor is JNJ-3133, abatacept, or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-CD28 inhibitor is JNJ-3133 or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-CD28 inhibitor is abatacept or a pharmaceutically acceptable salt thereof.

[0207] In some embodiments, the additional agent is a type I IL-1 receptor antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the type I IL-1 receptor antagonist is anakinra or a pharmaceutically acceptable salt thereof.

[0208] In some embodiments, the additional agent is a CD4 antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the CD4 antagonist is IT-1208 or a pharmaceutically acceptable salt thereof.

[0209] In some embodiments, the additional agent is a CD40 gene inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the CD40 gene inhibitor is NJA-730 or a pharmaceutically acceptable salt thereof.

[0210] In some embodiments, the additional agent is a chaperonin-binding immunoglobulin protein or a pharmaceutically acceptable salt thereof. In some embodiments, the chaperonin-binding immunoglobulin protein is IRL-201805 or a pharmaceutically acceptable salt thereof.

[0211] In some embodiments, the additional agent is a COT protein kinase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the COT protein kinase inhibitor is GS-4875 or a pharmaceutically acceptable salt thereof.

[0212] In some embodiments, the additional agent is a glucocorticoid receptor agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid receptor agonist is budesonide, beclomethasone dipropionate, dexamethasone sodium phosphate, or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid receptor agonist is budesonide or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid receptor agonist is beclomethasone dipropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid receptor agonist is dexamethasone sodium phosphate or a pharmaceutically acceptable salt thereof.

[0213] In some embodiments, the additional agent is an HIF prolyl hydroxylase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the HIF prolyl hydroxylase inhibitor is DS-1093, AKB-4924, or a pharmaceutically acceptable salt thereof. In some embodiments, the HIF prolyl hydroxylase inhibitor is DS-1093 or a pharmaceutically acceptable salt thereof. In some embodiments, the HIF prolyl hydroxylase inhibitor is AKB-4924 or a pharmaceutically acceptable salt thereof.

[0214] In some embodiments, the additional agent is a histone deacetylase-6 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the histone deacetylase-6 inhibitor is CKD-506 or a pharmaceutically acceptable salt thereof.

[0215] In some embodiments, the additional agent is a neuregulin-4 ligand or a pharmaceutically acceptable salt thereof. In some embodiments, the neuregulin-4 ligand is NRG-4 or a pharmaceutically acceptable salt thereof.

[0216] In some embodiments, the additional agent is a microbiome modulator or a pharmaceutically acceptable salt thereof. In some embodiments, the microbiome modulator is ABI-M201 or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, the additional agent is a TrkA receptor antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the TrkA receptor antagonist is SNA-125 or a pharmaceutically acceptable salt thereof.

[0218] In some embodiments, the additional agent is a JAK inhibitor. In some embodiments, the JAK inhibitor is AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110, restaurtinib, momerotinib (CYT0387), NS-018, pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib, XL019, upadacitinib (ABT-494), filgotinib, GLPG-0555, SHR-0302, brepocitinib (PF-06700841), or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is AT9283 or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is AZD1480 or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is baricitinib or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is BMS-911543 or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is fedratinib or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is filgotinib (GLPG0634) or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is gandotinib (LY2784544) or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is INCB039110 or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is restaurtinib or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is momerotinib (CYT0387) or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is NS-018 or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is pacritinib (SB1518) or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is ruxolitinib or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is tofacitinib or a pharmaceutically acceptable salt thereof.In some embodiments, the JAK inhibitor is XL019 or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is upadacitinib (ABT-494) or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is filgotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is GLPG-0555 or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is SHR-0302 or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is brepocitinib (PF-06700841) or a pharmaceutically acceptable salt thereof.

[0219] In some embodiments, additional agents include obefazimod (ABX-4640), adalimumab, aricahorsen, ALLO-ASC-CD, AMG-966, anakinra, apremilast, Alequel, AMG-139, amicelimod, ASD-003, ASP-3291, AX-1505, BBT-401, valsalazid, beclomethasone dipropionate, BI-655130, BMS-986184, budesonide, CEQ-508, certolizumab, ChAdOx2-HAV, dexamethasone sodium phosphate, DNVX-078, etanercept, cibinetide, and Clostridium butyricum. Butyricum, ETX-201, Golimumab, GS-4997, GS-9876, GS-4875, GS-4059, Infliximab, Mesalazine, HLD-400, LYC-30937 EC, IONIS-JB11-2.5Rx, JNJ-64304500, JNJ-4447, Naltrexone, Natalizumab, Neiflizumab, Orsalazine, PH-46-A, Propionyl-L-Carnitine, PTG-100, Remestemcell-L, Tacrolimus, Teduglutide, Tofacitinib, ASP-1002, Ustekinumab, Vedolizumab, AVX-470, INN-108, SGM-1019, PF-06480605, PF- 06651600, PF-06687234, RBX-8225, SER-287, Thetanix, TOP-1288, VBY-129, 99mTc-Annexin V-128, Vertilimumab, DLX-105, Dolcanatide, FFP-104, Filgotinib, Foralumab, GED-0507-34-Levo, Gibinostat, GLPG-0974, Iberogast, JNJ-40346527, K(D )PT, KAG-308, KHK-4083, KRP-203, Larazotide Acetate, LY-3074828, Midismase, Orokizumab, OvaSave, P-28-GST, PF-547659, Prednisolone, QBECO, RBX-2660, RG-7835, JKB-122, SB-012, STNM-01, Debio-0512, TRK-170, Zukapsaicin, ABT-494, Ampion, BI-655066, carotegastmethyl, covitrimod, ellafibranol, etrolizumab, GS-5745, HMPL-004, LP-02, ozanimod, peficitinib, quetomolimab (E-6011), RHB-104, rifaximin, tildrakizumab, tralokinumab, brodalumab, lakinimod, precanatide, vidofludimus, AZD-058, or pharmaceutically acceptable salts thereof.

[0220] In some embodiments, the JAK inhibitor is a compound such as those disclosed in U.S. Patent No. 9,233,934.

[0221] In some embodiments, the additional therapeutic agent is administered simultaneously with the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered at a lower frequency than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered at a higher frequency than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered before the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein.

[0222] In some embodiments, additional therapeutic agents are drugs for treating metabolic disorders. These drugs include pancreatic lipase inhibitors (e.g., orlistat); insulin; insulin sensitizers including biguanides (e.g., buformin, metformin, and phenformin) and glitazones (e.g., pioglitazone and rosiglitazone); sulfonylureas (e.g., acetohexamide, chlorpropamide, trazamide, tolbutamide, gliclazide, glimepiride, glipizide, and glibride); and meglitinides (e.g., nateglinide and Examples include insulin secretagogues (including lepaglinide); α-glucosidase inhibitors (e.g., acarbose and miglitol); glucagon-like peptide analogs and agonists (e.g., exenatide, liraglutide, and taspoglutide); dipeptidyl peptidase-4 inhibitors (e.g., alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin); and amyrin analogs (e.g., pramlintide).

[0223] In some embodiments, the additional therapeutic agent is a drug for treating impaired wound healing. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, an analgesic, an antipruritic, or an anti-infective agent.

[0224] Examples of anti-inflammatory drugs include nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. Representative NSAIDs include apazon, aspirin, celecoxib, diclofenac (with and without misoprostol), diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, sodium meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozine, phenylbutazone, piroxicam, choline salicylate and magnesium salicylate, salsalate, and sulindac. Representative corticosteroids include betamethasone, cortisone acetate, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone. Typical analgesics include acetaminophen and morphine sulfate, as well as codeine, hydrocodone, oxycodone, propoxyfen, and tramadol (all used in combination with or without acetaminophen). Typical antipruritic agents for systemic use include cyproheptadine, diphenhydramine, gabapentin, hydroxyzine, and ondansetron.

[0225] Examples of anti-infective agents include antibacterial agents, antifungal agents, and antiviral agents.

