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 having 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. Also provided herein is a kit comprising a CCR9 inhibitor compound and an anti-IL-23 antibody.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 002,747, filed March 31, 2020, the disclosure of which is incorporated by reference herein in its entirety for all purposes. BACKGROUND

[0003] Inflammatory Bowel Disease (IBD) is a group of chronic inflammatory conditions that affect part or all of the gastrointestinal (GI) tract such as the mouth, esophagus, stomach, small intestine, large intestine (colon), rectum, and anus. IBD includes Crohn’s disease (CD), ulcerative colitis (UC), and indeterminate colitis. CD and UC can be distinguished by clinical, endoscopic, and pathological features.

[0004] 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, rectal urgency, and right lower quadrant swelling.

[0005] UC is a chronic remitting and relapsing inflammatory disease of the colon. The disease is characterized by recurrent episodes of inflammation, primarily involving superficial mucosal lesions passing through the rectum and extending upward through the colon. Acute episodes are characterized by chronic diarrhea or constipation, rectal bleeding, cramping, and abdominal pain.

[0006] IBD is characterized by inflammation and infiltration of white blood cells, such as lymphocytes, granulocytes, monocytes, and macrophages, from the blood into the intestinal mucosa or epithelial layer. Multiple inflammatory cell types, including lymphocytes, neutrophils, macrophages, and dendritic cells, contribute to IBD. For example, T lymphocytes infiltrate the mucosa of the gastrointestinal tract 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 receptor CCR9 and its ligand CCL25, also play a role in the migration of inflammatory cells, such as effector memory T helper cells, to the intestinal epithelium of IBD.

[0007] In summary, it is clear that an effective treatment regimen for IBD that is able to block multiple pathways and / or multiple cell types involved in lymphocyte infiltration into the intestinal tissue would be useful in treating the disease. The present invention provides such therapies as well as pharmaceutical compositions and related methods of treatment. SUMMARY

[0008] In one aspect, the disclosure provides a method of treating or reducing the development of inflammatory bowel disease in a mammal, the method comprising administering a suitable amount of a CCR9 inhibitor, 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).

[0009] 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.

[0010] In some embodiments, the CCR9 small molecule inhibitor provided herein can be represented by Formula (I) or a salt thereof:

[0011]

[0012] wherein X 1 , X 2 , X 3 , X 4 , X 5 , Y 1 , Y 2 , Y 3 , Y 4 , L 1 and Z 1 are defined below.

[0013] In some embodiments, the CCR9 small molecule inhibitor provided herein can be represented by Formula (II) or a salt thereof:

[0014]

[0015] wherein 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 are defined below.

[0016] In some embodiments, the anti-IL-23 or anti-IL-23R blocking antibody is risankizumab, guselkumab ustekinumab, briakinumab, brodalumab, mirikizumab, tralokinumab, or a biosimilar, a biosimilar or a biologic equivalent thereof.

[0017] In some embodiments, the CCR9 inhibitor and the anti-IL-23 blocking antibody are administered in a combination 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 prior to the anti-IL-23 blocking antibody. In another embodiment, the CCR9 inhibitor is administered after the anti-IL-23 blocking antibody.

[0018] In some embodiments, the CCR9 inhibitor is a compound having the formula:

[0019] or

[0020] In some embodiments, the CCR9 inhibitor is a compound selected from the group consisting of:

[0021]

[0022] In another aspect, the present disclosure provides a composition for treating or reducing the development 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.

[0023] In some embodiments, the inflammatory bowel disease is Crohn’s disease (CD) or ulcerative colitis (UC).

[0024] In yet another aspect, the present disclosure provides a kit for treating or reducing the development 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.

[0025] In some embodiments, the CCR9 inhibitor and the anti-IL-23 or anti-IL-23R blocking antibody are formulated for sequential administration. In some embodiments, the CCR9 inhibitor and the anti-IL-23 or anti-IL-23R blocking antibody are formulated for concomitant administration.

[0026] In some embodiments, the anti-IL-23 or anti-IL-23R blocking antibody is risankizumab, guselkumab ustekinumab, briakinumab, brodalumab, mirikizumab, tralokinumab, or a biosimilar, a biosimilar or a biologic equivalent thereof.

[0027] Other objects, features, and advantages of the present application will become apparent to one with ordinary skill in the art upon examination of the following BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1 Plasma concentrations of compounds 1 and 2 at trough at day 3 are shown.

[0029] Figure 2 Colon weight to length ratio is shown for wild type compared to MDR- / - mice.

[0030] Figure 3 Colon weight to length ratio is shown for compound 1 treated and control groups.

[0031] Figure 4 Colon weight to length ratio is shown for compound 2 treated and control groups. DETAILED DESCRIPTION

[0032] I. INTRODUCTION

[0033] The present disclosure is based, in part, on the unexpected finding that combination therapy of a CCR9 inhibitor (e.g., a small molecule inhibitor of CCR9) and an antibody against IL-23 or IL-23 receptor can synergistically treat inflammatory bowel disease, such as Crohn’s disease, ulcerative colitis, and indeterminate 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 having IBD a therapeutically effective amount of a CCR9 inhibitor and an anti-IL-23 or anti-IL-23R antibody to elicit a clinical response or to maintain clinical remission in the subject.

[0034] II. DEFINITIONS

[0035] When describing the compounds, compositions, methods, and processes of this application, the following terms have the following meanings, unless otherwise indicated.

[0036] As used herein, the terms “a” and “an” and “the” do not denote a limitation of quantity, and are to be construed to cover both the singular and plural forms, unless otherwise indicated herein or otherwise clearly contradicted by the context. Thus, for example, reference to “a cell” includes a plurality of such cells and reference to “the agent” includes reference to one or more agents known to one of skill in the art, and so forth.

[0037] The terms“about” and“approximately” generally mean an acceptable degree of error for the quantity being measured or expressed under the normal circumstances and using normal techniques of measurement, regardless of the manner in which the measurement is made. Typical exemplary degrees of error can be within 20 percent (%), preferably within 10%, and more preferably within 5% of a given value or range of values. Alternatively, and particularly in biological systems, the terms“about” and“approximately” can mean values within an order of magnitude, preferably within 5-fold and more preferably within 2-fold of a given value. Unless otherwise stated, the numerical values given herein are approximate and the terms“about” or“approximately” can be inferred even if not expressly stated.

[0038] The term“inflammatory bowel disease” or“IBD” includes gastrointestinal diseases such as Crohn’s disease (CD), ulcerative colitis (UC), indeterminate colitis (IC), and IBD that is indeterminate for CD versus UC (“indeterminacy”). Inflammatory bowel disease (e.g., CD, UC, IC, and indeterminate bowel disease) is distinguished from all other disorders, syndromes, and abnormalities of the gastrointestinal tract, including irritable bowel syndrome (IBS). Examples of IBD-related diseases include collagenous colitis and lymphocytic colitis.

[0039] The term“ulcerative colitis” or“UC” refers to a chronic remitting and relapsing inflammatory bowel disease (IBD) of the colon or large intestine characterized by surface mucosal damage extending to the rectum and developing proximally. Different types of ulcerative colitis are classified according to the localization and extent of inflammation. Examples of UC include, but are not limited to, ulcerative proctitis, proctosigmoiditis, left-sided colitis, and pancolitis (entire colon).

[0040] The term“Crohn’s disease” or“CD” refers to a chronic inflammatory disease that can affect any part of the gastrointestinal tract. Usually, the distal part of the small intestine, the ileum and caecum, are affected. In other cases, the disease is limited to the small intestine, colon, or anorectal region. CD occasionally involves the duodenum and stomach, and rarely the esophagus and mouth. Examples of CD include, but are not limited to, ileocolitis, ileitis, gastroduodenal Crohn’s disease, jejunoileitis, and Crohn’s (granulomatous) colitis.

[0041] The term“subject,”“individual,” or“patient” refers to an animal, such as a mammal, including but not limited to a primate (e.g., human) a cow, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, a mouse, and the like.

[0042] The term "C-C chemokine receptor type 9," "CCR9," or "CCR9 chemokine receptor" refers to the receptor for the chemokine CCL25, also known as TECK and SCYA25. Human CCR9 polypeptide sequences are set forth in, e.g., GenBank Accession Nos. NP_001243298, NP_006632, NP_112477, and XP_011531614. Human CCR9 mRNA (coding) sequences are set forth in, e.g., GenBank Accession Nos. NM_001256369, NM_006641, NM_031200, and XM_011533312.

[0043] The term "C-C chemokine receptor type 9 inhibitor," "CCR9 inhibitor," or "CCR9 chemokine receptor inhibitor" refers to an inhibitor or antagonist of a CCR9 receptor polypeptide, a variant thereof, or a fragment thereof.

[0044] 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.

[0045] 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 fragment thereof. Fragments of IL-23 include IL12b and IL23a. In certain instances, an IL-23 blocking antibody can block the interaction of IL-23 with any of its ligands. The term "anti-IL-23R blocking antibody" refers to an antibody or fragment thereof that specifically binds to an IL-23 receptor or fragment thereof. As used herein, IL-23 is intended to refer to the human cytokine that exists as a heterodimer composed of subunits IL12b and IL23a. The structure of IL-23 is further described in, e.g., Oppmann B, et al., Immunity, November 2000, 13(5):715-725.

