WO2022133480A1 - Aryl hydrocarbon receptor (ahr) agonists and uses thereof - Google Patents

Aryl hydrocarbon receptor (ahr) agonists and uses thereof Download PDF

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WO2022133480A1
WO2022133480A1 PCT/US2021/072976 US2021072976W WO2022133480A1 WO 2022133480 A1 WO2022133480 A1 WO 2022133480A1 US 2021072976 W US2021072976 W US 2021072976W WO 2022133480 A1 WO2022133480 A1 WO 2022133480A1
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compound
ring
cancer
pharmaceutically acceptable
yield
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French (fr)
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Alfredo C. Castro
Karen J. Mcgovern
Michael Burke
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Ikena Oncology, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D515/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings

Definitions

  • the present invention relates to compounds and methods useful for activating aryl hydrocarbon receptor (AHR).
  • the invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.
  • BACKGROUND [0002]
  • the aryl hydrocarbon receptor (AHR) is a ligand-inducible transcription factor that mediates a number of important biological and pharmacological processes. AHR agonists have been shown to be potentially useful for treating disorders such as cancer (U.S.
  • Patent 8,604,067 Wang et al., 2013, Cheng et al., 2015), obesity (U.S. Patent 7,419,992), and conditions related to imbalanced actions of the immune system (Quintana et al., 2010, Nugent et al., 2013).
  • AHR has also been shown to be involved in immune regulation, hematopoiesis, cell cycle, carcinogenesis and in the maintenance of intestinal barrier integrity and homeostasis.
  • SUMMARY OF THE INVENTION [0003] It has now been found that compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective as AHR agonists.
  • the instant invention provides a compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.
  • Compounds of the present invention, and pharmaceutically acceptable compositions thereof are useful for treating a variety of diseases, disorders or conditions, associated with AHR. Such diseases, disorders, or conditions include, for example, cancer, obesity, and inflammatory disorders as described herein. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description of Certain Embodiments of the Invention: [0005] Compounds of the present invention, and pharmaceutical compositions thereof, are useful as AHR agonists.
  • compounds of the present invention may activate AHR and thus treat certain diseases, disorders, or conditions associated with AHR, such as those described herein.
  • compounds of this invention, and pharmaceutically acceptable compositions thereof are effective as AHR agonists.
  • aliphatic or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms.
  • aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C 3 -C 6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system.
  • the term includes any permissible ring fusion, such as ortho-fused or spirocyclic.
  • heterocyclic is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc.
  • a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
  • Exemplary bicyclic rings include: Exemplary bridged bicyclics include: [0010] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group.
  • lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • lower haloalkyl refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • unsaturated as used herein, means that a moiety has one or more units of unsaturation.
  • bivalent C1-8 (or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
  • alkylene refers to a bivalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., –(CH 2 )n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • cyclopropylenyl refers to a bivalent cyclopropyl group of the following structure: .
  • halogen means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • heteroaryl and “heteroar—,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar—”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin–3(4H)–one.
  • heteroaryl group may be mono– or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4–dihydro– 2H–pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N–substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
  • a heterocyclyl group may be mono– or bicyclic.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the invention may contain “optionally substituted” moieties.
  • substituted means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • R * is C 1–6 aliphatic
  • R * is optionally substituted with halogen, – R ⁇ , -(haloR ⁇ ), -OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2, or – NO2, wherein each R ⁇ is independently selected from C1–4 aliphatic, –CH 2 Ph, –O(CH 2 )0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ⁇ is unsubstituted or where preceded by halo is substituted only with one or more halogens.
  • An optional substituent on a substitutable nitrogen is independently –R ⁇ , –NR ⁇ 2 , – C(NH)NR ⁇ 2, or –N(R ⁇ )S(O)2R ⁇ ; wherein each R ⁇ is independently hydrogen, C1–6 aliphatic, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when R ⁇ is C 1–6 aliphatic, R ⁇ is optionally substituted with halogen, –R ⁇ , -(haloR
  • 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, S. M. 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 this invention 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 used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • 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, pec
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1–4 alkyl) 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, loweralkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • the term “agonist” is defined as a compound that binds to and/or activates AHR with measurable affinity.
  • an agonist has an IC 50 and/or binding constant of less than about 100 ⁇ M, less than about 50 ⁇ M, less than about 1 ⁇ M, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.
  • measurable affinity and “measurably activate,” as used herein, means a measurable change in AHR activity between a sample comprising a compound of the present invention, or composition thereof, and AHR, and an equivalent sample comprising AHR, in the absence of said compound, or composition thereof. 3.
  • Ring A is an optionally substituted 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S, or an optionally substituted 6-10 membered bicyclic or bridged bicyclic saturated or partially unsaturated carbocyclic ring.
  • Ring A is an optionally substituted 5-membered heteroaromatic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • Ring A is an unsubstituted 5-membered heteroaromatic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • Ring A is a 5-membered heteroaromatic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S, which is substituted 1 or 2 times by R 12 , wherein each R 12 is independently an optional substituent as defined above and described in embodiments herein.
  • Ring A is an optionally substituted 6-membered heteroaromatic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • Ring A is an unsubstituted 6-membered heteroaromatic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • Ring A is a 6-membered heteroaromatic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S, which is substituted 1 or 2 times by R 12 , wherein each R 12 is independently an optional substituent as defined above and described in embodiments herein.
  • Ring A is optionally substituted , , or .
  • Ring A is optionally substituted , , , , , , .
  • Ring A is optionally each of which is substituted 1 or 2 times by R 12 , wherein each R 12 is independently an optional substituent as defined above and described in embodiments herein.
  • Ring each of which is substituted 1 or 2 times by R 12 wherein each R 12 is independently an optional substituent as defined above and described in embodiments herein.
  • Ring A is , wherein each of R 7 and R 8 is independently an optional substituent as defined above and described in embodiments herein.
  • Ring A is , wherein R 12 is an optional substituent as defined above and described in embodiments herein. [0040] In some embodiments, Ring A is unsubstituted , , .
  • Ring A is unsubstituted [0041] In some embodiments, Ring A is optionally substituted , , , , each of which is substituted 1 or 2 times by R 12 , wherein each R 12 is independently an optional substituent as defined above and described in embodiments herein. In some embodiments, , wherein each R 12 is independently an optional substituent as defined above and described in embodiments herein. [0042] In some embodiments, Ring A is , wherein each of R 7 and R 8 is independently an optional substituent as defined above and described in embodiments herein. In some embodiments, Ring A is , wherein each of R 7 and R 8 is independently an optional substituent as defined above and described in embodiments herein.
  • Ring A is an optionally substituted 6-, 7-, 8-, 9-, or 10- membered bicyclic or bridged bicyclic saturated or partially unsaturated carbocyclic ring. In some embodiments, Ring A is an optionally substituted 6-membered bridged bicyclic saturated or partially unsaturated carbocyclic ring. In some embodiments, Ring A is an optionally substituted 7-membered bridged bicyclic saturated or partially unsaturated carbocyclic ring. In some embodiments, Ring A is an optionally substituted . In some embodiments, Ring A is , wherein each of R 12 is independently an optional substituent as defined above and described in embodiments herein.
  • R 7 is -N(R W )- S(O) 2 -R W , wherein each R W is independently as defined below and described in embodiments herein.
  • R 7 is -OS(O)2-R W , wherein R W is as defined below and described in embodiments herein.
  • R 7 is -S(O)-R W , wherein R W is as defined below and described in embodiments herein.
  • R 7 is -N(R W )-S(O)-R W , wherein each R W is independently as defined below and described in embodiments herein.
  • R 7 is -OS(O)-R W , wherein R W is as defined below and described in embodiments herein. [0048] In some embodiments, R 7 is F. In some embodiments, R 7 is Cl. In some embodiments, R 7 is Br. In some embodiments, R 7 is optionally substituted -C1-6 aliphatic. In some embodiments, R 7 is unsubstituted -C 1-6 aliphatic. In some embodiments, R 7 is unsubstituted -C 1-6 alkyl. In some embodiments, R 7 is -C1-6 aliphatic substituted 1-6 times by halogen. In some embodiments, R 7 is -C1-6 alkyl substituted 1-6 times by halogen.
  • R 7 is -C1-6 alkyl substituted 1-6 times by F. In some embodiments, R 7 is –CF 3 .
  • R 8 is -S(O) 2 -R W , wherein R W is as defined below and described in embodiments herein.
  • R 8 is -N(R W )- S(O)2-R W , wherein each R W is independently as defined below and described in embodiments herein.
  • R 8 is -OS(O) 2 -R W , wherein R W is as defined below and described in embodiments herein.
  • R 8 is -S(O)-R W , wherein R W is as defined below and described in embodiments herein.
  • R 8 is -N(R W )-S(O)-R W , wherein each R W is independently as defined below and described in embodiments herein. In some embodiments, R 8 is -OS(O)-R W , wherein R W is as defined below and described in embodiments herein. [0053] In some embodiments, R 8 is F. In some embodiments, R 8 is Cl. In some embodiments, R 8 is Br. In some embodiments, R 8 is optionally substituted -C 1-6 aliphatic. In some embodiments, R 8 is unsubstituted -C1-6 aliphatic. In some embodiments, R 8 is unsubstituted -C1-6 alkyl.
  • R 8 is -C1-6 aliphatic substituted 1-6 times by halogen. In some embodiments, R 8 is -C 1-6 alkyl substituted 1-6 times by halogen. In some embodiments, R 8 is -C 1-6 alkyl substituted 1-6 times by F. In some embodiments, R 8 is –CF 3 .
  • R 12 is -N(R W )-S(O) 2 -R W , wherein each R W is independently as defined below and described in embodiments herein.
  • R 12 is -OS(O)2-R W , wherein R W is as defined below and described in embodiments herein.
  • R 12 is -S(O)-R W , wherein R W is as defined below and described in embodiments herein.
  • R 12 is -N(R W )-S(O)- R W , wherein each R W is independently as defined below and described in embodiments herein.
  • R 12 is -OS(O)-R W , wherein R W is as defined below and described in embodiments herein.
  • R 12 is F.
  • R 12 is Cl.
  • R 12 is Br.
  • R 12 is optionally substituted -C 1-6 aliphatic.
  • R 12 is unsubstituted -C1-6 aliphatic.
  • R 12 is unsubstituted -C1-6 alkyl.
  • R 12 is -C1-6 aliphatic substituted 1-6 times by halogen.
  • R 12 is -C 1-6 alkyl substituted 1-6 times by halogen.
  • R 12 is -C1-6 alkyl substituted 1-6 times by F. In some embodiments, R 12 is –CF3.
  • Ring A is selected from those depicted in Table 1, below.
  • Ring B is selected from above and described in embodiments herein, both singly and in combination, provided that, when Ring A is an optionally substituted 5-membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S, at least one 6
  • X is N or CR . In some embodiments, X is N. In some embodiments, X is CR 6 .
  • Y is N or CR 2 .
  • Y is N. In some embodiments, Y is CR 2 . [0065] In some embodiments, Z is N or CR 4 . In some embodiments, Z is N. In some embodiments, Z is CR 4 . [0066] In some embodiments, W is NR 1 , O, or S. In some embodiments, W is NR 1 . In some embodiments, W is O. In some embodiments, W is S.
  • Ring A is an optionally substituted 5-membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S
  • Ring wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is as defined above and described in embodiments herein, both singly and in combination.
  • Ring B wherein each of R 1 , R 2 , R 3 , R 4 , and R 5 is as defined above and described in embodiments herein, both singly and in combination.
  • Ring B is , wherein each of R 1 , R 2 , R 3 , R 5 , and R 6 is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, Ring B is , wherein each of R 1 , R 3 , R 4 , R 5 , and R 6 is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, Ring B is , wherein each of R 1 , R 3 , R 5 , and R 6 is as defined above and described in embodiments herein, both singly and in combination.
  • Ring wherein X is N or CR 6 ; and Z is N or CR 4 , and wherein each of R 3 , R 4 , R 5 , and R 6 is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, Ring wherein each of R 3 , R 5 , and R 6 is as defined above and described in embodiments herein, both singly and in combination. [0069] In some embodiments, Ring , wherein X is N or CR 6 ; and Y is N or CR 2 , and wherein each of R 1 , R 2 , R 5 , and R 6 is as defined above and described in embodiments herein, both singly and in combination.
  • Ring wherein each of R 1 , R 2 , R 5 , and R 6 is as defined above and described in embodiments herein, both singly and in combination.
  • Ring wherein X is N or CR 6 ; Z is N o 4 r CR ; and W is NR 1 , O, or S, and wherein each of R 1 , R 4 , R 5 , and R 6 is as defined above and described in embodiments herein, both singly and in combination.
  • Ring B is , wherein R 5 is as defined above and described in embodiments herein.
  • Ring wherein each of R 1 , R 2 , R 3 , R 4 , and R 6 is as defined above and described in embodiments herein, both singly and in combination. [ defined above and described in embodiments herein, both singly and in combination. [0073] In some embodiments, Ring B is selected from those depicted in Table 1, below.
  • R 1 is -N(R W )- S(O)2-R W , wherein each R W is independently as defined below and described in embodiments herein.
  • R 1 is -OS(O)2-R W , wherein R W is as defined below and described in embodiments herein.
  • R 1 is -S(O)-R W , wherein R W is as defined below and described in embodiments herein.
  • R 1 is -N(R W )-S(O)-R W , wherein each R W is independently as defined below and described in embodiments herein.
  • R 1 is -OS(O)-R W , wherein R W is as defined below and described in embodiments herein.
  • R 2 is -S(O)2-R W , wherein R W is as defined below and described in embodiments herein.
  • R 2 is -N(R W )- S(O) 2 -R W , wherein each R W is independently as defined below and described in embodiments herein.
  • R 2 is -OS(O)2-R W , wherein R W is as defined below and described in embodiments herein.
  • R 2 is -S(O)-R W , wherein R W is as defined below and described in embodiments herein.
  • R 2 is -N(R W )-S(O)-R W , wherein each R W is independently as defined below and described in embodiments herein.
  • R 2 is -OS(O)-R W , wherein R W is as defined below and described in embodiments herein.
  • R 3 is halogen.
  • R 3 is –CN.
  • R 3 is -NO2.
  • R 3 is R W as defined below and described in embodiments herein.
  • R 3 is -C(O)-R W , wherein R W is as defined below and described in embodiments herein.
  • R 3 is -S(O) 2 -R W , wherein R W is as defined below and described in embodiments herein.
  • R 3 is -N(R W )- S(O)2-R W , wherein each R W is independently as defined below and described in embodiments herein.
  • R 3 is -OS(O) 2 -R W , wherein R W is as defined below and described in embodiments herein.
  • R 3 is -S(O)-R W , wherein R W is as defined below and described in embodiments herein.
  • R 3 is -N(R W )-S(O)-R W , wherein each R W is independently as defined below and described in embodiments herein.
  • R 3 is -OS(O)-R W , wherein R W is as defined below and described in embodiments herein.
  • R 4 is halogen.
  • R 4 is –CN.
  • R 4 is -NO 2 .
  • R 4 is R W as defined below and described in embodiments herein.
  • R 4 is -S(O)-R W , wherein R W is as defined below and described in embodiments herein.
  • R 4 is -N(R W )-S(O)-R W , wherein each R W is independently as defined below and described in embodiments herein.
  • R 4 is -OS(O)-R W , wherein R W is as defined below and described in embodiments herein.
  • R 6 is halogen.
  • R 6 is –CN.
  • R 6 is -NO2.
  • R 6 is R W as defined below and described in embodiments herein.
  • R 6 is -OS(O) 2 -R W , wherein R W is as defined below and described in embodiments herein.
  • R 6 is -S(O)-R W , wherein R W is as defined below and described in embodiments herein.
  • R 6 is -N(R W )-S(O)-R W , wherein each R W is independently as defined below and described in embodiments herein.
  • R 6 is -OS(O)-R W , wherein R W is as defined below and described in embodiments herein.
  • each of R 1 , R 2 , R 3 , R 4 , and R 6 is independently selected from hydrogen, Cl, Br, F, -OH, -OCH 3 , -CH 3 , -C(O)OC(CH 3 ) 3 , -S(O) 2 OH, -NH 2 , -OCH 2 CH 3 , -COOH, [0081] In some embodiments, each of R 1 , R 2 , R 3 , R 4 , and R 6 is independently selected from those depicted in Table 1, below.
  • R 5 is -R, wherein R is as defined below and described in embodiments herein.
  • R 5 is -C(O)-R W , wherein R W is as defined below and described in embodiments herein.
  • R 5 is -S(O) 2 -R W , wherein R W is as defined below and described in embodiments herein. In some embodiments, R 5 is -S(O)-R W , wherein R W is as defined below and described in embodiments herein. [0084] In some embodiments, R 5 is H. In some embodiments, R 5 is optionally substituted C 1- 6 aliphatic. In some embodiments, R 5 is optionally substituted C 1-6 alkyl. . [0086] In some embodiments, R 5 is selected from those depicted in Table 1, below.
  • R W is -R, -N(R) 2 , -NR-OR, -N(R)-N(R) 2 , -N(OR)-N(R) 2 , -N(R)-N(OR)R, -OR, -O-N(R)2, or –SR.
  • R W is -R, wherein R is as defined below and described in embodiments herein.
