NZ727475B2 - Aryl receptor modulators and methods of making and using the same - Google Patents

Abstract

The present invention is generally directed towards compounds capable of binding the aryl hydrocarbon receptor and modulating its activity,methods of treating inflammatory conditions such as Crohn's disease using such compounds, and pharmaceutical compositions comprising such compounds. Also provided are methods of increasing levels of IL-22 in a subject and/or decreasing levels of IFN-? in a subject.

Description

ARYL RECEPTOR MODULATORS AND METHODS OF MAKING AND USING THE RELATED APPLICATIONS This application claims the bene?t of US. Provisional Application No. 62/017,959, ?led June 27, 2014, and US. Provisional Application No. 62/056,054, ?led September 26, 2014, the entire ts of each of which are incorporated by nce herein.

BACKGROUND Aryl hydrocarbon receptor (AhR), a basic helix-loop-helix protein, is a member of the Per—ARNT—Sim (PAS) amily ofproteins. Physio lly, many of these proteins act by sensing molecules and stimuli from the cellular/tissue microenvironment, thereby initiating signaling cascades necessary to elicit appropriate cellular responses.

In its inactive state, AhR resides in the cytosol bound to several co-chaperones, but after activation, it migrates into the nucleus and binds its dimerization partner, ARNT (another bHLH—PAS protein), thus initiating the transcription of a variety of genes with promoters containing a dioxin (DRE) or otic consensus ce (XME). Pioneering studies in AhR—de?cient mice have emphasized the role ofAhR in the development and functions of various organs. More recent studies have shown that AhR controls speci?c immune responses (see, for example, Stockinger et al., Semin. Immunol. 2011, 23, 99-105).

[0004] AhR is highly expressed by T cells and controls Thl/Th2/Th17 cell-associated immunity. In humans and in mouse models of in?ammatory bowel disease, activation ofAhR led to a diminished sion of IFN-y and T-bet, the main transcription factor that drives the Thl polarization. The basic ism by which AhR inhibits IFN-y production remains to be ascertained, however, it has been trated that AhR ing enhances Aiolos, a member ofthe Ikaros family, that negatively regulates IFN-y production and colitis in mice. AhR activation in lymphoid cells can also regulate production of interleukin-22 ), a cytokine that can exert protective effects in various organs and time-course studies showed that suppression of IFN-y and T-bet preceded IL-22 induction.

In light of the potential for ive AhR modulators to affect immunity and ation and thus treat a variety of in?ammatory conditions, there exists a need for potent and selective compounds that modulate AhR activity.

SUMMARY [0005a] According to a first aspect, the present disclosure provides a compound according to a I: (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: Ar is represented by ; G1 is N and G2, G3, and G4 are CH2; G1 is CH, G2 and G4 are NH, and G3 is CH2; or G1 is N, G2 and G4 are CH2, and G3 is NH; and X1 if present is selected independently for each ence from the group consisting of halogen, –OH, –CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, –O– phenyl, –N(R1)2, –NO2, –C1-6 alkylene–N(R1)2, –C(O)N(R3)2, –CO2R3, –C(O)R3, –SR3, –SO2R3, –SO3R3, and –SO2N(R3)2; X2 if t is selected independently for each ence from the group consisting of halogen, –OH, –CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, –O– phenyl, –N(R1)2, –NO2, –C1-6 alkylene–N(R1)2, –C(O)N(R3)2, , –SR3, –SO2R3, –SO3R3, or –SO2N(R3)2; R1 is independently for each occurrence H or C1-6 alkyl; R2 is independently for each occurrence H or C1-6 alkyl; R3 is independently for each ence selected from the group consisting of H, C1-6 alkyl, phenyl, or heteroaryl; n is independently for each occurrence 0, 1, 2, or 3; and m is independently for each occurrence 0, 1, 2, 3, or 4; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, or –O–phenyl may each be optionally substituted independently for each occurrence with 1, 2, or 3 substituents each independently ed from the group consisting of halogen, –OH, –CN, –NR’R’’, – R’R’’), and –C(O)R’, wherein R’ and R’’ are each independently selected from H, methyl, ethyl, propyl or butyl, or R’ and R’’ taken together form a 4-6 membered heterocycle. [0005b] According to another aspect, the present sure provides a nd of the following formula: , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein Ar is represented by ; X1, if present, is selected independently for each occurrence from the group consisting of halogen, –OH, –CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, –O– phenyl, –N(R1)2, –NO2, –C1-6 alkylene–N(R1)2, –C(O)N(R3)2, –CO2R3, –C(O)R3, –SR3, , –SO3R3, and –SO2N(R3)2; R1 is independently for each occurrence H or C1-6 alkyl; R3 is independently for each occurrence selected from the group consisting of H, C1-6 alkyl, phenyl, and heteroaryl; and m is independently for each occurrence 0, 2, 3, or 4, wherein each instance of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, or –O–phenyl may be optionally substituted with 1, 2, or 3 tuents each independently selected from the group consisting of halogen, –OH, –CN, –NR’R’’, – C(O)N(R’R’’), and –C(O)R’, and n R’ and R’’ are each independently selected from the group consisting of H, methyl, ethyl, propyl, and butyl, or R’ and R’’ taken together form a 4- 6 membered heterocycle. [0005c] According to another aspect, the present sure provides a pharmaceutical composition, comprising a compound according to the invention; and a pharmaceutically acceptable carrier. [0005d] According to another aspect, the t disclosure provides use of a compound according to the invention or a pharmaceutical composition according to the invention in the manufacture of a ment for sing IFN-? levels. [0005e] According to another aspect, the t disclosure es use of a compound according to the invention or a ceutical composition according to the invention in the cture of a medicament for increasing IL-22 levels. [0005f] According to another aspect, the t disclosure provides use of a compound according to the invention or a pharmaceutical composition according to the invention in the manufacture of a medicament for increasing IL-22 levels and decreasing IFN-? levels. [0005g] According to another aspect, the present disclosure provides use of a compound according to the invention or a pharmaceutical composition according to the invention in the manufacture of a medicament for inhibiting lipid peroxidation. [0005h] According to another aspect, the t disclosure provides use of a compound according to the invention or a pharmaceutical composition according to the invention in the manufacture of a medicament for modulating an aryl hydrocarbon or (AhR). [0005i] According to another aspect, the present disclosure es use of a compound according to the invention or a pharmaceutical composition according to the invention in the manufacture of a medicament for treating an inflammatory disease or condition. [0005j] According to another , the present disclosure provides use of a compound according to the invention or a pharmaceutical composition according to the invention in the manufacture of a ment for preventing, treating, or reducing fibrostenosis or intestinal fibrosis.

The present disclosure, in an embodiment, provides potent and selective AhR-binding nds. In one , the present disclosure provides a nd according to Formula I: wherein the variables are as defined below.

In one aspect, the present disclosure relates to a compound according to Formula I-A: (I-A) n the variables are as defined below.

In one aspect, the t disclosure relates to a compound according to Formula II: wherein the variables are as defined below.

In one aspect, the present disclosure relates to a compound according to Formula III: (III) wherein the variables are as defined below. 2d followed by page 3 In one aspect, the present sure relates to a compound according to Formula IV: 0 Ar wherein the les are as de?ned below.

The present sure also provides s of treating an in?ammatory disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described above. In certain embodiments, the atory disease or condition is selected from the group consisting of in?ammatory bowel disease, cartilage in?ammation, bone degradation, ulcerative colitis, psoriasis, arthritis, psoriatic arthritis, rheumatoid arthritis, juvenile arthritis, juvenile rheumatoid arthritis, autoimmune hepatitis, s disease, lupus erythematosus, multiple sclerosis, mer’s disease, dermatitis, atopic dermatitis, acne, Type I diabetes mellitus, Raynaud’s phenomenon, Graves’ disease, and Addison’s disease.

In certain embodiments, the in?ammatory e or condition is selected from the group consisting of s disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, diversion colitis, Behcet’s e, idiopathic in?ammatory bowel disease, irritable bowel syndrome, regional enteritis, spastic colon, microscopic colitis, Crohn’s colitis, perianal disease, indeterminate colitis, lymphocytic gastritis, and eosinophilic enteritis.

In certain embodiments, the in?ammatory disease or condition is Crohn’s disease. In n embodiments, the Crohn’s disease is selected from the group consisting of ileocolitis, s, gastroduodenal Crohn’s disease, j ejunoileitis, and granulomatous ileocolitis. In certain embodiments, the Crohn’s disease includes intestinal s. In certain embodiments, the Crohn’s disease is ?brostenotic Crohn’s disease.

In another aspect, the present disclosure provides a method of preventing, treating, or reducing ?brostenosis or intestinal ?brosis in a t, comprising stering to a subject in need thereof a eutically effective amount of a nd disclosed herein. In certain ments, the ?brostenosis or intestinal ?brosis is associated with Crohn’s disease.

In another aspect, the present invention provides a compound as described above for use as a medicament. The present invention further provides a compound as described above for use in a method of treating an in?ammatory e or condition. The method comprises administering to a subject in need f a therapeutically effective amount of said compound.

In certain embodiments, the in?ammatory disease or condition is ed from the group consisting of in?ammatory bowel e, cartilage in?ammation, bone degradation, ulcerative s, psoriasis, arthritis, psoriatic arthritis, rheumatoid arthritis, juvenile arthritis, juvenile toid arthritis, autoimmune hepatitis, Crohn’s disease, lupus erythematosus, multiple sclerosis, mer’s disease, dermatitis, atopic dermatitis, acne, Type I diabetes us, Raynaud’s phenomenon, Graves’ disease, and Addison’s disease. In n embodiments, the in?ammatory disease or condition is selected from the group consisting of Crohn’s disease, ulcerative colitis, enous colitis, lymphocytic colitis, diversion colitis, Behcet’s disease, idiopathic in?ammatory bowel disease, irritable bowel me, regional enteritis, c colon, microscopic colitis, Crohn’s colitis, perianal disease, indeterminate colitis, lymphocytic gastritis, and eosinophilic enteritis. In certain embodiments, the in?ammatory disease or condition is Crohn’s disease. In certain embodiments, the Crohn’s disease is selected from the group ting of ileocolitis, ileitis, gastroduodenal Crohn’s disease, jejunoileitis, and granulomatous ileocolitis. In certain embodiments, the Crohn’s e includes intestinal ?brosis. In certain ments, the Crohn’s disease is ?brostenotic Crohn’s disease.

In yet another aspect, the present invention provides the compound as described above for use in a method of preventing, treating or reducing ?brostenosis or intestinal ?brosis in a subject. The method comprises administering to a subject in need thereof a therapeutically effective amount of said nd. In certain embodiments, the ?brostenosis or intestinal ?brosis is associated with Crohn’s disease.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 shows a series of -l,2,3,4-tetrahydro-B-carboline derivatives.

Figure 2 shows modi?cations made to the l-aryl—l,2,3,4-tetrahydro-B-carboline ld to study the SAR and provide improved properties.

Figure 3 shows modi?cations made to the l-aryl—l,2,3,4-tetrahydro-B-carboline scaffold to study the SAR and provide improved properties.

[0020] Figure 4 shows modi?cations made to the l-aryl—l,2,3,4-tetrahydro-B-carboline scaffold to study the SAR and provide improved properties.

Figure 5 shows modi?cations made to the Leflunomide scaffold to study the SAR and provide improved properties.

Figure 6 shows the chemical structures of various compounds evaluated for ADMET and other properties in the present disclosure.

Figure 7 shows the chemical structures of various compounds evaluated for ADMET and other properties in the present sure.

Figure 8 shows the chemical structures of s compounds evaluated for ADMET and other properties in the present disclosure.

Figure 9 shows the chemical structures of various compounds evaluated for ADMET and other properties in the present disclosure.

Figure 10 shows calculated bioavailability data for compounds of the present disclosure. All ADME data were calculated using ADME Suite v4.9.5.3. Human oral ilability (%F) Human oral bioavailability (%F) is the compound fraction that reaches systematic circulation after oral administration. In order to be bioavailable, a drug must comply with the following requirements: dissolve in the stomach or intestine under variable pH; withstand acid hydrolysis at pH < 2; permeate through intestinal ne by passive or active transport; and P-gp ef?ux in concert with metabolic enzymes in intestine; and withstand ?rst pass metabolism in liver.

Figure 11 shows calculated aqueous solubility (log Sw) ofvarious compounds of the present disclosure. Solubility (log Sw) of a compound in pure water at 25 CC and at various physiologically important pH values was predicted.

Figure 12 shows ated pH ent solubility for various compounds of the present disclosure.

Figure 13 shows calculated human intestinal passive absorption for various compounds of the present disclosure. The human intestinal permeability was ed h estimation ofmaximum intestinal passive absorption of a compound taking into account the transcellular and paracellular routes of permeability. Absorption related ties such as jejunum and Caco—2 permeabilities, and absorption rates (ka) values were also calculated using ilicity (log P) and ionization (pKa) constants.

Figure 14 shows calculated active transport across the intestinal barrier for various compounds of the t sure. The ated transport included estimation of PepTl (oligopeptide transporter) and ASBT (bile acid transporter) substrate prediction.

Figure 15 shows calculated P—glycoprotein speci?city for s nds of the present disclosure. The algorithm identi?es P—gp substrates and/or inhibitors. Substrates are compounds that are orted (ef?uxed) by P-gp. tors are compounds that block P—gp transport of the rd substrates (calcein—AM and others).

Figure 16 shows calculated tissue distribution of various compound of the present disclosure. The software predicts the extent ofplasma protein binding to obtain the percentage ofcompound that circulates in free, pharmaco logically active form, and calculates the apparent volume of distribution for an estimation of the distribution of compounds between plasma and body tissue.

Figure 17 shows calculated interaction of various compounds of the present disclosure with cytochrome P45 0s. The software calculates how nds will interact with the ?ve cytochrome P450 (CYP) ms: 3A4, 2D6, 2C9, 2C19, and 1A2, that are responsible for the majority of metabolic reactions.

Figure 18 shows data calculated with Tox Suite v 2.95 expressing the likelihood of genotoxicity resulting from various compounds ofthe present disclosure. Genotoxicity = Probability of positive Ames test. The Ames test is one of the most popular tests for assessing mutagenic properties of compounds. It is a short term bacterial reverse mutation test. This test is performed on various S. thyphimurz’um and E. 0011' bacteria strains. The Ames test is used worldwide as an initial screen to determine mutagenic properties ofNCEs in the drug and chemical industry.

