Compositions and methods for treating inflammatory bowel disease using CCR9 inhibitors and anti-IL-23 blocking antibodies

Abstract

Provided herein are compositions, methods, and kits for treating inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis, in a mammal in need thereof. The methods include administering to a subject with IBD a combination therapy comprising a therapeutically effective amount of a chemokine receptor 9 (CCR9) inhibitor compound and a therapeutically effective amount of an anti-IL-23 antibody. Kits comprising the CCR9 inhibitor compound and the anti-IL-23 antibody are also provided herein.

Description

Related Applications

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 002,747, filed March 31, 2020, the disclosure of which is incorporated herein by reference in its entirety for all purposes. [Background technology]

[0002] Inflammatory bowel disease (IBD) is a group of chronic inflammatory conditions that affect part or all of the gastrointestinal (GI) tract, including the mouth, esophagus, stomach, small intestine, large intestine (colon), rectum, and anus. IBD includes Crohn's disease (CD), ulcerative colitis (UC), and undifferentiated colitis. CD and UC can be distinguished by clinical, endoscopic, and pathological features.

[0003] CD is a chronic inflammatory disease that can involve any part of the GI tract. Characteristic symptoms of the disease include severe abdominal pain, frequent diarrhea, rectal bleeding, urgency, and swelling in the right lower quadrant of the abdomen.

[0004] UC is a chronically remitting and relapsing inflammatory disease of the colon. The disease is characterized by recurrent episodes of inflammation primarily involving superficial mucosal lesions that extend through the rectum and upward through the colon. Acute episodes are characterized by chronic diarrhea or constipation, rectal bleeding, cramps, and abdominal pain.

[0005] IBD is characterized by inflammation and the infiltration of leukocytes, such as lymphocytes, granulocytes, monocytes, and macrophages, from the blood into the mucosal or epithelial lining of the intestine. Multiple inflammatory cell types, including lymphocytes, neutrophils, macrophages, and dendritic cells, contribute to IBD. For example, T lymphocytes infiltrate the gastrointestinal mucosa through coordinated interactions between adhesion molecules on the surface of T lymphocytes and their cognate ligands on the endothelium. Chemokine receptors and ligands, such as the receptor CCR9 and its ligand CCL25, also play a role in the migration of inflammatory cells, such as effector memory T helper cells, into the intestinal epithelium in IBD.

[0006] In view of the above, it is apparent that an effective treatment regimen for IBD that can block multiple pathways and / or multiple cell types involved in lymphocyte infiltration into intestinal tissues would be useful in treating the disease. The present invention provides such therapies, along with pharmaceutical compositions and related methods of treatment. Summary of the Invention

[0007] In one aspect, the disclosure provides a method of treating or reducing the incidence of inflammatory bowel disease in a mammal, the method comprising administering a suitable amount of a CCR9 inhibitor together with an anti-IL-23 or anti-IL-23 receptor (anti-IL-23R) blocking antibody. In some embodiments, the inflammatory bowel disease is Crohn's disease (CD) or ulcerative colitis (UC).

[0008] In some embodiments, the CCR9 chemokine receptor inhibitor is a small molecule receptor inhibitor having a molecular weight of less than 1500. The CCR9 small molecule receptor inhibitor can have a molecular weight of about 1495, 1450, 1400, 1300, 1200, 1100, 1000, 900, 800, 700, 600, 500 or less.

[0009] In some embodiments, the CCR9 small molecule inhibitors provided herein can be represented by formula (I): [ka] In the formula, X 1 , X 2 , X 3 , X 4 , X 5 , Y 1 , Y 2 , Y 3 , Y 4 , L 1 , and Z 1 is defined as follows:

[0010] In some embodiments, the CCR9 small molecule inhibitors provided herein can be represented by formula (II): [ka] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L.A. 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 is defined as follows:

[0011] In some embodiments, the anti-IL-23 or anti-IL-23R blocking antibody is risankizumab, guselkumab (TREMFYA®), ustekinumab, briakinumab, brazikumab, mirikizumab, tildrakizumab, or a biosimilar, biobetter, or bioequivalent thereof.

[0012] In some embodiments, the CCR9 inhibitor and the anti-IL-23 blocking antibody are administered in a combined formulation. In other embodiments, the CCR9 inhibitor and the anti-IL-23 blocking antibody are administered sequentially. In yet other embodiments, the CCR9 inhibitor is administered before the anti-IL-23 blocking antibody. In another embodiment, the CCR9 inhibitor is administered after the administration of the anti-IL-23 blocking antibody.

[0013] In some embodiments, the CCR9 inhibitor is a compound having the following formula: [ka]

[0014] In some embodiments, the CCR9 inhibitor is a compound selected from the following: [ka]

[0015] In another aspect, the disclosure provides a composition for treating or reducing the incidence of inflammatory bowel disease in a mammal, the composition comprising a therapeutically effective amount of a CCR9 inhibitor, a therapeutically effective amount of an anti-IL-23 or anti-IL-23R blocking antibody, and a pharmaceutically acceptable carrier or excipient.

[0016] In some embodiments, the inflammatory bowel disease is Crohn's disease (CD) or ulcerative colitis (UC).

[0017] In yet another aspect, the disclosure provides a kit for treating or reducing the incidence of inflammatory bowel disease in a mammal, the kit comprising a therapeutically effective amount of a CCR9 inhibitor, a therapeutically effective amount of an anti-IL-23 or anti-IL-23R blocking antibody, and instructions for effective administration.

[0018] In some embodiments, the CCR9 inhibitor and the anti-IL-23 or anti-IL-23R blocking antibody are formulated for sequential administration, hi other embodiments, the CCR9 inhibitor and the anti-IL-23 or anti-IL-23R blocking antibody are formulated for simultaneous administration.

[0019] In some embodiments, the anti-IL-23 or anti-IL-23R blocking antibody is risankizumab, guselkumab (TREMFYA®), ustekinumab, briakinumab, brazikumab, mirikizumab, tildrakizumab, or a biosimilar, biobetter, or bioequivalent thereof.

[0020] Aspects of the present invention also include the following. 1. A method for treating or alleviating the development of inflammatory bowel disease in a mammal, said method comprising administering a suitable amount of a CCR9 inhibitor together with an anti-IL-23 or anti-IL-23 receptor blocking antibody; The CCR9 chemokine receptor inhibitor is a compound having the formula (I) or a salt thereof: [ka] In the formula, R 1 is substituted or unsubstituted C 2-8 Alkyl, substituted or unsubstituted C 1-8 Alkoxy, substituted or unsubstituted C 1-8 Alkylamino, and substituted or unsubstituted C 3-10 heterocyclyl; R 2 is H, F, Cl, or substituted or unsubstituted C 1-8 alkoxy, or R 1 and R 2 together with the carbon atoms to which they are attached form a non-aromatic carbocyclic or heterocyclic ring, R 3 H, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 1-8 alkoxy or halo; R 4 is H or F, R 5 is H, F, Cl, or -CH 3 and R 6 H, halo, -CN, -CO 2 R a , -CONH 2 , -NH 2 , substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 1-8 Alkoxy, or substituted or unsubstituted C 1-8 is an aminoalkyl, R a is H, or substituted or unsubstituted C 1-8 is alkyl, R 5 and R 6 may together form a carbocyclic ring, L is a bond, -CH 2 - or -CH(CH 3 )- and A 1 、A 2 、A 3 、A 4、A 5 、A 6 、A 7 , and A 8 each independently represents N, NO, and -CR 8 - selected from the group consisting of A 1 、A 2 、A 3 、A 4 、A 5 、A 6 、A 7 , and A 8 at least one and not more than two of are N or NO; R 8 each independently represents H, halo, —CN, —OH, oxo, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 1-8 Alkoxy, -NR 20 R 21 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; R 20 and R 21 are each independently H or substituted or unsubstituted C 1-8 The method is alkyl. Aspect 2 The method of embodiment 1, wherein the inflammatory bowel disease is Crohn's disease (CD) or ulcerative colitis (UC). Aspect 3 3. The method of aspect 1 or 2, wherein said anti-IL-23 or anti-IL-23 receptor blocking antibody is risankizumab, guselkumab, ustekinumab, briakinumab, brazikumab, mirikizumab, tildrakizumab, or a biosimilar, biobetter, or bioequivalent thereof. Aspect 4 The method according to any one of aspects 1 to 3, wherein the CCR9 inhibitor and the anti-IL-23 or anti-IL-23 receptor-blocking antibody are administered in a combined formulation. Aspect 5 The method according to any one of aspects 1 to 3, wherein the CCR9 inhibitor and the anti-IL-23 or anti-IL-23 receptor-blocking antibody are administered sequentially. Aspect 6 The method of aspect 5, wherein the CCR9 inhibitor is administered before the anti-IL-23 or the anti-IL-23 receptor-blocking antibody. Aspect 7 The method of aspect 5, wherein the CCR9 inhibitor is administered after administration of the anti-IL-23 or the anti-IL-23 receptor-blocking antibody. Aspect 8 A1 or A 2 One of the is N or NO, and A 1 、A 2 、A 3 、A 4 、A 5 、A 6 、A 7 , and A 8 The remainder of the 8 - and each R 8 A method according to any one of aspects 1 to 7, wherein: Aspect 9 A 2 、A 3 、A 4 , and A 5 Two of the are N or NO, and A 1 、A 2 、A 3 、A 4 、A 5 、A 6 、A 7 , and A 8 The remainder of the 8 - and each R 8 A method according to any one of aspects 1 to 7, wherein: Aspect 10 the inhibitor is a compound having the formula (III) or a salt thereof,

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[0021] [Figure 1] Trough plasma concentrations of Compounds 1 and 2 on day 3 are shown. [Figure 2] Colon weight-to-length ratios of wild-type compared to MDR- / - mice are shown. [Figure 3] Colon weight to length ratios for Compound 1 treated groups and controls are shown. [Figure 4] Colon weight to length ratios for Compound 2 treated groups and controls are shown. DETAILED DESCRIPTION OF THE INVENTION

[0022] I. Prologue The present disclosure is based, in part, on the unexpected discovery that combination therapy of a CCR9 inhibitor, e.g., a small molecule inhibitor of CCR9, with an antibody to IL-23 or an antibody to the IL-23 receptor can act synergistically in the treatment of inflammatory bowel diseases such as Crohn's disease, ulcerative colitis, and undifferentiated colitis. Provided herein are methods, compositions, and kits for treating IBD in a subject, e.g., a human or animal subject, in need thereof. In some embodiments, the method comprises administering to a subject with IBD a therapeutically effective amount of a CCR9 inhibitor and an anti-IL-23 or anti-IL-23R antibody to induce a clinical response or maintain clinical remission in the subject.

[0023] II. Definition When describing the compounds, compositions, methods and processes of the invention, the following terms have the following meanings unless otherwise indicated.

[0024] As used herein, the terms "a," "an," or "the" include not only embodiments having one member, but also embodiments having a plurality of members. For example, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to a "cell" includes a plurality of such cells, a reference to an "agent" includes a reference to one or more agents known to those of skill in the art, and so forth.

[0025] The terms "about" and "approximately" are generally intended to refer to an acceptable degree of error for the measured quantity, given the nature or precision of the measurement. Typical exemplary degrees of error are within 20 percent (%), preferably within 10%, and more preferably within 5% of a given value or range of values. Alternatively, particularly in biological systems, the terms "about" and "approximately" can refer to values ​​that are within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold of a given value. Numerical quantities set forth herein are approximate unless otherwise specified, and the term "about" or "approximately" means that they can be inferred when not explicitly stated.