  • R W is -N(R) 2 , wherein each R is independently as defined below and described in embodiments herein.
  • R W is -NR-OR, wherein each R is independently as defined below and described in embodiments herein.
  • R W is -N(R)-N(R) 2 , wherein each R is independently as defined below and described in embodiments herein. In some embodiments, R W is -N(OR)-N(R)2, wherein each R is independently as defined below and described in embodiments herein. In some embodiments, R W is -N(R)-N(OR)R, wherein each R is independently as defined below and described in embodiments herein. In some embodiments, R W is -OR, wherein R is as defined below and described in embodiments herein. In some embodiments, R W is –O-N(R) 2 , wherein each R is independently as defined below and described in embodiments herein.
  • R W is -SR, wherein R is as defined below and described in embodiments herein. .
  • R W is selected from those depicted in Table 1, below.
  • R is hydrogen, optionally substituted C1-6 aliphatic, an optionally substituted 3-7 membered carbocyclic ring, or an optionally substituted 3-7 membered heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, or two R’s together with the nitrogen to which they attach form an optionally substituted 5-7 membered heterocyclic ring having 0-2 heteroatoms independently selected from N, O, or S in addition to the nitrogen to which the two R’s attach.
  • R is hydrogen. In some embodiments, R is optionally substituted C 1-6 aliphatic. In some embodiments, R is optionally substituted C 1-6 alkyl. In some embodiments, R is unsubstituted -C 1-6 aliphatic. In some embodiments, R is unsubstituted -C 1-6 alkyl. In some embodiments, R is -C1-6 aliphatic which is substituted by –CH3, –CF3, –OH, – OCH3, –OCF3, -N(CH3)2, -N + (CH3)3, ,
  • R is -C 1-6 aliphatic substituted 1-6 times by halogen. In some embodiments, R is -C1-6 alkyl substituted 1-6 times by halogen. In some embodiments, R is -C1-6 alkyl substituted 1-6 times by F. In some embodiments, R is -CH3. In some embodiments, R is – CH 2 CH 3 . In some embodiments, R is –CH 2 CH 2 CH 3 . In some embodiments, R is –CH(CH 3 ) 2 . In some embodiments, R is –CH 2 CH 2 CH 2 CH3. In some embodiments, R is –CH 2 CH(CH3)2. In some embodiments, R is –C(CH3)3.
  • R is -CF3.
  • R is an optionally substituted 3, 4, 5, 6, or 7 membered carbocyclic ring.
  • R is a 3, 4, 5, 6, or 7 membered carbocyclic ring, which ,
  • R is an optionally substituted 3, 4, 5, 6, or 7 membered heterocyclic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • R is a 3, 4, 5, 6, or 7 membered heterocyclic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S, which is substituted 1-5 times by –CH3, –CF3, –OH, – OCH3, –OCF3, -N(CH3)2, -N + (CH3)3, ,
  • R is optionally substituted , .
  • R is optionally substituted , .
  • two R’s together with the nitrogen to which they attach form an optionally substituted 5-7 membered heterocyclic ring having 0-2 heteroatoms independently selected from N, O, or S in addition to the nitrogen to which the two R’s attach.
  • two R’s together with the nitrogen to which they attach form an optionally substituted 5-7 membered heterocyclic ring having 0 or 1 heteroatom independently selected from N, O, or S in addition to the nitrogen to which the two R’s attach.
  • -N(R) 2 is optionally substituted . [ or . [0099] In some embodiments, R is selected from those depicted in Table 1, below. [00100] In some embodiments, the present invention provides a compound selected from Formulas (II-a) to (II-p):
  • the present invention provides a compound selected from Formulas (III-a) to (III-l):
  • the present invention provides a compound of Formula (IV-a) or (IV-b): (IV-a) (IV-b) or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both singly and in combination.
  • Exemplary compounds of the invention are set forth in Table 1, below. Table 1.
  • the present invention provides a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof.
  • the compounds of this invention may be prepared or isolated in general by synthetic and/or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein.
  • the present invention provides a compound or an intermediate compound as described in the Examples, or a salt thereof. 4.
  • Pharmaceutically acceptable compositions [00106] According to another embodiment, the invention provides a pharmaceutical composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound in compositions of this invention is such that is effective to measurably activate AHR, or a variant or mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably activate AHR, or a variant or mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient. [00107]
  • patient means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention refers to a non- toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropy
  • a “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an active metabolite or residue thereof.
  • active metabolite or residue thereof means that a metabolite or residue thereof also activates AHR, or a mutant thereof.
  • active metabolite or residue thereof also means that a metabolite or residue thereof activates AHR, or a variant or mutant thereof.
  • compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or di- glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions of this invention can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • pharmaceutically acceptable compositions of this invention can be administered in the form of suppositories for rectal administration.
  • compositions of this invention can also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. [00120] Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.
  • compositions of the present invention that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration.
  • provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient depends upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the present invention provides a method of using a compound as described herein for treating a disease or disorder associated with AHR.
  • a disease or disorder associated with AHR is an angiogenesis implicated disorder as described herein.
  • a disease or disorder associated with AHR is a cancer as described herein.
  • a disease or disorder associated with AHR is an inflammatory disorder as described herein.
  • a disease or disorder associated with AHR is a disease or disorder as described in Gutiérrez-Vázquez C.
  • angiogenesis Implicated Disorders [00124]
  • the present invention provides a method for treating or preventing or reducing the risk of an angiogenesis implicated disorder in a patient comprising administering to the patient a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • an angiogenesis implicated disorder is associated with a reduced expression or activation of an AHR.
  • an angiogenesis implicated disorder is a retinopathy, psoriasis, rheumatoid arthritis, obesity, or cancer (for example, as described below).
  • Cancer the present invention provides a method for treating or preventing or reducing the risk of cancer in patient comprising administering to the patient a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • a cancer is associated with a reduced expression or activation of an aryl hydrocarbon receptor (AHR).
  • AHR aryl hydrocarbon receptor
  • the cancer or proliferative disorder or tumor to be treated using the compounds and methods and uses described herein include, but are not limited to, a hematological cancer, a lymphoma, a myeloma, a leukemia, a neurological cancer, skin cancer, breast cancer, a prostate cancer, a colorectal cancer, lung cancer, head and neck cancer, a gastrointestinal cancer, a liver cancer, a pancreatic cancer, a genitourinary cancer, a bone cancer, renal cancer, and a vascular cancer.
  • a cancer includes, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin’s disease or non-Hodgkin’s disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angios
  • leukemias e
  • a cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.
  • GBM glioblastoma multiforme
  • medulloblastoma craniopharyngioma
  • ependymoma pinealoma
  • hemangioblastoma acoustic neuroma
  • oligodendroglioma oligodendroglioma
  • schwannoma oligodendroglioma
  • GBM Glioblastoma
  • the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor.
  • the patient is an adult human. In some embodiments, the patient is a child or pediatric patient.
  • Cancer includes, in another embodiment, without limitation, mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymph
  • a cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma.
  • Solid tumors generally comprise an abnormal mass of tissue that typically does not include cysts or liquid areas.
  • the cancer is selected from renal cell carcinoma, or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyo
  • HCC hepatocellular
  • a cancer is hepatocellular carcinoma (HCC).
  • the cancer is hepatoblastoma.
  • the cancer is colon cancer.
  • the cancer is rectal cancer.
  • the cancer is ovarian cancer, or ovarian carcinoma.
  • the cancer is ovarian epithelial cancer.
  • the cancer is fallopian tube cancer.
  • the cancer is papillary serous cystadenocarcinoma.
  • the cancer is uterine papillary serous carcinoma (UPSC).
  • the cancer is hepatocholangiocarcinoma.
  • the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis-1 associated MPNST.
  • MPNST peripheral nerve sheath tumors
  • a cancer is Waldenstrom’s macroglobulinemia. In some embodiments, the cancer is medulloblastoma.
  • a cancer is a viral-associated cancer, including human immunodeficiency virus (HIV) associated solid tumors, human papilloma virus (HPV)-16 positive incurable solid tumors, and adult T-cell leukemia, which is caused by human T-cell leukemia virus type I (HTLV-I) and is a highly aggressive form of CD4+ T-cell leukemia characterized by clonal integration of HTLV-I in leukemic cells (See https://clinicaltrials.gov/ct2/show/study/ NCT02631746); as well as virus-associated tumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel cell carcinoma.
  • HCV human immunodeficiency virus
  • HPV human papilloma virus
  • a cancer is melanoma cancer.
  • a cancer is breast cancer.
  • a cancer is lung cancer.
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • a cancer is selected from prostate cancer, liver cancer, and ovarian cancer.
  • the present invention provides a method for treating or preventing or reducing the risk of an inflammatory disorder in patient comprising administering to the patient a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • an inflammatory disorder is associated with a reduced expression or activation of an aryl hydrocarbon receptor (AHR).
  • AHR aryl hydrocarbon receptor
  • AHR aryl hydrocarbon receptor
  • Inflammatory disorders include a large number of disorders or conditions that are involved in a variety of diseases, including those involving the immune system, including those demonstrated in allergic reactions and myopathies, or non-immune diseases with causal origins in inflammatory processes including, but not limited to cancer, atherosclerosis, and ischemic heart disease.
  • disorders associated with inflammation include, but are not limited to, acne vulgaris, asthma, autoimmune diseases, autoinflammatory diseases, celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, hypersensitivities, inflammatory bowel diseases, interstitial cystitis, otitis, pelvic inflammatory disease, reperfusion injury, rheumatic fever, rheumatoid arthritis, sarcoidosis, transplant rejection, and vasculitis.
  • an inflammatory disorder is necrotizing enterocolitis, inflammatory bowel disease (IBD), autoimmune diseases, Crohn's disease, celiac disease, ulcerative colitis, cardiovascular disease, ocular Behcet's disease, breast cancer, and others.
  • IBD inflammatory bowel disease
  • autoimmune diseases Crohn's disease
  • celiac disease celiac disease
  • ulcerative colitis cardiovascular disease
  • ocular Behcet's disease ocular Behcet's disease
  • breast cancer and others.
  • inflammatory disease include, without limitation, acne, acid- induced lung injury, Addison's disease, adrenal hyperplasia, adrenocortical insufficiency, adult- onset Still's disease, adult respiratory distress syndrome (ARDS), age-related macular degeneration, aging, alcoholic hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopulmonary, allergic conjunctivitis, allergic contact dermatitis, allergies, allergic encephalomyelitis, allergic neuritis, allograft rejection, alopecia, alopecia areata, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, angina pectoris, angioedema, angiofibroma, anhidrotic ectodermal dysplasia-ill, anti-glomerular basement membrane disease, antigen- antibody complex mediated diseases, ankylosing spondylitis, antiphospholipid syndrome, aphthous sto
  • IBD inflammatory bowel disease
  • Other forms of IBD that can be treated with the presently disclosed compounds, compositions and methods include diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis, autistic enterocolitis, indeterminate colitis, Behget's disease, gastroduodenal CD, jejunoileitis, ileitis, ileocolitis, Crohn’s (granulomatous) colitis, irritable bowel syndrome, mucositis, radiation induced enteritis, short bowel syndrome, celiac disease, stomach ulcers, diverticulitis, pouchitis, proctitis, and chronic diarrhea.
  • treating or preventing an inflammatory disease also includes ameliorating or reducing one or more symptoms of the inflammatory disease.
  • the term “symptoms of IBD” can refer to detected symptoms such as abdominal pain, diarrhea, rectal bleeding, weight loss, fever, loss of appetite, and other more serious complications, such as dehydration, anemia and malnutrition.
  • a number of such symptoms are subject to quantitative analysis (e.g., weight loss, fever, anemia, etc.).
  • Some symptoms are readily determined from a blood test (e.g., anemia) or a test that detects the presence of blood (e.g., rectal bleeding).
  • the term “wherein said symptoms are reduced” refers to a qualitative or quantitative reduction in detectable symptoms, including but not limited to, a detectable impact on the rate of recovery from disease (e.g., rate of weight gain).
  • the diagnosis is typically determined by way of an endoscopic observation of the mucosa, and pathologic examination of endoscopic biopsy specimens.
  • the course of IBD varies, and is often associated with intermittent periods of disease remission and disease exacerbation.
  • Various methods have been described for characterizing disease activity and severity of IBD as well as response to treatment in subjects having IBD. Treatment according to the present methods is generally applicable to a subject having IBD of any level or degree of disease activity.
  • the compounds and compositions, according to the method of the present invention can be administered using any amount and any route of administration effective for activating AHR and treating or lessening the severity of a disease, for example, as those described herein.
  • the exact amount required varies from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease or condition, the particular agent, its mode of administration, and the like.
  • Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated.
  • the specific effective dose level for any particular patient or organism depends upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • patient means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the disease or disorder being treated.
  • the compounds of the invention can be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents,
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • a compound of the present invention In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, can depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type can also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They can optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions examples include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound can be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms can also comprise buffering agents. They can optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • Co-Administration with One or More Other Therapeutic Agent(s) [00153] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents that are normally administered to treat that condition, can also be present in the compositions of this invention.
  • the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein.
  • the method includes co-administering one additional therapeutic agent.
  • the method includes co-administering two additional therapeutic agents.
  • the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.
  • a compound of the current invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds.
  • One or more other therapeutic agent(s) can be administered separately from a compound or composition of the invention, as part of a multiple dosage regimen.
  • one or more other therapeutic agent(s) may be part of a single dosage form, mixed together with a compound of this invention in a single composition.
  • one or more other therapeutic agent(s) and a compound or composition of the invention can be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours from one another.
  • one or more other therapeutic agent(s) and a compound or composition of the invention are administered as a multiple dosage regimen within greater than 24 hours apart.
  • the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention.
  • a compound of the present invention can be administered with one or more other therapeutic agent(s) simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present invention provides a single unit dosage form comprising a compound of the current invention, one or more other therapeutic agent(s), and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of a compound of the invention and one or more other therapeutic agent(s) (in those compositions which comprise an additional therapeutic agent as described above) that can be combined with the carrier materials to produce a single dosage form varies depending upon the host treated and the particular mode of administration.
  • a composition of the invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of a compound of the invention can be administered.
  • the one or more other therapeutic agent(s) and a compound of the invention can act synergistically. Therefore, the amount of the one or more other therapeutic agent(s) in such compositions may be less than that required in a monotherapy utilizing only that therapeutic agent.
  • a dosage of between 0.01 - 1,000 g/kg body weight/day of the one or more other therapeutic agent(s) can be administered.
  • the amount of one or more other therapeutic agent(s) present in the compositions of this invention may be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of one or more other therapeutic agent(s) in the presently disclosed compositions ranges from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • one or more other therapeutic agent(s) is administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered for that agent.
  • the phrase "normally administered” means the amount an FDA approved therapeutic agent is approved for dosing per the FDA label insert.
  • the compounds of this invention, or pharmaceutical compositions thereof can also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • vascular stents for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury).
  • patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor.
  • Implantable devices coated with a compound of this invention are another embodiment of the present invention.
  • Exemplary Other Therapeutic Agents [00162]
  • agents for treatment of an inflammatory disease or condition include alpha- fetoprotein modulators; adenosine A3 receptor antagonist; adrenomedullin ligands; AKT1 gene inhibitors; antibiotics; antifungals; ASK1 inhibitors; ATPase inhibitors; beta adrenoceptor antagonists; BTK inhibitors; calcineurin inhibitors; carbohydrate metabolism modulators; cathepsin S inhibitors; CCR9 chemokine antagonists; CD233 modulators; CD29 modulators; CD3 antagonists; CD40 ligand inhibitors; CD40 ligand receptor antagonists; chemokine CXC ligand inhibitors; CHST15 gene inhibitors; collagen modulators; CSF-1 antagonists; CX3CR1 chemokine modulators; ecobiotics; eotaxin ligand inhibitors; EP4 prostanoid receptor agonists; FI FO ATP synthase modulators; farnesoid
  • the one or more other therapeutic agents is an anti-inflammatory agent.
  • Anti-inflammatory agents include but are not limited to NSAIDs, non-specific and COX-2 specific cyclooxgenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptors antagonists, immunosuppressants and methotrexate.
  • Non- limiting examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine, tolmetin sodium, and hydroxychloroquine.
  • NSAIDs also include COX-2 specific inhibitors (i.e., a compound that inhibits COX-2 with an IC50 that is at least 50-fold lower than the IC50for COX-1) such as celecoxib, valdecoxib, lumiracoxib, etoricoxib and/or rofecoxib.
  • the anti-inflammatory agent is a salicylate.
  • Salicylates include, but are not limited to, acetylsalicylic acid or aspirin, sodium salicylate, and choline and magnesium salicylates.
  • the anti-inflammatory agent can also be a corticosteroid.
  • the corticosteroid can be chosen from cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, and prednisone.
  • the anti-inflammatory therapeutic agent is a gold compound such as gold sodium thiomalate or auranofin.
  • the anti-inflammatory agent is a metabolic inhibitor such as a dihydrofolate reductase inhibitor, such as methotrexate or a dihydroo rotate dehydrogenase inhibitor, such as leflunomide.