Figure 19 shows data expressing the calculated likelihood that various compounds of the t disclosure will inhibit hERG. Studies of hERG potassium ion channel tion constitute an emerging ?eld in pharmacological safety ch. ctions of drugs with the hERG channel may lead to long QT syndrome, manifesting as characteristic ‘Torsades de Pointes’ arrhythmia, leading to occasional fatality caused by ventricular ?brillation. In recent years several ing drugs have been withdrawn from the market due to a number of sudden cardiac death occasions triggered by hERG channel inhibition. Thus, early identi?cation of leads possessing potential safety issues is of extreme importance to prevent costly failures of R&D projects.

Figure 20 shows the ated probability of health effects for various compounds ofthe present disclosure. Predictions on health effects are based on erm toxicity studies with adverse effects reported on particular organs or organ systems.

Figure 21 shows calculated LDso values for various compounds ofthe present disclosure. LDso values can be viewed as an indication of the “cumulative ial” to cause various acute effects and death of animals and are the most widely used measure of the “acute systemic toxicity” ofthe chemical.

Figure 22 shows the effects, at a ?nal concentration of 200 nM, of various nds of the present disclosure on IL-22 and IFN—y levels.

[0039] Figure 23 shows the effects of various compounds of the present disclosure on IL—22 and IFN-y levels, as well as the chemical structure of known AhR binder Ficz.

Figure 24 shows the s of various nds of the present sure on IL—22 and IFN—y levels. For each entry, the ?rst number refers to the compound number and the second number refers to the concentration in nM, thus, “02 100” refers to administration of compound 2 at a concentration of 100 nM, “04 200” to stration of compound 4 at a concentration of 200 nM, etc.

Figure 25 (A) shows evaluation of AhR ripts in ?broblasts isolated from gut mucosa of 6 normal patients (control group; CTR), 7 patients with ulcerative colitis (UC), and 7 with Crohn’s disease (CD) by real time PCR and normalized to B-actin. Figure 25 (B) shows ?ow cytometry analysis ofAhR in ?broblasts isolated from 5 normal patients (CTR), 5 patients with UC, and 5 patients with CD. Right insets show representative histograms ofAhR- expressing ?broblasts isolated from one CTR, one patient with UC, and one patient with CD.

Staining with an isotype control IgG is also shown. Data indicate mean +/- SD of all experiments. Taken together, these data demonstrate that intestinal ?broblasts constitutively express AhR.

Figure 26 (A) shows the results of stimulating Crohn’s disease (CD) intestinal ?broblasts with TGF-B (1 ng/mL) in the presence or absence of Ficz (100, 200, or 400 nM).

Figure 26 (B) shows the s of stimulating CD intestinal ?broblasts with TNF-(x (15 ng/mL) in the presence or absence of Ficz (100, 200, or 400 nM). CollAl, Col3A1, and u-SMA were examined by real-time PCR after 24 hours. Data indicate mean +/- SD of 3 experiments. Taken er, these data demonstrate that AhR activation inhibits ?broblast collagen expression induced by pro—?brotic cytokines.

Figure 27 (A) shows the results of stimulating Crohn’s disease (CD) intestinal ?broblasts with TGF-B (1 ng/mL) in the presence or absence of CH223 l9l (a-AhR, ?nal concentration 10 nM). Figure 27 (B) shows the results of stimulating CD intestinal ?broblasts with TNF-o. (15 ng/mL) in the presence or absence of CH223 l9l (a-AhR, ?nal concentration 10 uM). CollAl, , and d-SMA were analyzed by real-time PCR after 24 hours. Data indicate mean +/- SD of 3 experiments.

Figures 28 (A) — (D) show total collagen analysis of tants of Crohn’s disease (CD) ?broblasts stimulated with TGF-B (1 ng/mL) ((A) and (C)) or TNF-(x (15 ng/mL) ((B) and (D)) in the ce or absence of Ficz ((A) and (B)) or CH223191 (a-AhR, ?nal concentration nM) ((C) and (D)) for 48 hours. Data indicate mean +/- SD of 3 experiments. Taken together, these data show that AhR controls collagen secretion.

Figure 29 (A) shows percentages of CD inal ?broblasts expressing p-p38+, p- ERK1/2+, p-NF-kBp65+, or p-Smad2/3+ that were either unstimulated (Unst) or stimulated with TGF-B (1 ng/mL) or TNF-d (15 ng/mL) in the presence or absence of Ficz (?nal concentration 200 nM) or CH223 l9l (a-AhR, ?nal concentration 10 nM) for 24 h. Assessment of p-P38 (pT180/le82), p-ERKl/2(pT202/pY204)(pT184/le86), p-NF-kBp65, and p-Smad2/3 was accomplished by ?ow try. Numbers te the tages of p-p3 8+, p-ERK1/2+, p- NF—kBp65+, or p-Smad2/3+ cells in the designated gates. Isotype control stain is also indicated.

One of 3 representative experiments in which cells of 3 ts were used is shown. Figure 29 (B) shows percentages of p-p3 8+, p—ERK1/2+, p—NF-kBp65+, or 2/3+ ?broblasts isolated from 3 CD patients stimulated either with TGF-B (1 ng/mL) or TNF-d (15 ng/mL) in the ce or absence of Ficz (?nal concentration 200 nM) or CH223191 (a-AhR, ?nal concentration 10 nM) for 24 h. Data indicate the mean :: SD of 3 experiments. * p <0.04 vs. unstimulated; ** p <0.001 vs. unstimulated; # p <0.03 vs. TGF-B; + p <0.02 vs. TNF-(x. Taken together, these data demonstrate that AhR activation leads to inactivation ofp38 and ERKl/2 in Crohn’s disease (CD) ?broblasts.

Figure 30 (A) shows a schematic view of TNBS-induced intestinal ?brosis model.

Balb/c mice were given weekly TNBS treatments and Ficz or 91 (a-AhR) were administered starting after the ?fth TNBS administration. Figure 30 (B) shows representative colon cross-sections of control (CTR) mice and TNBS-treated mice receiving Ficz or CH223191 (a—AhR) stained with Masson’s trichrome. tages of animals harboring mild, moderate, and severe ?brosis are also indicated. Figure 30 (C) shows relative RNA sion data for CollA2 in colonic samples taken from CTR mice and TNBS-treated mice injected with Ficz or CH223191 (a-AhR) analyzed by ime PCR. Figure 30 (D) shows total collagen content data (pg/mg) analyzed by colorimetric assay. Data indicate mean +/- SD of 3 separate experiments (n = 12 mice total per group). Taken together, these data demonstrate that Ficz- treated mice are largely protected from TNBS—induced intestinal ?brosis.

DETAILED DESCRIPTION In one aspect, the present disclosure provides a compound according to Formula I: (3.4-G3 A \ G/l N\ \Ar (1) or a pharmaceutically acceptable salt thereof, n: (?gS | A is' n or ; Ar is represented by ; G1 is CR4 or N; G2, G3, and G4 are each independently CR42 or NR1; X1 is independently for each occurrence H, n, —OH, —CN, C1_6 alkyl, C2_6 alkenyl, C26 alkynyl, C3_6 lkyl, C1_6 alkoxy, —O—phenyl, —N(R1)2, —N02, —C1_6 alkylene—N(R1)2, — C(O)N(R3)2, —C02R3, —C(O)R3, —SR3, —SOzR3, —SOgR3, 01‘ —SOzN(R3)2; X2 is independently for each occurrence H, halogen, —OH, —CN, C1_6 alkyl, C2_6 alkenyl, C245 alkynyl, C3_6 cycloalkyl, C1_6 alkoxy, nyl, —N(R1)2, —N02, —C1_6 alkylene—N(R])2, — C(O)N(R3)2, , —SR3, —SOzR3, —SO3R3, 01' —SOzN(R3)2; R1 is independently for each occurrence H or C1-6 alkyl; R2 is independently for each occurrence H or C1-6 alkyl; R3 is independently for each occurrence selected from the group consisting of H, CH; alkyl, phenyl, or heteroaryl; R4 is independently for each occurrence selected from the group consisting of H, C1-6 alkyl, and halogen; n is independently for each ence 0,], 2, or 3; and m is independently for each occurrence 0, l, 2, 3, or 4; wherein each instance of C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C3—6 lkyl, C1—6 alkoxy, or —O—phenyl may be optionally tuted with l, 2, or 3 substituents each independently selected from the group consisting of halogen, —OH, —CN, —NR’R” — C(O)N(R’R’ ’), and —C(O)R’ (wherein R’ and R” are each independently selected from H, methyl, ethyl, propyl or butyl, or R’ and R” taken together form a 4-6 membered heterocycle); wherein when A is G1 is CH, G3, and G4 are CH2, and G2 is NR1, X2 is not H (i.e., is not present, 11 is 0).

In certain embodiments, G1 is N.

[0049] In certain embodiments, G2 is NH.

In n embodiments, G1 is CH, G2 is NH, and G3 and G4 are CH2.

In certain embodiments, G1 is N and G2, G3, and G4 are CH2.

In n embodiments, G1 is N, G2 and G3 are CH2, and G4 is NH.

In certain embodiments, G1 is N, G2 and G4 are CH2, and G3 is NH.

[0054] In certain embodiments, G1 is CH, G2 and G4 are NH, and G3 is CH2.

In certain embodiments, Ar is 0M3 and m is l or 2. x1 OMe In certain embodiments, Ar is 0M9 In certain ments, X1 is H, halogen, —CN, or —OMe.

In certain embodiments, X1 is —OMe.

In certain ments, X2 is selected from the group consisting of H, halogen, — OH, —CN, C1-6 alkoxy, and CF3.

[0060] In certain embodiments, X2 is CF3 and n is l.

In certain embodiments, the compound is selected from the group consisting of NH HN X2 X2 x2 FC3 NH \ \ |\\ \ |\\ \ I\ \ N, N Ar / / / N Ar N Ar N , Ar, H a H H a H x2W X2 HN’» x2 NH \ l\\ ,\\ N> 8 NH \ N \ / \ H N Ar / N \Ar / \Ar N Ar ‘Me = H , H

[0062] In one aspect, the present disclosure relates to a compound according to Formula I-A: X2 N—R5 ? / \ ——\6x )n1 (I-A) or a pharmaceutically acceptable salt thereof, n: X1 is if present independently for each occurrence C1—6 alkyl, C1—6 alkoxy, —O—C16 alkylene—phenyl, C1_6 acyl, —C02R3, —N02, —OH, or —N(R1)2; or two instances ofX1 taken together may be —O(CH2)2O—; X2 is selected from the group consisting of H, C1_6 alkyl, C1_6 alkoxy, —O—C1_6 alkylene— phenyl, and —OH; R1 is independently for each occurrence H or C1—6 alkyl; R3 is independently for each occurrence H, C1_6 alkyl, phenyl, or aryl; R5 is selected from the group ting of H,C1-6 alkyl, C1-5 acyl, and —C02R3; and nis 0, l, 2, or 3; wherein each instance of C1—6 alkyl, C245 alkenyl, C2—6 alkynyl, C3—6 lkyl, C145 alkoxy, or nyl may be optionally substituted with l, 2, or 3 substituents each independently selected from the group consisting of halogen, —OH, —CN, —NR’R” — C(O)N(R’R’ ’), and —C(O)R’ (wherein R’ and R” are each independently ed from H, methyl, ethyl, propyl or butyl, or R’ and R” taken together form a 4-6 membered heterocycle).

In certain embodiments, X2 is ed from the group consisting of H, —OMe, ethyl, —OH, and —OCH2Ph.

In certain embodiments, R5 is selected from the group consisting of H, acetyl, propyl, isopropyl, butyl, isobutyl, tert—butyl, pentyl, isopentyl, and —COzCH2Ph.

[0065] In certain embodiments, X1 is independently for each occurrence H, —OMe, —N02, — COzMe, , —OC(O)Me, —OCH2Ph, —OH, —NH2, or tert—butyl; or two instances of X1 taken together may be —O(CH2)2O—.

In certain embodiments, n is 3.

In one aspect, the present disclosure relates to a compound according to a II: Ar or a pharmaceutically acceptable salt thereof, wherein: Y N Y R1 I I C 1s Ar or Ar; , m Ar is represented by 3 X1 is independently for each occurrence, if present, selected from halogen, —OH, —CN, C1_6 alkyl, C2_6 alkenyl, C245 alkynyl, C3_6 cycloalkyl, C1_5 , —O—phenyl, —N(R])2, —N02, — C1.6 alkylene—N(R1)2, —C(O)N(R3)2, —C02R3, —C(O)R3, —SR3, —SOzR3, —SOgR3, or —SOzN(R3)2; X2 is independently for each ence if present, selected from, halogen, —OH, —CN, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_6 cycloalkyl, C1_6 alkoxy, —O—phenyl, —N(R1)2, —N02, — C1_6 a]kylene—N(R1)2, —C(O)N(R3)2, —C02R3, —SR3, —SOzR3, —SO3R3, or —SOzN(R3)2; R1 is independently for each occurrence H or C1—6 alkyl, R3 is independently for each occurrence H, C1_6 alkyl, phenyl, or aryl; R4 is selected from the group consisting of H, C1_6 alkyl, C2_6 alkenyl, C26 l, — N(Rl)z, —C1—6 alkylene—N(R1)2, —C(O)N(R3)2, and —C02R3; n is independently for each occurrence 0,1, 2, or 3; m is independently for each occurrence 0, 1, 2, 3, or 4; wherein each instance of C1—6 alkyl, C245 alkenyl, C2—6 alkynyl, C3—6 cycloalkyl, C145 alkoxy, or —O—phenyl may be optionally substituted with l, 2, or 3 substituents each independently ed from the group consisting of halogen, —OH, —CN, —NR’R” — R’R’ ’), and —C(O)R’ (wherein R’ and R” are each independently selected from H, methyl, ethyl, propyl or butyl, or R’ and R” taken together form a 4-6 membered heterocycle); X3 is N or CR4; X4 is NR1, O, or S; and Y is a bond, (:16 alkylene or —N(R1)—; wherein when B is and X4 is S, X2 is not H (i.e., is not present).

In n embodiments of Formula 11 Y is CH2 or NH.

In certain embodiments, R4 is ed from the group consisting of C2_6 alkenyl, C2_6 alkynyl, —C1_6 alkylene—N(R1)2, and —C(O)N(R3)2.

[0070] In certain embodiments, R4 is allyl orW Me In certain embodiments, Ar is 0M9 and m is l or 2.

X1 OMe In certain embodiments, Ar is 0M3 In certain embodiments, X1 is H (i.e., n is 0), halogen, —CN, or —OMe.

In certain embodiments, A, B and L taken together are compounds represented by: (X20\n H “2% S N s < \ I /)—H-Ar \ | />/\Ar “(q/Wm / / N IIa, N IIb, and n H 110.

In certain embodiments, X2 is selected from the group consisting of H, halogen, — OH, —CN, C1-6 alkoxy, and CF3.

In certain embodiments, X2 is CF3 and n is l.

