(1h-indol-3-yl)(pyridin-2-yl)methanone derivatives as aryl hydrocarbon receptor (AHR) agonists for the treatment of inflammatory, autoimmune, metabolic or proliferative diseases

Abstract

The present invention relates to compounds for the formulae (I) to (IV); as well as to structurally related specific (1H-indol-3-yl)(pyridin-2-yl) methanone derivatives not encompassed by any of these formulae. Said compounds are hydrocarbon receptor (AHR) agonists for the treatment of e.g. inflammatory, autoimmune, metabolic or proliferative diseases, such as e.g. metabolic syndrome, type I diabetes, steatosis, colitis (in particular ulcerative colitis), inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, pancreatitis, insulitis, atherosclerosis, graft versus host disease, or cancer.

Description

ARYL HYDROCARBON RECEPTOR (AHR) AGONISTS AND USES THEREOF RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to United States Provisional Application, U.S.S.N.63 / 681,402, filed August 9, 2024, the entire contents of which is incorporated herein by reference. GOVERNMENT SUPPORT

[0002] This invention was made with government support under grant DK132284 awarded by the National Institutes of Health and grant W81XWH-21-1-0369 awarded by the United States Army. The government has certain rights in the invention. BACKGROUND

[0003] Inflammatory bowel disease (IBD) is an umbrella term used to describe disorders that involve chronic inflammation of the digestive tract, and as such can be considered a metabolic disorder, an immune disorder, and an inflammatory disease. Inflammatory bowel disease is the consequence of a sustained inflammatory response to commensal microorganisms in a genetically susceptible host with excessive production of proinflammatory cytokines, such as TNFα and IL-1β (1, 2). As a consequence, interventions designed to induce and maintain remission of active disease have largely focused on the use of T cell suppressive agents, such as corticosteroids, azathioprine, and 6-mercaptopurine, among others; all of which have been limited by toxicity (3-10). Most recently, biologics targeting specific cytokines, such as TNFα, or the α4β7 receptor have been introduced as disease-modifying drugs (11-17). While higher rates of remission and mucosal healing have been observed, these agents have been limited by an increased risk of infection, malignancy, reduced efficacy due to the development of anti-drug antibodies, and high cost (15, 18, 19). All told, one-third of patients with IBD do not respond appropriately to existing therapies (20, 21). Recent evidence now suggests that the exacerbated inflammatory response observed in IBD is initiated and maintained by loss of gut epithelial integrity manifest by increased barrier permeability, impaired mucin production, and reduced secretion of antimicrobial peptides with an ensuing dysbiosis and accompanying bacterial translocation and invasion (22-30). However, current therapies for IBD are often ineffective despite the use of immunosuppressive agents and recently developed biologic drugs.

[0004] The aryl hydrocarbon receptor (AHR) is a member of the basic-helix-loop-helix (bHLH) / Per-Arnt- Sim (PAS) family of transcription factors, which is bound to several co-chaperones and present in an inactive form in the cytosol (84). Upon ligand binding, AHR dissociates from its chaperones and translocates to the nucleus, where it dimerizes with the aryl hydrocarbon receptor nuclear translocator (ARNT) to induce gene transcription. AHR is an essential regulator of the gut innate immune system and mediates processes responsible for microbial homeostasis, enabling commensal bacteria to outcompete pathogenic bacteria, as well as those events that support gut tissue integrity and promote epithelial repair (59, 79, 81, 84-87). In large measure, AHR accomplishes these outcomes by regulating the expression ofIL-22 (58, 59, 80-82). IL-22 is produced in mice and humans by ILC3 cells (36, 37, 47, 77, 82, 88, 89) and γδ T cells (31, 33, 50) but can also be produced in the gut by Th17 cells (90, 91), all in response to AHR activation (58, 59, 80-82). AHR-deficient mice display reduced expression of IL-22, dysbiosis, and an increased risk of bacterial infection and colitis (78, 79, 81, 82) and genome-wide association studies have also identified AHR as a susceptibility locus for IBD (92, 93). These effects can be reproduced by diets deficient in AHR ligands or by constitutive expression of CYP1A1 in intestinal epithelial cells, which increases the metabolism of AHR ligands with increased susceptibility to enteric infection (78, 79, 87). In turn, genetic deletion of CYP1 enzymes delays ligand metabolism with increased protection against intestinal infection (78, 79, 87). Sources of AHR ligands include dietary compounds (94, 95), microbial virulence factors (96), and metabolites derived through microbiota- or host-mediated tryptophan metabolism (58, 69, 97, 98). Indeed, CARD9-deficient mice exhibit impaired metabolism of tryptophan into AHR ligands, decreased production of IL-22, and increased susceptibility to colitis (69). Impaired microbial production of AHR ligands has also been observed in patients with IBD and correlates with an IBD-associated genetic polymorphism within CARD9 (69). In a recent clinical trial, serum levels of tryptophan were inversely correlated with serum levels of IL-22 and the severity of IBD in patients with Crohn’s disease and ulcerative colitis (65).

[0005] Endogenous AHR agonists are derived from a variety of dietary metabolites, including tryptophan, flavonoids, stilbenes, carotenoids, and indoles through microbial- or host-mediated metabolism (58, 69, 99-101). Indeed, the beneficial effect of Lactobacillus species as a commensal organism is likely achieved by metabolic production of AHR ligands (69). For example, L. reuteri and L. johnsonii can generate indole-3-aldehyde, which activates AHR, increases IL-22 production in ILC3 cells, and inhibits dextran sulfate sodium (DSS) induced colitis (58, 102). Although the metabolic route for many indole related AHR ligands has not been well defined, 6-formylindolo[3,2-b]carbazole (FICZ), 3,3′- diindolylmethane (DIM), and 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) ameliorate 2,4,6-trinitrobenzene sulfonic acid- (TNBS-), DSS-, and T cell transfer-induced colitis (97, 103-107). These compounds increase IL-22 production with beneficial effects abrogated by treatment with an IL-22 blocking antibody or an AHR antagonist (69, 80, 83, 103, 108). Adsorbed indole can also be metabolized by the gut microbiota to indirubin, a 3,2′-bisindole isomer, which is the active metabolite in indigo naturalis, a group of Old World plants that have been used in traditional Chinese medicine as a treatment for IBD (109). As a ligand for AHR, indirubin increases expression of IL-22 and reduces disease severity in TNBS and DSS models of colitis, which is not observed in AHR-deficient mice (110). In a recent study, administration of indigo naturalis to 20 patients with UC was associated with 61% mucosal healing and a 72% response rate (109). These reports demonstrate the therapeutic potential of endogenous, indole based, AHR agonists. Nonetheless, the effectiveness of these metabolites and some synthetic derivatives have been limited by a number of factors, including low activity, an undesirable pharmacokinetic profile due to rapid metabolism and short compound half-life, as well as poor biodistribution and off target effects (111-116).SUMMARY

[0006] Examples of aryl hydrocarbon receptor (AHR) agonists and methods of using the same are described in, e.g., International Patent Application Publication No. WO 2019 / 195682 A1, the entire contents of which is incorporated herein by reference.

[0007] Provided herein are new aryl hydrocarbon receptor agonists. These compounds can non-covalently bind aryl hydrocarbon receptors and induce aryl hydrocarbon receptor activity. In contrast to many currently reported small molecule aryl hydrocarbon receptor agonists, these compounds are not as rapidly metabolized as endogenous AHR agonists, allowing for an improved pharmacokinetic profile and sustained AHR activation in vivo. Importantly, these compounds do not appear to be toxic, indicating improved specificity over currently available metabolites and other compounds.

[0008] Provided herein are compounds, including compounds of any of the formulae described herein (e.g., Formulae (I)-(IV) and structures provided in Table 1), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, hydrates, isotopically labeled derivatives, and prodrugs thereof. Compounds provided herein can bind aryl hydrocarbon receptors (AHRs) and induce AHR activity and are therefore useful in the treatment and / or prevention of diseases, disorders, and conditions (e.g., diseases, disorders, and conditions associated with reduced AHR activity). Also provided herein are pharmaceutical compositions comprising the compounds provided herein, and kits comprising the same. Additionally, the disclosure provides methods of preparing the compounds and pharmaceutical compositions described herein, and intermediates useful thereto.

[0009] In certain embodiments, for example, a compound disclosed herein is selected from those in Table 1, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof. Table 1

[0010] In another aspect, provided herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, and one or more pharmaceutically acceptable carriers and / or excipients. In certain embodiments, a pharmaceutical composition provided herein comprises an effective amount (e.g., therapeutically effective amount) of a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0011] As described, compounds and pharmaceutical compositions provided herein can induce AHR activity and are therefore useful in the treatment and / or prevention of diseases, disorders, and conditions (e.g., indications in which reduced AHR activity is implicated).

[0012] In other aspects, provided herein are methods and uses of the compounds and pharmaceutical compositions provided herein, including methods and uses for treating and / or preventing AHR-associated diseases. In another aspect, provided herein are compounds disclosed herein, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in any of the methods provided herein. In another aspect, provided herein are compounds disclosed herein, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use as medicaments and / or in the preparation of medicaments.

[0013] In another aspect, provided herein are kits comprising a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. The kits described herein may include a single dose or multiple doses of the compound or pharmaceutical composition thereof. The kits described herein are useful in any method or use provided herein, and optionally further comprise instructions for using the kit (e.g., instructions for using the compound or composition included in the kit).

[0014] Also provided herein are methods of preparing compounds disclosed herein, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof. Synthetic intermediates useful in the preparation of the compounds and compositions are also provided herein.

[0015] The details of certain embodiments of the disclosure are set forth in the Detailed Description, as described below. Other embodiments of the disclosure will be apparent from the Definitions, Examples, Abstract, and Claims. DEFINITIONS Chemical Definitions

[0016] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry,University Science Books, Sausalito, 1999; Michael B. Smith, March’s Advanced Organic Chemistry, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0017] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw– Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0018] Unless otherwise provided, formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms (“isotopically labeled derivatives”). For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays. The term “isotopes” refers to variants of a particular chemical element such that, while all isotopes of a given element share the same number of protons in each atom of the element, those isotopes differ in the number of neutrons.

[0019] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example, “C1-6alkyl” encompasses, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6alkyl.

[0020] Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0021] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0022] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1–20alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1–12alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9alkyl”). In someembodiments, an alkyl group has 1 to 8 carbon atoms (“C1–8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1–2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6alkyl”). Examples of C1–6alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert- amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), n-dodecyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1–12alkyl (such as unsubstituted C1–6alkyl, e.g., −CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec- Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1–12alkyl (such as substituted C1–6alkyl, e.g., –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, –CH2CF3, or benzyl (Bn)).

[0023] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms (“C1–20haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms (“C1–10haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms (“C1–9haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1–8haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C1–7haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1–6haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C1–5haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1–4haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1–3haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1–2haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a “perfluoroalkyl” group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include –CHF2, −CH2F, −CF3, −CH2CF3, −CF2CF3, −CF2CF2CF3, −CCl3, −CFCl2, −CF2Cl, and the like.

[0024] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorouswithin (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, the heteroalkyl group is an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–20heteroalkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–12heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–11heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–10heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–9heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–8heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–7heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–6heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C1–5heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C1–4heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“C1–3heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“C1–2heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“C1heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C2-6heteroalkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents.

[0025] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 20 carbon atoms (“C2-20alkenyl”). In some embodiments, an alkenyl group has 2 to 12 carbon atoms (“C2–12alkenyl”). In some embodiments, an alkenyl group has 2 to 11 carbon atoms (“C2–11alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2–10alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2–9alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2–8alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2–7alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2–6alkenyl”). In some embodiments, an alkenyl group has 2 to5 carbon atoms (“C2–5alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2–4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2–3alkenyl”). In some embodiments, an alkenyl group has 2 carbon atom (“C2alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2–4alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2–6alkenyl groups include the aforementioned C2–4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., −CH=CHCH3or) may be in the (E)- or (Z)- configuration.

[0026] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, the heteroalkenyl group is an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2–20heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2–12heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2–11heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2–10heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“C2–9heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2–8heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2–7heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2–6heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“C2–5heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“C2–4heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“C2–3heteroalkenyl”). In some embodiments, aheteroalkenyl group has 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“C2heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“C2–6heteroalkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents.

[0027] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2-20alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2- butynyl) or terminal (such as in 1-butynyl). Examples of C2-4alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents.

[0028] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, the heteroalkynyl group is an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2–20heteroalkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2–10heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2–9heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2–8heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2–7heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2–6heteroalkynyl”). In some embodiments, a heteroalkynylgroup has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“C2–5heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent chain (“C2–4heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“C2–3heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“C2heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“C1–6heteroalkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents.

[0029] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14carbocyclyl”) and zero heteroatoms in the non- aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3-13carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10carbocyclyl”). Exemplary C3-6carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8carbocyclyl groups include the aforementioned C3-6carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10carbocyclyl groups include the aforementioned C3-8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplary C3-8carbocyclyl groups include the aforementioned C3-10carbocyclyl groups as well as cycloundecyl (C11), spiro[5.5]undecanyl (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fusedwith one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.

[0030] “Cycloalkyl” refers to a saturated carbocyclyl group. In some embodiments, a cycloalkyl group has from 3 to 14 ring carbon atoms (“C3-14cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 7 ring carbon atoms (“C3-7cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10cycloalkyl”). Examples of C5-6cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6cycloalkyl groups include the aforementioned C5-6cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8cycloalkyl groups include the aforementioned C3-6cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.

[0031] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, silicon, boron, and phosphorous (“3-14 membered heterocyclyl”). In certain embodiments, the heterocyclyl group is a radical of a 3- to 14-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. The point of attachment can be either to a ring carbon atom or a ring heteroatom of the heterocyclyl group, as valency permits. For example, in heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 8-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.

[0032] In some embodiments, a heterocyclyl group is a 5–10 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–8 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0033] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6- membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzo- thienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydro- pyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7- dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3- b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0034] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). In some embodiments, an aryl group has 6-10 ring carbon atoms (“C6-10aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1–naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.

[0035] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, silicon, boron, and phosphorous (“5-14 membered heteroaryl”). In certain embodiments, the heteroaryl group is a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. The point of attachment can be either to a ring carbon atom or a ring heteroatom of the heteroaryl group, as valency permits. For example, in heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0036] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents.

[0037] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0038] The term “acyl” refers to a group having the general formula −C(=O)Raa, −C(=O)ORaa, −C(=O)−O−C(=O)Raa, −C(=O)SRaa, −C(=O)N(Rbb)2, −C(=S)Raa, −C(=S)N(Rbb)2, −C(=S)S(Raa), −C(=NRbb)Raa, −C(=NRbb)ORaa, −C(=NRbb)SRaa, and −C(=NRbb)N(Rbb)2, wherein Raaand Rbbare as defined herein. Exemplary acyl groups include aldehydes (−CHO), carboxylic acids (−CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.

[0039] The term “halo” or “halogen” refers to fluorine (fluoro, −F), chlorine (chloro, −Cl), bromine (bromo, −Br), or iodine (iodo, −I).

[0040] The term “silyl” refers to the group –Si(Raa)3, wherein Raais as defined herein.

[0041] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which is substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds and includes any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen, oxygen, and sulfur may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The embodiments described herein are not limited in any manner by the exemplary substituents described herein.

[0042] Exemplary substituents (e.g., carbon atom substituents) include halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORaa, −ON(Rbb)2, −N(Rbb)2, −N(Rbb)3+X−, −N(ORcc)Rbb, −SH, −SRaa, −SSRcc, −C(=O)Raa, −CO2H, −CHO, −C(ORcc)2, −CO2Raa, −OC(=O)Raa, −OCO2Raa, −C(=O)N(Rbb)2, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −OC(=NRbb)Raa, −OC(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −OC(=NRbb)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −C(=O)NRbbSO2Raa, −NRbbSO2Raa, −SO2N(Rbb)2, −SO2Raa, −SO2ORaa, −OSO2Raa, −S(=O)Raa, −OS(=O)Raa, −Si(Raa)3, −OSi(Raa)3−C(=S)N(Rbb)2, −C(=O)SRaa, −C(=S)SRaa, −SC(=S)SRaa, −SC(=O)SRaa, −OC(=O)SRaa, −SC(=O)ORaa, −SC(=O)Raa, −P(=O)(Raa)2, −P(=O)(ORcc)2, −OP(=O)(Raa)2, −OP(=O)(ORcc)2, −P(=O)(N(Rbb)2)2, −OP(=O)(N(Rbb)2)2, −NRbbP(=O)(Raa)2, −NRbbP(=O)(ORcc)2, −NRbbP(=O)(N(Rbb)2)2, −P(Rcc)2, −P(ORcc)2, −P(Rcc)3+X−, −P(ORcc)3+X−, −P(Rcc)4, −P(ORcc)4, −OP(Rcc)2, −OP(Rcc)3+X−, −OP(ORcc)2, −OP(ORcc)3+X−, −OP(Rcc)4, −OP(ORcc)4, −B(Raa)2, −B(ORcc)2, −BRaa(ORcc), C1–20alkyl, C1–20perhaloalkyl, C2–20alkenyl, C2–20alkynyl, C1–20heteroalkyl, C2–20heteroalkenyl, C2–20heteroalkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5- 14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein X−is a counterion;or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; wherein: each instance of Raais, independently, selected from C1–20alkyl, C1–20perhaloalkyl, C2–20alkenyl, C2–20alkynyl, C1–20heteroalkyl, C2–20heteroalkenyl, C2–20heteroalkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)(N(Rcc)2)2, C1–20alkyl, C1–20perhaloalkyl, C2–20alkenyl, C2–20alkynyl, C1–20heteroalkyl, C2–20heteroalkenyl, C2–20heteroalkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from hydrogen, C1–20alkyl, C1–20perhaloalkyl, C2–20alkenyl, C2–20alkynyl, C1–20heteroalkyl, C2–20heteroalkenyl, C2–20heteroalkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORee, −ON(Rff)2, −N(Rff)2, −N(Rff)3+X−, −N(ORee)Rff, −SH, −SRee, −SSRee, −C(=O)Ree, −CO2H, −CO2Ree, −OC(=O)Ree, −OCO2Ree, −C(=O)N(Rff)2, −OC(=O)N(Rff)2, −NRffC(=O)Ree, −NRffCO2Ree, −NRffC(=O)N(Rff)2, −C(=NRff)ORee, −OC(=NRff)Ree, −OC(=NRff)ORee, −C(=NRff)N(Rff)2, −OC(=NRff)N(Rff)2, −NRffC(=NRff)N(Rff)2, −NRffSO2Ree, −SO2N(Rff)2, −SO2Ree, −SO2ORee, −OSO2Ree, −S(=O)Ree, −Si(Ree)3, −OSi(Ree)3, −C(=S)N(Rff)2, −C(=O)SRee, −C(=S)SRee, −SC(=S)SRee, −P(=O)(ORee)2, −P(=O)(Ree)2, −OP(=O)(Ree)2, −OP(=O)(ORee)2, C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C1–10heteroalkyl, C2–10heteroalkenyl, C2–10heteroalkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents are joined to form=O or =S, and wherein X−is a counterion; each instance of Reeis, independently, selected from C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C1–10heteroalkyl, C2–10heteroalkenyl, C2–10heteroalkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C1–10heteroalkyl, C2–10heteroalkenyl, C2–10heteroalkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rggis, independently, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −OC1–6alkyl, −ON(C1–6alkyl)2, −N(C1–6alkyl)2, −N(C1–6alkyl)3+X−, −NH(C1–6alkyl)2+X−, −NH2(C1–6alkyl)+X−, −NH3+X−, −N(OC1–6alkyl)(C1–6alkyl), −N(OH)(C1–6alkyl), −NH(OH), −SH, −SC1–6alkyl, −SS(C1–6alkyl), −C(=O)(C1–6alkyl), −CO2H, −CO2(C1–6alkyl), −OC(=O)(C1–6alkyl), −OCO2(C1–6alkyl), −C(=O)NH2, −C(=O)N(C1–6alkyl)2, −OC(=O)NH(C1–6alkyl), −NHC(=O)( C1–6alkyl), −N(C1–6alkyl)C(=O)( C1–6alkyl), −NHCO2(C1–6alkyl), −NHC(=O)N(C1–6alkyl)2, −NHC(=O)NH(C1–6alkyl), −NHC(=O)NH2, −C(=NH)O(C1–6alkyl), −OC(=NH)(C1–6alkyl), −OC(=NH)OC1–6alkyl, −C(=NH)N(C1–6alkyl)2, −C(=NH)NH(C1–6alkyl), −C(=NH)NH2, −OC(=NH)N(C1–6alkyl)2, −OC(NH)NH(C1–6alkyl), −OC(NH)NH2, −NHC(NH)N(C1–6alkyl)2, −NHC(=NH)NH2, −NHSO2(C1–6alkyl), −SO2N(C1–6alkyl)2, −SO2NH(C1–6alkyl), −SO2NH2, −SO2C1–6alkyl, −SO2OC1–6alkyl, −OSO2C1–6alkyl, −SOC1–6alkyl, −Si(C1–6alkyl)3, −OSi(C1–6alkyl)3−C(=S)N(C1–6alkyl)2, C(=S)NH(C1–6alkyl), C(=S)NH2, −C(=O)S(C1–6alkyl), −C(=S)SC1–6alkyl, −SC(=S)SC1–6alkyl, −P(=O)(OC1–6alkyl)2, −P(=O)(C1–6alkyl)2, −OP(=O)(C1–6alkyl)2, −OP(=O)(OC1–6alkyl)2, C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C1–10heteroalkyl, C2–10heteroalkenyl, C2–10heteroalkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; and each X−is a counterion.