[0046] The term "biogeneric" refers to a biological product that is highly similar to an FDA-approved biological product (reference product) and that is considered by the FDA to be no less safe and effective than the reference product in terms of clinical meaning.

[0047] The term "biological equivalent" refers to a biological product that is pharmaceutically equivalent and has similar bioavailability to an FDA-approved biological product (reference product). For example, according to the FDA, the term bioequivalence is defined as "the absence of a significant difference in the rate and extent of the active ingredient or active moiety of a drug product becoming available at the site of drug action when administered at the same molar dose under similar conditions" (U.S. Food and Drug Administration, "Guidance for Industry: Bioavailability and Bioequivalence Studies - General, " 2003, Center for Drug Evaluation and Research).

[0048] The term "biological equivalent" refers to a biological product that is pharmaceutically equivalent and has similar bioavailability to an FDA-approved biological product (reference product). For example, according to the FDA, the term bioequivalence is defined as "the absence of a significant difference in the rate and extent of the active ingredient or active moiety of a drug product becoming available at the site of drug action when administered at the same molar dose under similar conditions" (U.S. Food and Drug Administration, "Guidance for Industry: Bioavailability and Bioequivalence Studies - General, " 2003, Center for Drug Evaluation and Research).

[0049] The term "therapeutically effective amount" refers to an amount of a therapeutic agent sufficient to improve a targeted condition or symptom. For example, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100% for a given parameter. Therapeutic efficacy can also be expressed as a "fold" increase or decrease. For example, a therapeutically effective amount can have at least 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect relative to a control.

[0050] The terms "administer" and its 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 as a suppository, and topical administration. Those of skill in the art will appreciate additional methods for administering a therapeutically effective amount of a compound of the present application to prevent or alleviate one or more symptoms associated with a disease.

[0051] The term "treatment" refers to the treatment of a disease or medical condition (such as inflammation) in a patient, such as a mammal (particularly a human or an animal), which includes: improving the disease or medical condition, i.e., eliminating or causing regression of the disease or medical condition in the patient; inhibiting the disease or medical condition, i.e., slowing or arresting the development of the disease or medical condition in the patient; or relieving the symptoms of the disease or medical condition in the patient. The term encompasses prophylactic treatment to prevent or reduce the risk of infection or development of a certain disease, or to prevent or reduce the risk of recurrence of a disease.

[0052] "Alkyl" by itself or as part of another substituent refers to a hydrocarbon group that can be straight-chain, cyclic, or branched, or a combination thereof, having the indicated number of carbon atoms. For example, "C1-C6alkyl" refers to an alkyl group having from one to six carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, hexyl, 3-methyl-2-pentyl, 2,3-dimethyl-2-butyl, and the like. 1-8(Representing 1 to 8 carbon atoms). The term "cycloalkyl" itself, or as part of another substituent, refers to a cyclic alkyl group having a specified number of carbon atoms and is a subset of the term "alkyl". Other subsets of the term "alkyl" include "straight-chain" and "branched-chain" alkyl groups, which refer to two different types of acyclic alkyl groups. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, cyclohexyl, cyclopentyl, (cyclohexyl)methyl, cyclopropylmethyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. In this list of examples, the examples of methyl, ethyl, n-propyl, and n-butyl alkyl are also examples of "straight-chain alkyl" groups. Similarly, isopropyl and tert-butyl are examples of "branched-chain alkyl" groups. Cyclopentyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, bicyclo[2.2.1]heptane, and 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 is represented as -CH(CH2)CH-. "The alkyl group may be substituted or unsubstituted unless otherwise stated. Examples of substituted alkyl groups include haloalkyl, thioalkyl, aminoalkyl, etc. Other examples of suitable substituted alkyl groups 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, methylthiomethyl, methoxymethyl, 3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl and pentafluoroethyl. Suitable substituents for substituted alkyl groups include halogen, -CN, -CO2R', -C(O)R." '、-C(O)NR'R”、Oxygenated (=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 Aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclic groups. Possible substituent numbers range from zero to (2m'+1), where m' is the total number of carbon atoms in the radical. For substituted alkyl groups, R', R”, and R”' each independently refer to various groups, including hydrogen, substituted or unsubstituted C… 1-8 Alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryloxyalkyl. When R' and R" are attached to the same nitrogen atom, they can combine 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). In addition, R' and R", R" and R'" or R' and R'" can together with the atoms to which they are attached form a substituted or unsubstituted 5-, 6-, or 7-membered ring.

[0053] "Alkoxy" refers to -O-alkyl. Examples of alkoxy groups include methoxy, ethoxy, n-propyloxy, and the like.

[0054] "Alkenyl" refers to an unsaturated hydrocarbon group that can be straight, cyclic, or branched or a combination thereof. Alkenyl groups preferably have from 2 to 8 carbon atoms. Alkenyl groups can include 1, 2, or 3 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. Unless stated otherwise, alkenyl groups can be substituted or unsubstituted.

[0055] "Alkenyl" refers to an unsaturated hydrocarbon group that can be straight, cyclic, or branched or a combination thereof. Alkenyl groups preferably have from 2 to 8 carbon atoms. Alkenyl groups can include 1, 2, or 3 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. Unless stated otherwise, alkenyl groups can be substituted or unsubstituted.

[0056] "Alkylamino" refers to -N(alkyl)2or -NH(alkyl). When an alkylamino group includes two alkyl groups, the alkyl groups can combine together to form a carbocyclic or heterocyclic ring. It will be appreciated that the alkyl groups of an alkylamino group can be substituted or unsubstituted. Examples of alkylamino groups include methylamino, t-butylamino, dimethylamino, diisopropylamino, morpholino, and the like.

[0057] "Aminoalkyl" as a substituted alkyl group refers to mono- or poly-aminoalkyl groups, most typically substituted with 1-2 amino groups. Examples include aminomethyl, 2-aminoethyl, 2-diethylaminoethyl, and the like.

[0058] "Aryl" refers to a polyunsaturated aromatic hydrocarbon group having a single ring (bi-cyclic) or multiple rings (preferably bi-cyclic), which can be fused together or covalently linked. Preferred aryl groups have 6-10 carbon atoms, where the number of carbon atoms can be indicated, for example, by C6-10. Examples of aryl groups include phenyl and naphthalene-1-yl, naphthalene-2-yl, biphenyl, and the like. Unless otherwise indicated, aryl groups can be substituted or unsubstituted. Substituted aryl groups can be substituted with one or more substituents. Suitable substituents for aryl groups include substituted or unsubstituted C1-8alkyl groups and those substituents discussed above for substituted alkyl groups.

[0059] "Halogen" by itself or as part of a substituent group, means a chloro, bromo, iodo, or fluoro atom.

[0060] "Haloalkyl group" as a substituted alkyl group refers to a mono-haloalkyl or poly-haloalkyl group, most typically substituted with 1-3 halogen atoms. Examples include 1-chloroethyl, 3-bromopropyl, trifluoromethyl, and the like.

[0061] "Heterocyclyl" refers to a saturated or unsaturated non-aromatic group that includes at least one heteroatom selected from nitrogen, oxygen, or sulfur (typically from 1 to 5 heteroatoms). Preferably, these groups contain 0-5 nitrogen atoms, 0-2 sulfur atoms, and 0-2 oxygen atoms. More preferably, these groups contain 0-3 nitrogen atoms, 0-1 sulfur atom, and 0-1 oxygen atom. Examples of heterocyclyl groups include pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolinone, 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, and the like. Preferred heterocyclyl groups are monocyclic, although they can be fused or covalently linked to aryl or heteroaryl ring systems.

[0062] Exemplary heterocyclyl groups can be represented by the following formula (AA):

[0063]

[0064] wherein formula (AA) is attached to M 1 or M 2 above; M 1 represents O, NR e or S(O) l ; M 2 represents CR f R g , O, S(O) l or NR e ; where it can be necessary to omit one R f , R g or Re M 1 or M 2 is substituted with a free valence, for example CR f , CR g , or N; I 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; and R a , R b , R c , R d , R e , R f , and R g are independently selected from the group consisting of 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 , -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 , wherein Q1 The answer is C. 1-4 Alkylene, C 2-4 imide and C 2-4 Members of the group composed of ynyl groups, and R h R i and R j Independently selectable from hydrogen and C 1-8 A group consisting of alkyl groups, wherein each R a R b R c R d R e R f R g R h R i The aliphatic portion of the R substituent 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)2NR 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)NH2and -NR n S(O)2NHR o one to three members selected from the group consisting of hydrogen, halogen, unsubstituted or substituted C n , R o and R p are independently unsubstituted C 1-8 alkyl. Furthermore, any two of R a , R b , R c , R d , R e , R f and R g may combine to form a bridged or spirocyclic ring system.