  • the anti-inflammatory compound is an anti-C5 monoclonal antibody (such as eculizumab or pexelizumab), a TNF antagonist, such as entanercept, or infliximab, which is an anti-TNF alpha monoclonal antibody.
  • a compound described herein is administered in combination with an immunosuppressant.
  • the immunosuppressant is methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, or mycophenolate mofetil.
  • an AHR agonist compound described herein is administered in combination with a class of agent for treatment of IBD.
  • classes of agents for treatment of IBD include ASK1 inhibitors, beta adrenoceptor antagonists, BTK inhibitors, beta-glucuronidase inhibitors, bradykinin receptor modulators, calcineurin inhibitors, calcium channel inhibitors, cathepsin S inhibitors, CCR3 chemokine antagonists, CD40 ligand receptor antagonists, chemokine CXC ligand inhibitors, CHST15 gene inhibitors, collagen modulators, CSF-1 antagonists, cyclooxygenase inhibitors, cytochrome P450 3A4 inhibitors, eotaxin ligand inhibitors, EP4 prostanoid receptor agonists, erythropoietin receptor agonists, fractalkine ligand inhibitors, free fatty acid receptor 2 antagonists, G
  • agents for treatment of IBD include those provided herein for the treatment of an inflammatory disease or condition, and ABX- 464, adalimumab; alicaforsen, ALLO-ASC-CD, AMG-966, anakinra, apremilast; Alequel; AMG- 139; amiselimod, ASD-003, ASP-3291 , AX-1505, BBT-401 , balsalazide; beclomethasone dipropionate; BI-655130, BMS-986184; budesonide; CEQ-508; certolizumab; ChAdOx2-HAV, dexamethasone sodium phosphate
  • Step 2 1H-Indol-3-yl-[6-(trifluoromethyl)-2-pyridyl]methanone [00175] To a solution of indole (15.09 g, 128.85 mmol, 1.5 eq) in DCE (400 mL) was added 6-(trifluoromethyl)pyridine-2-carbonyl chloride (18 g, 85.90 mmol, N/A purity, 1 eq) in DCE (500 mL) at 0 °C under N 2 atmosphere.
  • Step 4 6-(1H-Indole-3-carbonyl)pyridine-2-carbonitrile
  • indole 73.50 mg, 627.38 ⁇ mol, 1.1 eq
  • DCE 3 mL
  • 6-cyanopyridine-2-carbonyl chloride 100 mg, 570.35 ⁇ mol, 1 eq
  • AlCl 3 228.15 mg, 1.71 mmol, 3 eq
  • the mixture was stirred at 45 °C for 16 h under N 2 atmosphere.
  • the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3).
  • Step 2 1H-Indol-3-yl-(6-methoxy-2-pyridyl)methanone [00181] To a solution of indole (107.02 mg, 913.56 ⁇ mol, 1.1 eq) in THF (3 mL) at 0 °C under N 2 was added a solution of 6-methoxypyridine-2-carbonyl chloride (150 mg, 830.51 ⁇ mo, 1 eq) in THF (3 mL). AlCl 3 (332.22 mg, 2.49 mmol, 3 eq) was added under N 2 . The mixture was stirred at 50 °C for 16 h under N2 atmosphere.
  • Step 2 (2-Chloropyrimidin-4-yl)-(1H-indol-3-yl)methanone [00184] To a solution of indole (1.44 g, 12.31 mmol, 1.1 eq) in DCM (10 mL) was added chloro(diethyl)alumane (1 M, 22.37 mL, 2 eq) dropwise at -70 o C. The mixture was stirred at -70 o C for 30 min.
  • Step 3 1H-Indol-3-yl-(2-methoxypyrimidin-4-yl)methanone [00185] To a solution of Na (24.54 mg, 1.07 mmol, 25.29 ⁇ L, 5 eq) in MeOH (5 mL) was stirred at 20 o C for 2 h. (2-Chloropyrimidin-4-yl)-(1H-indol-3-yl)methanone (55 mg, 213.45 ⁇ mol, 100.0% purity, 1 eq) was added to the mixture. The mixture was stirred at 20 o C for 2 h.
  • reaction mixture was concentrated to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C 18150 * 25 mm * 5 ⁇ m; mobile phase: [water (0.05% NH 3 H 2 O+10 mM NH 4 HCO 3 )-ACN]; B%: 27%-57%, 10 min), followed by lyophilization to yield 1H-indol-3-yl-(2-methoxypyrimidin-4-yl)methanone (35.53 mg, 140.29 ⁇ mol, 65.7% yield, 100.0% purity) as a light green solid.
  • Step 1 Methyl (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-(4-formyl-2-nitro- phenoxy)tetrahydropyran-2-carboxylate [00186] To a solution of methyl (2S,3S,4S,5R,6R)-3,4,5-triacetoxy-6-bromo-tetrahydropyran- 2-carboxylate (1.5 g, 3.78 mmol, 1 eq) and 4-hydroxy-3-nitro-benzaldehyde (631.16 mg, 3.78 mmol, 1 eq) in ACN (20 mL) was added Ag2O (4.38 g, 18.88 mmol, 5 eq) under N2 atmosphere.
  • Step 2 Methyl (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-[4-(hydroxymethyl)-2-nitro- phenoxy]tetrahydropyran-2-carboxylate [00187] To a solution of methyl (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-(4-formyl-2-nitro- phenoxy)tetrahydropyran-2-carboxylate (1.5 g, 2.79 mmol, 90%, 1 eq) in DCM (20 mL) and i- PrOH (4 mL) was added NaBH 4 (84.52 mg, 2.23 mmol, 0.8 eq) at 0 °C under N 2 atmosphere.
  • Step 3 [3-Nitro-4-[(2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-methoxycarbonyl-tetrahydropyran- 2-yl]oxy-phenyl]methyl 3-[6-(trifluoromethyl)pyridine-2-carbonyl]indole-1-carboxylate
  • Step 4 (2S,3S,4S,5R,6S)-3,4,5-Trihydroxy-6-[2-nitro-4-[[3-[6-(trifluoromethyl)pyridine-2- carbonyl]indole-1-carbonyl]oxymethyl]phenoxy]tetrahydropyran-2-carboxylic acid
  • reaction mixture was concentrated to yield a residue which was purified by preparative HPLC (column: Welch Xtimate C18150 * 25 mm * 5 ⁇ m; mobile phase: [water (10 mM NH 4 HCO 3 )-ACN]; B%: 22%- 52%, 10 min) and lyophilized to yield (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-[2-nitro-4-[[3-[6- (trifluoromethyl)pyridine-2-carbonyl]indole-1-carbonyl]oxymethyl]phenoxy]tetrahydropyran-2- carboxylic acid (11.03 mg, 16.58 ⁇ mol, 26.6% yield, 99.4% purity) as a white solid.
  • Step 2 (6-Methoxy-1H-indol-3-yl)-(6-methoxy-2-pyridyl)methanone [00191] To a solution of 6-methoxy-1H-indole (94.12 mg, 639.49 ⁇ mol, 1.1 eq) in THF (5 mL) at 0 °C under N 2 was added a solution of 6-methoxypyridine-2-carbonyl chloride (105 mg, 581.36 ⁇ mol, 1 eq) in THF (5 mL). AlCl3 (77.52 mg, 581.36 ⁇ mol, 31.77 ⁇ L, 1 eq) was added under N2. The mixture was stirred at 50 °C for 6 h under N2.
  • Step 4 (6-Ethoxy-2-pyridyl)-(1H-indol-3-yl)methanone [00195] To a solution of indole (239.84 mg, 2.05 mmol, 2 eq) in DCM (6 mL) was added dropwise 6-ethoxypyridine-2-carbonyl chloride (200 mg, 1.02 mmol, 95% purity, 1 eq)at 0 °C. AlCl3 (272.99 mg, 2.05 mmol, 111.88 ⁇ L, 2 eq) was added dropwise at 0 °C. The resulting mixture was stirred at 20 °C for 12 h.
  • Step 3 Benzyl N-[6-chloro-2-(trifluoromethyl)-3-pyridyl]carbamate
  • Step 4 Methyl 5-(benzyloxycarbonylamino)-6-(trifluoromethyl)pyridine-2-carboxylate [00199] To a solution of benzyl N-[6-chloro-2-(trifluoromethyl)-3-pyridyl]carbamate (500 mg, 1.25 mmol, 1 eq) in MeOH (10 mL) was added TEA (380.96 mg, 3.76 mmol, 524.02 ⁇ L, 3 eq) and Pd(dppf)Cl 2 (91.83 mg, 125.50 ⁇ mol, 0.1 eq). The suspension was degassed under vacuum and purged with CO several times.
  • Step 5 5-(Methoxycarbonylamino)-6-(trifluoromethyl)pyridine-2-carboxylic acid [00200] To a solution of methyl 5-(benzyloxycarbonylamino)-6-(trifluoromethyl)pyridine-2- carboxylate (330 mg, 745.17 ⁇ mol, 1 eq) in MeOH (3 mL) was added LiOH (1 M, 3.73 mL, 5 eq). The mixture was stirred at 25 °C for 2 h.
  • Step 6 Methyl N-[6-chlorocarbonyl-2-(trifluoromethyl)-3-pyridyl]carbamate
  • N-[6-chlorocarbonyl-2-(trifluoromethyl)-3-pyridyl]carbamate To a solution of 5-(methoxycarbonylamino)-6-(trifluoromethyl)pyridine-2-carboxylic acid (100 mg, 264.99 ⁇ mol, 1 eq) in DCM (3 mL) was added (COCl) 2 (100.91 mg, 794.98 ⁇ mol, 69.59 ⁇ L, 3 eq). The mixture was stirred at 25 °C for 2 h.
  • Step 7 Methyl N-[6-(1H-indole-3-carbonyl)-2-(trifluoromethyl)-3-pyridyl]carbamate [00202] To a solution of indole (34.82 mg, 297.24 ⁇ mol, 1.2 eq) in DCM (3 mL) were added AlCl 3 (33.03 mg, 247.70 ⁇ mol, 1 eq) and methyl N-[6-chlorocarbonyl-2-(trifluoromethyl)-3- pyridyl]carbamate (70 mg, 247.70 ⁇ mol, 1 eq).
  • Step 8 [5-Amino-6-(trifluoromethyl)-2-pyridyl]-(1H-indol-3-yl)methanone [00203] To a solution of methyl N-[6-(1H-indole-3-carbonyl)-2-(trifluoromethyl)-3- pyridyl]carbamate (30 mg, 74.32 ⁇ mol, 1 eq) in H 2 O (1 mL) and EtOH (1 mL) was added KOH (20.85 mg, 371.60 ⁇ mol, 5 eq). The mixture was stirred at 80 °C for 2 h.
  • Step 2 1H-Benzo[g]indole [00205] To a solution of (E)-N,N-dimethyl-2-(1-nitro-2-naphthyl)ethenamine (2.8 g, 10.40 mmol, 90%, 1 eq) in EtOH (40 mL) and H 2 O (5 mL) was added Fe (2.90 g, 52.01 mmol, 5 eq) and NH 4 Cl (5.56 g, 104.02 mmol, 10 eq). The mixture was stirred at 80 °C for 6 h. The mixture was filtered, and the filter cake was rinsed with PE (10 mL x 2), dried to yield a residue.
  • PE 10 mL x 2
  • Step 3 1H-Benzo[g]indole-3-carbaldehyde
  • POCl3 660.26 mg, 4.31 mmol, 400.16 ⁇ L, 1.2 eq
  • DMF 2 mL
  • 1H-benzo[g]indole 600 mg, 3.59 mmol, 100%, 1 eq
  • DMF 0.7 mL
  • the reaction mixture was quenched by addition of water (50 mL), extracted with EtOAc (30 mL x 3).
  • Step 4 1-(2-Trimethylsilylethoxymethyl)benzo[g]indole-3-carbaldehyde [00207] To a solution of 1H-benzo[g]indole-3-carbaldehyde (570 mg, 2.92 mmol, 100%, 1 eq) in THF (10 mL) was added NaH (291.96 mg, 7.30 mmol, 60%, 2.5 eq) at 0 °C. After stirring 30 min, SEM-Cl (973.60 mg, 5.84 mmol, 1.03 mL, 2 eq) was added to the above mixture dropwise and stirred at 0 °C for 1 h.
  • Step 6 Methyl 5-(benzhydrylideneamino)-2-[1-(2- trimethylsilylethoxymethyl)benzo[g]indole-3-carbonyl]thiazole-4-carboxylate [00209] To a solution of methyl 5-(benzhydrylideneamino)-2-[hydroxy-[1-(2- trimethylsilylethoxymethyl)benzo[g]indol-3-yl]methyl]thiazole-4-carboxylate (1 g, 864.39 ⁇ mol, 56%, 1 eq) in 1,2-dichlorethane (15 mL) was added MnO2 (1.50 g, 17.29 mmol, 20 eq).
  • the mixture was stirred at 80 °C for 1 h.
  • the mixture was filtered, and the filter cake was rinsed with PE (10 mL x 2), dried to yield a residue.
  • the reaction mixture was quenched by addition of water (50 mL), extracted with EtOAc (30 mL x 3).
  • Step 7 Methyl 5-amino-2-(1H-benzo[g]indole-3-carbonyl)thiazole-4-carboxylate [00210] To a solution of methyl 5-(benzhydrylideneamino)-2-[1-(2- trimethylsilylethoxymethyl)benzo[g]indole-3-carbonyl]thiazole-4-carboxylate (480 mg, 668.90 ⁇ mol, 90%, 1 eq) in DCM (10 mL) was added TFA (2.22 g, 19.45 mmol, 1.44 mL, 29.08 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated at 25 °C to yield a residue.
  • Step 2 Methyl 5-((diphenylmethylene)amino)-2-(hydroxy(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)thiazole-4- carboxylate [00212] To a stirred solution of DIPA (593.24 mg, 5.86 mmol, 828.55 ⁇ L, 3 eq) in THF (60 mL) was added n-BuLi (2.5 M, 2.35 mL, 3 eq) dropwise under N 2 atmosphere at -75 °C.
  • Step 3 Methyl 5-((diphenylmethylene)amino)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridine-3-carbonyl)thiazole-4-carboxylate [00213] To a solution of methyl 5-(benzhydrylideneamino)-2-[hydroxy-[1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-3-yl]methyl]thiazole-4-carboxylate (500 mg, 751.52 ⁇ mol, 90.0% purity, 1 eq) in CHCl3 (10 mL) was added MnO2 (1.96 g, 22.55 mmol, 30 eq).
  • Step 4 Methyl 5-amino-2-(1-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridine-3- carbonyl)thiazole-4-carboxylate [00214] To a solution of methyl 5-(benzhydrylideneamino)-2-[1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-3-carbonyl]thiazole-4-carboxylate (400 mg, 603.25 ⁇ mol, 90% purity, 1 eq) in DCM (1 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 22.39 eq) at 23 °C.
  • Step 5 Methyl 5-amino-2-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)thiazole-4-carboxylate [00215] To a solution of methyl 5-amino-2-[1-(hydroxymethyl)pyrrolo[2,3-b]pyridine-3- carbonyl]thiazole-4-carboxylate (200 mg, 601.80 ⁇ mol, N/A purity, 1 eq) in THF (100 mL) was added KOH (5 M, 120.36 ⁇ L, 1 eq). The mixture was stirred under N2 atmosphere at 25 °C for 0.1 h. The mixture was adjusted pH to 7 with 1 N HCl and extracted with EtOAc (20 mL x 3).
  • Step 1 Methyl 3-(4-isopropylthiazole-2-carbonyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxylate [00216] To a solution of 4-isopropylthiazole-2-carbonyl chloride (172.25 mg, 908.20 ⁇ mol, 1 eq) in DCM (5 mL) was added AlCl 3 (605.50 mg, 4.54 mmol, 5 eq) and methyl 1H-pyrrolo[2,3- b]pyridine-6-carboxylate (160 mg, 908.20 ⁇ mol, 1 eq). The mixture was stirred at 75 °C for 12 h.
  • Step 2 2-Isopropyl-N,N-dimethyl-imidazole-1-sulfonamide
  • 2-isopropyl-1H-imidazole (2 g, 18.16 mmol, 1 eq) in DMF (20 mL) was added NaH (2.18 g, 54.47 mmol, 60%, 3 eq).
  • N,N- dimethylsulfamoyl chloride (3.39 g, 23.60 mmol, 2.53 mL, 1.3 eq) was added at 0 °C under N2.
  • the mixture was stirred at 25 °C for 1 h.
  • Step 3 5-[Hydroxy-[1-(2-trimethylsilylethoxymethyl)indazol-3-yl]methyl]-2-isopropyl-N,N- dimethyl-imidazole-1-sulfonamide
  • 2-isopropyl-N,N-dimethyl-imidazole-1-sulfonamide (495.84 mg, 2.23 mmol, 97.9%, 1.3 eq) in THF (20 mL) was added n-BuLi (2.5 M, 2.06 mL, 3 eq) at -70 °C under N2. After being stirred for 30 min, the solution was warmed to 0 °C, left stirred another 30 min.