[0026] The term "inflammatory bowel disease" or "IBD" includes gastrointestinal disorders such as, for example, Crohn's disease (CD), ulcerative colitis (UC), unspecified colitis (IC), and IBD that is not definitively CD or UC ("indeterminate"). Inflammatory bowel disease (e.g., CD, UC, IC, and indeterminate) is distinct from all other disorders, syndromes, and abnormalities of the gastrointestinal tract, including irritable bowel syndrome (IBS). Examples of IBD-related disorders include collagenous colitis and lymphocytic colitis.

[0027] The term "ulcerative colitis" or "UC" refers to a chronically remitting and relapsing inflammatory bowel disease (IBD) of the colon or large intestine, characterized by superficial mucosal lesions that spread through the rectum and progress upward. Different types of ulcerative colitis are classified according to the location and degree of inflammation. Examples of UC include, but are not limited to, ulcerative proctitis, proctosigmoiditis, left-sided colitis, and panulcerative (pan) colitis.

[0028] The term "Crohn's disease" or "CD" refers to a chronic inflammatory disease that can involve any part of the gastrointestinal tract. It typically affects the distal portion of the small intestine, i.e., the ileum and cecum. In other cases, the disease is limited to the small intestine, colon, or anorectal region. CD occasionally involves the duodenum and stomach, and more rarely, the esophagus and mouth. Examples of UC include, but are not limited to, ileocolitis, ileitis, gastroduodenal Crohn's disease, jejunoileitis, and Crohn's (granulomatous) colitis.

[0029] The terms "subject," "individual," or "patient" refer to animals such as mammals, including but not limited to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc.

[0030] The terms "CC chemokine receptor type 9," "CCR9," or "CCR9 chemokine receptor" refer to the receptor for the chemokine CCL25, also known as TECK and SCYA25. Human CCR9 polypeptide sequences are described, for example, in GenBank accession numbers NP_001243298, NP_006632, NP_112477, and XP_011531614. Human CCR9 mRNA (coding) sequences are described, for example, in GenBank accession numbers NM_001256369, NM_006641, NM_031200, and XM_011533312.

[0031] The terms "CC chemokine receptor 9 inhibitor," "CCR9 inhibitor," or "CCR9 chemokine receptor inhibitor" refer to an inhibitor or antagonist of a CCR9 receptor polypeptide, a variant thereof, or a fragment thereof.

[0032] The term "small molecule inhibitor" refers to a small molecule or low molecular weight organic compound that inactivates, inhibits, or antagonizes a target molecule, biomolecule, protein, or other biological product.

[0033] The term "anti-IL-23 blocking antibody" or "anti-IL-23 neutralizing antibody" refers to an antibody or fragment thereof that specifically binds to an IL-23 polypeptide or a fragment thereof. Fragments of IL-23 include IL12b and IL23a. In some cases, an IL-23 blocking antibody blocks the interaction of IL-23 with one of its ligands. The term "anti-IL-23R blocking antibody" refers to an antibody or fragment thereof that specifically binds to the IL-23 receptor or a fragment thereof. As used herein, IL-23 is intended to refer to a human cytokine that exists as a heterodimer composed of the subunits IL12b and IL23a. The structure of IL-23 is further described, for example, in Oppmann B, et al., Immunity, November 2000, 13(5):715-725.

[0034] The term "biosimilar" refers to a biological product that is highly similar to an FDA-approved biological product (reference product) and that does not have clinically meaningful differences from the reference product in terms of pharmacokinetics, safety, and efficacy.

[0035] The term "bioequivalent" refers to a biological product that is pharmaceutically equivalent to and has similar bioavailability to an FDA-approved biological product (reference product). For example, according to the FDA, the term bioequivalence is defined as "there is no significant difference in the rate or extent to which the active ingredient or active portion of a pharmaceutical equivalent or pharmaceutical substitute becomes available at the site of drug action when administered at the same molar dose under similar conditions in a well-designed study" (United States Food and Drug Administration, "Guidance for Industry: Bioavailability and Bioequicalence Studies for Orally Administered Drug Products - General Considerations," 2003, Center for Drug Evaluation and Research).

[0036] The term "biobetter" refers to a biological product that is in the same class as, but not identical to, an FDA-approved biological product (the reference product) and that has improvements over the reference product in terms of safety, efficacy, stability, etc.

[0037] The term "therapeutically effective amount" refers to an amount of a therapeutic agent sufficient to ameliorate a targeted condition or symptom. For example, for a given parameter, a therapeutically effective amount may exhibit at least a 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least a 100% increase or decrease. The therapeutic effect may also be expressed as a "fold" increase or decrease. For example, a therapeutically effective amount may have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or greater effect over a control.

[0038] The terms "administering" or "administration" and their derivatives refer to methods that can be used to enable delivery of an agent or composition to a desired site of biological action. These methods include, but are not limited to, parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, intrathecal, intranasal, intravitreal, infusion, and local injection), transmucosal injection, oral administration, administration as a suppository, and topical administration. Those skilled in the art will know additional methods for administering a therapeutically effective amount of a compound of the present invention to prevent or alleviate one or more symptoms associated with a disease.

[0039] The term "treating" or "treatment" refers to the treatment or care of a disease or condition (such as inflammation) in a patient, such as a mammal (particularly a human or animal), and includes ameliorating the disease or condition, i.e., eliminating or causing regression of the disease or condition in the patient, inhibiting the disease or condition, i.e., slowing or arresting the progression of the disease or condition in the patient, or alleviating the symptoms of the disease or condition in the patient. The term encompasses prophylactic treatment of diseases to prevent or reduce the risk of acquiring or developing a particular disease or to prevent or reduce the risk of recurrence of the disease.

[0040] "Alkyl" by itself or as part of another substituent refers to a hydrocarbon radical which may be linear, cyclic, branched, or combinations thereof, having the specified number of carbon atoms (i.e., C 1-8means 1 to 8 carbon atoms). The term "cycloalkyl," by itself or as part of another substituent, refers to a cyclic alkyl group having the specified number of carbons and is a subset of the term "alkyl." Other subsets of the term "alkyl" include "straight-chain" and "branched" alkyl groups, which refer to two different types of acyclic alkyl groups. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, cyclopentyl, (cyclohexyl)methyl, cyclopropylmethyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like. In this list of examples, the methyl, ethyl, n-propyl, and n-butyl alkyl examples are also examples of "straight-chain alkyl" groups. Similarly, isopropyl and t-butyl are also examples of "branched alkyl" groups. Cyclopentyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane are examples of "cycloalkyl" groups. In some embodiments, cyclopropyl may be used as a bridging group between two other moieties and may be represented as -CH(CH)CH-. "Alkyl groups can be substituted or unsubstituted unless otherwise indicated. Examples of substituted alkyls include haloalkyl, thioalkyl, aminoalkyl, and the like. Additional examples of suitable substituted alkyls include, but are not limited to, hydroxy-isopropyl, -C(CH3)2-OH, aminomethyl, 2-nitroethyl, 4-cyanobutyl, 2,3-dichloropentyl, and 3-hydroxy-5-carboxyhexyl, 2-aminoethyl, pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl, ethoxycarbonylmethyl, methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, and pentafluoroethyl. Suitable substituents for substituted alkyl include halogen, -CN, -CO2R', -C(O)R', -C(O)NR'R'', oxo (=O or -O -), -OR', -OC(O)R', -OC(O)NR'R''-NO2, -NR'C(O)R'', -NR'''C(O)NR'R'', -NR'R'', -NR'CO2R'', -NR'S(O)R'', -NR'S(O)2R''', -NR'''S(O)NR'R'', |-NR'''S(O)2NR'R'', -SR', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NR'-C(NHR'')=NR''', -SiR'R”R”', -OSiR'R”R”', -N3, substituted or unsubstituted C 6-10 Examples of substituted alkyl include aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl. The number of possible substituents ranges from zero to (2m'+1), where m' is the total number of carbon atoms in such a group. For substituted alkyl, R', R'', and R''' are each independently hydrogen, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 2-8 Alkenyl, substituted or unsubstituted C 2-8 " refers to a variety of groups, including alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted aryloxyalkyl. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring (e.g., -NR'R" includes 1-pyrrolidinyl and 4-morpholinyl). Furthermore, R' and R", R" and R'", or R' and R'", together with the atom to which they are attached, can form a substituted or unsubstituted 5-, 6-, or 7-membered ring.

[0041] "Alkoxy" refers to -O-alkyl. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, and the like.

[0042] "Alkenyl" refers to an unsaturated hydrocarbon group that can be linear, cyclic, or branched, or a combination thereof. Alkenyl groups having 2 to 8 carbon atoms are preferred. Alkenyl groups can contain one, two, or three carbon-carbon double bonds. Examples of alkenyl groups include ethenyl, n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl, cyclohexenyl, cyclopentenyl, and the like. Alkenyl groups can be substituted or unsubstituted, unless otherwise specified.

[0043] "Alkynyl" refers to an unsaturated hydrocarbon group which may be linear, cyclic, or branched, or a combination thereof. Alkynyl groups having 2 to 8 carbon atoms are preferred. Alkynyl groups may contain one, two, or three carbon-carbon triple bonds. Examples of alkynyl groups include ethynyl, n-propynyl, n-but-2-ynyl, n-hex-3-ynyl, and the like. Alkynyl groups may be substituted or unsubstituted, unless otherwise specified.

[0044] "Alkylamino" refers to -N(alkyl)2 or -NH(alkyl). When an alkylamino group contains two alkyl groups, the alkyl groups may be combined together to form a carbocyclic or heterocyclic ring. It is understood that the alkyl group of an alkylamino group may be substituted or unsubstituted. Examples of alkylamino groups include methylamino, tert-butylamino, dimethylamino, diisopropylamino, morpholino, and the like.

[0045] "Aminoalkyl" as a substituted alkyl group refers to a monoaminoalkyl or polyaminoalkyl group, most typically substituted with one to two amino groups. Examples include aminomethyl, 2-aminoethyl, 2-diethylaminoethyl, and the like.

[0046] "Aryl" refers to a polyvalent unsaturated aromatic hydrocarbon group having a single ring (bicyclic) or multiple rings (preferably bicyclic) that can be fused or covalently linked together. Aryl groups having 6 to 10 carbon atoms are preferred, and this number of carbon atoms can be represented, for example, by C6-10. Examples of aryl groups include phenyl and naphthalen-1-yl, naphthalen-2-yl, biphenyl, and the like. An aryl group can be substituted or unsubstituted unless otherwise indicated. A substituted aryl can be substituted with one or more substituents. Suitable substituents for aryl include substituted or unsubstituted C1-8 alkyl, and the substituents discussed above for substituted alkyl.

[0047] "Halo" or "halogen," by itself or as part of a substituent, refers to a chlorine, bromine, iodine, or fluorine atom.

[0048] "Haloalkyl" as a substituted alkyl group refers to a monohaloalkyl or polyhaloalkyl group that is most typically substituted with 1 to 3 halogen atoms. Examples include 1-chloroethyl, 3-bromopropyl, trifluoromethyl, and the like.

[0049] "Heterocyclyl" refers to a saturated or unsaturated non-aromatic group containing at least one heteroatom (typically 1 to 5 heteroatoms) selected from nitrogen, oxygen, or sulfur. Preferably, these groups contain 0 to 5 nitrogen atoms, 0 to 2 sulfur atoms, and 0 to 2 oxygen atoms. More preferably, these groups contain 0 to 3 nitrogen atoms, 0 to 1 sulfur atoms, and 0 to 1 oxygen atoms. Examples of heterocyclic groups include pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-dioxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, etc. Preferred heterocyclic groups are monocyclic, although they can be fused to or covalently attached to an aryl or heteroaryl ring system.