[0043] In certain embodiments, the molecular weight of a substituent (e.g., carbon atom substituent) is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms.

[0044] In certain embodiments, exemplary substituents (e.g., carbon atom substituents) include halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORaa, −N(Rbb)2, −N(Rbb)3+X−, −SH, −SRaa, −C(=O)Raa, −CO2H, −CHO, −CO2Raa, −OC(=O)Raa, −OCO2Raa, −C(=O)N(Rbb)2, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −NRbbSO2Raa, −SO2N(Rbb)2, −SO2Raa, −SO2ORaa, −OSO2Raa, −S(=O)Raa, −OS(=O)Raa, −Si(Raa)3, −OSi(Raa)3, −P(=O)(Raa)2, −P(=O)(ORcc)2, −OP(=O)(Raa)2, −OP(=O)(ORcc)2, −P(=O)(N(Rbb)2)2, −OP(=O)(N(Rbb)2)2, −NRbbP(=O)(Raa)2, −NRbbP(=O)(ORcc)2, −NRbbP(=O)(N(Rbb)2)2, −B(Raa)2, −B(ORcc)2, −BRaa(ORcc), C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C1–10heteroalkyl, C2–10heteroalkenyl, C2–10heteroalkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein X−is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; each instance of Raais, independently, selected from C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, C2-10heteroalkenyl, C2-10heteroalkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; each instance of Rbbis, independently, selected from hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)(N(Rcc)2)2, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, C2-10heteroalkenyl, C2-10heteroalkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; and each instance of Rccis, independently, selected from hydrogen, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, C2-10heteroalkenyl, C2-10heteroalkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring.

[0045] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (e.g., including one formal negative charge). An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F–, Cl–, Br–, I–), NO3–, ClO4–, OH–, H2PO4–, HCO3−, HSO4–, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p–toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid–2– sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4−, PF4–, PF6–, AsF6–, SbF6–, B[3,5-(CF3)2C6H3]4]–, B(C6F5)4−, BPh4–, Al(OC(CF3)3)4–, and carborane anions (e.g., CB11H12–or (HCB11Me5Br6)–). Exemplary counterions which may be multivalent include CO32−, HPO42−, PO43−, B4O72−, SO42−, S2O32−, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0046] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The embodiments provided herein are not limited in any manner by the above exemplary listing of substituents. Other Definitions

[0047] The following definitions are more general terms used throughout the present application.

[0048] As used herein, the term “salt” refers to any and all salts and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of the present disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0049] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4alkyl)4−salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0050] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.

[0051] “Stereoisomers” that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+)- or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture.”

[0052] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to- enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

[0053] The term “solvate” refers to forms of a compound, including salts thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.“Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0054] The term “hydrate” refers to a solvate wherein the compound is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R×x H2O, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R×0.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R×2 H2O) and hexahydrates (R×6 H2O)).

[0055] The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. See, e.g., Bundgard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985. Prodrugs include acid derivatives such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester-type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the subject.

[0056] Throughout the present disclosure, references to “the compound” and “a compound” provided herein are intended to encompass the compound or group of compounds, and also pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof. Isotopically labeled derivatives are also included.

[0057] The terms “composition” and “formulation” are used interchangeably.

[0058] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non- human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease, disorder, or condition.

[0059] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, providing or otherwise introducing a compound described herein, or a composition thereof, in, to or on a subject.

[0060] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0061] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population.

[0062] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0063] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, an effective amount is an amount sufficient for inducing AHR activity (e.g., in a subject or in a cell in vitro).

[0064] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a disease, disorder, or condition (e.g., a disease, disorder, or condition associated with reduced AHR activity) in a subject. In certain embodiments, a therapeutically effective amount is an amount sufficient for inducing AHR activity in a subject.

[0065] A “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or incombination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a disease, disorder, or condition (e.g., a disease, disorder, or condition associated with reduced AHR activity) in a subject. In certain embodiments, a prophylactically effective amount is an amount sufficient for inducing AHR activity in a subject.

[0066] As used herein an “agonist” refers to a compound that can increase or induce the activity of an aryl hydrocarbon receptor relative to vehicle. In some embodiments, the cell is in vivo. In general, an agonist binds to a receptor (e.g., an aryl hydrocarbon receptor) to induce a biological response. Without wishing to be bound by any particular theory, activation of the acyl hydrocarbon receptor (e.g., by binding to an agonist) results in changes in gene expression, leading to modulation of expression of proteins (e.g., cytokines) to influence inflammatory, metabolic, and other biological responses. Modulation of biological responses by aryl hydrocarbon receptors is discussed in, e.g., Bieschlag TV et al. (2008) The aryl hydrocarbon receptor complex and the control of gene expression. Crit Rev Eukaryot Gene Expr 18, 207-250; Nebert DW et al. (2000) Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis. Biochemical Pharmacology 59, 65-85; Quintana FJ et al. (2008) Control of Tregand TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453, 65-71; and Puga A et al. (2009) The aryl hydrocarbon receptor cross-talks with multiple signal transduction pathways. Biochemical Pharmacology 77, 713-722 ; each of which is incorporated herein by reference in its entirety. In some embodiments, the agonist is a full agonist. A “full agonist” refers to an agonist that binds to a receptor (e.g., an aryl hydrocarbon receptor) and induces the maximum biological response that an agonist can elicit at the receptor. In some embodiments, the agonist is a partial agonist. A “partial agonist” refers to an agonist that binds to a receptor (e.g., an aryl hydrocarbon receptor) but only induces a partial biological response compared to the biological response that a full agonist can induce, even at maximum receptor occupancy.

[0067] “Aryl hydrocarbon receptor.” An aryl hydrocarbon receptor (AhR, AHR, ahr, or ahR) is a ligand- activated transcription factor involved in the regulation of biological responses induced by planar aromatic (i.e., aryl) hydrocarbons. In humans, the aryl hydrocarbon receptor is encoded by the AHR gene. The aryl hydrocarbon receptor is a member of the family of basic helix-loop-helix transcription factors. AhR is a cytosolic transcription factor that is normally inactive, bound to several co-chaperones. Without wishing to be bound by any particular theory, upon ligand binding, the chaperones dissociate resulting in AhR translocating into the nucleus and dimerizing with ARNT (AhR nuclear translocator), leading to changes in gene transcription (see, e.g., Bieschlag TV et al. (2008) The aryl hydrocarbon receptor complex and the control of gene expression. Crit Rev Eukaryot Gene Expr 18, 207-250; which is incorporated herein by reference in its entirety). In some embodiments, the gene is CYP1A1. Cypa1a protein expression may be induced in an AHR-dependent manner in the presence of a compound described herein. In some embodiments, the gene is Muc1, Muc3, or Bcl21.

[0068] “Modulate,” as used herein, means to decrease (e.g., inhibit, reduce, suppress) or increase (e.g., induce, stimulate, activate, enhance) a level, response, property, activity, pathway, or process. A “modulator” is an agent capable of modulating a level, response, property, activity, pathway, or process. A modulator may be an inhibitor, antagonist, activator, or agonist. In some embodiments modulation may refer to an alteration, e.g., inhibition or increase, of the relevant level, response, property, activity, pathway, or process by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, relative to control. In certain embodiments, a compound provided herein is an agonist that increases AHR activity by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, relative to control. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0069] Provided herein are compounds, including compounds of any of the formulae described herein (e.g., compounds provided in Table 1 or compounds of any one of Formulae (I)-(IV)), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, hydrates, isotopically labeled derivatives, and prodrugs thereof. Compounds provided herein can bind aryl hydrocarbon receptors (AHRs) and induce AHR activity and are therefore useful in the treatment and / or prevention of diseases, disorders, and conditions (e.g., diseases, disorders, and conditions associated with reduced AHR activity). Also provided herein are pharmaceutical compositions comprising the compounds provided herein, and kits comprising the same. Additionally, the disclosure provides methods of preparing the compounds and pharmaceutical compositions described herein, and intermediates useful thereto. Compounds

[0070] Provided herein are compounds selected from those in Table 1, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof. In certain embodiments, a compound disclosed herein is selected from the compounds recited in Table 1, and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof. In certain embodiments, a compound disclosed herein is selected from the compounds recited in Table 1, and pharmaceutically acceptable salts thereof. In certain embodiments, a compound disclosed herein is selected from the compounds recited in Table 1 (in free base form). Table 1

[0071] In some aspects, provided herein are compounds of Formula (I):and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, wherein: R1is -CF3or -CN; R2is halogen, -CN, or -OR2a, wherein R2ais hydrogen, optionally substituted C1-6alkyl, C1-6haloalkyl, or optionally substituted C3-6cycloalkyl; each instance of R3and R4is independently halogen, optionally substituted C1-6alkyl, C1-6haloalkyl, or optionally substituted C3-6cycloalkyl; and m and n are each independently 0, 1, 2, or 3.

[0072] In certain embodiments, the compound of Formula (I) is of one of the following formulae:or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0073] Also provided herein are compounds of Formula (II):and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, wherein: R1is -CF3or -CN; R2is halogen, -CN, or -OR2a, wherein R2ais hydrogen, optionally substituted C1-6alkyl, C1-6haloalkyl, or optionally substituted C3-6cycloalkyl; each instance of R3and R4is independently halogen, optionally substituted C1-6alkyl, C1-6haloalkyl, or optionally substituted C3-6cycloalkyl; and m and n are each independently 0, 1, 2, or 3.

[0074] In certain embodiments, the compound of Formula (II) is of one of the following formulae:or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0075] Also provided herein are compounds of Formula (III):and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, wherein: R1is -CF3or -CN; R2is halogen, -CN, or -OR2a, wherein R2ais hydrogen, optionally substituted C1-6alkyl, C1-6haloalkyl, or optionally substituted C3-6cycloalkyl; each instance of R3and R4is independently halogen, optionally substituted C1-6alkyl, C1-6haloalkyl, or optionally substituted C3-6cycloalkyl; m is 0, 1, 2, 3, or 4; and n is 0, 1, or 2.

[0076] In certain embodiments, the compound of Formula (III) is of one of the following formulae:or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0077] Also provided herein are compounds of Formula (IV):and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, wherein: R1is -CF3or -CN; each instance of R3and R4is independently halogen, optionally substituted C1-6alkyl, C1-6haloalkyl, optionally substituted C3-6cycloalkyl, -CN, or -OR2a, wherein R2ais hydrogen, optionally substituted C1-6alkyl, C1-6haloalkyl, or optionally substituted C3-6cycloalkyl; m is 0, 1, 2, 3, or 4; and n is 0, 1, 2, or 3.

[0078] In certain embodiments, a compound provided herein is a compound of Formulae (I)-(IV) or any subgenus or species thereof, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate thereof. In certain embodiments, a compound provided herein is a compound of Formulae (I)-(IV) or any subgenus or species thereof, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. In certain embodiments, a compound provided herein is a compound of Formulae (I)-(IV) or any subgenus or species thereof, or a pharmaceutically acceptable salt thereof. In certain embodiments, a compound provided herein is a compound of Formulae (I)-(IV) or any subgenus or species thereof, as a free base.

[0079] The following definitions and embodiments apply to all generic formulae comprising the relevant groups (e.g., Formulae (I)-(IV) or any subgeneric formula thereof) provided herein. The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable hereinincludes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0080] As defined herein, R1is -CF3or -CN.

[0081] In certain embodiments, R1is -CF3.

[0082] In certain embodiments, R1is -CN.

[0083] As defined herein, R2is halogen, -CN, or -OR2a.

[0084] In certain embodiments, R2is halogen. In certain embodiments, R2is F. In certain embodiments, R2is Cl. In certain embodiments, R2is Br. In certain embodiments, R2is I.

[0085] In certain embodiments, R2is -CN.

[0086] In certain embodiments, R2is -OR2a. In certain embodiments, R2is -OH. In certain embodiments, R2is -OMe. In certain embodiments, R2is -OEt. In certain embodiments, R2is -OCH2Ph.

[0087] As defined herein, R2ais hydrogen, optionally substituted C1-6alkyl, C1-6haloalkyl, or optionally substituted C3-6cycloalkyl.

[0088] In certain embodiments, R2ais hydrogen.

[0089] In certain embodiments, R2ais optionally substituted C1-6alkyl. In certain embodiments, R2ais unsubstituted C1-6alkyl. In certain embodiments, R2ais unsubstituted C1-3alkyl. In certain embodiments, R2ais methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0090] In certain embodiments, R2ais C1-6haloalkyl. In certain embodiments, R2ais C1-3haloalkyl. In certain embodiments, R2ais C1haloalkyl. In certain embodiments, R2ais trihalomethyl.

[0091] In certain embodiments, R2ais optionally substituted C3-6cycloalkyl. In certain embodiments, R2ais unsubstituted C3-6cycloalkyl.

[0092] As defined herein, each instance of R3is independently halogen, optionally substituted C1-6alkyl, C1-6haloalkyl, or optionally substituted C3-6cycloalkyl.

[0093] In certain embodiments, at least one instance of R3is halogen. In certain embodiments, at least one instance of R3is F. In certain embodiments, at least one instance of R3is Cl. In certain embodiments, at least one instance of R3is Br. In certain embodiments, at least one instance of R3is I.

[0094] In certain embodiments, at least one instance of R3is optionally substituted C1-6alkyl. In certain embodiments, at least one instance of R3is unsubstituted C1-6alkyl. In certain embodiments, at least one instance of R3is unsubstituted C1-3alkyl. In certain embodiments, at least one instance of R3is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0095] In certain embodiments, at least one instance of R3is C1-6haloalkyl. In certain embodiments, at least one instance of R3is C1-3haloalkyl. In certain embodiments, at least one instance of R3is C1haloalkyl. In certain embodiments, at least one instance of R3is trihalomethyl.

[0096] In certain embodiments, at least one instance of R3is optionally substituted C3-6cycloalkyl. In certain embodiments, at least one instance of R3is unsubstituted C3-6cycloalkyl.

[0097] As defined herein, each instance of R4is independently halogen, optionally substituted C1-6alkyl, C1-6haloalkyl, or optionally substituted C3-6cycloalkyl.

[0098] In certain embodiments, at least one instance of R4is halogen. In certain embodiments, at least oneinstance of R4is F. In certain embodiments, at least one instance of R4is Cl. In certain embodiments, at least one instance of R4is Br. In certain embodiments, at least one instance of R4is I.

[0099] In certain embodiments, at least one instance of R4is optionally substituted C1-6alkyl. In certain embodiments, at least one instance of R4is unsubstituted C1-6alkyl. In certain embodiments, at least one instance of R4is unsubstituted C1-3alkyl. In certain embodiments, at least one instance of R4is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0100] In certain embodiments, at least one instance of R4is C1-6haloalkyl. In certain embodiments, at least one instance of R4is C1-3haloalkyl. In certain embodiments, at least one instance of R4is C1haloalkyl. In certain embodiments, at least one instance of R4is trihalomethyl.

[0101] In certain embodiments, at least one instance of R4is optionally substituted C3-6cycloalkyl. In certain embodiments, at least one instance of R4is unsubstituted C3-6cycloalkyl.

[0102] In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4.

[0103] In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. Pharmaceutical Compositions, Kits, and Administration

[0104] The present disclosure provides pharmaceutical compositions comprising a compound provided herein (e.g., a compound of Formulae (I)-(IV) or of Table 1), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, and one or more pharmaceutically acceptable carriers and / or excipients. In certain embodiments, a compound described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0105] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0106] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0107] Relative amounts of the active ingredient, the pharmaceutically acceptable carrier or excipient, and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered.

[0108] Pharmaceutically acceptable carriers / excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, solvents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, oils, butters, and / or waxes. Excipients such as coloring agents, coating agents, sweetening agents, flavoring agents, and fragrances may also be present in the composition.

[0109] The compounds and compositions provided herein can be administered by any route, including enteral (e.g. , oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g. , whether the subject is able to tolerate oral administration).

[0110] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0111] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0112] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of acompound described herein.

[0113] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophy tactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects.

[0114] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form a single unit dosage form. Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating and / or preventing a disease, disorder, or condition in a subject in need thereof.

[0115] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits provide instructions for treating a disease in a subject in need thereof. In certain embodiments, the kits provide instructions for preventing a disease in a subject in need thereof. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.Methods of Treatment and Uses

[0001] Also provided herein are methods of using the compounds described herein as described herein to modulate the function of an aryl hydrocarbon receptor.

[0002] For example, in one aspect, provided is a method of modulating an aryl hydrocarbon receptor, the method comprising contacting a cell with a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, the activity of the aryl hydrocarbon receptor increases in the presence of the compound.

[0003] In another aspect, provided herein is a method of increasing expression of a gene in a cell. The expression of genes that are operably linked to aryl hydrocarbon response elements (e.g., XRE) can beinduced once the aryl hydrocarbon receptor is activated (e.g., by a compound of described herein). In some embodiments, the method comprising contacting the cell with a compound of a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, the expression of the gene is activated in the present of an activated aryl hydrocarbon receptor. In some embodiments, the gene is CYP1A1, CYP1A2, CYP1B1, ALDH3A1, NQO1, or UGT1A1. In some embodiments, the gene is CYP1A1. In some embodiments, the gene is Muc1, Muc3, or Bcl21.

[0004] In another aspect, provided is a method of regulating the expression of a cytokine in a cell, the method comprising contacting the cell with a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, the expression of the cytokine is increased. In some embodiments, the expression of the cytokine is decreased. In some embodiments, the cell is in vitro. In some embodiments, the cell is in vivo. In some embodiments, the cytokine is a chemokine, interferon, interleukin, lymphokine, or tumor necrosis factor. In some embodiments, the cytokine is an interleukin.

[0005] In another aspect, provided is a method of regulating the expression of an interleukin in a cell, the method comprising contacting the cell with a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, the expression of the interleukin is increased. In some embodiments, the expression of the interleukin is decreased. In some embodiments, the cell is in vitro. In some embodiments, the cell is in vivo. In some embodiments, the interleukin is interleukin 22 (IL-22), interleukin 6 (IL-6), interleukin 10 (IL-10), or interleukin 17 (IL-17). In some embodiments, the interleukin is interleukin 22 (IL-22). In some embodiments, the interleukin is interleukin 6 (IL-6). In some embodiments, the interleukin is interleukin 10 (IL-10). In some embodiments, the interleukin is interleukin 17 (IL-17). In some embodiments, the expression of interleukin 22 (IL-22) is increased. In some embodiments, the expression of interleukin 22 (IL-22) is decreased. In some embodiments, the expression of interleukin 6 (IL-6) is increased. In some embodiments, the expression of interleukin 6 (IL- 6) is decreased. In some embodiments, the expression of interleukin 10 (IL-10) is increased. In some embodiments, the expression of interleukin 10 (IL-10) is decreased. In some embodiments, the expression of interleukin 17 (IL-17) is increased. In some embodiments, the expression of interleukin 17 (IL-17) is decreased.

[0006] In another aspect, provided is a method of regulating secretion of an interleukin from a cell, the method comprising contacting the cell with a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, secretion of the interleukin is increased. In some embodiments, secretion of the interleukin is decreased. In some embodiments, the cell is in vitro. In some embodiments, the cell is in vivo. In some embodiments, the interleukin is interleukin 22 (IL-22), interleukin 6 (IL-6), interleukin 10 (IL-10), or interleukin 17 (IL-17). In some embodiments, theinterleukin is interleukin 22 (IL-22). In some embodiments, the interleukin is interleukin 6 (IL-6). In some embodiments, the interleukin is interleukin 10 (IL-10). In some embodiments, the interleukin is interleukin 17 (IL-17). In some embodiments, secretion of interleukin 22 (IL-22) is increased. In some embodiments, secretion of interleukin 22 (IL-22) is decreased. In some embodiments, secretion of interleukin 6 (IL-6) is increased. In some embodiments, secretion of interleukin 6 (IL-6) is decreased. In some embodiments, secretion of interleukin 10 (IL-10) is increased. In some embodiments, secretion of interleukin 10 (IL-10) is decreased. In some embodiments, secretion of interleukin 17 (IL-17) is increased. In some embodiments, secretion of interleukin 17 (IL-17) is decreased.

[0007] In yet another aspect, provided is a method of modulating the function of an immune cell, the method comprising contacting the immune cell with a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, the activity of the immune cell is increased upon contacting the cell with the compound. In some embodiments, the activity of the immune cell is decreased upon contacting the cell with the compound. In some embodiments, the immune cell is a T cell, a mast cell, a natural killer cell, a B cell, or an innate lymphoid cell. In some embodiments, the T cell is a regulatory T (Treg) cell. In some embodiments, the T cell is a helper T (TH) cell. In some embodiments, the helper T (TH) cell is a TH17 cell. In some embodiments, the helper T (TH) cell is a TH22 cell.

[0008] In yet another aspect, provided is a method of treating a disease or condition associated with the activity of an aryl hydrocarbon receptor, the method comprising administering a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, to a subject in need thereof in an amount sufficient to modulate the aryl hydrocarbon receptor. Such methods include therapeutic as well as prophylactic (preventative) methods. In some embodiments, the disease or condition is associated with reduced activity of an aryl hydrocarbon receptor. In some embodiments, the disease or condition is associated with reduced activity of an aryl hydrocarbon receptor compared to the activity of the aryl hydrocarbon receptor in a normal (i.e., non-disease) cell.