  • Step 4 2-Isopropyl-N,N-dimethyl-5-[1-(2-trimethylsilylethoxymethyl)indazole-3- carbonyl]imidazole-1-sulfonamide
  • DCE dimethyl sulfoxide
  • Step 5 (2-Isopropyl-1H-imidazol-5-yl)-[1-(2-trimethylsilylethoxymethyl)indazol-3- yl]methanone [00222] To a solution of 2-isopropyl-N,N-dimethyl-5-[1-(2- trimethylsilylethoxymethyl)indazole-3-carbonyl]imidazole-1-sulfonamide (75 mg, 152.54 ⁇ mol, 1 eq) in THF (5 mL) was added conc. HCl (12 M, 1 mL, 78.67 eq) under N 2 . The mixture was stirred at 20 °C for 2 h.
  • Step 6 1H-Indazol-3-yl-(2-isopropyl-1H-imidazol-5-yl)methanone [00223] To a solution of (2-isopropyl-1H-imidazol-5-yl)-[1-(2- trimethylsilylethoxymethyl)indazol-3-yl]methanone (52 mg, 135.22 ⁇ mol, 1 eq) in DCM (10 mL) was added TFA (4.62 g, 40.52 mmol, 3 mL, 299.64 eq) under N 2 . The mixture was stirred at 20 °C for 12 h.
  • reaction mixture was concentrated to yield a residue which was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5 ⁇ m; mobile phase: [water (0.05% NH3H 2 O+10mM NH4HCO3)-ACN]; B%: 25%- 55%, 10 min), followed by lyophilization to yield 1H-indazol-3-yl-(2-isopropyl-1H-imidazol-5- yl)methanone (15.75 mg, 61.94 ⁇ mol, 45.8% yield, 100% purity) as a white solid.
  • AHR activity is activation of a reporter gene, such as luciferase, downstream of one or multiple DRE elements. Luciferase activity will reflect activation and inhibition of AHR in the cells expressing this reporter.
  • a reporter gene such as luciferase
  • Luciferase activity will reflect activation and inhibition of AHR in the cells expressing this reporter.
  • Murine Hepa1-6 or Hepa-1c1c7 or other murine cell line with a DRE-luciferase reporter either stably or transiently transfected are plated in media in plates (96-well, 384-well or other plates) and incubated overnight at 37C in a CO2 incubator.
  • human HepG2 or other human cell line with a DRE-luciferase reporter either stably or transiently transfected are plated in media in plates (96-well, 384-well or other plates) and incubated overnight at 37C in a CO2 incubator.
  • an AHR agonist compound is added. Cells are incubated for 6, 16 or 24 hours or another time point and then lysed for determination of luciferase activity as a read-out of the AHR activation.
  • Luciferase can be measured with a commercial kit such as the Promega Luciferase kit or any kit or reagents that provide the luciferin substrate for measuring luciferase activity.
  • the level of luciferase with only activating ligand e.g. such as TCDD, kynurenine, ITE (2-(1H-indole-3-ylcarbonyl)-4-thiazolecarboxylic methyl ester), VAF347, BNF (beta- naphthoflavone), ICZ (6-formylindolo(3,2-b) carbazole or other AHR ligands) added is the maximum signal while the luciferase with no ligand is the minimum signal.
  • EC50s can be determined as the concentration which activates half of the maximum luciferase activity. [00227] In some embodiments, compounds have an EC50 > 1 ⁇ M.
  • compounds have an EC50 ⁇ 1 ⁇ M. In some embodiments, compounds have an EC50 ⁇ 0.1 ⁇ M. In some embodiments, compounds have an EC50 ⁇ 0.01 ⁇ M.
  • DRE Dioxin Responsive Elements
  • One measure of AHR activity is P450 CYP1A1 protein levels determined by measuring CYP1A1 enzyme activity using a luminogenic CYP1A1 luciferin-based substrate. Luciferase activity will reflect CYP1A1 activity resulting from activation of AHR in the cells.
  • Murine Hepa1-6 or Hepa-1c1c7 or other murine cell line, human HepG2 or other human cell line are plated in media (96-well, 384-well or other plates) and incubated overnight at 37C in a CO2 incubator.
  • an AHR agonist compound is added. Cells are incubated for 6, 16 or 24 hours or another time point and then lysed and incubated with a CYP1A1 luciferase-based substrate (e.g., Luciferin-CEE) for 3, 6, or 12 hours of another time point.
  • a CYP1A1 luciferase-based substrate e.g., Luciferin-CEE
  • Determination of luciferase activity as a read-out of CYP1A1 enzyme activity can be measured with a commercial kit such as the Promega P450 Glo CYP1A1 detection reagent or any kit or reagents that provide for measuring luciferase activity.
  • the level of luciferase with only activating ligand e.g., such as TCDD, kynurenine, ITE (2-(1H-indole-3-ylcarbonyl)-4-thiazolecarboxylic methyl ester), VAF347, BNF (beta-naphthoflavone), ICZ (6-formylindolo(3,2-b) carbazole or other AHR ligands) added is the maximum signal while the luciferase with no ligand is the minimum signal.
  • EC50s can be determined as the concentration which activates half of the maximum luciferase activity.
  • mice are dosed orally with one dose of the AHR agonist compound(s) that are in a suspension and mixed well before dosing.
  • animals are euthanized and plasma and tissue taken for compound levels (PK) and compound effect (PD) on gene expression. Liver samples and proximal colon are weighed and then frozen for subsequent RNA extraction and RT-PCR analysis.
  • AHR activation is determined by measuring Cyp1a1 gene expression relative to a housekeeping gene, such as GAPDH or HPRT. Cyp1a1 expression levels in the liver are compared to Cyp1a1 levels in the colon to determine a colon:liver ratio, in order to assess the level of “GI-preferred” AHR activation.
  • Example 4 DSS IBD Study Method
  • C57Bl/6 mice are weighed and randomized into treatment groups based on body weight.
  • treatment groups are given 2.5% DSS in drinking water and treatment is initiated on the same day, with either vehicle or AHR agonist compound(s).
  • DSS drinking water is replaced with normal drinking water for the remainder of the study.
  • Body weight is measured daily during the entire study.
  • animals are anesthetized with Isoflurane and bled to exsanguination followed by cervical dislocation. The entire colon is removed and measured for length, weight, and weight per length.
  • test AR agonist compounds is based on body weight, colon length, and colon histopathology.
  • Histopathology data is assessed for appropriate parameters, as determined by a pathologist and the parameters for these DSS studies can include inflammation, erosion, gland loss, edema, hyperplasia, neutrophil count ,mucosal thickening, lymphoid aggregate count and lymphoid aggregate size. The different parameter scores can be added for a summed score for the study histopathology.
  • Example 5 Th17 Assay
  • naive CD62L+ human T-Cells are plated in a 96 well plate (25,000 cells in 200uL media).
  • Cells are activated with human CD3/CD28 tetramer (12.5 ⁇ L/1x10 6 cells) and differentiated with human Th17 cytokines (50 ng/mL IL-6, 20 ng/mL IL-1 ⁇ , 10 ng/mL IL-23, 1 ng/mL TGF- ⁇ , 12 ⁇ g/mL anti-human IFN- o antibody and 10 ⁇ g/mL anti-human IL-4 antibody) for 10 days. Media containing cytokine cocktail and CD3/CD28 is refreshed every 2-3 days. [00239] On Day 10, cell supernatant is collected and frozen for cytokine analysis. Cells are stimulated with 1x Cell Stimulation Cocktail (PMA and Ionomycin) for 5 hours.
  • PMA and Ionomycin 1x Cell Stimulation Cocktail
  • cytokines human CD4, IL-17A, IL-22.
  • Samples are run on BD LSR FORTESSA and analyzed in FLOWJO software.
  • Treg Assay On day 0, na ⁇ ve T cells from cryopreserved human derived PBMCs are isolated. These cells are plated in 48 well plate at 500,000 cells/mL concentration with human CD3/CD28 activation tetramer (12.5 ⁇ L/1x10 6 cells) and differentiated into regulatory T cells (Tregs) with 1 ng/mL TGF- ⁇ and 5 ng/mL human recombinant IL-2 in the presence of DMSO or different concentrations of AHR agonist compounds.
  • Tregs regulatory T cells
  • Tregs are counted and washed.
  • CD25- Effector T cells (Teffs) are isolated from the same human donor and labeled with Cell Trace Violet.
  • the Tregs and Teffs are cocultured for 4 days in 96 well plate at 1:2 or 1:1 ratio with human CD3/CD28 tetramer (12.5 ⁇ L/1x10 6 cells).
  • Teffs CD25- Effector T cells
  • the Tregs and Teffs are cocultured for 4 days in 96 well plate at 1:2 or 1:1 ratio with human CD3/CD28 tetramer (12.5 ⁇ L/1x10 6 cells).
  • the cells are washed and stained with LiveDead stain. The cells are run on a flow cytometer and analyzed using FLOWJO software.
  • Example 7 T cell Transfer IBD model
  • donor Balb/C mice are terminated, and spleens obtained for CD4 + CD45RB high cell isolation (Using a SCID IBD Cell Separation Protocol). After cells have been sorted and obtained, each recipient SCID animal receives an IP injection of, at a minimum, 4 X 10 5 cells (200 ⁇ l/mouse injections).
  • SCID mice are weighed and randomized into treatment groups based on body weight. On study day 14, AHR agonist compound treatments are initiated and dosed orally daily; the control group receiving anti-IL12 (0.5 mg/mouse) is dosed IP once a week.
  • Crohn’s Disease or ulcerative colitis donor samples are obtained with full ethical consent from patients undergoing therapeutic resection for Crohn’s disease or ulcerative colitis.
  • a minimum of 18 x 5 mm 2 mucosal biopsies are taken using a scalpel.
  • Three baseline biopsy samples are collected at time 0, and a minimum of 9 biopsies are incubated in 12 well culture plates. Tissues are placed apical (mucosal) side facing upwards on a Netwell filter.
  • the biopsies are then cultured in either control media or media fortified with the appropriate AHR agonist compound in an incubator at 37 °C and high O2 atmospheric conditions (95% O2/5% CO2).
  • the biopsies are cultured in the presence of the inflammatory stimulant Staphylococcal Enterotoxin B (SEB) to normalize cytokine levels.
  • SEB Staphylococcal Enterotoxin B
  • the positive control BIRB796 (Selleck Chemicals catalogue No: S1574) is purchased as a powder. A 1 mM stock solution is prepared in DMSO and used at 1 ⁇ M. At approximately 18 hours post-culture start, media samples are collected, protease inhibitor is added and samples are stored at -80 °C.
  • cytokine analysis is collected at the 18-hour timepoint and divided into aliquots for cytokine analysis: analysis of cytokines, such as TNF- ⁇ , IFN- o, IL-1 ⁇ , IL17- ⁇ , IL-22, and IL-10) are performed in duplicate after completion of each set of 3 donors.

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Abstract

The present invention provides AHR agonists, composites thereof, and methods of using the same.

Description

ARYL HYDROCARBON RECEPTOR (AHR) AGONISTS AND USES THEREOF TECHNICAL FIELD OF THE INVENTION [0001] The present invention relates to compounds and methods useful for activating aryl hydrocarbon receptor (AHR). The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders. BACKGROUND [0002] The aryl hydrocarbon receptor (AHR) is a ligand-inducible transcription factor that mediates a number of important biological and pharmacological processes. AHR agonists have been shown to be potentially useful for treating disorders such as cancer (U.S. Patent 8,604,067, Wang et al., 2013, Cheng et al., 2015), obesity (U.S. Patent 7,419,992), and conditions related to imbalanced actions of the immune system (Quintana et al., 2010, Nugent et al., 2013). AHR has also been shown to be involved in immune regulation, hematopoiesis, cell cycle, carcinogenesis and in the maintenance of intestinal barrier integrity and homeostasis. SUMMARY OF THE INVENTION [0003] It has now been found that compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective as AHR agonists. In one aspect, the instant invention provides a compound of formula (I):
Figure imgf000002_0001
(I), or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein. [0004] Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with AHR. Such diseases, disorders, or conditions include, for example, cancer, obesity, and inflammatory disorders as described herein. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description of Certain Embodiments of the Invention: [0005] Compounds of the present invention, and pharmaceutical compositions thereof, are useful as AHR agonists. Without wishing to be bound by any particular theory, it is believed that compounds of the present invention, and pharmaceutical compositions thereof, may activate AHR and thus treat certain diseases, disorders, or conditions associated with AHR, such as those described herein. [0006] It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as AHR agonists. In one aspect, the present invention provides a compound of Formula (I):
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, wherein: Ring A is an optionally substituted 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S, or an optionally substituted 6-10 membered bicyclic or bridged bicyclic saturated or partially unsaturated carbocyclic ring; Ring B is selected from
Figure imgf000003_0002
wh 6 2 4 1
Figure imgf000003_0003
erein X is N or CR ; Y is N or CR ; Z is N or CR ; and W is NR , O, or S; each of R1, R2, R3, R4, and R6 is independently halogen, -CN, -NO2, RW, -C(O)-RW, -C(=NRW)- RW, -N(RW)-C(O)-RW, -N(RW)-C(=NRW)-RW, -OC(O)-RW, -OC(=NRW)-RW, -S(O)2-RW, - N(RW)-S(O)2-RW, -OS(O)2-RW, -S(O)-RW, -N(RW)-S(O)-RW, or -OS(O)-RW; R5 is -R, -C(O)-RW, -C(=NRW)-RW, -S(O)2-RW, or -S(O)-RW; RW is -R, -N(R)2, -NR-OR, -N(R)-N(R)2, -N(OR)-N(R)2, -N(R)-N(OR)R, -OR, -O-N(R)2, -N=NR, or –SR; and R is hydrogen, optionally substituted C1-6 aliphatic, or an optionally substituted ring selected from a 3-7 membered carbocyclic ring, a 3-7 membered heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, phenyl, and a 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S, or two R’s together with the nitrogen to which they attach form an optionally substituted 4-7 membered heterocyclic ring having 0-2 heteroatoms independently selected from N, O, or S in addition to the nitrogen to which the two R’s attach, provided that, when Ring A is an optionally substituted 5-membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S, at least one of X, Y, and Z of is N, and with the proviso that the compound is not
Figure imgf000004_0001
. 2. Compounds and Definitions: [0007] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. [0008] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle," “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. [0009] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include:
Figure imgf000006_0001
Exemplary bridged bicyclics include:
Figure imgf000006_0002
[0010] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. [0011] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms. [0012] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)). [0013] The term “unsaturated”, as used herein, means that a moiety has one or more units of unsaturation. [0014] As used herein, the term “bivalent C1-8 (or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein. [0015] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., –(CH2)n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. [0016] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. [0017] As used herein, the term “cyclopropylenyl” refers to a bivalent cyclopropyl group of the following structure:
Figure imgf000007_0001
. [0018] The term “halogen” means F, Cl, Br, or I. [0019] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. [0020] The terms “heteroaryl” and “heteroar–,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin–3(4H)–one. A heteroaryl group may be mono– or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. [0021] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4–dihydro– 2H–pyrrolyl), NH (as in pyrrolidinyl), or +NR (as in N–substituted pyrrolidinyl). [0022] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono– or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. [0023] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined. [0024] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. [0025] Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; –(CH2)0–4R º; –(CH2)0–4OR º; -O(CH2)0-4Ro, –O–(CH2)0– 4C(O)OR°; –(CH2)0–4CH(OR º)2; –(CH2)0–4SR º; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; – N3; -(CH2)0–4N(R º)2; –(CH2)0–4N(R º)C(O)R º; –N(R º)C(S)R º; –(CH2)0– 4N(R º)C(O)NR º2; -N(R º)C(S)NR º2; –(CH2)0–4N(R º)C(O)OR º; – N(R º)N(R º)C(O)R º; -N(R º)N(R º)C(O)NR º2; -N(R º)N(R º)C(O)OR º; –(CH2)0–4C(O)R º; – C(S)R º; –(CH2)0–4C(O)OR º; –(CH2)0–4C(O)SR º; -(CH2)0–4C(O)OSiR º3; –(CH2)0–4OC(O)R º; – OC(O)(CH2)0–4SR–, SC(S)SR°; –(CH2)0–4SC(O)R º; –(CH2)0–4C(O)NR º2; –C(S)NR º2; –C(S)SR°; –SC(S)SR°, -(CH2)0–4OC(O)NR º2; -C(O)N(OR º)R º; –C(O)C(O)R º; –C(O)CH2C(O)R º; – C(NOR º)R º; -(CH2)0–4SSR º; –(CH2)0–4S(O)2R º; –(CH2)0–4S(O)2OR º; –(CH2)0–4OS(O)2R º; – S(O)2NR º2; –S(O)(NR°)R°; –S(O)2N=C(NR°2)2; -(CH2)0–4S(O)R º; -N(R º)S(O)2NR º2; – N(R º)S(O)2R º; –N(OR º)R º; –C(NH)NR º2; –P(O)2R º; -P(O)R º2; -OP(O)R º2; –OP(O)(OR º)2; SiR º3; –(C1–4 straight or branched alkylene)O–N(R º)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R º)2. [0026] Each R º is independently hydrogen, C1–6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R º, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by a divalent substituent on a saturated carbon atom of R º selected from =O and =S; or each R º is optionally substituted with a monovalent substituent independently selected from halogen, – (CH2)0–2R ●, –(haloR ●), –(CH2)0–2OH, –(CH2)0–2OR ●, –(CH2)0–2CH(OR ●)2; -O(haloR ●), –CN, –N3, –(CH2)0–2C(O)R ●, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR ●, –(CH2)0–2SR ●, –(CH2)0–2SH, –(CH2)0– 2NH2, –(CH2)0–2NHR ●, –(CH2)0–2NR ●2, –NO2, –SiR ●3, –OSiR ●3, -C(O)SR ●, –(C1–4 straight or branched alkylene)C(O)OR ●, or –SSR ●. [0027] Each R ● is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5– 6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ● is unsubstituted or where preceded by halo is substituted only with one or more halogens; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R* 2))2–3O–, or – S(C(R* 2))2–3S–, or a divalent substituent bound to vicinal substitutable carbons of an “optionally substituted” group is –O(CR*2)2–3O–, wherein each independent occurrence of R* is selected from hydrogen, C1–6 aliphatic or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0028] When R* is C1–6 aliphatic, R* is optionally substituted with halogen, – R ●, -(haloR ●), -OH, –OR ●, –O(haloR ●), –CN, –C(O)OH, –C(O)OR ●, –NH2, –NHR ●, –NR ●2, or – NO2, wherein each R ● is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ● is unsubstituted or where preceded by halo is substituted only with one or more halogens. [0029] An optional substituent on a substitutable nitrogen is independently –R†, –NR† 2, –
Figure imgf000011_0001
C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R† is independently hydrogen, C1–6 aliphatic, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when R† is C1–6 aliphatic, R† is optionally substituted with halogen, –R ●, -(haloR ●), -OH, –OR ●, –O(haloR ●), – CN, –C(O)OH, –C(O)OR ●, –NH2, –NHR ●, –NR ●2, or –NO2, wherein each R ● is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ● is unsubstituted or where preceded by halo is substituted only with one or more halogens. [0030] As used herein, 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, S. M. 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 this invention 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 used 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, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. [0031] 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, loweralkyl sulfonate and aryl sulfonate. [0032] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. [0033] As used herein, the term “agonist” is defined as a compound that binds to and/or activates AHR with measurable affinity. In certain embodiments, an agonist has an IC50 and/or binding constant of less than about 100 ^M, less than about 50 ^M, less than about 1 ^M, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. [0034] The terms “measurable affinity” and “measurably activate,” as used herein, means a measurable change in AHR activity between a sample comprising a compound of the present invention, or composition thereof, and AHR, and an equivalent sample comprising AHR, in the absence of said compound, or composition thereof. 3. Description of Exemplary Embodiments: [0035] In one aspect, the present invention provides a compound of Formula (I):
Figure imgf000013_0001