[0050] Exemplary heterocyclic groups may be represented by the following formula (AA): [ka] Formula (AA) is M 1 or M 2 bonded via one of the free valences of M 1 , O, NR e , or S(O) l represents M 2 is CR f R g , O, S(O) l , or NR e represents R f , R g , or R e You can omit one of them, for example, CR f , C.R. g , or M such as N 1 or M 2 where l is 0, 1, or 2, j is 1, 2, or 3, and k is 1, 2, or 3, provided that j+k is 3, 4, or 5;a , R b , R c , R d , R e , R f , and R g are independently hydrogen, halogen, unsubstituted or substituted C 1-8 Alkyl, unsubstituted or substituted C 2-8 Alkenyl, unsubstituted or substituted C 2-8 Alkynyl, -COR h , -CO2R h , -CONR h R i , -NR h COR i , -SO2R h -SO2NR h R i , -NR h SO2R i -NR h R i , -OR h , -SiR h R i R j , -OSiR h R i R j , -Q 1 COR h , -Q 1 CO2R h , -Q 1 CONR h R i , -Q 1 NR h COR i , -Q 1 SO2R h , -Q 1 SO2NR h R i , -Q 1 NR h SO2R i , -Q 1 NR h R i , -Q 1 OR h and Q is selected from the group consisting of 1 is C 1-4 Alkylene, C 2-4 Alkenylene, and C 2-4alkynylene, and R h , R i , and R j are independently hydrogen and C 1-8 alkyl; R a , R b , R c , R d , R e , R f , R g , R h , R i The aliphatic portion of each of the R substituents is optionally selected from halogen, —OH, —OR n , -OC(O)NHR n , -OC(O)NR n R o , -SH, -SR n , -S(O)R n , -S(O)2R n -S(O)2NHR n , -S(O)NR n R o , -NHS(O)2R n , -NR n S(O)2R o , -C(O)NH2, -C(O)NHR n , -C(O)NR n R o , -C(O)R n , -NHC(O)R o , -NR n C(O)R o , -NHC(O)NH2, -NR n C(O)NH2, -NR n C(O)NHR o , -NHC(O)NHR n , -NR n C(O)NR o R p , -NHC(O)NR n R o , -CO2H, -CO2R n , -NHCO2R n , -NR n CO2R o , -CN, -NO2, -NH2, -NHRn , -NR n R o , -NR n S(O)NH2 and -NR n S(O)2NHR o and R is substituted with one to three members selected from the group consisting of n , R o , and R p are independently unsubstituted C 1-8 In addition, R a , R b , R c , R d , R e , R f , and R g Any two of may be joined to form a bridged or spiro ring system.

[0051] Preferably, R is other than hydrogen. a +R b +R c +R d The number of groups is 0, 1, or 2. More preferably, R a , R b , R c , R d , R e , R f , and R g are independently hydrogen, halogen, unsubstituted or substituted C 1-8 Alkyl, -C(O)R h , -CO2R h , -C(O)NR h R h , -NR h COR i , -SO2R h , -SO2NR h R i , -NSO2R h R i , -NR h R i , and -OR h and R h and R i are independently hydrogen and unsubstituted C 1-8alkyl; R a , R b , R c , R d , R e , R f , and R g The aliphatic portion of each of the substituents may optionally be selected from the group consisting of halogen, —OH, —OR n , -OC(O)NHR n , -OC(O)NR n R o , -SH, -SR n , -S(O)R o , -SO2R n , -SO2NH2, -SO2NHR n , -SO2NR n OR o , -NHSO2R n , -NR n SO2R o , -C(O)NH2, -C(O)NHR n , -C(O)NR n R o , -C(O)R n , -NHC(O)R n , -NR n C(O)R o , -NHC(O)NH2, -NR n C(O)NH2, -NR n C(O)NHR o , -NHC(O)NHR n , -NR n C(O)NR n R o , -NHC(O)NR n R o , -CO2H, -CO2R n , -NHCO2R n , -NR n CO2R o , -CN, -NO2, -NH2, -NHR n , -NR n R o , -NR n S(O)NH2 and -NR n S(O)2NHRo and R is substituted with one to three members selected from the group consisting of n , R o , and R p are independently unsubstituted C 1-8 It is alkyl.

[0052] More preferably, Ra, Rb, Rc, Rd, Re, Rf, and Rg are independently hydrogen or In another preferred embodiment, at least three of Ra, Rb, Rc, Rd, Re, Rf, and Rg are hydrogen.

[0053] "Heteroaryl" refers to an aromatic group containing at least one heteroatom. Examples include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, or thienyl. Preferred heteroaryl groups are those having at least one aryl ring nitrogen atom, such as quinolinyl, quinoxalinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzothiazolyl, indolyl, quinolyl, isoquinolyl, etc. Preferred six-ring heteroaryl systems include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, etc. Preferred five-ring heteroaryl systems include isothiazolyl, pyrazolyl, imidazolyl, thienyl, furyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, thiazolyl, etc.

[0054] Heterocyclyl and heteroaryl can be bonded at any available ring carbon or heteroatom. Each heterocyclyl and heteroaryl can have one or more rings. When multiple rings are present, they can be fused or covalently linked together. Each heterocyclyl and heteroaryl must contain at least one heteroatom (typically 1 to 5 heteroatoms) selected from nitrogen, oxygen, or sulfur. Preferably, these groups contain 0 to 5 nitrogen atoms, 0 to 2 sulfur atoms, and 0 to 2 oxygen atoms. More preferably, these groups contain 0 to 3 nitrogen atoms, 0 to 1 sulfur atom, and 0 to 1 oxygen atom. Heterocyclyl and heteroaryl groups can be substituted or unsubstituted unless otherwise specified. For substituents, the substitution can be on a carbon or heteroatom. For example, if the substitution is oxo (=O or O-), the resulting group can have either a carbonyl (-C(O)-) or an N-oxide (-N+-O-) or -S(O)- or -S(O)2-.

[0055] Suitable substituents for substituted alkyl, substituted alkenyl, and substituted alkynyl include, in a number ranging from zero to (2m'+1), halogen, -CN, -CO2R', -C(O)R', -C(O)NR'R'', oxo (=O or -O-), -OR′, -OC(O)R′, -OC(O)NR′R″-NO2, -NR′C(O)R″, -NR′″C(O)NR′R″, -NR′R″, -NR'CO2R'', -NR'S(O)2R''', -SR', -S(O)R', -S(O)2R', -S(O)2NR'R'', -SiR'R''R''', -N3, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, and substituted or unsubstituted 3-10 membered heterocyclyl, where m' is the total number of carbon atoms in such group.

[0056] Suitable substituents for substituted aryl, substituted heteroaryl, and substituted heterocyclyl include halogen, -CN, -CO2R', -C(O)R', -C(O)NR'R'', oxo (=O or -O-), -OR′, -OC(O)R′, -OC(O)NR′R″-NO2, -NR′C(O)R″, -NR′C(O)NR''R''', -NR′R″, -NR′CO2R″, -NR′S(O)2R″, -SR′, -S(O)R′, -S(O)2R′, -S(O)2NR′R″, Examples include -NR'-C(NHR")=NR'", -SiR'R"R'", -N3, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, and substituted or unsubstituted 3-10 membered heterocyclyl. The number of possible substituents ranges from zero to the total number of open valences on the aromatic ring system.

[0057] As used above, with respect to substituted alkyl, R', R", and R'" each independently refer to various groups including hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted aryloxyalkyl. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring (e.g., -NR'R" includes 1-pyrrolidinyl and 4-morpholinyl). Furthermore, R' and R", R" and R"", or R' and R"", together with the atom to which they are attached, can form a substituted or unsubstituted 5-, 6-, or 7-membered ring.

[0058] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CH)U-, where T and U are independently -NR""-, -O-, -CH-, or a single bond, and q is an integer from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A'-(CH)B'-, where A' and B' are independently -CH-, -O-, -NR""-, -S-, -S(O)-, -S(O)-, -S(O)NR""-, or a single bond, and r is an integer from 1 to 3. One of the single bonds in the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -(CH)X-(CH)-, where s and t are independently integers from 0 to 3, and X is -O-, -NR""-, -S-, -S(O)-, -S(O)-, or -S(O)NR'-. The substituent R"" in -NR""- and -S(O)NR""- is hydrogen or unsubstituted C alkyl.

[0059] "Heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0060] A "pharmaceutically acceptable" carrier, diluent, or excipient is a carrier, diluent, or excipient compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0061] "Pharmaceutically acceptable salt" refers to a salt acceptable for administration to a patient, such as a mammal (e.g., a salt having acceptable mammalian safety for a given dosing regimen). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids, depending on the particular substituents found on the compounds described herein. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either near or in a suitable inert solvent. Salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, tertiary, and quaternary amines, including substituted amines, cyclic amines, and naturally occurring amines, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either near or in a suitable inert solvent.Salts derived from pharmaceutically acceptable acids include acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, camphosulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glucoronic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like.

[0062] Also included are salts of amino acids such as arginine salts, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge, SM, et al., "Pharmaceutical Salts," J. Pharmaceutical Science, 1977, 66:1-19). Certain specific compounds of the present invention contain both basic and acidic functional groups, which allow the compounds to be converted into either base or acid addition salts.

[0063] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for purposes of this disclosure.

[0064] "Salt thereof" refers to a compound formed when a hydrogen of an acid is replaced by a cation, such as a metal cation or an organic cation. Preferably, the salt is a pharmaceutically acceptable salt, although this is not necessary for salts of intermediate compounds that are not intended for administration to a patient.

[0065] In addition to salt forms, the present invention provides compounds in prodrug form. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration, whereas the parent drug is not. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, including those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example of a prodrug is, but is not limited to, a compound of the present invention that is administered as an ester (the "prodrug"), which is subsequently metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of the compounds of the present invention.

[0066] Prodrugs of the compounds described herein are compounds that easily undergo chemical changes under physiological conditions to provide the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0067] Prodrugs can be prepared by modifying functional groups present in a compound so that the modifications are cleaved to the parent compound either by routine manipulation or in vivo. Prodrugs include compounds in which a hydroxyl, amino, sulfhydryl, or carboxyl group is bonded to any group that cleaves to form the free hydroxyl, amino, sulfhydryl, or carboxyl group, respectively, upon administration to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention. The preparation, selection, and use of prodrugs are described in T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series; "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is incorporated herein by reference in its entirety.

[0068] The compounds of the present invention may exist in the form of their pharmaceutically acceptable metabolites. The term "metabolite" refers to a pharmaceutically acceptable form of a metabolic derivative of a compound of the present invention (or a salt thereof). In some embodiments, a metabolite may be a functional derivative of a compound that is readily convertible into an active compound in vivo. In other embodiments, a metabolite may be an active compound.

[0069] The term "acid isostere," unless otherwise specified, refers to a group that can substitute for a carboxylic acid, having acidic functionality and steric and electronic properties that provide a similar level of activity (or other compound property, such as solubility) to the carboxylic acid. Representative acid isosteres include hydroxamic acids, sulfonic acids, sulfinic acids, sulfonamides, acyl-sulfonamides, phosphonic acids, phosphinic acids, phosphoric acids, tetrazoles, and oxo-oxadiazoles.

