Inhibitors of interleukin-23 receptor

Abstract

The present disclosure provides compounds that are capable of modulating the activity of the interleukin-23 receptor (IL-23R). The present disclosure further provides corresponding pharmaceutical compositions, methods and / or uses for treatment of autoimmune inflammation and related diseases and disorders.

Description

[0001] INHIBITORS OF INTERLEUKIN-23 RECEPTOR

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U. S. Provisional Application Number 63 / 739,763, filed December 30, 2024, the entire disclosure of which is hereby incorporated herein by reference.

[0003] BACKGROUND

[0004] The interleukin-23 (IL-23) cytokine is a heterodimer composed of a unique pl 9 subunit and the p40 subunit shared with IL- 12, which is a cytokine involved in the development of interferon-y (IFN-y)-producing T helper 1 (TH1) cells. Although IL-23 and IL-12 both contain the p40 subunit, they have different phenotypic properties. For example, animals deficient in IL-12 are susceptible to inflammatory autoimmune diseases, whereas IL-23 deficient animals are resistant to these diseases, presumably due to a reduced number of CD4+T cells producing IL-6, IL-17, and TNF in the CNS of TL-23 -deficient animals. IL-23 binds to IL-23R, which is a heterodimeric receptor composed of IL-12Rβ1 and IL-23R subunits. Binding of IL-23 to IL-23R activates the Jak-Stat signaling molecules Jak2, Tyk2, Stat1, Stat 3, Stat 4, and Stat 5, although Stat4 activation is substantially weaker and different DNA-binding Stat complexes form in response to IL-23 as compared with IL-12. IL-23R associates constitutively with Jak2 and in a ligand-dependent manner with Stat3. In contrast to IL- 12, which acts mainly on naive CD4(+) T cells, IL-23 preferentially acts on memory CD4(+) T cells.

[0005] IL-23 has been implicated as playing a crucial role in the pathogenesis of autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohn’s disease. Studies in acute and chronic mouse models of IBDs revealed a primary role of interleukin-23 receptor (IL-23R) and downstream effector cytokines in disease pathogenesis. IL-23R is expressed on various adaptive and innate immune cells including Thl7 cells, y5 T cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphoid cells, which are found abundantly in the intestine. At the intestine mucosal surface, the gene expression and protein levels of IL-23R are found to be elevated in IBD patients. It is believed that IL-23 mediates this effect by promoting the development of a pathogenic CD4+T cell population that produces IL-6, IL-17, and tumor necrosis factor (TNF).

[0006] As discussed in WO 2021 / 146441 and US 2021 / 0261622, the disclosures of which are incorporated herein by reference in their entireties, the following peptide binds to IL-23R:

[0007]

[0008] This peptide is referred to herein as Compound 1.

[0009] There is an ongoing need for new and effective pharmaceuticals to treat and prevent IL-23 and / or IL-23R associated diseases, especially those associated with autoimmune inflammation (e.g., inflammatory bowel disease (1BD), ulcerative colitis, Crohn’s Disease (CD), psoriasis, or psoriatic arthritis). The compounds, compositions, and methods described herein meet this and other needs.

[0010] BRIEF SUMMARY

[0011] The present disclosure provides, inter alia, a compound of Formula (I):

[0012]

[0013] R3^O

[0014] (I).

[0015] or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are as defined herein. In some embodiments, the compound of Formula (I) is substantially isolated.

[0016] In some embodiments, the present disclosure provides a compound of Formula (la-1):R5

[0017]

[0018] (la-1),

[0019] or a pharmaceutically acceptable salt thereof, wherein R4, R5, R6, R7, and R9are as defined herein. In some embodiments, the compound of Formula (la-1) is substantially isolated.

[0020] In some embodiments, the present disclosure provides a compound selected from the group consisting of Compounds 2-21, as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is substantially isolated.

[0021] In some embodiments, the present disclosure provides a compound selected from the group consisting of Compounds 2, 3, 4, 5, and 8, as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is substantially isolated.

[0022] The present disclosure further provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0023] The present disclosure still further provides a method for treating a disease or disorder associated with interleukin 23 (IL-23) / interleukin 23 receptor (IL-23R) in a subject in need thereof, said method comprising administering to the subject an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0024] DETAILED DESCRIPTION

[0025] Provided herein are compounds of Formula (I), and pharmaceutically acceptable salts thereof, corresponding pharmaceutical compositions, and methods and / or uses for the treatment of inflammatory diseases, autoimmune diseases, and / or related disorders.Definitions

[0026] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art.

[0027] As used in the specification and in the claims, the “comprise(s),” “comprising,” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named features, groups, ingredients, or steps and does not exclude the presence of additional features, groups, ingredients, or steps. The term “comprise(s),” “comprising,” “include(s),” “having,” “has,” “can,” or “contain(s),” can include embodiments encompassed by the term "consisting essentially of" or "consisting of."

[0028] The terms “peptide,” “polypeptide,” and “protein” are used interchangeably herein and typically refer to a molecule comprising a chain of two or more amino acids (e.g., L-amino acids, D-amino acids, modified amino acids, amino acid analogs, amino acid mimetics, etc.).

[0029] The term “therapeutically effective amount” or “pharmaceutically effective amount” means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human, that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes preventing, treating or ameliorating the symptoms of a syndrome, disorder or disease being treated.

[0030] The term “pharmaceutically acceptable” means approved or approvable by a regulatory agency of Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U. S. Pharmcopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0031] “Pharmaceutically acceptable excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0032] “Composition” or “pharmaceutical composition” as used herein is intended to encompass a product comprising the specified active pharmaceutical ingredient (API) (i.e., a compound of the present disclosure), which may include pharmaceutically acceptable excipients, carriers or diluents as described herein, such as in specified amounts defined throughout the disclosure.Compositions or pharmaceutical compositions of the present disclosure may be in different pharmaceutically acceptable forms, which may include, but are not limited to a liquid composition, a tablet or matrix composition, a capsule composition, etc.. When the composition is a tablet composition, the tablet may include, but is not limited to different layers two or more different phases, including an internal phase and an external phase that can comprise a core. The tablet composition can also include, but is not limited to one or more coatings.

[0033] Provided are also pharmaceutically acceptable salts and tautomeric forms of the compounds described herein.