In one aspect, the present disclosure relates to a nd according to Formula III: Ar (III) or a pharmaceutically able salt f, wherein: Dis " , , ; Ar is represented by ; X1 may be present, and may be selected independently for each occurrence from, n, —OH, —CN, C1—6 alkyl, C2-5 alkenyl, C2—6 alkynyl, C3—6 cycloalkyl, C1—6 alkoxy, —O— phenyl, —N(R1)2, —N02, —C1-5 alkylene—N(R1)2, —C(O)N(R3)2, —C02R3, —C(O)R3, —SR3, —S02R3, —S03R3, or —S02N(R3)2; X2 may be present, and may be selected independently for each occurrence from, halogen, —OH, —CN, C1—6 alkyl, C2—6 alkenyl, C2-6 alkynyl, C3—6 cycloalkyl, C1—6 alkoxy, —O— phenyl, 2, —N02, —C1_6 alkylene—N(R1)2, —C(O)N(R3)2, —C02R3, —SR3, —S02R3, —S03R3, or —S02N(R3)2; R1 is independently for each occurrence H or C1—6 alkyl; R3 is independently for each occurrence H, C1-6 alkyl, , or heteroaryl; n is independently for each occurrence 0, 1, 2, or 3; and m is independently for each occurrence 0, 1, 2, 3, or 4; wherein each instance of C1—6 alkyl, C245 l, C2—6 alkynyl, C3—6 cycloalkyl, C145 , or —O—phenyl may be optionally substituted with l, 2, or 3 substituents each independently selected from the group consisting of halogen, —OH, —CN, —NR’R” — C(O)N(R’R’ ’), and ’ (wherein R’ and R” are each independently selected from H, methyl, ethyl, propyl or butyl, or R’ and R” taken together form a 4-6 membered heterocycle); wherein when D is X2 is not H (i.e., X2 is not present and n is 0).

In certain embodiments, Ar is 0M9 and m is l or 2.

X1 OMe

[0079] In certain embodiments, Ar is 0M9 In n embodiments, X1 is H, halogen, —CN, or —OMe.

In certain embodiments, X1 is —OMe.

In certain embodiments, X2 is selected from the group consisting of H, n, — OH, —CN, C1_6 alkoxy, and CF3.

In certain ments, X2 is CF3 and n is 1.

In one aspect, the present disclosure relates to a compound according to Formula IV: 0 Ar or a pharmaceutically acceptable salt thereof, wherein: E is a ring selected from the group consisting of heterocyclyl, ered heteroaromatic, 6-membered heteroaromatic, aromatic, and C3.6 cycloalkyl, wherein the ring is optionally substituted with 1, 2, or 3 X2; Ar is represented by ; X1 is if present, selected independently for each occurrence from the group consisting of H, n, —OH, —CN, C1—6 alkyl, C2—6 l, C2—6 alkynyl, C3—6 cycloalkyl, C1-6 alkoxy, —O— phenyl, —N(R1)2, —N02, —C1_6 alkylene—N(R1)2, (R3)2, —C02R3, —C(O)R3, —SR3, —SozR3 \- —SO3R3, or —S02N(R3)2; X2 is independently for each occurrence selected from the group consisting of halogen, — OH, —CN, C1-6 alkyl, C2-5 alkenyl, C26 alkynyl, C3-6 lkyl, C1-5 alkoxy, —O—phenyl, — N(Rl)2, —N02, —C1-6 a1kylene—N(R1)2, —C(O)N(R3)2, —C02R3, —SR3, —S02R3, —S03R3, or — Y is selected from the group consisting of a bond, NR’ or C1-6alkylene (e.g., a bond or C1_2alkylene); R1 is independently for each ence H or C1—6 alkyl; R3 is independently for each occurrence selected from the group consisting of H, CH; alkyl, phenyl, or heteroaryl; and m is independently for each occurrence 0, 1, 2, 3, or 4; wherein each instance of C16 alkyl, C245 alkenyl, C2-5 alkynyl, C36 cycloalkyl, C145 alkoxy, or —O—phenyl may be optionally substituted with l, 2, or 3 substituents each independently selected from the group consisting of halogen, —OH, —CN, —NR’R” — C(O)N(R’R’ ’), and —C(O)R’ in R’ and R” are each independently selected from H, methyl, ethyl, propyl or butyl, or R’ and R” taken er form a 4-6 membered heterocycle).

In certain embodiments, of Formula IV, Y is a bond, CH2 or NH; (for example Y may be a bond).

In certain embodiments, Ar is 0M3 and m is l or 2. x1 OMe In certain embodiments, Ar is OM? In certain embodiments, X1 is H, halogen, —CN, or —OMe.

In certain embodiments, X1 is —0Me.

[0090] In certain embodiments, X2 is selected from the group consisting of H, halogen, — OH, —CN, C1-6 alkoxy, and CF3.

In certain embodiments, X2 is CF3.

In one aspect, the present disclosure relates to a pharmaceutical composition, comprising a compound described above; and a pharmaceutically acceptable carrier.

De?nitions The term “saturated” as used herein means the compound or group so modi?ed has no carbon-carbon double and no -carbon triple bonds, except as noted below. The term does not preclude carbon—heteroatom multiple bonds, for example a carbon oxygen double bond or a carbon nitrogen double bond. Moreover, it does not preclude a carbon—carbon double bond, that may occur as part of keto—enol tautomerism or imine/enamine erism.

The term “alkyl” refers to a lent ted aliphatic group with a carbon atom as the point of attachment, a linear or branched, cyclic or acyclic structure, and no atoms other than carbon and hydrogen. Thus, as used herein cycloalkyl is a subset of alkyl. The groups —CH3 (Me), —CH2CH3 (Et), ~CH2CH2CH3 , —CH(CH3)2 (i-Pr), —CH(CH2)2 (cyclopropyl), —CH2CH2CH2CH3 (rt-Bu), —CH(CH3)CH2CH3 (sec-butyl), —CH2CH(CH3)2 (z'so-butyl), —C(CH3)3 (tert—butyl), —CH2C(CH3)3 ntyl), cyclobutyl, cyclopentyl, cyclohexyl, and, cyclohexylmethyl are non-limiting examples of alkyl groups. The term “alkylene” refers to a divalent ted aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched, cyclo, cyclic or acyclic structure, no carbon—carbon double or triple bonds, and no atoms other than, carbon and hydrogen. The groups, —CH2— (methylene), _CH2CH2— —CH2C(CH3)2CH2—, —CH2CH2CH2—, andm are non-limiting examples of alkylene groups.

The term “alkenyl” refers to a monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched, cyclic or acyclic structure, at least one nonaromatic —carbon double bond, no carbon—carbon triple bonds, and no atoms other than carbon and hydrogen. Non—limiting examples of alkenyl groups include: —CH=CH2 (Vinyl), —CH=CHCH.3, —CH=CHCH2CH3, —CH2CH=CH2 (allyl), ~CH2CH=CHCH3, and —CH=CH—C6H5.

The term “alkynyl” refers to an monovalent unsaturated. aliphatic group with a carbon atom as the point of attachment, a linear or branched, cyclo, cyclic or acyclic structure, at least one carbon—carbon triple bond, and no atoms other than carbon and hydrogen. As used herein, the term alkynyl does not preclude the presence of one or more non—aromatic carbon— carbon double bonds. The groups —CECH, ~CECCH3, and —CH2CECCH3, are non—limiting examples of alkynyl groups.

The term “aryl” refers to a monovalent group with an ic carbon atom as the point of attachment, said carbon atom forming part of one or more six—membered aromatic ring structure(s) wherein the ring atoms are all carbon, and wherein the monovalent group consists of no atoms other than carbon and hydrogen. Non-limiting examples of aryl groups e phenyl (Ph), methylphenyl, (dimethyl)phenyl, CH2CH3 (ethylphenyl), —C5H4—CH2CH2CH3 (propylphenyl), —C6H4—CH(CH3)2, CH(CH2)2, —C6H3(CH3)CH2CH3 (methylethylphenyl), —C6H4—CH=CH2 (Vinylphenyl), —C6H4—CH=CHCH3, —C5H4CECH, —C5H4CECCH3, naphthyl, and the monovalent group d from yl.

The term “heteroaryl” refers to a lent aromatic group with an ic carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more aromatic ring structures wherein at least one of the ring atoms is nitrogen, oxygen or , and wherein the heteroaryl group consists of no atoms other than carbon, hydrogen, aromatic en, aromatic oxygen and aromatic . As used herein, the term does not preclude the presence of one or more alkyl, aryl, and/or aralkyl groups (carbon number limitation permitting) attached to the aromatic ring or aromatic ring system. If more than one ring is present, the rings may be fused or unfused. Non-limiting examples of heteroaryl groups include furanyl, imidazolyl, indolyl, indazolyl, isoxazolyl, methylpyridinyl, oxazolyl, phenylpyridinyl, pyridinyl, pyrrolyl, pyrimidinyl, pyrazinyl, yl, quinazolyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thienyl, and lyl.

The term. “heterocyclyl” refers to a monovalent non-aromatic group with a carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom g part of one or more non—aromatic ring ures wherein at least one of the ring atoms is nitrogen, oxygen or sulfur, and wherein the heterocyclyl group consists of no atoms other than , hydrogen, nitrogen, oxygen and sulfur. As used herein, the term does not preclude the presence of one or more alkyl groups (carbon number limitation ting) attached to the ring or ring system. If more than one ring is present, the rings may be fused or unfused. Non— limiting examples of heterocyclyl groups include aziridinyl, idinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothio furanyl, tetrahydropyranyl, and pyranyl.

The term “acyl” refers to the group —C(O)R, in which R is a hydrogen, alkyl, aryl, aralkyl or aryl, as those terms are de?ned above. The groups —CHO, —C(O)CH3 (acetyl, Ac), H2CH3, H2CH2CH3, —C(O)CH(CH3)2, —C(O)CH(CH2)2, —C(0)C5H5, —C(O)C6H4—CH3, —C(O)CH2C6H5, —C(O)(imidazolyl) are non—limiting examples of acyl groups.

A “thioacyl” is de?ned in an analogous manner, except that the oxygen atom ofthe group —C(O)R has been replaced with a sulfur atom.

[00101] The term “alkoxy” refers to the group —OR, in which R is an alkyl, as that term is de?ned above. Non—limiting examples of alkoxy groups e: ~OCH3, ~0CH2CH3, ~0CH2CH2CH3, ‘OCH(CH3)2, ~OCH(CH2)2, —O—cyclopentyl, and —O~—-cyclohexyl.

The de?nition of “pharmaceutically acceptable” is meant to encompass any carrier, salt form, or other agent, which does not interfere with effectiveness of the biological activity of the active ingredient and. that is not toxic to the host to which it is administered. As used herein, “pharmaceutically acceptable carrier” means buffers, carriers, diluents, and excipients suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable bene?t/risk ratio. The carrier(s) should be “acceptable” in the sense of being compatible with the other ingredients of the ations and not deleterious to the recipient. Pharmaceutically acceptable carriers include s, solvents, sion media, gs, isotonic and absorption ng agents, and the like, that are compatible with pharmaceutical administration.

“Pharmaceutically acceptable salts” means salts of compounds of the present disclosure which are pharmaceutically acceptable, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, romic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with c acids such as 1,2-ethanedisulfonic acid, 2—hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3- phenylpropionic acid, ethylenebis (3-hydroxy—2-ene—l-carboxylic acid), 4-methylbicyclo [2.2.2]0ctene-l-carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic ic acids, benzenesulfonic acid, c acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, ic acid, ynaphthoic acid, lactic acid, laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o—(4—hydroxybenzoyl)benzoic acid, oxalic acid, p—chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, p—toluenesulfonic acid, pyruvic acid, lic acid, stearic acid, succinic acid, ic acid, tertiarybutylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide.

Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N—methylglucamine and the like. It should be recognized. that the ular anion or cation forming a part of any salt ofthis invention is not critical, so long as the salt, as a whole, is pharmacologically able. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook ofPharmaceutical Salts Properties, and Use (P. H. Stahl & C. G. Wermuth eds, Verlag Helvetica Chimica Acta, 2002), which is incorporated herein by reference.

The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “(-),” “R” or “S,” ing on the con?guration of substituents around the stereogenic carbon atom, but the d artisan will recognize that a structure may denote a chiral center implicitly. The present invention encompasses various stereoisomers of these compounds and mixtures thereof. es of enantiomers or diastereomers may be designated “(::)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.

The compounds of the disclosure may n one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symbol — s a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” ration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise speci?ed, structures ing double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be ed to as “cis” or “trans,” where “cis” represents tuents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.

Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of tuents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are ated as being in the “Z” or “E” con?guration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless ise speci?ed, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents around a carbocyclic or heterocyclic ring may also be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane ofthe ring. Mixtures of compounds n the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans.” Individual enantiomers and diasteriomers of compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of tion are exempli?ed by (l) attachment of a e of enantiomers to a chiral ary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well- known methods, such as chiral-phase liquid tography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic on in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the ormation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations, and may involve the use of chiral auxiliaries. For examples, see Carreira and , Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

The compounds disclosed herein can exist in so lvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of rphs. In another embodiment, the compound is in a crystalline form.

The invention also es isotopically labeled compounds of the invention which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, ?uorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31F, 32F, 358, 18F, and 36Cl, respectively. For example, a compound of the invention may have one or more H atom replaced with deuterium.

Certain isotopically-labeled disclosed compounds (e.g., those labeled with 3H and 14C) are use?il in compound and/or ate tissue bution . Tritiated (i.e., 3H) and carbon-l4 (z'.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (1.6., 2H) may afford certain therapeutic ages resulting from greater lic ity (e.g., increased in viva half-life or reduced dosage requirements) and hence may be preferred in some circumstances.

Isotopically labeled compounds of the invention can lly be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled t.

] A “patient” or “subject” as described herein, refers to any animal at risk for, suffering from or diagnosed for an in?ammatory condition, including, but not limited to, mammals, es, and humans. In certain embodiments, the patient may be a non-human mammal such as, for example, a cat, a dog, or a horse. A patient may be an dual diagnosed with a high risk of developing an in?ammatory condition, someone who has been diagnosed with an in?ammatory condition, someone who previously suffered from an in?ammatory ion, or an individual ted for symptoms or indications of an in?ammatory condition.