[0070] Certain compounds of the present invention can exist in unsolvated forms and solvated forms, including hydrated forms. Generally, both solvated and unsolvated forms are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms (i.e., polymorphs). Generally, all physical forms are equivalent to the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0071] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present invention. The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes such as tritium (H), iodine-125 (I), or carbon-14 (C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0072] The compound of the present invention may contain a detectable label. Detectable labels are a group that can be detected at low concentrations, usually submicromolar, possibly subnanomolar, and in some cases subpicomolar, and can be easily distinguished from other molecules due to differences in molecular properties (e.g., molecular weight, mass-to-charge ratio, radioactivity, redox potential, luminescence, fluorescence, electromagnetic properties, binding properties, etc.). Detectable labels can be detected by spectroscopic, photochemical, biochemical, immunochemical, electrical, magnetic, electromagnetic, optical, or chemical means, etc.

[0073] Hapten labels (e.g., biotin, or labels used in conjunction with a detectable antibody such as a horseradish peroxidase antibody); mass tag labels (e.g., stable isotope labels); radioisotope labels (including 3H, 125I, 35S, 14C, or 32P); metal chelate labels; luminescent labels, including fluorescent labels (such as fluorescein, isothiocyanate, Texas Red, rhodamine, green fluorescent protein), phosphorescent labels, and chemiluminescent labels, typically with a quantum yield greater than 0.1; electroactive and electron transfer labels; coenzymes, organometallic catalysts such as horseradish peroxidase, and acetyltransferases. A wide variety of detectable labels are within the scope of the present invention, including enzyme modulator labels, including alkaline phosphatase and others commonly used in ELISAs; photosensitizer labels; magnetic bead labels, including Dynabeads; colorimetric labels such as colloidal gold, silver, selenium, or other metal and metal sol labels (see U.S. Pat. No. 5,120,643, incorporated herein by reference in its entirety for all purposes), or colored glass or plastic (e.g., polystyrene, polypropylene, latex, etc.) bead labels; and carbon black labels. Patents that teach the use of such detectable labels include U.S. Patent Nos. 3,817,837, 3,850,752, 3,939,350, 3,996,345, 4,277,437, 4,275,149, 4,366,241, 6,312,914, 5,990,479, Nos. 6,207,392, 6,423,551, 6,251,303, 6,306,610, 6,322,901, 6,319,426, 6,326,144, and 6,444,143, which are incorporated by reference herein in their entireties for all purposes.

[0074] Detectable labels are commercially available or can be prepared as known to those skilled in the art. Detectable labels can be covalently attached to compounds using reactive functional groups that can be located at any suitable position. Methods for attaching detectable labels are known to those skilled in the art. When the reactive group is attached to an alkyl or substituted alkyl chain connected to an aryl nucleus, the reactive group can be located at the terminal position of the alkyl chain. III. Detailed Description of the Embodiments A. Treatment of Inflammatory Bowel Disease with Combination Therapy

[0075] The present disclosure provides methods, compositions, and kits based on a combination therapy comprising a CCR9 inhibitor and an anti-IL-23 or anti-IL-23R antibody. This therapy is useful for treating IBD, such as Crohn's disease (CD) and ulcerative colitis (UC), in a subject. The present invention is based, in part, on the unexpected discovery that a synergistic combination of a CCR9 inhibitor and an anti-IL-23 or anti-IL-23R antibody is effective in treating IBD.

[0076] 1. Crohn's disease The compositions, methods, and kits of the present invention can be used in subjects with CD, including all types of CD. The combination therapy of a CCR9 inhibitor and an anti-IL-23 or anti-IL-23R antibody can be administered in an amount effective to induce a clinical response or maintain clinical remission in a subject with CD. In some embodiments, the combination therapy alleviates, reduces, or minimizes the severity of one or more symptoms of CD.

[0077] Symptoms of CD include diarrhea, fever, fatigue, abdominal pain or cramps, bloody stools, sores in the mouth, loss of appetite, weight loss, and perianal disease. Additional symptoms or characteristics of CD can be assessed by endoscopic examinations, such as esophagogastroduodenoscopy, colonoscopy, sigmoidoscopy, endoscopic retrograde cholangiopancreatography, endoscopic ultrasound, and balloon endoscopy, as well as histology of biopsies from the GI tract. Disease severity can be classified as mild to moderate, moderate to severe, and severe / fulminant disease. Additional descriptions of CD can be found, for example, in Lichtenstein et al., Am J Gastroenterol, 2009, 104(2):2465-83.

[0078] The severity of CD and clinical response to combination therapy can be determined using a clinical index such as the Crohn's Disease Activity Index or CDAI (Best et al., Gastroenterology, 1976, 70:439-44). This index is used to quantify the symptoms of patients with CD. The CDAI can be used to define clinical response or remission of CD. The CDAI is composed of eight components, each of which is added (summed) after adjusting for a weighting factor or multiplier. The eight components include the number of liquid stools, abdominal pain, general health status, extraintestinal symptoms, antidiarrheal medications, abdominal mass, hematocrit, and weight. Remission of Crohn's disease is generally defined as a decline or reduction in the CDAI of less than 150 points. Severe disease is typically defined as a value greater than 450 points. In certain embodiments, response to a particular drug therapy in a Crohn's disease patient is defined as a decline in the CDAI of more than 70 points from baseline (week 0 of treatment).

[0079] Clinical indicators such as CDAI can be used to determine whether the combination therapy described herein induces a clinical response or clinical remission in patients with Crohn's disease. In some embodiments, a patient demonstrates a clinical response if their CDAI score decreases by 70 points or more from baseline upon receiving the combination therapy. If their CDAI score decreases to less than 150 points at the end of the induction phase of therapy, the patient is in clinical remission from CD.

[0080] 2. Ulcerative colitis The compositions, methods, and kits of the present invention can be used in subjects with UC, including all types of UC. The combination therapy of a CCR9 inhibitor and an anti-IL-23 or anti-IL-23R antibody can be administered in an amount effective to induce a clinical response or maintain clinical remission in a subject with UC. In some embodiments, the combination therapy alleviates, reduces, or minimizes the severity of one or more symptoms of UC.

[0081] Symptoms of UC include, but are not limited to, diarrhea, abdominal pain and cramps, rectal pain, rectal bleeding, bowel urgency, inability to defecate, weight loss, fatigue, fever, or anemia.The severity of the disease can be classified into mild to moderate, moderate to severe, and severe / fulminant disease.See, for example, Kornbluth et al., Am J Gastroenterol, 2004,99(7):1371-85.

[0082] UC disease activity and response to treatment can be evaluated by quantitative analysis using a composite index scoring system. Generally, clinicians consider at least four factors or variables when evaluating UC disease activity: clinical symptoms, quality of life, endoscopic evaluation, and histological evaluation. For example, the Colitis Activity Index (CAI) is a quantitative measurement that incorporates the following disease symptoms: colon inflammation, diarrhea, abdominal pain and cramps, and bloody stool based on colonoscopy. Standardized endoscopic scoring systems, such as the UC Endoscopic Severity Index (UCEIS), are useful for establishing a patient's disease index score. Other useful disease activity indices include the Mayo Clinic score (see, e.g., Rutgeert et al., N Eng J Med, 2005, 353(23):2462-76) and the modified Mayo Disease Activity Index (MMDAI, see, e.g., Schroeder et al., N Eng J Med, 1987, 317(26):1625-9). The four components used in the Mayo Clinic scoring system include stool (bowel) frequency, rectal bleeding, endoscopic findings, and the physician's overall assessment of disease severity (e.g., daily abdominal discomfort and general well-being).

[0083] Compared to the Mayo Clinic score, the MMDAI includes the removal of "friability" from the endoscopic score of 1. Thus, the presence of friability reflects an endoscopic score of 2 or 3. The MMDAI assesses four subscores (stool frequency, rectal bleeding, endoscopic appearance, and physician's global assessment), each on a scale of 0 to 3, with a maximum total score of 12.

[0084] In some embodiments, a clinical response by a subject with UC to a combination therapy provided herein corresponds to a reduction of 2 or more points from baseline and a reduction of 25% or more from baseline in the MMDAI score, and / or a reduction of 1 or more points from baseline in the rectal bleeding subscore. In other embodiments, a clinical response corresponds to a reduction of 3 or more points and a 30% or more from baseline in the Mayo Clinic score.

[0085] Clinical remission in a subject with UC receiving combination therapy may correspond to a score of 0 for rectal bleeding and a total score of 2 points or less for stool frequency and physician's assessment using the MMDAI subscales. In other embodiments, clinical remission in a subject with UC refers to a Mayo Clinic score of 2 points or less, with no individual subscores (stool frequency, rectal bleeding, endoscopic appearance, and physician's global assessment) greater than 1 point. B. Combination therapy of CCR9 inhibitor and anti-IL-23 antibody

[0086] Provided herein are methods, compositions, and kits that utilize the synergistic effects of a CCR9 inhibitor and an anti-IL-23 or anti-IL-23R antibody in reducing inflammation in subjects with IBD. A combination treatment including both a CCR9 inhibitor and an anti-IL-23 or anti-IL-23R antibody is more effective in treating one or more symptoms of IBD compared to either compound / antibody alone.

[0087] 1. Chemokine receptor type 9 (CCR9) inhibitors The present invention provides compounds that modulate CCR9 activity. Specifically, the present invention provides compounds with anti-inflammatory or immunomodulatory activity. The compounds of the present invention are believed to interfere with inappropriate T cell trafficking by specifically modulating or inhibiting chemokine receptor function. Chemokine receptors are integral membrane proteins that interact with extracellular ligands, such as chemokines, and mediate cellular responses to the ligands, such as chemotaxis and increases in intracellular calcium ion concentration. Therefore, modulation of chemokine receptor function, for example, interference with chemokine receptor-ligand interaction, can not only inhibit or reduce chemokine receptor-mediated responses, but also treat or prevent chemokine receptor-mediated conditions or diseases.

[0088] Without being bound by any particular theory, it is believed that the compounds provided herein interfere with the interaction between CCR9 and its ligand CCL25.For example, the compounds of the present invention act as potent CCR9 antagonists, and this antagonist activity has been further confirmed in animal tests for inflammation, one of the pathologies characteristic of CCR9.Compounds contemplated by the present invention include, but are not limited to, the exemplary compounds provided herein and their salts.

[0089] For example, useful compounds act as potent CCR9 antagonists, and this antagonist activity has been further confirmed in animal studies for inflammation, one of the pathologies characterized by CCR9. Accordingly, the compounds provided herein are useful in pharmaceutical compositions and methods for the treatment of inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease.

[0090] In some embodiments, the CCR9 small molecule inhibitors provided herein can be represented by formula (I): [ka] In the formula, X 1 , X 2 , X 3 , X 4 , X 5 are each independently hydrogen, halogen, -CN, -NO2, -OR 1a , -C(O)R 1a , -CO2R 1a , -O(CO)R 1a , -OC(O)NR 1a R 2a , -SR 1a , -SOR 1a , -SO2R 1a , -NR 1a R 2a , -NR 1a C(O)R 2a , -NR 1a C(O)2R 2a , -NR 1a (CO)NR 1aR 2a , unsubstituted or substituted C 1-8 Alkyl, unsubstituted or substituted C 2-8 Alkenyl, unsubstituted or substituted C 2-8 Alkynyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5- or 6-membered heteroaryl, and unsubstituted or substituted 4- to 7-membered heterocyclyl, provided that X 1 , X 2 , X 3 , X 4 , and X 5 is other than hydrogen.