[0034] A “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of compounds represented by Formula (I) that are non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. It should possess the desired pharmacological activity of the parent compound. See, generally, G. S. Paulekuhn, et al., “Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database”, J. Med. Chem., 2007, 50:6665-72, S. M. Berge, et al., “Pharmaceutical Salts”, J Pharm Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. A compound of Formula (I) may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

[0035] The compounds of the present disclosure, pharmaceutically acceptable salts, and / or other forms thereof may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (5)- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms of the compounds of the present disclosure. Optically active (+) and (-), ( / ?)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

[0036] “Tautomer” refers to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroarylgroups containing a ring atom attached to both a ring -NH- and a ring =N- such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

[0037] In some embodiments, the compounds of the present disclosure are substantially isolated. As used herein, the phrase “substantially isolated” means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compound of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound.

[0038] The term “administering” with respect to the methods of the present disclosure, means a method for therapeutically or prophylactically preventing, treating or ameliorating a syndrome, disorder or disease as described herein by using a compound of the disclosure, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof. Such methods include administering a therapeutically effective amount of a compound of the disclosure, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof, at different times during the course of a therapy or concurrently or sequentially as a combination therapy.

[0039] “Patient” or “subject,” which are used interchangably, refer to a living organism, preferably a mammal, most preferably a human, whom will be or has been treated by a method according to an embodiment of the application. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHPs) such as monkeys or apes, humans, etc., more preferably a human.

[0040] As used herein, the term “treatment” or “treating,” is defined as the application or administration of a therapeutic agent, i.e., a compound of the present disclosure (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a disorder or disease as described herein, a symptom thereof; or the potential to develop such disorder or disease, where the purpose of the application or administration is to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder or disease, its symptoms, or the potential to develop said disorder or disease. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.

[0041] As used herein, the term “prevent” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there hadalready been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.

[0042] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly or conventionally understood by one of ordinary skill in the art. In the chemical arts a dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. A dashed line indicates an optional bond. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or the point at which it is attached to the remainder of the molecule. A prefix such as “Cu-v” or (Cu-Cv) indicates that the following group has from u to v carbon atoms. For example, “Ci ealkyl” and “Ci-Ce alkyl” both indicate that the alkyl group has from 1 to 6 carbon atoms.

[0043] Furthermore, it is intended that within the scope of the present invention, any element, in particular when mentioned in relation to a compound of the disclosure, or pharmaceutically acceptable salt thereof, shall comprise all isotopes and isotopic mixtures of said element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, a reference to hydrogen includes within its scope1H,2H (z. e., deuterium or D), and3H (i.e., tritium or T). In some embodiments, the compounds described herein include a2H (i.e., deuterium) isotope. By way of example, the group denoted -C(1-6)alkyl includes not only -CH but also CD3; not only CH2CH3, but also CD2CD3, etc. Similarly, references to carbon and oxygen include within their scope respectively12C,13C and14C and15O and16O and17O and18O. The isotopes may be radioactive or non-radioactive. Radiolabelled compounds of the disclosure may include a radioactive isotope selected from the group comprising3H,11C,18F,35S,122I,123I,125I,131I,75Br,76Br,77Br and82Br. Preferably, the radioactive isotope is selected from the group of3H,11C and18F.

[0044] Abbreviation, “(V / V)” refers to the phrase “volume for volume,” i.e., the proportion of a particular substance within a mixture, as measured by volume or a volume amount of a component of the composition disclosed herein relative to the total volume amount of the composition. Accordingly, the quantity is unit less and represents a volume percentage amount of a component relative to the total volume of the composition. For example, a 2% (V / V) solvent mixture can indicate 2 mL of one solvent is present in 100 mL of the solvent mixture.

[0045] “Bioavailability” refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action. Bioavailability of adrug could be impacted by the factors such as properties of the dosage form and properties of the drug.

[0046] Compounds

[0047] The present disclosure provides, inter alia, compounds that are metabolites of the IL-23R inhibitor Compound 1:

[0048]

[0049] (Compound 1).

[0050] In an aspect, the disclosure provides a compound that is the product of a deamidation of Compound 1. As used herein, the term “deamidation” refers to the conversion of an amide group (-C(0)NH2) to a carboxylic acid (-C(O)OH). In some embodiments, the present disclosure provides a deamidation product of Compound 1, wherein one amide group is converted to a carboxylic acid. In some embodiments, the present disclosure provides a deamidation product of Compound 1, wherein two amide groups are converted to carboxylic acids. In some embodiments, the present disclosure provides a deamidation product of Compound 1, wherein three amide groups are converted to carboxylic acids. In some embodiments, the present disclosure provides a deamidation product of Compound 1, wherein four amide groups are converted to carboxylic acids. In some embodiments, the deamidation product is substantially isolated.

[0051] In another aspect, the disclosure provides a compound that is the product of an acetylation of Compound 1. As used herein, the term “acetylation” refers to the addition of an acetyl group to the compound, e.g., by replacement of a hydrogen atom of a hydroxyl (-OH) or amino (-NH2) group. In some embodiments, the present disclosure provides an acetylationproduct of Compound 1, wherein one hydroxyl or amino group is acetylated. In some embodiments, the present disclosure provides an acetylation product of Compound 1, wherein two hydroxyl or amino groups are acetylated. In some embodiments, the acetylation product is substantially isolated.

[0052] In yet another aspect, the present disclosure provides a compound of Formula (I):

[0053]

[0054] (I),

[0055] or a pharmaceutically acceptable salt thereof, wherein:

[0056] RHS:

[0057]

[0058] R3is selected from the group consisting of

[0059]

[0060]

[0061] R4is -OH or -NH2;

[0062] R3is -H or -C(O)C(i-6)alkyl;

[0063] R6is -H, -C(O)C(1-6)alkyl, or a sugar; and

[0064] R7is -OH or -NH2;

[0065] R8is -OH or -NH2;

[0066] provided the compound does not have the following structure:

[0067]

[0068] In some embodiments, the compound of Formula (I) is substantially isolated.

[0069] In some embodiments, the compound of Formula (I) is a compound of Formula (la):

[0070]

[0071] (la),

[0072] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (la) is substantially isolated.

[0073] In some embodiments, the compound of Formula (I) is a compound of Formula (lb):

[0074] R5

[0075]

[0076] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (lb) is substantially isolated.