[00111] “A patient in need”, as used herein, refers to a patient suffering from any of the symptoms or manifestations of an in?ammatory condition, e. g., in?ammatory bowel disease, a patient who may suffer from any ofthe symptoms or stations of an in?ammatory ion, or any patient who might bene?t from a method of the invention for treating an in?ammatory ion. A patient in need may include a patient who is diagnosed with a risk of developing an in?ammatory condition such as in?ammatory bowel disease, a patient who has suffered from an in?ammatory condition, or a patient who has previously been treated for such a The terms ”, “treatment”, “treating” and the like are used herein to generally mean obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of partially or completely curing a e and/or e effect attributed to the disease. The term “treatment” as used herein covers any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, 2'. e. preventing the disease from increasing in severity or scope; (c) relieving the disease, 2'. e. causing partial or complete amelioration of the disease; or (d) preventing relapse of the disease, 2'. e. preventing the disease from returning to an active state following us successful treatment of symptoms of the e or treatment of the disease.

[00113] “Effective amount,” as used herein, refers to the amount of an agent that is ent to at least partially treat a condition when stered to a patient. The therapeutically effective amount will vary depending on the severity of the ion, the route of administration of the component, and the age, weight, etc. of the patient being treated.

Accordingly, an effective amount of a compound of the present disclosure is the amount of such a compound necessary to treat one or more conditions or diseases contemplated herein in a patient such that administration of the agent prevents the condition(s) from occurring in a subject, prevents progression of the condition (e.g, prevents the onset or increased ty of symptoms of the condition), or relieves or completely ameliorates all ated symptoms of the condition, z‘.e. causes sion of the condition. An effective amount may also be the amount of such a compound necessary to bring about a desired biological , e.g. decreasing INF-y levels.

Efficacy of treatment may be ted by means of evaluation of gross ms associated with the in?ammatory condition, analysis of tissue histology, biochemical assay, g methods such as, for example, magnetic resonance imaging, or other known methods.

For instance, ef?cacy oftreatment may be ted by analyzing gross symptoms of the condition such as changes in tissue in?ammation, abdominal pain, vomiting, diarrhea, rectal bleeding, cramps, muscle spasms, weight loss, malnutrition, fever, anemia or other aspects of gross pathology associated with an atory condition following administration of a compound described herein.

Ef?cacy of treatment may also be evaluated at the tissue or cellular level, for example, by means of obtaining a tissue biopsy (e.g., a gastrointestinal tissue biopsy) and evaluating gross tissue or cell morphology or staining properties. Biochemical assays that examine protein or RNA sion may also be used to evaluate ef?cacy oftreatment. For instance, one may evaluate IL-22, IFN-y, or levels of another protein or gene product indicative ofone or more in?ammatory condition(s), in?ammatory cytokine production, or an IL-22 mediated in?ammatory response in dissociated cells or non-dissociated tissue via immunocytochemical, immunohistochemical, Western blotting, or Northern blotting methods, or methods useful for evaluating RNA levels such as quantitative or semi-quantitative rase chain reaction. One may also evaluate the presence or level of expression of useful biomarkers found in fecal matter, plasma, or serum to evaluate disease state and ef?cacy of treatment.

Methods The present disclosure provides a method of treating an in?ammatory condition in a patient in need thereof, comprising administering an effective amount of a compound disclosed herein to the patient. Exemplary in?ammatory conditions contemplated herein include Crohn’s disease, gastroduodenal Crohn’s disease, s (granulomatous) colitis, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet’s disease, microscopic colitis, ulcerative proctitis, sigrnoiditis, jejunoileitis, left-sided colitis, pancolitis, ileocolitis, s, indeterminate colitis and eosinophilic tis. Other contemplated in?ammatory conditions include cartilage ation, bone degradation, rheumatoid arthritis, arthritis, psoriatic arthritis, hypersensitivity pneumonitis, liver diseases such as fatty liver, tis, hepatic steatosis, and nonalcoholic steatohepatitis (NASH), ?brosis (e.g., intestinal s, lung s, or liver s), mune polyendocrine syndrome, Addison’s disease, Goodpasture’s syndrome, Graves’ disease, Guillain-Barré syndrome, Hashimoto’s encephalopathy, psoriasis, Hashimoto’s thyroiditis, juvenile arthritis (e.g., juvenile idiopathic arthritis), lupus erythematous, multiple sclerosis, Alzheimer’s disease, dermatitis, atopic dermatitis, acne, Type I diabetes mellitus, autoimmune hepatitis, Meniere’s disease, d’s phenomenon, Sjogren’s syndrome, ankylosing spondylitis, chronic fatigue syndrome, rheumatic polymyalgia, osteoarthritis, prostatitis, and Reiter me. In certain embodiments the patient is a mammal. In certain other embodiments the patient is a human.

In certain ments, a method of treating an atory disease or condition is provided, wherein the disease or condition is selected from the group consisting of in?ammatory bowel disease, cartilage in?ammation, bone degradation, ulcerative colitis, psoriasis, arthritis, psoriatic arthritis, rheumatoid arthritis, le arthritis, juvenile rheumatoid arthritis, autoimmune hepatitis, Crohn’s disease, lupus erythematosus, multiple sclerosis, Alzheimer’s disease, dermatitis, atopic dermatitis, acne, Type I diabetes mellitus, Raynaud’s phenomenon, Graves’ disease, and Addison’s disease, and wherein the method comprises stering to a patient in need thereof an effective amount of a disclosed compound. In n embodiments the patient is a mammal. In certain other embodiments the patient is a human.

A method of treating Crohn’s disease is provided, and/or ulcerative colitis, and/or in?ammatory bowel e, comprising stering to a patient in need thereof an effective amount of a disclosed nd. In certain embodiments the patient is a mammal. In certain other embodiments the patient is a human.

In certain embodiments, the in?ammatory disease or condition is selected from the group consisting of Crohn’s e, ulcerative s, collagenous colitis, lymphocytic colitis, diversion colitis, Behcet’s disease, idiopathic in?ammatory bowel e, irritable bowel syndrome, regional enteritis, spastic colon, microscopic colitis, Crohn’s colitis, perianal disease, and indeterminate colitis.

In certain embodiments, the in?ammatory disease or condition is s disease. In certain embodiments, the Crohn’s disease is selected from the group consisting of ileocolitis, s, gastroduodenal Crohn’s disease, j ejunoileitis, and omatous litis. In certain embodiments, the Crohn’s disease includes intestinal ?brosis. In certain embodiments, the Crohn’s disease is ?brostenotic s disease.

In another aspect, the present disclosure provides a method of preventing, treating, or reducing ?brostenosis or intestinal ?brosis in a subject, comprising administering to a subject in need thereof a eutically effective amount of a compound disclosed herein. In certain embodiments, the ?brostenosis or intestinal ?brosis is associated with Crohn’s disease.

] It may be appreciated that in?ammatory bowel disease may be associated with a number of symptoms. Accordingly, the present disclosure provides a method of relieving one or more symptoms of in?ammatory bowel disease selected from the group consisting of abdominal pain, vomiting, diarrhea, rectal bleeding, severe , muscle spasms, weight loss, malnutrition, fever, anemia, skin s, joint pain, eye ation, liver disorders, arthritis, pyoderma gangrenosum, primary sclerosing cholangitis, non-thyroidal illness syndrome, and growth defects in children, comprising administering to a patient in need thereof an effective amount of a disclosed compound.

In one aspect, the present disclosure relates to a method of decreasing IFN-y levels and/or inhibiting IFN-y, comprising stering to a subject in need thereof a eutically effective amount of a disclosed compound. iting IFN-y,” as used herein, may refer to a complete or partial reduction in IFN-y sion or activity. Thus, inhibiting IFN—y may refer to alterations in IFN-y gene or chromatin state or altered interaction with regulators of gene transcription or gene ibility that results in a complete or l reduction in expression of IFN-y gene products, e.g., IFN-y RNA, IFN-y protein, or e sequences of IFN-y. ting IFN-y may also refer to inhibition of processes crucial to IFN-y gene product expression, including, but not limited to IFN-y transcription, IFN-y RNA processing, IFN-y protein translation, or IFN-y post-translational modi?cation. Additionally, inhibiting IFN-y may refer to inhibiting activity of IFN-y gene products, including es of IFN-y, nucleotide ts of IFN—y (e.g., IFN—y mRNA), and IFN-y protein. Inhibiting activity of IFN-y gene products may include a reduction in IFN-y signaling or direct or indirect interaction of IFN-y with other cellular components (e.g., proteins, peptides, DNA, RNA, , or ing molecules) including r, organelle, cytosolic, membrane, and extracellular components. For example, inhibiting IFN-y ty may include inhibiting IFN-y binding or activation of CSFlR or inhibiting CSFlR downstream signaling effects (e.g. , MAP Kinase phosphorylation or macrophage eration).

In one aspect, the present disclosure relates to a method of increasing IL-22 levels, comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed compound. Such increase may be for improving or strengthening immunity or to provide an immunoprotective function.

The invention also provides methods of increasing IL-22 production in cells of a patient suffering from an in?ammatory condition, comprising administering to a patient in need thereof an effective amount of a disclosed compound. IL-22 production may be increased in any cell in which IL-22 expression or activity occurs, including cells of the gastrointestinal tract, immune system, and blood. Cells of the gastrointestinal tract (including cells of the stomach, duodenum, jejunum, ileum, colon, rectum and anal canal), include columnar lial cells, mucosal epithelial cells, zymogenic cells, neck mucus cells, parietal cells, gastrin cells, goblet cells, paneth cells, oligomucus cells, and villus absorptive cells. Cells of the immune system include leukocytes, phagocytes (e.g., macrophages, neutrophils, and dendritic cells), monocytes, mast cells, phils, basophils, l killer cells, innate cells, lymphocytes, B cells, and T cells. Blood cells include red blood cells (erythrocytes) and white blood cells (leukocytes, monocytes, and platelets).

In one aspect, the present disclosure relates to a method of increasing IL-22 levels and decreasing IFN-y levels, comprising administering to a subject in need f a eutically effective amount of a compound described above.

In one aspect, the present disclosure relates to a method of inhibiting lipid peroxidation, comprising administering to a t in need thereof a therapeutically effective amount of a compound described above.

In one aspect, the present disclosure relates to a method of modulating an aryl arbon receptor (AhR), comprising administering a ive AhR modulator; wherein said selective AhR modulator is a compound described above.

[00129] In another aspect, the present invention provides a compound as bed herein for use as a medicament. In r aspect, the present invention provides a compound as described herein for use in a method of treating an in?ammatory e or condition. The in?ammatory disease or condition may be as de?ned above. In yet another aspect, the present invention provides a compound as described herein for use in a method of treating s disease and/or ulcerative s, and/or in?ammatory bowel disease. The Crohn’s disease may be as de?ned above. In another aspect, the present disclosure provides a compound as bed herein for use in a method of preventing, treating, or reducing ?brostenosis or intestinal ?brosis. In certain embodiments, the ?brostenosis or intestinal ?brosis is associated with Crohn’s disease. In another embodiment, the present invention provides a compound as described herein for use in a method of relieving one or more symptoms of in?ammatory bowel disease. The symptoms may be as de?ned above. In one aspect, the present invention provides a compound as described herein relates to a method of decreasing IFN-y levels and/or inhibiting IFN-y in a subject in need thereof Inhibiting IFN—y may be as de?ned above. In a further aspect, the present provides a compound as described herein for use in a method of increasing IL-22 levels in a subject. Such increase may be for ing or strengthening immunity or to provide an immunoprotective ?anction. The invention also es a compound as described above for use in a method of increasing IL-22 production in cells of a patient suffering from an in?ammatory condition. The in?ammatory condition may be as de?ned above. In another aspect, the present invention provides a compound as described herein for use in a method of increasing IL-22 levels and decreasing IFN—y levels in a subject. The present invention also provides a compound as described herein for use in a method of inhibiting lipid dation in a subject. The present invention also provides a compound for use in a method of modulating an aryl hydrocarbon receptor (AhR) in a subject. ceutical Compositions and Routes of Administration The present invention also provides pharmaceutical itions comprising a nd described herein. In another aspect, the invention provides a pharmaceutical composition for use in treating an in?ammatory condition. The pharmaceutical composition may comprise a compound described herein and a pharmaceutically acceptable carrier. As used herein the term “pharmaceutical composition” means, for example, a mixture containing a speci?ed amount of a therapeutic compound, e.g, a therapeutically effective , of a therapeutic compound in a pharmaceutically acceptable carrier to be administered to a mammal, e. g., a human, in order to treat an in?ammatory ion.

Compounds ofthe present disclosure can be specially formulated for administration ofthe compound to a subject in solid, liquid or gel form, ing those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), lozenges, dragees, capsules, pills, tablets (e.g., those targeted for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes for application to the ; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile on or suspension, or sustained-release formulation; (3) l application, for example, as a cream, ointment, or a lled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; (8) ucosally; or (9) nasally. Examples of dosage forms include, but are not limited to: tablets; caplets; capsules, such as hard gelatin capsules and soft elastic n capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; rs; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquids such as suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water- in-oil liquid emulsions), solutions, and elixirs; and sterile solids (e.g, crystalline or amorphous solids) that can be reconstituted to e liquid dosage forms. ceutical compositions containing a compound bed herein can be ted in a dosage unit form and can be prepared by any suitable method. A pharmaceutical composition should be formulated to be ible with its intended route of administration.

Use?il formulations can be prepared by methods well known in the pharmaceutical art. For example, see Remington ’s Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990) Pharmaceutical formulations preferably are e. Sterilization can be accomplished, for example, by ?ltration through sterile ?ltration membranes. Where the composition is lyophilized, ?lter sterilization can be conducted prior to or following lyophilization and titution.

The pharmaceutical compositions of the invention can be ated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, subcutaneous, intralesional, or intraperitoneal routes. The preparation of an aqueous composition, such as an aqueous ceutical composition containing a compound described herein, will be known to those of skill in the art in light of the present disclosure. lly, such itions can be prepared as inj ectables, either as liquid solutions or suspensions; solid forms suitable for using to prepare solutions or sions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsi?ed.

] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous ene glycol; and e powders for the extemporaneous preparation of sterile inj ectable solutions or dispersions.

In all cases the form must be sterile and must be ?uid to the extent that easy syringability exists.

It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

Solutions of active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.

Dispersions can also be ed in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. In addition, sterile, ?xed oils may be employed as a solvent or suspending medium.

For this e any bland ?xed oil can be employed including synthetic mono- or diglycerides.

In addition, fatty acids such as oleic acid can be used in the preparation of injectables. The sterile injectable preparation may also be a sterile inj ectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3- butanediol. Among the able es and solvents that may be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In one embodiment, the compound may be suspended in a carrier ?uid comprising 1% (w/v) sodium carboxymethylcellulose and 0.1% (v/v) TWEENTM 80. Under ordinary conditions of storage and use, these preparations n a preservative to prevent the growth of microorganisms.