[0226] Typical antibacterial agents include aminoglycosides, such as amikacin, gentamicin, kanamycin, neomycin, paromomycin, and tobramycin; carbapenems, such as doripenem, ertapenem, imipenem, and meropenem; cephalosporins, including combinations with β-lactamase inhibitors such as ceftazidime / avibactam and ceftolozane / tazobactam; first-generation cephalosporins, such as cefadroxil, cefazolin, cephalexin, and cefradin; second-generation cephalosporins, such as cefotetan and cefprodil. Cefuroxime, efoxitin, and loracalbef; third-generation cephalosporins, e.g., cefdinir, cefditoren, cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibutene, ceftizoxime, and ceftriaxone; and fourth-generation and next-generation cephalosporins, e.g., cefepime and cephthaloline; glycopeptide antibiotics, e.g., dalbavancin, oritavancin, teravancin, and vancomycin; glycylcyclines, e.g., tigecycline; lincomycin and its derivatives, e.g., cyanoacrylate Lindamycin; macrolides, such as azithromycin, clarithromycin, erythromycin, and fidaxomicin, and macrolide derivatives including ketolides such as telithromycin; oxazolidinone antibiotics, such as linezolid and tedizolid; aminopenicillins, such as penicillins including amoxicillin and ampicillin; anti-Pseudomonas penicillins, such as carbenicillin, piperacillin, and ticarcillin; amoxicillin / clavulanic acid, ampicillin / sulbactam, piperacillin / tazobactam, and ticarcillin Penicillin with β-lactamase inhibitors such as clavulanic acid; natural penicillins, e.g., penicillin G benzathine, penicillin V potassium, and procaine penicillin; penicillinase-resistant penicillins, e.g., dicloxacillin, nafcillin, and oxacillin; quinolones, e.g., cinoxacin, ciprofloxacin, delafloxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, and trovafloxacin;Examples of antimicrobial agents include sulfonamides, such as sulfamethoxazole / trimethoprim and sulfisoxazole; tetracyclines and their derivatives, such as demeclocycline, doxycycline, doxycycline / ω-3 polyunsaturated fatty acids, doxycycline / salicylic acid, minocycline, and oxytetracycline. Other representative antimicrobial agents include atovaquone, aztreonam, bacitracin, chloramphenicol, colistin methate, dalfopristin / quinupristin, daptomycin, erythromycin / sulfisoxazole, fosfomycin, metronidazole, pentamidine, rifaximin, spectinomycin, and trimethrexate.

[0227] Representative antifungal agents include azole antifungals such as clotrimazole, fluconazole, isabconazonium, itraconazole, ketoconazole, miconazole, posaconazole, and voriconazole; echinocandins such as anidurafungin, caspofungin, and micafungin; and polyenes such as amphotericin B, amphotericin B cholesteryl sulfate, amphotericin B lipid complex, and nystatin. Other representative antifungal agents include flucytosine, griseofulvin, and terbinafine.

[0228] Representative antiviral agents include purine nucleosides, such as acyclovir, cidofovir, famciclovir, ganciclovir, ribavirin, valacyclovir, and valganciclovir.

[0229] In some embodiments, additional therapeutic agents are anticancer agents. In some embodiments, additional therapeutic agents are chemotherapeutic agents (i.e., cytotoxic agents, or antineoplastic agents) such as alkylating agents, antibiotics, antimetabolites, plant-derived agents, and topoisomerase inhibitors, as well as molecularly targeted drugs that block cancer growth and spread by interfering with specific molecules involved in tumor growth and progression. Molecularly targeted drugs include both small molecules and biologics.

[0230] Typical alkylating agents include bischloroethylamine (nitrogen mustard) containing chlorambucil, cyclophosphamide, ifosfamide, mechloretamine, melphalan, and uracil mustard; aziridines containing thiotepa; alkylalconsulfonates containing busulfan; nitrosoureas containing carmustine, lomustine, and streptozocine; non-classical alkylating agents containing altretamine, dacarbazine, and procarbazine; and platinum compounds containing carboplatin, cisplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate.

[0231] Representative antibiotics include anthracyclines, such as acralubicin, amrubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, barurubicin, and zorubicin; anthracendions, such as mitoxantrone and pixantrone; and streptomyces, such as actinomycin, bleomycin, dactinomycin, mitomycin C, and plicamycin.

[0232] Representative antimetabolites include dihydrofolate reductase inhibitors containing aminopterin, methotrexate, and pemetrexed; hemidylate synthase inhibitors containing larcitrexed and pemetrexed; folinic acid containing leucovorin; adenosine deaminase inhibitors containing pentostatin; halogenated / ribonucleotide reductase inhibitors containing cladribine, clofarabine, and fludarabine; thiopurines containing thioguanine and mercaptopurine; thymidylate synthase inhibitors containing fluorouracil, capecitabine, tegafur, carmofur, and floxuridine; DNA polymerase inhibitors containing cytarabine; ribonucleotide reductase inhibitors containing gemcitabine; hypomethylating agents containing azacitidine and decitabine; ribonucleotide reductase inhibitors containing hydroxyurea; and asparagine depletion agents containing asparaginase.

[0233] Representative plant-derived agents include vinca alkaloids, such as vincristine, vinblastine, vindesine, binzolidine, and vinorelbine; podophyllotoxins, such as etoposide and teniposide; and taxanes, such as docetaxel, larotaxel, ortataxel, paclitaxel, and tesetaxel.

[0234] Representative type I topoisomerase inhibitors include berotecan, irinotecan, rubitecan, and camptothecin, which contains topotecan. Representative type II topoisomerase inhibitors include amsacrin, etoposide, etoposide phosphate, and teniposide, which are derivatives of epipodophyllotoxin.

[0235] Molecular targeted therapies include biologics such as cytokines and other immunomodulators. Useful cytokines include interleukin-2 (IL-2, aldesleukin), interleukin-4 (IL-4), interleukin-12 (IL-12), and interferon, which include more than 23 related subtypes. Other cytokines include granulocyte colony-stimulating factor (CSF) (filgrastim) and granulocyte-macrophage CSF (salglamostim). Other immunomodulators include Bacillus Calmette-Guerin, levamisole, and octreotide; monoclonal antibodies against tumor antigens, such as trastuzumab and rituximab; and cancer vaccines that induce an immune response against tumors.

[0236] In addition, molecularly targeted drugs that interfere with specific molecules involved in tumor growth and progression include epidermal growth factor (EGF), transforming growth factor-α (TGFα), TGFp, heregulin, insulin-like growth factor (IGF), fibroblast growth factor (FGF), keratinocyte growth factor (KGF), colony-stimulating factor (CSF), erythropoietin (EPO), interleukin-2 (IL-2), nerve growth factor (NGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), angiopoietin, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), HER4, insulin-like growth factor 1 receptor (IGF1R), IGF2R, fibroblast growth factor 1 receptor (FGF1R), FGF2R, and FGF. Examples of inhibitors include 3R, FGF4R, vascular endothelial growth factor receptor (VEGFR), tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domain 2 (Tie-2), platelet-derived growth factor receptor (PDGFR), Abl, Bcr-Abl, Raf, FMS-like tyrosine kinase 3 (FLT3), c-Kit, Src, protein kinase c (PKC), tropomyosin receptor kinase (Trk), Ret, mammalian target of rapamycin (mTOR), Aurora kinase, polo-like kinase (PLK), mitogen-activated protein kinase (MEK), mesenchymal-epithelial conversion factor (c-MET), cyclin-dependent kinase (CDK), Akt, extracellular signal-regulated kinase (ERK), and poly(ADP)ribose polymerase (PARP).

[0237] Specific molecularly targeted drugs include selective estrogen receptor modulators such as tamoxifen, toremifene, fulvestrant, and raloxifene; antiandrogens such as bicalutamide, nilutamide, megestrol, and flutamide; and aromatase inhibitors such as exemestane, anastrozole, and letrozole. Other specific molecularly targeted drugs include signaling inhibitors such as imatinib, dasatinib, nilotinib, trastuzumab, gefitinib, erlotinib, cetuximab, lapatinib, panitumumab, and temsirolimus; apoptosis-inducing drugs such as bortezomib; angiogenesis-blocking drugs such as bevacizumab, sorafenib, and sunitinib; drugs that help the immune system destroy cancer cells such as rituximab and alemtuzumab; and monoclonal antibodies that deliver toxic molecules to cancer cells, such as gemtuzumab ozogamicin, tocitumomab, 131I-tocitumomab, and ibritumomab tiuxetan.