[0077] In some embodiments, the compound of Formula (I) is a compound of Formula (Ic):

[0078]

[0079] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (Ic) is substantially isolated.In some embodiments, the compound of Formula (I) is a compound of Formula (Id):

[0080]

[0081] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (Id) is substantially isolated.

[0082] In some embodiments, R1is -OH.

[0083] In some embodiments, R1is:

[0084] HN

[0085]

[0086] In some embodiments, R2is -H.

[0087] In some embodiments, R2is:

[0088] In some embodiments, R2is:

[0089]

[0090] In some embodiments, R3is:

[0091] HN

[0092]

[0093] In some embodiments, R3is:

[0094]

[0095] In some embodiments, R3is:

[0096]

[0097] In some embodiments, R3is:

[0098]

[0099] In some embodiments, R3is:

[0100]

[0101] In some embodiments, R3is:

[0102]

[0103] In some embodiments, R3is:

[0104]

[0105] In some embodiments, R3is:

[0106]

[0107] In some embodiments, the present disclosure provides a compound of Formula (la- 1 ):

[0108] R5

[0109]

[0110] (la-1),

[0111] or a pharmaceutically acceptable salt thereof, wherein:

[0112] R4is -OH or -NH2;

[0113] R5is -H or -C(O)C(i-6)alkyl;

[0114] R6is -H, -C(O)C<i-6)alkyl, or a sugar;

[0115] R7is -OH or -NH2; and

[0116]

[0117] provided the compound does not have the following structure:

[0118]

[0119] In some embodiments, the present disclosure provides a compound of Formula (la-1):

[0120] R5

[0121]

[0122] (la-1),

[0123] or a pharmaceutically acceptable salt thereof, wherein:

[0124] R4is -OH or -NH2;

[0125] R5is -H or -C(O)C(i-6)alkyl;

[0126] R6is -H, -C(O)C<i-6)alkyl, or a sugar;R7is -OH or -NH2; and

[0127] H0Y-NA

[0128] R

[0129]

[0130] 9is -OH, O1, 01- O1

[0131] provided that at least one of the following is true:

[0132] (1) R4is -OH;

[0133] (2) R5is -C(O)C(i-6)alkyl;

[0134] (3) R6is -C(O)C(i-6jalkyl or a sugar;

[0135] (4) R7is -OH; or

[0136] HOy-N

[0137] (

[0138]

[0139] 5) R9is -OH or 01

[0140] In some embodiments, the compound of Formula (la- 1) is substantially isolated. In some embodiments, the present disclosure provides a compound of Formula (la-1), or a pharmaceutically acceptable salt thereof, wherein:

[0141] R4is -OH or -NH2;

[0142] R’ is -H or -C(O)C(i-6)alkyl;

[0143] R6is -II;

[0144] R7is -NH2; and

[0145] HOY^N^

[0146] R

[0147]

[0148] 9is -OH, O1, or O1;

[0149] and wherein the compound is substantially isolated.

[0150] In some embodiments, the present disclosure provides a compound of Formula (la-1), or a pharmaceutically acceptable salt thereof, wherein:

[0151] R4is -OH or -NH2;

[0152] R5is -H or -C(O)CH3;

[0153] R6is -H;

[0154] R7is -NH2; and

[0155]

[0156] R9is -OH, O1, or O1;

[0157] and wherein the compound is substantially isolated.

[0158] In some embodiments, the present disclosure provides a compound of Formula (la-1), or a pharmaceutically acceptable salt thereof, wherein:

[0159] R4is -OH or -NH2; and

[0160]

[0161] wherein the compound is substantially isolated; and

[0162] provided that at least one of the following is true:

[0163] R4is-OH; or

[0164]

[0165] In some embodiments, the present disclosure provides a compound of Formula (la-1), or a pharmaceutically acceptable salt thereof, wherein at least one of the following is true:

[0166] (1) R4is -OH;

[0167] (2) R5is -C(O)C(i-6)alkyl;

[0168] (3) R7is -OH; or

[0169] HV-rA

[0170] (

[0171]

[0172] 4) R9is -OH or O1

[0173] In some embodiments, the present disclosure provides a compound of Formula (la- 1 ), or a pharmaceutically acceptable salt thereof, wherein at least one of the following is time:

[0174] (l) R4is -OH;

[0175] (2) R5is -C(O)CH3; or

[0176] HOy-iA

[0177] (

[0178]

[0179] 3) R9is -OH or 01

[0180] In some embodiments, R4is -OH.

[0181] In some embodiments, R4is -NH2.

[0182] In some embodiments, -H or -C(O)CH3

[0183] In some embodiments, R3is -H.

[0184] In some embodiments, R3is -C(O)C(i-6)alkyl.

[0185] In some embodiments, R5is -C(O)CIl3.

[0186] In some embodiments, R6is -H, -C(O)CH3, or glucose.

[0187] In some embodiments, R6is -H.

[0188] In some embodiments, R6is -C(O)C(i-6)alkyl.

[0189] In some embodiments, R6is -C(O)CH3.

[0190] In some embodiments, R6is a sugar.

[0191] In some embodiments, R6is a glucose.

[0192] In some embodiments, R7is -OH.In some embodiments, R7is -NH2.

[0193] In some embodiments, R8is -OH.

[0194] In some embodiments, R8is -NH2.

[0195] In some embodiments, R9is -OH.

[0196] In some embodiments, R9is:

[0197]

[0198] In some embodiments, R9is:

[0199] H2NY-N

[0200]

[0201] 0

[0202] The present disclosure further provides a compound selected from the group consisting

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212] 19

[0213] M C

[0214] I

[0215] 20 H2N^O z

[0216] 1

[0217] <0

[0218] > OH

[0219] 9 HN

[0220] A A P "

[0221] _ o Z '

[0222] I o; ' '

[0223] z ' Sx

[0224] q

[0225] NH2

[0226] HO'^'O? and

[0227] 21 0 OH

[0228] 0;=: /

[0229] HNO„7

[0230] sx

[0231] NH2

[0232] HO^O?

[0233]

[0234] or a pharmaceutically acceptable salt thereof.

[0235] In some embodiments, the present disclosure provides the following compound:

[0236]

[0237] In some embodiments, the present disclosure provides one of the following compounds:

[0238]

[0239] In some embodiments, the present disclosure provides a compound selected from the group consisting of Compounds 2-22, or a pharmaceutically acceptable salt thereof.