[00137] Injectable preparations, for example, sterile injectable aqueous or oleaginous sions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic sion medium and the required other ingredients from those enumerated above. Sterile inj ectable solutions of the invention may be prepared by incorporating a compound described herein in the required amount of the appropriate solvent with various of the other ingredients enumerated above, as required, followed by ?ltered sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-?ltered solution f. The inj ectable formulations can be sterilized, for example, by ?ltration through a bacteria-retaining ?lter.

The preparation of more, or highly concentrated solutions for intramuscular injection is also contemplated. In this regard, the use of DMSO as solvent is preferred as this will result in extremely rapid penetration, delivering high concentrations of the compound to a small area.

Suitable preservatives for use in such a solution include benzalkonium chloride, benzethonium chloride, chlorobutanol, thimerosal and the like. le buffers include boric acid, sodium and potassium bicarbonate, sodium and potassium borates, sodium and potassium carbonate, sodium acetate, sodium phate and the like, in amounts suf?cient to maintain the pH at between about pH 6 and pH 8, and preferably, n about pH 7 and pH 7.5.

Suitable tonicity agents are dextran 40, dextran 70, se, glycerin, potassium de, propylene glycol, sodium chloride, and the like, such that the sodium chloride lent of the solution is in the range 0.9 plus or minus 0.2%. Suitable antioxidants and stabilizers include sodium bisul?te, sodium metabisul?te, sodium thiosul?te, thiourea and the like. le wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol. Suitable viscosity-increasing agents include dextran 40, dextran 70, gelatin, glycerin, yethylcellulose, ymethylpropylcellulose, lanolin, methylcellulose , petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, ymethylcellulose and the like.

] In some embodiments, contemplated herein are compositions suitable for oral ry of a nd described herein, e. g., tablets, that include an enteric g, e.g., a gastro—resistant coating, such that the compositions may deliver the compound to, e.g., the gastrointestinal tract of a patient.

For example, a tablet for oral administration is provided that ses granules (e.g, is at least partially formed from granules) that include a compound described herein, and one or more pharmaceutically acceptable excipients. Such a tablet may be coated with an enteric coating. Contemplated tablets may include pharmaceutically acceptable excipients such as , binders, disintegrants, and/or lubricants, as well as coloring agents, e agents, coating , sweetening, ?avoring agents such as Wintergreen, orange, xylitol, sorbitol, fructose, and extrin, and perfuming agents, preservatives and/or antioxidants.

In some embodiments, contemplated pharmaceutical formulations include an intra- granular phase that includes a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable filler. For example, the nd and a filler may be blended together, optionally, with other excipients, and formed into granules. In some embodiments, the intragranular phase may be formed using wet granulation, e.g. a liquid (6.g. , water) is added to the blended compound and filler, and then the combination is dried, milled and/or sieved to produce es. One of skill in the art would understand that other processes may be used to achieve an intragranular phase.

In some embodiments, contemplated formulations include an extra-granular phase, which may include one or more pharmaceutically acceptable excipients, and which may be blended with the intragranular phase to form a disclosed ation.

A disclosed formulation may include an intragranular phase that es a ?ller.

Exemplary ?llers include, but are not limited to, cellulose, gelatin, calcium phosphate, lactose, sucrose, glucose, mannitol, sorbitol, rystalline cellulose, pectin, rylates, dextrose, cellulose acetate, hydroxypropylmethyl ose, partially pregelatinized starch, calcium carbonate, and others including combinations thereof.

In some embodiments, a disclosed formulation may include a intragranular phase and/or a extragranular phase that includes a , which may generally ?inction to hold the ients of the pharmaceutical formulation together. Exemplary binders of the invention may e, but are not limited to, the following: starches, sugars, cellulose or modi?ed cellulose such as hydroxypropyl ose, lactose, pregelatinized maize starch, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, low substituted ypropyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, sugar alcohols and others including combinations thereof.

Contemplated formulations, e.g., that include an intragranular phase and/or an extragranular phase, may include a disintegrant such as but are not limited to, starch, cellulose, crosslinked polyvinyl pyrrolidone, sodium starch glyco late, sodium carboxymethyl cellulose, tes, corn starch, crosmellose sodium, crosslinked carboxymethyl cellulose, low substituted hydroxypropyl cellulose, acacia, and others including combinations thereof. For example, an intragranular phase and/or an ranular phase may include a disintegrant.

In some embodiments, a contemplated formulation includes an granular phase comprising a compound described herein and excipients chosen from: mannitol, microcrystalline ose, hydroxypropylmethyl cellulose, and sodium starch glyco late or combinations thereof, and an extra-granular phase sing one or more of: microcrystalline cellulose, sodium starch glyco late, and magnesium stearate or mixtures thereof.

] In some embodiments, a contemplated formulation may include a lubricant, e.g. an extra-granular phase may contain a lubricant. Lubricants include but are not limited to talc, silica, fats, n, magnesium stearate, calcium phosphate, silicone dioxide, calcium silicate, calcium phosphate, colloidal silicon dioxide, metallic stearates, hydrogenated vegetable oil, corn starch, sodium benzoate, hylene glycols, sodium acetate, calcium stearate, sodium lauryl sulfate, sodium chloride, magnesium lauryl sulfate, talc, and stearic acid.

In some embodiments, the pharmaceutical formulation comprises an enteric coating.

Generally, enteric gs create a barrier for the oral medication that controls the location at which the drug is absorbed along the digestive tract. Enteric coatings may e a r that disintegrates a different rates according to pH. Enteric coatings may include for example, cellulose acetate phthalate, methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxylpropylmethyl cellulose phthalate, methyl methacrylate-methacrylic acid copolymers, ethylacrylate-methacrylic acid copolymers, methacrylic acid copolymer type C, polyvinyl acetate-phthalate, and cellulose e phthalate.

[00150] Exemplary enteric gs include Opadry® AMB, Acryl-EZE®, Eudragit® grades.

In some embodiments, an enteric coating may comprise about 5% to about 10%, about 5% to about 20%, 8 to about 15%, about 8% to about 20%, about 10% to about 20%, or about 12 to about 20%, or about 18% of a contemplated tablet by weight. For example, enteric coatings may include an ethylacrylate-methacrylic acid copolymer.

[00151] For example, in a contemplated embodiment, a tablet is provided that ses or consists essentially of about 0.5% to about 70%, e.g. about 0.5% to about 10%, or about 1% to about 20%, by weight of a compound described herein or a pharmaceutically acceptable salt thereof. Such a tablet may e for example, about 0.5% to about 60% by weight of mannitol, e. g. about 30% to about 50% by weight mannitol, e. g. about 40% by weight mannitol, and/or about 20% to about 40% by weight of microcrystalline cellulose, or about 10% to about % by weight of microcrystalline ose. For e, a disclosed tablet may comprise an intragranular phase that es about 30% to about 60%, e.g. about 45% to about 65% by weight, or alternatively, about 5 to about 10% by weight of a compound described herein, about % to about 50%, or alternatively, about 5% to about 15% by weight mannitol, about 5% to about 15% microcrystalline cellulose, about 0% to about 4%, or about 1% to about 7% hydroxypropylmethylcellulose, and about 0% to about 4%, e.g. about 2% to about 4% sodium starch glyco late by weight.

In another plated embodiment, a pharmaceutical tablet formulation for oral administration of a compound described herein comprises an intra-granular phase, n the intra—granular phase includes a compound described herein or a pharmaceutically acceptable salt thereof (such as a sodium salt), and a pharmaceutically acceptable ?ller, and which may also include an extra-granular phase, that may include a pharmaceutically acceptable excipient such as a disintegrant. The granular phase may include components chosen from microcrystalline cellulose, magnesium stearate, and mixtures f. The pharmaceutical composition may also include an enteric g of about 12% to 20% by weight ofthe tablet.

For example, a pharmaceutically acceptable tablet for oral use may comprise about .5% to 10% by weight of a compound described herein or a pharmaceutically acceptable salt thereof, about % to 50% by weight mannitol, about 10% to 30% by weight microcrystalline cellulose, and an c coating comprising an crylate-methacrylic acid copolymer.

In another example, a pharmaceutically acceptable tablet for oral use may comprise an intra-granular phase, sing about 5 to about 10% by weight of a compound described herein or a pharmaceutically acceptable salt thereof, about 40% by weight mannitol, about 8% by weight microcrystalline cellulose, about 5% by weight hydropropylmethyl cellulose, and about 2% by weight sodium starch ate, an extra-granular phase comprising about 17% by weight microcrystalline cellulose, about 2% by weight sodium starch glycolate, about 0.4% by weight magnesium stearate, and an enteric coating over the tablet comprising an ethylacrylate— methacrylic acid copolymer.

In some embodiments the pharmaceutical composition may contain an enteric coating comprising about 13% or about 15%, 16%, 17% or 18% by weight, e.g., AcyrlEZE® (see, e.g., PCT ation No. WO2010/054826, which is hereby incorporated by reference in its entirety).

The rate at which point the coating dissolves and the active ingredient is released is its dissolution rate. In an embodiment, a plated tablet may have a dissolution pro?le, e.g. when tested in a USP/EP Type 2 apparatus e) at 100 rpm and 37 CC in a phosphate buffer with a pH of 7.2, of about 50% to about 100% of a compound bed herein releasing after about 120 minutes to about 240 minutes, for example after 180 minutes. In another embodiment, a contemplated tablet may have a dissolution pro?le, e.g. when tested in a USP/EP Type 2 apparatus (paddle) at 100 rpm and 37 0C in diluted HCl with a pH of 1.0, where substantially none of the compound is released after 120 minutes. A contemplated tablet, in another embodiment, may have a dissolution pro?le, e.g. when tested in USP/EP Type 2 apparatus (paddle) at 100 rpm and 37 °C in a phosphate buffer with a pH of 6.6, of about 10% to about 30%, or not more than about 50%, of the compound releasing after 30 minutes.

In some embodiments, s ed herein may ?irther include administering at least one other agent that is directed to treatment of ions, diseases, and disorders disclosed herein. In one embodiment, contemplated other agents may be co-administered (e.g., sequentially or simultaneously).

Non-limiting examples of such combination therapy include combination of one or more compounds of the invention with an anti—in?ammatory agent, an antibiotic agent, an immunosuppressant, an. immunomodulator, or an analgesic agent.

Agents contemplated include immunosuppressive agents including glucocorticoids, cytostatics, antibodies, agents acting on immunophilins, interferons, opioids, TNF binding proteins, enolate, and small biological agents. For example, plated immunosuppressive agents include, but are not limited to: tacrolimus, cyclosporine, pimecrolimus, sirolimus, everolimus, mycophenolic acid, fmgolimod, dexamethasone, ?udarabine, cyclophosphamide, rexate, azathioprine, le?unomide, teri?unomide, anakinra, anti-thymocyte globulin, ymphocyte globulin, muromonab-CD3, afutuzumab, rituximab, teplizumab, efalizumab, daclizumab, basiliximab, adalimumab, in?iximab, certolizumab pegol, natalizumab, and etanercept. Other contemplated agents include anti— diarrheals, laxatives, iron ments, and calcium or Vitamin D or B—12 supplements.

Exemplary formulations include dosage forms that comprise or consist essentially of about 35 mg to about 500 mg of a compound described herein. For example, ations that include about 35 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, or 250 mg ofa compound described herein are contemplated. In one embodiment, a ation may e about 40 mg, 80 mg, or 160 mg of a compound described herein. In some embodiments, a ation may include at least 100 ug of a compound described herein. For example, formulations may include about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg ofa nd described herein. The amount administered Will depend on variables such as the type and extent of disease or indication to be treated, the overall health and size of the patient, the in viva potency ofthe compound, the pharmaceutical formulation, and the route of stration.

The initial dosage can be increased beyond the upper level in order to y achieve the desired blood-level or tissue level. Alternatively, the initial dosage can be smaller than the optimum, and the dosage may be ssively increased during the course of treatment.

Dosing frequency can vary, depending on factors such as route of administration, dosage amount and the disease being treated. Exemplary dosing frequencies are once per day, once per week and once every two weeks. In some embodiments, g is once per day for 7 days.

EXAMPLES The invention is further illustrated by the following es. The examples are provided for illustrative purposes only, and are not to be construed as limiting the scope or content of the invention in any way.

Example 1: Synthesis of Sample 2 Sample 2 was prepared as shown below in Scheme 1. Compound numbers used in this Example pertain only to this Example; Sample 2 is ed to elsewhere as compound 2.

S—IEt3 HO-’ F3C TBAF \ CBr4 SiEt3—> PdCI2(d ppf) N\ N PhP3 NH2 H N3 NH2 \ NaN F30 PPh F30 _3- \ _3- \ —, m N N CH0 H H 6 7 \ 8 sample 2 thesis of 2- 2- trieth lsil l tri?uorometh l -1H-indol 1 ethanol 3 A mixture of 2-iodo(tri?uoromethyl)aniline (1) (5.00 g, 17.4 mmol), 4- (triethylsilyl)but—3-yn—1-ol (2) (3.85 g, 1.2 mmol), bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.64 g, 0.87 mmol), m chloride (0.732 g, 17.4 mmol) and sodium carbonate (3.7 g, 34.8 mmol)) in 50 mL ofN,N- dimethylformamide (DMF) was stirred at 100 °C for 15 h. The reaction mixture was diluted with water and extracted with ethyl e. The organic extract was dried over Na2804 and concentrated under reduced pressure. The crude material was puri?ed by silica gel tography to afford 7.00 g of the title compound as yellow oil, which contained ~20% of starting material (2). The product was used in the next step without further puri?cation. 1H NMR (300 MHz, CDClg) 5 8.2 (bs, 1H), 7.9 (s, 1H), 7.45 (s, 2H), 3.85 (q, .1: 8.0 Hz, 2H), 3.15 (t, J: 6.4 Hz, 2H), 1.46 (t, J: 6.0 Hz, 1H), 1.2 (m, 15H); MS (APCI+) m/z = 344 (M+H).

S thesis of 2- 5- tri?uorometh l -1H—indol—3- 1 ethanol 4 A solution of triethy1silyl)(tri?uoromethyl)—lH—indo l—3-yl)ethanol (3) (2.00 g, 5.83 mmol) in 15 mL of tetrahydrofuran (THF) was added tetrabutylammonium ?uoride (7.0 mL, 1 M in THF) and the reaction e was stirred at room temperature (rt) for 72 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was dried over NazSO4 and trated under d pressure. The crude material was puri?ed by silica gel chromatography to afford 1.02 g (75%) of the title compound as pale yellow oil. 1H NMR (300 MHz, CDC13) 8 8.3 (bs, 1H), 7.96 (s, 1H), 7.45 (s, 2H), 7.2 (s, 1H), 3.90 (t, J: 6.8 Hz, 2H), 3.05 (t, J: 6.8 Hz, 2H); MS (APCI+) m/Z = 230 (M+H).