[0238] Treatment methods Disclosed herein are methods for treating a disease or disorder in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the disease or disorder is an inflammatory epithelial disease. In some embodiments, the disease or disorder is inflammatory bowel disease (IBD). In some embodiments, the disease or disorder is ulcerative colitis ("UC") or Crohn's disease ("CD"). In some embodiments, the disease or disorder is ulcerative colitis ("UC"). In some embodiments, the disease or disorder is Crohn's disease ("CD").

[0239] Inflammatory bowel disease (IBD) IBD is a broad term used to describe chronic inflammatory disorders of the gastrointestinal tract. Types of IBD include ulcerative colitis ("UC") and Crohn's disease ("CD"). The symptoms of IBD vary and depend on the severity and location of the inflammation. According to GlobalData, in 2019, 1.7 million UC patients were diagnosed in eight major markets (the United States, the five EU countries, Japan, and Canada), and market sales for that year reached $6.8 billion (furthermore, there were 1.3 million diagnosed UC patients in the eight major markets (the United States, the five EU countries, Japan, and Canada), and market sales reached $7.4 billion).

[0240] Inflammatory bowel disease (PHD) is characterized by repeated inflammation and wounding of the mucosa, as well as loss of intestinal epithelial barrier function, which allows bacteria or bacterial products to migrate from the intestinal lumen to the serosal membrane and then into the bloodstream, leading to systemic bacteremia and endotoxemia. PHD inhibition has been shown to reduce disease severity in a mouse model of colitis at several levels of clinical scoring. The proposed mechanism for the therapeutic activity of PHD inhibitors is through the stabilization of HIF-1α, which drives the enhancement and healing of the epithelial barrier.

[0241] While current treatments with anti-inflammatory or immunosuppressant agents are effective, the majority of IBD patients do not respond adequately to currently available therapies and do not achieve long-term remission. PHD inhibitors may offer a new treatment option for IBD and may enhance efficacy when combined with available anti-inflammatory drugs.

[0242] In some embodiments, inflammatory epithelial disease is a disease affecting the airways, mucous membranes, skin, gastrointestinal tract, the inner lining of major organs and endocrine glands, vascular tissue, or any combination thereof. In some embodiments, inflammatory epithelial disease is a disease affecting the airways. In some embodiments, inflammatory epithelial disease is a disease affecting the mucous membranes. In some embodiments, inflammatory epithelial disease is a disease affecting the skin. In some embodiments, inflammatory epithelial disease is a disease affecting the gastrointestinal tract. In some embodiments, inflammatory epithelial disease is a disease affecting the inner lining of major organs. In some embodiments, inflammatory epithelial disease is a disease affecting the inner lining of endocrine glands. In some embodiments, inflammatory epithelial disease is a disease affecting vascular tissue.

[0243] In some embodiments, the inflammatory epithelial disease is ulcerative colitis, Crohn's disease, collagenous colitis, lymphocytic colitis, ischemic colitis, fecal-flow-diverting colitis, Behçet's syndrome, or unclassifiable colitis. In some embodiments, the inflammatory epithelial disease is ulcerative colitis. In some embodiments, the inflammatory epithelial disease is Crohn's disease. In some embodiments, the inflammatory epithelial disease is collagenous colitis. In some embodiments, the inflammatory epithelial disease is lymphocytic colitis. In some embodiments, the inflammatory epithelial disease is ischemic colitis. In some embodiments, the inflammatory epithelial disease is fecal-flow-diverting colitis. In some embodiments, the inflammatory epithelial disease is Behçet's syndrome. In some embodiments, the inflammatory epithelial disease is unclassifiable colitis.

[0244] dosage In certain embodiments, compositions containing the compounds(s) described herein are administered for prophylactic and / or therapeutic purposes. In certain therapeutic uses, compositions are administered to patients already suffering from a disease or condition in an amount sufficient to cure or at least partially block at least one symptom of the disease or condition. The effective dose for this use depends on the severity and course of the disease or condition, the patient's medical history, their health status, weight, and response to the drug, as well as the judgment of the physician administering the treatment. The therapeutically effective dose may be determined arbitrarily by methods including, but not limited to, dose escalation and / or dose-range exploration clinical trials.

[0245] For prophylactic use, compositions containing the compounds described herein are administered to patients who are susceptible to, or otherwise at risk of, a particular disease, disorder, or condition. Such amounts are defined as “a prophylactically effective amount or dose.” In this use, the exact amount is also determined by the patient’s health, weight, etc. When used in a patient, the effective amount for this use is determined by the severity and course of the disease, disorder, or condition, the patient’s treatment history, the patient’s health and response to the drug, and the judgment of the physician administering the treatment. In one embodiment, prophylactic treatment involves administering a pharmaceutical composition containing the compounds described herein, or a pharmaceutically acceptable salt thereof, to a mammal that has previously experienced at least one symptom or risk factor of the disease being treated and is currently in remission, in order to prevent recurrence of symptoms of the disease or condition.

[0246] In certain embodiments where the patient's condition does not improve, the compound may, at the physician's discretion, be administered chronically, i.e., over a long period, including throughout the patient's lifetime, to improve, otherwise control, or limit the symptoms of the patient's disease or condition.

[0247] Once improvement in the patient's condition is observed, a maintenance dose is administered as needed. Subsequently, in certain embodiments, the dose, frequency, or both are reduced depending on the symptoms until the improved disease, disorder, or condition is maintained. However, in certain embodiments, the patient requires long-term intermittent or daily treatment when symptoms recur.

[0248] The amount of a given drug corresponding to such a quantity varies depending on factors such as the specific compound, the disease state and its severity, and the characteristics of the subject or host requiring treatment (e.g., weight, sex). Nevertheless, it is determined according to the specific circumstances surrounding the case, including, for example, the specific drug administered, the route of administration, the condition being treated, and the subject or host being treated.

[0249] The toxicity and therapeutic efficacy of such treatment regimens are as follows: 10 and ED 90 This is determined by standard pharmaceutical procedures in cell culture or experimental animals, including but not limited to the determination of the LD50. The dose ratio between toxic and therapeutic effects is the therapeutic index, LD50. 50 and ED 50 It is expressed as a ratio between [a certain value] and [another value]. In certain embodiments, data obtained from cell culture assays and animal experiments are used in formulating therapeutically effective daily dose ranges and / or therapeutically effective unit doses for use in mammals, including humans. In some embodiments, the daily dose of the compounds described herein is ED with minimal toxicity. 50 It is within the range of circulating concentrations, including [specific component]. In certain embodiments, the daily dose range and / or unit dose vary within this range depending on the dosage form used and the route of administration utilized.

[0250] In some embodiments, administration is by oral administration. In some embodiments, administration is by colonic administration.

[0251] Pharmaceutical composition / formulation The compounds or agents described herein are administered to subjects requiring them, in accordance with standard pharmaceutical procedures, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition. In one embodiment, the compounds may be administered to animals.

[0252] In another embodiment, pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient are provided herein. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound or drug into a pharmaceutically usable preparation. The appropriate formulation depends on the selected route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995), Hoover, John E. Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975, Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999) (such disclosures are incorporated herein by reference).

[0253] In some embodiments, pharmaceutically acceptable additives are selected from carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, humectants, plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers, antioxidants, preservatives, and any combination thereof.

[0254] The pharmaceutical compositions described herein are administered to a subject by an appropriate route of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes. The formulations described herein include, but are not limited to, aqueous liquid dispersants, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersants, solid solutions, liposome dispersants, aerosols, solid oral dosage forms, powders, immediate-release formulations, controlled-release formulations, rapidly dissolving formulations, tablets, capsules, pills, powders, sugar-coated tablets, effervescent formulations, lyophilized formulations, delayed-release formulations, sustained-release formulations, pulsed-release formulations, multi-particle formulations, and mixed formulations of immediate-release and controlled-release formulations.

[0255] Pharmaceutical compositions comprising compounds or agents described herein, or pharmaceutically acceptable salts or stereoisomers thereof, are manufactured by conventional methods, for example, conventional mixing processes, dissolution processes, granulation processes, sugar-coated tablet manufacturing processes, levigating processes, emulsification processes, encapsulation processes, or compression processes.