[0065] Preferably, R a + R b + R c + R d is 0, 1 or 2. More preferably, R a , R b , R c , R d , R e , R f and R g are independently selected from the group consisting of hydrogen, halogen, unsubstituted or substituted C 1-8 alkyl, -C(O), -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 , wherein R h and R i are independently selected from the group consisting of hydrogen and unsubstituted C 1-8 alkyl; and wherein the aliphatic portion of each R a , R b , R c , R d , R e , R f and R g substituent is optionally substituted with a member selected from the group consisting of halogen, -OH, -ORn -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, -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)2NHR o one to three members selected from the group consisting of hydrogen, halogen, -OR n , -NR o , and -NR p are independently unsubstituted C 1-8 alkyl.

[0066] More preferably, Ra, Rb, Rc, Rd, Re, Rf, and Rg are independently hydrogen or C1-4alkyl. In another preferred embodiment, at least three of Ra, Rb, Rc, Rd, Re, Rf, and Rg are hydrogen.

[0067] "Heteroaryl" refers to an aromatic group containing at least one heteroatom. Examples include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalonitrile, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, phenylisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienyl, furazanyl, pyrrolinyl, imidazolyl, benzothiazolyl, benzoinazolinyl, benzothienyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furanyl, or thiophene. Preferred heteroaryl groups are those having at least one aromatic ring nitrogen atom, such as quinolinyl, quinoxalinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzothiazolyl, indolyl, quinolinyl, isoquinolinyl, and the like. Preferred 6-ring heteroaryl systems include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, and the like. Preferred 5-ring heteroaryl systems include isothiazolyl, pyrazolyl, imidazolyl, thienyl, furanyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, thiazolyl, and the like.

[0068] Heterocyclyl and heteroaryl groups can be attached at any available ring carbon or heteroatom. Each heterocyclyl and heteroaryl group can have one or more rings. When multiple rings are present, they can be fused together or covalently linked. Each heterocyclyl and heteroaryl group must include at least one heteroatom selected from nitrogen, oxygen, or sulfur (typically 1 to 5 heteroatoms). Preferably, these groups contain 0-5 nitrogen atoms, 0-2 sulfur atoms, and 0-2 oxygen atoms. More preferably, these groups contain 0-3 nitrogen atoms, 0-1 sulfur atoms, and 0-1 oxygen atoms. Heterocyclyl and heteroaryl groups can be substituted or unsubstituted, unless otherwise indicated. For substituted groups, substitution can be on a carbon or heteroatom. For example, when substituted with oxo (=0 or O-), the resulting group can have a carbonyl (-C(O)-) or N-oxide (-N+-0-), or -S(O)- or -S(O)2-.

[0069] Suitable substituents for substituted alkyl, substituted alkenyl, and substituted alkynyl 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", -SiR'R"R", -N3, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl, in a number ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such radical.

[0070] 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", -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- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl. The number of possible substituents varies from zero to the total number of open valences on the aromatic ring system.

[0071] As used above, R', R", and R'" each independently refer to a variety of 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 aralkyl, and substituted or unsubstituted aryloxyalkyl. When R' and R" are attached to the same nitrogen atom, they can combine 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). In addition, R' and R", R" and R'", or R' and R'" can together with the atoms to which they are attached form a substituted or unsubstituted 5-, 6-, or 7-membered ring.

[0072] Two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with substituents of the formula -TC(O)-(CH2)qU-, where T and U are independently -NR″″-, -O-, -CH2-, or single bonds, and q is an integer from 0 to 2. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with substituents of the formula -A'-(CH2)r-B'-, where A' and B' are independently -CH2-, -O-, -NR″″-, -S-, -S(O)-, -S(O)2-, -S(O)2NR″″-, or single bonds, and r is an integer from 1 to 3. One of the single bonds in the newly formed ring may optionally be replaced by a double bond. Alternatively, the two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with substituents of the formula -(CH2)sX-(CH2)t-, where s and t are independently integers from 0 to 3, and X is -O-, -NR″″-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituent R”” in -NR””- and -S(O)2NR””- is hydrogen or an unsubstituted C1-8 alkyl group.

[0073] "Heteroatoms" are intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0074] A "pharmaceutically acceptable" carrier, diluent, or excipient is a carrier, diluent, or excipient that is compatible with other components of the formulation and is harmless to its recipients.

[0075] "Pharmaceutically acceptable salt" refers to acceptable salts used for administration to a patient, such as a mammal (e.g., a salt that has acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids, depending on the particular substituents found on the compounds described herein. Base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat 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, and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines, and the like, 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, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. Acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Salts derived from pharmaceutically acceptable acids include acetic, ascorbic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glucuronic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, lactobionic, maleic, malic, mandelic, methanesulfonic, mucic, naphthalenesulfonic, nicotinic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.

[0076] Also included are salts of amino acids such as arginate and salts of organic acids like glucuronic acid or galactunoric acid (see, e.g., Berge, S.M., et al, "Pharmaceutical Salts", J. Pharmaceutical Science, 1977, 66: 1-19). Certain specific compounds of the application contain both basic and acidic functionalities, allowing the compounds to be converted into both base and acid addition salts.

[0077] The neutral form of the compounds can be regenerated by contacting the salts with bases or acids 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 the physical form of the compound is otherwise without material difference to its utility as a pharmaceutical.

[0078] "Salts" refers to compounds formed when the hydrogen of an acid is replaced by a cation such as a metal cation or an organic cation. Preferably, the salts are pharmaceutically acceptable salts, although salts that are not pharmaceutically acceptable are within the scope of this application, for use in the preparation of the compounds of use in intermediates.

[0079] In addition to salt forms, the present application provides compounds which are in a prodrug form. Prodrugs are often useful when a compound is administered orally or via inhalation. For example, a prodrug can be less polar than the parent drug and therefore more easily absorbed by the patient. Prodrugs of a compound of the present application include, for example, acetate, formate, and benzoate derivatives of a compound of the present application. The preparation of prodrugs is well known in the art (see, e.g., Nogrady, Medicinal Chemistry A Biochemical Approach, Oxford Biological Publishing, Inc., 1985, especially Chapters 10 and 11; Burger's Medicinal Chemistry and Drug Discovery, 5th Edition, Vols. 1-5, Ed.: Wermuth, CRC Press, 1995, especially Chapters 19 and 20; and Design of Prodrugs, H. Bundgaard, Elsevier, 1987).

[0080] Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present application. Additionally, prodrugs can be converted by metabolic processes to the compounds of the present application in the body. For example, a prodrug can be slowly converted into a compound of the present application when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0081] Prodrugs can be prepared by modifying functional groups present on the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to form the parent compound. Prodrugs include compounds wherein a hydroxy, amino, sulfhydryl, or carboxy group is bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxy group. 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 present application. The preparation, selection, and use of prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. 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.

[0082] The compounds of the present application can 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 application (or salt thereof). In some aspects, the metabolite can be a functional derivative of the compound that can be readily converted into the active compound in vivo. In other aspects, the metabolite can be the active compound.

[0083] Unless otherwise indicated, the term "acid isostere" refers to a group that can replace a carboxylic acid, which has both steric and electronic properties that provide a similar level of activity (or other compound property, such as solubility) as a 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.

[0084] Certain compounds of the present application can exist in unsolvated as well as solvated forms, including hydrated forms. In general, both solvated and unsolvated forms are intended to be encompassed within the scope of the present application. Certain compounds of the present application can exist in multiple crystalline or amorphous forms (i.e., as polymorphs). In general, all physical forms are equivalent for the uses contemplated by the present application and are intended to be within the scope of the present application.

[0085] Certain compounds of the present application 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 application. The compounds of the present application can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes such as for example tritium ( 3 H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present application, whether radioactive or not, are intended to be encompassed within the scope of the present application.

[0086] The compounds of the present application can include detectable labels. A detectable label refers to a moiety that can be detected at low concentrations (typically sub-micromolar, possibly sub-nanomolar and possibly sub-picomolar) and that is readily distinguishable 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.

[0087] A variety of detectable labels are within the scope of the application, including hapten labels (e.g., biotin, or labels used in conjunction with detectable antibodies such as horseradish peroxidase antibodies); mass tag labels (e.g., stable isotope labels); radioisotope labels (including3H,125I,35S,14C, or32P); metal chelate labels; luminescent labels, including fluorescent labels (such as fluorescein, isothiocyanate, Texas Red, rhodamine, green fluorescent protein, etc.), phosphorescent labels, and chemiluminescent labels, typically having a quantum yield greater than 0.1; electroactive and electron transfer labels; enzyme modulator labels, including coenzymes, organometallic catalysts horseradish peroxidase, alkaline phosphatase, and other enzymes commonly used in ELISA; photosensitizers; magnetic bead labels, including immunomagnetic beads; colorimetric labels, such as colloidal gold, silver, selenium, or other metals and metal sol labels (see U.S. Patent No. 5,120,643, which is 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 teaching 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; 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.

[0088] Detectable labels are commercially available or can be prepared in a manner known to those skilled in the art. The detectable label can be covalently attached to the compound using a reactive functional group, which can be positioned in any suitable location. 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 tethered to the aryl core, the reactive group can be positioned at the terminal position of the alkyl chain.

[0089] III. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0090] A. Treatment of Inflammatory Bowel Disease with Combination Therapy

[0091] The present disclosure provides methods, compositions, and kits based on combination therapy comprising a CCR9 inhibitor and an anti-IL-23 or anti-IL-23R antibody. The therapy can be used to treat IBD, such as Crohn's disease (CD) and ulcerative colitis (UC) in a subject. The present invention is based, in part, on the unexpected finding that a synergistic combination of a CCR9 inhibitor and an anti-IL-23 or anti-IL-23R antibody is effective in treating IBD.