S?thesis of 3-1 2-bromoethyl]]tri?uoromethyl[- lH-indole [5] A solution of 2-(5-(tri?uoromethyl)—1H—indol—3-yl)ethanol (4) (1.00 g, 4.36 mmol) in THF (10 ml) was added to a solution of triphenyl phosphine (2.30 g, 8.72 mmol) and perbromomethane (4.40 g, 13.1 mmol) in THF (10 mL) pre-stirred for 1 h. The resulting mixture was stirred at rt for 3 h. The on mixture was then ?ltered and concentrated under reduced pressure. The crude material was d by silica gel chromatography to afford 0.66 g (51%) of the title compound as yellow oil. 1H NMR (300 MHz, CDClg) 5 8.25 (bs, 1H), 7.9 (s, 1H), 7.4 (s, 2H), 7.2 (s, 1H), 3.7 (t, J: 7.8 Hz, 2H), 3.27 (t, J: 7.8 Hz, 2H).

Synthesis of 3-(2-azidoethyl)(tri?uoromethyl)—1H—indole (6)

[00165] A mixture of 3-(2-bromoethyl)(tri?uoromethyl)-1H—indole (5) (0.66 g, 2.26 mmol) and sodium azide (0.44 g; 6.8 mmol) in DMF (10 mL) was stirred at 70 0C for 4 h. The reaction mixture was diluted with water and extracted with ethyl e. The organic layer was successively washed with brine, sodium thiosulfate, dried and concentrated under reduced pressure. The crude material was d by silica gel chromatography to afford 0.61 g (100%) ofthe title compound as a brown oil. 1H NMR (300 MHz, CDC13) 8 8.15 (bs, 1H), 7.87 (s, 1H), 7.44 (d, J: 1.5 Hz, 2H), 7. 19 (s, 1H), 3.55-3.61 (t, J: 7 Hz, 2H), 3.08 (t, J: 7.2 Hz, 2H).

Synthesis of 2-(5-(tri?uoromethyl)-(1H-indol—3-yl))ethanamine (7) A mixture of 3-(2-azidoethyl)(tri?uoromethyl)-H—indole (6) (0.61 g, 2.45 mmol) and triphenyl phosphine (1.93 g, 7.41 mmol) in methanol (10 mL) was stirred at 70 °C for 2 h.

The reaction e was concentrated under reduced pressure and the crude material was puri?ed by silica gel chromatography to afford 0.44 g (75%) of the title compound as a brown oil. 1H NMR (300 MHz, CDCl;) 6 8.4 (bs, 1H), 7.9 (s, 1H), 7.4 (s, 2H), 7.25 (s, 1H), 7.13—7.14 (d, J= 2.4 Hz, 1H), 3.04 (m, 4H); MS (APCI-) m/z = 326 (M-H).

Synthesis of l-(3 .4-dimethoxyphenyl)(tri?uoromethyl)-2.3 ,4,9-tetrahydro- 1H-pyrido[3.4— b indole Sam le 2

[00167] A e of 2-(5-(tri?uoromethyl)—lH—indol—3-yl))ethanamine (7) (0.40 g, 1.76 mmol) and 3,4-dimethoxybenzaldehyde (8) (0.322 g, 1.93 mmol) in acetic acid (8 ml) was stirred at 80 0C for 24 h. The reaction mixture was concentrated under d pressure and the crude material was purified by silica gel chromatography to afford 0.16 g (33%) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3) 5 7.9 (s, 1H), 7.71 (bs, 1H), 7.33 (m, 1H), 6.84 (d, J: 3.8 Hz, 2H), 5.12 (s, 1H), 3.88 (S, 3H), 3.81 (s, 3H), 3.15 (m, 1H), 2.88 (m, 2H); MS (APCI+) m/Z = 377 (M+H).

Example 2: Synthesis of Sample 4a Sample 4a was prepared as shown below in Scheme 2. Compound numbers used in this Example pertain only to this Example; Sample 4a is ed to elsewhere as compound 4a.

Sche_m62 \ MeO OMe \ CHO OMe m._.M6' 3 \ \ 5 I I —.

N NaH N N NaCNBH3 H \ \ Me Me 1 2 4 t—BuONa \ OMe I M oe BINAP \ OMe \ toluene M9 6 sampeI 4a MeO OMe Synthesis 0 f 2-iodomethyl— 1H—indo le (2) A solution of 2-iodo-1H—indole (1) (1.50 g, 6.17 mmol) in THF (20 mL) was added to a suspension of 60% NaH (0.37 g, 9.25 mmol) at 0 oC and the resulting solution was d for 10 min. Methyl iodide (1.75 g, 12.3 mmol) was added se and the reaction mixture was allowed to warm slowly from 0 0C to rt over 1 h. The reaction was quenched with saturated NH4C1 solution (15 mL) and extracted with ethyl acetate. The organic layer was dried over NaZSO4 and concentrated under reduced pressure. The crude material was puri?ed by silica gel chromatography to afford 1.27 g (80%) of the title compound as a pale yellow oil. 1H NMR (400 MHz, CDC13) 5 7.71 (d, J = 7.6 Hz, 1H), 7.29 (d, J: 8 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.06 (t, J= 7.6 Hz, 1H), 6.78 (s, 1H), 3.74 (s, 3H).

Synthesis 0 f 3 -(2-iodomethyl- 1H-indol—3-yl)propanal (4) To a stirred solution of acrolein (3) (1.38 g, 24.7 mmol) and N—methylaniline (0.16 g, 1.48 mol) at 0 °C was added TFA (0.16 g, 1.48 mmol) dropwise and the reaction mixture was stirred at 0 CC for 10 min. 2-Iodomethyl-lH-indole (2) (1.27 g, 4.94 mmol) in CH2C12 (4 mL) was added and the reaction mixture was slowly stirred from 0 0C to rt for 3 h. The reaction mixture was d with water and extracted with dichloromethane (DCM). The organic layer was dried over Na2S04 and concentrated under reduced pressure. The crude material was puri?ed by silica gel chromatography to afford 920 mg (59%) of the title compound as light yellow foam. 1H NMR (400 MHz, CDC13) 8 9.85 , 7.51 (d, J= 8.0 Hz, 1H), 7.30 (d, J= 8.4Hz, 1H), 7.16(t, J: 9.8 Hz, 1H), 7.08 (t, J= 8 Hz, 1H), 3.75 (s, 3H), 3.75 (s, 3H), 3.09 (t, J: 7.6 Hz, 2H), 2.76 (t, J: 8.2 Hz, 2H); MS (ESI+) m/z = 314 (M+H).

Synthesis 0 fN—(3 -(2-iodomethyl- 1H-indo 1—3—yl))_propyl-3 ,4,5 -trimethoxyaniline (6) To a solution of 3-(2-iodo-l-methyl-lH—indolyl)propanal (4) (920 mg, 2.93 mmol) and 3,4,5- trimethoxyaniline (5) (806 mg, 4.40 mmol) in methanol (15 mL) was added 1 drop of acetic acid and the reaction mixture was d for 10 min. 3 (0.46 g, 7.32 mmol) was added and stirring continued for 16 h. The on mixture was diluted with water and extracted with DCM. The organic layer was dried over NazSO4 and concentrated under reduced pressure. The crude material was puri?ed by silica gel chromatography to afford 1.07 g (74%) ofthe title compound as an off-white foam. 1H NMR (400 MHz, CDClg) 5 7.53 (d, J = 7.8 Hz, 1H), 7.31 (d, J: 8.1 Hz, 1H), 7.16 (t, J = 9 Hz, 1H), 7.06 (t, J: 7.8 Hz, 1H), 5.77 (s, 2H), 3.75 (s, 3H), 3.14 (t, J: 7.05 Hz, 2H), 2.88 (t, J: 7.2 Hz, 2H), 1.26 (m, 2H); MS (ESI+) m/Z = 481 (M+H).

S thesis of 9-meth l-l- 3 4 5-trimethox hen l -2 3 4 9-tetrah dro-lH- (Sample 4a) To a solution of N—(3-(2-iodomethyl-1H—indol—3-yl))propyl)-3,4,5- trimethoxyaniline (6) (1.07 g, 2.22 mmol) in toluene (5 mL) was added tris(dibenzylideneacetone) dipalladium(0) (0.1 g, 0.108 mmol), 2,2’-bis(diphenylphosphino) 1"-binaphthalene (0.12 g, 0.216 mmol) and t—BuONa (0.21 g, 2.16 mmol) and the reaction e was stirred at 100 0C for 2 h. The mixture was concentrated under reduced pressure and the crude material was d by silica gel chromatography to afford 280 mg (36%) of the title compound as a white solid. 1H NMR (400 MHz, CDCls) 5 7.45 (d, 1H), 7.15 (m, 3H), 6.19 (s, 2H), 3.82 (s, 3H), 3.71 (m, 8H), 3.26 (s, 3H), 2.79 (t, J: 6.6 Hz, 2H), 1.87 (m, 2H); MS (ESI+) m/Z = 353 (M+H).

Example 3: Synthesis of Sample 13 Sample 13 was prepared as shown below in Scheme 3. Compound numbers used in this Example n only to this Example; Sample 13 is referred to elsewhere as compound 13.

Scheme 3 N OMe Br < } MeO OMe Br N3 N3 OMe OMe / / \ 2 / \ N N,a 3 / \ 5 ‘ CH0 5 OMe s s s CH0 1 3 4 O s OMe Xylenes / OMe I NaBH4 —> —> H OMe O sample13 Synthesis of 3—bromothiophenecarbaldehyde (3) ] To a solution of lithium diisopropylamide (31.6 mmol) in 50 mL of THF at —78 CC was added 3-bromothiophene (3.0 g, 31 mmol) (1). After stirring for 1 h, formylpiperidine (3.50 g, 31.6 mol) (2) was added and the reaction was warmed to 0 0C. After 12 h, the on mixture was partitioned between DCM and sat. NH4Cl and the organic layer was separated, dried over MgSO4, ?ltered, and concentrated under reduced re. The crude material was puri?ed by silica gel chromatography to afford 1.90 g (54%) of the title compound as a yellow oil. 1H NMR (400 MHz,CDC13)8 9.99 (s, 1H), 7.71 (d, J: 5.2 Hz, 1H), 7.15 (d, J: 4.8 Hz, 1H).

Svnthesis of othiophenecarbaldehyde (4) A solution of 3-bromothiophenecarbaldehyde (3) (1.90 g, 0.99 mmol) and sodium azide (3.23 g, 50 mmol) in 50 mL of 1,3—dimethyl—3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) was heated to 50 OC and stirred for 36 h. The reaction mixture was poured onto ice water and then extracted with DCM. The organic t was dried over Na2S04, ?ltered, and concentrated under reduced pressure. The crude material was puri?ed by silica gel chromatography to afford 1.00 g (66%) of the title compound as a yellow oil. 1H NMR (400 MHz, CDC13)5 9.93 (s, 1H), 7.72 (d, J = 5.2 Hz, 1H), 7.04 (d, J: 5.2 Hz, 1H).

Synthesis 0 f (E)(3 -azidothiophen—2-yl)(3 rimethoxyphenyl)propen— 1 -one (6)

[00176] To a mixture of 3-azidothiophenecarbaldehyde (4) (0.80 g, 5.22 mmol) and l- (3,4,5—trimethoxyphenyl)ethanone (5) (1.64 g, 7.84 mmol) in MeOH (5 mL) was added a solution ofNaOH (0.62 g, 15.66 mmol) in water (2 mL) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water and ted with DCM. The organic extract was dried over Na2S04, ?ltered and concentrated under reduced pressure. The crude material was puri?ed by silica gel chromatography to afford 1.10 g (61%) of the title compound as a yellow solid. 1H NMR (400 MHz, CDClg) 5 7.88 (d, J: 15.6 Hz, 1H), 7.42 (d, J: 5.2 Hz, 1H), 7.21 (d, J: 15.2 Hz, 3H), 7.00 (d, J: 5.2 Hz, 1H), 3.94 (d, J: 5.2 Hz, 9H); MS (ESI+) m/Z = 346 (M+H).

Synthesis of (4H—thieno[3,2-b]pyrrol—5-yl)(3,4,5-trimethoxyphenyl)methanone (7) A solution of (E)(3-azidothiophen—2-yl)-l-(3,4,5-trimethoxyphenyl)prop—2—en-l- one (6) (1.20 g, 3.48 mmol) in 10 mL of xylenes was stirred at 150 CC for 30 min. The reaction mixture was concentrated under reduced pressure and the crude material was puri?ed by Silica gel chromatography to afford 1.00 g (91%) of the title compound as an off-white solid. 1H NMR (300 MHz, CDClg) 8 9.48 (bs, 1H), 7.42 (d,J = 5.4 Hz, 1H), 7.20 (s, 2H), 7.11 (s, 1H), 7.01 (d, J = 5.7 Hz, 1H), 3.94 (d, J: 1.8 Hz, 9H); MS (ESI+) m/z = 318 (M+H).

Synthesis of 5-(3,4,5-trimethoxybenzyl)-4H—thieno[3.2-b]pyrrole (Sample 13)

[00178] A mixture of (4H—thieno[3,2-b]pyrrol—5-yl)(3,4,5-trimethoxyphenyl)methanone (7) (0.80 g; 2.52 mmol) and sodium borohydride (480 mg, 12.7 mmol) in 2-propanol (10 mL) was stirred in a sealed tube at 100 CC for 2 h. The reaction mixture was cooled and d with water and extracted with DCM. The organic t was dried over Na2S04 and concentrated.

The crude material was puri?ed by silica gel chromatography to afford 280 mg (37%) of the title compound as a white solid. 1H NMR (300 MHz, CDCls) 5 7.92 (bs, 1H), 6.99 (d, J = 5.1 Hz, 1H), 6.86 (d, J = 5.1 Hz, 1H), 6.46 (s, 2H), 6.26 (S, 1H), 4.02 (s, 2H), 3.83 (t, J = 3.75 Hz, 9H); MS (ESI+) m/z = 304 (M+H).

Example 4: Synthesis of Sample 15 Sample 15 was prepared as shown below in Scheme 4. nd numbers used in this e pertain only to this Example; Sample 15 is referred to elsewhere as compound 15.

Scheme 4 F3C O/ S F30 S SH NHZNH2 F3C />—NH2 2 /> —> N THF, reflux N EtOH, reflux NH2 1 3 4 OMe OMe on's (IS N sample 15 reagent S thesis of 6— tri?uorometh l benzo thiazole 3 To a solution of 6-(tri?uoromethyl)benzothiazo1—2-amine ( 1) (2.00 g, 9.17 mmol) in mL of THF was added isoamyl nitrite (3.22 g, 27.5 mmol). The mixture was heated to re?ux for 30 min, quenched with water, and extracted with ethyl acetate. The organic extract was dried over Na2S04 and concentrated under d pressure. The crude al was puri?ed by silica gel chromatography to afford 860 mg (46%) of the title compound as a yellow solid. 1H NMR (400 MHz, CDClg) 5 9.16 (s, 1H), 8.26 (m, 2H), 7.78 (d, J: 1.2 Hz, 1H).