[0256] Pharmaceutical compositions for oral use are obtained by mixing one or more solid additives with one or more compounds or agents described herein, optionally grinding the resulting mixture, adding suitable auxiliary agents as desired, and then processing the granular mixture to obtain tablets or sugar-coated tablet cores. Suitable additives include, for example, fillers such as sugars containing lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, etc.; or other substances such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Optionally, disintegrants such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or its salts (such as sodium alginate) may be added. In some embodiments, dyes or pigments may be added to the tablet or sugar-coated tablet coating for identification or to characterize different combinations of active compound doses.

[0257] Examples of orally administered pharmaceutical compositions include gelatin-based push-in capsules and soft, sealed capsules made of gelatin and a plasticizer (such as glycerol or sorbitol). Push-in capsules contain an active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally, a stabilizer. In soft capsules, the active compound or drug is dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added.

[0258] Pharmaceutical compositions for parenteral use are formulated as injectable or injectable preparations. In some embodiments, pharmaceutical compositions suitable for injection or infusion include sterile aqueous solutions, dispersants, or sterile powders containing the compounds described herein, or pharmaceutically acceptable salts or stereoisomers thereof. In some embodiments, the pharmaceutical composition includes a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium, including, for example, water, saline solution, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and any combination thereof. In some embodiments, the pharmaceutical composition further includes a preservative to inhibit microbial growth.

[0259] All compounds can be synthesized according to the methods disclosed in International Publication No. 2023072257, which is incorporated herein by reference in its entirety. [Examples]

[0260] Example A.1: Combination of compound 29 and 5-aminosalicylic acid (5-ASA) in a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced inflammatory bowel disease (IBD) model. Materials and methods Eight-week-old female BALB / c mice, weighing approximately 18-20g, purchased from Charles River Laboratories, were housed in temperature-controlled (20±2℃) rooms with a 12-hour light-dark cycle in pathogen-free IVC cages (four mice per cage). Solid feed and tap water were provided free access. Sham mice received an intracolonic injection of 50% ethanol (0.1 mL) on day 0, while mice in the other four TNBS colitis model groups received an intracolonic injection of 2% TNBS solution (0.1 mL) on day 0. These mice were euthanized on day 8 (day 10 of the experiment), and samples were immediately collected for the final endpoint.

[0261] The mice were divided into five groups of 10 mice each. The mesalamine group received mesalamine in 0.5% CMC sodium once daily via force-feeding from day 1 to day 7, while the vehicle group received 0.5% carboxymethylcellulose (CMC) and 2% tween80 (in water) once daily via force-feeding. Compound 29 in 0.5% carboxymethylcellulose (CMC) and 2% tween80 (in water) was administered to the mice via force-feeding. The administration regimens and group settings are shown in Table 2.

[0262] [Table 2]

[0263] Animal body weight and DAI score are monitored daily. At the endpoint, serum can be selected for cytokine testing, and colon tissue can be Swiss-rolled and PFA-fixed for histological studies.

[0264] To assess colitis, body weight and disease activity index (DAI) scores were recorded daily. The DAI score was the sum of the weight loss score, stool score, and bleeding subscore. A blinded scoring system was employed to assess colitis. DAI scorers, blinded for group information and animal ID, were responsible for assessing stool consistency and bleeding. The DAI scoring criteria were as follows, according to Table 3.

[0265] [Table 3]

[0266] If blood was not visible to the naked eye, a fecal occult blood (FOB) test was performed using a fecal occult blood test strip (modified pyramidon method). The FOB score (0-2) was interpreted as follows: 0, no color appears after 2 minutes; 1, the color becomes fainter between 1 and 2 minutes; 2, the color becomes brighter (deeper) between 1 and 2 minutes.

[0267] The colon was removed, and the mesentery and adipose tissue were carefully removed. The colon was placed on ruled paper and photographed. The length of the colon was then measured, and the weight of the colon was measured by removing the internal contents and rinsing with cold PBS. The colonic index, as a marker of tissue edema, was obtained by calculating the ratio of colonic weight to length.

[0268] result As shown in Figure 1, the group of mice administered with mesalamine (line C) showed a therapeutic effect with a decrease in DAI score over the following days. The group of mice administered with compound 29 (line D) showed a more rapid decrease in DAI score compared to mesalamine. The group of mice administered with a combination of mesalamine and compound 29 (line E) showed a greater decrease in DAI score over the following days. Siamese mice (line A) and vehicles (line B) were used as controls.

[0269] As shown in Figure 2, the group of mice administered with mesalamine (Bar C) had a colon index of approximately 60. The group of mice administered with compound 29 (Bar D) had a colon index of over 40. The group of mice administered with a combination of mesalamine and compound 29 (Bar E) had a colon index of less than 40. Siamese mice (Bar A) and vehicles (Bar B) were used as controls.

[0270] Example A.2: Example of the combination of compound 29 and cyclosporine in a dextran sulfate sodium (DSS)-induced IBD model Methods and materials Eight-week-old female C57 BL / 6J mice, weighing approximately 18-20g, purchased from Charles River Laboratories, were housed in temperature-controlled (20±2℃) rooms with a 12-hour light-dark cycle in pathogen-free IVC cages (5 mice per cage). Solid feed and tap water were provided free access. To induce dextran sulfate sodium (DSS)-induced acute colitis, the mice were induced for 7 consecutive days with 3% DSS (molecular weight 36,000-50,000; MP Biomedicals, Santa Ana, California, USA) in their drinking water, and then switched to normal water. The DSS solution was prepared and replaced daily. These mice were euthanized on day 8 (day 9 of the experiment), and samples were immediately taken for the final endpoint.

[0271] The naive group was administered blank drinking water, while the other four model groups were administered 3% DSS for seven consecutive days (days 0-6). The CsA group mice received cyclosporine A (CsA) once daily via force-feeding in saline, while the vehicle group mice received 0.5% CMC-Na once daily via force-feeding. Groups 4 and 5 mice received compound 29 in 0.5% CMC-Na via force-feeding. The administration regimens and group assignments are shown in Table 4.

[0272] [Table 4]

[0273] To assess colitis, body weight and DAI score were recorded daily. The DAI score was the sum of the weight loss score, stool score, and bleeding subscore. A blinded scoring system was used to assess colitis. A DAI scorer, blinded for group information and animal ID, was responsible for assessing stool consistency and bleeding. The DAI scoring criteria shown in Table 5 were followed.

[0274] If blood was not visible to the naked eye, a fecal occult blood (FOB) test was performed using a fecal occult blood test strip (modified pyramidon method). The FOB score (0-2) was interpreted as follows: 0, no color appears after 2 minutes; 1, the color becomes fainter between 1 and 2 minutes; 2, the color becomes brighter between 1 and 2 minutes.

[0275] The colon was removed, and the mesentery and adipose tissue were carefully removed. The colon was placed on paper and photographed. The length of the colon was then measured, and the weight of the colon was determined by removing the internal contents and rinsing with cold PBS. The colonic index, as a marker of tissue edema, was obtained by calculating the ratio of colonic weight to length.

[0276] result As shown in Figure 3, the group of mice administered with CsA (Line C) showed a therapeutic effect with a decrease in DAI score over the following days. The group of mice administered with compound 29 (Line D) showed a decrease in DAI. The group of mice administered with a combination of CsA and compound 29 (Line E) showed a greater decrease in DAI score over the following days. Siamese mice (Line A) and vehicles (Line B) were used as controls.

[0277] As shown in Figure 4, the group of mice administered with CsA (Bar C) had a colon index of approximately 35. The group of mice administered with compound 29 (Bar D) had a colon index of less than 40. The group of mice administered with a combination of CsA and compound 29 (Bar E) had a colon index of approximately 30. Siamese mice (Bar A) and vehicle mice (Bar B) were used as controls.

[0278] Example A.3: Example of the combination of compound 29 and anti-TNFα antibody (etanercept, Boehringer Ingelheim) in a dextran sulfate sodium (DSS)-induced IBD model. Methods and materials Female BALB / c mice were divided into five groups (10 mice per group). The sham group mice received an intracolonic injection of 50% ethanol (0.1 mL) on day 0, while the mice in the other six colitis model groups received an intracolonic injection of 2% TNBS solution (0.1 mL) on day 0. The mice were administered from day -1 to day 6, with day 7 being the endpoint. The administration regimens and group settings are shown in Table 5.