[0091] R 1a and R 2a are each independently hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, Aryl-C 1-4 Alkyl, aryloxy-C 1-4 Alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocycle, or R 1a and R 2a may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring;

[0092] X 1 , X 2 , X 3 , X 4 , or X 5 But substitution C 1-8 Alkyl, substituted C 2-8 Alkenyl and substituted C 2-8 When it is alkynyl, it is halogen, —CN, ═O, —OC(O)R 1a , -OR 1a , -C(O)R 1a , -CONR 1a R 2a , -NR 2a C(O)R 1a , -CO2R 1a , -NR 1a R 2a, -SR 1a , -S(O)R 1a , -S(O)2R 1a , -NR 1a SO2R 2a , unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, and unsubstituted or substituted heteroaryl. 1-8 Alkyl is halogen, -CN, =O, -OR 1a , -C(O)R 1a , -CONR 1a R 2a , -NR 2a C(O)R 1a , -CO2R 1a , -NR 1a R 2a , -SO2R 1a , unsubstituted or substituted 5- or 6-membered heteroaryl, and 5- or 6-membered unsubstituted or substituted heterocyclyl.

[0093] When X1, X2, X3, X4, or X5 is a substituted C6-10 alkyl, a substituted 5- or 6-membered heteroaryl, or a substituted 4- to 7-membered heterocycle, it is not limited to halogen, —CN, —OR1a, ═O, —OC(O)R1a, It may have 1 to 3 substituents independently selected from the group consisting of -CO2R1a, -C(O)R1a, -CONR1aR2a, -NR2aC(O)R1a, -NR1aR2a, -SR1a, -S(O)R1a, -S(O)2R1a, -NR1aSO2R2a, unsubstituted C1-8 alkyl, and unsubstituted C1-8 haloalkyl.

[0094] When X1, X2, X3, X4, or X5 is a substituted 5- or 6-membered heteroaryl, or a substituted 5- or 6-membered heteroaryl, it preferably has 1 to 3 substituents independently selected from the group consisting of halogen, —OR1a, —C(O)R1a, —CONR1aR2a, —NR2aC(O)R1a, —NR1aR2a, —S02R1a, unsubstituted or substituted C1-8 alkyl, and unsubstituted or substituted C1-8 haloalkyl.

[0095] In one embodiment of Formula (I), at least one of X1, X2, X3, X4, and X5 is other than hydrogen.

[0096] In one embodiment of formula (I), X1 is other than hydrogen and at least two of X2, X3, X4, and X5 are hydrogen. Preferably, at least three of X2, X3, X4, and X5 are hydrogen, and more preferably, X2, X3, X4, and X5 are hydrogen.

[0097] In one embodiment of Formula (I), Y1, Y2, Y3, and Y4 are each independently selected from the group consisting of hydrogen, halogen, —CN, —NO2, —OR3a, —C(O)R3a, —SR3a, —CF3, —SOR3a, —SO2R3a, and substituted or unsubstituted C1-4 alkyl.

[0098] In one embodiment of Formula (I), R3a is independently selected from the group consisting of hydrogen, unsubstituted C1-8 alkyl, unsubstituted C2-8 alkenyl, unsubstituted C2-8 alkynyl, unsubstituted C6-10 aryl, and unsubstituted 5-10 membered heteroaryl.

[0099] In one embodiment of formula (I), L1 is -C(O)-, -S-, -S(O)-, or -S(O)2-. In one embodiment, L1 is preferably -C(O)-. In another embodiment of formula (I), L1 is preferably -S-, -S(O)-, or -S(O)2-.

[0100] In another embodiment of formula (I), when Z1 is substituted phenyl or substituted or unsubstituted 5-membered heteroaryl, L1 is preferably -S-, -S(O)-, or -S(O)2-.

[0101] In one embodiment of Formula (I), Z represents substituted phenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, or substituted 4- to 7-membered heterocyclyl. Suitably, the substituted 5- or 6-membered heteroaryl may have 1 to 3 substituents independently selected from the group consisting of halogen, unsubstituted or substituted C alkyl, unsubstituted or substituted C alkenyl, unsubstituted or substituted C alkynyl, ═O, —CN, —NO, —OR, —OC(O)R, —COR, —C(O)R, —CONR,R, —NRC(O)R, —NR, —SR, —SOR, —SOR, —SONR, —NRSO, unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, and unsubstituted or substituted 4- to 7-membered heterocyclyl. When present, one substituent is preferably positioned ortho to one of the heteroatoms in the ring or is an oxygen atom directly bonded to a ring heteroatom (ie, N-oxide).

[0102] R4a and R5a are each independently selected from the group consisting of hydrogen, unsubstituted C1-8 alkyl, unsubstituted C2-8 alkenyl, unsubstituted C2-8 alkynyl, unsubstituted C6-10 aryl, unsubstituted 5- to 10-membered heteroaryl, and unsubstituted 3- to 10-membered heterocycle.

[0103] In one embodiment of formula (I), Z1 represents substituted phenyl. In one embodiment of any of formula (I), at least one substituent on group Z1 is unsubstituted C1-6 alkyl (especially methyl) or C1-6 haloalkyl (especially -CF3).

[0104] In one embodiment of any of formula (I), Z1 is the following residue: [ka]

[0105] In one embodiment of any of formula (I), Z 1 is selected from one of the following residues: [ka]

[0106] In another embodiment of any of formula (I), Z 1 is selected from one of the following residues: [ka]

[0107] In some embodiments, the CCR9 inhibitors, e.g., CCR9 small molecule inhibitors, of the present disclosure are represented by formula (II) or a salt thereof: [ka] In the formula, R 1 is substituted or unsubstituted C 2-8 Alkyl, substituted or unsubstituted C 1-8 Alkoxy, substituted or unsubstituted C 1-8 Alkylamino, and substituted or unsubstituted C 3-10 heterocyclyl; R 2 is H, F, Cl, or substituted or unsubstituted C 1-8 alkoxy, or R 1 and R 2 together with the carbon atoms to which they are attached form a non-aromatic carbocyclic or heterocyclic ring, R 3 H, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 1-8 alkoxy or halo; R 4 is H or F, R 5 is H, F, Cl, or —CH3; R 6 H, halo, -CN, -CO2R a , -CONH2, -NH2, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 1-8 Alkoxy, or substituted or unsubstituted C 1-8is an aminoalkyl, R a is H, or substituted or unsubstituted C 1-8 is alkyl, R 5 and R 6 may together form a carbocyclic ring, L is a bond, —CH—, or —CH(CH)—; A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 each independently represents N, NO, and -CR 8 - selected from the group consisting of A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 at least one and not more than two of are N or NO; R 8 each independently represents H, halo, —CN, —OH, oxo, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 1-8 Alkoxy, -NR 20 R 21 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; R 20 and R 21 are each independently H or substituted or unsubstituted C 1-8 It is alkyl.

[0108] In some embodiments of Formula (II), one of A1 or A2 is N or NO, and the remainder of A1, A2, A3, A4, A5, A6, A7, and A8 are -CR8-, and each R8 is independently selected.

[0109] In some embodiments, two of A2, A3, A4, and A5 are N or NO, and the remainder of A1, A2, A3, A4, A5, A6, A7, and A8 are -CR8-, and each R8 is independently selected.

[0110] In some embodiments, the compound or composition of Formula (II) is represented by Formula (III) or a salt thereof: [ka] In the formula, R 1 is substituted or unsubstituted C 2-8 Alkyl, substituted or unsubstituted C 1-8 Alkoxy, substituted or unsubstituted C 1-8 Alkylamino, and substituted or unsubstituted C 3-10 heterocyclyl; R 2 is H, F, Cl, or substituted or unsubstituted C 1-8 alkoxy, or R 1 and R 2 together with the carbon atoms to which they are attached form a non-aromatic carbocyclic or heterocyclic ring, R 3 H, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 1-8 alkoxy or halo; R 4 is H or F, R 5 is H, F, Cl, or —CH3; R 6 H, halo, -CN, -CO2R a , -CONH2, -NH2, substituted or unsubstituted C 1-8 Aminoalkyl, substituted or unsubstituted C 1-8 Alkyl, or substituted or unsubstituted C 1-8 It is Alcoshki, R a is H, or substituted or unsubstituted C 1-8 is alkyl, R 5 and R 6may together form a carbocyclic ring, L is a bond, —CH—, or —CH(CH)—; Z, [ka] and N-oxides thereof, wherein the Z group can be unsubstituted or substituted with 1 to 3 independently selected R8 substituents; each R8 independently represents H, halo, -CN, -OH, oxo, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C1-8 alkoxy; -NR20R21, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; R20 and R21 are each independently H, substituted or unsubstituted C1-8 alkyl.

[0111] In some embodiments of Formula (III), Z is selected from the group consisting of substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted 1,6-naphthyridinyl, substituted or unsubstituted cinnolinyl, substituted or unsubstituted phthalazinyl, and substituted or unsubstituted quinazolinyl.

[0112] In one embodiment, the compound or composition of Formula (II) provided herein is represented by Formula (IIIa) or (IIIb), or a salt thereof: [ka] wherein R1 is selected from the group consisting of substituted or unsubstituted C2-8 alkyl, substituted or unsubstituted C1-8 alkoxy, substituted or unsubstituted C1-8 alkylamino, and substituted or unsubstituted C3-10 heterocyclyl; R2 is H, F, Cl, or substituted or unsubstituted C1-8 alkoxy; R1 and R2 together with the carbon atoms to which they are attached form a non-aromatic carbocyclic or heterocyclic ring; R3 is H, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C1-8 alkoxy, or halo; R4 is H or F; R5 is H, F, Cl, or —CH3; R6 is H, halo, -CN, -CO2Ra, -CONH2, -NH2, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C1-8 alkoxy, or substituted or unsubstituted C1-8 aminoalkyl; Ra is H or substituted or unsubstituted C1-8 alkyl; Or R 5 and R 6 together with the carbon atoms to which they are attached to form a carbocyclic ring, Each R 8 are independently H, halo, -CN, -OH, oxo, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 1-8 Alkoxy, -NR 20 R 21 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; R 20 and R 21 are each independently H or substituted or unsubstituted C 1-8 is alkyl, n is 0, 1, 2, or 3.

[0113] In one embodiment of Formula (IIIa) or (IIIb) or a salt thereof, R1 is -CH2CH3, -CH(CH3)2, -C(CH3)3, -C(CH3)2CH2CH3, -C(CH2CH2)CN, -C(OH)(CH3)2, -OCH3, -OCH2CH3, -OCH(CH3)2, -OC(CH3)3, R is selected from the group consisting of -OCHCH(CH), -OCF, and morpholino, and R is H, F, or Cl; or R and R may together form -OC(CH)CH- or -C(CH)CHCH-, and R is H, -CH, or -OCH; R is H or F; R is H; and R is H, -CH, -CHCH, -CH(CH), -C, H, -CHF, -CHF, -CFCH, -CF; and each R is independently selected from the group consisting of H, F, Cl, Br, -CH, -OH, -OCH, -OCHCH, -NH, -N(CH), and -CN. In some instances, R is -C(CH).

[0114] In other embodiments of Formula (IIIa) or Formula (IIIb), R2 is H or F, R3 is H, R4 is H, and R6 is -CH3, -CH2F, -CHF2, or -CF3.

[0115] In one embodiment, the compounds and compositions of formula (IIIa) or (IIIb), or salts thereof, [ka] [ka] is selected from the group consisting of:

[0116] In some embodiments, the CCR9 inhibitors, e.g., CCR9 small molecule inhibitor compounds and compositions provided herein are [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and N-oxides thereof.