[0009] Also provided herein are compounds, or pharmaceutical compositions thereof, for use for modulating the activity of an aryl hydrocarbon receptor in a cell. The compounds, or pharmaceutical compositions thereof, may be used to treat diseases or conditions associated with the reduced activity of an aryl hydrocarbon receptor in a cell. Thus, provided herein are compounds, or pharmaceutical compositions thereof, for use in treating a proliferative disease, inflammatory disease, autoimmune disease, or metabolic disorder in a subject in need thereof.

[0010] In some embodiments, the compound is an aryl hydrocarbon receptor agonist. In some embodiments, the compound is a partial aryl hydrocarbon receptor agonist. In some embodiments, the compound modulates the aryl hydrocarbon receptor by increasing the activity of the aryl hydrocarbon receptor. In some embodiments, increased activity of the aryl hydrocarbon receptor leads to an increase in gene expression in the cell. In some embodiments, the cell is in vitro. In some embodiments, the cell isin vivo.

[0011] Exemplary diseases associated with the activity of an aryl hydrocarbon receptor include, but are not limited to, proliferative diseases, inflammatory diseases, autoimmune diseases, and metabolic disorders.

[0012] In certain embodiments, the disease or condition associated with activity of an aryl hydrocarbon receptor is a proliferative disorder. Exemplary proliferative diseases include, but are not limited to, tumors, begnin neoplasms, pre–malignant neoplasms (carcinoma in situ), and malignanat neoplasms (cancers). In some embodiments, the proliferative disease is cancer

[0013] Exemplary cancers include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast), brain cancer (e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma; medulloblastoma), bronchus cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarinoma), Ewing’s sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familiar hypereosinophilia, gall bladder cancer, gastric cancer (e.g., stomach adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma (OSCC), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B–cell ALL, T– cell ALL), acute myelocytic leukemia (AML) (e.g., B–cell AML, T–cell AML), chronic myelocytic leukemia (CML) (e.g., B–cell CML, T–cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B– cell CLL, T–cell CLL); lymphoma such as Hodgkin lymphoma (HL) (e.g., B–cell HL, T–cell HL) and non–Hodgkin lymphoma (NHL) (e.g., B–cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B–cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B–cell lymphomas (e.g., mucosa–associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B–cell lymphoma, splenic marginal zone B–cell lymphoma), primary mediastinal B–cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., “Waldenström's macroglobulinemia”), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B–lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T–cell NHL such as precursor T–lymphoblastic lymphoma / leukemia, peripheral T–cell lymphoma (PTCL) (e.g., cutaneous T–cell lymphoma (CTCL) (e.g., mycosis fungiodes, Sezary syndrome), angioimmunoblastic T–cell lymphoma, extranodal natural killer T–cell lymphoma, enteropathy type T–cell lymphoma, subcutaneous panniculitis–like T–cell lymphoma, anaplastic largecell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumors, immunocytic amyloidosis, kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non–small cell lung cancer (NSCLC), adenocarcinoma of the lung), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g., polycythemia Vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP–NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors), penile cancer (e.g., Paget’s disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g., appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer), urethral cancer, vaginal cancer and vulvar cancer (e.g., Paget’s disease of the vulva).

[0014] In some embodiments, the cancer is stomach cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is hematopoietic cancer. In some embodiments, the hematopoietic cancer is leukemia.

[0015] In certain embodiments, the disease or condition associated with activity of an aryl hydrocarbon receptor is an inflammatory disorder. The term “inflammatory disorder” refers to those diseases or conditions that are characterized by signs of pain (dolor, from the generation of noxious substances and the stimulation of nerves), heat (calor, from vasodilatation), redness (rubor, from vasodilatation and increased blood flow), swelling (tumor, from excessive inflow or restricted outflow of fluid), and / or loss of function (functio laesa, which can be partial or complete, temporary or permanent. Inflammation takes on many forms and includes, but is not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous,pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and / or ulcerative inflammation.

[0016] Exemplary inflammatory disorders include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, haemolytic autoimmune anaemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu’s arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter’s arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, colitis (e.g., ulcerative colitis), conjunctivitis, Chagas disease, chronic obstructive pulmonary disease (COPD), cermatomyositis, diverticulitis, diabetes (e.g., type I diabetes mellitus, type 2 diabetes mellitus), a skin condition (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itch)), endometriosis, Guillain–Barre syndrome, infection, ischaemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g., migraine headaches, tension headaches), ileus (e.g., postoperative ileus and ileus during sepsis), idiopathic thrombocytopenic purpura, insulitis, interstitial cystitis (painful bladder syndrome), gastrointestinal disorder (e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), graft versus host disease, inflammatory bowel disease (IBD) (e.g., Crohn’s disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet’s syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, morphea, myeasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious aneaemia, peptic ulcers, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (e.g., Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease), pancreatitis, prostatitis, chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematosus, schleroderma, scierodoma, sarcoidosis, spondyloarthopathies, Sjogren’s syndrome, thyroiditis, transplantation rejection, tendonitis, trauma or injury (e.g., frostbite, chemical irritants, toxins, scarring, burns, physical injury), vasculitis, vitiligo and Wegener’s granulomatosis.

[0017] In certain embodiments, the inflammatory disorder is colitis. In certain embodiments, the inflammatory disorder is inflammatory bowel disease. In certain embodiments, the inflammatory disorder is Crohn’s disease. In certain embodiments, the inflammatory disorder is rheumatoid arthritis. In certain embodiments, the inflammatory disorder is multiple sclerosis. In certain embodiments, the inflammatory disorder is psoriasis. In certain embodiments, the inflammatory disorder is dermatitis. In certain embodiments, the inflammatory disorder is pancreatitis. In certain embodiments, the inflammatory disorder is insulitis. In certain embodiments, the inflammatory disorder is atherosclerosis.

[0018] In certain embodiments, the disease or condition associated with activity of an aryl hydrocarbon receptor is an autoimmune disorder. Exemplary autoimmune disorders include, but are not limited to, arthritis (including rheumatoid arthritis, spondyloarthopathies, gouty arthritis, degenerative joint diseasessuch as osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease, haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amylosis, acute painful shoulder, psoriatic, and juvenile arthritis), asthma, atherosclerosis, osteoporosis, bronchitis, tendonitis, bursitis, skin condition (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itch)), enuresis, eosinophilic disease, gastrointestinal disorder (e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), and disorders ameliorated by a gastroprokinetic agent (e.g., ileus, postoperative ileus and ileus during sepsis; gastroesophageal reflux disease (GORD, or its synonym GERD); eosinophilic esophagitis, gastroparesis such as diabetic gastroparesis; food intolerances and food allergies and other functional bowel disorders, such as non–ulcerative dyspepsia (NUD) and non–cardiac chest pain (NCCP, including costo–chondritis)).

[0019] In certain embodiments, the disease or condition associated with activity of an aryl hydrocarbon receptor is a metabolic disorder. The term "metabolic disorder" refers to any disorder that involves an alteration in the normal metabolism of carbohydrates, lipids, proteins, nucleic acids, or a combination thereof. A metabolic disorder is associated with either a deficiency or excess in a metabolic pathway resulting in an imbalance in metabolism of nucleic acids, proteins, lipids, and / or carbohydrates. Factors affecting metabolism include, and are not limited to, the endocrine (hormonal) control system (e.g., the insulin pathway, the enteroendocrine hormones including GLP-1, PYY or the like), the neural control system (e.g., GLP-1 in the brain), or the like. Examples of metabolic disorders include, but are not limited to, diabetes (e.g., Type I diabetes, Type II diabetes, gestational diabetes), hyperglycemia, hyperinsulinemia, insulin resistance, steatosis (e.g., fatty liver disease), and obesity.

[0020] In some embodiments, the metabolic disorder is type I diabetes. In some embodiments, the metabolic disorder is steatosis.

[0021] In some embodiments, the metabolic disorder is metabolic syndrome. “Metabolic syndrome” refers to a cluster of conditions that can occur together to increase the risk of heart disease, stroke, and / or diabetes in a patient. Exemplary conditions that can be present in a subject with metabolic syndrome include, but are not limited to, increased blood pressure, high blood sugar, excess body fat around the waist (e.g., obesity), abnormal cholesterol levels, and abnormal triglyceride levels. Metabolic syndrome can be linked to obesity, inactivity, and / or insulin resistance.

[0022] Also provided herein are compounds described herein, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in any of the methods described herein. Also provided herein are uses of compounds described herein, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceuticalcompositions thereof, for use as medicaments or for use in the manufacture of medicaments. Aryl Hydrocarbon Receptor Modulators Therapy for IBD is often ineffective despite the use of immunosuppressive agents and new biologic drugs

[0116] Inflammatory bowel disease (IBD) is the consequence of a sustained inflammatory response to commensal microorganisms in a genetically susceptible host with excessive production of proinflammatory cytokines, such as TNFα and IL-1β (1, 2). As a consequence, interventions designed to induce and maintain remission of active disease have largely focused on the use of T cell suppressive agents, such as corticosteroids, azathioprine, and 6-mercaptopurine, among others; all of which have been limited by toxicity (3-10). Most recently, biologics targeting specific cytokines, such as TNFα, or the α4β7 receptor have been introduced as disease-modifying drugs (11-17). While higher rates of remission and mucosal healing have been observed, these agents have been limited by an increased risk of infection, malignancy, reduced efficacy due to the development of anti-drug antibodies, and high cost (15, 18, 19). All told, one-third of patients with IBD do not respond appropriately to existing therapies (20, 21). Recent evidence now suggests that the exacerbated inflammatory response observed in IBD is initiated and maintained by loss of gut epithelial integrity manifest by increased barrier permeability, impaired mucin production, and reduced secretion of antimicrobial peptides with an ensuing dysbiosis and accompanying bacterial translocation and invasion (22-30). Crucial to the maintenance of epithelial barrier integrity, as well as gut microbial homeostasis and protection from pathogenic microorganisms is the mucosal innate immune system. Intestinal barrier integrity and microbial homeostasis is dependent upon the mucosal innate immune system

[0023] Among the cellular components of the gut innate immune system, both intraepithelial lymphocytes (IEL) and innate lymphoid cells (ILC) are critically important for the preservation of epithelial barrier integrity and intestinal homeostasis (26, 29, 31-33). In particular, Group 3 innate lymphoid cells (ILC3) promote mucosal wound healing by regulating intestinal stem cell regeneration, inducing epithelial and goblet cell proliferation (34-40), and enhancing the expression of mucins (41-43). Microbial homeostasis is supported by the capacity of ILC3 cells to enhance epithelial expression of fucose, which is catabolized by commensal bacteria (44), as well as the secretion of a variety of antimicrobial peptides that prevent dissemination of pathogenic bacteria (45-49). Intraepithelial lymphocytes and specifically, tissue-resident γδ T cells, promote tissue repair, dampen pro-inflammatory responses, and inhibit cytotoxic effector functions of αβ T cells (31, 33, 50). Recent evidence demonstrates that γδ T cells and ILC3 cells mediate these effects by production of IL-22 (36, 40, 44, 45, 51-59). Indeed, disease responses in murine models of colitis are dramatically exacerbated by genetic deletion of IL-22 or by administration of an IL-22 blocking antibody (60, 61). In contrast, treatment with IL-22 promotes goblet and epithelial cell restitution, expression of mucins and antimicrobial peptides, and accelerates mucosal healing with attenuation of local inflammation (40, 54, 59, 62, 63). Studies inpatients with Crohn’s disease demonstrate decreased IL-22-secreting ILCs in the lamina propria (64) and serum levels of IL-22 is associated with disease activity in both UC and Crohn’s disease (65). CARD9 is an adaptor protein that integrates signals from innate immune receptors to selectively activate the IL-22 pathway (66-68). CARD9 deficient mice exhibit impaired production of IL-22, microbial dysbiosis, and increased susceptibility to colitis (69). Significantly, genome-wide association studies have identified genetic polymorphisms of CARD9 that confer IBD risk or protection (70-76). A key regulator of the gut innate immune system, including the role of innate immune cells in IL-22 expression, intestinal barrier surveillance, microbial homeostasis, and mucosal repair is the aryl hydrocarbon receptor (AHR) (58, 59, 77-83). AHR is a critical regulator of the gut innate immune system, IL-22 expression, and intestinal integrity and repair

[0024] The aryl hydrocarbon receptor is a member of the basic-helix-loop-helix (bHLH) / Per-Arnt-Sim (PAS) family of transcription factors, which is bound to several co-chaperones and present in an inactive form in the cytosol (84). Upon ligand binding, AHR dissociates from its chaperones and translocates to the nucleus, where it dimerizes with the aryl hydrocarbon receptor nuclear translocator (ARNT) to induce gene transcription. AHR is an essential regulator of the gut innate immune system and mediates processes responsible for microbial homeostasis, enabling commensal bacteria to outcompete pathogenic bacteria, as well as those events that support gut tissue integrity and promote epithelial repair (59, 79, 81, 84-87). In large measure, AHR accomplishes these outcomes by regulating the expression of IL-22 (58, 59, 80- 82). IL-22 is produced in mice and humans by ILC3 cells (36, 37, 47, 77, 82, 88, 89) and γδ T cells (31, 33, 50), but can also be produced in the gut by Th17 cells (90, 91), all in response to AHR activation (58, 59, 80-82). AHR-deficient mice display reduced expression of IL-22, dysbiosis, and an increased risk of bacterial infection and colitis (78, 79, 81, 82) and genome-wide association studies have also identified AHR as a susceptibility locus for IBD (92, 93). These effects can be reproduced by diets deficient in AHR ligands or by constitutive expression of CYP1A1 in intestinal epithelial cells, which increases the metabolism of AHR ligands with increased susceptibility to enteric infection (78, 79, 87). In turn, genetic deletion of CYP1 enzymes delays ligand metabolism with increased protection against intestinal infection (78, 79, 87). Sources of AHR ligands include dietary compounds (94, 95), microbial virulence factors (96), and metabolites derived through microbiota- or host-mediated tryptophan metabolism (58, 69, 97, 98). Indeed, CARD9 deficient mice exhibit impaired metabolism of tryptophan into AHR ligands, decreased production of IL-22, and increased susceptibility to colitis (69). Impaired microbial production of AHR ligands has also been observed in patients with IBD and correlates with an IBD-associated genetic polymorphism within CARD9 (69). In a recent clinical trial, serum levels of tryptophan were inversely correlated with serum levels of IL-22 and the severity of IBD in patients with Crohn’s disease and ulcerative colitis (65). Dietary metabolites afford AHR agonists that modulate innate immune responses and promote mucosalrepair

[0025] Endogenous AHR agonists are derived from a variety of dietary metabolites including tryptophan, flavonoids, stilbenes, carotenoids, and indoles through microbial- or host-mediated metabolism (58, 69, 99-101). Indeed, the beneficial effect of Lactobacillus species as a commensal organism is likely achieved by metabolic production of AHR ligands (69). For example, L. reuteri and L. johnsonii can generate indole-3-aldehyde, which activates AHR, increases IL-22 production in ILC3 cells, and inhibits DSS induced colitis (58, 102). Although the metabolic route for many indole related AHR ligands has not been well defined, 6-formylindolo[3,2-b]carbazole (FICZ), 3,3’-diindolylmethane (DIM) and 2-(1’H- indole-3’-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) ameliorate TNBS-, DSS-, and T cell transfer-induced colitis (97, 103-107). These compounds increase IL-22 production with beneficial effects abrogated by treatment with an IL-22 blocking antibody or an AHR antagonist (69, 80, 83, 103, 108). Adsorbed indole can also be metabolized by the gut microbiota to indirubin, a 3,2’-bisindole isomer, which is the active metabolite in indigo naturalis, a group of Old World plants that have been used in traditional Chinese medicine as a treatment for IBD (109). As a ligand for AHR, indirubin increases expression of IL-22 and reduces disease severity in TNBS and DSS models of colitis, which is not observed in AHR deficient mice (110). In a recent study, administration of indigo naturalis to 20 patients with UC was associated with 61% mucosal healing and a 72% response rate (109). These reports demonstrate the therapeutic potential of endogenous, indole based, AHR agonists. References 1. Ananthakrishnan AN. Epidemiology and risk factors for IBD. Nat Rev Gastroenterol Hepatol 2015; 12:205-217. 2. 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[0117] In order that the present disclosure may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting in their scope.

[0118] The examples provided below include procedures, intermediates, and characterization data useful, e.g., for the preparation of compounds provided herein. All synthetic steps, procedures, compounds (e.g., synthetic intermediates), reaction conditions, reaction mixtures, reagents, etc. are included herein as aspects of the present disclosure. Synthesis of Compounds Material and Methods

[0119] All reagents and solvents were purchased from commercially available sources (Sigma-Aldrich, Fisher Scientific, Ambeed, and Combi-Blocks) and used without further purification. Analytical thin layer chromatography (TLC) was performed on silica gel (TLC Silica gel 60 F₂₅₄, Sigma-Aldrich). Preparative thin layer chromatography (PTLC) was performed on silica gel (TLC Uniplates™, 1000 micron, Analtech). Normal Phase Flash Chromatography was performed manually on silica gel (SiliaFlash® P60, SILICYCLE, 230– 400 mesh) or on an Interchim PufiFlash XS520Plus (PuriFlash Columns, Interchim). Reversed-Phase Flash Chromatography was performed on an Interchim PufiFlash XS520Plus (column: PF-15C18HP-F0040; eluent: water + 0.1% HOOH (A) / Acetonitrile + 0.1% HCOOH (B), 0 – 3 CV: 5% B; 3 – 15 CV: linear-gradient from 5 to 95% B; 15 - 20 min: 95% B; flow rate: 26 ml / min). Preparative HPLC (prepHPLC) was performed on an Agilent 1260 Infinity system equipped with a Hypersil GOLD™ PREP C18 HPLC Column (particle size 5 μm, dimensions: 250 mm x 21.2 mm) (eluent: water + 0.1% HOOH (A) / Acetonitrile + 0.1% HCOOH (B); 0 – 3 min: 10% B; 3 – 20 min: linear-gradient from 10 to 95% B; 20 -25 min: 95% B; 25 - 30 min: linear gradient from 95% to 10% B; flow rate: 20.0 ml / min). Retention times (Rt) are reported in minutes. Mass spectrometry (MS) was performed on an Advion expression® compact mass spectrometers (CMS) equipped with anelectrospray ion source (ESI) and are reported as m / z. HPLC-MS analyses were performed on a JASCO HPLC system coupled with ESI Advion expression® CMS or an Agilent 1260 Infinity HPLC system equipped with an Agilent 6130 mass spectroscopic detector. Compounds for analysis were dissolved in 100% acetonitrile and analyzed using HPLC-MS methods A, B, or C vide infra. Retention times (Rt) are reported in minutes. All compounds reported were obtained in a purity of > 95% at 254 nm. High- resolution mass spectrometry (HRMS) was performed on an Agilent 6530 QTOF Mass Spectrometer with 1290 Infinity Binary LC using HPLC-MS methods A, B, or C vide infra.1H spectra were recorded on a 400 MHz Varian Mercury plus NMR spectrometer and reported as chemical shifts (δ) in ppm relative to the internal CHCl3signal at 7.26 ppm or the internal D3CSOCHD2 signal at 2.50 ppm as the standard. Spin multiplicities are reported as singlet (s), doublet (d), triplet (t), and quartet (q) with coupling constants (J) given in Hz or multiplet (m). Broad peaks are marked as br.19F NMR spectra were recorded on a 400 MHz Varian Mercury plus NMR spectrometer and reported as chemical shifts (δ) in ppm.13C NMR spectra were recorded on a 400 MHz Varian Mercury plus NMR spectrometer and reported as chemical shifts (δ) in ppm relative to the internal CDCl3signal at 77.16 ppm or the internal D3CSOCD3signal at 39.52 ppm as the standard.1H and13C resonances were assigned with the aid of additional information from 1D and 2D NMR spectra when necessary (H, H-COSY, NOESY, DEPT 135, HSQC, and HMBC). HPLC-MS methods HPLC-MS method A

[0120] HPLC system: Agilent 1260 Infinity HPLC system equipped with an Agilent 6130 mass spectroscopic detector. UV-Vis detection was followed at 254 nm.

[0121] Column: Thermo scientific Accucore C18100 x 2.1 (2.6 μ). The column was kept at room temperature.

[0122] Eluent: water + 0.1% HOOH (A) / Acetonitrile + 0.1% HCOOH (B); 0 – 2 min: 0% B; 2 – 17 min: linear-gradient from 0 to 95% B; 17 - 18 min: 95% B; 18 - 19 min: linear gradient from 95% to 0% B; 19 – 20 min: 0% B. Flow rate: 1.0 ml / min. HPLC-MS method B

[0123] HPLC system: JASCO HPLC system coupled with ESI Advion expression® CMS. UV-Vis detection was followed at 254 nm.

[0124] Column: PrincetonCore 100 C18150 x 4.6 (5 μ). The column was kept at 25 ºC in a column oven.

[0125] Eluent: water + 0.1% HOOH (A) / Acetonitrile + 0.1% HCOOH (B); 0 – 1 min: 0% B; 1 – 5 min: linear-gradient from 0 to 95% B; 5 - 8 min: 95% B; 8 - 9 min: linear gradient from 95% to 0% B; 9 – 10 min: 0% B. Flow rate: 1.0 ml / min. HPLC-MS method C

[0126] HPLC system: JASCO HPLC system coupled with ESI Advion expression® CMS. UV-Vis detection was followed at 254 nm.

[0127] Column: PrincetonCore 100 C18150 x 4.6 (5 μ). The column was kept at 25 ºC in a column oven.