[0279] [Table 5]

[0280] Animal body weight and DAI score were monitored daily. At the endpoint, the colon was resected, and the mesentery and adipose tissue were carefully removed. The colon was placed on paper and photographed. The length of the colon was then measured, and the colonic weight was measured by removing the internal contents of the colon and rinsing with cold PBS. The colonic index, as a marker of tissue edema, was obtained by calculating the colonic weight / length ratio.

[0281] Compound 29 is dissolved in 0.5% sodium carboxymethylcellulose (CMC-Na) and 2% tween 80, and the anti-TNFα solution is diluted with DPBS. This is prepared every three days and stored at 4°C to maintain stability.

[0282] result As shown in Figure 5, the group of mice administered with TNFα Ab (Line C) showed a therapeutic effect with a decrease in DAI score over the following days. The group of mice administered with compound 29 (Line D) showed a decrease in DAI score. The group of mice administered with a combination of TNFα Ab and compound 29 (Line E) showed a greater decrease in DAI score over the following days. Siamese mice (Line A) and vehicles (Line B) were used as controls.

[0283] As shown in Figure 6, the group of mice administered with TNFα Ab (bar C) had a colon index of approximately 40. The group of mice administered with compound 29 (bar D) also had a colon index of approximately 40. The group of mice administered with a combination of TNFα Ab and compound 29 (bar E) had a colon index of approximately 30. Siamese mice (bar A) and vehicle mice (bar B) were used as controls.

Claims

1. A method for treating an inflammatory epithelial disease in a subject requiring treatment, wherein the method involves, (a) Compounds of formula (I), or pharmaceutically acceptable salts or stereoisomers thereof: 【Chemistry 1】 (In the formula, R １ is one or more R １ａ It is a monocyclic heterocycloalkyl that is arbitrarily and independently substituted, Each R １ａ is, independently, halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ , -NR ｃ C(=O)NR ｄ R ｂ , -NR ａ C(=O)R ｂ , -NR ｂ C(=O)OR ｂ , -NR ２ S(=O) ａ R ａ , -C(=O)R ｂ , -C(=O)OR ｃ , -C(=O)NR ｄ R １ , C ６ ~C １ alkyl, C ６ ~C １ haloalkyl, C ６ ~C １ hydroxyalkyl, C ６ ~C １ aminoalkyl, C ６ ~C ２ heteroalkyl, C ６ ~C ２ alkenyl, C ６ ~C alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or Or, two R atoms on the same atom １ａ However, together they form an oxo, X is N or CR ２ And, R ２ These are hydrogen, fluoro, chloro, bromo, -CN, and -NO ２ -OH, -OR ａ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ It is heteroalkyl, R ３ These are hydrogen, halogen, -CN, and -NO ２ -OH, -OR ａ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ It is heteroalkyl, R ４ is hydrogen, halogen, -CN, -NO ２ , -OH, -OR ａ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ alkyl, C １ ~C ６ haloalkyl, C １ ~C ６ hydroxyalkyl, C １ ~C ６ aminoalkyl, or C １ ~C ６ heteroalkyl, and R ５ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ It is heteroalkyl, Y is -O-, -S-, or NR ６ - and R ６ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ It is heteroalkyl, L is -(CR ７ R ８ ) ｐ - and Each R ７ and R ８ These are, independently, hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ Is it heteroalkyl? Or, R on the same carbon ７ and R ８ However, together they form a cycloalkyl or heterocycloalkyl group, each containing one or more R ７ａ It is arbitrarily replaced with, Each R ７ａ These are, independently, halogen, -CN, and -NO ２ -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ It is heteroalkyl, p is between 0 and 4. Ring A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring. Each R ９ These are, independently, halogen, -CN, and -NO ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or more R ９ａ It can be arbitrarily and independently replaced, Or, two R atoms on the same atom ９ However, together they form an oxo, Each R ９ａ These are, independently, halogen, -CN, and -NO ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ It is an alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. Or, two R atoms on the same atom ９ａ However, together they form an oxo, n is between 0 and 4. Each R ａ Independently, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ The alkylene (heteroaryl) is an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group that can be independently and arbitrarily substituted with one or more R groups. Each R ｂ These are, independently, hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ The alkylene (heteroaryl) is an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group that can be independently and arbitrarily substituted with one or more R groups. Each R ｃ and R ｄ These are, independently, hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ It is an alkylene (heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl can be independently and arbitrarily substituted with one or more Rs. Or, R ｃ and R ｄ However, together with the atoms to which they are bonded, they form a heterocycloalkyl group optionally substituted with one or more R atoms. Each R is independently halogen, -CN, -OH, -OC １ ~C ６ Alkyl, -S(=O)C １ ~C ６ Alkyl, -S (=O) ２ C １ ~C ６ Alkyl, -S (=O) ２ NH ２ , -S (=O) ２ NHC １ ~C ６ Alkyl, -S (=O) ２ N(C) １ ~C ６ Alkyl) ２ , -NH ２ , - NHC １ ~C ６ Alkyl, -N(C) １ ~C ６ Alkyl) ２ , -NHC(=O)OC １ ~C ６ Alkyl, -C(=O)C １ ~C ６ Alkyl, -C(=O)OH, -C(=O)OC １ ~C ６ Alkyl, -C(=O)NH ２ , -C(=O)N(C １ ~C ６ Alkyl) ２ , -C(=O)NHC １ ~C ６ Alkyl, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ It is either heteroalkyl or, Two R atoms on the same atom combine to form an oxo. (b) Additional drugs or pharmaceutically acceptable salts thereof This includes administering, A method wherein the combined amount of (a) and (b) is a therapeutically effective amount for treating the inflammatory epithelial disease.

2. The method according to claim 1, wherein the compound of formula (I) is one of the compounds in Table 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

3. The compound of formula (I) above, 【Chemistry 2】 The method according to claim 1 or 2, wherein the compound is (compound 29), or a pharmaceutically acceptable salt or stereoisomer thereof.

4. The method according to any one of claims 1 to 3, wherein the inflammatory epithelial disease is a disease affecting the airways, mucous membranes, skin, gastrointestinal tract, major organs and the inner lining of endocrine glands, vascular tissue, or any combination thereof.

5. The method according to any one of claims 1 to 4, wherein the inflammatory epithelial disease is inflammatory bowel disease.

6. The method according to any one of claims 1 to 4, wherein the inflammatory epithelial disease is ulcerative colitis, Crohn's disease, collagenous colitis, lymphocytic colitis, ischemic colitis, fecal diversion colitis, Behçet's syndrome, or unclassifiable colitis.