[0117] In some embodiments, preferred R 1 The substituents are as follows: In formulas (II, III, IIIa, and IIIb), R 1 is a substituted or unsubstituted C 2-8 Alkyl, substituted or unsubstituted C 1-8 Alkoxy, substituted or unsubstituted C 1-8 Alkylamino, and substituted or unsubstituted C 3-10 R is selected from the group consisting of heterocyclyl. 1 When R is a substituted alkyl, the alkyl group is preferably substituted with halo or hydroxy. 1 When R is a substituted alkoxy, the alkoxy group is preferably substituted with halo. 1 is C 3-8 Cycloalkyl, C 2-8 Haloalkyl, C 1-8 Hydroxyalkyl, unsubstituted C 1-8 Alkoxy, C 1-8 Haloalkoxy, and C 1-8 Unsubstituted C, including alkylamino 2-8 alkyl, more preferably unsubstituted C 2-8 Alkyl, C 2-8 Haloalkyl, unsubstituted C 1-8 Alkoxy, and C 1-8alkylamino, and even more preferably unsubstituted C 2-8 Alkyl, unsubstituted C 1-8 Alkoxy, and morpholino, and even more preferably unsubstituted C 2-8 and most preferably t-butyl.

[0118] In some embodiments, preferred R6 substituents are as follows: In formulas (II, III, IIIa, and IIIb), R6 is H, halo, -CN, -CO2Ra, -CONH2, -NH2, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C1-8 alkoxy, or substituted or unsubstituted C1-8 aminoalkyl. When R6 is substituted alkyl, the alkyl group is preferably substituted with halo, hydroxy, alkoxy, or cyano. Preferably, R6 is -CN, -CONH2, -NH2, unsubstituted C1-8 alkyl, unsubstituted C1-8 haloalkyl, and unsubstituted C1-8 alkoxy, more preferably unsubstituted C1-8 alkyl or unsubstituted C1-8 haloalkyl, even more preferably unsubstituted C1-8 alkyl, and most preferably methyl.

[0119] In one embodiment, the CCR9 small molecule inhibitor is Compound 1. [ka]

[0120] In one embodiment, the CCR9 small molecule inhibitor is Compound 2. [ka]

[0121] In one embodiment, the CCR9 small molecule inhibitor is compound 3. [ka]

[0122] In one embodiment, the CCR9 small molecule inhibitor is compound 4. [ka]

[0123] Detailed descriptions of the CCR9 inhibitor compounds provided herein and methods for preparing such compounds can be found, for example, in U.S. Pat. No. 6,939,885, U.S. Pat. No. 8,916,601, and U.S. Patent Application Publication Nos. 2013 / 0267492, 2013 / 0059893, 2012 / 0245138, 2012 / 0165303, and 2011 / 00 21523, 2010 / 0331302, 2010 / 0227902, 2010 / 0190762, 2010 / 0152186, 2010 / 0056509, 2009 / 0163498, and 2009 / 0005410, the disclosures of which are incorporated herein by reference in their entireties for all purposes.

[0124] The compounds provided herein can be synthesized using a variety of standard organic chemical transformations. Certain general reaction types that are widely used to synthesize target compounds in the present invention are summarized in the Examples. Specifically, general procedures for sulfonamide formation and aza-aryl N-oxide formation are described and routinely used.

[0125] Although not intended to be exhaustive, representative synthetic organic transformations that can be used to prepare compounds of the present invention are included herein. These include standard functional group manipulations, such as nitro to amino reduction, oxidation of functional groups including alcohols and aza-aryls, aryl substitution by IPSO or other mechanisms to introduce various groups including nitriles, methyls, and halogens, introduction and removal of protecting groups, Grignard formation and reaction with electrophiles, metal-mediated cross-coupling reactions including, but not limited to, Bückwald, Suzuki, and Sonigashira reactions, halogenation and other electrophilic aromatic substitution reactions, formation and reaction of diazonium salts of these species, etherification, cyclic condensation, dehydration, oxidation, and reduction leading to heteroaryl groups, arylmetallation and transmetallation, and subsequent reaction of arylmetal species with electrophiles such as acid chlorides or Weinreb amides, amidation, esterification, nucleophilic substitution reactions, alkylation, acylation, sulfonamide formation, chlorosulfonylation, ester and related hydrolysis, etc.

[0126] Certain molecules claimed in this patent can exist in different enantiomeric and diastereomeric forms, and all such variants of these compounds are within the scope of the present invention.

[0127] In the synthetic descriptions that follow, some precursors were obtained from commercial sources, including Aldrich Chemical Co., Acros Organics, Ryan Scientific Incorporated, Oakwood Products Incorporated, Lancaster Chemicals, Sigma Chemical Co., Lancaster Chemical Co., TCI-America, Alfa Aesar, Davos Chemicals, and GFS Chemicals.

[0128] 2. Pharmaceutical formulations of CCR9 inhibitors In another aspect, the present disclosure provides compositions or formulations for modulating CCR9 activity. Generally, compositions or formulations for modulating chemokine receptor activity in a subject, such as a human or animal, will include a compound provided herein and a pharmaceutically acceptable excipient or diluent.

[0129] As used herein, the term "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from combining the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0130] The pharmaceutical composition for administering the compound of the present invention can be conveniently presented in unit dosage form, and can be prepared by any method known in the pharmaceutical arts.All methods include the step of associating the active ingredient with the carrier, which constitutes one or more accessory ingredients.Generally, pharmaceutical compositions are prepared by uniformly and intimately associating the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.In pharmaceutical compositions, the active substance compound is contained in an amount sufficient to produce the desired effect on the process or condition of disease.

[0131] In some embodiments, the CCR9 inhibitor of the present disclosure is a pharmaceutical compound having a crystalline form.Non-limiting examples of such crystalline forms of CCR9 inhibitors are described, for example, in U.S. Patent No. 9,133,124, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0132] Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions and self-emulsifying formulations described in U.S. Pat. No. 6,451,399, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically elegant and palatable preparation. Tablets contain the active ingredient mixed with other non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as PVP, cellulose, PEG, starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated, or they may be enterally or otherwise coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. They may also be coated by the techniques described in U.S. Patent Nos. 4,256,108, 4,166,452, and 4,265,874 to form osmotic therapeutic tablets for controlled release.

[0133] The preparation for oral use can also be presented as a hard gelatin capsule, in which active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or as a soft gelatin capsule, in which active ingredient is mixed with water or oil medium, such as peanut oil, liquid paraffin or olive oil.In addition, emulsion can be prepared with non-water-miscible ingredients such as oil, and stabilized with surfactants such as mono-diglycerides, PEG esters, etc.

[0134] Aqueous suspensions contain the active substance in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth, and gum arabic, and dispersing or wetting agents may be naturally occurring phospholipids, such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0135] Oily suspensions can be formulated by suspending the active ingredient in vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in mineral oil such as liquid paraffin.Oily suspensions can contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol.Sweeteners such as those mentioned above and flavoring agents can be added to provide a palatable oral preparation.These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0136] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring, and coloring agents, may also be present.

[0137] The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring gums, such as gum arabic or gum tragacanth, naturally occurring phospholipids, such as soybeans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide, such as polyoxyethylenesorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents.

[0138] Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain demulcents, preservatives, and flavoring and coloring agents. Oral solutions may be prepared in combination with, for example, cyclodextrin, PEG, and surfactants.

[0139] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, axed oils are conventionally used as solvents or suspending media. For this purpose, any sterile, fixed oil may be used, including synthetic mono- or diglycerides. Additionally, fatty acids such as oleic acid are used in the preparation of injectables.

[0140] The compounds disclosed herein can also be administered in the form of suppositories for rectal administration of drugs.These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at normal temperature but liquid at rectal temperature, thereby dissolving in the rectum and releasing the drug.Such materials include cocoa butter and polyethylene glycol.In addition, the compounds can be administered via ocular delivery by solution or ointment.Furthermore, transdermal delivery of the target compounds can be achieved by iontophoresis patches and the like.

[0141] For topical use, creams, ointments, jellies, solutions or suspensions containing the compounds of the present invention are employed. As used herein, topical application is also intended to include the use of mouthwashes and rinses.

[0142] The pharmaceutical compositions and methods of the present invention may further comprise other therapeutically active compounds as described herein, such as those indicated for the treatment of the above-mentioned pathological conditions.

[0143] 3. Anti-IL-23 blocking antibody Anti-IL-23 antibodies suitable for use in treating inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis, include antibodies from any desired source that inhibit the binding of IL-23 to any one of its ligands. Anti-IL-23R antibodies bind to the IL-23 receptor or a fragment thereof. Anti-IL-23 or anti-IL-23R antibodies can be engineered antibodies, such as human antibodies, murine antibodies, rabbit antibodies, chimeric antibodies, humanized antibodies, and antigen-binding fragments of antibodies, such as Fab, Fv, scFv, Fab', and F(ab')2 fragments.

[0144] Non-limiting examples of anti-IL-23 antibodies for use in the methods or compositions described herein include risankizumab, guselkumab (TREMFYA®), ustekinumab, briakinumab, brazikumab, mirikizumab, tildrakizumab, or biosimilars, biobetters, or bioequivalents thereof. Additional useful anti-IL-23 antibodies include bioequivalents, biosimilars, and biobetters of any of the anti-IL-23 antibodies described herein. In some embodiments, the anti-IL-23 blocking antibody is risankizumab. In some embodiments, the anti-IL-23 blocking antibody is guselkumab. In some embodiments, the anti-IL-23 blocking antibody is ustekinumab. In some embodiments, the anti-IL-23 blocking antibody is briakinumab. In some embodiments, the anti-IL-23R blocking antibody is brazikumab. In some embodiments, the anti-IL-23 blocking antibody is mirikizumab. In some embodiments, the anti-IL-23 blocking antibody is tildrakizumab.

[0145] In some embodiments, an anti-IL-23 antibody of the disclosure is an antibody having an amino acid sequence with at least 70%, at least 80%, at least 90%, at least 95%, or more sequence identity to an anti-IL-23 reference antibody, such as risankizumab, or other anti-IL-23 antibodies known to those of skill in the art. In some embodiments, an anti-IL-23R antibody of the disclosure is an antibody having an amino acid sequence with at least 70%, at least 80%, at least 90%, at least 95%, or more sequence identity to an anti-IL-23R reference antibody, such as brazikumab, or other anti-IL-23R antibodies known to those of skill in the art. In some cases, the antibody variant has one or more amino acid substitutions, deletions, and / or additions at certain amino acid positions of the reference antibody, but retains antigen-binding activity.

[0146] Those skilled in the art will recognize that "percent sequence identity" can be determined by comparing two optimally aligned sequences over a comparison window, or designated region of the sequences, where the portion of the polypeptide sequence within the comparison window may contain additions or deletions (i.e., gaps) compared to the reference sequence (which does not contain additions or deletions) due to optimal alignment of the two sequences. The percentage can be calculated by determining the number of positions where identical nucleic acid bases or amino acid residues occur in both sequences to calculate the number of matching positions, dividing the number of matching positions by the total number of positions within the comparison window, and multiplying the result by 100 to calculate the percentage sequence identity. Percent sequence identity can be measured using the BLAST or BLAST 2.0 sequence comparison algorithm, using default parameters, or by manual alignment and visual inspection.

[0147] Antibodies, fragments thereof, variants thereof, and derivatives thereof can be produced using a variety of standard methods recognized by those skilled in the art. See, for example, Harlow, E. and Lane, D.P., Antibodies: A Laboratory Manual. Cold Spring Harbor Laboratory Press, 1988. Antigen-binding fragments, such as Fab and F(ab')2 fragments, can be produced by genetic engineering. Procedures for producing chimeric and further engineered monoclonal antibodies include those described in Riechmann et al., Nature, 1988, 332:323; Liu et al., Proc. Nat. Acad. Sci. USA, 1987, 84:3439; Larrick et al., Bio / Technology, 1989, 7:934; and Winter et al., TIPS, 1993, 14:139. Examples of techniques for the production and use of transgenic animals to produce human or partially human antibodies are described, for example, in Davis et al., 2003, Production of human antibodies from transgenic mice in Lo, ed. Antibody Engineering Methods and Protocols, Humana Press, NJ:191-200.