[0128] Eluent: water + 0.1% HOOH (A) / Acetonitrile + 0.1% HCOOH (B); 0 – 1 min: 5% B; 1 – 5 min: linear-gradient from 5 to 95% B; 5 - 8 min: 95% B; 8 - 9 min: linear gradient from 95% to 5% B; 9 – 10 min: 5% B. Flow rate: 1.0 ml / min. Abbreviations

[0129] CV: Column volume; DMF: N,N-Dimethylformamide; DMSO: Dimethyl sulfoxide; EtOAc: Ethyl acetate; HPLC: High-performance liquid chromatography; MS: Mass spectrometry; o / n: Overnight; PBS: Phosphate buffer saline; prepHPLC: Preparative high-performance liquid chromatography; PTLC: Preparative thin layer chromatography; rt: room temperature; THF: Tetrahydrofuran; TLC: thin layer chromatography; TMS: Tetramethylsilane; Synthesis of AhR Agonists

[0130] General procedures A (for the synthesis of 3-acylindoles via Pd catalyzed C-H activation). See Jiang, T-S; Wang, G-W. Synthesis of 3‑Acylindoles by Palladium-Catalyzed Acylation of Free (N-H) Indoles with Nitriles. Org. Lett.2013, 15, 788-791. To a microwave vial equipped with a magnetic stirring bar were added indole / substituted indoles (1.0 eq), nitrile compounds (1.5 eq), D-(+)-CSA (1.1 eq), Pd(OAc)2(0.10 eq), 2,2’-bipyridine (0.12 eq), followed by N-methylacetamide (0.4 M) and water (2.0 eq). The vial was sealed with an aluminum seal with septa. The reaction mixture was heated at 120 ºC in an oil bath for 8 h using a magnetic stirrer. The reaction mixture was then cooled down to room temperature and diluted with ethyl acetate. The resulting solution was filtered through a pad of silica gel. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography to yield the desired products.Scheme S1. (a) 6-(trifluoromethyl)picolinonitrile, D-(+)-CSA, Pd(OAc)2, 2,2’-bipyridine, water, N- methylacetamide, 120 ºC, 48 h, 35% (62), 26% (14), 11% (7224% (7), 32% (12), 48% (47), 49% (4), 8% (78), 23% (22).

[0131] Compound 62 ((4-chloro-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (91 mg, 35%, pale yellow solid) was synthesized from 4-chloroindole (121 mg, 0.8 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF-30SIHP / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 0% EtOAc, 3-15 CV: linear-gradient 0-50% EtOAc, 15-20 CV: 50% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was further purified by reversed-phase flashchromatography to yield the desired product. Rf(EtOAc / hexane 3:7): 0.28;1H NMR (400 MHz, DMSO- d6): 12.37 (s, 1H), 8.33 (t,3JH-H= 7.8 Hz, 1H), 8.26 (d,3JH-H= 7.8 Hz, 1H), 8.19 (s, 1H), 8.14 (dd,3JH-H= 7.6 Hz,4JH-H= 1.2 Hz, 1H), 7.52 (dd,3JH-H= 7.0 ,4JH-H= 1.9 Hz, 1H), 7.30 – 7.20 (m, 2H); HPLC-MS (method C): Rt= 5.74 min, 325 ([M+H]+).

[0132] Compound 14 ((5-chloro-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (34 mg, 26%, yellow solid) was synthesized from 5-chloroindole (61 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF-50SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 10% EtOAc, 3-15 CV: linear gradient 10-50% EtOAc, 15-20 CV: 50% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was triturated with CH2Cl2to yield the desired product. Rf(EtOAc / hexane 3:7): 0.41;1H NMR (400 MHz, DMSO-d6): 12.30 (s, 1H), 8.78 (s, 1H), 8.37 – 8.27 (m, 3H), 8.14 (dd,3JH-H= 6.5 Hz,4JH-H= 2.4 Hz, 1H), 7.57 (d,3JH-H= 8.6 Hz, 1H), 7.29 (dd,3JH-H= 8.6 Hz,4JH-H= 2.2 Hz, 1H);19F NMR (376 MHz, DMSO-d6):-66.40 (3F); HPLC-MS (method B), Rt= 7.45 min, 325 ([M+H]+).

[0133] Compound 72 ((5-iodo-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (18 mg, 11%, white solid) was synthesized from 5-iodoindole (97 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF-30SIHP / 25G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 0% EtOAc, 3-15 CV: linear-gradient 0-40% EtOAc, 15-20 CV: 40% EtOAc; flow rate: 15 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum to yield the desired product. Rf(EtOAc / hexane 3:7): 0.52;1H NMR (400 MHz, DMSO-d6): 12.33 (s, 1H), 8.77 – 8.71 (m, 2H), 8.40 – 8.29 (m, 2H), 8.18 (dd,3JH-H= 7.1 Hz,4JH-H= 1.7 Hz, 1H), 7.57 (dd,3JH-H= 8.5 Hz,4JH-H= 1.7 Hz, 1H), 7.43 (d,3JH-H= 8.5 Hz, 1H);19F NMR (376 MHz, DMSO-d6): -66.36 (3F); HPLC-MS (method C): Rt= 6.42 min, 417 ( [M+H]+).

[0134] Compound 7 ((6-fluoro-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (60 mg, 24%, white solid) was synthesized from 6-fluorolindole (108 mg, 0.8 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF-30SIHP / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 50% EtOAc, 3-15 CV: linear-gradient 50-71% EtOAc, 15-20 CV: 71% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was triturated with CH2Cl2to yield the desired product. Rf(EtOAc / hexane 1:1): 0.30;1H NMR (400 MHz, DMSO-d6): 12.19 (s, 1H), 8.73 (s, 1H), 8.40 – 8.29 (m, 3H), 8.17 (dd,3JH-H= 6.9 Hz,4JH-H= 1.9 Hz, 1H), 7.37 (dd,3JH-F = 9.6 Hz,4JH-H= 2.4 Hz, 1H), 7.14 (ddd,3JH-F = 9.8 Hz,3JH-H= 8.7 Hz,4JH-H= 2.4 Hz, 1H);19F NMR (376 MHz, DMSO-d6):-66.46 (3F), -119.01 (1F); HPLC-MS (method A): Rt= 10.8 min, 309 ([M+H]+).

[0135] Compound 12 ((6-chloro-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (41 mg, 32%, pale purple solid) was synthesized from 6-chlorolindole (61 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF-15SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 10% EtOAc, 3-15 CV: linear-gradient 10-90% EtOAc, 15-20 CV: 90% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. Thesolvents were removed under vacuum. The crude product was triturated with CH2Cl2to yield the desired product. Rf(EtOAc / hexane 2:8): 0.35;1H NMR (400 MHz, DMSO-d6): 12.24 (s, 1H), 8.75 (s, 1H), 8.40 – 8.29 (m, 3H), 8.17 (dd,3JH-H= 7.0 Hz,4JH-H= 1.8 Hz, 1H), 7.62 (d,4JH-H= 1.9 Hz, 1H), 7.30 (dd,3JH-H= 8.5 Hz,4JH-H= 1.9 Hz, 1H);19F NMR (376 MHz, DMSO-d6):-66.38 (3F); HPLC-MS (method C): Rt= 6.23 min, 325 / 327 ( [M+H]+).

[0136] Compound 47 ((6-iodo-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (80 mg, 48%, grey solid) was synthesized from 6-iodoindole (97 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF-15SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 10% EtOAc, 3-15 CV: linear-gradient 10-50% EtOAc, 15-20 CV: 50% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was triturated with CH2Cl2to yield the desired product. Rf(EtOAc / hexane 3:7): 0.35;1H NMR (400 MHz, DMSO-d6): 12.18 (s, 1H), 8.68 (s, 1H), 8.39 – 8.28 (m, 2H), 8.22 – 8.10 (m, 2H), 7.93 (d,4JH-H= 1.5 Hz, 1H), 7.57 (dd,3JH-H= 8.4 Hz,4JH-H= 1.5 Hz, 1H);19F NMR (376 MHz, DMSO-d6):-66.39 (3F), HPLC-MS (method B): Rt= 6.48 min, 416 ( [M+H]+).

[0137] Compound 4 ((7-fluoro-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (183 mg, 49%, pale yellow solid) was synthesized from 7-fluoroindole (162 mg, 1.2 mmol) following general procedure A. The crude product was purified by flash chromatography (column: PF-50SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 5% EtOAc, 3-15 CV: linear gradient 5-40% EtOAc, 15-20 CV: 40% EtOAc; flow rate: 26 ml / min). Rf(EtOAc / hexane 3:7): 0.17;1H NMR (400 MHz, DMSO-d6): 12.72 (s, 1H), 8.78 (s, 1H), 8.40 – 8.31 (m, 2H), 8.23 – 8.12 (m, 2H), 7.29 – 7.22 (m, 1H), 7.17 – 7.09 (m, 1H);19F NMR (376 MHz, DMSO-d6): -66.45 (s, 3F), -132.44 (dd,3JH-F= 11.1 Hz,4JH-F= 4.9 Hz, 1F); HPLC- MS (method A), Rt= 10.8 min, 309 ([M+H]+).

[0138] Compound 78 ((7-bromo-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (12 mg, 8%, yellow solid) was synthesized from 7-bromoindole (78 mg, 0.4 mmol) with 1.5 eq of D-(+)-CSA following general procedure A. The crude product was purified by flash chromatography (column: PF- 50SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 5% EtOAc, 3-15 CV: linear gradient 5- 40% EtOAc, 15-20 CV: 40% EtOAc; flow rate: 26 ml / min). Fractions contained the desired product were combined. The solvents were removed under vacuum. The residue was further purified by prepHPLC (Rt= 19.1 min). Rf(EtOAc / hexane 3:7): 0.20;1H NMR (400 MHz, DMSO-d6): 12.40 (s, 1H), 8.81 (s, 1H), 8.43 – 8.31 (m, 3H), 8.18 (dd,3JH-H= 5.9,4JH-H= 2.9 Hz, 1H), 7.52 (d,3JH-H= 7.6 Hz, 1H), 7.23 (t,3JH-H= 7.8 Hz, 1H);19F NMR (376 MHz, DMSO-d6): -66.45 (s, 3F); HPLC-MS (method B): Rt= 7.7 min, 369 / 371 ([M+H]+)

[0139] Compound 22 ((7-iodo-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (38 mg, 23%, yellow oil) was synthesized from 7-iodoindole (97 mg, 0.4 mmol) following general procedure A. The crude product was purified by flash chromatography (column: PF-50SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 0% EtOAc, 3-15 CV: linear gradient 0-50% EtOAc, 15-20 CV: 50% EtOAc; flow rate: 26 ml / min). Rf(EtOAc / hexane 3:7): 0.43;1H NMR (400 MHz, DMSO-d6): 12.08 (s, 1H), 8.80 (s, 1H), 8.41 (dt,3JH-H= 7.9 Hz,4JH-H= 1.0 Hz, 1H), 8.37 – 8.30 (m, 2H), 8.26 – 8.12 (m,1H), 7.69 (dt,3JH-H= 7.6,4JH-H= 1.0 Hz, 1H), 7.09 (td,3JH-H= 7.8,4JH-H= 1.0 Hz, 1H);19F NMR (376 MHz, DMSO-d6): -66.47 (s, 3F); HPLC-MS (method B): Rt= 7.6 min, 417 ([M+H]+).Scheme S2. (a) 6-(trifluoromethyl)picolinonitrile, D-(+)-CSA, Pd(OAc)2, 2,2’-bipyridine, water, N- methylacetamide, 120 ºC, 48 h, 40% (32), 25% (38), 54% (9), 34% (34), 31% (33), 34% (37).

[0140] Compound 32 ((5,6-difluoro-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (52 mg, 40%, white solid) was synthesized from 5,6-difluoroindole (61 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (SiO2: 35 g, linear-gradient 0-40% EtOAc in Hexane). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was triturated with CH2Cl2to yield the desired product. Rf(EtOAc / hexane 3:7): 0.27;1H NMR (400 MHz, DMSO-d6): 12.27 (s, 1H), 8.80 (s, 1H), 8.39 – 8.32 (m, 2H), 8.25 – 8.15 (m, 2H), 7.62 (dd,3JH-H= 10.8, 7.0 Hz, 1H);19F NMR (376 MHz, DMSO-d6):-66.40 (3F), -142.19 - -142.37 (m, 1F); -144.60 - -144.77 (m, 1F); HPLC-MS (method B): Rt= 6.17 min, 327 ([M+H]+).

[0141] Compound 38 ((5,7-difluoro-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (33 mg, 25%, white solid) was synthesized from 5,7-difluoroindole (61 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (SiO2: 30 g, linear-gradient 0-30% EtOAc in hexane). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was triturated with CH2Cl2to yield the desired product. Rf(EtOAc / hexane 3:7): 0.65;1H NMR (400 MHz, DMSO-d6): 12.86 (s, 1H), 8.84 (s, 1H), 8.41 – 8.31 (m, 2H), 8.18 (dd,3JH-H= 6.2 Hz,4JH-H= 2.7 Hz, 1H), 7.96 – 7.88 (m, 1H), 7.27 – 7.16 (m, 1H);19F NMR (376 MHz, DMSO-d6):-66.45 (3F), -117.88 - -118.05 (m, 1F), -128.34 – 128.44 (m, 1F); HPLC-MS (method B): Rt= 6.24 min, 327 ([M+H]+).

[0142] Compound 9 ((6-chloro-5-fluoro-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (74 mg, 54%, pale orange solid) was synthesized from 5-fluoro-6-chlorolindole (68 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF- 15SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 0% EtOAc, 3-15 CV: linear-gradient 0- 50% EtOAc, 15-20 CV: 50% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum to yield the desired product. Rf(EtOAc / hexane 3:7): 0.50;1H NMR (400 MHz, DMSO-d6): 12.30 (s, 1H), 8.83 (s, 1H), 8.41 – 8.29 (m, 2H), 8.24 – 8.14 (m 2H), 7.80 – 7.73 (m, 1H);19F NMR (376 MHz, DMSO-d6):-66.40 (3F), -123.77 - - 123.88 (m, 1F); HPLC-MS (method A): Rt= 11.7 min, 343 / 345 ([M+H]+).

[0143] Compound 34 ((6-bromo-5-fluoro-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (53 mg, 34%, colorless solid) was synthesized from 6-bromo-5-fluoroindole (85 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (SiO2: 35 g, linear- gradient 0-40% EtOAc in Hexane). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was triturated with CH2Cl2to yield the desired product. Rf(EtOAc / hexane 3:7): 0.33;1H NMR (400 MHz, DMSO-d6): 12.29 (s, 1H), 8.82 (s, 1H), 8.40 – 8.30 (m, 2H), 8.22 – 8.14 (m, 2H), 7.89 (d,3JH-H= 6.0 Hz, 1H);19F NMR (376 MHz, DMSO-d6):-66.39 (3F); -116.17 (dd,3JH-F = 10.0 Hz,4JH-F = 6.1 Hz, 1F); HPLC-MS (method B): Rt= 6.41 min, 386 / 388 ([M+H]+).

[0144] Compound 33 ((5,6-dichloro-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (45 mg, 31%, pale yellow solid) was synthesized from 5,6-dichloroindole (74 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (SiO2: 35 g, linear-gradient 0- 40% EtOAc in Hexane). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was triturated with CH2Cl2to yield the desired product. Rf(EtOAc / hexane 3:7): 0.33;1H NMR (400 MHz, DMSO-d6): 12.33 (s, 1H), 8.82 (s, 1H), 8.50 (s, 1H), 8.39 – 8.28 (m, 2H), 8.16 (dd,3JH-H= 6.8 Hz,4JH-H= 2.1 Hz, 1H), 7.82 (s, 1H);19F NMR (376 MHz, DMSO- d6):-66.40 (3F); HPLC-MS (method B): Rt= 6.62 min, 359 / 361 ([M+H]+).

[0145] Compound 37 ((6-chloro-7-fluoro-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (46 mg, 34%, tan solid) was synthesized from 6-chloro-7-fluoroindole (68 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (SiO2: 30 g, linear-gradient 10- 30% EtOAc in hexane). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was triturated with CH2Cl2to yield the desired product. Rf(EtOAc / hexane 3:7): 0.41;1H NMR (400 MHz, DMSO-d6): 12.93 (s, 1H), 8.81 (s, 1H), 8.41 – 8.32 (m, 2H), 8.24 – 8.14 (m, 2H), 7.39 (dd,3JH-H= 8.6, 6.7 Hz, 1H);19F NMR (376 MHz, DMSO-d6):-66.43 (3F), -134.90 (d,3JH-F= 6.7 Hz, 1F); HPLC-MS (method B): Rt= 6.47 min, 343 ([M+H]+).Scheme S3. (a) (COCl)2, DMF, CH2Cl2, rt, 1 h; (b) indole derivatives, Et2AlCl, -78 ºC to -15 ºC (30 min), -15 ºC to rt (2 h), under Ar, 19% (16), 31% (8), 39% (3).

[0146] General procedures B (for the synthesis of 3-acylindoles via Fridel-Crafts reaction). To a solution of 6-(trifluoromethyl)picolinic acid (1.0 eq) in CH2Cl2(0.2 M) was added oxalyl chloride (1.2 eq), followed by one drop of dimethyl formamide (DMF). The reaction mixture was stirred at roomtemperature (rt) for 1 h. The solvent was then removed under vacuum. The residue was dissolved in CH2Cl2(0.4 M) to form the solution of 6-(trifluoromethyl)picolinoyl chloride for Fridel-Crafts reaction.

[0147] Fridel-Crafts reaction: To a solution of indole / substituted indoles (1.0 eq) in CH2Cl2(0.6 M) at -78 ºC (acetone / dry ice bath), under Ar atmosphere was added diethylaluminum chloride solution (1.0 eq, 1.0 M solution in hexane) dropwise. The reaction mixture was stirred at -78 ºC for 30 min. The reaction mixture was then warmed up to -15 ºC (benzyl alcohol / dry ice bath). To the reaction mixture was added the freshly prepared 6-(trifluoromethyl)picolinoyl chloride solution (1.0 eq, 0.4 M solution in CH2Cl2) dropwise. The reaction mixture was warmed up to rt and stirred at this temperature for another 2 h. The reaction mixture was diluted using EtOAc and quenched with PBS buffer (pH = 7.0). A saturated aqueous solution of NaHCO3was added until the reaction mixture became basic (pH > 8.0). The organic layer was then separated. The aqueous layer was extracted with EtOAc (2 times). The organic layers were combined, dried over anhydrous Na2SO4, and filtered. The solvent was removed under vacuum. The residue was triturated with a small amount of CH2Cl2, filtered, and dried under vacuum to yield the crude product, which was further purified by flash chromatography.

[0148] Compound 16 ((5-bromo-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (22 mg, 19%, tan solid) was synthesized from 5-bromoindole (61 mg, 0.3 mmol) following general procedure B for the synthesis of 3-acylindole via Friedel-Craft reaction. The crude product was triturated with CH2Cl2to yield the desired product. Rf(EtOAc / hexane 3:7): 0.19;1H NMR (400 MHz, DMSO-d6): 12.34 (s, 1H), 8.78 (d,4JH-H= 3.2 Hz, 1H), 8.53 (d,4JH-H= 2.0 Hz, 1H), 8.40 – 8.30 (m, 2H), 8.17 (dd,3JH-H= 6.7 Hz,4JH-H= 2.0 Hz, 1H), 7.55 (d,3JH-H= 8.6 Hz, 1H), 7.42 (dd,3JH-H= 8.6 Hz,4JH-H= 2.0 Hz, 1H);19F NMR (376 MHz, DMSO-d6):-66.38 (3F); HPLC-MS (method A): Rt= 11.5 min, 369 / 371 ([M+H]+).

[0149] Compound 8 ((6-bromo-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (90 mg, 31%, white solid) was synthesized from 6-bromoindole (152 mg, 0.78 mmol) following general procedure B for Friedel-Craft reaction. The crude product was triturated with CH2Cl2, then recrystallized from EtOAc / hexane to yield the desired product. Rf(EtOAc / hexane 3:7): 0.22;1H NMR (400 MHz, DMSO-d6): 12.23 (s, 1H), 8.74 (d,4JH-H= 2.9 Hz, 1H), 8.40 – 8.27 (m, 3H), 8.16 (dd,3JH-H= 7.0 Hz,4JH-H= 1.9 Hz, 1H), 7.76 (d,4JH-H= 3.9 Hz, 1H), 7.42 (dt,3JH-H= 8.8,4JH-H= 2.9 Hz, 1H);19F NMR (376 MHz, DMSO-d6): -66.38 (3F); HPLC-MS (method A): Rt= 11.6 min, 369 / 371 ([M+H]+).

[0150] Compound 3 ((7-chloro-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (40 mg, 39%, tan solid) was synthesized from 7-chloroindole (47 mg, 0.3 mmol) following general procedure B. The crude product was purified by flash chromatography (SiO2, 40 g, EtOAc / hexane 1:9). Rf(EtOAc / hexane 1:9): 0.22;1H NMR (400 MHz, DMSO-d6): 12.54 (s, 1H), 8.82 (d,4JH-H= 2.8 Hz, 1H), 8.40 – 8.32 (m, 3H), 8.22 – 8.11 (m, 1H), 7.42 – 7.34 (m, 1H), 7.29 – 7.25 (m, 1H);19F NMR (376 MHz, DMSO-d6): -66.48 (s, 3F); HPLC-MS (method A): Rt= 11.4 min, 325 / 327 ([M+H]+).Scheme S4. (a) 6-(trifluoromethyl)picolinonitrile, D-(+)-CSA, Pd(OAc)2, 2,2’-bipyridine, water, N- methylacetamide, 120 ºC, 48 h, 32% (13), 42% (65), 69% (63), 7% (68), 44% (64).