or a pharmaceutically acceptable salt thereof, wherein: Ring A is an optionally substituted 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S, or an optionally substituted 6-10 membered bicyclic or bridged bicyclic saturated or partially unsaturated carbocyclic ring;
Figure imgf000013_0002
wherein X is N or CR6; Y 2 4 1
Figure imgf000013_0003
is N or CR ; Z is N or CR ; and W is NR , O, or S; each of R1, R2, R3, R4, and R6 is independently halogen, -CN, -NO2, RW, -C(O)-RW, -C(=NRW)- RW, -N(RW)-C(O)-RW, -N(RW)-C(=NRW)-RW, -OC(O)-RW, -OC(=NRW)-RW, -S(O)2-RW, - N(RW)-S(O)2-RW, -OS(O)2-RW, -S(O)-RW, -N(RW)-S(O)-RW, or -OS(O)-RW; R5 is -R, -C(O)-RW, -C(=NRW)-RW, -S(O)2-RW, or -S(O)-RW; RW is -R, -N(R)2, -NR-OR, -N(R)-N(R)2, -N(OR)-N(R)2, -N(R)-N(OR)R, -OR, -O-N(R)2, or –SR; and R is hydrogen, optionally substituted C1-6 aliphatic, or an optionally substituted ring selected from a 3-7 membered carbocyclic ring, a 3-7 membered heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, phenyl, and a 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S, or two R’s together with the nitrogen to which they attach form an optionally substituted 4-7 membered heterocyclic ring having 0-2 heteroatoms independently selected from N, O, or S in addition to the nitrogen to which the two R’s attach, provided that, when Ring A is an optionally substituted 5-membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S, at least one of X, Y, and Z of
Figure imgf000014_0001
, . [0036] As defined generally above, Ring A is an optionally substituted 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S, or an optionally substituted 6-10 membered bicyclic or bridged bicyclic saturated or partially unsaturated carbocyclic ring. [0037] In some embodiments, Ring A is an optionally substituted 5-membered heteroaromatic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S. In some embodiments, Ring A is an unsubstituted 5-membered heteroaromatic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S. In some embodiments, Ring A is a 5-membered heteroaromatic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S, which is substituted 1 or 2 times by R12, wherein each R12 is independently an optional substituent as defined above and described in embodiments herein. [0038] In some embodiments, Ring A is an optionally substituted 6-membered heteroaromatic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S. In some embodiments, Ring A is an unsubstituted 6-membered heteroaromatic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S. In some embodiments, Ring A is a 6-membered heteroaromatic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S, which is substituted 1 or 2 times by R12, wherein each R12 is independently an optional substituent as defined above and described in embodiments herein. [0039] In some embodiments, Ring A is optionally substituted
Figure imgf000015_0001
, , or
Figure imgf000015_0003
. In some embodiments, Ring A is optionally substituted
Figure imgf000015_0002
, , ,
Figure imgf000015_0004
, , , . In some embodiments, Ring A is optionally
Figure imgf000015_0005
Figure imgf000015_0006
each of which is substituted 1 or 2 times by R12, wherein each R12 is independently an optional substituent as defined above and described in embodiments herein. In some embodiments, Ring
Figure imgf000015_0007
Figure imgf000015_0008
each of which is substituted 1 or 2 times by R12, wherein each R12 is independently an optional substituent as defined above and described in embodiments herein. In some embodiments, Ring A is
Figure imgf000015_0009
, wherein each of R7 and R8 is independently an optional substituent as defined above and described in embodiments herein. In some embodiments, Ring A is
Figure imgf000016_0001
, wherein R12 is an optional substituent as defined above and described in embodiments herein. [0040] In some embodiments, Ring A is unsubstituted
Figure imgf000016_0002
, , . In some embodiments, Ring A is unsubstituted
Figure imgf000016_0003
Figure imgf000016_0004
[0041] In some embodiments, Ring A is optionally substituted
Figure imgf000016_0005
, , ,
Figure imgf000016_0006
Figure imgf000016_0007
, each of which is substituted 1 or 2 times by R12, wherein each R12 is independently an optional substituent as defined above and described in embodiments herein. In some embodiments,
Figure imgf000016_0008
Figure imgf000017_0001
, wherein each R12 is independently an optional substituent as defined above and described in embodiments herein. [0042] In some embodiments, Ring A is
Figure imgf000017_0002
, wherein each of R7 and R8 is independently an optional substituent as defined above and described in embodiments herein. In some embodiments, Ring A is , wherein each of R7 and R8 is independently an optional substituent as defined above and described in embodiments herein. [0043]
Figure imgf000017_0003
[0045] In some embodiments, Ring A is an optionally substituted 6-, 7-, 8-, 9-, or 10- membered bicyclic or bridged bicyclic saturated or partially unsaturated carbocyclic ring. In some embodiments, Ring A is an optionally substituted 6-membered bridged bicyclic saturated or partially unsaturated carbocyclic ring. In some embodiments, Ring A is an optionally substituted 7-membered bridged bicyclic saturated or partially unsaturated carbocyclic ring. In some embodiments, Ring A is an optionally substituted
Figure imgf000018_0001
. In some embodiments, Ring A is
Figure imgf000018_0002
, wherein each of R12 is independently an optional substituent as defined above and described in embodiments herein. [0046] In some embodiments, each of R7, R8, and R12 is independently halogen, -CN, -NO2, RW, -C(O)-RW, -C(=NRW)-RW, -N(RW)-C(O)-RW, -N(RW)-C(=NRW)-RW, -OC(O)-RW, - OC(=NRW)-RW, -S(O)2-RW, -N(RW)-S(O)2-RW, -OS(O)2-RW, -S(O)-RW, -N(RW)-S(O)-RW, or - OS(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. [0047] In some embodiments, R7 is halogen. In some embodiments, R7 is –CN. In some embodiments, R7 is -NO2. In some embodiments, R7 is RW as defined below and described in embodiments herein. In some embodiments, R7 is -C(O)-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R7 is -C(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R7 is -N(RW)-C(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R7 is -N(RW)-C(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R7 is -OC(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R7 is -OC(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R7 is -S(O)2-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R7 is -N(RW)- S(O)2-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R7 is -OS(O)2-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R7 is -S(O)-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R7 is -N(RW)-S(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R7 is -OS(O)-RW, wherein RW is as defined below and described in embodiments herein. [0048] In some embodiments, R7 is F. In some embodiments, R7 is Cl. In some embodiments, R7 is Br. In some embodiments, R7 is optionally substituted -C1-6 aliphatic. In some embodiments, R7 is unsubstituted -C1-6 aliphatic. In some embodiments, R7 is unsubstituted -C1-6 alkyl. In some embodiments, R7 is -C1-6 aliphatic substituted 1-6 times by halogen. In some embodiments, R7 is -C1-6 alkyl substituted 1-6 times by halogen. In some embodiments, R7 is -C1-6 alkyl substituted 1-6 times by F. In some embodiments, R7 is –CF3.
Figure imgf000019_0001
[0051] In some embodiments,
Figure imgf000019_0002
[0052] In some embodiments, R8 is halogen. In some embodiments, R8 is –CN. In some embodiments, R8 is -NO2. In some embodiments, R8 is RW as defined below and described in embodiments herein. In some embodiments, R8 is -C(O)-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R8 is -C(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R8 is -N(RW)-C(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R8 is -N(RW)-C(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R8 is -OC(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R8 is -OC(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R8 is -S(O)2-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R8 is -N(RW)- S(O)2-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R8 is -OS(O)2-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R8 is -S(O)-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R8 is -N(RW)-S(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R8 is -OS(O)-RW, wherein RW is as defined below and described in embodiments herein. [0053] In some embodiments, R8 is F. In some embodiments, R8 is Cl. In some embodiments, R8 is Br. In some embodiments, R8 is optionally substituted -C1-6 aliphatic. In some embodiments, R8 is unsubstituted -C1-6 aliphatic. In some embodiments, R8 is unsubstituted -C1-6 alkyl. In some embodiments, R8 is -C1-6 aliphatic substituted 1-6 times by halogen. In some embodiments, R8 is -C1-6 alkyl substituted 1-6 times by halogen. In some embodiments, R8 is -C1-6 alkyl substituted 1-6 times by F. In some embodiments, R8 is –CF3. [
Figure imgf000020_0001
[ [
Figure imgf000021_0001
[0057] In some embodiments, R12 is halogen. In some embodiments, R12 is –CN. In some embodiments, R12 is -NO2. In some embodiments, R12 is RW as defined below and described in embodiments herein. In some embodiments, R12 is -C(O)-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R12 is -C(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R12 is -N(RW)-C(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R12 is -N(RW)-C(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R12 is -OC(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R12 is -OC(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R12 is -S(O)2-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R12 is -N(RW)-S(O)2-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R12 is -OS(O)2-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R12 is -S(O)-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R12 is -N(RW)-S(O)- RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R12 is -OS(O)-RW, wherein RW is as defined below and described in embodiments herein. [0058] In some embodiments, R12 is F. In some embodiments, R12 is Cl. In some embodiments, R12 is Br. In some embodiments, R12 is optionally substituted -C1-6 aliphatic. In some embodiments, R12 is unsubstituted -C1-6 aliphatic. In some embodiments, R12 is unsubstituted -C1-6 alkyl. In some embodiments, R12 is -C1-6 aliphatic substituted 1-6 times by halogen. In some embodiments, R12 is -C1-6 alkyl substituted 1-6 times by halogen. In some embodiments, R12 is -C1-6 alkyl substituted 1-6 times by F. In some embodiments, R12 is –CF3.
Figure imgf000022_0001
[0061] In some embodiments, Ring A is selected from those depicted in Table 1, below. [0062] As defined generally above, Ring B is selected from
Figure imgf000023_0001
Figure imgf000023_0003
above and described in embodiments herein, both singly and in combination, provided that, when Ring A is an optionally substituted 5-membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S, at least one 6
Figure imgf000023_0002
[0063] In some embodiments, X is N or CR . In some embodiments, X is N. In some embodiments, X is CR6. [0064] In some embodiments, Y is N or CR2. In some embodiments, Y is N. In some embodiments, Y is CR2. [0065] In some embodiments, Z is N or CR4. In some embodiments, Z is N. In some embodiments, Z is CR4. [0066] In some embodiments, W is NR1, O, or S. In some embodiments, W is NR1. In some embodiments, W is O. In some embodiments, W is S. [
Figure imgf000023_0004
embodiments herein, both singly and in combination, provided that, when Ring A is an optionally substituted 5-membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S, at least one
Figure imgf000024_0001
some embodiments, Ring
Figure imgf000024_0002
wherein each of R1, R2, R3, R4, R5, and R6 is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, Ring B
Figure imgf000024_0003
wherein each of R1, R2, R3, R4, and R5 is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, Ring B is
Figure imgf000024_0004
, wherein each of R1, R2, R3, R5, and R6 is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, Ring B is
Figure imgf000024_0005
, wherein each of R1, R3, R4, R5, and R6 is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, Ring B is
Figure imgf000024_0006
, wherein each of R1, R3, R5, and R6 is as defined above and described in embodiments herein, both singly and in combination. [0068] In some embodiments, Ring
Figure imgf000025_0001
, wherein X is N or CR6; and Z is N or CR4, and wherein each of R3, R4, R5, and R6 is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, Ring
Figure imgf000025_0002
wherein each of R3, R5, and R6 is as defined above and described in embodiments herein, both singly and in combination. [0069] In some embodiments, Ring
Figure imgf000025_0003
, wherein X is N or CR6; and Y is N or CR2, and wherein each of R1, R2, R5, and R6 is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, Ring
Figure imgf000025_0004
wherein each of R1, R2, R5, and R6 is as defined above and described in embodiments herein, both singly and in combination. [0070] In some embodiments, Ring wherein X is N or CR6; Z is N o 4
Figure imgf000025_0005
r CR ; and W is NR1, O, or S, and wherein each of R1, R4, R5, and R6 is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, Ring B is
Figure imgf000025_0006
, wherein R5 is as defined above and described in embodiments herein. [0071] In some embodiments, Ring
Figure imgf000026_0001
wherein each of R1, R2, R3, R4, and R6 is as defined above and described in embodiments herein, both singly and in combination. [
Figure imgf000026_0002
defined above and described in embodiments herein, both singly and in combination. [0073] In some embodiments, Ring B is selected from those depicted in Table 1, below. [0074] As defined generally above, each of R1, R2, R3, R4, and R6 is independently halogen, - CN, -NO2, RW, -C(O)-RW, -C(=NRW)-RW, -N(RW)-C(O)-RW, -N(RW)-C(=NRW)-RW, -OC(O)-RW, -OC(=NRW)-RW, -S(O)2-RW, -N(RW)-S(O)2-RW, -OS(O)2-RW, -S(O)-RW, -N(RW)-S(O)-RW, or - OS(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. [0075] In some embodiments, R1 is halogen. In some embodiments, R1 is –CN. In some embodiments, R1 is -NO2. In some embodiments, R1 is RW as defined below and described in embodiments herein. In some embodiments, R1 is -C(O)-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R1 is -C(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R1 is -N(RW)-C(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R1 is -N(RW)-C(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R1 is -OC(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R1 is -OC(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R1 is -S(O)2-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R1 is -N(RW)- S(O)2-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R1 is -OS(O)2-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R1 is -S(O)-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R1 is -N(RW)-S(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R1 is -OS(O)-RW, wherein RW is as defined below and described in embodiments herein. [0076] In some embodiments, R2 is halogen. In some embodiments, R2 is –CN. In some embodiments, R2 is -NO2. In some embodiments, R2 is RW as defined below and described in embodiments herein. In some embodiments, R2 is -C(O)-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R2 is -C(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R2 is -N(RW)-C(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R2 is -N(RW)-C(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R2 is -OC(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R2 is -OC(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R2 is -S(O)2-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R2 is -N(RW)- S(O)2-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R2 is -OS(O)2-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R2 is -S(O)-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R2 is -N(RW)-S(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R2 is -OS(O)-RW, wherein RW is as defined below and described in embodiments herein. [0077] In some embodiments, R3 is halogen. In some embodiments, R3 is –CN. In some embodiments, R3 is -NO2. In some embodiments, R3 is RW as defined below and described in embodiments herein. In some embodiments, R3 is -C(O)-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R3 is -C(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R3 is -N(RW)-C(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R3 is -N(RW)-C(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R3 is -OC(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R3 is -OC(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R3 is -S(O)2-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R3 is -N(RW)- S(O)2-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R3 is -OS(O)2-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R3 is -S(O)-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R3 is -N(RW)-S(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R3 is -OS(O)-RW, wherein RW is as defined below and described in embodiments herein. [0078] In some embodiments, R4 is halogen. In some embodiments, R4 is –CN. In some embodiments, R4 is -NO2. In some embodiments, R4 is RW as defined below and described in embodiments herein. In some embodiments, R4 is -C(O)-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R4 is -C(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R4 is -N(RW)-C(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R4 is -N(RW)-C(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R4 is -OC(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R4 is -OC(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R4 is -S(O)2-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R4 is -N(RW)- S(O)2-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R4 is -OS(O)2-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R4 is -S(O)-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R4 is -N(RW)-S(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R4 is -OS(O)-RW, wherein RW is as defined below and described in embodiments herein. [0079] In some embodiments, R6 is halogen. In some embodiments, R6 is –CN. In some embodiments, R6 is -NO2. In some embodiments, R6 is RW as defined below and described in embodiments herein. In some embodiments, R6 is -C(O)-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R6 is -C(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R6 is -N(RW)-C(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R6 is -N(RW)-C(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R6 is -OC(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R6 is -OC(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R6 is -S(O)2-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R6 is -N(RW)- S(O)2-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R6 is -OS(O)2-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R6 is -S(O)-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R6 is -N(RW)-S(O)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R6 is -OS(O)-RW, wherein RW is as defined below and described in embodiments herein. [0080] In some embodiments, each of R1, R2, R3, R4, and R6 is independently selected from hydrogen, Cl, Br, F, -OH, -OCH3, -CH3, -C(O)OC(CH3)3, -S(O)2OH, -NH2, -OCH2CH3, -COOH,
Figure imgf000029_0001
[0081] In some embodiments, each of R1, R2, R3, R4, and R6 is independently selected from those depicted in Table 1, below. [0082] As defined generally above, R5 is -R, -C(O)-RW, -C(=NRW)-RW, -S(O)2-RW, or -S(O)- RW, wherein each RW is independently as defined below and described in embodiments herein. [0083] In some embodiments, R5 is -R, wherein R is as defined below and described in embodiments herein. In some embodiments, R5 is -C(O)-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R5 is -C(=NRW)-RW, wherein each RW is independently as defined below and described in embodiments herein. In some embodiments, R5 is -S(O)2-RW, wherein RW is as defined below and described in embodiments herein. In some embodiments, R5 is -S(O)-RW, wherein RW is as defined below and described in embodiments herein. [0084] In some embodiments, R5 is H. In some embodiments, R5 is optionally substituted C1- 6 aliphatic. In some embodiments, R5 is optionally substituted C1-6 alkyl.