[0240] In some embodiments, the present disclosure provides a compound selected from the group consisting of Compounds 2-24, or a pharmaceutically acceptable salt thereof.In some embodiments, the present disclosure provides a compound selected from the group consisting of Compounds 2-21, or a pharmaceutically acceptable salt thereof, wherein the compound is substantially isolated.

[0241] In some embodiments, the present disclosure provides a compound selected from the group consisting of Compounds 2-22, or a pharmaceutically acceptable salt thereof, wherein the compound is substantially isolated.

[0242] In some embodiments, the present disclosure provides a compound selected from the group consisting of Compounds 2-24, or a pharmaceutically acceptable salt thereof, wherein the compound is substantially isolated.

[0243] In some embodiments, the present disclosure provides a compound selected from the group consisting of:

[0244] Cpd No. Structure

[0245] 2 HO^OH0-.

[0246] T X / A

[0247] AAA A

[0248] 0 HN NH. —,..

[0249] / \,NHH 0 NH

[0250] 9 HB 9 H L B HHC°

[0251] 0 1 / oHJ 0 JX J o

[0252] O VNZHO X^O A X yT Q y

[0253] A NH2

[0254]

[0255]

[0256] 5

[0257] g *

[0258] CL

[0259] OQO Z=

[0260] o ZI

[0261] / MI

[0262] O TZ

[0263] \ ko \

[0264] \ o — \

[0265] ZT Z O= / =\ / — \

[0266] X p \ / \=\ \

[0267] X\ / \x

[0268] M >?o Tn

[0269] \ O N>? / Z

[0270] 8 H2N^OHX

[0271] TH H / X

[0272] O HN NHHN" J UOp X / I — n \

[0273] X X )

[0274] \12X ) r i o o AT oHA 0HSAHN-X0 ° “ H°\N N NvS

[0275] _ j o J o °

[0276] O ANZHCZ XA XX O

[0277] y J T

[0278] °'X / ^NH2

[0279]

[0280] or a pharmaceutically acceptable salt thereof.

[0281] In some embodiments, the present disclosure provides a compound selected from the group consisting of Compounds 2, 3, 4, 5, 8, and 22 or a pharmaceutically acceptable salt thereof.

[0282] In some embodiments, the present disclosure provides a compound selected from the group consisting of Compounds 2, 3, 4, 5, 8, and 22 or a pharmaceutically acceptable salt thereof, wherein the compound is substantially isolated.In some embodiments, the present disclosure provides a compound selected from the group consisting of Compounds 2, 3, 4, 5, and 8, or a pharmaceutically acceptable salt thereof, wherein the compound is substantially isolated.

[0283] In some embodiments, the present disclosure provides the following compound:

[0284]

[0285] (Compound 2)

[0286] or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 2, or the pharmaceutically acceptable salt thereof, is substantially isolated.

[0287] In some embodiments, the present disclosure provides the following compound:

[0288]

[0289] (Compound 3)or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 3, or the pharmaceutically acceptable salt thereof, is substantially isolated.

[0290] In some embodiments, the present disclosure provides the following compound:

[0291]

[0292] (Compound 4)

[0293] or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 4, or the pharmaceutically acceptable salt thereof, is substantially isolated.

[0294] In some embodiments, the present disclosure provides the following compound:

[0295]

[0296] (Compound 5)or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 5, or the pharmaceutically acceptable salt thereof, is substantially isolated.

[0297] In some embodiments, the present disclosure provides the following compound:

[0298]

[0299] (Compound 8)

[0300] or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 8, or the pharmaceutically acceptable salt thereof, is substantially isolated.

[0301] In some embodiments, the present disclosure provides the following compound:

[0302] O

[0303]

[0304] (Compound 22)or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 22, or the pharmaceutically acceptable salt thereof, is substantially isolated.

[0305] Methods of 5

[0306]

[0307] The compounds described herein may be synthesized by many techniques that are known to those skilled in the art. In some aspects, the present disclosure provides a method of chemically synthesizing a peptidyl compound of the present disclosure. In some embodiments, a portion of the peptidyl compound is recombinantly synthesized, instead of being chemically synthesized. In some aspects, methods of producing a peptidyl compound further include cyclizing the peptide precursor after the constituent subunits have been attached.

[0308] Pharmaceutical C

[0309]

[0310] The present disclosure further relates to a pharmaceutical composition comprising a compound described herein. In particular, the present disclosure includes pharmaceutical compositions comprising one or more compounds of the present disclosure and a pharmaceutically acceptable earner, diluent or excipient. The pharmaceutically acceptable carrier, diluent or excipient may be a solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like.

[0311] The pharmaceutical compositions may be administered orally, parenterally, intracistemally, intravaginally, intraperitoneally, intrarectally, topically (as by powders, ointments, drops, suppository, or transdemial patch), by inhalation (such as intranasal spray), ocularly (such as intraocularly) or buccally. The term “parenteral” as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal and intraarticular injection and infusion. Accordingly, in certain embodiments, the compositions are formulated for delivery by any of these routes of administration. A pharmaceutical composition may be formulated for and administered orally. A pharmaceutical composition may be formulated for and administered parenterally.

[0312] The compounds of the present disclosure may be prepared and / or formulated as pharmaceutically acceptable salts and / or other forms thereof or when appropriate in neutral form. Pharmaceutically acceptable salts are non-toxic salts of a neutral form of a compound that possess the desired pharmacological activity of the neutral form. These salts may be derivedfrom inorganic or organic acids or bases. For example, a compound that contains a basic nitrogen may be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21stEdition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0313] The present disclosure relates to pharmaceutical compositions comprising a compound described herein or pharmaceutically acceptable salts, isomers, or a mixture thereof, in which one or more hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D. As known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds may increase resistance to metabolism, and thus may be useful for increasing the half-life of the compounds described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof when administered to a mammal. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0314] Examples of isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36Cl,123I, and125I, respectively. Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

[0315] When used in at least one of the treatments or delivery systems described herein, a compound of the present disclosure may be employed as a free base or, where such forms exist, in pharmaceutically acceptable salt form.

[0316] The total daily usage of the compound and compositions of the present disclosure can be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including: a) the disorder being treated and the severity of the disorder; b) activity of the specific compound employed; c) the specific composition employed, the age, body weight, general health, sex and diet of the patient; d) the time of administration, route of administration, and rate of excretion of the specific compound employed; e) the duration of the treatment; f)drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.