[0092] 1. Crohn's Disease

[0093] The compositions, methods, and kits of the present invention can be used in a subject suffering from CD of all types. The combination therapy of a CCR9 inhibitor and an anti-IL-23 or anti-IL-23R antibody can be administered at an effective dose to induce a clinical response or to maintain clinical remission in a subject with CD. In some embodiments, the combination therapy reduces, decreases, or minimizes the severity of one or more symptoms of CD.

[0094] Symptoms of CD include diarrhea, fever, fatigue, abdominal pain or cramping, blood in the stool, mouth sores, loss of appetite, weight loss, and perianal disease. Additional symptoms or characteristics of CD can be assessed by endoscopy, such as esophagogastroduodenoscopy, colonoscopy, sigmoidoscopy, endoscopic retrograde cholangiopancreatography, endoscopic ultrasonography, and balloon enteroscopy, and histological examination from GI tract biopsy sections. The severity of the disease can be classified as mild to moderate, moderate to severe, and severe / fulminant disease. See, e.g., Lichtenstein et al., Am J Gastroenterol, 2009, 104(2):2465-83 for additional descriptions of CD.

[0095] The severity of CD and clinical response to the 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). The index is used to quantify symptoms in patients with CD. The CDAI can be used to define clinical response or remission of CD. The CDAI is composed of eight factors that are added (summed) after adjustment using weighted factors or multipliers. The eight factors include amount of fluid stool, abdominal pain, general well-being, extraintestinal complications, antidiarrheal agents, abdominal mass, hematocrit, and weight. Remission of Crohn's disease is generally defined as a decrease or reduction in CDAI of less than 150 points. Severe disease is generally defined as a value greater than 450 points. In certain aspects, a Crohn's disease patient's response to a particular drug is defined as a decrease in CDAI from baseline (week 0 of treatment) of greater than 70 points.

[0096] Clinical indices such as CDAI can be used to determine whether the combination therapy described herein elicits a clinical response or clinical remission in patients with Crohn’s disease. In some embodiments, a patient has a clinical response if their CDAI score is reduced by 70 points or more from baseline while receiving the combination therapy. A patient is in clinical remission of CD if their CDAI score is reduced to less than 150 points at the end of the induction phase of therapy.

[0097] 2. Ulcerative colitis

[0098] The compositions, methods, and kits of the present application can be used in subjects with UC, including all types of UC. The combination therapy of a CCR9 inhibitor with an anti-IL-23 or anti-IL-23R antibody can be administered at effective doses to induce a clinical response or to maintain clinical remission in a subject with UC. In some embodiments, the combination therapy reduces, decreases, or minimizes the severity of one or more symptoms of UC.

[0099] Symptoms of UC include, but are not limited to, diarrhea, abdominal pain and cramping, rectal pain, rectal bleeding, urgency to defecate, inability to defecate, weight loss, fatigue, fever, or anemia. The severity of the disease can be classified as mild to moderate, moderate to severe, and severe / fulminant disease. See, e.g., Kornbluth et al., Am J Gastroenterol, 2004, 99(7): 1371-85.

[0100] Disease activity and response to therapy in UC can be assessed by quantitative analysis of composite index scoring systems. Typically, a clinician will consider at least four factors or variables in assessing UC disease activity: clinical symptoms, quality of life, endoscopic assessment, and histological assessment. For example, the Colitis Activity Index (CAI) is a quantitative measure that incorporates the following disease symptoms: colonoscopic-based colonic inflammation, diarrhea, abdominal pain and cramping, and hematochezia. Standardized endoscopic scoring systems, such as the UC Endoscopic Severity Index (UCEIS), can be used to establish 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 factors used in the Mayo Clinic Scoring system include stool (bowel) frequency, rectal bleeding, endoscopic findings, and the physician’s global assessment of disease severity (e.g., daily abdominal discomfort and overall sense of well-being).

[0101] The MMDAI includes the removal of "crumbiness" from the endoscopic score 1 compared to the Mayo Clinic Score. Thus, the presence of crumbiness reflects an endoscopic score of 2 or 3. The MMDAI assesses 4 subscores (bowel frequency, rectal bleeding, endoscopic findings, and physician's global assessment), each subscore ranging from 0 to 3, with a maximum total score of 12.

[0102] In some embodiments, a clinical response of a subject having UC to the combination therapy provided herein corresponds to a reduction of 2 points or more in the MMDAI score relative to baseline, and a reduction of 25% or more relative to baseline, and / or a reduction of 1 point or more in the rectal bleeding subscore relative to baseline. In other embodiments, the clinical response corresponds to a reduction of 3 points or more in the Mayo Clinic Score, and a reduction of 30% relative to baseline.

[0103] A clinical remission of a UC subject administered the combination therapy can correspond to a score of 0 for rectal bleeding, and a combined score of 2 points or less for bowel frequency and physician's global assessment assessed using the MMDAI subscale. In other embodiments, a clinical remission of a subject having UC means having a Mayo Clinic Score of 2 points or less, and no individual subscore (bowel frequency, rectal bleeding, endoscopic findings, and physician's global assessment) exceeding 1 point.

[0104] B. Combination therapy of CCR9 inhibitors and anti-IL-23 antibodies

[0105] Provided herein are methods, compositions, and kits that take advantage of the synergistic effects of CCR9 inhibitors and anti-IL-23 or anti-IL-23R antibodies in reducing inflammation in IBD subjects. Combination therapy comprising 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 the use of either compound / antibody alone.

[0106] 1. Inhibitors of chemokine receptor type (CCR9)

[0107] The present invention provides compounds that modulate CCR9 activity. In particular, the present invention provides compounds having 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 (e.g., chemotaxis, increases in intracellular calcium ion concentration, etc.). Thus, modulating chemokine receptor function, e.g., interfering with chemokine receptor-ligand interactions, can inhibit or reduce chemokine receptor-mediated responses, as well as treat or prevent chemokine receptor-mediated conditions or diseases.

[0108] 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 application act as potent CCR9 antagonists, and this antagonistic activity has been further demonstrated in animal inflammation tests, one of the hallmark disease states for CCR9. The compounds contemplated by the application include, but are not limited to, the exemplary compounds provided herein and salts thereof.

[0109] For example, useful compounds act as potent CCR9 antagonists, and this antagonistic activity has been further demonstrated in animal inflammation tests, one of the hallmark disease states for CCR9. Accordingly, the compounds provided herein are useful in pharmaceutical compositions and methods for treating inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease).

[0110] In some embodiments, the CCR9 small molecule inhibitors provided herein can be represented by Formula (I) or a salt thereof:

[0111]

[0112] wherein X 1 , X 2 , X 3 , X 4 , X 5 each independently is selected from the group consisting of hydrogen, halogen, -CN, -NO2, 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, with the proviso that one of X 1 , X 2 , X 3 , X 4 , X 5 is not hydrogen.

[0113] and each independently is selected from the group consisting of 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 heterocyclyl, or wherein and may form, together with the atom to which they are attached, a substituted or unsubstituted 5-, 6- or 7-membered ring;

[0114] when X1, X2, X3, X4or X5is substituted C6-10aryl, substituted 5- or 6-membered heteroaryl and substituted 4- to 7-membered heterocycle, it can have 1 to 3 substituents independently selected from the group consisting of halogen, -CN, -OR1a, =0, -OC(0)R1a, -C02R1a, -C(O)R1a, -CONR1aR2a, -NR2aC(O)R1a, -NR1aR2a, -SR1a, -S(O)R1a, -S(O)2R1a, -NR1aSO2R2a, unsubstituted C1-8alkyl and unsubstituted C1-8haloalkyl. 1 , X 2 , X 3 , X 4 or X 5 is substituted C 1-8 alkyl, substituted C 2-8 alkenyl and substituted C 2-8 alkynyl, it can have 1 to 3 substituents independently selected from the group consisting of halogen, -CN, =0, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl and unsubstituted or substituted heteroaryl. Preferred substituted C 1-8 alkyl has 1 to 3 substituents independently selected from the group consisting of halogen, -CN, =0, unsubstituted or substituted 5- or 6-membered heteroaryl and 5- or 6-membered unsubstituted or substituted heterocyclyl.

[0115] when X1, X2, X3, X4or X5is substituted C6-10aryl, substituted 5- or 6-membered heteroaryl and substituted 4- to 7-membered heterocycle, it can have 1 to 3 substituents independently selected from the group consisting of halogen, -CN, -OR1a, =0, -OC(0)R1a, -C02R1a, -C(O)R1a, -CONR1aR2a, -NR2aC(O)R1a, -NR1aR2a, -SR1a, -S(O)R1a, -S(O)2R1a, -NR1aSO2R2a, unsubstituted C1-8alkyl and unsubstituted C1-8haloalkyl.

[0116] when X1, X2, X3, X4or X5is substituted 5- or 6-membered heteroaryl or 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, -SO2R1a, unsubstituted or substituted C1-8alkyl and unsubstituted or substituted C1-8haloalkyl.