Figure imgf000030_0001
. [0086] In some embodiments, R5 is selected from those depicted in Table 1, below. [0087] As defined generally above, RW is -R, -N(R)2, -NR-OR, -N(R)-N(R)2, -N(OR)-N(R)2, -N(R)-N(OR)R, -OR, -O-N(R)2, or –SR. [0088] In some embodiments, RW is -R, wherein R is as defined below and described in embodiments herein. In some embodiments, RW is -N(R)2, wherein each R is independently as defined below and described in embodiments herein. In some embodiments, RW is -NR-OR, wherein each R is independently as defined below and described in embodiments herein. In some embodiments, RW is -N(R)-N(R)2, wherein each R is independently as defined below and described in embodiments herein. In some embodiments, RW is -N(OR)-N(R)2, wherein each R is independently as defined below and described in embodiments herein. In some embodiments, RW is -N(R)-N(OR)R, wherein each R is independently as defined below and described in embodiments herein. In some embodiments, RW is -OR, wherein R is as defined below and described in embodiments herein. In some embodiments, RW is –O-N(R)2, wherein each R is independently as defined below and described in embodiments herein. In some embodiments, RW is -SR, wherein R is as defined below and described in embodiments herein.
Figure imgf000031_0002
. [0090] In some embodiments, RW is selected from those depicted in Table 1, below. [0091] As defined generally above, R is hydrogen, optionally substituted C1-6 aliphatic, an optionally substituted 3-7 membered carbocyclic ring, or an optionally substituted 3-7 membered heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, or two R’s together with the nitrogen to which they attach form an optionally substituted 5-7 membered heterocyclic ring having 0-2 heteroatoms independently selected from N, O, or S in addition to the nitrogen to which the two R’s attach. [0092] In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C1-6 aliphatic. In some embodiments, R is optionally substituted C1-6 alkyl. In some embodiments, R is unsubstituted -C1-6 aliphatic. In some embodiments, R is unsubstituted -C1-6 alkyl. In some embodiments, R is -C1-6 aliphatic which is substituted by –CH3, –CF3, –OH, – OCH3, –OCF3, -N(CH3)2, -N+(CH3)3,
Figure imgf000031_0001
,
Figure imgf000032_0001
[0093] In some embodiments, R is -C1-6 aliphatic substituted 1-6 times by halogen. In some embodiments, R is -C1-6 alkyl substituted 1-6 times by halogen. In some embodiments, R is -C1-6 alkyl substituted 1-6 times by F. In some embodiments, R is -CH3. In some embodiments, R is – CH2CH3. In some embodiments, R is –CH2CH2CH3. In some embodiments, R is –CH(CH3)2. In some embodiments, R is –CH2CH2CH2CH3. In some embodiments, R is –CH2CH(CH3)2. In some embodiments, R is –C(CH3)3. In some embodiments, R is -CF3. [0094] In some embodiments, R is an optionally substituted 3, 4, 5, 6, or 7 membered carbocyclic ring. In some embodiments, R is a 3, 4, 5, 6, or 7 membered carbocyclic ring, which ,
Figure imgf000032_0003
[0095] In some embodiments, R is an optionally substituted 3, 4, 5, 6, or 7 membered heterocyclic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S. In some embodiments, R is a 3, 4, 5, 6, or 7 membered heterocyclic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S, which is substituted 1-5 times by –CH3, –CF3, –OH, – OCH3, –OCF3, -N(CH3)2, -N+(CH3)3,
Figure imgf000032_0002
,
Figure imgf000033_0001
substituted 6-membered heterocyclic ring having 1 or 2 heteroatoms independently selected from N, O, or S. In some embodiments, R is optionally substituted
Figure imgf000033_0002
, . In some embodiments, R is optionally substituted
Figure imgf000033_0003
, . [
Figure imgf000033_0005
[0097] In some embodiments, two R’s together with the nitrogen to which they attach form an optionally substituted 5-7 membered heterocyclic ring having 0-2 heteroatoms independently selected from N, O, or S in addition to the nitrogen to which the two R’s attach. In some embodiments, two R’s together with the nitrogen to which they attach form an optionally substituted 5-7 membered heterocyclic ring having 0 or 1 heteroatom independently selected from N, O, or S in addition to the nitrogen to which the two R’s attach. In some embodiments, -N(R)2 is optionally substituted
Figure imgf000033_0004
. [ or
Figure imgf000034_0001
. [0099] In some embodiments, R is selected from those depicted in Table 1, below. [00100] In some embodiments, the present invention provides a compound selected from Formulas (II-a) to (II-p):
Figure imgf000034_0002
Figure imgf000035_0001
(II-o) (II-p) or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both singly and in combination. [00101] In some embodiments, the present invention provides a compound selected from Formulas (III-a) to (III-l):
Figure imgf000035_0002
Figure imgf000036_0001
, (III-j) (III-k) (III-l) or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both singly and in combination, and with the proviso that the
Figure imgf000036_0002
[00102] In some embodiments, the present invention provides a compound of Formula (IV-a) or (IV-b):
Figure imgf000036_0003
(IV-a) (IV-b) or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both singly and in combination. [00103] Exemplary compounds of the invention are set forth in Table 1, below. Table 1.
Figure imgf000037_0001
Figure imgf000038_0001
[00104] In some embodiments, the present invention provides a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof. [00105] The compounds of this invention may be prepared or isolated in general by synthetic and/or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein. In some embodiments, the present invention provides a compound or an intermediate compound as described in the Examples, or a salt thereof. 4. Uses, Formulation and Administration: Pharmaceutically acceptable compositions [00106] According to another embodiment, the invention provides a pharmaceutical composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this invention is such that is effective to measurably activate AHR, or a variant or mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably activate AHR, or a variant or mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient. [00107] The term “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human. [00108] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non- toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat. [00109] A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an active metabolite or residue thereof. [00110] As used herein, the term "active metabolite or residue thereof" means that a metabolite or residue thereof also activates AHR, or a mutant thereof. The term "active metabolite or residue thereof" also means that a metabolite or residue thereof activates AHR, or a variant or mutant thereof. [00111] Compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. [00112] For this purpose, any bland fixed oil can be employed including synthetic mono- or di- glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. [00113] Pharmaceutically acceptable compositions of this invention can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. [00114] Alternatively, pharmaceutically acceptable compositions of this invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. [00115] Pharmaceutically acceptable compositions of this invention can also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. [00116] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used. [00117] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. [00118] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum. [00119] Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. [00120] Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food. [00121] The amount of compounds of the present invention that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions. [00122] It should also be understood that a specific dosage and treatment regimen for any particular patient depends upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition also depends upon the particular compound in the composition. Uses of Compounds and Pharmaceutically Acceptable Compositions [00123] In some embodiments, the present invention provides a method of using a compound as described herein for treating a disease or disorder associated with AHR. In some embodiments, a disease or disorder associated with AHR is an angiogenesis implicated disorder as described herein. In some embodiments, a disease or disorder associated with AHR is a cancer as described herein. In some embodiments, a disease or disorder associated with AHR is an inflammatory disorder as described herein. In some embodiments, a disease or disorder associated with AHR is a disease or disorder as described in Gutiérrez-Vázquez C. et al., Immunity 2018, 48(1):19-33, and Rothhammer V., et al., Nat Rev Immunol. 2019;19(3):184-197, each of which is incorporated herein by reference in its entirety. Angiogenesis Implicated Disorders [00124] In one aspect, the present invention provides a method for treating or preventing or reducing the risk of an angiogenesis implicated disorder in a patient comprising administering to the patient a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, an angiogenesis implicated disorder is associated with a reduced expression or activation of an AHR. [00125] In some embodiments, an angiogenesis implicated disorder is a retinopathy, psoriasis, rheumatoid arthritis, obesity, or cancer (for example, as described below). Cancer [00126] In some embodiments, the present invention provides a method for treating or preventing or reducing the risk of cancer in patient comprising administering to the patient a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, a cancer is associated with a reduced expression or activation of an aryl hydrocarbon receptor (AHR). [00127] The cancer or proliferative disorder or tumor to be treated using the compounds and methods and uses described herein include, but are not limited to, a hematological cancer, a lymphoma, a myeloma, a leukemia, a neurological cancer, skin cancer, breast cancer, a prostate cancer, a colorectal cancer, lung cancer, head and neck cancer, a gastrointestinal cancer, a liver cancer, a pancreatic cancer, a genitourinary cancer, a bone cancer, renal cancer, and a vascular cancer. [00128] In some embodiments, a cancer includes, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin’s disease or non-Hodgkin’s disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma). [00129] In some embodiments, a cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma. [00130] In some embodiments, a cancer is acoustic neuroma, astrocytoma (e.g. Grade I – Pilocytic Astrocytoma, Grade II – Low-grade Astrocytoma, Grade III – Anaplastic Astrocytoma, or Grade IV – Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma. In some embodiments, the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor. In some embodiments, the patient is an adult human. In some embodiments, the patient is a child or pediatric patient. [00131] Cancer includes, in another embodiment, without limitation, mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, non-Hodgkins’s lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers. [00132] In some embodiments, a cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma. Solid tumors generally comprise an abnormal mass of tissue that typically does not include cysts or liquid areas. In some embodiments, the cancer is selected from renal cell carcinoma, or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST); Waldenstrom’s macroglobulinemia; or medulloblastoma. [00133] In some embodiments, a cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma. In some embodiments, the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis-1 associated MPNST. In some embodiments, the cancer is Waldenstrom’s macroglobulinemia. In some embodiments, the cancer is medulloblastoma. [00134] In some embodiments, a cancer is a viral-associated cancer, including human immunodeficiency virus (HIV) associated solid tumors, human papilloma virus (HPV)-16 positive incurable solid tumors, and adult T-cell leukemia, which is caused by human T-cell leukemia virus type I (HTLV-I) and is a highly aggressive form of CD4+ T-cell leukemia characterized by clonal integration of HTLV-I in leukemic cells (See https://clinicaltrials.gov/ct2/show/study/ NCT02631746); as well as virus-associated tumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel cell carcinoma. (See on the worldwide web at clinicaltrials.gov/ct2/show/study/NCT02488759; see also on the worldwide web at clinicaltrials.gov/ct2/show/study/NCT0240886; on the worldwide web at clinicaltrials.gov/ct2/show/ NCT02426892) [00135] In some embodiments, a cancer is melanoma cancer. In some embodiments, a cancer is breast cancer. In some embodiments, a cancer is lung cancer. In some embodiments, a cancer is small cell lung cancer (SCLC). In some embodiments, a cancer is non-small cell lung cancer (NSCLC). In some embodiments, a cancer is selected from prostate cancer, liver cancer, and ovarian cancer. Inflammatory Disorders [00136] In some embodiments, the present invention provides a method for treating or preventing or reducing the risk of an inflammatory disorder in patient comprising administering to the patient a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, an inflammatory disorder is associated with a reduced expression or activation of an aryl hydrocarbon receptor (AHR). In some embodiments, an inflammatory disorder is associated with a reduced expression or reduced activation of an aryl hydrocarbon receptor (AHR). [00137] Inflammatory disorders include a large number of disorders or conditions that are involved in a variety of diseases, including those involving the immune system, including those demonstrated in allergic reactions and myopathies, or non-immune diseases with causal origins in inflammatory processes including, but not limited to cancer, atherosclerosis, and ischemic heart disease. Non-limiting examples of disorders associated with inflammation include, but are not limited to, acne vulgaris, asthma, autoimmune diseases, autoinflammatory diseases, celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, hypersensitivities, inflammatory bowel diseases, interstitial cystitis, otitis, pelvic inflammatory disease, reperfusion injury, rheumatic fever, rheumatoid arthritis, sarcoidosis, transplant rejection, and vasculitis. [00138] In some embodiments, an inflammatory disorder is necrotizing enterocolitis, inflammatory bowel disease (IBD), autoimmune diseases, Crohn's disease, celiac disease, ulcerative colitis, cardiovascular disease, ocular Behcet's disease, breast cancer, and others. [00139] Other non-limiting examples of inflammatory disease include, without limitation, acne, acid- induced lung injury, Addison's disease, adrenal hyperplasia, adrenocortical insufficiency, adult- onset Still's disease, adult respiratory distress syndrome (ARDS), age-related macular degeneration, aging, alcoholic hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopulmonary, allergic conjunctivitis, allergic contact dermatitis, allergies, allergic encephalomyelitis, allergic neuritis, allograft rejection, alopecia, alopecia areata, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, angina pectoris, angioedema, angiofibroma, anhidrotic ectodermal dysplasia-ill, anti-glomerular basement membrane disease, antigen- antibody complex mediated diseases, ankylosing spondylitis, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, ascites, aspergillosis, asthma, atherosclerosis, atherosclerotic plaques, atopic dermatitis, atrophic thyroiditis, autoimmune diseases, autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria), autoimmune polyendocrinopathies, autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia), autoimmune hepatitis, autoimmune thyroid disorders, autoinflammatory diseases, back pain, Bacillus anthracis infection, Bechet's disease, bee sting- induced inflammation, Behget’s syndrome, Bell’s palsy, berylliosis, Blau syndrome, bone pain, bronchiolitis, bullous pemphigoid (BP) asthma, burns, bursitis, cardiac hypertrophy, carpal tunnel syndrome, Castleman's disease, catabolic disorders, cataracts, Celiac disease, cerebral aneurysm, chemical irritant-induced inflammation, chorioretinitis, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, chronic heart failure, chronic lung disease of prematurity, chronic obstructive pulmonary disease (COPD), chronic pancreatitis, chronic prostatitis, chronic recurrent multifocal osteomyelitis, cicatricial alopecia, colitis, complex regional pain syndrome, complications of organ transplantation, conjunctivitis, connective tissue disease, contact dermatitis, corneal graft neovascularization, corneal ulcer, Crohn's disease, cryopyrin- associated periodic syndromes, cutaneous lupus erythematosus (CLE), cryptococcosis, cystic fibrosis, deficiency of the interleukin-1 receptor antagonist (DIRA), dermatitis, dermatitis