[0317] The compositions may conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. Techniques and compositions generally are found in Remington’s Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0318] Non-Invasive Detection of Intestinal Inflammation

[0319] The compounds of the present disclosure may be used for detection, assessment and diagnosis of intestinal inflammation by microPET imaging, wherein the compound is labeled with a chelating group or a detectable label, as part of a non-invasive diagnostic procedure. In certain embodiments, a compound of the present disclosure is conjugated with a bifunctional chelator. In certain embodiments, a compound of the present disclosure is radiolabeled. The labeled compound is then administered to a subject orally or rectally. In certain embodiments, the compound is included in drinking water. Following uptake of the compound, microPET imaging may be used to visualize inflammation throughout the subject’s bowels and digestive track.

[0320] Methods of Treatment and Uses

[0321] The present disclosure relates to methods for treating a subject afflicted with a condition or indication associated with IL-23 or IL-23R activity (e.g., activation of the IL-23 / IL-23R signaling pathway), wherein the method comprises administering to the subject a compound disclosed herein. In one aspect, the present disclosure provides a method for treating a subject afflicted with a condition or indication characterized by aberrant or dysregulated IL-23 or IL-23R activity or signaling, comprising administering to the subject a compound of the present disclosure in an amount sufficient to inhibit (partially or fully) binding of IL-23 to an IL-23R in the subject. The inhibition of IL-23 binding to IL-23R may occur in particular organs or tissues of the subject, e.g., the stomach, small intestine, large intestine / colon, intestinal mucosa, lamina propria, Peyer’s Patches, mesenteric lymph nodes, or lymphatic ducts.The present disclosure relates to methods comprising providing a compound described herein to a subject in need thereof. The subject in need thereof may be a subject that has been diagnosed with or has been determined to be at risk of developing a disease or disorder associated with IL-23 / IL-23R. The subject may be a mammal. The subject may be, in particular, a human.

[0322] The disease or disorder to be treated by treatment with a compound of the present disclosure may be an inflammatory disease or disorder, an autoimmune inflammation diseases or disorder, and / or related disorders, including multiple sclerosis, asthma, rheumatoid arthritis, inflammation of the gut, inflammatory bowel diseases (IBDs), juvenile IBD, adolescent IBD, Crohn’s disease, ulcerative colitis, sarcoidosis, Systemic Lupus Erythematosus, ankylosing spondylitis (axial spondyloarthritis), psoriatic arthritis, or psoriasis. In particular, the disease or disorder may be psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, Palmo-Plantar Pustulosis, psoriasis vulgaris, or erythrodermic psoriasis), atopic dermatitis, acne ectopica, ulcerative colitis, Crohn’s disease, Celiac disease (nontropical Sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis / esophagitis, colitis associated with radio- or chemo-therapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficiency- 1, chronic granulomatous disease, glycogen storage disease type lb, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich Syndrome, pouchitis, pouchitis resulting after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulindependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral-associated enteropathy, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft versus host disease.

[0323] The present disclosure provides a method or use of a compound of the present disclosure for treating an inflammatory disease or disorder in a subject in need thereof that includes administering to the subject a therapeutically effective amount of a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a composition disclosed herein comprising a compound of the present disclosure.

[0324] The present disclosure provides a method or use of a compound of the present disclosure for treating an autoimmune disease or disorder in a subject in need thereof that includes administering to the subject a therapeutically effective amount of a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a composition disclosed herein comprising a compound of the present disclosure.The present disclosure provides a method or use of a compound of the present disclosure for treating an autoimmune inflammation disease or disorder in a subject in need thereof that includes administering to the subject a therapeutically effective amount of a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a composition disclosed herein comprising a compound of the present disclosure.

[0325] Suitable inflammatory diseases, autoimmune inflammation diseases, and / or related disorders for treatment with a compound or pharmaceutically acceptable salt thereof, or a composition of the present disclosure, may include, but are not limited to inflammatory bowel disease (IBD), Crohn’s disease (CD), ulcerative colitis (UC), psoriasis (PsO), or psoriatic arthritis (PsA) and the like. The inflammatory disease to be treated may be inflammatory bowel disease (IBD), Crohn’s disease, or ulcerative colitis. The inflammatory disease to be treated may be selected from psoriasis or psoriatic arthritis. The inflammatory disease to be treated may be psoriasis The inflammatory disease to be treated may be psoriatic arthritis. The inflammatory disease to be treated may be IBD. The inflammatory disease to be treated may be Crohn’s disease. The inflammatory disease to be treated may be ulcerative colitis. The inflammatory disease to be treated may be psoriasis. The inflammatory disease to be treated may be psoriatic arthritis.

[0326] Production of IL-23 is enriched in the intestine, where it is believed to play a key role in regulating the balance between tolerance and immunity through T-cell-dependent and T-cell-independent pathways of intestinal inflammation through effects on T-helper 1 (Thl) and Thl7-associated cytokines, as well as restraining regulatory T-cell responses in the gut, favoring inflammation. In addition, polymorphisms in the IL-23 receptor (IL-23R) have been associated with susceptibility to inflammatory bowel diseases (IBDs), further establishing the critical role of the IL-23 pathway in intestinal homeostasis. Compounds and methods for specific targeting of the IL-23R from the luminal side of the gut may provide therapeutic benefit to IBD patients suffering from local inflammation of the intestinal tissue.

[0327] Accordingly, the present disclosure also provides a method of treating or preventing inflammatory bowel disease (IBD), Crohn’s disease (CD), or ulcerative colitis (UC), in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein comprising a compound described herein. In some embodiments, the method is for treating or preventing inflammatory bowel disease (IBD). In some embodiments, the method is for treating or preventing Crohn’s disease (CD). In some embodiments, the method is for treating or preventing ulcerative colitis (UC).Psoriasis, a chronic skin disease affecting about 2%-3% of the general population has been shown to be mediated by the body’s T cell inflammatory response mechanisms. IL-23 is one of several interleukins implicated as a key player in the pathogenesis of psoriasis, purportedly by maintaining chronic autoimmune inflammation via the induction of interleukin-17, regulation of T memory cells, and activation of macrophages. Expression of IL-23 and IL-23R has been shown to be increased in tissues of patients with psoriasis, and antibodies that neutralize IL-23 showed IL-23-dependent inhibition of psoriasis development in animal models of psoriasis. Orally bioavailable inhibitors of IL-23 may provide both a non-steroidal treatment option for patients with mild to moderate psoriasis and treatment for moderate to severe psoriasis that does not require delivery by infusion.