[0151] Compound 13 ((5-methyl-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (39 mg, 32%, yellow solid) was synthesized from 5-methylindole (53 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF-15SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 10% EtOAc, 3-15 CV: linear-gradient 10-50% EtOAc, 15-20 CV: 50% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum and the crude product was triturated with CH2Cl2to yield the desired product. Rf(EtOAc / hexane 3:7): 0.40;1H NMR (400 MHz, DMSO-d6): 12.06 (s, 1H), 8.65 (s, 1H), 8.38 – 8.26 (m, 2H), 8.23 – 8.19 (m, 1H), 8.14 (dd,3JH-H= 7.2 Hz,4JH-H= 1.7 Hz, 1H), 7.43 (d,3JH-H= 8.2 Hz, 1H), 7.11 (dd,3JH-H= 8.2 Hz,4JH-H= 1.7 Hz, 1H), 2.45 (s, 3H);19F NMR (376 MHz, DMSO-d6):-66.42 (3F); HPLC-MS (method B): Rt= 7.17 min, 305 ([M+H]+).

[0152] Compound 65 ((5-ethyl-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (53 mg, 42%, yellow solid) was synthesized from 5-ethylindole (58 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF-30SIHP / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 0% EtOAc, 3-15 CV: linear-gradient 0-50% EtOAc, 15-20 CV: 50% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was further purified by reversed-phase flash chromatography to yield the desired product. Rf(EtOAc / hexane 1:1): 0.64;1H NMR (400 MHz, DMSO-d6): 12.07 (s, 1H), 8.67 (d,4JH-H= 2.4 Hz, 1H), 8.39 – 8.27 (m, 2H), 8.22 (d,4JH-H= 1.7 Hz, 1H), 8.15 (dd,3JH-H= 7.4 Hz,4JH-H= 1.4 Hz, 1H), 7.45 (d,3JH-H= 8.3 Hz, 1H), 7.15 (dd,3JH-H= 8.3 Hz,4JH-H= 1.7 Hz, 1H), 2.75 (q,3JH-H= 7.6 Hz, 2H), 1.26 (td,3JH-H= 7.6 Hz,4JH-H= 0.9 Hz, 3H);19F NMR (376 MHz, DMSO-d6):-66.40 (3F); HPLC-MS (method C): Rt= 6.22 min, 319 ([M+H]+).

[0153] Compound 63 ((5-(tert-butyl)-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (96 mg, 69%, tan solid) was synthesized from 5-t-butylindole (69 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF-30SIHP / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 0% EtOAc, 3-15 CV: linear-gradient 0-50% EtOAc, 15-20 CV: 50% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was further purified by reversed-phase flash chromatography to yield the desired product. Rf(EtOAc / hexane 1:1): 0.85;1H NMR (400 MHz, DMSO- d6): 12.06 (s, 1H), 8.69 (d,4JH-H= 3.2 Hz, 1H), 8.42 (t,4JH-H= 1.3 Hz, 1H), 8.39 – 8.28 (m, 2H), 8.15 (dd,3JH-H= 7.2 Hz,3JH-H= 1.5 Hz, 1H), 7.47 (d,3JH-H= 8.6 Hz, 1H), 7.37 (dd,3JH-H= 8.6,4JH-H= 2.0 Hz, 1H), 1.38 (s, 9H);19F NMR (376 MHz, DMSO-d6):-66.40 (3F); HPLC-MS (method C): Rt= 6.51 min, 347 ([M+H]+).

[0154] Compound 68 ((6-methyl-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (8.0 mg, 7%, tan solid) was synthesized from 6-methylindole (52 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF-30SIHP / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 0% EtOAc, 3-15 CV: linear-gradient 0-60% EtOAc, 15-20 CV: 60% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was further purified by reversed-phase flash chromatography to yield the desired product. Rf(EtOAc / hexane 1:1): 0.50;1H NMR (400 MHz, DMSO-d6): 12.02 (s, 1H), 8.63 (d,4JH-H= 3.1 Hz, 1H), 8.38 – 8.27 (m, 2H), 8.24 (d,3JH-H= 8.1 Hz, 1H), 8.14 (dd,3JH-H= 7.3 Hz,4JH-H= 1.5 Hz, 1H), 7.33 (s, 1H), 7.11 (d,3JH-H= 8.1 Hz, 1H), 2.44 (s, 3H);19F NMR (376 MHz, DMSO- d6):-66.41 (3F); HPLC-MS (method C): Rt= 6.04 min, 305 ([M+H]+).

[0155] Compound 64 ((7-methyl-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (54 mg, 44%, yellow solid) was synthesized from 7-methylindole (52 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF-30SIHP / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 0% EtOAc, 3-15 CV: linear-gradient 0-50% EtOAc, 15-20 CV: 50% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was further purified by reversed-phase flash chromatography to yield the desired product. Rf(EtOAc / hexane 1:1): 0.60;1H NMR (400 MHz, DMSO-d6): 12.21 (s, 1H), 8.73 (s, 1H), 8.39 – 8.29 (m, 2H), 8.21 (d,3JH-H= 7.9 Hz, 1H), 8.16 (dt,3JH-H= 6.7 Hz,4JH-H= 1.4 Hz, 1H), 7.22 – 7.14 (m, 1H), 7.09 (dt,3JH-H= 7.0 Hz,4JH-H= 1.1 Hz, 1H), 2.52 (s, 3H);19F NMR (376 MHz, DMSO-d6):-66.47 (3F); HPLC-MS (method C): Rt= 6.04 min, 305 ([M+H]+).

[0156] General procedures C (for the deprotection of benzyl ether protecting group). To a three-neck round bottom flask was added benzyl ether protected starting material (1.0 eq), followed by 10% to 20% w / w of Pd / C. The reaction flask was equipped with a magnetic stirring bar, and a balloon of H2. The flask was evacuated and back-filled with H2(3 times) using a Schlenk line. THF (0.1 M) was then added. After 4 h or o / n (as indicated) of stirring at rt, the reaction mixture was diluted with EtOAc, filtered through a pad of silica gel. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography to yield the desired product.Scheme S5. (a) (COCl)2, DMF, CH2Cl2, rt, 1 h; (b) 7-benzyloxyindole, Et2AlCl, -78 ºC to -15 ºC (30 min), -15 ºC to rt (2 h), under Ar, 24%; (c) Pd / C, H2atmosphere (balloon), THF, rt, o / n, 10%.

[0157] Compound 1 ((7-(benzyloxy)-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (38 mg, 24%, pale yellow solid) was synthesized from 7-benzyloxyindole(76 mg, 0.3 mmol) following general procedure B. The crude product was purified by flash chromatography (SiO2, 40 g, EtOAc / hexane 1:9). Rf(EtOAc / hexane 1:9): 0.11;1H NMR (400 MHz, CDCl3): 9.03 (d,4JH-H= 3.1 Hz, 1H), 8.98 (s, 1H), 8.44 (d,3JH-H= 8.0 Hz, 1H), 8.20 (d,3JH-H= 8.0 Hz, 1H), 8.08 (t,3JH-H= 7.9 Hz, 1H), 7.84 (dd,3JH-H= 7.9 Hz,4JH-H= 1.0 Hz, 1H), 7.53 – 7.46 (m, 2H), 7.45 – 7.34 (m, 3H), 7.28 (d,3JH-H= 8.0 Hz, 1H), 6.87 (d,3JH-H= 7.9 Hz, 1H), 5.24 (s, 2H);19F NMR (376 MHz, CDCl3): -67.81 (s, 3F); HRMS (ESI, +ve) calcd for C22H16F3N2O2([M+H]+): 397.1164, found: 397.1130.

[0158] Compound 2 ((7-hydroxy-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (3.0 mg, 10%, yellow solid) was synthesized from 1 (39 mg, 0.1 mmol) with 20% w / w of Pd / C o / n following general procedure C. The crude product was purified by PTLC (SiO2, EtOAc / hexane 1:1). The band contained the desired product was extracted with EtOAc. The solvent was removed under vacuum. The residue was further purified by prepHPLC. Rf(EtOAc / hexane 3:7): 0.19;1H NMR (400 MHz, DMSO- d6): 12.14 (s, 1H), 9.99 (s, 1H), 8.61 (s, 1H), 8.37 – 8.27 (m, 2H), 8.14 (dd,3JH-H= 6.9 Hz,4JH-H= 2.0 Hz, 1H), 7.83 (dd,3JH-H= 7.9 Hz,4JH-H= 0.9 Hz, 1H), 7.05 (t,3JH-H= 7.8 Hz, 1H), 6.69 (dd,3JH-H= 7.8,4JH-H= 0.9 Hz, 1H);19F NMR (376 MHz, DMSO-d6): -66.41 (s, 3F); HPLC-MS (method A): Rt= 9.2 min, 307 ([M+H]+).

[0159] General procedures D (for the protection of hydroxyl indole with TBDMS group). To a solution of hydroxyindole (1.0 eq) in DMF (1.0 M) was added imidazole (2.2 eq), followed by TBDMSCl (1.06 eq) under Ar. The reaction mixture was stirred at rt for 30 min. Then the reaction mixture was diluted with EtOAc. The organic layer was washed with water and brine, then dried over anhydrous Na2SO4. The organic layer was filtered. The filtrate was concentrated under vacuum. Theresidue was purified by flash chromatography to yield the desired product.Scheme S6. (a) TBDMSCl, Imidazole, DMF, under Ar, rt, 30 min, 83%; (b) (COCl)2, DMF, CH2Cl2, rt, 1 h; (c) Et2AlCl, -78 ºC to -15 ºC (30 min), -15 ºC to rt (2 h), under Ar, 53%; (d) TBAF, THF, rt, o / n, 55%.

[0160] Compound 79 (6-((tert-butyldimethylsilyl)oxy)-1H-indole) (155 mg, 83%, white solid) was synthesized from 6-hydroxyindole (100 mg, 0.75 mmol) following general procedure D. The crude product was purified by flash chromatography (SiO2, EtOAc / hexane 1:9). Rf(EtOAc / hexane 1:9): 0.45;1H NMR (400 MHz, CDCl3): 7.94 (s, 1H), 7.46 (d,3JH-H= 8.4 Hz, 1H), 7.09 (dd,4JH-H= 3.2 Hz,4JH-H= 2.3 Hz, 1H), 6.85 (dd,4JH-H= 2.0 Hz,5JH-H= 1.0 Hz, 1H), 6.70 dd,3JH-H= 8.4 Hz,4JH-H= 2.0 Hz, 1H), 6.49 – 6.46 (m, 1H), 1.01 (s, 9H), 0.21 (s, 7H).

[0161] Compound 80 ((6-((tert-butyldimethylsilyl)oxy)-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2- yl)methanone) (42 mg, 35%, pale yellow solid) was synthesized from 79 (55.4 mg, 0.29 mmol) following general procedure B. The crude product was purified by flash chromatography (SiO2, EtOAc / hexane gradient from 1:10 to 1:9). Rf(EtOAc / hexane 1:9): 0.25;1H NMR (400 MHz, CDCl3): 8.95 (d,4JH-H= 3.1 Hz, 1H), 8.56 (s, 1H), 8.42 (td,3JH-H= 7.5 Hz,5JH-H= 1.1 Hz, 2H), 8.07 (t,3JH-H= 7.9 Hz, 1H), 7.83 (dd,3JH-H= 7.9,5JH-H= 1.1 Hz, 1H), 6.93 – 6.87 (m, 2H), 1.01 (s, 9H), 0.22 (s, 6H); HPLC- MS (method A): Rt= 13.8 min, 421 ([M+H]+).

[0162] Compound 6 ((6-hydroxy-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone). To a solution of 80 (42 mg, 0.1 mmol) in THF was added TBAF (110 µL, 1.0 M solution in THF, 0.11 mmol). The reaction mixture was stirred at rt under Ar o / n. The reaction mixture was purified by flashchromatography (SiO2, EtOAc / hexane 3:7). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was further purified by prepHPLC to yield the desired product as a yellow solid (17 mg, 55%). Rf(EtOAc / hexane 3:7): 0.21;1H NMR (400 MHz, DMSO-d6): 11.81 (s, 1H), 9.28 (s, 1H), 8.51 (s, 1H), 8.37 – 8.25 (m, 2H), 8.17 – 8.09 (m, 2H), 6.88 (d,4JH-H= 2.1 Hz, 1H), 6.77 (dd,3JH-H= 8.6 Hz,4JH-H= 2.1 Hz, 1H);19F NMR (376 MHz, DMSO-d6): -66.42 (3F); HPLC-MS (method A): Rt= 8.8 min, 307 ([M+H]+).Scheme S7. (a) 6-(trifluoromethyl)picolinonitrile, D-(+)-CSA, Pd(OAc)2, 2,2’-bipyridine, water, N- methylacetamide, 120 ºC, 48 h, 30% (15), 23% (20).

[0163] Compound 15 ((5-methoxy-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (39 mg, 30%, yellow solid) was synthesized from 5-methoxy indole (59 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF-50SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 10% EtOAc, 3-15 CV: linear-gradient 10-50% EtOAc, 15-20 CV: 50% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was triturated with CH2Cl2to yield the desired product. Rf(EtOAc / hexane 3:7): 0.19;1H NMR (400 MHz, DMSO-d6): 12.06 (s, 1H), 8.67 (s, 1H), 8.38 – 8.27 (m, 2H), 8.14 (dd,3JH-H= 6.9 Hz,4JH-H= 1.9 Hz, 1H), 7.92 (d,4JH-H= 2.5 Hz, 1H), 7.45 (d,3JH-H= 8.8 Hz, 1H), 6.91 (dd,3JH-H= 8.8 Hz,4JH-H= 2.5 Hz, 1H), 3.83 (s, 3H);19F NMR (376 MHz, DMSO-d6):- 66.41 (3F); HPLC-MS (method B): Rt= 6.73 min, 321 ([M+H]+).

[0164] Compound 20 ((6-methoxy-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (30 mg, 23%, yellow solid) was synthesized from 6-methoxyindole (59 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF-50SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 10% EtOAc, 3-15 CV: linear-gradient 10-70% EtOAc, 15-20 CV: 70% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was further purified by reversed-phase flash chromatography to yield the desired product. Rf(EtOAc / hexane 3:7): 0.28;1H NMR (400 MHz, DMSO- d6): 11.95 (s, 1H), 8.60 (s, 1H), 8.38 – 8.27 (m, 2H), 8.23 (d,3JH-H= 8.7 Hz, 1H), 8.14 (d,3JH-H= 7.2 Hz, 1H), 7.05 (d,4JH-H= 2.4 Hz, 1H), 6.91 (dd,3JH-H= 8.7 Hz,4JH-H= 2.4 Hz, 1H), 3.82 (s, 3H);19F NMR (376 MHz, DMSO-d6):-66.47 (3F); HPLC-MS (method B): Rt= 5.85 min, 321 ([M+H]+).

[0165] General procedures E (for demethylation). To a solution (or suspension) of methoxyindoles (1.0 eq) in anhydrous CH2Cl2(0.2 M) was added a solution of BBr3(4.0 eq) in CH2Cl2(0.2 M) drop-wise at - 78 ºC (acetone + dry ice bath). The reaction mixture was stirred and allowed to warm up to rt overnight.A mixture of water / diethyl ether (1:6) was added to quench the reaction. The reaction mixture was diluted with water and extracted with EtOAc (3 times). The organic layers were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography to yield the desired product.Scheme S8. (a) 6-(trifluoromethyl)picolinonitrile, D-(+)-CSA, Pd(OAc)2, 2,2’-bipyridine, water, N- methylacetamide, 120 ºC, 48 h, 17% (81), 39% (30), 20% (82), 11% (83), 38% (53), 14% (23), 11% (28), 38% (84); (b) BBr3, CH2Cl2, -78 ºC to rt, o / n, 33% (25), 7% (26), 58% (27), 69% (35), 63% (31), 88% (36), 81% (24), 58% (29), 62% (21).

[0166] Compound 85 ((4,7-dimethoxy-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (24 mg, 17%, yellow solid) was synthesized from 4,7-dimethoxyindole (71 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF-50SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 20% EtOAc, 3-15 CV: linear-gradient 20-100% EtOAc, 15-20 CV: 100% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was further purified by reversed-phase flash chromatography to yield the desired product.1H NMR (400 MHz, DMSO-d6): 12.23 (s, 1H), 8.26 (t,3JH-H= 7.8 Hz, 1H), 8.11 – 8.02 (m, 2H), 7.94 (s, 1H), 6.68 (d,3JH-H= 8.5 Hz, 1H), 6.46 (d,3JH-H= 8.5 Hz, 1H), 3.90 (s, 3H), 3.36 (s, 3H);19F NMR (376 MHz, DMSO-d6):-66.50 (3F); HPLC-MS (method B): Rt= 5.57 min, 356 ([M+H]+).

[0167] Compound 25 ((7-hydroxy-4-methoxy-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (8.5 mg, 93%, orange solid) and

[0168] 26 ((4-hydroxy-7-methoxy-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (0.6 mg, 7%, yellow solid) were synthesized from 85 (9.6 mg, 0.027 mmol) following general procedure E for demethylation. The residue was purified by flash chromatography (column: PF-15SIHC / 25G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 20% EtOAc, 3-15 CV: linear-gradient 20-100% EtOAc, 15-20 CV: 100% EtOAc; flow rate: 15 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum and the crude products were further purified by reversed-phase flash chromatography to yield the desired product.25. Rf(EtOAc): 0.83;1H NMR (400 MHz, DMSO- d6): 12.67 (s, 1H), 10.93 (s, 1H), 8.67 (d,4JH-H= 3.4 Hz, 1H), 8.41 – 8.32 (m, 2H), 8.19 (dd,3JH-H= 5.9 Hz,3JH-H= 2.9 Hz, 1H), 6.76 (d,3JH-H= 8.4 Hz, 1H), 6.49 (d,3JH-H= 8.4 Hz, 1H), 3.88 (s, 3H);19F NMR (376 MHz, DMSO-d6):-66.51 (3F); HPLC-MS (method B): Rt= 5.93 min, 337 ([M+H]+).26.1H NMR (400 MHz, DMSO-d6): 12.85 (s, 1H), 11.30 (s, 1H), 8.55 (s, 1H), 8.40 – 8.29 (m, 2H), 8.18 (dd,3JH-H= 7.1 Hz,4JH-H= 1.7 Hz, 1H), 7.20 – 7.09 (m, 2H);19F NMR (376 MHz, DMSO-d6):-66.44 (3F).

[0169] Compound 27 ((4,7-dihydroxy-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (1.4 mg, 58%, orange solid) were synthesized from 25 (2.5 mg, 0.0074 mmol) following general procedure E for demethylation. The residue was purified by reversed-phase flash chromatography to yield the desired product.1H NMR (400 MHz, DMSO-d6): 12.45 (s, 1H), 10.80 (s, 1H), 9.36 (s, 1H), 8.63 (s, 1H), 8.38 – 8.32 (m, 2H), 8.18 (dd,3JH-H= 6.5 Hz,4JH-H= 2.3 Hz, 1H), 6.58 (d,3JH-H= 8.3 Hz, 1H), 6.37 (d,3JH-H= 8.3 Hz, 1H);19F NMR (376 MHz, DMSO-d6):-66.44 (3F); HPLC-MS (method B): Rt= 5.38 min, 324 ([M+H]+).

[0170] Compound 30 ((4-fluoro-5-methoxy-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2- yl)methanone) (53 mg, 39%, pale yellow solid) was synthesized from 4-fluoro-5-methoxyindole (66 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF-15SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 10% EtOAc, 3-15 CV: linear-gradient 10-100% EtOAc, 15-20 CV: 100% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum to yield the desired product. Rf(EtOAc / hexane 1:1): 0.43;1H NMR (400 MHz, DMSO-d6): 12.22 (s, 1H), 8.38 – 8.28 (m, 2H), 8.23 (d,3JH-H= 7.8 Hz, 1H), 8.13 (dd,3JH-H= 7.8 Hz,4JH-H= 1.1 Hz, 1H), 7.29 (dd,3JH-H= 8.7 Hz,4JH-H= 0.9 Hz, 1H), 7.17 (dd,3JH-H= 8.8, 7.4 Hz, 1H), 3.86 (s, 3H);19F NMR (376 MHz, DMSO-d6):-66.49 (3F), - 131.60 (1F); HPLC-MS (method B): Rt= 5.54 min, 339 ([M+H]+).

[0171] Compound 82 ((4-chloro-5-methoxy-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2- yl)methanone) (28 mg, 20%, colorless solid) was synthesized from 4-chloro-5-methoxyindole (73 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF-15SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 0% EtOAc, 3-15 CV: linear-gradient 0- 100% EtOAc, 15-20 CV: 100% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was further purified by reversed-phase flash chromatography to yield the desired product. Rf(EtOAc / hexane 1:1): 0.37;1H NMR (400 MHz, DMSO-d6): 12.17 (s, 1H), 8.32 (t,3JH-H= 7.8 Hz, 1H), 8.24 (d,3JH-H= 7.8 Hz, 1H), 8.15 –8.08 (m, 2H), 7.48 (d,3JH-H= 8.8 Hz, 1H), 7.17 (d,3JH-H= 8.8 Hz, 1H), 3.86 (s, 3H);19F NMR (376 MHz, DMSO-d6):-66.46 (3F); HPLC-MS (method B): Rt= 5.60 min, 355 ([M+H]+).