7. The aforementioned additional drugs include 5-aminosalicylic acid (5-ASA), anti-inflammatory agents, ASK1 inhibitors, α-fetoprotein modulators, adenosine A3 receptor antagonists, adrenomedullin ligands, AKT1 gene inhibitors, anti-CD28 inhibitors, antibiotics, antifungal agents, ATPase inhibitors, β-adrenergic receptor antagonists, BTK inhibitors, β-glucuronidase inhibitors, bradykinin receptor modulators, calcineurin inhibitors, chaperonin-binding immunoglobulin proteins, calcium channel inhibitors, cathepsin S inhibitors, CCR3 chemokine antagonists, CD40 ligand receptor antagonists, chemokine CXC ligand inhibitors, CHST15 gene inhibitors, collagen modulators, CSF-1 antagonists, cyclooxygenase inhibitors, and cytochrome P450. 3A4 inhibitors, carbohydrate metabolism modulators, CCR9 chemokine antagonists, CD233 modulators, CD29 modulators, CD3 antagonists, CD4 antagonists, CD40 ligand inhibitors, CD40 gene inhibitors, CX3CR1 chemokine modulators, COT protein kinase inhibitors, eotaxin ligand inhibitors, EP4 prostanoid receptor agonists, erythropoietin receptor agonists, ecobiotics, F1F0 ATP synthase modulators, farnesoid X receptor (FXR and NR1H4) agonists or modulators, fecal microbiota transplantation (FMT), fractalkine ligand inhibitors, free fatty acid receptor 2 antagonists, GATA3 Transcription factor inhibitors, glucagon-like peptide-2 agonists, glucocorticoid receptor modulators, glucocorticoid receptor agonists, guanylate cyclase receptor agonists, histone deacetylase inhibitors, histone deacetylase-6 inhibitors, HLA class II antigen modulators, immunosuppressants, IL-12 antagonists, IL-13 antagonists, IL-23 antagonists, IL-6 antagonists, IL-6 receptor modulators, IL-7 receptor modulators, IL-7 antagonists, IL-8 antagonists, integrin α4 / β1 antagonists, integrin α4 / β7 antagonists, integrin αE antagonists, integrin antagonists, integrin β7 antagonists, interleukin ligand inhibitors, interleukin-2 ligands, interleukin receptor 17A antagonists, interleukin-1β ligands Interleukin-1β ligand modulator, IRAK4 inhibitor, ICAM1 gene inhibitor, IL-1β ligand modulator, IL-18 antagonist, IL-22 agonist, IL-23A inhibitor, interleukin-1-like receptor 2 inhibitor, JAK inhibitor, JAK tyrosine kinase inhibitor, Jak1 tyrosine kinase inhibitor, Jak3 tyrosine kinase inhibitor, LanC-like protein 2 modulator, lipoxygenase modulator, lactoferrin stimulant, leukocyte elastase inhibitor, leukocyte proteinase-3 inhibitor, MAdCAM inhibitor, matrix metalloproteinase inhibitor, melanocortin agonist, melanocortin MC1 agonist, metalloproteinase-9 inhibitor, melanin-concentrating hormone (MCH-1) antagonist, microbiome modulator, natriuretic peptide receptor C agonist, neuregulin-4 ligand, NKG2 D-activated NK receptor antagonists, NLRP3 inhibitors, neuregulin-4 ligands, nuclear factor κB inhibitors, opioid receptor antagonists, opioid receptor δ antagonists, oxidoreductase inhibitors, OX40 ligand inhibitors, Pellino homolog 1 inhibitors, P2X7 prenoceptor agonists, PDE4 inhibitors, phagocytic peptide modulators, potassium channel inhibitors, PPARα agonists, PPARδ agonists, PPARγ agonists, fimH protein inhibitors, P-selectin glycoprotein ligand-1 inhibitors, Ret tyrosine kinase receptor inhibitors, RNA polymerase inhibitors, RIP-1 kinase inhibitors, RIP-2 kinase inhibitors, tissue transglutaminase inhibitors, sphingosine-1-phosphate phosphatase-1 stimulants, sphingosine-1-phosphate phosphatase modulators, sphingosine-1-phosphate receptor-1 agonists, sphingosine Sphingosine-1-phosphate receptor-1 antagonist, sphingosine-1-phosphate receptor-1 modulator, sphingosine-1-phosphate receptor-5 modulator, STAT3 gene inhibitor, stem cell antigen-1 inhibitor, superoxide dismutase modulator, superoxide dismutase stimulant, SYK inhibitor, TGFβ1 ligand inhibitor, thymrine agonist, TLR antagonist, TLR agonist, TNFα ligand inhibitor, TNF antagonist, tumor necrosis factor superfamily member 14 modulator, type II TNF receptor modulator, Tpl The method according to any one of claims 1 to 6, wherein the inhibitor is a TLR-3 antagonist, a TLR-4 antagonist, a TLR-8 inhibitor, a TLR-9 agonist, a TNF ligand inhibitor, a TNFα ligand modulator, a TPL-2 inhibitor, a tumor necrosis factor superfamily member 15 inhibitor, a Tyk2 tyrosine kinase inhibitor, a type I IL-1 receptor antagonist, a TrkA receptor antagonist, a vanilloid VR1 agonist, a zonulin inhibitor, or a pharmaceutically acceptable salt thereof.

8. The method according to claim 7, wherein 5-ASA is valsalazide, sulfasalazine, mesalazine, olsalazine, mesalamine, or a pharmaceutically acceptable salt thereof.

9. The method according to claim 7, wherein the anti-inflammatory agent is a corticosteroid, a nonsteroidal anti-inflammatory drug (NSAID), a nonspecific cyclooxygenase enzyme inhibitor, or a COX-2 specific cyclooxygenase enzyme inhibitor, or a pharmaceutically acceptable salt thereof.

10. The method according to claim 9, wherein the corticosteroid is cortisone, dexamethasone, methylprednisolone, prednisolone, sodium prednisolone phosphate, prednisone, or a pharmaceutically acceptable salt thereof.

11. The method according to claim 9, wherein the NSAID is ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, a combination of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, nabumeton sodium, sulfasalazine, tolmetin sodium, hydroxychloroquine, or a pharmaceutically acceptable salt thereof.

12. The method according to claim 9, wherein the COX-2 specific cyclooxygenase enzyme inhibitor is celecoxib, valdecoxib, lumiracoxib, etoricoxib, rofecoxib, or a pharmaceutically acceptable salt thereof.

13. The method according to claim 7, wherein the anti-inflammatory agent is sodium aurthiomalate, auranofin, or a pharmaceutically acceptable salt thereof.

14. The method according to claim 7, wherein the immunosuppressant is mercaptopurine, methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, or a pharmaceutically acceptable salt thereof.

15. The method according to claim 14, wherein the immunosuppressant is cyclosporine or a pharmaceutically acceptable salt thereof.

16. The method according to claim 7, wherein the ASK1 inhibitor is GS-4997 or a pharmaceutically acceptable salt thereof.

17. The method according to claim 7, wherein the β-adrenergic receptor antagonist is NM-001 or a pharmaceutically acceptable salt thereof.

18. The method according to claim 7, wherein the BTK inhibitor is GS-4059 or a pharmaceutically acceptable salt thereof.

19. The method according to claim 7, wherein the calcineurin inhibitor is tacrolimus or cyclosporine, or a pharmaceutically acceptable salt thereof.

20. The method according to claim 7, wherein the CD40 ligand receptor antagonist is FFP-104, BI-655064, or a pharmaceutically acceptable salt thereof.

21. The method according to claim 7, wherein the cathepsin S inhibitor is VBY-129 or a pharmaceutically acceptable salt thereof.

22. The method according to claim 7, wherein the chemokine CXC ligand inhibitor is LY-3041658 or a pharmaceutically acceptable salt thereof.

23. The method according to claim 7, wherein the CHST15 gene inhibitor is STNM-01 or a pharmaceutically acceptable salt thereof.

24. The method according to claim 7, wherein the collagen modulator is ECCS-50 (DCCT-10) or a pharmaceutically acceptable salt thereof.

25. The method according to claim 7, wherein the CSF-1 antagonist is JNJ-40346527 (PRV-6527), SNDX-6352, or a pharmaceutically acceptable salt thereof.

26. The method according to claim 7, wherein the eotaxin ligand inhibitor is vertilimumab or a pharmaceutically acceptable salt thereof.

27. The method according to claim 7, wherein the EP4 prostanoid receptor agonist is KAG-308 or a pharmaceutically acceptable salt thereof.

28. The method according to claim 7, wherein the fractalkine ligand inhibitor is quetomolimab (E-6011) or a pharmaceutically acceptable salt thereof.

29. The method according to claim 7, wherein the free fatty acid receptor 2 antagonist is GLPG-0974 or a pharmaceutically acceptable salt thereof.

30. The method according to claim 7, wherein the GATA 3 transcription factor inhibitor is SB-012 or a pharmaceutically acceptable salt thereof.

31. The method according to claim 7, wherein the glucagon-like peptide 2-agonist is teduglutide, apraglutide, or a pharmaceutically acceptable salt thereof.

32. The method according to claim 7, wherein the guanylate cyclase receptor agonist is dolcanatide or a pharmaceutically acceptable salt thereof.

33. The method according to claim 7, wherein the histone deacetylase inhibitor is gibinostat or a pharmaceutically acceptable salt thereof.

34. The method according to claim 7, wherein the HLA class II antigen modulator is an HLA class II protein modulator.

35. The method according to claim 7, wherein the IL-12 antagonist is ustekinumab (IL12 / IL23), MEDI2070, or a pharmaceutically acceptable salt thereof.

36. The method according to claim 7, wherein the IL-13 antagonist is tralokinumab or a pharmaceutically acceptable salt thereof.