[0148] 4. Pharmaceutical preparations of anti-IL-23 antibodies Provided herein are formulations of anti-IL-23 or anti-IL-23R antibodies that can stabilize the antibody, reduce antibody aggregate formation, slow antibody degradation, and / or minimize antibody immunogenicity. The formulations may include an antioxidant or chelating agent, at least one free amino acid, a surfactant, a non-reducing sugar, and / or a buffering agent.

[0149] The antioxidant or chelating agent can be citrate, ethylenediaminetetraacetic acid (EDTA), ethyleneglycoltetraacetic acid (EGTA), dimercaprol, diethylenetriaminepentaacetic acid, or N,N-bis(carboxymethyl)glycine, preferably citrate or EDTA. The free amino acids can be histidine, alanine, arginine, glycine, glutamic acid, and combinations thereof. Surfactants include polysorbate 20; polysorbate 80; TRITON (t-octylphenoxypolyethoxyethanol), a nonionic detergent; sodium dodecyl sulfate (SDS); sodium lauryl sulfate; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl-, or stearyl-sarcosine; linoleyl-, myristyl-, or cetyl-betaine; lauramidopropyl-, cocamidopropyl-, linoleamidopropyl-, myristate. Stamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (e.g., lauroamidopropyl); myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine; sodium cocoyl methyl taurate or disodium oleyl methyl taurate; sorbitan monopalmitate; polyethyl glycol (PEG), polypropylene glycol (PPG), and copolymers of poloxyethylene and poloxypropylene glycol; preferably polysorbate 80.

[0150] The buffering agent can be one capable of adjusting the pH of the formulation to about 5.0 to about 7.5, about pH 5.5 to about 7.5, about pH 6.0 to about 7.0, or about pH 6.3 to about 6.5. Non-limiting examples of buffering agents include acetate, succinate, gluconate, histidine, citrate, phosphate, maleate, cacodylate, 2-[N-morpholino]ethanesulfonic acid (MES), bis(2-hydroxyethyl)iminotris[hydroxymethyl]methane (bis-tris), N-[2-acetamido]-2-iminodiacetic acid (ADA), glycylglycine, and other organic acid buffers, preferably histidine or citrate.

[0151] In some embodiments, the anti-IL-23 or anti-IL-23R antibody is a lyophilized formulation, e.g., in a dry form. Optionally, the lyophilized formulation comprises the antibody and one or more excipients, e.g., a non-reducing sugar, a buffer, a free amino acid, and / or a surfactant.

[0152] In some cases, the lyophilized formulation contains at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, at least about 120 mg, at least about 140 mg, at least about 180 mg, at least about 200 mg, at least about 220 mg, at least about 240 mg, at least about 280 mg, at least about 300 mg, at least about 400 mg, at least about 500 mg, at least about 600 mg, at least about 700 mg, at least about 800 mg, or at least about 900 mg of antibody. In some cases, the lyophilized formulation is stored as a single dose in a single vial.

[0153] In some embodiments, the anti-IL-23 or anti-IL-23R antibody is in a liquid formulation. Such a formulation may include an antibody, a buffer, a non-reducing sugar, and / or a free amino acid.

[0154] The amount of antibody present in the liquid formulation can be at least about 25 mg / ml to about 200 mg / ml of anti-IL-23 antibody, for example, 25 mg / ml to about 200 mg / ml, 25 mg / ml to about 150 mg, 25 mg / ml to about 100 mg / ml, 50 mg / ml to about 200 mg / ml, 50 mg / ml to about 150 mg / ml, 50 mg / ml to about 100 mg / ml, 100 mg / ml to about 200 mg / ml, or 150 mg / ml to about 200 mg / ml of antibody.

[0155] The non-reducing sugar can be, but is not limited to, mannitol, sorbitol, sucrose, trehalose, raffinose, stachyose, melezitose, dextran, maltitol, lactitol, isomaltulose, palatinite, and combinations thereof. In some embodiments, the ratio of non-reducing sugar to anti-IL-23 antibody is at least 400:1 (mol:mol), at least 400:1 (mol:mol), at least 400:1 (mol:mol), at least 600:1 (mol:mol), at least 625:1 (mol:mol), at least 650:1 (mol:mol), at least 700:1 (mol:mol), at least 750:1 (mol:mol), at least 800:1 (mol:mol), at least 10 ... 1 (mol:mol), at least 1100:1 (mol:mol), at least 1200:1 (mol:mol), at least 1300:1 (mol:mol), at least 1400:1 (mol:mol), at least 1500:1 (mol:mol), at least 1600:1 (mol:mol), at least 1700:1 (mol:mol), at least 1800:1 (mol:mol), at least 1900:1 (mol:mol), or at least 2000:1 (mol:mol). C. Methods of Administration of Combination Therapy

[0156] In another aspect, the present disclosure provides a combination therapy for the treatment of IBD, e.g., CD and UC. The combination therapy comprises a therapeutically effective amount of a CCR9 inhibitor and a therapeutically effective amount of an anti-IL-23 or anti-IL-23R blocking antibody. The combination of therapeutic agents can act synergistically to treat or prevent various disorders. Using this approach, therapeutic efficacy can be achieved with lower doses of each agent, thereby reducing the potential for adverse side effects.

[0157] The term "therapeutically effective amount" means an amount of a subject compound that elicits the biological or medical response in a cell, tissue, system, or animal, such as a human, that is desired by a researcher, veterinarian, physician, or other medical provider.

[0158] Depending on the disease state and the condition of the subject, the compounds, antibodies, and formulations of the present disclosure can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical routes of administration. Furthermore, the compounds and antibodies, alone or together, can be formulated in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate for each administration route. The present disclosure also contemplates administration of the compounds and antibodies of the present disclosure in depot formulations.

[0159] In the treatment of IBD, such as Crohn's disease and UC, appropriate dosage levels of CCR9 inhibitors are generally about 0.001 to 100 mg / kg of patient body weight per day, which can be administered in single or multiple doses. Preferably, dosage levels are about 0.01 to about 50 mg / kg per day, more preferably about 0.05 to about 10 mg / kg per day. Suitable dosage levels may be about 0.01 to 50 mg / kg per day, about 0.05 to 10 mg / kg per day, or about 0.1 to 5 mg / kg per day. Within this range, dosages may be 0.005 to 0.05 mg / kg per day, 0.05 to 0.5 mg / kg per day, 0.5 to 5.0 mg / kg per day, or 5.0 to 50 mg / kg per day.

[0160] For oral administration, the CCR9 inhibitors are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of active ingredient, particularly 1.0 mg, 5.0 mg, 10.0 mg, 15.0 mg, 20.0 mg, 25.0 mg, 50.0 mg, 75.0 mg, 100.0 mg, 150.0 mg, 200.0 mg, 250.0 mg, 300.0 mg, 400.0 mg, 500.0 mg, 600.0 mg, 750.0 mg, 800.0 mg, 900.0 mg, and 1000.0 mg of active ingredient for symptomatic adjustment of dosage to the patient being treated.

[0161] The CCR9 inhibitor may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

[0162] In the treatment of IBD, such as Crohn's disease and UC, an appropriate dosage level of an anti-IL-23 or anti-IL-23R antibody provides an amount of the antibody or a formulation thereof effective to induce remission of IBD in a human patient. In some embodiments, a therapeutically effective amount of an anti-IL-23 or anti-IL-23R antibody is sufficient to achieve a mean trough serum concentration of the antibody at the end of the induction period of about 5 μg / ml to about 60 μg / ml, e.g., a mean trough serum concentration of the anti-IL-23 or anti-IL-23R antibody at the end of the induction period of about 5 μg / ml to about 60 μg / ml, about 10 μg / ml to about 50 μg / ml, about 15 μg / ml to about 45 μg / ml, about 20 μg / ml to about 30 μg / ml, about 25 μg / ml to about 35 μg / ml, or about 30 μg / ml to about 60 μg / ml.

[0163] Suitable dosages of antibodies can be administered at about 0.1 mg / kg, about 0.3 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg.

[0164] In some embodiments, the total dose is about 6 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 650 mg, or more. In some embodiments, the antibody is administered by subcutaneous injection with an initial dose of about 400 mg given as two subcutaneous injections of 200 mg. In some embodiments, the antibody is administered at weeks 2 and 4, and if a response occurs, 400 mg of the antibody is administered every four weeks.

[0165] In some embodiments, the induction phase is at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, or at least about 10 weeks of treatment.

[0166] The treatment regime during the induction phase can include high-dose administration, frequent administration, or a combination of high-dose and frequent administration of the anti-IL-23 antibody or formulation thereof. Optionally, during the induction phase, the dose is administered once per day, every other day, every third day, every third day, once per week, every 10 days, once every two weeks, once every three weeks, or once per month.

[0167] In some embodiments, induction doses are provided once at the start of treatment (day 0) and approximately once every two weeks after the start of treatment. The duration of the induction phase can be six weeks. In other embodiments, the duration of the induction phase is six weeks, with multiple induction doses administered during the first two weeks. For example, if a human patient has severe IBD or has not responded to anti-IL-23 therapy, the induction phase will be longer in duration than in patients with mild to moderate IBD.

[0168] Furthermore, in the treatment of IBD, an appropriate dosage level of an anti-IL-23 antibody provides an amount of the antibody or a formulation thereof effective to maintain remission of IBD in a human patient. Thus, during the maintenance phase of treatment, a therapeutically effective amount of an anti-IL-23 or anti-IL-23R antibody provides a mean steady-state trough serum concentration of the anti-IL-23 or anti-IL-23R antibody of about 1 μg / ml to about 25 μg / ml during the maintenance phase, e.g., about 1 μg / ml to about 25 μg / ml, about 1 μg / ml to about 20 μg / ml, about 1 μg / ml to about 15 μg / ml, about 1 μg / ml to about 10 μg / ml, or about 1 μg / ml to about 5 μg / ml of the anti-IL-23 or anti-IL-23R antibody at the end of the induction phase. is sufficient to achieve a mean steady-state trough serum concentration of about 5 μg / ml to about 25 μg / ml, about 5 μg / ml to about 20 μg / ml, about 5 μg / ml to about 15 μg / ml, about 5 μg / ml to about 10 μg / ml, about 15 μg / ml to about 25 μg / ml, about 15 μg / ml to about 20 μg / ml, about 10 μg / ml to about 25 μg / ml, about 10 μg / ml to about 20 μg / ml, about 10 μg / ml to about 15 μg / ml, or about 20 μg / ml to about 25 μg / ml.

[0169] The maintenance dose can be administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, or once every ten weeks. In some embodiments during the maintenance phase, the same dosage is administered. In other embodiments during the maintenance phase, one or more different dosages are administered throughout the maintenance phase. In addition, the frequency of administration can be increased depending on the progression of the disease.

[0170] An anti-IL-23 or anti-IL-23R antibody or formulation thereof can be administered by injection, e.g., intravenous, intramuscular, subcutaneous, intraarterial, intraperitoneal, intravitreal, etc. If the formulation is in solid or lyophilized form, the process of administering the antibody may include reconstituting the dried formulation into a liquid formulation. In some embodiments, the antibody or formulation thereof may be administered topically, e.g., with a patch, cream, aerosol, or suppository. In other embodiments, topical administration routes include intranasal, inhalation, or transdermal administration.