[0117] In one embodiment of formula (I), at least one of X1, X2, X3, X4and X5is not hydrogen.

[0118] In one embodiment of formula (I), X1is not hydrogen and at least 2 of X2, X3, X4and X5are hydrogen. Preferably, at least 3 of X2, X3, X4and X5are hydrogen; more preferably, X2, X3, X4and X5are hydrogen.

[0119] In one embodiment of formula (I), Y1, Y2, Y3, and Y4are each independently selected from the group consisting of hydrogen, halogen, -CN, -NO2, -OR3a, -C(O)R3a, -SR3a, -CF3, -SOR3a, -SO2R3a, and substituted or unsubstituted C1-4alkyl.

[0120] In one embodiment of formula (I), R3ais independently selected from the group consisting of hydrogen, unsubstituted C1-8alkyl, unsubstituted C2-8alkenyl, unsubstituted C2-8alkynyl, unsubstituted C6-10aryl, and unsubstituted 5-10-membered heteroaryl.

[0121] In one embodiment of formula (I), L1is -C(O)-, -S-, -S(O)-, or -S(O)2-. In one embodiment, L1is preferably -C(O)-. In another embodiment of formula (I), L1is preferably -S-, -S(O)-, or -S(O)2-.

[0122] In another embodiment of formula (I), when Z1is substituted phenyl or substituted or unsubstituted 5-membered heteroaryl, L1is preferably -S-, -S(O)-, or -S(O)2-.

[0123] In one embodiment of formula (I), Z1represents substituted phenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, or substituted 4- to 7-membered heterocyclyl. Suitably substituted 5- or 6-membered heteroaryl can have 1 to 3 substituents independently selected from the group consisting of halogen, unsubstituted or substituted C1-8alkyl, unsubstituted or substituted C2-8alkenyl, unsubstituted or substituted C2-8alkynyl, =O, -CN, -NO2, -OR4a, -OC(O)R4a, -CO2R4a, -C(O)R4a, -CONR4aR5a, -NR4aC(O)R5a, -NR4aR5a, -SR4a, -SOR4a, -SO2R4a, -SO2NR4aR5a, -NR4aSO2R5a, unsubstituted or substituted phenyl, unsubstituted or substituted 5 or 6 membered heteroaryl, and unsubstituted or substituted 4 to 7 membered heterocyclyl. If present, one substituent is preferably located ortho to one of the ring heteroatoms or is an oxygen atom directly attached to a ring heteroatom (i.e., N-oxide).

[0124] R4aand R5aare each independently selected from the group consisting of hydrogen, unsubstituted C1-8alkyl, unsubstituted C2-8alkenyl, unsubstituted C2-8alkynyl, unsubstituted C6-10aryl, unsubstituted 5 to 10 membered heteroaryl, and unsubstituted 3 to 10-membered heterocycle.

[0125] In one embodiment of formula (I), Z1represents substituted phenyl. In any one embodiment of formula (I), at least one substituent on the group Z1is unsubstituted C1-6alkyl (particularly methyl) or C1-6haloalkyl (particularly -CF3).

[0126] In any one embodiment of formula (I), Z1is the following residue:

[0127]

[0128] In any one embodiment of formula (I), Z 1 is selected from one of the following residues:

[0129]

[0130] In any one embodiment of formula (I), Z 1 is selected from one of the following residues:

[0131]

[0132] In some embodiments, the CCR9 inhibitor, e.g., the CCR9 small molecule inhibitor of the disclosure, is represented by formula (II) or a salt thereof:

[0133]

[0134] wherein R 1 is selected from the group consisting of 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, and;

[0135] R 2 is H, F, Cl, or substituted or unsubstituted C 1-8 alkoxy; or

[0136] R 1 and R 2 together with the carbon atom to which they are attached form a non-aromatic carbocyclic or heterocyclic ring;

[0137] R 3 is H, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, or halogen;

[0138] R 4 is H or F;

[0139] R 5 is H, F, Cl, or -CH3;

[0140] R 6 is H, halogen, -CN, -CO2R a , -CONH2, -NH2, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, or substituted or unsubstituted C 1-8 aminoalkyl;

[0141] R a is H or substituted or unsubstituted C 1-8 alkyl;

[0142] wherein R 5 and R 6 may together form a carbocyclic ring;

[0143] L is a bond, -CH2- or -CH(CH3)-;

[0144] A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 and A 8 are each independently selected from the group consisting of N, N-O and -CR 8 ; wherein at least one and not more than two of A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 and A 8 is N or N-O;

[0145] R 8 are each independently selected from the group consisting of H, halogen, -CN, -OH, oxo, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy and -NR 20 R 21 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl; and

[0146] R 20 and R 21 are each independently H, or substituted or unsubstituted C 1-8 alkyl.

[0147] In some embodiments of formula (II), one of A1or A2is N or N-O, and the rest of A1, A2, A3, A4, A5, A6, A7, and A8are -CR8-, where each R8is independently selected.

[0148] In some embodiments, two of A2, A3, A4, A5are N or N-O, and the rest of A1, A2, A3, A4, A5, A6, A7, and A8are -CR8-, where each R8is independently selected.

[0149] In some embodiments, the compound or composition of formula (II) is represented by formula (III), or a salt thereof:

[0150]

[0151] wherein R 1 is selected from the group consisting of 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;

[0152] R 2 is H, F, Cl, or substituted or unsubstituted C 1-8 alkyl; or

[0153] R 1 and R 2 together with the carbon atom to which they are attached form a non-aromatic carbocyclic or heterocyclic ring;

[0154] R 3 is H, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, or halogen;

[0155] R 4 is H or F;

[0156] R 5 is H, F, Cl, or -CH3;

[0157] R 6 is H, halogen, -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 alkoxy;

[0158] R a is H or substituted or unsubstituted C 1-8 alkyl;

[0159] wherein R 5 and R 6 may together form a carbocyclic ring;

[0160] L is a bond, -CH2- or -CH(CH3)-; and

[0161] Z is selected from the group consisting of:

[0162]

[0163] and N-oxides thereof; wherein the Z group can be unsubstituted or substituted with 1 to 3 independently selected R8substituents;

[0164] each R8is independently selected from the group consisting of H, halogen, -CN, -OH, oxo, substituted or unsubstituted Ci-8alkyl, substituted or unsubstituted Ci-8alkoxy, and -NR20R21, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; and

[0165] R20and R21are each independently H, substituted or unsubstituted Ci-8alkyl.

[0166] 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, substituted or unsubstituted quinazolinyl.

[0167] In one embodiment, the compound or composition of formula (II) provided herein is represented by formula (IIIa) or (IIIb), or a salt thereof:

[0168]

[0169] wherein R1is selected from the group consisting of substituted or unsubstituted C2-8alkyl, substituted or unsubstituted Ci-8alkoxy, substituted or unsubstituted Ci-8alkylamino, and substituted or unsubstituted C3-10heterocyclyl;

[0170] R2is H, F, Cl, or substituted or unsubstituted Ci-8alkoxy; or

[0171] R1and R2together with the carbon atom to which they are attached form a non-aromatic carbocyclic or heterocyclic ring;

[0172] R3is H, substituted or unsubstituted Ci-8alkyl, substituted or unsubstituted Ci-8alkoxy, or halogen;

[0173] R4is H or F;

[0174] R5is H, F, Cl, or -CH3;

[0175] R6is H, halogen, -CN, -CO2Ra, -CONH2, -NH2, substituted or unsubstituted Ci-8 aminoalkyl, substituted or unsubstituted Ci-8 alkyl, or substituted or unsubstituted Ci-8 alkoxy;

[0176] Ra is H or substituted or unsubstituted Ci-8 alkyl;

[0177] or wherein R 5 and R 6 together with the carbon atom to which they are attached form a carbocyclic ring;

[0178] each R 8 is independently selected from the group consisting of H, halogen, -CN, -OH, oxo, substituted or unsubstituted Ci-8 alkyl, substituted or unsubstituted Ci-8 alkoxy, and -NR 1-8 R 1-8 R 20 R 21 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;

[0179] R 20 and R 21 are each independently H, or substituted or unsubstituted Ci-8 alkyl; and 1-8 R

[0180] n is 0, 1, 2, or 3.

[0181] In one embodiment of Formula (IIIa) or (IIIb), or a salt thereof, R1is selected from the group consisting of -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, -OCH2CH(CH3)2, -OCF3, and morpholino; R2is H, F, or Cl; or R1and R2may together form -OC(CH3)2CH2- or -C(CH3)2CH2CH2-; R3is H, -CH3, or -OCH3; R4is H or F; R5is H; R6is H, -CH3, -CH2CH3, -CH(CH3)2, -C3H7, -CH2F, -CHF2, -CF2CH3, -CF3, -CH2OCH3, -CH2OH, -CH2CN, -CN, or -CONH2; each R8is independently selected from the group consisting of H, F, Cl, Br, -CH3, -OH, -OCH3, -OCH2CH3, -NH2, -N(CH3)2, and -CN. In certain instances, R1is -C(CH3)3.

[0182] In other embodiments of Formula (IIIa) or Formula (IIIb), R2is H or F; R3is H; R4is H; and R6is -CH3, -CH2F, -CHF2, or -CF3.