37. The method according to claim 7, wherein the IL-23 antagonist is tildrakizumab, risankizumab (BI-655066), mirikizumab (LY-3074828), brazicumab (AMG-139), PTG-200, or a pharmaceutically acceptable salt thereof.

38. The method according to claim 7, wherein the IL-6 antagonist is olokizumab or a pharmaceutically acceptable salt thereof.

39. The method according to claim 7, wherein the IL-6 receptor modulator is oramxept or a pharmaceutically acceptable salt thereof.

40. The method according to claim 7, wherein the IL-7 receptor antagonist is OSE-127 or a pharmaceutically acceptable salt thereof.

41. The method according to claim 7, wherein the IL-8 receptor antagonist is clotrimazole or a pharmaceutically acceptable salt thereof.

42. The method according to claim 7, wherein the integrin α4 / β1 antagonist is natalizumab or a pharmaceutically acceptable salt thereof.

43. The method according to claim 7, wherein the integrin α4 / β7 antagonist is etrolizumab (a4b7 / aEb7), vedolizumab, carotegastmethyl, TRK-170 (a4b7 / a4b1), PN-10943, PTG-100, or a pharmaceutically acceptable salt thereof.

44. The method according to claim 7, wherein the integrin antagonist is E-6007 or a pharmaceutically acceptable salt thereof.

45. The method according to claim 7, wherein the interleukin ligand inhibitor is bimekizumab (IL-17A / IL-17F) or a pharmaceutically acceptable salt thereof.

46. The method according to claim 7, wherein the interleukin receptor 17A antagonist is brodalumab or a pharmaceutically acceptable salt thereof.

47. The method according to claim 7, wherein the interleukin-1β ligand is K(D)PT or a pharmaceutically acceptable salt thereof.

48. The method according to claim 7, wherein the JAK tyrosine kinase inhibitor is tofacitinib, peficitinib, TD-3504, TD-1473, or a pharmaceutically acceptable salt thereof.

49. The method according to claim 7, wherein the Jak3 tyrosine kinase inhibitor is PF-06651600 or a pharmaceutically acceptable salt thereof.

50. The method according to claim 7, wherein the LanC-like protein 2 modulator is BT-11 or a pharmaceutically acceptable salt thereof.

51. The method according to claim 7, wherein the MAdCAM inhibitor is SHP-647 (PF-547659) or a pharmaceutically acceptable salt thereof.

52. The method according to claim 7, wherein the melanocortin MC1 receptor agonist is ASP-3291, PL-8177, or a pharmaceutically acceptable salt thereof.

53. The method according to claim 7, wherein the natriuretic peptide receptor C agonist is precanatide or a pharmaceutically acceptable salt thereof.

54. The method according to claim 7, wherein the NKG2 D-activated NK receptor antagonist is JNJ-4500 or a pharmaceutically acceptable salt thereof.

55. The method according to claim 7, wherein the opioid receptor antagonist is naltrexone, IRT-103, or a pharmaceutically acceptable salt thereof.

56. The method according to claim 7, wherein the oxidoreductase inhibitor is orsalazine or a pharmaceutically acceptable salt thereof.

57. The method according to claim 7, wherein the P2X7 prenoceptor modulator is SGM-1019 or a pharmaceutically acceptable salt thereof.

58. The method according to claim 7, wherein the PDE4 inhibitor is apremilast or a pharmaceutically acceptable salt thereof.

59. The method according to claim 7, wherein the PPARα agonist or PPARδ agonist is ellafibranol (GFT-1007) or a pharmaceutically acceptable salt thereof.

60. The method according to claim 7, wherein the PPARγ agonist is GED-0507-34-Levo or a pharmaceutically acceptable salt thereof.

61. The method according to claim 7, wherein the protein fimH inhibitor is cibofimloc (EB-8018) or a pharmaceutically acceptable salt thereof.

62. The method according to claim 7, wherein the P-selectin glycoprotein ligand-1 inhibitor is SEL-K2, AbGn-168H, naiflizumab, or a pharmaceutically acceptable salt thereof.

63. The method according to claim 7, wherein the sphingosine-1-phosphate phosphatase-1 stimulant is etrasimodo or a pharmaceutically acceptable salt thereof.

64. The method according to claim 7, wherein the sphingosine-1-phosphate receptor-1 agonist is ozanimod, moklavimod (KRP-203), BMS-986166, or a pharmaceutically acceptable salt thereof.

65. The method according to claim 7, wherein the sphingosine-1-phosphate receptor-5 agonist is ozanimod or a pharmaceutically acceptable salt thereof.

66. The method according to claim 7, wherein the sphingosine-1-phosphate receptor-1 antagonist is amicelimod (MT-1303) or a pharmaceutically acceptable salt thereof.

67. The method according to claim 7, wherein the sphingosine-1-phosphate receptor-1 modulator is OPL-002 or a pharmaceutically acceptable salt thereof.

68. The method according to claim 7, wherein the stem cell antigen-1 inhibitor is ampion (DMI-9523) or a pharmaceutically acceptable salt thereof.

69. The method according to claim 7, wherein the superoxide dismutase modulator is midismase or a pharmaceutically acceptable salt thereof.

70. The method according to claim 7, wherein the SYK inhibitor is GS-9876 or a pharmaceutically acceptable salt thereof.

71. The method according to claim 7, wherein the TNFα ligand inhibitor is adalimumab, certolizumab pegol, infliximab, golimumab, DLX-105, Debio-0512, MHPL-004, CYT-020-TNFQb, Hemay-007, V-565, an anti-TNFα antibody, or a pharmaceutically acceptable salt thereof.

72. The method according to claim 71, wherein the TNFα ligand inhibitor is an anti-TNFα antibody or a pharmaceutically acceptable salt thereof.

73. The method according to claim 7, wherein the tumor necrosis factor superfamily member 14 modulator is AEVI-002 or a pharmaceutically acceptable salt thereof.

74. The method according to claim 7, wherein the TNF antagonist is AVX-470, tournercept, etanercept, or a pharmaceutically acceptable salt thereof.

75. The method according to claim 7, wherein the zonulin inhibitor is larazotide acetate or a pharmaceutically acceptable salt thereof.

76. The method according to claim 7, wherein the CD40 ligand inhibitor is SAR-441344, letrizumab, or a pharmaceutically acceptable salt thereof.

77. The method according to claim 7, wherein the adenosine A3 receptor antagonist is PBF-677 or a pharmaceutically acceptable salt thereof.

78. The method according to claim 7, wherein the adrenomedullin ligand is adrenomedullin or a pharmaceutically acceptable salt thereof.

79. The method according to claim 7, wherein the antibiotic is ciprofloxacin, clarithromycin, metronidazole, vancomycin, rifamycin, rifaximin, tosufloxacin, or a pharmaceutically acceptable salt thereof.

80. The method according to claim 7, wherein the α-fetoprotein modulator is ACT-101 or a pharmaceutically acceptable salt thereof.

81. The method according to claim 7, wherein the carbohydrate metabolism modulator is ASD-003 or a pharmaceutically acceptable salt thereof.

82. The method according to claim 7, wherein the CCR9 chemokine antagonist is CCX-507 or a pharmaceutically acceptable salt thereof.

83. The method according to claim 7, wherein the CD233 modulator is GSK-2831781 or a pharmaceutically acceptable salt thereof.

84. The method according to claim 7, wherein the CD29 modulator is PF-06687234 or a pharmaceutically acceptable salt thereof.

85. The method according to claim 7, wherein the CD3 antagonist is NI-0401 or a pharmaceutically acceptable salt thereof.

86. The method according to claim 7, wherein the CX3CR1 chemokine modulator is E-6130 or a pharmaceutically acceptable salt thereof.

87. The method according to claim 7, wherein the ecobiotic is SER-287 or a pharmaceutically acceptable salt thereof.

88. The method according to claim 7, wherein the F1F0 ATP synthase modulator is LYC-30937 EC or a pharmaceutically acceptable salt thereof.

89. The method according to claim 7, wherein the glucocorticoid receptor modulator is ABBV-3373 or a pharmaceutically acceptable salt thereof.

90. The method according to claim 7, wherein the TNF ligand inhibitor is ABBV-3373 or a pharmaceutically acceptable salt thereof.