Synthesis 0 f 2-amino(tri?uoromethyl)benzenethiol (4)

[00181] A solution of 6-(tri?uoromethyl)benzo[d]thiazole (3) (830 mg, 4.08 mmol) and hydrazine monohydrate (1.52 g, 30.6 mmol) in ethanol (20 mL) was heated to re?ux for 1.5 h.

The mixture was added to a solution of acetic acid (3 mL) in water (100 mL) and ted with DCM. The organic extract was dried over NazSO4 and concentrated under reduced pressure.

The crude material was puri?ed by silica gel chromatography to afford 670 mg (84%) of the title compound as a yellow oil. 1H NMR (400 MHz, CDClg) 8 7.62 (d, J: 1.2 Hz, 1H), 7.39 (dd, J: 8.4, 2.0 Hz, 1H), 6.75 (d, J: 8.4 Hz, 1H), 4.49 (s, 2H), 2.95 (s, 1H).

Synthesis of 2-(3,4-dimethoxybenzyl)(tri?uoromethyl)benzo[d]thiazole (Sample 15) 2-amino(tri?uoromethyl)benzenethiol (4) (400 mg, 2.07 mmol), 2-(3,4- oxyphenyl) acetic acid (5) and Lawesson’s reagent (0.29 g, 0.72 mmol) in a sealed tube was subjected to microwave heating at 190 CC for 5 min. The crude material was puri?ed by silica gel chromatography to afford 320 mg (43%) of the title compound as a white solid. 1H NMR (400 MHz, CDClg) 8 8.08 (s, 1H), 8.06 (s, 1H), 7.69 (d, J: 7.5 Hz, 1H), 6.91 (m, 3H), 4.40 (s, 1H), 3.87 (d, J: 6.0 Hz, 6H); MS (ESI+) m/Z = 354 (M+H).

Example 5: Synthesis of Sample 17 Sample 17 was prepared as shown below in Scheme 5. Compound numbers used in this Example pertain only to this e; Sample 17 is referred to ere as compound 17.

Scheme 5 MeO OMe MeO OMe H gMe H GOMe ©:N’>_CI N)—/ NH KH2P04, n-BuOH 90 °c, 16 h sample 17 Synthesis ofN—(3,4,5-trimethoxyphenyl)- zo[a’]imidazol—2-amine (Sample 17).

A mixture of 2-chloro-lH—benzo[d]imidazole (1) (0.40 g, 2.63 mmol), potassium dihydrogenphosphate (0.36 g, 2.63 mmol) and 3,4,5-trimethoxyaniline (0.48 g, 2.63 mmol) in 20 mL ofn-BuOH was stirred at 90 CC for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic t was dried over Na2S04 and concentrated under reduced pressure. The crude material was puri?ed by silica gel chromatography to afford 0.43 g (54%) of the title compound as an off-white solid. 1H NMR (300 MHZ, CDCl3) 6 10.8 (s, 1H), 9.29 (s, 1H), 7.28 (bs, 2H), 7.12 (s, 2H), 6.97 (bs, 2H), 3.79 (s, 6H), 3.62 (s, 3H); MS (ESI+) m/Z = 300 (M+H).

Example 6: Synthesis of Sample 24 Sample 24 was prepared as shown below in Scheme 6. Compound numbers used in this Example pertain only to this Example; Sample 24 is ed to elsewhere as compound 24.

Scheme 6 (COCI)2 MeO OMe C"'2‘3'2 MeO OMe UNBocCF3COOH QTFA —4>OMe S H CH2C|2 NH2 DIPEA CHZCIZ sample 24 Synthesis ofthiophen—2-amine-TFA salt (2) To a solution of tert—butyl thiophenylcarbamate (1) (0.50 g, 2.51 mmol) in 10 mL ofDCM was added 2,2,2-tri?uoroacetic acid (1.43 g, 12.55 mmol). The mixture was stirred at rt for 2 h. The reaction mixture was trated under reduced pressure to afford ~0.50 g of the title compound, which was directly used for the next step without puri?cation.

Synthesis of 2-(3,4,5-trimethoxyphenyl)acetyl de (4) To an ice-cold solution of 2-(3,4,5—trimethoxyphenyl)acetic acid (3) (0.40 g, 1.77 mmol) in 10 mL ofDCM was added oxalyl chloride (0.67 g, 5.30 mmol) followed by 1 drop of DMF. The mixture was stirred from 0 CC to rt for 2 h. The reaction mixture was trated under reduced pressure to afford ~0.50 g of the title compound, which was used in the next step without puri?cation.

Synthesis ofN—(thiophen—2-yl)(3,4,5-trimethoxyphenyl) acetamide (Sample 24) To an ld on of thiophen—2-amine0TFA salt (2) (~0.50 g, crude) and diisopropylethylamine (DIPEA) (0.99 g, 7.65 mmol) in 10 mL ofDCM was added a solution of 2-(3,4,5—trimethoxyphenyl)acetyl chloride (4) (~0.50 g, crude) in 5 mL ofDCM and the reaction mixture was d to warm from 0 °C to rt over 2 h with stirring. The reaction mixture was diluted with water and extracted with DCM. The organic extract was dried over NazSO4 and concentrated under reduced pressure. The crude material was puri?ed by silica gel tography to afford 0.25 g of the title compound as a white solid. 1H NMR (300 MHZ, CDC13) 8 7.80 (bs, 1H), 6.87 (m, 1H), 6.81 (m, 1H), 6.56 (m, 1H), 6.51 (s, 2H), 3.86 (s, 9H), 3.70 (s, 2H); MS (ESI+) m/Z = 308 (M+H).

Exam le 7: Desi n and In Vitro Activi of Selective Ah Rece tor Modulators SAhRM ting Anti-In?ammatory Properties As a starting point for the development of the presently sed compounds, a group of 47 compounds belonging to a series of l-aryl-l,2,3,4-tetrahydro-B-carboline derivatives (Figure l) were evaluated in vitro for their ability to increase the production of IL-22 and to se the production of IFN—y (Figure 23). Figure 24 shows in vitro results for a number of compounds described above. The compounds decrease the production of IFN—y. Notably, in addition to decreasing IFN-y production, compounds 15 and 17, for example, also strongly increases the tion of IL-22.

Conformational analysis Conformational analysis of all compounds in the series was d out in order to determine the spatial position of their substituents and to ?nd among the lowest energy conformers, their putative bioactive mations.

Molecular modeling studies were performed using SYBYL software n 6.92.

Three dimensional models of all compounds were built from a standard fragments library, and their geometry was subsequently optimized using the Tripos force ?eld including the electrostatic term ated from Gasteiger and Huckel atomic charges. The method of Powell available in the n2 procedure was used for energy minimization until the gradient value was smaller than 0.0001 kcal/mol AZ.

For each compound, a conformational search using the random search process as implemented in SYBYL was med to identify its lowest energy conformations. Random conformational searching is a que to locate energy minima of a molecule. It involves making random n changes to selected bonds, followed by a minimization. The cycle of random changes and minimization is repeated many times. After each cycle the new conformation is compared against all others found so far to see if it is unique. For the random search, the main options used are the maximum hits (11 = 6) which de?ned the minimum number oftimes each conformation must be found to stop searching for new conformations, the RMS threshold (RMS = 0.2 A) which de?ned the maximum RMS difference between two conformations before they are considered different.

The conformations produced by the random conformational search are fully optimized and can be used immediately for their geometry reoptimization with the semi— empirical MOPAC package n 6.0 using the Hamiltonian AM1 (keywords: PRECISE, NOMM, PARASOK), and Coulson partial atomic s were calculated using the same method. Table 1 shows conformational spaces for selected compounds.

Table 1 Compounds 11 Emin (kcal) Emax (kcal) L-A03 2 80.76 83.82 CTL—01L-A04 16 43.15 47.70 CTL-01—07-L-B05 157 26.34 61.71 CTL—10L-C08 126 -5. 12 30.49 CTL—10—26—L-C09 66 —27.40 -10.60 CTL26-L-C10 26 31.33 40.74 CTL26-L-F07 30 29.75 47.35 CTL—10L-F09 97 26.64 51.86 CTL—10L-G10 135 -40.40 -3.65 CTL—10L-H04 202 -8.80 20.56 CTL—10L-H05 106 26.05 45.80 CTL—10L-H06 49 8.01 13.62 L-A05 253 -43.79 -7. 10 SGA360 853 -95.57 -63.71 Le?unomide 29 -124.59 -121.31 n: number of conformers, Emin: lowest energy mer, Emax: highest energy conformer Le?unomide, but not its active metabolite, A771726, activates the AhR (Scheme 7). SGA 360 is a SAhRM that exhibits anti-in?ammatory properties in viva.

Scheme 7 Le?ummide Example 8: AhR g Peripheral blood mononuclear cells (PBMC), isolated from 3 healthy subjects, were isolated by density gradient centrifugation (Lymphoprep; Nycorned Pharma) from 5 mL heparinized blood samples. PBMC were resuspended in RPMI 1640 supplemented with 10% fetal calf serum at a concentration of 1X106 cells/mL, cultured in 24-well culture plates (Falcon Plastic) and stimulated with medium alone or anti-CD3/anti—CD28 nyi Biotec) antibodies with or without 100, 200, or 400 nM ofAhR g compounds (02, 04, 13, 15, 17, or 24), dimethyl sulfoxide or 6-formylindolo[3,2-b]carbazole (Ficz, . Total RNA was extracted from cells cultured for 24 hours. For RNA preparation, cells were lysed in 1 mL of guanidium thiocyanate buffer and subjected to pheno l/chloroform extraction using TRizol reagent (Invitrigen). The sample obtained was quantitated by absorbance at 260 nm and complementary DNA (cDNA) was synthetized from 1mg oftotal RNA. cDNA was ampli?ed using the ing conditions: denaturation for 1 minute at 95 °C; ing for 30 seconds at 58 °C for IFN-y, and 60 °C for B-actin; and followed by 30 seconds of ion at 72 °C. Primer sequences were as follows: human IFN-y, forward (SEQ ID NO. 1) 5’- TGGAGACCATCAAGGAAGAC-3', reverse (SEQ ID N02) 5’- GCGTTGGACATTCAAGTCAG-3’. IL-22 was evaluated using commercially available TaqMan probes (Applied Biosystems). B-actin (forward (SEQ ID NO. 3) 5’- AAGATGACCCAGATCATGTTTGAGACC-3', reverse (SEQ ID NO. 4) 5’- AGCCAGTCCAGACGCAGGAT-3’) was used as a housekeeping gene. Gene sion was ated using the AACt algorithm.

Example 9: Aryl Hydrocarbon Receptor-Driven Signals Inhibit Collagen Synthesis in the Using both in vitro and in vivo models of ?brosis, we have determined that AhR is a regulator of collagen synthesis in the gut, as described below.

Materials and Methods Patients and samples Mucosal samples were taken from surgical specimens of 10 patients with ?brostenosing CD (median age, 37 years; range: 27—56 years); 7 of these 10 patients were receiving corticosteroids, and the ing patients were on corticosteroids and azathioprine.

Mucosal samples were also taken from 3 patients with ulcerative colitis (UC) undergoing colectomy for a chronic disease unresponsive to medical treatment and 6 UC patients undergoing endoscopy for recent ?are-ups (median age, 38 years; range 29—55 years). Four UC patients were receiving corticosteroids while the remaining were treated with mesalazine.

Normal controls ed s taken from 4 patients with irritable bowel syndrome and from macroscopically and microscopically unaffected areas of 6 patients undergoing colectomy for colon cancer (median age, 49 years; range 33—68 years).

Isolation and culture ofintestinal?broblasts All reagents were purchased from Aldrich (Milan, Italy) unless ed.

Intestinal ?broblasts were isolated and phenotypically characterized as described elsewhere. In all experiments, ?broblasts were used n passages 3 and 8. To examine r AhR regulates collagen production, ?broblasts isolated from CD patients were starved overnight and then stimulated with TGF-Bl (TGF-B; 1 ng/mL; Peprotech EC, London, UK) or TNF-OL (15 ng/mL; R&D Systems, Abingdon, UK) in the presence or absence of Ficz (?nal concentration, 100—400 nM; Alexis, Milan, Italy) or 2-methyl—2H—pyrazolecarboxylic acid (CH223191; ?nal concentration 10 uM; Calbiochem, gham, England), an AhR antagonist, for 24-48 hours.

At the end, cells were used to extract RNA and cell-free atants were analyzed for collagen content.

Induction ofcolonic?brosis

[00198] Trinitrobenzene sulfonic acid (TNBS) was dissolved in 45% ethanol and administered ectally to 8-week-old female balb/c mice for 7 weeks as previously described.

Ficz (l ug/mouse) or AhR antagonist (CH223191; 10 ug/mouse) was dissolved in phosphate- buffered saline (PBS) and given intraperitoneally every 48 hours after the ?fth week ofTNBS administration. Control mice were given PBS alone. Mice were examined 3 times a week for signs of colitis including weight loss and killed at week 8; afterwards tissues were collected for histology, RNA is and en analysis. Colonic sections were stained with H&E and with Masson’s trichrome to detect connective deposition. Fibrosis was scored as mild, moderate, or severe as previously reported.

RNA extraction, complementary DNA preparation and real time polymerase chain reaction RNA isolation, reverse ription of the RNA and real-time PCR were d out as previously described. RNA was extracted by using TRIzol reagent according to the manufacturer’s instructions (Invitrogen, Carlsbad, CA). A constant amount ofRNA (1 pg per sample) was reverse transcribed into complementary DNA, and this was ampli?ed using the following conditions: denaturation for 1 minute at 95 CC; annealing for 30 seconds at 60 °C for human collagen I (CollAl), human , human alpha smooth muscle actin (Ot-SMA), and B- actin, at 58 °C for human AhR and mouse CollA2, followed by 30 seconds of extension at 72 °C. Primer sequences were as follows: human CollAl (SEQ ID NO. 5) 5'- GGACACAGAGGTTTCAGTGG-3', (SEQ ID NO. 5) GACTTTGGAGACACAGG-5'; Col3A1 (SEQ ID NO. 6) 5’-GGAGAATGTTGTGCAGTTTGC-3’, (SEQ ID NO. 6) 3’- CGTTTGACGTGTTGTAAGAGG-S’; human (x-SMA (SEQ ID NO. 7) 5’- TCTGGAGATGGTGTCACCCA-3’, (SEQ ID NO. 7) 3’-ACCCACTGTGGTAGAGGTCT-5’; human AhR (SEQ ID NO. 8) 5’-GAGCACAAATCAGAGACTGG-3’, (SEQ ID NO. 9) 5'- TGGAGGAAGCATAGAAGACC-3’; mouse CollA2 (SEQ ID NO. 10) 5’- TGGTATGGATGGAC-3’, (SEQ ID NO. 10) 3’-CAGGTAGGTATGGTGACACA- '; B—actin ((SEQ ID NO.3) 5’-AAGATGACCCAGATCATGTTTGAGACC-3’, (SEQ ID NO. 4) 5'—AGCCAGTCCAGACGCAGGAT-3') was used as a housekeeping gene. Gene expression was ated using the AACt algorithm.