[0172] Compound 35 ((4-chloro-5-hydroxy-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2- yl)methanone) (14.4 mg, 69%, tan solid) was synthesized from 82 (22 mg, 0.061 mmol) and BBr3 (30 µl, 0.31 mmol) following general procedure E for demethylation. The residue was purified by flash chromatography (SiO2: 35 g, linear-gradient 0-40% EtOAcin hexane). Fractions containing the desired product were combined. The solvents were removed under vacuum to yield the desired product. Rf(EtOAc / hexane 1:1): 045;1H NMR (400 MHz, DMSO-d6): 12.06 (s, 1H), 9.44 (s, 1H), 8.31 (t,3JH-H= 7.8 Hz, 1H), 8.22 (d,3JH-H= 7.8 Hz, 1H), 8.11 (dd,3JH-H= 7.8 Hz,4JH-H= 1.1 Hz, 1H), 8.02 (d,4JH-H= 3.3 Hz, 1H), 7.32 (d,3JH-H= 8.6 Hz, 1H), 6.97 (d,3JH-H= 8.6 Hz, 1H);19F NMR (376 MHz, DMSO-d6):- 66.44 (3F); HPLC-MS (method B): Rt= 5.17 min, 341 ([M+H]+).

[0173] Compound 83 ((4-bromo-5-methoxy-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2- yl)methanone) (18 mg, 11%, yellow solid) was synthesized from 4-bromo-5-methoxyindole (90 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF- 15SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 10% EtOAc, 3-15 CV: linear-gradient 10- 100% EtOAc, 15-20 CV: 100% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was triturated with CH2Cl2to yield the desired product. Rf(EtOAc / hexane 1:1): 0.43;1H NMR (400 MHz, DMSO-d6): 12.14 (s, 1H), 8.32 (t,3JH-H= 7.8 Hz, 1H), 8.26 (dd,3JH-H= 8.0 Hz,4JH-H= 1.2 Hz, 1H), 8.15 – 8.06 (m, 2H), 7.52 (d,3JH-H= 8.8 Hz, 1H), 7.14 (d,3JH-H= 8.8 Hz, 1H), 3.85 (s, 3H);19F NMR (376 MHz, DMSO-d6):- 66.40 (3F), HPLC-MS (method B): Rt= 5.64 min, 398 / 400 ([M+H]+).

[0174] Compound 31 ((4-bromo-5-hydroxy-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2- yl)methanone) (7.5 mg, 63%, pale yellow solid) was synthesized from 83 (12.0 mg, 0.031 mmol) following general procedure E for demethylation. The residue was purified by flash chromatography (column: PF-15SIHC / 25G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 10% EtOAc, 3-15 CV: linear- gradient 10-100% EtOAc, 15-20 CV: 100% EtOAc; flow rate: 15 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum to yield the desired product. Rf(EtOAc / hexane 1:1): 0.27;1H NMR (400 MHz, DMSO-d6): 12.03 (s, 1H), 9.53 (s, 1H), 8.31 (t,3JH-H= 7.8 Hz, 1H), 8.24 (d,3JH-H= 7.8 Hz, 1H), 8.11 (dd,3JH-H= 7.6 Hz,4JH-H= 1.1 Hz, 1H), 7.98 (d,4JH-H= 3.2 Hz, 1H), 7.36 (d,3JH-H= 8.6 Hz, 1H), 6.96 (d,3JH-H= 8.6 Hz, 1H);19F NMR (376 MHz, DMSO-d6):- 66.52 (3F); HPLC-MS (method B): Rt= 5.20 min, 384 / 386 ([M+H]+).

[0175] Compound 53 ((5-methoxy-6-methyl-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2- yl)methanone) (40 mg, 30%, yellow solid) was synthesized from 5-methoxy-6-methylindole (65 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF- 15SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 0% EtOAc, 3-15 CV: linear-gradient 0- 70% EtOAc, 15-20 CV: 70% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was further purified by reversed-phase flash chromatography to yield the desired product. Rf(EtOAc / hexane 1:1): 0.71;1H NMR(400 MHz, DMSO-d6): 11.95 (s, 1H), 8.59 (s, 1H), 8.38 – 8.27 (m, 2H), 8.14 (dd,3JH-H= 7.3 Hz,4JH-H= 1.5 Hz, 1H), 7.88 (s, 1H), 7.32 (s, 1H), 3.87 (s, 3H), 2.28 (s, 3H);19F NMR (376 MHz, DMSO-d6):-66.41 (3F); HPLC-MS (method B): Rt= 6.09 min, 334 ([M+H]+).

[0176] Compound 36 ((5-hydroxy-6-methyl-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2- yl)methanone) (26 mg, 88%, yellow solid) was synthesized from 53 (31 mg, 0.092 mmol) and BBr3 (44 µl, 0.46 mmol) following general procedure E for demethylation. The organic layer wash filtered through a pad of silica gel. The solvent was then removed under vacuum to yield the desired product. Rf(EtOAc / hexane 1:1): 064;1H NMR (400 MHz, DMSO-d6): 11.81 (s, 1H), 9.08 (s, 1H), 8.49 (d,4JH-H= 3.2 Hz, 1H), 8.36 – 8.24 (m, 2H), 8.12 (dd,3JH-H= 7.4 Hz,4JH-H= 1.4 Hz, 1H), 7.82 (s, 1H), 7.22 (s, 1H), 2.24 (s, 3H);19F NMR (376 MHz, DMSO-d6):-66.42 (3F); HPLC-MS (method B): Rt= 5.41 min, 321 ([M+H]+).

[0177] Compound 23 ((5-chloro-6-methoxy-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2- yl)methanone) (20 mg, 14%, yellow solid) was synthesized from 5-chloro-6-methoxyindole (73 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF- 15SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 30% EtOAc, 3-15 CV: linear-gradient 30- 70% EtOAc, 15-20 CV: 70% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was further purified by reversed-phase flash chromatography to yield the desired product. Rf(EtOAc): 0.78;1H NMR (400 MHz, DMSO-d6): 12.09 (s, 1H), 8.68 (s, 1H), 8.39 – 8.29 (m, 3H), 8.16 (dd,3JH-H= 7.0 Hz,4JH-H= 1.9 Hz, 1H), 7.24 (s, 1H), 3.91 (s, 3H);19F NMR (376 MHz, DMSO-d6):-66.40 (3F); HPLC-MS (method B): Rt= 6.71 min, 354 / 356 ([M+H]+).

[0178] Compound 24 ((5-chloro-6-hydroxy-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2- yl)methanone) (12 mg, 81%, yellow solid) was synthesized from 23 (15.8 mg, 0.045 mmol) following general procedure E for demethylation. The residue was purified by flash chromatography (column: PF- 15SIHC / 25G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 30% EtOAc, 3-15 CV: linear-gradient 30- 100% EtOAc, 15-20 CV: 100% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum to yield the desired product. Rf(EtOAc): 0.76;1H NMR (400 MHz, DMSO-d6): δ 11.93 (s, 1H), 9.99 (s, 1H), 8.60 (d,4JH-H= 3.1 Hz, 1H), 8.38 – 8.24 (m, 3H), 8.14 (dd,3JH-H= 7.2 Hz,4JH-H= 1.6 Hz, 1H), 7.12 (s, 1H);19F NMR (376 MHz, DMSO- d6):-66.46 (3F); HPLC-MS (method B): Rt= 5.61 min, 340 / 341 ([M+H]+).

[0179] Compound 28 ((4-bromo-7-methoxy-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2- yl)methanone) (19 mg, 11%, yellow solid) was synthesized from 4-bromo-7-methoxyindole (100 mg, 0.44 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF-50SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 0% EtOAc, 3-15 CV: linear-gradient 0- 70% EtOAc, 15-20 CV: 70% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was further purified by reversed-phase flash chromatography to yield the desired product.1H NMR (400 MHz, DMSO-d6): 12.47 (s, 1H), 8.36 – 8.24 (m, 2H), 8.13 (dd,3JH-H= 7.5 Hz,4JH-H= 1.3 Hz, 1H), 8.03 (s, 1H), 7.32 (d,3JH-H=8.5 Hz, 1H), 6.80 (d,3JH-H= 8.5 Hz, 1H), 3.97 (s, 3H);19F NMR (376 MHz, DMSO-d6):-66.44 (3F); HPLC-MS (method B): Rt= 5.92 min, 398 / 400 ([M+H]+).

[0180] Compound 29 ((4-bromo-7-hydroxy-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2- yl)methanone) (9.0 mg, 58%, yellow solid) was synthesized from 28 (17.0 mg, 0.04 mmol) following general procedure E for demethylation. The residue was purified by flash chromatography (column: PF- 50SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 20% EtOAc, 3-15 CV: linear-gradient 20- 100% EtOAc, 15-20 CV: 100% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum to yield the desired product. Rf(EtOAc / hexane 1:1): 0.26;1H NMR (400 MHz, DMSO-d6): 12.26 (s, 1H), 10.22 (s, 1H), 8.36 – 8.23 (m, 2H), 8.12 (dd,3JH-H= 7.6 Hz,4JH-H= 1.2 Hz, 1H), 8.00 (d,4JH-H= 3.2 Hz, 1H), 7.18 (d,3JH-H= 8.2 Hz, 1H), 6.62 (d,3JH-H= 8.2 Hz, 1H);19F NMR (376 MHz, DMSO-d6):-66.51 (3F); HPLC-MS (method B): Rt= 5.45 min, 384 / 386 ([M+H]+).

[0181] Compound 84 ((5-bromo-7-methoxy-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2- yl)methanone) (61 mg, 38%, yellow solid) was synthesized from 5-bromo-6-methoxyindole (90 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF- 15SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 10% EtOAc, 3-15 CV: linear-gradient 10- 70% EtOAc, 15-20 CV: 70% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum and the crude product was further purified by reversed-phase flash chromatography to yield the desired product.1H NMR (400 MHz, DMSO-d6): 12.54 (s, 1H), 8.69 (s, 1H), 8.39 – 8.29 (m, 2H), 8.21 – 8.11 (m, 2H), 7.03 (d,4JH-H= 1.6 Hz, 1H), 3.99 (s, 3H);19F NMR (376 MHz, DMSO-d6):-66.43 (3F); HPLC-MS (method B): Rt= 6.42 min, 398 / 400 ([M+H]+).

[0182] Compound 21 ((5-bromo-7-hydroxy-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2- yl)methanone) (17 mg, 62%, yellow solid) was synthesized from 84 (29 mg, 0.07 mmol) and BBr3(30 µl, 0.28 mmol) following general procedure E for demethylation. The residue was purified by flash chromatography (column: PF-15SIHP / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 30% EtOAc, 3-15 CV: linear-gradient 30-100% EtOAc, 15-20 CV: 100% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum to yield the desired product. Rf(EtOAc): 0.76;1H NMR (400 MHz, DMSO-d6): 12.33 (s, 1H), 10.52 (s, 1H), 8.67 (d,4JH-H= 2.4 Hz, 1H), 8.39 – 8.29 (m, 2H), 8.16 (dd,3JH-H= 6.7 Hz,4JH-H= 2.1 Hz, 1H), 8.00 (d,4JH-H= 1.8 Hz, 1H), 6.84 (d,4JH-H= 1.8 Hz, 1H);19F NMR (376 MHz, DMSO-d6):-66.42 (3F); HPLC-MS (method B): Rt= 5.86 min, purity: 99.2%, 384 / 386 ([M+H]+).

[0183] General procedures F (for the reduction of nitro- group). To a three-neck round bottom flask was added nitro derivatives (1.0 eq), followed by 10% w / w of Pd / C. The reaction flask was equipped with a magnetic stirring bar, and a balloon of H2. The flask was evacuated and back-filled with H2(3 times) using a Schlenk line. DMF (0.1 M) was then added. After 4 h of stirring at rt, the reaction mixture was diluted with EtOAc, then washed with saturated aqueous NaHCO3, and brine. The organic layer was dried over anhydrous Na2SO4, filtered through a pad of silica gel. The filtrated was concentrated under vacuum. The residue was purified by flash chromatography to yield the desired product.Scheme S9. (a) 6-(trifluoromethyl)picolinonitrile, D-(+)-CSA, Pd(OAc)2, 2,2’-bipyridine, water, N- methylacetamide, 120 ºC, 48 h, 1% (69), 5% (77), 47% (87); (b) Pd / C, H2atmosphere (balloon), DMF, rt, 4 h, 24% (74).

[0184] Compound 69 ((5-nitro-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (16 mg, 1%, tan solid) was synthesized from 5-nitroindole (991 mg, 6.10 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF-50SIHP / 80G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 10% EtOAc, 3-15 CV: linear-gradient 10-70% EtOAc, 15-20 CV: 70% EtOAc; flow rate: 46 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was triturated with CH2Cl2and further purified by reversed- phase flash chromatography to yield the desired product. Rf(EtOAc / hexane 1:1): 0.29;1H NMR (400 MHz, DMSO-d6): 12.70 (s, 1H), 9.25 (d,4JH-H= 2.3 Hz, 1H), 8.98 (d,4JH-H= 1.2 Hz, 1H), 8.44 – 8.36 (m, 2H), 8.25 – 8.14 (m, 2H), 7.81 – 7.74 (m, 1H);19F NMR (376 MHz, DMSO-d6): -66.36 (3F); HPLC- MS (method C): Rt= 5.96 min, 335 ([M+H]+).

[0185] Compound 77 ((6-nitro-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (97 mg, 5%, yellow solid) was synthesized from 6-nitroindole (991 mg, 6.1 mmol) following general procedure A. The residue was purified by reversed-phase flash chromatography to yield the desired product.1H NMR (400 MHz, DMSO-d6): 12.68 (s, 1H), 9.04 (d,4JH-H= 1.1 Hz, 1H), 8.57 – 8.47 (m, 2H), 8.43 – 8.33 (m, 2H), 8.25 – 8.13 (m, 2H);19F NMR (376 MHz, DMSO-d6): -66.35 (3F); HPLC-MS (method C): Rt= 6.07 min, 336 ([M+H]+).

[0186] Compound 87 ((7-nitro-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (63 mg, 47%, yellow solid) was synthesized from 7-nitroindole (65 mg, 0.4 mmol) following general procedure A. The crude product was triturated with a small amount of CH2Cl2, filtered, and dried under vacuum to yield the desired product. Rf(EtOAc / hexane 3:7): 0.44;1H NMR (400 MHz, DMSO-d6): 12.71 (s, 1H), 8.94 (s, 1H), 8.84 (dd,3JH-H= 7.8 Hz,4JH-H= 1.1 Hz, 1H), 8.40 – 8.36 (m, 2H), 8.28 – 8.17 (m, 2H), 7.51 (t,3JH-H= 8.0 Hz, 1H);19F NMR (376 MHz, DMSO-d6): -66.45 (s, 3F); HPLC-MS (method A): Rt= 11.8 min, purity: 94.8%, 336 ([M+H]+); HPLC-MS (method A): Rt= 11.8 min, 336 ([M+H]+).

[0187] Compound 74 ((7-amino-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (13 mg, 24%, yellow solid) was synthesized from 87 (61 mg, 0.18 mmol) following general procedure F. The crude product was purified by flash chromatography (column: PF-15SIHC / 40G; eluent: EtOAc / hexane,eluent gradient: 0-3 CV: 50% EtOAc, 3-15 CV: linear gradient 50-100% EtOAc, 15-20 CV: 100% EtOAc; flow rate: 26 ml / min). Rf(EtOAc): 0.44;1H NMR (400 MHz, DMSO-d6): 11.79 (s, 1H), 8.56 (d,4JH-H= 3.3 Hz, 1H), 8.36 – 8.23 (m, 2H), 8.13 (dd,3JH-H= 7.5 Hz,4JH-H= 1.2 Hz, 1H), 7.62 (d,3JH-H= 7.9 Hz, 1H), 6.98 (t,3JH-H= 7.7 Hz, 1H), 6.51 (dd,3JH-H= 7.7,4JH-H= 1.0 Hz, 1H), 5.22 (s, 2H);19F NMR (376 MHz, DMSO-d6): -66.40 (s, 3F); HPLC-MS (method B): Rt= 5.20 min, 306 ([M+H]+).

[0188] General procedures G (for reductive amination). To a solution of indole carboxaldehyde (1.0 eq) in 1,2-dichloroethane were added amine (3.0 eq), followed by two drops of AcOH. The reaction mixture was stirred at rt for 1 h. Then STAB (5.0 eq) was added. And the reaction mixture was stirred at rt o / n. The reaction mixture was diluted with CH2Cl2, quenched with sat. aq. NaHCO3. The organic layer was washed with brine, then separated, dried over anh. Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography to yield the desired product.Scheme S10. (a) piperidine, AcOH, STAB, DCE, rt, o / n, 56%; (b) D-(+)-CSA, Pd(OAc)2, 2,2’- bipyridine, water, N-methylacetamide, 120 ºC, 48 h, 7%

[0189] Compound 88 (5-(piperidin-1-ylmethyl)-1H-indole) (119 mg, 56%, colorless solid) was synthesized from indole-5-carboxaldehyde (145 mg, 1.0 mmol) following general procedure G. The crude product was purified by flash chromatography (SiO2, eluent: MeOH / CH2Cl21:9). Rf(MeOH / CH2Cl21:9): 0.26;1H NMR (400 MHz, CDCl3): 9.16 (s, 1H), 7.57 – 7.52 (m, 1H), 7.31 (d,3JH-H= 8.3 Hz, 1H), 7.22 – 7.12 (m, 2H), 6.53 – 6.47 (m, 1H), 3.87 (s, 2H), 2.71 – 2.61 (m, 4H), 1.75 – 1.65 (m, 4H), 1.51 – 1.39 (m, 2H).

[0190] Compound 19 ((5-(piperidin-1-ylmethyl)-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2- yl)methanone) (15 mg, 7%, pale yellow solid) was synthesized from 88 (119 mg, 0.56 mmol) following general procedure A. The residue was purified by reversed-phased flash chromatography. Fractions containing the desired product were combined. The solvents were removed under vacuum to yield the desired product.1H NMR (400 MHz, DMSO-d6): 12.18 (s, 1H), 8.69 (s, 1H), 8.39 – 8.27 (m, 3H), 8.22 – 8.12 (m, 2H), 7.50 (d,3JH-H= 8.2 Hz, 1H), 7.26 (dd,3JH-H= 8.2 Hz,4JH-H= 1.7 Hz, 1H), 3.67 (s, 2H), 2.49 – 2.42 (m, 4H), 1.58 – 1.48 (m, 4H), 1.46 – 1.37 (m, 2H);19F NMR (376 MHz, DMSO-d6): -66.41 (3F); HPLC-MS (method B): Rt= 4.20 min, 388 ([M+H]+).Scheme S11. (a) piperidine, Pd2dba3, DavePhos, LiHMDS, THF, 65 ºC, under Ar, 24 h, 20%; (b) D-(+)- CSA, Pd(OAc)2, 2,2’-bipyridine, water, N-methylacetamide, 120 ºC, 48 h, 7%

[0191] General procedures H (for Buchwald-Hartwig amination). To a microwave vial were added bromo indoles (1.0 eq), Pd2dba3(0.01 eq), and DavePhos (0.024 eq). The vial was sealed, evacuated, and back-filled with argon (3 times) using a Schlenk line. To the reaction mixture were added THF (1.0 M), followed by LiHMDS (2.2 eq, 1.0 M solution in THF), and amine (1.2 eq). The reaction mixture was stirred on a pre-heated oil bath at 65 ºC for 24 h. The vial was then cooled down to rt. To the reaction mixture was added 1 M aq. HCl (2.0 ml / mmol), and stirred for 5 min. The reaction mixture was poured into a separatory funnel containing sat. aq. NaHCO3. EtOAc was used to extract the organic compounds from the reaction mixture (3 times x 20 ml / mmol). The organic layers were combined, washed with brine, dried over anh. Na2SO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography to yield the desired product.

[0192] Compound 89 (6-(piperidin-1-yl)-1H-indole) (40 mg, 20%, white solid) was synthesized from 6- bromoindole (196 mg, 1.0 mmol) following general procedure H for Buchwald-Hartwig amination. The crude product was purified by flash chromatography (column: PF-50SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 10% EtOAc, 3-15 CV: linear gradient 10-50% EtOAc, 15-20 CV: 50% EtOAc; flow rate: 26 ml / min). Fractions contained the desired product were combined. The solvents were removed under vacuum to yield the desired product. Rf(EtOAc / hexane 1:1): 0.47;1H NMR (400 MHz, CDCl3): 7.96 (s, 1H), 7.50 (d,3JH-H= 9.3 Hz, 1H), 7.26 (s, 1H), 7.09 – 7.05 (m, 1H), 6.92 – 6.89 (m, 2H), 6.46 – 6.41 (m, 1H), 3.15 – 3.11 (m, 4H), 1.79 – 1.74 (m, 4H), 1.64 – 1.52 (m, 4H).