[0328] Accordingly, the present disclosure also provides a method of treating or preventing psoriasis (PsO) or psoriatic arthritis (PsA) in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein comprising a compound described herein. In some embodiments, the method is for treating or preventing psoriasis (PsO). In some embodiments, the method is for treating or preventing psoriatic arthritis (PsA).

[0329] The present disclosure further relates to a method of selectively inhibiting IL-23 or IL-23R signaling (or the binding of IL-23 to IL-23R) in a subject (e.g., in a subject in need thereof), comprising administering to the subject a compound described herein. In some embodiments, the present disclosure includes and provides a method of selectively inhibiting IL-23 or IL-23R signaling (or the binding of IL-23 to IL-23R) in the GI tract of a subject (e.g., a subject in need thereof), comprising providing to the subject a compound of the present disclosure by oral administration. The exposure of GI tissues (e.g., small intestine or colon) to the administered compound may be at least 10-fold, at least 20-fold, at least 50-fold, or at least 100-fold greater than the exposure (level) in the blood. In particular embodiments, the present disclosure includes a method of selectively inhibiting IL23 or IL23R signaling (or the binding of IL23 to IL23R) in the GI tract of a subject (e.g., a subject in need thereof), comprising providing to the subject a compound described herein, wherein the compound does not block the interaction between IL-6 and IL-6R or antagonize the IL- 12 signaling pathway. In a further related embodiment, the present disclosure provides a method of inhibiting GI inflammation and / or neutrophil infiltration to the GI, comprising providing to a subject in need thereof a compound of the present disclosure. In some embodiments, methods of the present disclosure comprise providing a compound of the present disclosure (i.e., a first therapeutic agent) to a subject (e.g., a subject inneed thereof) in combination with a second therapeutic agent. In certain embodiments, the second therapeutic agent is provided to the subject before and / or simultaneously with and / or after the compound of the present disclosure is administered to the subject. In particular embodiments, the second therapeutic agent is an anti-inflammatory agent. In certain embodiments, the second therapeutic agent is a non-steroidal anti-inflammatory drug, steroid, or immune modulating agent. In certain embodiments, the method comprises administering to the subject a third therapeutic agent. In certain embodiments, the second therapeutic agent is an antibody that binds IL-23 or IL-23R.

[0330] The present disclosure also relates to methods of inhibiting IL-23 binding to an IL-23R on a cell, comprising contacting the IL-23R with a compound disclosed herein. The cell may be a mammalian cell. The method may be performed in vitro or in vivo. Inhibition of binding may be determined by a variety of routine experimental methods and assays known in the art.

[0331] The present disclosure relates to methods of inhibiting IL-23 signaling by a cell, comprising contacting the IL-23R with a compound described herein. In certain embodiments, the cell is a mammalian cell. In particular embodiments, the method is performed in vitro or in vivo. In particular embodiments, the inhibition of IL-23 signaling may be determined by measuring changes in phospho-STAT3 levels in the cell.

[0332] Examples

[0333] The following examples are not intended to limit the scope of the present disclosure, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present disclosure. While particular aspects of the present disclosure are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the disclosure.

[0334] Example 1: Preparation of Peptide Compounds of the Disclosure

[0335] Compounds 2-13 and 22 can be synthesized using Merrifield solid phase synthesis techniques on Protein Technology's Symphony multiple channel synthesizer. Representative conditions are detailed, for example, in WO 2021 / 146441 and below.

[0336] The peptides may be assembled using HBTU (0-Benzotriazole-N, N, N', N’-tetramethyl-uronium- hexafluoro-phosphate), Diisopropylethylamine(DIEA) coupling conditions.

[0337] Alternately, for some amino acid couplings, PyAOP(7 -Azahenzotriazol- 1 -yloxyjtripyrrolidinophosponium hexafluorophosphate) and DIEA conditions may used. Rink Amide MBHA resin (100-200 mesh, 0.57 mmol / g) may be used for peptides with C-terminalamides. Pre-loaded Wang Resin with N-a-Fmoc protected amino acids may be used for peptides with C-terminal acids. The coupling reagents (HBTU and DIEA premixed) and the amino acid solutions can be prepared, e.g., at 100 mmol concentrations.

[0338] Representative assembly, cleavage, cyclization, and purification methodologies are described below:

[0339] Assembly

[0340] Peptide compounds may be assembled using standard Symphony protocols. Resin (250 mg, 0.14 mmol) in each reaction vial was washed twice with 4ml of DMF followed by treatment with 2.5ml of 20% 4-methyl piperidine (Fmoc deprotection) for 10 min. The resin was then filtered and washed two times with DMF (4ml) and retreated with N-methylpiperidine for an additional 30 minute. The resin was again washed three times with DMF (4 ml) followed by addition of 2.5ml of amino acid and 2.5ml of HBTU-DIEA mixture. After 45min of frequent agitation, the resin was filtered and washed three timed with DMF (4 ml each). Double couplings were performed. After completing the coupling reaction, the resin was washed three times with DMF (4 ml each) before proceeding to the next amino acid coupling.

[0341] Cleavage

[0342] Following completion of the peptide assembly, the peptide was cleaved from the resin by treatment with a cleavage reagent comprising 90% trifluoroacetic acid, 5% water, 2.5% 1,2-ethanedithiol, and 2.5% tri-isopropylsilane. The cleaved peptides were precipitated in cold diethyl ether followed by two washings with ethyl ether. The filtrate was poured off, a second aliquot of cold ether was added, and the procedure repeated. The crude peptide was dissolved in a solution of acetonitrile: water (7:3 with 1% TFA) and filtered, thereby providing the unoxidized crude peptide.

[0343] Disulfide Bond Formation via Oxidation

[0344] Crude, cleaved peptide possessing two penicillamine residues was dissolved in 20ml of water: acetonitrile. Saturated iodine in acetic acid was then added drop wise with stirring until yellow color persisted. The solution was stirred for 15 minutes, and the reaction was monitored with analytic HPLC and LCMS. When the reaction was completed, solid ascorbic acid was added until the solution became clear. The solvent mixture was then purified by first being diluted with water and then loaded onto a reverse phase HPLC machine (Luna C18 support, 10u, 100A, Mobile phase A: water containing 0.1% TFA, mobile phase B: Acetonitrile (ACN) containing 0.1% TFA, gradient began with 5% B, and changed to 50% B over 60 minutes at aflow rate of 15ml / min). Fractions containing pure product were then freeze-dried on a lyophilyzer.