Flow cytometry To assess the intracellular expression ofAhR and the phosphorylated (p) form of p38, Erk1/2, NF-kB/p65 and Smad2/3, cells were ?xed with 1% formaldehyde for 20 minutes and subsequently permeabilized with 0.5% saponin in 1% bovine serum albumin and stained with anti-AhR (1 :50, ?nal on; Abcam, Cambridge, UK), anti-p-p38 (pT180/pY182)—PE (?nal dilution 1:50; BD Biosciences, San Jose, CA), anti-p-ERK1/2 (pT202/pY204; pT184/pY186)-PE (?nal on 1:50; BD ences), anti-p-NF-kB/p65-FITC (1 :50 ?nal on; eBioscience, San Diego, CA), and anti—p—Smad2/3 (1:50 ?nal dilution; Cell Signaling, Danvers, MA). Appropriate ary antibody and isotype-matched controls (BD Biosciences) were included in all experiments. Cells were analyzed using a FACS Verse?ow cytometer and FACS Suite software (BD Biosciences).

Collagen assay Total collagen was measured in ?broblasts-free supernatants and mouse tissue samples by Sircol en Assay Kit (Biocolor Ltd, Belfast, UK) in accordance with the manufacturer’ s instructions.

Statistical analysis Differences between groups were ed using the Student’s t-test.

Results AhR activation negatively regulates collagen production by intestinal?broblasts AhR RNA transcripts were constitutively expressed in ?broblasts isolated from the gut of patients with CD, patients with UC and normal controls with no signi?cant differences among groups (Figure 25 (A)). Flow cytometry analysis showed that nearly 50% of intestinal ?broblasts expressed AhR in both IBD and controls (Figure 25 (B)). To determine whether AhR activation regulates collagen production, asts ed from FS of CD patients were treated with TGF-Bl or TNF-a, two known rs of collagen, in the presence or absence of Ficz for 24 hours. As expected, stimulation of ?broblasts with TGF-Bl or TNF-a induced a signi?cant increase of transcripts for CollAl, Col3Al , and a-SMA, a marker of ?broblast activation (Figures 26 (A) — 26 (B)). Treatment of ?broblasts with Ficz did not alter the basal RNA sion of CollAl, , and (x—SMA but signi?cantly reduced TGF-Bl or TNF—a— driven RNA transcripts for CollAl, Col3Al, and a—SMA (Figures 26 (A) — 26 (B)). To further assess the role ofAhR in the control of collagen expression, CD ?broblasts were stimulated with TGF—Bl or TNF-a in the presence or absence of CH223 l9l. CH223 191 signi?cantly enhanced CollAl RNA transcripts in ulated ?broblasts as well as RNA expression of CollAl CollA3, and a-SMA in ?broblasts stimulated with TGF-Bl or TNF-a (Figures 27 (A) — 27 (B)).

Analysis of soluble forms of collagen in ?broblast culture supernatants con?rmed that, in unstimulated cells, CH223 191 but not Ficz collagen cantly up-regulated collagen secretion (Figures 28 (A) — 28 (D)). Moreover, Ficz dose-dependently inhibited TGF-Bl and TNF—OL—induced collagen ion while CH223191 inhibited such a synthesis es 28 (A) — 28 (D)). Neither Ficz nor CH223191 changed ?broblast viability or eration (data not AhR controls Map kinase activation in CD?broblasts tion of p38 and ERKl/2 MAP kinases has been involved in the TGF—Bl and TNF—OL—driven collagen induction. Therefore, we next investigated whether the AhR-mediated control of collagen synthesis was associated with changes of this intracellular pathway. To this end, we monitored p38 and ERK1/2 activation by ?ow-cytometry using c antibodies, which recognize the phosphorylated/active forms of these proteins.

In unstimulated conditions, the fractions of cells expressing p-p38 or p-ERK1/2 were not affected by Ficz while being signi?cantly increased by CH223 l9l (Figures 29 (A) — 29 (B)).

TGF—Bl and TNF-d signi?cantly se the percentages of ?broblasts expressing p-p38 and p- ERK1/2, and this effect was either decreased or increased by Ficz or CH223 191, tively (Figures 29 (A) — 29 (B)). TGF-Bl and TNF—d also enhanced the fractions of cells sing p- Smad2/3 or NF-kB/p65 respectively, but neither Ficz nor CH223 191 d such percentages (Figures 29 (A) — 29 (B)).

AhR controls TNBS-induced intestinal?brosis in mice To translate these data in vivo, we used an experimental model of intestinal ?brosis d in Balb/c mice by repeated, rectal administration of low-doses of TNBS. To determine whether AhR activation interferes with collagen synthesis and ?brosis pment, mice were given peritoneally either Ficz or CH223191 after the ?fth week ofTNBS administration (Figures 30 (A) — 30 (B)). This time point was selected on the basis of previous s showing that deposition of collagen begins at week 4 after the ?rst TNBS administration. Extent and severity of in?ammation and s were assessed in animals sacri?ced on week 8. As expected, mice treated with repeated doses ofTNBS exhibited minimal intestinal in?ammation but marked thickening of the colon wall. Masson’s trichrome staining of colonic sections and collagen RNA and protein analysis using whole colonic samples con?rmed the increased collagen induction in TNBS-treated mice as compared to controls. Mice given Ficz exhibited a signi?cant reduction of collagen sion while those receiving CH223 l9l produced more collagen as compared to TNBS-treated mice es 30 (B) — 30 (C)).

Discussion This study investigated the role ofAhR in the control of intestinal ?brosis. AhR was constitutively expressed in intestinal ?broblasts isolated from FS of CD patients as well as in inal ?broblasts ofUC patients and normal controls. Although treatment of CD ?broblasts with Ficz did not modify the basal expression of collagen, inhibition ofAhR with CH223191 led to increased collagen production, suggesting that constitutive AhR activation in these cells types is essential to keep collagen sis in check. Fibroblasts isolated from sites ofF8 in CD have enhanced ty to respond to pro-?brotic cytokines by producing collagen. Since studies in other systems have shown that AhR negatively regulates intracellular pathways activated by pro-?brotic cytokines, it was next evaluated whether AhR activation is involved in TGF—B and TNF-(x induced en production. CD ?broblasts displayed a different capacity to synthesize collagen when treated with Ficz or CH223191. In particular, Ficz dose-dependently reduced collagen RNA and n expression while inhibition ofAhR was followed by enhanced collagen production in response to TGF-B and TNF-(x. Interestingly however, even at the greatest doses used in our system, Ficz did not completely abolish cytokine-induced collagen synthesis, raising the possibility that AhR does not control all the cytokine-driven intracellular pathways that lead to collagen production. Indeed, analysis of such signals revealed that Ficz abrogated tion of both p38 and ERK1/2 without affecting activation of 3 and NF— kB in ?broblasts stimulated with TGF-B or TNF-a, respectively. The fact that ediated abrogation ofp38 and ERK1/2 tion was accompanied by a 60% reduction of cytokine— driven collagen synthesis tes a major role for MAP s in the control of collagen production in CD ?broblasts. The lack of effect of both Ficz and CH223191 on Smad2/3 and NF-kB activation in response to TGF-B or TNF—(x is noteworthy, as these ?ndings indicate that AhR activation does not induce a state of global unresponsiveness in intestinal ?broblasts, perhaps explaining why Ficz or CH223191 did not affect proliferation and survival of these cells.

The AhR-mediated negative regulation of collagen production was supported by in vivo studies in mice g that Ficz was effective for minimizing ?brosis associated with c long-term in?ammation. In contrast, mice receiving CH223191 exhibited a more intense collagen deposition as compared to control mice. In these studies, treatment with both Ficz and CH223191 started at a time point (week 5) that is characterized by pathological accumulation of collagen in the colon of TNBS-treated mice. ore, it is unlikely that the AhR-mediated inhibition of collagen production is secondary to suppression of the ongoing colitis.

In conclusion, these results show that AhR activation negatively controls collagen synthesis in the gut. These novel ?ndings suggest that lated nds could help prevent and/or revert FS in patients with CD.

INCORPORATION BY REFERENCE The entire disclosure of each of the patent documents and scienti?c articles cited herein is incorporated by reference for all purposes.

EQUIVALENTS The ion can be ed in other speci?c forms with departing from the essential characteristics thereof. The foregoing embodiments therefore are to be considered illustrative rather than ng on the invention described herein. The scope of the invention is indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims (21)

What is claimed is:

1. A compound according to Formula I: or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: Ar is represented by ; G1 is N and G2, G3, and G4 are CH2; G1 is CH, G2 and G4 are NH, and G3 is CH2; or G1 is N, G2 and G4 are CH2, and G3 is NH; and X1 if t is selected independently for each occurrence from the group consisting of n, –OH, –CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, –O– phenyl, –N(R1)2, –NO2, –C1-6 alkylene–N(R1)2, –C(O)N(R3)2, –CO2R3, –C(O)R3, –SR3, , –SO3R3, and R3)2; X2 if present is selected independently for each occurrence from the group consisting of halogen, –OH, –CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, –O– phenyl, –N(R1)2, –NO2, –C1-6 alkylene–N(R1)2, –C(O)N(R3)2, –CO2R3, –SR3, –SO2R3, –SO3R3, or –SO2N(R3)2; R1 is independently for each occurrence H or C1-6 alkyl; R2 is independently for each occurrence H or C1-6 alkyl; R3 is independently for each ence selected from the group consisting of H, C1-6 alkyl, phenyl, or heteroaryl; n is independently for each ence 0, 1, 2, or 3; and m is independently for each occurrence 0, 1, 2, 3, or 4; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 lkyl, C1-6 alkoxy, or –O–phenyl may each be optionally substituted independently for each occurrence with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, –OH, –CN, –NR’R’’, – C(O)N(R’R’’), and –C(O)R’, wherein R’ and R’’ are each independently selected from H, methyl, ethyl, propyl or butyl, or R’ and R’’ taken together form a 4-6 membered heterocycle.

2. The compound of claim 1, wherein Ar is .

3. The compound of claim 1 or 2, n the compound is selected from the group consisting of , , and .

4. A compound of the following formula: or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein Ar is represented by ; X1, if t, is selected independently for each occurrence from the group consisting of halogen, –OH, –CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, –O– , –N(R1)2, –NO2, –C1-6 alkylene–N(R1)2, –C(O)N(R3)2, , 3, –SR3, –SO2R3, –SO3R3, and –SO2N(R3)2; R1 is independently for each occurrence H or C1-6 alkyl; R3 is independently for each occurrence selected from the group consisting of H, C1-6 alkyl, phenyl, and heteroaryl; and m is independently for each ence 0, 2, 3, or 4, wherein each instance of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, or –O–phenyl may be optionally tuted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, –OH, –CN, –NR’R’’, – C(O)N(R’R’’), and –C(O)R’, and wherein R’ and R’’ are each independently selected from the group consisting of H, methyl, ethyl, propyl, and butyl, or R’ and R’’ taken together form a 4- 6 membered heterocycle.

5. The compound of claim 4, wherein the compound is or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition, comprising a compound according to any one of claims 1-6; and a pharmaceutically acceptable carrier.

8. Use of a compound according to any one of claims 1-6 or the pharmaceutical composition according to claim 7 in the manufacture of a ment for decreasing IFN-? levels.

9. Use of a compound according to any one of claims 1-6 or the ceutical ition according to claim 7 in the manufacture of a medicament for increasing IL-22 .

10. Use of a compound according to any one of claims 1-6 or the pharmaceutical composition according to claim 7 in the manufacture of a medicament for increasing IL-22 levels and decreasing IFN-? levels.

11. Use of a compound ing to any one of claims 1-6 or the pharmaceutical composition according to claim 7 in the manufacture of a medicament for inhibiting lipid peroxidation.

12. Use of a compound according to any one of claims 1-6 or the pharmaceutical composition according to claim 7 in the manufacture of a medicament for ting an aryl hydrocarbon receptor (AhR).

13. Use of a compound according to any one of claims 1-6 or the pharmaceutical composition according to claim 7 in the manufacture of a medicament for treating an inflammatory e or condition.

14. The use of claim 13, wherein the inflammatory disease or condition is selected from the group consisting of inflammatory bowel disease, age inflammation, bone degradation, ulcerative colitis, psoriasis, arthritis, psoriatic arthritis, rheumatoid arthritis, juvenile arthritis, juvenile rheumatoid arthritis, autoimmune hepatitis, Crohn’s disease, lupus matosus, multiple sclerosis, Alzheimer’s e, dermatitis, atopic dermatitis, acne, Type I diabetes us, Raynaud’s phenomenon, Graves’ disease, and Addison’s disease.

15. The use of claim 13, wherein the inflammatory disease or condition is selected from the group consisting of Crohn’s disease, ulcerative s, enous colitis, lymphocytic colitis, diversion colitis, Behçet’s disease, idiopathic inflammatory bowel e, irritable bowel syndrome, regional enteritis, spastic colon, microscopic colitis, Crohn’s colitis, perianal disease, lymphocytic gastritis, eosinophilic tis, and indeterminate colitis.

16. The use of claim 13, wherein the inflammatory disease or condition is Crohn’s disease.

17. The use of claim 16, wherein the Crohn’s e is ed from the group consisting of ileocolitis, ileitis, gastroduodenal Crohn’s disease, jejunoileitis, and granulomatous ileocolitis.

18. The use of claim 16 or claim 17, wherein the s disease includes intestinal fibrosis.

19. The use of claim 16 or claim 17, wherein the Crohn’s disease is fibrostenotic Crohn’s disease.

20. Use of a compound according to any one of claims 1-6 or the pharmaceutical composition according to claim 7 in the manufacture of a medicament for ting, treating, or reducing fibrostenosis or intestinal fibrosis.

21. The use of claim 20, wherein the fibrostenosis or intestinal fibrosis is associated with s disease. 467 9 9 2 7 1 1 0 4 ! 6"! #! # $ %4 & ' ( ) * $ ! 9 ! $ * " $9 + *!, ! $ 29 " !# -4 62%4.67 /4 2 .%04