[0183] In one embodiment, the compounds and compositions of Formula (IIIa) or (IIIb) or salts thereof are selected from the group consisting of:

[0184]

[0185]

[0186] In some embodiments, the CCR9 inhibitor, e.g., the CCR9 small molecule inhibitor compounds and compositions provided herein are selected from the group consisting of:

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196] and N-oxides thereof.

[0197] In some embodiments, preferred R 1 substituents are as follows. In Formula (II, III, Ilia, and IIIb), R 1 is selected from the group consisting of 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. When R 1 is substituted alkyl, the alkyl is preferably substituted with halogen or hydroxyl. When R 1 is substituted alkoxy, the alkoxy is preferably substituted with halogen. Preferably, R 1 is unsubstituted C2-8 alkyl, including 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 alkylamino; more preferably unsubstituted C 2-8 alkyl, C 2-8 haloalkyl, unsubstituted C 1-8 alkoxy and C 1-8 alkylamino; even more preferably unsubstituted C 2-8 alkyl, unsubstituted C 1-8 alkoxy and morpholino; still more preferably unsubstituted C 2-8 ; most preferably tert-butyl.

[0198] In some embodiments, preferred R6substituents are as follows. In formulae (II, III, Ilia and Illb), R6is H, halogen, -CN, -CO2Ra, -CONH2, -NH2, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted C1-8alkoxy, or substituted or unsubstituted C1-8aminoalkyl. When R6is substituted alkyl, the alkyl is preferably substituted with halogen, hydroxyl, alkoxy or cyano. Preferably, R6is -CN, -CONH2, -NH2, unsubstituted C1-8alkyl, unsubstituted C1-8haloalkyl and unsubstituted C1-8alkoxy; more preferably unsubstituted C1-8alkyl, or unsubstituted C1-8haloalkyl, even more preferably unsubstituted C1-8alkyl; most preferably methyl.

[0199] In one embodiment, the CCR9 small molecule inhibitor is Compound 1.

[0200]

[0201] Compound 1

[0202] In one embodiment, the CCR9 small molecule inhibitor is Compound 2.

[0203]

[0204] Compound 2

[0205] In one embodiment, the CCR9 small molecule inhibitor is Compound 3.

[0206]

[0207] Compound 3

[0208] In one embodiment, the CCR9 small molecule inhibitor is Compound 4.

[0209]

[0210] Compound 4

[0211] Detailed descriptions of CCR9 inhibitor compounds provided herein and methods of making such compounds are found, for example, in U.S. Patent No. 6,939,885, U.S. Patent No. 8,916,601, and U.S. Patent Application Publication Nos. 2013 / 0267492, 2013 / 0059893, 2012 / 0245138, 2012 / 0165303, 2011 / 0021523, 2010 / 0331302, 2010 / 0227902, 2010 / 0190762, 2010 / 0152186, 2010 / 0056509, 2009 / 0163498, and 2009 / 0005410, the disclosures of which are incorporated herein by reference for all purposes.

[0212] The compounds provided herein can be synthesized using a variety of standard organic chemistry transformations. Certain general reaction types that are widely used in the synthesis of the target compounds of the application are summarized in the Examples. Specifically, general procedures for sulfonamide formation and azaheteroaryl N-oxide formation are described herein and are routinely employed.

[0213] While not intended to be exhaustive, representative synthetic organic transformations that can be used to make the compounds of the application are included herein. These representative transformations include: standard functional group manipulations; reductions such as the reduction of nitro groups to amines; oxidations of functional groups including alcohols and azaheteroaryls; aryl substitutions by IPSO or other mechanisms for the introduction of a variety of groups including nitriles, methyl groups, and halogens; introduction and removal of protecting groups; Grignard formation and reaction with electrophiles; metal mediated cross-couplings including but not limited to Buckwald reactions, Suzuki reactions, and Sonigashira reactions; halogenations and other electrophilic aromatic substitution reactions; diazonium salt formation and reactions of these species; etherification; cyclocondensations, dehydrations, oxidations, and reductions to generate heteroaryls; aryl metalations and transmetallations and subsequent reactions of the aryl metal species with electrophiles such as acidic chlorides or Weinreb amides; amidations; esterifications; nucleophilic substitution reactions; alkylations; acylations; sulfonamide formations; chlorosulfonylations; ester and related hydrolyses; and the like.

[0214] Certain molecules claimed in this patent can exist in different enantiomeric and diastereomeric forms, and all such variations of these compounds are within the scope of the application.

[0215] In the subsequent synthesis descriptions, some precursors are obtained from commercial sources. These commercial sources include Aldrich Chemical Company, Acros Organics Company, Inc., Ryan Scientific, Oakwood Products, Inc., Lancaster Chemicals Company, Sigma Chemical Company, Lancaster Synthesis, Inc., TCI America, Inc., Alfa Aesar, Davos Chemicals, and GFS Chemicals.

[0216] 2. Pharmaceutical formulations of CCR9 inhibitors

[0217] In another aspect, the present disclosure provides compositions or formulations that modulate CCR9 activity. Generally, a composition or formulation for modulating chemokine receptor activity in a subject, such as a human or an animal, will include a compound provided herein and a pharmaceutically acceptable excipient or diluent.

[0218] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of 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.

[0219] Pharmaceutical compositions for administration of the compounds of the present application can conveniently be presented in unit dosage form and can be prepared by any methods well known in the art of pharmacy. All methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately associating the active ingredient with a liquid carrier or finely divided solid carrier or both and then, if necessary, shaping the product into the desired formulation form. In such pharmaceutical compositions the active object compound is included in an amount sufficient to contribute to the desired effect in the process or condition of disease.

[0220] In some embodiments, the CCR9 inhibitors of the present disclosure are pharmaceutical compounds having crystalline forms. Non-limiting examples of such crystalline forms of CCR9 inhibitors are described in, for example, U.S. Patent No. 9,133,124, the disclosure of which is incorporated by reference herein in its entirety for all purposes.

[0221] Pharmaceutical compositions containing the active ingredient can be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, and self-emulsifying solutions, hard or soft capsules, or syrups or elixirs, as described in U.S. Patent No. 6,451,399. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions. Such compositions can contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with other nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients can be for example, inert diluents, such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, dextrose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, PVP, cellulose, PEG, starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets can be uncoated or they can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over an extended period of time. For example, a time delay material such as a glyceryl monostearate or glyceryl distearate can be employed. These tablets can also be coated by the techniques described in U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release.

[0222] Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. Additionally, emulsions can be prepared using non-water miscible components, such as oils, and stabilized with surfactants, such as di-glycerides, PEG esters.

[0223] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be a naturally occurring phosphatide (for example, lecithin), or an oleic acid ester or a partial ester of a hexitol (for example, sorbitol monooleate), or a condensation product of an oleate ester with ethylene oxide (for example, polyoxyethylene sorbitol monooleate). The aqueous suspension can also contain one or more preservatives (for example, ethyl alcohol or n-propyl alcohol), one or more colorants, one or more flavoring agents, and one or more sweetening agents (such as sucrose or saccharin).

[0224] Oil suspensions can be formulated by suspending the active ingredients in a vegetable oil (for example, arachis oil, olive oil, sesame oil or coconut oil) or a mineral oil (for example, liquid paraffin). The oil suspensions can contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents (such as those set forth above) and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

[0225] 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, 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, can also be present.

[0226] The pharmaceutical compositions of this application can also be in the form of oil-in- water emulsions. The oily phase can be a vegetable oil (for example, olive oil or arachis oil), a mineral oil (for example, liquid paraffin) or a mixture of these. Suitable emulsifying agents can be naturally occurring gums (for example, acacia or tragacanth), naturally occurring phosphatides (for example, soybean, lecithin and egg phosphatidyl- choline and esters or partial esters derived from fatty acids) and hexadecylated alcohols (for example, sorbitan monooleate) and condensation products of these partial esters with ethylene oxide (for example, polyoxyethylene sorbitan monooleate). The emulsions can also contain sweetening and flavoring agents.

[0227] Syrups and elixirs can be formulated with sweetening agents (for example, glycerol, propylene glycol, sorbitol or sucrose) and can also contain a demulcent, preservative, flavoring and coloring agents. Oral solutions can be prepared with, for example, cyclodextrins, PEG and surfactants.

[0228] The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation can 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 can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0229] The compounds disclosed herein can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. Additionally, the compounds can be administered via ocular delivery by way of solution or ointment. Still further, transdermal delivery of the subject compounds can be achieved by means of iontophoresis patches and the like.

[0230] For topical use, creams, ointments, gels, solutions or suspensions can be employed containing the compounds of the present application. As used herein, topical application is also meant to include use of mouth washes and gargles.

[0231] The pharmaceutical compositions and methods of the present application can further comprise other therapeutically active compounds as described herein, such as those used in the treatment of the pathological conditions described above.