91. The method according to claim 7, wherein the ICAM1 gene inhibitor is aricahorsen or a pharmaceutically acceptable salt thereof.

92. The method according to claim 7, wherein the IL-18 antagonist is GSK-1070806 or a pharmaceutically acceptable salt thereof.

93. The method according to claim 7, wherein the IL-22 agonist is RG-7880 or a pharmaceutically acceptable salt thereof.

94. The method according to claim 7, wherein the IL-23A inhibitor is guselkumab or a pharmaceutically acceptable salt thereof.

95. The method according to claim 7, wherein the interleukin-1-like receptor 2 inhibitor is BI-655130 or a pharmaceutically acceptable salt thereof.

96. The method according to claim 7, wherein the lactoferrin stimulant is recombinant human lactoferrin (VEN-100) or a pharmaceutically acceptable salt thereof.

97. The method according to claim 7, wherein the leukocyte elastase inhibitor is ticplerestat or a pharmaceutically acceptable salt thereof.

98. The method according to claim 7, wherein the leukocyte proteinase-3 inhibitor is ticplerestat or a pharmaceutically acceptable salt thereof.

99. The method according to claim 7, wherein the melanin-concentrating hormone (MCH-1) antagonist is CSTI-100 or a pharmaceutically acceptable salt thereof.

100. The method according to claim 7, wherein the metalloproteinase-9 inhibitor is GS-5745 or a pharmaceutically acceptable salt thereof.

101. The method according to claim 7, wherein the NLRP3 inhibitor is dapanstril, BMS-986299, SB-414, MCC-950, IFM-514, JT-194, PELA-167, NBC-6, or a pharmaceutically acceptable salt thereof.

102. The method according to claim 7, wherein the farnesoid X receptor (FXR and NR1H4) agonist or modulator is AGN-242266, silofexol tromethamine (GS-9674), EDP-305, EYP-001, GNF-5120, MET-409, nidufexol (LMB-763), obeticholic acid, TERN-101, tropifexol, or a pharmaceutically acceptable salt thereof.

103. The method according to claim 7, wherein the nuclear factor κB inhibitor is Thetanix or a pharmaceutically acceptable salt thereof.

104. The method according to claim 7, wherein the OX40 ligand inhibitor is KHK-4083 or a pharmaceutically acceptable salt thereof.

105. The method according to claim 7, wherein the Pellino homolog 1 inhibitor is BBT-401 or a pharmaceutically acceptable salt thereof.

106. The method according to claim 7, wherein the Ret tyrosine kinase receptor inhibitor is GSK-3179106 or a pharmaceutically acceptable salt thereof.

107. The method according to claim 7, wherein the RIP-1 kinase inhibitor is GSK-2982772 or a pharmaceutically acceptable salt thereof.

108. The method according to claim 7, wherein the RIP-2 kinase inhibitor is GSK-2983559 or a pharmaceutically acceptable salt thereof.

109. The method according to claim 7, wherein the tissue transglutaminase inhibitor is zampilimab or a pharmaceutically acceptable salt thereof.

110. The method according to claim 7, wherein the TLR-3 antagonist is PRV-300 or a pharmaceutically acceptable salt thereof.

111. The method according to claim 7, wherein the TLR-4 antagonist is JKB-122 or a pharmaceutically acceptable salt thereof.

112. The method according to claim 7, wherein the TLR-8 inhibitor is E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motlimod, reximod, VTX-1463, VTX-763, or a pharmaceutically acceptable salt thereof.

113. The method according to claim 7, wherein the TLR-9 agonist is covitrimod, IMO-2055, IMO-2125, lephyrimod, ritenimod, MGN-1601, PUL-042, or a pharmaceutically acceptable salt thereof.

114. The method according to claim 7, wherein the TPL-2 inhibitor is GS-4875 or a pharmaceutically acceptable salt thereof.

115. The method according to claim 7, wherein the tumor necrosis factor superfamily member 15 inhibitor is PF-06480605, PRA023, or a pharmaceutically acceptable salt thereof.

116. The method according to claim 7, wherein the Tyk2 tyrosine kinase inhibitor is PF-06826647, BMS-986165, or a pharmaceutically acceptable salt thereof.

117. The method according to claim 7, wherein the type I IL-1 receptor antagonist is anakinra or a pharmaceutically acceptable salt thereof.

118. The method according to claim 7, wherein the anti-CD28 inhibitor is JNJ-3133, abatacept, or a pharmaceutically acceptable salt thereof.

119. The method according to claim 7, wherein the CD4 antagonist is IT-1208 or a pharmaceutically acceptable salt thereof.

120. The method according to claim 7, wherein the CD40 gene inhibitor is NJA-730 or a pharmaceutically acceptable salt thereof.

121. The method according to claim 7, wherein the chaperonin-binding immunoglobulin protein is IRL-201805 or a pharmaceutically acceptable salt thereof.

122. The method according to claim 7, wherein the COT protein kinase inhibitor is GS-4875 or a pharmaceutically acceptable salt thereof.

123. The method according to claim 7, wherein the glucocorticoid receptor agonist is budesonide, beclomethasone dipropionate, dexamethasone sodium phosphate, or a pharmaceutically acceptable salt thereof.

124. The method according to claim 7, wherein the histone deacetylase-6 inhibitor is CKD-506 or a pharmaceutically acceptable salt thereof.

125. The method according to claim 7, wherein the neuregulin-4 ligand is NRG-4 or a pharmaceutically acceptable salt thereof.

126. The method according to claim 7, wherein the microbiome modulator is ABI-M201 or a pharmaceutically acceptable salt thereof.

127. The method according to claim 7, wherein the TrkA receptor antagonist is SNA-125 or a pharmaceutically acceptable salt thereof.

128. The method according to claim 7, wherein the JAK inhibitor is AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110, restaurtinib, momerotinib (CYT0387), NS-018, pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib, XL019, upadacitinib (ABT-494), filgotinib, GLPG-0555, SHR-0302, brepocitinib (PF-06700841), or a pharmaceutically acceptable salt thereof.

129. The aforementioned additional drugs are obefazimod (ABX-4640), adalimumab, aricahorsen, ALLO-ASC-CD, AMG-966, anakinra, apremilast, Alequel, AMG-139, amicelimod, ASD-003, ASP-3291, AX-1505, BBT-401, valsalazid, beclomethasone dipropionate, BI-655130, and BMS-9861. 84, Budesonide, CEQ-508, Certolizumab, ChAdOx2-HAV, Dexamethasone sodium phosphate, DNVX-078, Etanercept, Cibinetide, Clostridium butyricum, ETX-201, Golimumab, GS-4997, GS-9876, GS-4875, GS-4059, Infliximab, Mesalazine, HLD-400, LYC-30937EC, IONIS-JB11-2.5Rx, JNJ-64304500, JNJ-4447, Naltrexone, Natalizumab, Neaflizumab, Orsalazine, PH-46-A, Propionyl-L-Carnitine, PTG-100, Remestemcell-L, Tacrolimus, Teduglutide, Tofacitinib, ASP-1002, Ustekinumab, Vedolizumab, AVX-470, INN-108, SGM-1019, PF-06480 605, PF-06651600, PF-06687234, RBX-8225, SER-287, Thetanix, TOP-1288, VBY-129, 99mTc-Annexin V-128, Vertilimumab, DLX-105, Dolcanatide, FFP-104, Filgotinib, Foralumab, GED-0507-34-Levo, Gibinostat, GLPG-0974, Iberogast, JNJ-40346527, K(D)P T, KAG-308, KHK-4083, KRP-203, Larazotide acetate, LY-3074828, Midismase, Orokizumab, OvaSave, P-28-GST, PF-547659, Prednisolone, QBECO, RBX-2660, RG-7835, JKB-122, SB-012, STNM-01, Debio-0512, TRK-170, Zukapsaicin, ABT-494, Ampion, BI-655066, Ka The method according to any one of claims 1 to 5, comprising rotegastmethyl, covitrimod, ellafibranol, etrolizumab, GS-5745, MHPL-004, LP-02, ozanimod, peficitinib, quetomolimab (E-6011), RHB-104, rifaximin, tildrakizumab, tralokinumab, brodalumab, lakinimod, precanatide, vidofludimus, AZD-058, or a pharmaceutically acceptable salt thereof.

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