endotoxemia, dermatomyositis, diabetic macular edema, diverticulitis, eczema, encephalitis, endometriosis, endotoxemia, eosinophilic pneumonias, epicondylitis, epidermolysis bullosa, erythema multiforme, erythroblastopenia, esophagitis, familial amyloidotic polyneuropathy, familial cold urticarial, familial Mediterranean fever, fetal growth retardation, fibromyalgia, fistulizing Crohn’s disease, food allergies, giant cell arteritis, glaucoma, glioblastoma, glomerular disease, glomerular nephritis, glomerulonephritis, gluten-sensitive enteropathy, gout, gouty arthritis, graft-versus-host disease (GVHD), granulomatous hepatitis, Graves' disease, growth plate injuries, Guillain-Barre syndrome, gut diseases, hair loss, Hashimoto's thyroiditis, head injury, headache, hearing loss, heart disease, hemangioma, hemolytic anemia, hemophilic joints, Henoch-Scholein purpura, hepatitis, hereditary periodic fever syndrome, heritable disorders of connective tissue, herpes zoster and simplex, hidradenitis suppurativa (HS), hip replacement, Hodgkin's disease, Huntington's disease, hyaline membrane disease, hyperactive inflammatory response, hyperammonemia, hypercalcemia, hypercholesterolemia, hypereosinophilic syndrome (HES), hyperimmunoglobulinemia D with recurrent fever (HIDS), hypersensitivity pneumonitis, hypertropic bone formation, hypoplastic and other anemias, hypoplastic anemia, ichthyosis, idiopathic demyelinating polyneuropathy, Idiopathic inflammatory myopathies (dermatomyositis, polymyositis), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, immunoglobulin nephropathies, immune complex nephritis, immune thrombocytopenic purpura (ITP), incontinentia pigmenti (IP, Bloch-Siemens syndrome), infectious mononucleosis, infectious diseases including viral diseases such as AIDS (HIV infection), hepatitis A, B, C, D, and E, herpes; inflammation, inflammation of the CNS, inflammatory bowel disease (IBD), inflammatory disease of the lower respiratory tract including bronchitis or chronic obstructive pulmonary diseases, inflammatory disease of the upper respiratory tract including the nose and sinuses such as rhinitis or sinusitis, inflammatory diseases of the respiratory tract, inflammatory ischemic event such as stroke or cardiac arrest, inflammatory lung disease, inflammatory myopathy such as myocarditis, inflammatory liver disease, inflammatory neuropathy, inflammatory pain, insect bite-induced inflammation, interstitial cystitis, interstitial lung disease, iritis, irritant-induced inflammation, ischemia/reperfusion, joint replacement, juvenile arthritis, juvenile rheumatoid arthritis, keratitis, kidney injury caused by parasitic infections, kidney transplant rejection, leptospirosis, leukocyte adhesion deficiency, lichen sclerosus (LS), Lambert-Eaton myasthenic syndrome, Loeffler's syndrome, lupus, lupus nephritis, Lyme disease, Marfan syndrome (MFS), mast cell activation syndrome, mastocytosis, meningitis, meningioma, mesothelioma, mixed connective tissue disease, Muckle-Wells syndrome (urticaria deafness amyloidosis), mucositis, multiple organ injury syndrome, multiple sclerosis, muscle wasting, muscular dystrophy, myasthenia gravis (MG), myelodysplastic syndrome, myocarditis, myositis, nasal sinusitis, necrotizing enterocolitis, neonatal onset multisystem inflammatory disease (NOMID), neovascular glaucoma, nephrotic syndrome, neuritis, neuropathological diseases, non-allergen induced asthma, obesity, ocular allergy, optic neuritis, organ transplant rejection, Osier-Weber syndrome, osteoarthritis, osteogenesis imperfecta, osteonecrosis, osteoporosis, osterarthritis, otitis, pachyonychia congenita, Paget’s disease, Paget’s disease of bone, pancreatitis, Parkinson's disease, pediatric rheumatology, pelvic inflammatory disease, pemphigus, pemphigus vulgaris (PV), bullous pemphigoid (BP), pericarditis, periodic fever, periodontitis, peritoneal endometriosis, pernicious anemia (Addison's disease), pertussis, PFAPA (periodic fever aphthous pharyngitis and cervical adenopathy), pharyngitis and adenitis (PFAPA syndrome), plant irritant-induced inflammation, pneumocystis infection, pneumonia, pneumonitis, poison ivy / urushiol oil-induced inflammation, polyarthritis nodosa, polychondritis, polycystic kidney disease, polymyalgia rheumatic, giant cell arteritis, polymyositis, pouchitis, reperfusion injury and transplant rejection, primary biliary cirrhosis, primary pulmonary hypertension, primary sclerosing cholangitis (PSC), proctitis, psoriasis, psoriasis vulgaris, psoriatic arthritis, psoriatic epidermis, psychosocial stress diseases, pulmonary disease, pulmonary fibrosis, pulmonary hypertension, pyoderma gangrenosum, pyogenic granuloma retrolental fibroplasias, pyogenic sterile arthritis, Raynaud’s syndrome, Reiter's disease, reactive arthritis, renal disease, renal graft rejection, reperfusion injury, respiratory distress syndrome, retinal disease, retrolental fibroplasia, Reynaud's syndrome, rheumatic carditis, rheumatic diseases, rheumatic fever, rheumatoid arthritis, rhinitis, rhinitis psoriasis, rosacea, sarcoidosis, Schnitzler syndrome, scleritis, sclerosis, scleroderma, scoliosis, seborrhea, sepsis, septic shock, severe pain, Sezary syndrome, sickle cell anemia, silica-induced disease (Silicosis), Sjogren's syndrome, skin diseases, skin irritation, skin rash, skin sensitization (contact dermatitis or allergic contact dermatitis), sleep apnea, spinal cord injury, spinal stenosis, spondyloarthropathies, sports injuries, sprains and strains, Stevens-Johnson syndrome (SJS), stroke, subarachnoid hemorrhage, sunburn, synovial inflammation, systemic inflammatory response syndrome (SIRS), systemic lupus erythematosus, systemic mast cell disease (SMCD), systemic vasculitis, systemic-onset juvenile idiopathic arthritis, temporal arteritis, tendinitis, tenosynovitis, thrombocytopenia, thyroditis, thyroiditis, tissue transplant, toxoplasmosis, trachoma, transplantation rejection, traumatic brain injury, tuberculosis, tubulointerstitial nephritis, tumor necrosis factor (TNF) receptor associated periodic syndrome (TRAPS), type 1 diabetes, type 2 diabetes, complications from type 1 or type 2 diabetes, ulcerative colitis, urticaria, uterine fibroids, uveitis, uveoretinitis, vascular restenosis, vasculitis, vasculitis (NHLBI), vitiligo, Wegener's granulomatosis, and Whipple's disease. [00140] The term “inflammatory bowel disease” or “IBD” as used herein is a collective term describing inflammatory disorders of the gastrointestinal tract, the most common forms of which are ulcerative colitis and Crohn’s disease. Other forms of IBD that can be treated with the presently disclosed compounds, compositions and methods include diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis, autistic enterocolitis, indeterminate colitis, Behget's disease, gastroduodenal CD, jejunoileitis, ileitis, ileocolitis, Crohn’s (granulomatous) colitis, irritable bowel syndrome, mucositis, radiation induced enteritis, short bowel syndrome, celiac disease, stomach ulcers, diverticulitis, pouchitis, proctitis, and chronic diarrhea. [00141] As used herein, treating or preventing an inflammatory disease also includes ameliorating or reducing one or more symptoms of the inflammatory disease. Where the inflammatory disease or disorder is IBD, the term “symptoms of IBD” can refer to detected symptoms such as abdominal pain, diarrhea, rectal bleeding, weight loss, fever, loss of appetite, and other more serious complications, such as dehydration, anemia and malnutrition. A number of such symptoms are subject to quantitative analysis (e.g., weight loss, fever, anemia, etc.). Some symptoms are readily determined from a blood test (e.g., anemia) or a test that detects the presence of blood (e.g., rectal bleeding). The term “wherein said symptoms are reduced” refers to a qualitative or quantitative reduction in detectable symptoms, including but not limited to, a detectable impact on the rate of recovery from disease (e.g., rate of weight gain). The diagnosis is typically determined by way of an endoscopic observation of the mucosa, and pathologic examination of endoscopic biopsy specimens. The course of IBD varies, and is often associated with intermittent periods of disease remission and disease exacerbation. Various methods have been described for characterizing disease activity and severity of IBD as well as response to treatment in subjects having IBD. Treatment according to the present methods is generally applicable to a subject having IBD of any level or degree of disease activity. [00142] The compounds and compositions, according to the method of the present invention, can be administered using any amount and any route of administration effective for activating AHR and treating or lessening the severity of a disease, for example, as those described herein. The exact amount required varies from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease or condition, the particular agent, its mode of administration, and the like. Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention is decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism depends upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term “patient”, as used herein, means an animal, preferably a mammal, and most preferably a human. [00143] Pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the disease or disorder being treated. In certain embodiments, the compounds of the invention can be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. [00144] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. [00145] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. [00146] Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [00147] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, can depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. [00148] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. [00149] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. [00150] Solid compositions of a similar type can also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They can optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like. [00151] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound can be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms can also comprise buffering agents. They can optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. [00152] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. Co-Administration with One or More Other Therapeutic Agent(s) [00153] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents that are normally administered to treat that condition, can also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated." [00154] In some embodiments, the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically. [00155] A compound of the current invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. [00156] One or more other therapeutic agent(s) can be administered separately from a compound or composition of the invention, as part of a multiple dosage regimen. Alternatively, one or more other therapeutic agent(s) may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as a multiple dosage regime, one or more other therapeutic agent(s) and a compound or composition of the invention can be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours from one another. In some embodiments, one or more other therapeutic agent(s) and a compound or composition of the invention are administered as a multiple dosage regimen within greater than 24 hours apart. [00157] As used herein, the term "combination," "combined," and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the present invention can be administered with one or more other therapeutic agent(s) simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the current invention, one or more other therapeutic agent(s), and a pharmaceutically acceptable carrier, adjuvant, or vehicle. [00158] The amount of a compound of the invention and one or more other therapeutic agent(s) (in those compositions which comprise an additional therapeutic agent as described above) that can be combined with the carrier materials to produce a single dosage form varies depending upon the host treated and the particular mode of administration. Preferably, a composition of the invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of a compound of the invention can be administered. [00159] In those compositions which comprise one or more other therapeutic agent(s), the one or more other therapeutic agent(s) and a compound of the invention can act synergistically. Therefore, the amount of the one or more other therapeutic agent(s) in such compositions may be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 - 1,000 g/kg body weight/day of the one or more other therapeutic agent(s) can be administered. [00160] The amount of one or more other therapeutic agent(s) present in the compositions of this invention may be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of one or more other therapeutic agent(s) in the presently disclosed compositions ranges from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. In some embodiments, one or more other therapeutic agent(s) is administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered for that agent. As used herein, the phrase "normally administered" means the amount an FDA approved therapeutic agent is approved for dosing per the FDA label insert. [00161] The compounds of this invention, or pharmaceutical compositions thereof, can also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of this invention are another embodiment of the present invention. Exemplary Other Therapeutic Agents [00162] In some embodiments, provided herein are methods of treatment in which an AHR agonist compound described herein is administered in combination with an agent for treatment of an inflammatory disease or condition. Examples of agents for treatment of an inflammatory disease or condition that can be used in combination with compounds described herein, include alpha- fetoprotein modulators; adenosine A3 receptor antagonist; adrenomedullin ligands; AKT1 gene inhibitors; antibiotics; antifungals; ASK1 inhibitors; ATPase inhibitors; beta adrenoceptor antagonists; BTK inhibitors; calcineurin inhibitors; carbohydrate metabolism modulators; cathepsin S inhibitors; CCR9 chemokine antagonists; CD233 modulators; CD29 modulators; CD3 antagonists; CD40 ligand inhibitors; CD40 ligand receptor antagonists; chemokine CXC ligand inhibitors; CHST15 gene inhibitors; collagen modulators; CSF-1 antagonists; CX3CR1 chemokine modulators; ecobiotics; eotaxin ligand inhibitors; EP4 prostanoid receptor agonists; FI FO ATP synthase modulators; farnesoid X receptor (FXR and NR1 H4) agonists or modulators; fecal microbiota transplantation (FMT); fractalkine ligand inhibitors; free fatty acid receptor 2 antagonists; GATA 3 transcription factor inhibitors; glucagon-like peptide 2 agonists; glucocorticoid agonists; Glucocorticoid receptor modulators; guanylate cyclase receptor agonists; HIF prolyl hydroxylase inhibitors; histone deacetylase inhibitors; HLA class II antigen modulators; hypoxia inducible factor- 1 stimulator; ICAM1 gene inhibitors; IL-1 beta ligand modulators; IL-12 antagonists; IL-13 antagonists; IL-18 antagonists; IL-22 agonists; IL-23 antagonists; IL-23A inhibitors; IL-6 antagonists; IL-7 receptor antagonists; IL-8 receptor antagonists; integrin alpha- 4/beta-1 antagonists; integrin alpha-4/beta-7 antagonists; integrin antagonists; interleukin ligand inhibitors; interleukin receptor 17A antagonists; interleukin-1 beta ligands; interleukin 1 like receptor 2 inhibitors; IL-6 receptor modulators; JAK tyrosine kinase inhibitors; Jak1 tyrosine kinase inhibitors; Jak3 tyrosine kinase inhibitors; lactoferrin stimulators; LanC like protein 2 modulators; leukocyte elastate inhibitors; leukocyte proteinase-3 inhibitors; MAdCAM inhibitors; melanin concentrating hormone (MCH-1) antagonist; melanocortin agonists; metalloprotease-9 inhibitors; microbiome-targeting therapeutics; natriuretic peptide receptor C agonists; neuregulin-4 ligands; NLPR3 inhibitors; NKG2 D activating NK receptor antagonists; nuclear factor kappa B inhibitors; opioid receptor antagonists; 0X40 ligand inhibitors; oxidoreductase inhibitors; P2X7 purinoceptor modulators; PDE 4 inhibitors; Pellino homolog 1 inhibitors; PPAR alpha/delta agonists; PPAR gamma agonists; protein fimH inhibitors; P-selectin glycoprotein ligand-1 inhibitors; Ret tyrosine kinase receptor inhibitors; RIP-1 kinase inhibitors; RIP-2 kinase inhibitors; RNA polymerase inhibitors; sphingosine 1 phosphate phosphatase 1 stimulators; sphingosine-1-phosphate receptor-1 agonists; sphingosine-1-phosphate receptor-5 agonists; sphingosine-1-phosphate receptor-1 antagonists; sphingosine-1 -phosphate receptor-1 modulators; stem cell antigen-1 inhibitors; superoxide dismutase modulators; SYK inhibitors; tissue transglutaminase inhibitor; TLR-3 antagonists; TLR-4 antagonists; Toll- like receptor 8 (TLR8) inhibitors; TLR-9 agonists; TNF alpha ligand inhibitors; TNF