[0171] It will be understood, however, that the specific dose level and frequency of administration for any particular patient may vary and will depend upon a variety of factors including the activity of the particular compound employed, the metabolic stability and length of action of that compound, age, body weight, genetic characteristics, general health, sex, diet, method and time of administration, rate of excretion, drug combination, severity of the particular condition, and the host undergoing therapy.

[0172] The weight ratio of a CCR9 inhibitor described herein to an anti-IL-23 or anti-IL-23R antibody of the present disclosure can vary and will depend on the effective dose of each component. Generally, an effective dose of each will be used. Thus, for example, when a CCR9 inhibitor is combined with an anti-IL-23 antibody, the weight ratio of the CCR9 inhibitor to the anti-IL-23 antibody will generally be in the range of about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200.

[0173] Combination therapy includes simultaneous administration of a CCR9 inhibitor and an anti-IL-23 antibody, sequential administration of a CCR9 inhibitor and an anti-IL-23 antibody, administration of a composition comprising a CCR9 inhibitor and an anti-IL-23 antibody, or simultaneous administration of separate compositions, such as one composition comprising a CCR9 inhibitor and another composition comprising an anti-IL-23 antibody.

[0174] Co-administration includes administering the CCR9 inhibitor of the present invention within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of the anti-IL-23 antibody of the present invention. Co-administration also includes administration simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. Furthermore, the CCR9 inhibitor and anti-IL-23 antibody can each be administered once daily, or two, three, or more times per day to provide a preferred daily dosage level.

[0175] The combination therapy can be administered during the induction or maintenance phase of a treatment regimen. During the induction phase, the combination therapy can be administered in an amount effective to induce immune tolerance to the antibodies of the therapy, induce a clinical response, and / or improve one or more symptoms of IBD. Also, during the maintenance phase, if one or more symptoms of IBD return or relapse from disease remission, the patient can be administered an amount corresponding to the treatment during the induction phase. During the maintenance phase, the combination therapy can be administered in an amount effective to continue the response achieved during induction therapy and / or to prevent the return or relapse of IBD symptoms.

[0176] In some embodiments, one or more additional active ingredients such as anti-inflammatory compounds, e.g., sulfasalazine, azathioprine, 6-mercaptopurine, 5-aminosalicylic acid containing anti-inflammatory agents, nonsteroidal anti-inflammatory compounds, and steroidal anti-inflammatory compounds; antibiotics commonly administered for the control of IBD, e.g., ciprofloxacin and metronidazole; or another biologic agent, e.g., a TNFα antagonist, can be administered in conjunction with the combination therapies disclosed herein. D. Kit

[0177] In some aspects, provided herein are kits comprising a CCR9 inhibitor and an anti-IL-23 or anti-IL-23R antibody disclosed herein, which are useful for treating diseases or disorders characterized by inflammation of the gastrointestinal tract, such as CD, UC, and IBD, including undifferentiated colitis. The kit may include a pharmaceutical composition comprising a CCR9 inhibitor compound, e.g., a small molecule inhibitor of CCR9, and a pharmaceutical composition comprising an anti-IL-23 or anti-IL-23R antibody. In some embodiments, the CCR9 inhibitor compound is a compound of Formula (I), (II), (III), (IIIa), or (IIIb). In some embodiments, the CCR9 inhibitor compound is Compound 1. In some embodiments, the CCR9 inhibitor compound is Compound 2. In some embodiments, the CCR9 inhibitor compound is Compound 3. In some embodiments, the CCR9 inhibitor compound is Compound 4. Optionally, the kit includes written materials, e.g., instructions for use of the compound, antibody, or pharmaceutical composition thereof. Without limitation, kits may include buffers, diluents, filters, needles, syringes, and package inserts containing instructions for practicing any of the methods disclosed herein.

[0178] IV. Working Examples The following examples are offered to illustrate, but not to limit, the claimed invention. Example 1: Piroxicam accelerated MDR1a in colitis - / - Model

[0179] Mice of the FVB strain that lack a functional MDR1 gene (also known as ABCB1, P-gp, or CD243) develop spontaneous inflammatory bowel disease. This disease can be accelerated by adding the drug piroxicam to their diet. FVB mice with a functional MDR1 gene are resistant to the disease.

[0180] Piroxicam will be included in the mice's diet for 10 days, and their health will be monitored both during and after piroxicam feeding for a total of 21 days, during which symptoms will include diarrhea severity and weight change.

[0181] Colonic inflammation manifests as thickening of the colon wall and shortening of the colon itself, and therefore the severity of the disease can be assessed by the ratio of colon weight to its length.

[0182] Female 6-week-old FVBMDR1a(+ / +) and FVBMDR1a(- / -) mice were used. Body weight (BW) was normalized when the mice reached 7 weeks of age, at which point their diets were switched to a powdered diet containing piroxicam for a total of 10 days. BW and diarrhea scores were monitored for 21 days (including the 10 days of piroxicam feeding). Blood was collected for trough compound levels on day 3 and at takedown. Rat IgG levels (anti-IL23 or isotype-matched control) were quantified by ELISA at the final blood draw. At takedown, colons were photographed, and weight / length ratios were calculated. Two colons from each group were fixed in formaldehyde for future pathology evaluation and disease scoring. The remaining colons from each group were dissected for flow cytometry analysis of infiltrating immune cells. [Table 1]

[0183] Compound 1 was administered subcutaneously at 90 mg / kg twice daily in 10% Cremophor-EL, and Compound 2 was administered subcutaneously at 30 mg / kg once daily in 1% HPMC. Vehicle 1 was 10% Cremophor-EL and administered subcutaneously twice daily. Vehicle 2 was 1% HPMC and administered subcutaneously once daily. Anti-mouse IL-23 clone G23-8 (rat IgG1) was administered at 300 μg / mouse once daily or every other day, and the isotype-matched control clone HRPN (rat IgG1) was administered at 300 μg / mouse once daily or every other day.

[0184] Trough blood was collected from all mice dosed with Compound 1 and Compound 2, and plasma was analyzed by liquid chromatography-mass spectrometry to determine concentrations. Trough blood was collected on day 3 post-dose (FIG. 1). Groups refer to the names shown in Table I. Trough Compound 1 (left panel) and Compound 2 (right panel) levels met or exceeded the minimum concentration (dotted line) that established 98% receptor coverage.

[0185] Differences in the colonic W:L ratio (i.e., the degree of chronic inflammation) in piroxicam response can be clearly observed between wild-type FVB mice (Fig. 2, open circles) and FVB mice lacking the MDR1a gene (Fig. 2, squares).

[0186] Figure 3 shows that the W:L ratio of mice treated with the combination of Compound 1 and anti-IL-23 was significantly improved from control-treated mice (p=0.0260, inverted triangles), but not in mice receiving anti-IL-23 alone (p=0.0931, triangles).

[0187] Figure 4 shows that the W:L ratio of mice treated with the combination of Compound 2 and anti-IL-23 was significantly improved from control-treated mice (p=0.0190, open inverted triangles), but not for mice receiving anti-IL-23 alone (p=0.2571, open triangles).

[0188] Compounds 1 and 2 synergized with anti-IL-23 to ameliorate colonic inflammation, as only the combination treatment significantly improved the W:L ratio.

[0189] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference.

Claims

1. 1. A pharmaceutical composition for use in treating or alleviating the development of inflammatory bowel disease in a mammal, comprising a suitable amount of a CCR9 inhibitor, The CCR9 inhibitor is a compound having the following structure or a salt thereof: 【Chemistry 1】 Furthermore, the CCR9 inhibitor is administered in combination with an anti-IL-23 antibody or an anti-IL-23 receptor blocking antibody. Pharmaceutical compositions.

2. 2. The pharmaceutical composition for use according to claim 1, wherein the inflammatory bowel disease is Crohn's disease (CD) or ulcerative colitis (UC).

3. 3. The pharmaceutical composition for use according to claim 1 or claim 2, wherein the anti-IL-23 antibody or the anti-IL-23 receptor blocking antibody is risankizumab, guselkumab, ustekinumab, briakinumab, brazikumab, mirikizumab, or tildrakizumab.

4. The pharmaceutical composition for use according to any one of claims 1 to 3, wherein the CCR9 inhibitor and the anti-IL-23 antibody or the anti-IL-23 receptor blocking antibody are administered in a combined formulation.

5. The pharmaceutical composition for use according to any one of claims 1 to 3, wherein the CCR9 inhibitor and the anti-IL-23 antibody or the anti-IL-23 receptor blocking antibody are administered sequentially.

6. The pharmaceutical composition for use according to claim 5, wherein the CCR9 inhibitor is administered before the anti-IL-23 antibody or the anti-IL-23 receptor-blocking antibody.

7. The pharmaceutical composition for use according to claim 5, wherein the CCR9 inhibitor is administered after administration of the anti-IL-23 antibody or the anti-IL-23 receptor-blocking antibody.

8. 1. A composition for use in treating or reducing the incidence of inflammatory bowel disease in a mammal, comprising a therapeutically effective amount of a CCR9 inhibitor; wherein the CCR9 inhibitor is the following compound or a pharmaceutically acceptable salt thereof: 【Chemistry 2】 and a therapeutically effective amount of an anti-IL-23 antibody or an anti-IL-23 receptor-blocking antibody, and a pharmaceutically acceptable carrier or excipient.

9. The composition of claim 8, wherein the anti-IL-23 receptor blocking antibody is infliximab, adalimumab, or golimumab.

10. 1. A kit for treating or ameliorating the development of inflammatory bowel disease in a mammal, said kit comprising a therapeutically effective amount of a CCR9 inhibitor; wherein the CCR9 inhibitor is the following compound or a pharmaceutically acceptable salt thereof: 【Transformation 3】 and a therapeutically effective amount of an anti-IL-23 antibody or an anti-IL-23 receptor-blocking antibody, together with instructions for effective administration.

11. 1. A pharmaceutical composition for use in treating or alleviating the development of inflammatory bowel disease in a mammal, comprising a suitable amount of a CCR9 inhibitor, The CCR9 inhibitor is a compound having the following structure or a salt thereof: 【Chemistry 4】 Furthermore, the CCR9 inhibitor is administered in combination with an anti-IL-23 antibody or an anti-IL-23 receptor blocking antibody. Pharmaceutical compositions.

12. 12. The pharmaceutical composition for use according to claim 11, wherein the inflammatory bowel disease is Crohn's disease (CD) or ulcerative colitis (UC).

13. 13. The pharmaceutical composition for use according to claim 11 or claim 12, wherein the anti-IL-23 antibody or anti-IL-23 receptor blocking antibody is risankizumab, guselkumab, ustekinumab, briakinumab, brazikumab, mirikizumab, or tildrakizumab.

14. The pharmaceutical composition for use according to any one of claims 11 to 13, wherein the CCR9 inhibitor and the anti-IL-23 antibody or anti-IL-23 receptor blocking antibody are administered in a combined formulation.

15. The pharmaceutical composition for use according to any one of claims 11 to 13, wherein the CCR9 inhibitor and the anti-IL-23 antibody or anti-IL-23 receptor blocking antibody are administered sequentially.

16. The pharmaceutical composition for use according to claim 15, wherein the CCR9 inhibitor is administered before the anti-IL-23 antibody or anti-IL-23 receptor-blocking antibody.

17. The pharmaceutical composition for use according to claim 15, wherein the CCR9 inhibitor is administered after administration of the anti-IL-23 antibody or anti-IL-23 receptor-blocking antibody.

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