[0232] 3. Anti-IL-23 blocking antibodies

[0233] Anti-IL-23 antibodies suitable for treating inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis) include antibodies from any desired source that inhibit the binding of IL-23 to any ligand. Anti-IL-23R antibodies bind to the IL-23 receptor or fragments thereof. Anti-IL-23 or anti-IL-23R antibodies can be human, mouse, rabbit, engineered antibodies such as chimeric antibodies, humanized antibodies, and antigen-binding fragments of antibodies such as Fab, Fv, scFv, Fab' and F(ab')2 fragments.

[0234] Non-limiting examples of anti-IL-23 antibodies for use in the methods or compositions described herein include risankizumab, guselkumab ustekinumab, briakinumab, briollumab, mirikizumab, risankizumab, or a biosimilar, biologically similar, or biologically equivalent drug thereof. Other useful anti-IL-23 antibodies include biosimilars, biogeneric, and biologically equivalent drugs 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 briollumab. In some embodiments, the anti-IL-23 blocking antibody is mirikizumab. In some embodiments, the anti-IL-23 blocking antibody is risankizumab.

[0235] In some embodiments, the anti-IL-23 antibody of the present disclosure is an antibody having an amino acid sequence that has at least 70%, at least 80%, at least 90%, at least 95%, or more sequence identity to an anti-IL-23 reference antibody known to one of skill in the art (e.g., risankizumab) or other anti-IL-23 antibody. In some embodiments, the anti-IL-23R antibody of the present disclosure is an antibody having an amino acid sequence that has at least 70%, at least 80%, at least 90%, at least 95%, or more sequence identity to an anti-IL-23R reference antibody known to one of skill in the art (e.g., briollumab) or other anti-IL-23R antibody. 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.

[0236] One of skill in the art recognizes that the "percent sequence identity" can be determined by comparing two optimally aligned sequences over a comparison window or designated region of the sequences, wherein the portion of the polypeptide sequence in the comparison window can include additions or deletions (i.e., gaps) as compared to the reference sequence (which does not include additions or deletions) for optimal alignment of the two sequences. The percent sequence identity is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the comparison window, and multiplying the result by 100 to yield the percent sequence identity. The percent sequence identity is measured using the BLAST or BLAST 2.0 sequence comparison algorithms with default parameters, or by manual alignment and visual inspection.

[0237] 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, e.g., Harlow, E. and Lane DP. Antibodies: A Laboratory Manual. Cold Spring Harbor: Cold Spring Harbor Laboratory Press, 1988. Antigen binding fragments such as Fab and F(ab')2 fragments can be produced by genetic engineering. Methods 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 producing and using transgenic animals to produce human or partially human antibodies are described in, e.g., Davis et al., 2003, Production of human antibodies from transgenic mice in Lo, ed. Antibody Engineering Methods and Protocols, Humana Press, NJ: 191-200.

[0238] 4. Pharmaceutical formulations of anti-IL-23 antibodies

[0239] The formulations of anti-IL-23 or anti-IL-23R antibodies provided herein can stabilize the antibodies, reduce antibody aggregate formation, slow antibody degradation, and / or minimize the immunogenicity of the antibodies. The formulations can include an antioxidant or chelating agent, at least one free amino acid, a surfactant, a non-reducing sugar, and / or a buffer.

[0240] The antioxidant or chelator can be citrate, ethylenediaminetetraacetic acid (EDTA), ethylene glycol tetraacetic acid (EGTA), dimercaprol, diethylenetriaminepentaacetic acid, or N,N-bis(carboxymethyl)glycine; preferably citrate or EDTA. The free amino acid can be histidine, alanine, arginine, glycine, glutamic acid, and combinations thereof. The surfactant can be polysorbate 20; polysorbate 80; TRITON (t- octylphenoxypolyethoxyethanol, a non-ionic 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; lauryl amidopropyl-, cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmitamidopropyl- or isostearamidopropyl- betaine (e.g., lauryl amidopropyl); myristamidopropyl-, palmitamidopropyl- or isostearamidopropyl-dimethylamine; sodium methyl cocoyl taurate or disodium methyl oleyl taurate; sorbitan monopalmitate; polyethylene glycol (PEG), polypropylene glycol (PPG), and copolymers of polyoxyethylene and polyoxypropylene; preferably polysorbate 80.

[0241] The buffer can be one that adjusts 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 pH about 6.3 to about 6.5. Non-limiting examples of buffers 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), bicine, and other organic acid buffers, preferably histidine or citrate.

[0242] In some embodiments, the anti-IL-23 or anti-IL-23R antibody is in a lyophilized formulation, e.g., a dry form. In some cases, the lyophilized formulation includes the antibody and one or more excipients, such as a non-reducing sugar, a buffer, a free amino acid, and / or a surfactant.

[0243] 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, at least about 900 mg of the antibody. In some cases, the lyophilized formulation is stored in a single dose in one vial.

[0244] In some embodiments, the anti-IL-23 or anti-IL-23R antibody is a liquid formulation. Such formulations can include the antibody, a buffer, a non-reducing sugar, and / or a free amino acid.

[0245] The amount of antibody present in the liquid formulation can be at least about 25 mg / ml to about 200 mg / ml of the anti-IL-23 antibody, e.g., 25 mg / ml to about 200 mg / ml, 25 mg / ml to about 150 mg / ml, 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 the antibody.

[0246] The non-reducing sugar can be, but is not limited to, mannitol, sorbitol, sucrose, trehalose, raffinose, stachyose, melezitose, dextran, maltitol, lactitol, isomaltulose, isomalt, and combinations thereof. In some embodiments, the ratio of the non-reducing sugar to the anti-IL-23 antibody is at least 400: 1 (mole:mole), at least 400: 1 (mole:mole), at least 400: 1 (mole:mole), at least 600: 1 (mole:mole), at least 625: 1 (mole:mole), at least 650: 1 (mole:mole), at least 700: 1 (mole:mole), at least 750: 1 (mole:mole), at least 800: 1 (mole:mole), at least 1000: 1 (mole:mole), at least 1100: 1 (mole:mole), at least 1200: 1 (mole:mole), at least 1300: 1 (mole:mole), at least 1400: 1 (mole:mole), at least 1500: 1 (mole:mole), at least 1600: 1 (mole:mole), at least 1700: 1 (mole:mole), at least 1800: 1 (mole:mole), at least 1900: 1 (mole:mole), or at least 2000: 1 (mole:mole).

[0247] C. Methods of administering combination therapy

[0248] In another aspect, the present disclosure provides combination therapies for the treatment of IBD, such as CD and UC. The combination therapies include 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 achieve a therapeutic or prophylactic effect on various disorders. Using this approach, lower dosages of each agent can be used to achieve a therapeutic effect, thereby reducing potential adverse side effects.

[0249] The term "therapeutically effective amount" means the amount of the subject compound that will elicit the biological or medical response of a cell, tissue, system or animal, such as a human, that is being sought by a researcher, veterinarian, medical doctor or other treatment provider.

[0250] The compounds, antibodies and formulations of the present disclosure can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracerebral injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical routes, depending on the disease state and condition of the subject. In addition, the compounds and antibodies can be formulated in dosage unit form, in suitable dosage unit formulations for each of the above-mentioned routes of administration. The present disclosure also contemplates administration of the compounds and antibodies of the present disclosure in a depot formulation.

[0251] In treating IBD, such as Crohn's disease and UC, an appropriate dosage level for a CCR9 inhibitor will generally be about 0.001 to 100 mg per kg of patient body weight per day in single or divided doses. Preferably, the dosage level will be 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 can 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 the dosage can 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.

[0252] For oral administration, the CCR9 inhibitor is preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, more 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 the active ingredient, for the symptomatic adjustment of the dosage to the patient to be treated.

[0253] The CCR9 inhibitor can be administered according to a regimen of one to four times per day, preferably once or twice per day.

[0254] In treating IBD such as Crohn's disease and UC, an appropriate dosage level of an anti-IL-23 or anti-IL-23R antibody provides an effective amount of the antibody or formulation thereof 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 of about 5 μg / ml to about 60 μg / ml at the end of the induction phase, e.g., a mean trough serum concentration of an anti-IL-23 or anti-IL-23R antibody 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 at the end of the induction phase.

[0255] A suitable dosage of the antibody 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.

[0256] In some embodiments, the total dosage 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; if a response occurs, the antibody is administered every four weeks at 400 mg.

[0257] In some embodiments, the induction phase is a treatment lasting 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.

[0258] Treatment regimens during the induction phase can include high dose administration, frequent administration, or a combination of high dose administration and frequent administration of the anti-IL-23 antibody or formulation thereof. In some cases during the induction phase, the dose is administered once a day, once every other day, once every two days, once every three days, once a week, once every 10 days, once every two weeks, once every three weeks, or once a month.

[0259] In some embodiments, the induction dosing is provided once at the start of treatment (Day 0) and once about two weeks after the start of treatment. The induction phase can last for six weeks. In other embodiments, the induction phase lasts for six weeks and multiple induction doses are administered during the first two weeks. In certain cases, the induction phase is longer in duration for a human patient who has severe IBD or who is unresponsive to anti-IL-23 therapy than for a patient who has mild to moderate IBD.