[0193] Compound 10 ((6-(piperidin-1-yl)-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (8.0 mg, 11%, yellow solid) was synthesized from 89 (40 mg, 0.2 mmol) following general procedure A. Upon completion, the reaction mixture was diluted with EtOAc. The organic layer was washed with an aqueous saturated solution of NaHCO3and then dried over anhydrous Na2SO4. The organic layer was filtered. The solvent was removed under vacuum. The crude product was purified by flash chromatography (column: PF-50SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 30% EtOAc, 3-15 CV: linear gradient 30-100% EtOAc, 15-20 CV: 100% EtOAc; flow rate: 26 ml / min). Fractions contained the desired product were combined. The solvents were removed under vacuum to yield the desired product. Rf(EtOAc / hexane 7:3): 0.66;1H NMR (400 MHz, DMSO-d6): 11.81 (s, 1H), 8.54 (s, 1H), 8.37 – 8.25 (m, 2H), 8.20 – 8.10 (m, 2H), 7.02 (dd,3JH-H= 8.8 Hz,4JH-H= 2.2 Hz, 1H), 6.95 (d,4JH-H= 2.2 Hz, 1H), 3.17 – 3.10 (m, 4H), 1.73 – 1.62 (m, 4H), 1.60 – 1.51 (m, 2H);19F NMR (376 MHz, DMSO-d6): -66.41 (3F); HPLC-MS (method A): Rt= 7.7 min, 374 ([M+H]+).Scheme S12. (a) 6-(trifluoromethyl)picolinonitrile,, D-(+)-CSA, Pd(OAc)2, 2,2’-bipyridine, water, N- methylacetamide, 120 ºC, 48 h, 42% (5), 38% (54), 40% (71)

[0194] Compound 5 (3-(6-(trifluoromethyl)picolinoyl)-1H-indole-7-carboxylic acid) (169 mg, 42%, white solid) was synthesized from indole-7-carboxylic acid (192 mg, 1.2 mmol) with 1.5 eq of D-(+)- CSA following general procedure A. The crude product was purified by flash chromatography (column: PF-50SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 50% EtOAc, 3-15 CV: linear gradient 50-80% EtOAc, 15-20 CV: 80% EtOAc; flow rate: 26 ml / min). Fractions contained the desired product were combined. The solvents were removed under vacuum. The residue was further purified by prepHPLC. Rf(EtOAc / hexane 7:3): 0.21;1H NMR (400 MHz, DMSO-d6): 13.33 (s, 1H), 12.02 (s, 1H), 8.83 (d,4JH-H= 3.3 Hz, 1H), 8.67 (dd,3JH-H= 7.9 Hz,4JH-H= 1.3 Hz, 1H), 8.41 – 8.31 (m, 2H), 8.22 – 8.13 (m, 1H), 7.90 (dd,3JH-H= 7.5 Hz,4JH-H= 1.2 Hz, 1H), 7.40 (td,3JH-H= 7.7 Hz,4JH-H= 1.2 Hz, 1H);19F NMR (376 MHz, DMSO-d6): -66.42 (s, 3F); HPLC-MS (method A): Rt= 10.0 min, 335 ([M+H]+).

[0195] Compound 54 ((7-ethoxy-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (51 mg, 38%, yellow solid) was synthesized from 7-ethoxyindole (65 mg, 0.4 mmol) following general procedure A. The residue was purified by reversed-phase flash chromatography to yield the desired product.1H NMR (400 MHz, DMSO-d6): 12.24 (s, 1H), 8.63 (d,4JH-H= 2.9 Hz, 1H), 8.39 – 8.28 (m, 2H), 8.19 – 8.11 (m, 1H), 7.95 (d,3JH-H= 8.0 Hz, 1H), 7.18 (t,3JH-H= 7.9Hz, 1H), 6.85 (d,3JH-H= 7.9, 1H), 4.25 (q,3JH-H= 7.0, 2H), 1.44 (t,3JH-H= 7.0, 3H);19F NMR (376 MHz, DMSO-d6):-66.44 (3F); HPLC-MS (method C): 6.51 min, 335 ([M+H]+).

[0196] Compound 71 ((5-(trifluoromethyl)-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2- yl)methanone) (57 mg, 40%, pink solid) was synthesized from 5-(trifluoromethyl)lindole (74 mg, 6.10 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF- 30SIHP / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 0% EtOAc, 3-15 CV: linear-gradient 0- 40% EtOAc, 15-20 CV: 40% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was triturated with CH2Cl2to yield the desired product. Rf(EtOAc / hexane 3:7): 0.47;1H NMR (400 MHz, DMSO-d6): 12.54 (s, 1H), 8.92 (d,4JH-H= 3.1 Hz, 1H), 8.71 (s, 1H), 8.42 – 8.33 (m, 2H), 8.20 (dd,3JH-H= 6.3 Hz,4JH-H= 2.5 Hz, 1H), 7.78 (d,3JH-H= 8.6 Hz, 1H), 7.61 (dd,3JH-H= 8.5 Hz,4JH-H= 1.9 Hz, 1H);19F NMR (376 MHz, DMSO-d6): -59.08 (3F), -66.36 (3F); HPLC-MS (method C): Rt= 4.37 min.Scheme S13. (a) 2-bromo-6-trifluoromethylpyridine, Pd(dppf)Cl2, K2CO3, dioxane / water 4:1, 110 ºC, under Ar, 2 h, 77%; (b) 6-(trifluoromethyl)picolinonitrile,, D-(+)-CSA, Pd(OAc)2, 2,2’-bipyridine, water, N-methylacetamide, 120 ºC, 48 h, 43%.

[0197] Compound 90 (6-(6-(trifluoromethyl)pyridin-2-yl)-1H-indole). To a microwave tube equipped with a magnetic stirring bar were added 6-BPin-indole (95 mg, 0.4 mmol), 2-bromo-6- trifluoromethylpyridine (90 mg, 0.4 mmol), K2CO3(166 mg, 1.2 mmol) and Pd(dppf)Cl2(29 mg, 0.04 mmol), followed by dioxane / water (4:1, 4.0 ml). The tube was sealed, and the reaction mixture was degassed by an Ar balloon for 20 min. The reaction mixture was heated at 110 ºC for 2h using a stirring plate. The reaction mixture was diluted with EtOAC and filtered through a thin pad of silica gel. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography (column: PF- 50SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 20% EtOAc, 3-15 CV: linear gradient 20- 60% EtOAc, 15-20 CV: 60% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum to yield the desired product as a white solid (78 mg, 77%). Rf(EtOAc / hexane 1:1): 0.62;1H NMR (400 MHz, DMSO-d6): 11.31 (s, 1H), 8.30 – 8.21 (m, 2H), 8.16 – 8.07 (m, 1H), 7.82 – 7.72 (m, 2H), 7.67 (d,3JH-H= 8.5 Hz, 1H), 7.48 (t,4JH-H= 2.8 Hz, 1H), 6.51 – 6.47 (m, 1H);19F NMR (376 MHz, DMSO-d6): -66.72 (3F).

[0198] Compound 11 ((6-(trifluoromethyl)pyridin-2-yl)(6-(6-(trifluoromethyl)pyridin-3-yl)-1H- indol-3-yl)methanone) (56 mg, 43%, tan solid) was synthesized from 90 (78 mg, 0.3 mmol) following general procedure A. The crude product was triturated with CH2Cl2to yield the desired product. Rf(EtOAc / hexane 1:1): 0.69;1H NMR (400 MHz, DMSO-d6): 12.34 (s, 1H), 8.85 (s, 1H), 8.49 (d,3JH-H= 8.4 Hz, 1H), 8.41 – 8.32 (m, 4H), 8.21 – 8.12 (m, 2H), 8.07 (dd,3JH-H= 8.4 Hz,5JH-H= 1.6 Hz, 1H), 7.82 (d,3JH-H= 7.7 Hz, 1H);19F NMR (376 MHz, DMSO-d6):-66.39 (3F), -66.69 (3F); HPLC-MS (method A): Rt= 12.6 min, 436 ([M+H]+).Scheme S14. (a) 5-(trifluoromethyl)picolinonitrile,, D-(+)-CSA, Pd(OAc)2, 2,2’-bipyridine, water, N- methylacetamide, 120 ºC, 48 h, 24%.

[0199] Compound 52 ((1H-indol-3-yl)(5-(trifluoromethyl)pyridin-2-yl)methanone) (28 mg, 24%, pale yellow solid) was synthesized from indole (47 mg, 0.4 mmol) and 5-(trifluoromethyl)picolinonitrile (103 mg, 0.6 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF-15SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 10% EtOAc, 3-15 CV: linear- gradient 10-100% EtOAc, 15-20 CV: 100% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was triturated with CH2Cl2to yield the desired product. Rf(EtOAc / hexane 3:7): 0.28;1H NMR (400 MHz, DMSO-d6): 12.20 (s, 1H), 9.18 – 9.12 (m, 1H), 8.73 (s, 1H), 8.45 (dd,3JH-H= 8.3 Hz,4JH-H= 2.3 Hz, 1H), 8.41 – 8.33 (m, 1H), 8.20 (d3JH-H= 8.3 Hz, 1H), 7.59 – 7.51 (m, 1H), 7.33 – 7.23 (m, 2H);19F NMR (376 MHz, DMSO-d6):-61.04 (3F), HPLC-MS (method B): Rt= 5.89 min, 291 ([M+H]+).Scheme S15. (a) 6-(trifluoromethyl)picolinonitrile, D-(+)-CSA, Pd(OAc)2, 2,2’-bipyridine, water, N- methylacetamide, 120 ºC, 48 h, 30%.

[0200] Compound 17 ((1,6,7,8-tetrahydrocyclopenta[g]indol-3-yl)(6-(trifluoromethyl)pyridin-2- yl)methanone) (44 mg, 30%, yellow solid) was synthesized from 1,6,7,8-tetrahydrocyclopenta[g]indole (63 mg, 0.4 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF-50SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 0% EtOAc, 3-15 CV: linear- gradient 0-40% EtOAc, 15-20 CV: 40% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum to yield the desired product. Rf(EtOAc / hexane 3:7): 0.63;1H NMR (400 MHz, DMF-d7): 12.37 (s, 1H), 9.00 (s, 1H), 8.64 – 8.52 (m, 2H), 8.48 (d,3JH-H= 8.1 Hz, 1H), 8.34 (dd,3JH-H= 6.4 Hz,4JH-H= 2.4 Hz, 1H), 7.38 (d,3JH-H= 8.1 Hz, 1H), 3.59 (s, 1H), 3.30 (t,3JH-H= 7.4 Hz, 2H), 3.19 (t,3JH-H= 7.4 Hz, 2H), 2.39 – 2.29 (p,3JH-H= 7.4 Hz, 2H);19F NMR (376 MHz, DMF-d7): -67.64 (3F); HPLC-MS (method A): Rt= 11.8 min, 331 ([M+H]+).Scheme S16. (a) 6-(trifluoromethyl)picolinonitrile,, D-(+)-CSA, Pd(OAc)2, 2,2’-bipyridine, water, N- methylacetamide, 120 ºC, 48 h, 30%.

[0201] Compound 18 ((1H-benzo[g]indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (39 mg, 30%, yellow solid) was synthesized from 1H-benzo[g]indole (67 mg, 0.4 mmol) following generalprocedure A. The residue was purified by flash chromatography (column: PF-50SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 0% EtOAc, 3-15 CV: linear-gradient 0-40% EtOAc, 15-20 CV: 40% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was triturated with CH2Cl2to yield the desired product. Rf(EtOAc / hexane 3:7): 0.49;1H NMR (400 MHz, DMF-d7): 13.23 (s, 1H), 9.10 (s, 1H), 8.78 (d,3JH-H= 8.7 Hz, 1H), 8.74 – 8.68 (m, 1H), 8.65 – 8.58 (m, 2H), 8.42 – 8.35 (m, 1H), 8.27 – 8.21 (m, 1H), 7.97 (d,3JH-H= 8.7 Hz, 1H), 7.85 – 7.77 (m, 1H), 7.74 – 7.70 (m, 1H);19F NMR (376 MHz, DMF-d7): - 66.44 (3F); HPLC-MS (method A): Rt= 11.9 min, 341 ([M+H]+).Scheme S17. (a) CuCN, NMP, 202 ºC, 24 h, under Ar, 64% (61), 62% (66).

[0202] General procedure I for Rosenmund-von Braun Reaction. To a MW tube was added halogenated starting material (1.0 eq), CuCN (3.0 eq), followed by NMP (0.4 M). The MW tube was sealed, purged with Ar 3 times and the reaction mixture was stirred at 202 ºC for 24h. The reaction mixture was diluted with EtOAc and filtered through a pad of silica gel. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography to yield the desired product.

[0203] Compound 61 (3-(6-(trifluoromethyl)picolinoyl)-1H-indole-6-carbonitrile) (41 mg, 64%, white solid) was synthesized following the general procedure I for Rosenmund-von Braun Reaction from 8 (74 mg, 0.2 mmol). The residue was purified by flash chromatography (column: PF-30SIHP / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 0% EtOAc, 3-15 CV: linear-gradient 0-70% EtOAc, 15-20 CV: 70% EtOAc; flow rate: 26 ml / min) to yield the desired product. Rf(EtOAc / hexane 1:1): 044;1H NMR (400 MHz, DMSO-d6): 12.59 (s, 1H), 8.95 (d,4JH-H= 2.8 Hz, 1H), 8.52 (d,3JH-H= 8.3 Hz, 1H), 8.41 – 8.32 (m, 2H), 8.24 – 8.14 (m, 1H), 8.09 (d,4JH-H= 1.5 Hz, 1H), 7.64 (dt,3JH-H= 8.2 Hz,4JH-H= 1.3 Hz, 1H); HPLC-MS (method C): Rt= 5.86 min, 316 ([M+H]+).

[0204] Compound 66 (3-(6-(trifluoromethyl)picolinoyl)-1H-indole-7-carbonitrile) (39 mg, 62%, white solid) was synthesized following the general procedure I for Rosenmund-von Braun Reaction from 78 (74 mg, 0.2 mmol). The residue was purified by flash chromatography (column: PF-30SIHP / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 0% EtOAc, 3-15 CV: linear-gradient 0-60% EtOAc, 15-20 CV: 60% EtOAc; flow rate: 26 ml / min) to yield the desired product. Rf(EtOAc / hexane 1:1): 071;1H NMR (400 MHz, DMSO-d6): 13.02 (s, 1H), 8.86 (s, 1H), 8.70 (dt,3JH-H= 8.2 Hz,4JH-H= 1.1 Hz, 1H), 8.41 – 8.32 (m, 2H), 8.24 – 8.16 (m, 1H), 7.80 (d,3JH-H= 7.4 Hz, 1H), 7.50 – 7.41 (m, 1H);19F NMR (376 MHz, DMSO-d6):-66.44 (3F); HPLC-MS (method C): Rt= 6.03 min, 316 ([M+H]+).Scheme S18. (a) HCHO, AcOH, STAB, EtOH, rt, o / n, 12%.

[0205] Compound 67 ((7-(dimethylamino)-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2- yl)methanone). To a solution of 74 (61 mg, 0.2 mmol) in EtOH (4.0 ml) was added 37% aqueous solution of HCHO (33 µl, 0.44 mmol), followed by a drop of acetic acid. The reaction mixture was stirred at rt for 30 min, then STAB (127 mg, 0.6 mmol) was added, and the reaction mixture was stirred at rt o / n. To the reaction mixture, was added saturated aqueous solution of NaHCO3to quench the excess STAB. The reaction mixture was extracted with EtOAC (3 times). The organic layers were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography (column: PF-15SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 30% EtOAc, 3-15 CV: linear-gradient 30-100% EtOAc, 15-20 CV: 100% EtOAc; flow rate: 26 ml / min). Fractions containing the product were combined and concentrated under vacuum. The crude product was further purified by reversed-phase flash chromatography to yield the desired product as a yellow solid (7.6 mg, 12%).1H NMR (400 MHz, DMSO-d6): 12.00 (s, 1H), 8.67 (s, 1H), 8.39 – 8.29 (m, 2H), 8.15 (dd,3JH-H= 6.6 Hz,4JH-H= 2.3 Hz, 1H), 8.05 – 7.99 (m, 1H), 7.17 (t,3JH-H= 7.8 Hz, 1H), 6.83 (d,3JH-H= 7.6 Hz, 1H), 2.84 (s, 6H);19F NMR (376 MHz, DMSO-d6):-66.43 (3F); HPLC-MS (method C): Rt= 5.82 min, 334 ([M+H]+).Scheme S19. (a) D-(+)-CSA, Pd(OAc)2, 2,2’-bipyridine, water, N-methylacetamide, 120 ºC, 48 h, 64%; (b) mCPBA, CH2Cl2, -78 ºC to rt, 3 h, 55% (76), 29% (75).

[0206] Compound 91 ((7-(methylthio)-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone) (173 mg, 64%, yellow solid) was synthesized from 7-(methylthio)indole (131 mg, 0.8 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF-15SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 0% EtOAc, 3-15 CV: linear-gradient 0-70% EtOAc, 15- 20 CV: 70% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The crude product was further purified to yield the desired product. Rf(EtOAc / hexane 4:6): 0.55;1H NMR (400 MHz, DMSO-d6): 12.23 (s, 1H), 8.75 (s, 1H), 8.40 – 8.31 (m, 2H), 8.31 – 8.23 (m, 1H), 8.22 – 8.14(m, 1H), 7.34 – 7.24 (m, 2H), 2.57 (s, 3H); HPLC-MS (method C): Rt= 6.25 min, 337 ([M+H]+).

[0207] Compound 76 ((7-(methylsulfonyl)-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2- yl)methanone) and

[0208] 75 ((7-(methylsulfinyl)-1H-indol-3-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone). To a suspension of 91 (25 mg, 0.074 mmol) in CH2Cl2(740 µL) at -78 ºC was added m-CPBA (18.2 mg, 0.074 mmol, 70%). The reaction was stirred and warmed up to rt in 3 h. The reaction mixture was diluted with EtOAc, and filtered through a pad of silica gel. The solvent was removed under vacuum. The residue was purified by flash chromatography (column: PF-15SIHP / 25G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 30% EtOAc, 3-15 CV: linear-gradient 30-100% EtOAc, 15-20 CV: 100% EtOAc; flow rate: 15 ml / min) to yield 76 (15 mg, 55%, white solid) and 75 (7.6 mg, 29%, white solid).76. Rf(EtOAc): 0.88;1H NMR (400 MHz, DMSO-d6): 12.22 (s, 1H), 8.90 (s, 1H), 8.76 (d,3JH-H= 7.9 Hz, 1H), 8.41 – 8.33 (m, 2H), 8.25 – 8.16 (m, 1H), 7.81 (d,3JH-H= 7.6 Hz, 1H), 7.53 (t,3JH-H= 7.6 Hz, 1H), 3.35 (s, 3H);19F NMR (376 MHz, DMSO-d6): -66.44 (3F); HPLC-MS (method C): Rt= 5.75 min, 369 ([M+H]+).75. Rf(EtOAc): 0.59;1H NMR (400 MHz, DMSO-d6): 12.42 (s, 1H), 8.82 (s, 1H), 8.56 (dd,3JH-H= 8.0 Hz,4JH-H= 1.1 Hz, 1H), 8.42 – 8.32 (m, 2H), 8.19 (dd,3JH-H= 6.0 Hz,4JH-H= 2.9 Hz, 1H), 7.61 (dd,3JH-H= 7.5 Hz,4JH-H= 1.1 Hz, 1H), 7.48 (t,3JH-H= 7.7 Hz, 1H), 2.92 (s, 3H).;19F NMR (376 MHz, DMSO-d6): -66.43 (3F); HPLC-MS (method C): Rt= 5.38 min, 353 ([M+H]+).

[0209] General procedures J (for the synthesis of 2-cyano pyridine analogs via Pd catalyzed C-H activation). As in ref. S1. To a microwave vial equipped with a magnetic stirring bar were added indole / substituted indoles (1.0 eq), dinitrile compounds (1.5 eq), D-(+)-CSA (1.0 eq), Pd(OAc)2(0.10 eq), 2,2’-bipyridine (0.12 eq), followed by N-methylacetamide (0.4 M) and water (2.0 eq). The vial was sealed with an aluminum seal with septa. The reaction mixture was heated at 120 ºC in an oil bath for 3 h using a magnetic stirrer. The reaction mixture was then cooled down to room temperature and diluted with ethyl acetate. The resulting solution was filtered through a pad of silica gel. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography to yield the desired products.Scheme S20. (a) Pyridine-2,6-dicarbonitrile, D-(+)-CSA, Pd(OAc)2, 2,2’-bipyridine, water, N- methylacetamide, 120 ºC, 48 h, 5% (43), 6% (42), 4% (40), 4% (41), 7% (44).

[0210] Compound 43 (6-(5-chloro-1H-indole-3-carbonyl)picolinonitrile) (5.8 mg, 5%, white solid) was synthesized from 5-chloroindole (73 mg, 0.48 mmol) following general procedure J. The residue was purified by flash chromatography (SiO2: 40 g, 5% step gradient 0-70% EtOAc in hexane). Fractionscontaining the desired product were combined. The solvents were removed under vacuum. The crude product was further purified by prepHPLC to yield the desired product.1H NMR (400 MHz, DMSO-d6): 12.31 (s, 1H), 8.76 (s, 1H), 8.41 – 8.17 (m, 4H), 7.60 (d,3JH-H= 8.6 Hz, 1H), 7.31 (dd,3JH-H= 8.6 ,4JH-H= 2.2 Hz, 1H); HPLC-MS (method B): Rt= 5.90 min, 282 ([M+H]+).

[0211] Compound 42 (6-(6-chloro-1H-indole-3-carbonyl)picolinonitrile) (6.7 mg, 5%, pale yellow solid) was synthesized from 6-chloroindole (73 mg, 0.48 mmol) following general procedure J. The residue was purified by flash chromatography (SiO2: 40 g, 5% step gradient 0-60% EtOAc in hexane). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was further purified by prepHPLC to yield the desired product. Rf(EtOAc / hexane 4:6): 0.41;1H NMR (400 MHz, DMSO-d6): 12.22 (s, 1H), 8.72 (s, 1H), 8.36 – 8.23 (m, 4H), 7.62 (d,4JH-H= 1.9 Hz, 1H), 7.30 (dd,3JH-H= 8.5,4JH-H= 1.9 Hz, 1H); HPLC-MS (method B): Rt= 5.91 min, 282 ([M+H]+).