[0345] Purification

[0346] Standard purification methods can be used to isolate and purify the peptide compounds, including analytical reverse-phase, high performance liquid chromatography (HPLC), salt exchange, and lyophilization.

[0347] The purity of certain synthesized and isolated peptide compounds of the present disclosure are provided in Table 1:

[0348] Table 1. Purity of Synthesized Compounds

[0349] Compound No. Purity (HPLC)

[0350] 2 99.2%

[0351] 3 99.4%

[0352] 8 98.5%

[0353]

[0354] 22 96.8%

[0355] Example 2: Identification of Metabolite Compounds of the Disclosure

[0356] Compounds 6-10 and 12-21 were identified from metabolic stability screenings of Compound 1 in rats.

[0357] Sample process

[0358] Plasma samples: Plasma samples were processed by protein precipitation with 4 volumes of acetonitrile / methanol (50 / 50) containing 0.1 % formic acid to extract the analyte. The mixture was vortex- mixed and then centrifuged at 4000 g at 4 °C for 15 minutes (Thermo Multifuge X3R). The supernatants were transferred to clean tubes and were evaporated to dryness under a gentle stream of nitrogen at room temperature, and the pellets were subjected to second extraction. The dried residues were reconstituted in 100 pL of water: acetonitrile (9:1 v / v) containing 0.1% formic acid for LC-MS analysis.

[0359] Urine samples: Urine collected from Day 1 to Day 4 were proportionally pooled across each time period (Dayl to Day 4) to include >90% of excretion from each animal. The urine samples were centrifuged at 4000 g at 4 °C for 15 minutes (Thermo Multifuge X3R) followed by filtering with 0.45 pm nylon filter at 10,000 rpm at room temperature for 10 minutes (Eppendorf, 5417R) prior to injection of 100 pL on LC-MS for analysis.

[0360] Feces: Fecal homogenates from Day 1 to Day 4 were proportionally pooled across each time period (Day 1 to Day 4) to include >90% of excretion for each rat. The pooled fecal homogenates were extracted with 6 volumes of acetonitrile / methanol (50 / 50 v / v) containing 0.1% formic acid followed by centrifugation at 4000 g at 4 °C for 15 minutes (ThermoMultifuge X3R). The supernatants were transferred to a clean tube to be evaporated to dryness under a gentle stream of nitrogen at room temperature and the pellets were subjected to second extraction. The residues were reconstituted in 200 pl of acetonitrile:water (1:9 v / v) containing 0.1% formic acid for LC-MS analysis.

[0361] LC-MS analysis

[0362] All mass spectrometry (MS) analyses were carried out with the QE operated in the positive electrospray ionization mode. An aliquot of 25-100 pL of reconstituted sample was injected for chromatographic separation of Compound 1 and its metabolites by gradient elution consisting of 0.1% formic acid in water and acetonitrile at a flow rate of 0.25 mL / min.

[0363] Chromatographic separation of the unchanged drug and its metabolites was achieved using a Luna C8(2) column (150 X 2.0 mm ID, 3 pm) kept at 40 °C. For MS analysis, the eluant from HPLC was nebulized with sheath, auxiliary and sweep gas flow set at 60, 15 and 5 arbitrary units, respectively. Desolvation of the solvent droplets was aided by heated capillary temperature of 300 °C, and auxiliary gas heater at 350 °C. The mass spectrometer was optimized by infusion of 15 ng / pL of Compound 1 in 50:50 acetonitrile / water directly into a 50:50 mobile phase at 0.125 mL / min. The mass analyses were carried out in a data-dependent accurate mass measurements manner at a resolving power of 17,500 for both full scan MS and MS2. The unchanged drug and its metabolites were detected in data dependent HCD (Higher-energy C-trap dissociation) mass analysis with an isolation width of 1.5 Da and stepped collision energy mode 20, 25, and 35%. Data acquisition and processing were carried out using XcaliburTM 4.1 (Thermo Scientific, Inc., San Jose, CA).

[0364] Metabolite identification

[0365] Metabolite structures were elucidated based on their elemental compositions obtained from HRMS analysis along with their fragmentation patterns from MS / MS analysis.

[0366] Example 3: IL23R Reporter Assay

[0367] Compounds 2, 3, 4, 5, and 8 were synthesized using solid phase peptide synthesis methods and were serially diluted in 100% (v / v) DMSO) and plated using an Echo acoustic dispenser (Labcyte) into 1536-well non-treated black assay plates (Corning # 9146). 3 pL of HEK293 cells containing IL-23R, IL-12Rβ1 and a firefly luciferase reporter gene driven by a STAT-inducible promoter (Promega) were added to the plates (4000 cells / well), followed by 3 pL of 10 ng / mL IL-23 (equivalent to EC90 concentration). After 5h at 37°C, 5% CO2, 95% relative humidity, cells were placed at 20°C and treated with BioGlo reagent (Promega) according to the Manufacturer’s instructions. Luminescence was measured on a Pherastar FSX(BMG LabTech). Data were normalized to IL-23 treatment (0% inhibition) and 30 pM of control inhibitor (100% inhibition), and IC50 values were determined using a 4-parameter Hill equation. Data for particular compounds of the disclosure are shown below.