[0260] In treating IBD, an appropriate dose level of the anti-IL-23 antibody provides an effective amount of the antibody or formulation thereof to maintain remission of IBD in a human patient. Thus, during the maintenance phase of treatment, a therapeutically effective amount of the anti-IL-23 or anti-IL-23R antibody is sufficient to achieve an average steady state trough serum concentration of anti-IL-23 or anti-IL-23R antibody of about 1 μg / ml to about 25 μg / ml during the maintenance phase, e.g., an average steady state trough serum concentration of anti-IL-23 or anti-IL-23R antibody of 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, about 1 μg / ml to about 5 μg / ml, 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 at the end of the induction phase.

[0261] The maintenance dose can be administered once a week, once every other week, once every three weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, or once every 10 weeks. In some embodiments during the maintenance phase, the same dosing amount is administered. In other embodiments during the maintenance phase, one or more different dosing amounts are administered over the maintenance phase. Additionally, the dosing frequency can be increased depending on the course of the disease.

[0262] The anti-IL-23 or anti-IL-23R antibody or formulation thereof can be administered by injection, e.g., intravenous injection, intramuscular injection, subcutaneous injection, intraarterial injection, intraperitoneal injection, intravitreal injection, etc. If the formulation is in solid or lyophilized form, the process of administering the antibody can include reconstituting the dry formulation into a liquid formulation. In some embodiments, the antibody or formulation thereof can be administered topically, e.g., in the form of a patch, cream, aerosol, or suppository. In other embodiments, topical routes of administration include nasal, inhalation, or transdermal administration.

[0263] It will be understood, however, that the specific dose level and frequency of dosage for any particular patient can be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition being treated, and the host undergoing therapy.

[0264] The weight ratio of the CCR9 inhibitor described herein to the anti-IL-23 or anti-IL-23R antibody of the present disclosure can vary and depends on the effective dose of each component. Generally, the effective dose of each will be used. Thus, for example, where the CCR9 inhibitor is combined with the 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 in the range of about 200: 1 to about 1 : 200.

[0265] Combination therapy includes co-administration of the CCR9 inhibitor and the anti-IL-23 antibody, sequential administration of the CCR9 inhibitor and the anti-IL-23 antibody, administration of a composition containing both the CCR9 inhibitor and the anti-IL-23 antibody, or simultaneous administration of separate compositions such that one composition contains the CCR9 inhibitor and the other composition contains the anti-IL-23 antibody.

[0266] Co-administration includes administration of 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 in any sequential order. Furthermore, the CCR9 inhibitor and the anti-IL-23 antibody can each be administered once daily, or twice, three times, or more times daily to provide the preferred dosage level per day.

[0267] The combination therapy can be administered during an induction phase or a 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 antibody of the therapy, to induce a clinical response, and / or to ameliorate one or more symptoms of IBD. In addition, if during the maintenance phase, one or more symptoms of IBD reappear, or if relapse from remission of the disease occurs, the patient can be administered an amount corresponding to the induction phase treatment. During the maintenance phase, the combination therapy can be administered in an amount effective to continue the response achieved during the induction therapy and / or to prevent reappearance or relapse of symptoms of IBD.

[0268] In some embodiments, one or more additional active ingredients, such as anti-inflammatory compounds, e.g., sulfasalazine, azathioprine, 6-mercaptopurine, 5-aminosalicylic acid with anti-inflammatory agents, non-steroidal anti-inflammatory compounds, and steroidal anti-inflammatory compounds; antibiotics, e.g., ciprofloxacin and metronidazole, typically administered to control IBD; or another biologic agent, e.g., a TNF alpha antagonist, can be administered in combination with the combination therapy disclosed herein.

[0269] D. Kits

[0270] In some aspects, provided herein are kits containing a CCR9 inhibitor and an anti-IL-23 or anti-IL-23R antibody disclosed herein, which can be used to treat a disease or disorder characterized by inflammation of the gastrointestinal tract, such as IBDs including CD, UC, and indeterminate colitis. The kits can include a pharmaceutical composition containing a CCR9 inhibitor compound, e.g., a small molecule inhibitor of CCR9, and a pharmaceutical composition containing an anti-IL-23 or anti-IL-23R antibody. In some embodiments, the CCR9 inhibitor compound is a compound of Formula (I), (II), (III), (Ilia), or (Illb). 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. In some cases, the kits include written material, e.g., instructions for use of the compounds, antibodies, or pharmaceutical compositions thereof. Without limitation, the kits can include buffers, diluents, filters, needles, syringes, and package inserts with instructions for use in performing any of the methods disclosed herein.

[0271] IV. Examples

[0272] The following examples are provided to demonstrate the claimed invention, but not to limit the claimed invention.

[0273] Example 1: Piroxicam accelerates MDR1a - / - Colitis model

[0274] FVB strain mice that lack a functional MDR1 gene (also known as ABCB1, P-gp or CD243) develop a spontaneous inflammatory bowel disease. This disease can be accelerated by the addition of the drug piroxicam to their food. FVB mice that carry a functional MDR1 gene are resistant to this disease.

[0275] Piroxicam was included in the mice's food for ten days, and the health of the mice was monitored for a total of 21 days, both during the piroxicam feeding and after. Symptoms monitored during this time included the severity of diarrhea and changes in body weight.

[0276] Colonic inflammation manifests as thickening of the colon wall and shortening of the colon itself. Thus, the severity of the disease can be assessed by the ratio of the weight of the colon to its length.

[0277] The mice used were female 6-week-old FVB MDR1a(+ / +) and FVB MDR1a(- / -). Mice were standardized for body weight (BW) at 7 weeks of age, at which time their diet was switched to powdered food 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 at day 3 and at the time of dosing to determine trough levels of the compound. Rat IgG levels (anti-IL23 or isotype-matched control) were quantified by ELISA at the terminal bleed. At sacrifice, the colon was photographed and the weight / length ratio was calculated. Two colons per group were formaldehyde-fixed for future pathological evaluation and disease scoring. The remaining colons per group were isolated for flow cytometry analysis of infiltrating immune cells.

[0278] Table 1: 21-day piroxicam-accelerated MDR1a - / - Colitis model: Anti-IL-23 + CCR9 inhibitor combination.

[0279]

[0280] Compound 1 was dosed at 90 mg / kg in 10% polyoxyl castor oil, SC, BID, and Compound 2 was dosed at 30 mg / kg in 1% HPMC, SC, QD. Vehicle 1 was 10% polyoxyl castor oil and was administered SC, BID. Vehicle 2 was 1% HPMC administered SC, QD. Anti-mouse IL-23 clone G23-8 (rat IgGl) was dosed at 300 μg / mouse, QD / QOD; isotype-matched control clone HRPN (rat IgGl) was dosed at 300 μg / mouse, QD / QOD.

[0281] Blood was collected from all mice dosed with Compound 1 and Compound 2 at trough and plasma was analyzed by liquid chromatography-mass spectrometry to determine concentrations. Trough blood was collected after 3 days post-dose Figure 1 The groups refer to the names shown in Table I for Compound 1 (left panel) and Compound 2 (right panel) at trough, which levels reached or exceeded the minimum concentration determined for 98% receptor coverage (dashed line).

[0282] A clear difference in the colon W:L ratio (i.e., the extent of chronic inflammation) in the piroxicam response can be observed between wild-type FVB mice Figure 2 ; circles) and FVB mice lacking the MDR1a gene Figure 2 ; squares).

[0283] Figure 3 It is shown that the W:L ratio was significantly improved in mice treated with Compound 1 and anti-IL-23 in combination (p = 0.0260, inverted triangles) compared to control mice, but not in mice receiving anti-IL-23 alone (p = 0.0931, triangles).

[0284] Figure 4 It is shown that the W:L ratio was significantly improved in mice treated with Compound 2 and anti-IL-23 in combination (p = 0.0190, open inverted triangles) compared to control mice, but not in mice receiving anti-IL-23 alone (p = 0.2571, open triangles).

[0285] Compound 1 and 2 improved colonic inflammation in synergy with anti-IL-23, as only the combination treatment significantly improved the W:L ratio.

[0286] While the foregoing application has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be apparent to those skilled in the art that certain changes and modifications can be practiced. Furthermore, each of the references provided herein are incorporated by reference in their entireties to the same extent as if each reference was individually incorporated by reference.

Claims

1. Use of a CCR9 inhibitor and an anti-IL-23 blocking antibody in the manufacture of a medicament for the treatment of inflammatory bowel disease in a mammal in need thereof, wherein the CCR9 inhibitor is: or a pharmaceutically acceptable salt thereof, and wherein the anti-IL-23 blocking antibody is risankizumab, guselkumab, ustekinumab, briakinumab, briecumab, mirikizumab, or tildrakizumab.

2. Use according to claim 1, wherein, The inflammatory bowel disease is Crohn’s disease (CD) or ulcerative colitis (UC).

3. Use according to claim 1 or claim 2, wherein, The CCR9 inhibitor and the anti-IL-23 blocking antibody are administered in a combined formulation.

4. The use according to claim 1 or claim 2, wherein, The CCR9 inhibitor and the anti-IL-23 blocking antibody are administered sequentially.

5. Use according to claim 4, wherein, The CCR9 inhibitor is administered prior to the anti-IL-23 blocking antibody.

6. The use according to claim 4, wherein, The CCR9 inhibitor is administered after the anti-IL-23 blocking antibody.

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