[0212] Compound 40 (6-(6-bromo-1H-indole-3-carbonyl)picolinonitrile) (6 mg, 4%, white solid) was synthesized from 6-bromoindole (71 mg, 0.48 mmol) following general procedure J. The residue was triturated with CH2Cl2,and then purified by prepHPLC to yield the desired product.1H NMR (400 MHz, DMSO-d6): 12.22 (s, 1H), 8.70 (s, 1H), 8.34 – 8.23 (m, 4H), 7.77 (d,4JH-H= 1.8 Hz, 1H), 7.42 (dd,3JH-H= 8.5 Hz,4JH-H= 1.8 Hz, 1H); HPLC-MS (method B): Rt= 5.91 min, purity: 98.3%, 326 / 328 ([M+H]+).

[0213] Compound 41 (6-(7-fluoro-1H-indole-3-carbonyl)picolinonitrile) (5.0 mg, 4%, white solid) was synthesized from 7-fluoroindole (65 mg, 0.48 mmol) following general procedure J. The residue was purified by flash chromatography (SiO2: 30 g, 5% step gradient 0-70% EtOAc in hexane). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was further purified by prepHPLC to yield the desired product. Rf(EtOAc / hexane 1:1): 0.33;1H NMR (400 MHz, DMSO-d6): 12.74 (s, 1H), 8.72 (s, 1H), 8.34 – 8.23 (m, 3H), 8.17 (d,3JH-H= 7.9 Hz, 1H), 7.26 (td,3JH-H= 8.0 Hz,4JH-F= 4.9 Hz, 1H), 7.14 (dd,3JH-F= 11.3 Hz, 7.9 Hz, 1H);19F NMR (376 MHz, DMSO-d6):- -132.23 (dd,3JH-F= 11.3, Hz,4JH-F= 4.9 Hz, 1F); HPLC-MS (method B): Rt= 5.66 min, 266 ([M+H]+).

[0214] Compound 44 (6-(7-chloro-1H-indole-3-carbonyl)picolinonitrile) (8.3 mg, 7%, white solid) was synthesized from 7-chloroindole (73 mg, 0.48 mmol) following general procedure J. The residue was purified by flash chromatography (SiO2: 40 g, 5% step gradient 0-70% EtOAc in hexane). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was further purified by prepHPLC to yield the desired product.1H NMR (400 MHz, DMSO-d6): 12.56 (s, 1H), 8.73 (s, 1H), 8.36 – 8.24 (m, 4H), 7.39 (dd,3JH-H= 7.7 Hz,4JH-H= 1.0 Hz, 1H), 7.29 (t,3JH-H= 7.7 Hz, 1H); HPLC-MS (method B): Rt= 5.93 min, 282 ([M+H]+).Scheme S21. (a) Pyridine-2,6-dicarbonitrile, D-(+)-CSA, Pd(OAc)2, 2,2’-bipyridine, water, N- methylacetamide, 120 ºC, 48 h, 5% (51), 1.4% (48), 36% (45), 23% (92); (b) BBr3, CH2Cl2, -78 ºC to rt, o / n, 38% (50), 6.4% (46), 34% (93).

[0215] Compound 51 (6-(4-methoxy-1H-indole-3-carbonyl)picolinonitrile) (5.6 mg, 5%, pale yellow solid) was synthesized from 4-methoxyindole (59 mg, 0.4 mmol) following general procedure J. The residue was purified by flash chromatography (column: PF-15SIHC / 40G; eluent: EtOAc / hexane 1:1; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was further purified by prepHPLC to yield the desired product. Rf(EtOAc / hexane 1:1): 0.18;1H NMR (400 MHz, DMSO-d6): 12.09 (s, 1H), 8.28 – 8.15 (m, 2H), 8.11 – 8.02 (m, 2H), 7.20 – 7.09 (m, 2H), 6.61 (dd,3JH-H= 7.4 Hz,4JH-H= 1.3 Hz, 1H), 3.28 (s, 3H); HPLC-MS (method B): Rt= 5.06 min, 278 ([M+H]+).

[0216] Compound 50 (6-(4-hydroxy-1H-indole-3-carbonyl)picolinonitrile) (2.0 mg, 38%, yellow solid) was synthesized from 51 (5.6 mg, 0.02 mmol) and BBr3 (12 µl, 0.12 mmol) following general procedure E for demethylation. The residue was purified by prepHPLC to yield the desired product.1H NMR (400 MHz, DMSO-d6): 12.47 (s, 1H), 11.40 (s, 1H), 8.68 (s, 1H), 8.34 – 8.25 (m, 3H), 7.15 (t,3JH-H= 7.9 Hz, 1H), 6.99 (d,3JH-H= 8.0 Hz, 1H), 6.58 (d,3JH-H= 7.9 Hz, 1H); HPLC-MS (method C): Rt= 5.52 min, 264 ([M+H]+).

[0217] Compound 48 (6-(5-methoxy-1H-indole-3-carbonyl)picolinonitrile) (1.6 mg, 1.4%, pale yellow solid) was synthesized from 5-methoxyindole (59 mg, 0.4 mmol) following general procedure J. The residue was purified by flash chromatography (SiO2: 40 g, 5% step gradient 0-80% EtOAc in hexane). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was further purified by prepHPLC to yield the desired product. Rf(EtOAc / hexane 1:1): 0.41;1H NMR (400 MHz, DMSO-d6): 12.05 (s, 1H), 8.61 (s, 1H), 8.34 – 8.21 (m, 3H), 7.88 (d,4JH-H= 2.5 Hz, 1H), 7.46 (d,3JH-H= 8.8 Hz, 1H), 6.91 (dd,3JH-H= 8.8 Hz,4JH-H= 2.5 Hz, 1H), 3.83 (s, 3H); HPLC-MS (method B): Rt= 5.40 min, 278 ([M+H]+).

[0218] Compound 45 (6-(6-methoxy-1H-indole-3-carbonyl)picolinonitrile) (40 mg, 36%, yellow solid) was synthesized from 6-methoxyindole (59 mg, 0.4 mmol) following general procedure J. The residue was purified by flash chromatography (SiO2: 40 g, 5% step gradient 0-80% EtOAc in hexane). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crudeproduct was further purified by prepHPLC to yield the desired product. Rf(EtOAc / hexane 1:1): 0.41;1H NMR (400 MHz, DMSO-d6): 11.95 (s, 1H), 8.54 (s, 1H), 8.33 – 8.17 (m, 4H), 7.05 (d,4JH-H= 2.3 Hz, 1H), 6.91 (dd,3JH-H= 8.7 Hz,4JH-H= 2.3 Hz, 1H), 3.82 (s, 3H); HPLC-MS (method B): Rt= 5.45 min, 278 ([M+H]+).

[0219] Compound 46 (6-(6-hydroxy-1H-indole-3-carbonyl)picolinonitrile) (2.2 mg, 6.4%, yellow solid) was synthesized from 45 (36 mg, 0.13 mmol) and BBr3 (75 µl, 0.78 mmol) following general procedure E for demethylation. The residue was purified by flash chromatography (column: PF- 15SIHP / 25G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 0% EtOAc, 3-15 CV: linear-gradient 0- 100% EtOAc, 15-20 CV: 100% EtOAc; flow rate: 15 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum, and the crude product was purified using reversed-phase flash chromatography to yield the desired product.1H NMR (400 MHz, DMSO-d6): 11.80 (s, 1H), 9.28 (s, 1H), 8.45 (s, 1H), 8.32 – 8.20 (m, 3H), 8.10 (d,3JH-H= 8.6 Hz, 1H), 6.90 (d,4JH-H= 2.1 Hz, 1H), 6.77 (dd,3JH-H= 8.6 Hz,4JH-H= 2.1 Hz, 1H); HPLC-MS (method C): Rt= 5.82 min, 264 ([M+H]+).

[0220] Compound 92 (6-(7-methoxy-1H-indole-3-carbonyl)picolinonitrile) (25 mg, 23%, yellow solid) was synthesized from 7-methoxyindole (71 mg, 0.48 mmol) following general procedure J. The residue was purified by flash chromatography (SiO2: 35 g, 5% step gradient 30-60% EtOAc in hexane). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was triturated with CH2Cl2and further purified by prepHPLC to yield the desired product. Rf(EtOAc / hexane 4:6): 0.25;1H NMR (400 MHz, DMSO-d6): 12.35 (s, 1H), 8.56 (s, 1H), 8.31 – 8.21 (m, 3H), 7.93 (d,3JH-H= 8.0 Hz, 1H), 7.20 (t,3JH-H= 7.9 Hz, 1H), 6.87 (d,3JH-H= 7.9 Hz, 1H), 3.97 (s, 3H); HPLC-MS (method B): Rt= 5.55 min, 278 ([M+H]+).

[0221] Compound 93 (6-(7-hydroxy-1H-indole-3-carbonyl)picolinonitrile) (6.3 mg, 34%, yellow solid) was synthesized from 92 (19 mg, 0.07 mmol) and BBr3(40 µl, 0.42 mmol) following general procedure E for demethylation. The residue was purified by flash chromatography (SiO2: 30 g, 5% step gradient 40- 70% EtOAc in hexane). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was further purified by prepHPLC to yield the desired product. Rf(EtOAc / hexane 1:1): 025;1H NMR (400 MHz, DMSO-d6): 12.12 (s, 1H), 9.97 (s, 1H), 8.54 (s, 1H), 8.32 – 8.21 (m, 3H), 7.80 (d,3JH-H= 7.9 Hz, 1H), 7.06 (t,3JH-H= 7.8 Hz, 1H), 6.70 (d,3JH-H= 7.8 Hz, 1H); HPLC-MS (method B): Rt= 5.03 min, 264 ([M+H]+).Scheme S22. (a) Pyridine-2,6-dicarbonitrile, D-(+)-CSA, Pd(OAc)2, 2,2’-bipyridine, water, N-methylacetamide, 120 ºC, 48 h, 11%.

[0222] Compound 49 (6-(7-(benzyloxy)-1H-indole-3-carbonyl)picolinonitrile) (32 mg, 11%, pale yellow solid) was synthesized from 7-benzyloxyindole (189 mg, 0.8 mmol) following general procedure J. The residue was purified by flash chromatography (column: PF-15SIHC / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 0% EtOAc, 3-15 CV: linear-gradient 0-70% EtOAc, 15-20 CV: 70% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was further purified by reversed-phase flash chromatography to yield the desired product. Rf(EtOAc / hexane 1:1): 0.66;1H NMR (400 MHz, DMSO-d6): 12.36 (s, 1H), 8.56 (s, 1H), 8.31 – 8.21 (m, 3H), 7.93 (d,3JH-H= 7.9 Hz, 1H), 7.58 (d,3JH-H= 7.5 Hz, 2H), 7.42 (dd,3JH- H = 8.3, 6.9 Hz, 2H), 7.39 – 7.30 (m, 1H), 7.21 – 7.14 (m, 1H), 6.97 (d,3JH-H= 7.9 Hz, 1H), 5.33 (s, 2H); HPLC-MS (method C): Rt= 6.42 min, 354 ([M+H]+).Scheme S23. (a) 5-bromo-3-methoxypicolinitrile, D-(+)-CSA, Pd(OAc)2, 2,2’-bipyridine, water, N- methylacetamide, 120 ºC, 48 h, 33%; (b) CuCN, NMP, 202 ºC, 24 h, 20% (70), 6% (73).

[0223] Compound 94 ((6-bromo-3-methoxypyridin-2-yl)(1H-indol-3-yl)methanone) (44 mg, 33%, tan solid) was synthesized from indole (47 mg, 0.4 mmol) and 5-bromo-3-methoxypicolinitrile (129 mg, 0.6 mmol) following general procedure A. The residue was purified by flash chromatography (column: PF- 30SIHP / 40G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 10% EtOAc, 3-15 CV: linear-gradient 10- 70% EtOAc, 15-20 CV: 70% EtOAc; flow rate: 26 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum to yield the desired product. Rf(EtOAc / hexane 1:1): 0.29;1H NMR (400 MHz, DMSO-d6): 12.10 (s, 1H), 8.14 (dd,3JH-H= 6.2 Hz,4JH-H= 2.6 Hz, 1H), 7.81 – 7.71 (m, 2H), 7.65 (d,3JH-H= 8.8 Hz, 1H), 7.56 – 7.46 (m, 1H), 7.32 – 7.20 (m, 2H), 3.79 (s, 3H); HPLC-MS (method C): Rt= 5.25 min, 331 / 333 ([M+H]+).

[0224] Compound 70 (5-hydroxy-6-(1H-indole-3-carbonyl)picolinonitrile) (11 mg, 20%, yellow solid) and 73 (6-(1H-indole-3-carbonyl)-5-methoxypicolinonitrile) (3.4 mg, 6%, white solid) were synthesized following the general procedure I for Rosenmund-von Braun Reaction from 94 (66 mg, 0.2 mmol). The residue was purified by flash chromatography (column: PF-15SIHP / 25G; eluent: EtOAc / hexane, eluent gradient: 0-3 CV: 0% EtOAc, 3-15 CV: linear-gradient 0-100% EtOAc, 15-20 CV: 100% EtOAc; flow rate: 15 ml / min). Fractions containing the desired product were combined. The solvents were removed under vacuum. The crude product was further purified by reversed-phase flash chromatography to yield the desired products.70. Rf(EtOAc / hexane 1:1): 056;1H NMR (400 MHz,DMSO-d6): 12.74 (s, 1H), 12.29 (s, 1H), 8.57 (d,4JH-H= 3.2 Hz, 1H), 8.32 – 8.24 (m, 1H), 8.08 (d,3JH-H= 8.7 Hz, 1H), 7.64 – 7.53 (m, 2H), 7.34 – 7.24 (m, 2H); HPLC-MS (method C): Rt= 6.04 min, 264 ([M+H]+).73. Rf(EtOAc): 047;1H NMR (400 MHz, DMSO-d6): 12.16 (s, 1H), 8.22 – 8.13 (m, 2H), 7.85 – 7.78 (m, 2H), 7.56 – 7.49 (m, 1H), 7.33 – 7.22 (m, 2H), 3.88 (s, 3H); HPLC-MS (method C): Rt= 5.02 min, 278 ([M+H]+). Biological Activity Aryl Hydrocarbon Receptor (AHR) HepG2 Assay

[0225] Human HepG2 cells were seeded in 96-well plates at 75,000 cells per well in full medium [Dulbecco’s modified Eagle’s medium (DMEM) and 10% fetal bovine serum (FBS)] for 24 hours. Transfection was performed with 150 ng of XRE-luciferase plasmid at a transfection reagent (FuGENE, Promega) / DNA ratio of 4:1 for 18 hours in Opti-MEM. Transfected cells, or AZ-AHR stable HepG2 luciferase reporter cells, were treated with test compound (10−5to 10−12M) for 4.5 hours in full medium. Cells were lysed and luciferase was activated using the Luciferase Assay System (Promega). Luminescence signals were measured with a FluroStar Omega microplate reader. Luminescence signals were normalized to a vehicle [dimethyl sulfoxide (DMSO)]–treated control group and plotted as a concentration-dependent fold change. For compounds that displayed a saturated activity curve, EC50was calculated by least-square curve fitting (GraphPad).

[0226] Compounds provided herein are agonists of AHRs as shown in Table 2. Table 2EQUIVALENTS AND SCOPE

[0227] In the claims, articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0228] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any elements) can be removed from the group. It should it be understood that, in general, where the present disclosure, or aspects of the present disclosure, is / are referred to as comprising particular elements and / or features, certain embodiments of the present disclosure or aspects of the present disclosure consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0229] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the present disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0230] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changesand modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

Claims

1. CLAIMS What is claimed is:

1. A compound selected from the group consisting of:and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof.

2. A compound of Formula (I):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein: R1is -CF3or -CN; R2is halogen, -CN, or -OR2a, wherein R2ais hydrogen, optionally substituted C1-6alkyl, C1-6haloalkyl, or optionally substituted C3-6cycloalkyl; each instance of R3and R4is independently halogen, optionally substituted C1-6alkyl, C1-6haloalkyl, or optionally substituted C3-6cycloalkyl; and m and n are each independently 0, 1, 2, or 3.

3. A compound of Formula (II):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein: R1is -CF3or -CN; R2is halogen, -CN, or -OR2a, wherein R2ais hydrogen, optionally substituted C1-6alkyl, C1-6haloalkyl, or optionally substituted C3-6cycloalkyl; each instance of R3and R4is independently halogen, optionally substituted C1-6alkyl, C1-6haloalkyl, or optionally substituted C3-6cycloalkyl; and m and n are each independently 0, 1, 2, or 3.

4. A compound of Formula (III):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein: R1is -CF3or -CN; R2is halogen, -CN, or -OR2a, wherein R2ais hydrogen, optionally substituted C1-6alkyl, C1-6haloalkyl, or optionally substituted C3-6cycloalkyl; each instance of R3and R4is independently halogen, optionally substituted C1-6alkyl, C1-6haloalkyl, or optionally substituted C3-6cycloalkyl; m is 0, 1, 2, 3, or 4; and n is 0, 1, or 2.

5. A compound of Formula (IV):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein: R1is -CF3or -CN; each instance of R3and R4is independently halogen, optionally substituted C1-6alkyl, C1-6haloalkyl, optionally substituted C3-6cycloalkyl, -CN, or -OR2a, wherein R2ais hydrogen, optionally substituted C1-6alkyl, C1-6haloalkyl, or optionally substituted C3-6cycloalkyl; m is 0, 1, 2, 3, or 4; and n is 0, 1, 2, or 3.

6. The compound of any one of claims 2-5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is -CF3.

7. The compound of any one of claims 2-5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is -CN.

8. The compound of any one of claims 2-7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2is Br, F, Cl, I, -CN, -OH, or -OMe.

9. The compound of any one of claims 2-8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein at least one instance of R3is F or Cl.

10. The compound of any one of claims 2-9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein m is 0.

11. The compound of any one of claims 2-10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein m is 1.

12. The compound of any one of claims 2-11, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein n is 0.

13. A compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

14. A compound of any one of the preceding claims, as a free base.

15. A pharmaceutical composition comprising a compound of any one of claims 1-14, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, and a pharmaceutically acceptable excipient.

16. A method of modulating an aryl hydrocarbon receptor of a cell, the method comprising contacting the cell with a compound of any one of claims 1-14, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

17. The method of claim 16, wherein the activity of the aryl hydrocarbon receptor of the cell increases in the presence of the compound.

18. A method of increasing expression of a gene in a cell, the method comprising contacting the cell with a compound of any one of claims 1-14, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

19. The method of claim 18, wherein the expression of the gene is activated in the present of an activated aryl hydrocarbon receptor.

20. The method of claim 18 or 19, wherein the gene is CYP1A1, CYP1A2, CYP1B1, ALDH3A1, NQO1, UGT1A1, Muc1, Muc3, or Bcl21.

21. The method of claim 20, wherein the gene is CYP1A1.

22. A method of regulating the expression of an interleukin in a cell, the method comprising contacting the cell with a compound of any one of claims 1-14, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

23. The method of claim 22, wherein expression of the interleukin is increased.

24. The method of claim 22, wherein expression of the interleukin is decreased.

25. A method of regulating secretion of an interleukin from a cell, the method comprising contactingthe cell with a compound of any one of claims 1-14, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

26. The method of claim 25, wherein secretion of the interleukin is increased.

27. The method of claim 25, wherein secretion of the interleukin is decreased.

28. The method of any one of claims 25-27, wherein the interleukin is interleukin 22 (IL-22), interleukin 6 (IL-6), interleukin 10 (IL-10), or interleukin 17 (IL-17).

29. The method of any one of claims 16-28, wherein the cell is in vitro.

30. The method of any one of claims 16-28, wherein the cell is in vivo.

31. A method of modulating the function of an immune cell, the method comprising contacting the immune cell with a compound of any one of claims 1-14, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

32. The method of claim 31, wherein the immune cell is a T cell, a mast cell, a natural killer cell, a B cell, or an innate lymphoid cell.

33. The method of claim 32, wherein the T cell is a regulatory T (Treg) cell or a helper T (TH) cell.

34. The method of claim 33, wherein the helper T (TH) cell is a TH17 cell or a TH22 cell.

35. A method of treating a disease or condition associated with activity of an aryl hydrocarbon receptor, the method comprising administering a compound of any one of claims 1-14, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

36. The method of claim 35, wherein the disease or condition is associated with reduced activity of an aryl hydrocarbon receptor.

37. The method of claim 35 or 36, wherein the disease or condition is an inflammatory disease, an autoimmune disease, a metabolic disorder, or a proliferative disease.

38. The method of claim 37, wherein the metabolic disorder is metabolic syndrome.

39. The method of claim 37, wherein the metabolic disorder is type I diabetes or steatosis.

40. The method of claim 37, wherein the inflammatory disease is colitis, inflammatory bowel disease, Crohn’s disease, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, pancreatitis, insulitis, atherosclerosis, or graft versus host disease.

41. The method of claim 40, wherein the colitis is ulcerative colitis.

42. The method of claim 37, wherein the proliferative disease is cancer.

43. The method of claim 42, wherein the cancer is stomach cancer, breast cancer, skin cancer, ovarian cancer, pancreatic cancer, liver cancer, or hematopoietic cancer.

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