[0368] Table 2. IL-23 Binding Data

[0369] KD fold difference

[0370] with respect to

[0371] Compound No. KD (pM) Compound 1

[0372] 1 7.1 - 2 4.9 0.7

[0373] 3 2546 359

[0374] 4 7.0 1

[0375] 5 16.4 2.3

[0376]

[0377] 8 31.2 4.4

[0378] Example 4: PBMC pSTAT3 Assay

[0379] Cryopreserved peripheral blood mononuclear cells (PBMCs) from healthy donors were thawed and washed twice in ImmunoCult-XF T cell expansion medium (XF-TCEM) supplemented with CTL anti-aggregate wash. The cells were counted, resuspended at 2-6xl05cells per mL XF-TCEM supplemented with penicillin / streptomycin and 100 ng / mL IL-1[3 (BioLegend, 579404), and cultured in tissue culture flasks coated with anti-CD3 (eBioscience, 16-0037-85 or BD Pharmingcn, 555329) at 37oC in 5% CO2. On day 4 of culture, PBMCs were collected, washed twice in RPMI-1640 supplemented with 0.1% BSA (RPMI-BSA), and incubated in RPMI-BSA in upright tissue culture flasks for ~4 hours at 37oC in 5% CO2. Following this ‘starvation,’ a total of 6x104 cells in 30 pL RPMI-BSA was transferred into each well of a 384-well plate pre-spotted with a compound of the present disclosure or DMSO. The cells were incubated for 30 minutes prior to the addition of IL-23 at a final concentration of 5 ng / mL. The cells were stimulated with cytokine for 30 minutes at 37oC in 5% CO2, transferred onto ice for 10 minutes, and lysed. Cell lysates were stored at -80°C until phosphorylated STAT3 was measured using the phospho-STAT panel kit (Meso Scale Discovery, K15202D). Results are provided below.

[0380] Table 3. PBMC pSTAT3 Assay Results

[0381] ICso fold

[0382] difference with

[0383] respect to

[0384] Compound No. IC50 (pM) Compound 1

[0385]

[0386] 1 6 -IC50fold difference with respect to Compound No. IC50(pM) Compound 1

[0387] 2 5.25 0.88

[0388] 3 6100 1017

[0389] 4 16 2.7

[0390] 5 15 2.5

[0391]

[0392] 8 47 7.8

[0393] While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and / or modifications as come within the scope of the following claims and their equivalents.

Claims

CLAIMS1. A compound of Formula (I):(I),or a pharmaceutically acceptable salt thereof, wherein:RHS:R3is selected from the group consisting ofR4is -OH or -NH2;R3is -H or -C(O)C(i-6)alkyl;R6is -H, -C(O)C(1-6)alkyl, or a sugar; andR7is -OH or -NH2;R8is -OH or -NH2;provided the compound does not have the following structure:

2. The compound of claim 1 that is a compound of Formula (la):(la),or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 that is a compound of Formula (la- 1 ):R5(la-1),or a pharmaceutically acceptable salt thereof, wherein:

4. The compound of claim 3, wherein:R4is -OH or -NH2;R5is -H or -C(O)CH3;R6is -H;R7is -NH2; and5. The compound of claim 1 that is a compound of Formula (lb):or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 that is a compound of Formula (Ic):or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 that is a compound of Formula (Id):(Id),or a pharmaceutically acceptable salt thereof.

8. The compound of any one of claims 1, 2, and 5-7, or a pharmaceutically acceptable salt thereof, wherein R3is9. The compound of any one of claims 1-3 and 5-8, or a pharmaceutically acceptable salt thereof, wherein R5is -H or -C(O)CH3.

10. The compound of any one of claims 1-3 and 5-9, or a pharmaceutically acceptable salt thereof, wherein R6is -H, -C(O)CH3, or glucose.

11. The compound of any one of claims 1-3 and 5-10, or a pharmaceutically acceptable salt thereof, wherein R7is -NH2.

12. The compound of claim 1, selected from the group consisting of:H2N^OT0HN HI\k, JSx CL>y-- NH2HN^O°^NH2N C? I z _JOA Bs 9 "> 7< X I—T o; / WZ. -H2N^OT0HN HN / <„sx cNH2HO^O •>21 9 OHHN / „.7SxS>v— NH2HO^'O,and22 0^ _H2N^O QT AKhN-X / P9 HN NH. —, Ak °A V\A \ HN.,.,7 HOITM 7\,NHH 0 N H2H oA A kt? H ]? H U? H0J 6HJ 6 £J <5 1O VNZH0 X "0 XJ o yNH2?or a pharmaceutically acceptable salt thereof.

13. The compound of claim 12, selected from the group consisting of:or a pharmaceutically acceptable salt thereof.

14. The compound of claim 13, wherein the compound is:or a pharmaceutically acceptable salt thereof.

15. The compound of claim 13, wherein the compound is:or a pharmaceutically acceptable salt thereof.

16. The compound of claim 13, wherein the compound is:or a pharmaceutically acceptable salt thereof.

17. The compound of claim 13, wherein the compound is:or a pharmaceutically acceptable salt thereof.or a pharmaceutically acceptable salt thereof.

19. The compound of claim 12, wherein the compound is:or a pharmaceutically acceptable salt thereof.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, which is substantially isolated.

21. A pharmaceutical composition comprising the compound of any one of claims 1 -20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

22. The pharmaceutical composition of claim 21, further comprising an enteric coating.

23. The pharmaceutical composition of claim 22, wherein the enteric coating protects and releases the pharmaceutical composition within a subject's lower gastrointestinal system.

24. A method for treating a disease or disorder associated with interleukin 23 (IL- 23 ) / interleukin 23 receptor (IL-23R) in a subject in need thereof, said method comprising administering to the subject an effective amount of the compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 21-23.

25. A method for treating a disease or disorder in a subject in need thereof, said method comprising administering to the subject an effective amount of the compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 21-23, wherein the disease or disorder is selected from the group consisting of an Inflammatory Bowel Disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), Celiac disease ( nontropical Sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radio- or chemo-therapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficiency- 1, chronic granulomatous disease, glycogen storage disease type lb, Hermansky- Pudlak syndrome, Chediak- Higashi syndrome, and Wiskott- Aldrich Syndrome, pouchitis resulting after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus. mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis (PsO), psoriatic arthritis (PsA). and graft versus host disease.

26. The method of claim 25, wherein the disease or disorder is an Inflammatory Bowel Disease (IBD).

27. The method of claim 25, wherein the disease or disorder is ulcerative colitis (UC).

28. The method of claim 25, wherein the disease or disorder is Crohn’s disease (CD).

29. The method of claim 25, wherein the disease or disorder is psoriasis (PsO).

30. The method of claim 25, wherein the disease or disorder is psoriatic arthritis (PsA).

31. The method of any one of claims 25-30, wherein the compound or pharmaceutical composition is provided to the subject by an oral, parenteral, intravenous, peritoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vaporization, nebulization. sublingual, buccal, parenteral, rectal, intraocular, inhalation, topically, vaginal, or topical route of administration.

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