ligand inhibitors; TNF alpha ligand modulators; TNF antagonists; TPL-2 inhibitors; tumor necrosis factor 14 ligand modulators; tumor necrosis factor 15 ligand inhibitors; Tyk2 tyrosine kinase inhibitors; type I IL- 1 receptor antagonists; vanilloid VR1 agonists; and zonulin inhibitors, and combinations thereof. [00163] In some embodiments, the one or more other therapeutic agents is an anti-inflammatory agent. Anti-inflammatory agents include but are not limited to NSAIDs, non-specific and COX-2 specific cyclooxgenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptors antagonists, immunosuppressants and methotrexate. Non- limiting examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine, tolmetin sodium, and hydroxychloroquine. Examples of NSAIDs also include COX-2 specific inhibitors (i.e., a compound that inhibits COX-2 with an IC50 that is at least 50-fold lower than the IC50for COX-1) such as celecoxib, valdecoxib, lumiracoxib, etoricoxib and/or rofecoxib. [00164] In a further embodiment, the anti-inflammatory agent is a salicylate. Salicylates include, but are not limited to, acetylsalicylic acid or aspirin, sodium salicylate, and choline and magnesium salicylates. [00165] The anti-inflammatory agent can also be a corticosteroid. For example, the corticosteroid can be chosen from cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, and prednisone. In some embodiments, the anti-inflammatory therapeutic agent is a gold compound such as gold sodium thiomalate or auranofin. [00166] In some embodiments, the anti-inflammatory agent is a metabolic inhibitor such as a dihydrofolate reductase inhibitor, such as methotrexate or a dihydroo rotate dehydrogenase inhibitor, such as leflunomide. [00167] In some embodiments, the anti-inflammatory compound is an anti-C5 monoclonal antibody (such as eculizumab or pexelizumab), a TNF antagonist, such as entanercept, or infliximab, which is an anti-TNF alpha monoclonal antibody. [00168] Included herein are methods of treatment in which a compound described herein, is administered in combination with an immunosuppressant. In some embodiments, the immunosuppressant is methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, or mycophenolate mofetil. [00169] Included herein are methods of treatment in which an AHR agonist compound described herein, is administered in combination with a class of agent for treatment of IBD. Examples of classes of agents for treatment of IBD that can be used in combination with a compound described herein include ASK1 inhibitors, beta adrenoceptor antagonists, BTK inhibitors, beta-glucuronidase inhibitors, bradykinin receptor modulators, calcineurin inhibitors, calcium channel inhibitors, cathepsin S inhibitors, CCR3 chemokine antagonists, CD40 ligand receptor antagonists, chemokine CXC ligand inhibitors, CHST15 gene inhibitors, collagen modulators, CSF-1 antagonists, cyclooxygenase inhibitors, cytochrome P450 3A4 inhibitors, eotaxin ligand inhibitors, EP4 prostanoid receptor agonists, erythropoietin receptor agonists, fractalkine ligand inhibitors, free fatty acid receptor 2 antagonists, GATA 3 transcription factor inhibitors, glucagon-like peptide 2 agonists, glucocorticoid agonists, guanylate cyclase receptor agonists, histone deacetylase inhibitors, HLA class II antigen modulators, IL-12 antagonists, IL- 13 antagonists, IL-23 antagonists, IL-6 antagonists, IL-6 receptor modulators, interleukin-7 receptor modulators, IL-7 antagonists, IL-8 antagonists, integrin alpha-4/beta-1 antagonists, integrin alpha-4/beta-7 antagonists, integrin alpha-E antagonists, integrin antagonists, integrin beta-7 antagonists, interleukin ligand inhibitors, interleukin-2 ligand, interleukin receptor 17A antagonists, interleukin-1 beta ligands, interleukin-1 beta ligand modulators, IRAK4 inhibitors, JAK tyrosine kinase inhibitors, Jak1 tyrosine kinase inhibitors, Jak3 tyrosine kinase inhibitors, LanC like protein 2 modulators, lipoxygenase modulators, MAdCAM inhibitors, matrix metalloprotease inhibitors, melanocortin agonists, metalloprotease-9 inhibitors, natriuretic peptide receptor C agonists, neuregulin-4 ligands, NKG2 D activating NK receptor antagonists, opioid receptor antagonists, opioid receptor delta antagonists, oxidoreductase inhibitors, P2X7 purinoceptor agonists, PDE 4 inhibitors, phagocytosis stimulating peptide modulators, potassium channel inhibitors, PPAR alpha agonists, PPAR delta agonists, PPAR gamma agonists, protein fimH inhibitors, P-selectin glycoprotein ligand-1 inhibitors, RNA polymerase inhibitors, sphingosine 1 phosphate phosphatase 1 stimulators, sphingosine 1 phosphate phosphatase modulators, sphingosine-1-phosphate receptor-1 agonists, sphingosine-1- phosphate receptor-1 antagonists, sphingosine-1-phosphate receptor-1 modulators, sphingosine-1-phosphate receptor-5 modulators, STAT3 gene inhibitors, stem cell antigen-1 inhibitors, superoxide dismutase modulators, superoxide dismutase stimulators, SYK inhibitors, TGF beta 1 ligand inhibitors, thymulin agonists, TLR antagonists, TLR agonists, TNF alpha ligand inhibitors, TNF antagonists, tumor necrosis factor 14 ligand modulators, type II TNF receptor modulators, Tpl 2 inhibitors, and Zonulin inhibitors. [00170] Included herein are methods of treatment in which a compound described herein is administered in combination with an agent for treatment of IBD. Examples of agents for treatment of IBD that can be used in combination with a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analog thereof, include those provided herein for the treatment of an inflammatory disease or condition, and ABX- 464, adalimumab; alicaforsen, ALLO-ASC-CD, AMG-966, anakinra, apremilast; Alequel; AMG- 139; amiselimod, ASD-003, ASP-3291 , AX-1505, BBT-401 , balsalazide; beclomethasone dipropionate; BI-655130, BMS-986184; budesonide; CEQ-508; certolizumab; ChAdOx2-HAV, dexamethasone sodium phosphate, DNVX-078, etanercept; cibinetide; Clostridium butyricum; ETX-201 , golimumab; GS-4997, GS-9876, GS-4875, GS- 4059, infliximab; mesalazine, HLD- 400, LYC-30937 EC; IONIS-JBI1-2.5Rx, JNJ-64304500, JNJ-4447, naltrexone; natalizumab; neihulizumab, olsalazine; PH-46-A, propionyl-L-carnitine; PTG-100; remestemcel-L; tacrolimus; teduglutide; tofacitinib; ASP-1002; ustekinumab; vedolizumab; AVX-470; INN-108; SGM-1019; PF-06480605; PF-06651600; PF-06687234; RBX-8225, SER-287; Thetanix; TOP-1288; VBY- 129; 99mTc-annexin V-128; bertilimumab; DLX-105; dolcanatide; FFP-104; filgotinib; foralumab; GED-0507-34-Levo; givinostat; GLPG- 0974; iberogast; JNJ-40346527; K(D)PT; KAG-308; KHK-4083; KRP-203; larazotide acetate; LY-3074828, midismase; olokizumab; OvaSave; P-28-GST; PF-547659; prednisolone; QBECO; RBX-2660, RG-7835; JKB-122; SB- 012; STNM-01 ; Debio-0512; TRK-170; zucapsaicin; ABT-494; Ampion; BI-655066; carotegast methyl; cobitolimod; elafibranor; etrolizumab; GS-5745; HMPL-004; LP-02, ozanimod; peficitinib; quetmolimab (E-6011); RHB- 104; rifaximin; tildrakizumab; tralokinumab; brodalumab; laquinimod; plecanatide; vidofludimus; and AZD-058. EXEMPLIFICATION [00171] The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Unless otherwise stated, one or more tautomeric forms of compounds of the examples described hereinafter may be prepared in situ and/or isolated. All tautomeric forms of compounds of the examples described hereafter should be considered to be disclosed. Temperatures are given in degrees centigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art. [00172] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesis the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art. Further, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples. Example 1: Synthesis of Exemplary Compounds [00173] Certain exemplary compounds are prepared following the following schemes. I-1
Figure imgf000062_0001
Step 1: 6-(Trifluoromethyl)pyridine-2-carbonyl chloride
Figure imgf000062_0002
[00174] To a solution of 6-(trifluoromethyl)pyridine-2-carboxylic acid (12 g, 62.79 mmol, 1 eq) in DCM (200 mL) was added oxalyl dichloride (9.56 g, 75.35 mmol, 6.60 mL, 1.2 eq) and DMF (229.47 mg, 3.14 mmol, 241.55 µL, 0.05 eq). The mixture was stirred at 15 °C for 3 h. TLC (a drop of mixture in MeOH, PE/EtOAc = 3/1, Rf = 0.80) showed the starting material was consumed completely and one major new spot was detected. The reaction mixture was concentrated to yield 6-(trifluoromethyl)pyridine-2-carbonyl chloride (18 g, crude) as yellow oil, which was used in the next step without further purification. Step 2: 1H-Indol-3-yl-[6-(trifluoromethyl)-2-pyridyl]methanone
Figure imgf000062_0003
[00175] To a solution of indole (15.09 g, 128.85 mmol, 1.5 eq) in DCE (400 mL) was added 6-(trifluoromethyl)pyridine-2-carbonyl chloride (18 g, 85.90 mmol, N/A purity, 1 eq) in DCE (500 mL) at 0 °C under N2 atmosphere. To the mixture was added AlCl3 (21.00 g, 157.49 mmol, 8.61 mL, 1.83 eq) and the reaction mixture was stirred under N2 atmosphere at 50 °C for 12 h. TLC (PE/EtOAc = 4/1, Rf = 0.40) showed starting material was consumed and one major new spot was detected.20% NaOH solution (600 mL) and H2O (200 mL) were added slowly to quench the reaction. The mixture was extracted with DCM (800 mL x 3). The combine organic layers were dried over anhydrous Na2SO4, filtered and concentrated. To the residue was added EtOAc (200 mL). The mixture was heated to 70 °C and filtered. The filtrate was concentrated to yield a residue which was recrystallized from EtOAc (100 mL) to yield the product. The product in MeOH (50 mL) was stirred at 15 °C for 0.5 h. The suspension was filtered and solid was washed with MeOH (10 mL x 2) and treated under vacuum to yield 1H-indol-3-yl-[6- (trifluoromethyl)-2-pyridyl]methanone (6 g, 20.67 mmol, 24.1% yield, 100.0% purity) as a yellow solid.1H NMR (500 MHz, CD3OD) δ ppm 8.89 (s, 1H), 8.46 (dd, J = 3.0, 6.5 Hz, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.24 (t, J = 8.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.52-7.47 (m, 1H), 7.32-7.24 (m, 2H); ES-LCMS m/z 291.0 [M+H]+. I-2
Figure imgf000063_0001
Step 1: Methyl 6-cyanopyridine-2-carboxylate
Figure imgf000063_0002
[00176] A mixture of methyl 6-bromopyridine-2-carboxylate (2 g, 9.26 mmol, 1 eq), CuCN (829.17 mg, 9.26 mmol, 1 eq) in DMF (50 mL) was stirred at 150 °C for 5 min under N2 atmosphere in microwave. TLC (PE/EtOAc = 1/1, Rf = 0.59) indicated the starting material was consumed completely and one new spot formed. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 2/1, TLC: PE/EtOAc = 1/1, Rf = 0.59) to yield methyl 6-cyanopyridine-2-carboxylate (610 mg, 3.57 mmol, 38.6% yield, 95.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.35 (d, J = 1.0, 8.1 Hz, 1H), 8.05 (t, J = 7.8 Hz, 1H), 7.89 (d, J = 0.9, 7.7 Hz, 1H), 4.05 (s, 3H); ES- LCMS m/z 163.3 [M+H]+. Step 2: 6-Cyanopyridine-2-carboxylic acid
Figure imgf000064_0001
[00177] A solution of methyl 6-cyanopyridine-2-carboxylate (610 mg, 3.57 mmol, 1 eq) in HCl (5 mL, 1 M) was stirred at 100 °C for 1 h. The reaction mixture was filtered to yield 6- cyanopyridine-2-carboxylic acid (350 mg, 2.24 mmol, 62.8% yield, 95.0% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 13.80 (s, 1H), 8.32-8.29 (m, 1H), 8.27-8.23 (m, 2H); ES-LCMS m/z 149.3 [M+H]+. Step 3: 6-Cyanopyridine-2-carbonyl chloride
Figure imgf000064_0002
[00178] To a solution of 6-cyanopyridine-2-carboxylic acid (200 mg, 1.28 mmol, 1 eq) in SOCl2 (2 mL) was added one drop of DMF. The mixture was stirred at 40 °C for 3 h. TLC (PE/EtOAc = 0/1, Rf = 0.37) indicated the starting material was consumed completely and one new spot formed. The reaction mixture was concentrated to yield 6-cyanopyridine-2-carbonyl chloride (100 mg, crude) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 8.32-8.28 (m, 1H), 8.27-8.23 (m, 2H). Step 4: 6-(1H-Indole-3-carbonyl)pyridine-2-carbonitrile
Figure imgf000064_0003
[00179] To a solution of indole (73.50 mg, 627.38 µmol, 1.1 eq) in DCE (3 mL) at 0 °C under N2 was added a solution of 6-cyanopyridine-2-carbonyl chloride (100 mg, 570.35 µmol, 1 eq) in DCE (2 mL). AlCl3 (228.15 mg, 1.71 mmol, 3 eq) was added under N2. The mixture was stirred at 45 °C for 16 h under N2 atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5um; mobile phase: [water(0.05% NH3H2O+10 mM NH4HCO3)-ACN]; B%: 35%- 65%,10min) followed by lyophilization to yield 6-(1H-indole-3-carbonyl)pyridine-2-carbonitrile (27.82 mg, 112.52 µmol, 19.7% yield, 100.0% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 12.19 (s, 1H), 8.67 (s, 1H), 8.37-8.33 (m, 1H), 8.31-8.24 (m, 3H), 7.60-7.53 (m, 1H), 7.32-7.25 (m, 2H); ES-LCMS m/z 248.3 [M+H]+. I-3
Figure imgf000065_0001
Step 1: 6-Methoxypyridine-2-carbonyl chloride
Figure imgf000065_0002
[00180] To a solution of 6-methoxypyridine-2-carboxylic acid (300 mg, 1.96 mmol, 1 eq) in DCM (5 mL) was added (COCl)2 (621.64 mg, 4.90 mmol, 428.72 µL, 2.5 eq). The mixture was stirred at 40 °C for 1 h. TLC (PE/EtOAc = 1/1, Rf = 0.75) indicated the starting material was consumed completely and one new spot formed. The reaction mixture was concentrated to yield 6-methoxypyridine-2-carbonyl chloride (300 mg, 1.66 mmol, 84.8% yield, 95.0% purity) as a white solid.1H NMR (500 MHz, DMSO-d6) δ ppm 7.86 (d, J = 7.3, 8.2 Hz, 1H), 7.66 (d, J = 0.6, 7.2 Hz, 1H), 7.07-7.03 (m, 1H), 3.90-3.89 (m, 3H). Step 2: 1H-Indol-3-yl-(6-methoxy-2-pyridyl)methanone
Figure imgf000065_0003
[00181] To a solution of indole (107.02 mg, 913.56 µmol, 1.1 eq) in THF (3 mL) at 0 °C under N2 was added a solution of 6-methoxypyridine-2-carbonyl chloride (150 mg, 830.51 µmo, 1 eq) in THF (3 mL). AlCl3 (332.22 mg, 2.49 mmol, 3 eq) was added under N2. The mixture was stirred at 50 °C for 16 h under N2 atmosphere. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5um; mobile phase: [water(0.05% NH3H2O+10 mM NH4HCO3)-ACN]; B%: 40%- 70%,10min), followed by lyophilization to yield 1H-indol-3-yl-(6-methoxy-2-pyridyl)methanone (19.40 mg, 76.90 µmol, 9.3% yield, 100.0% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 12.32-11.74 (m, 1H), 8.90 (s, 1H), 8.42-8.33 (m, 1H), 7.93 (d, J = 7.5, 8.2 Hz, 1H), 7.66 (d, J = 7.3 Hz, 1H), 7.56-7.50 (m, 1H), 7.28-7.22 (m, 2H), 7.08 (d, J = 8.1 Hz, 1H), 4.00 (s, 3H); ES-LCMS m/z 253.3 [M+H]+. I-6
Figure imgf000066_0001
Step 1: 1H-Indol-3-yl-(6-morpholino-2-pyridyl)methanone
Figure imgf000066_0002
[00182] To a solution of (6-fluoro-2-pyridyl)-(1H-indol-3-yl)methanone (80 mg, 323.02 µmol, 1 eq) in DMF (2 mL) was added morpholine (140.71 mg, 1.62 mmol, 142.13 µL, 5 eq). The mixture was stirred at 130 °C for 2 h under N2 atmosphere in microwave. The solvent was removed to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18150*25mm*5um; mobile phase: [water(0.05% NH3H2O+10 mM NH4HCO3)-ACN]; B%: 33%-63%,10min), followed by lyophilization to yield 1H-indol-3-yl-(6-morpholino-2- pyridyl)methanone (52.06 mg, 169.39 µmol, 52.4% yield, 100.0% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 12.00 (s, 1H), 8.67 (s, 1H), 8.38-8.32 (m, 1H), 7.78 (dd, J = 7.4, 8.6 Hz, 1H), 7.53-7.48 (m, 1H), 7.32 (d, J = 7.0 Hz, 1H), 7.26-7.20 (m, 2H), 7.09 (d, J = 8.6 Hz, 1H), 3.79-3.73 (m, 4H), 3.57-3.52 (m, 4H); ES-LCMS m/z 308.2 [M+H]+. I-8
Figure imgf000067_0001
Step 1: 2-Chloropyrimidine-4-carbonyl chloride
Figure imgf000067_0002
[00183] To a solution of 2-chloropyrimidine-4-carboxylic acid (2 g, 12.61 mmol, 1 eq) in DCM (15 mL) was added (COCl)2 (6.40 g, 50.46 mmol, 4.42 mL, 4 eq) and DMF (0.1 mL). The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated to yield 2- chloropyrimidine-4-carbonyl chloride (2.2 g, 11.19 mmol, 88.7% yield, 90.0% purity) as a black brown oil.1H NMR (500 MHz, CHCl3) δ ppm 8.98 (d, J = 4.7 Hz, 1H), 7.93 (d, J = 4.7 Hz, 1H). Step 2: (2-Chloropyrimidin-4-yl)-(1H-indol-3-yl)methanone
Figure imgf000067_0003
[00184] To a solution of indole (1.44 g, 12.31 mmol, 1.1 eq) in DCM (10 mL) was added chloro(diethyl)alumane (1 M, 22.37 mL, 2 eq) dropwise at -70 oC. The mixture was stirred at -70 oC for 30 min. Then a solution of 2-chloropyrimidine-4-carbonyl chloride (2.2 g, 11.19 mmol, 90.0% purity, 1 eq) in DCM (5 mL) was added to the mixture at -70 oC. The mixture was warmed up to 20 oC slowly. The mixture was stirred at 20 oC for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue which was diluted with H2O (50 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.5) to yield a residue which was added DCM/MeOH (1/0, 100 mL), and stirred at 20 °C for 2 h. The slurry was filtered and the cake was rinsed with DCM (30 mL x 2). The solid was collected and dried in vacuum to yield (2-chloropyrimidin-4-yl)-(1H-indol-3- yl)methanone (55 mg, 213.45 µmol, 1.9% yield, 100.0% purity) as a light yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 12.32 (s, 1H), 9.04 (d, J = 5.1 Hz, 1H), 8.62 (s, 1H), 8.35-8.29 (m, 1H), 8.00 (d, J = 5.1 Hz, 1H), 7.62-7.53 (m, 1H), 7.36-7.27 (m, 2H); ES-LCMS m/z 258.2 [M+H]+. Step 3: 1H-Indol-3-yl-(2-methoxypyrimidin-4-yl)methanone
Figure imgf000068_0001
[00185] To a solution of Na (24.54 mg, 1.07 mmol, 25.29 µL, 5 eq) in MeOH (5 mL) was stirred at 20 oC for 2 h. (2-Chloropyrimidin-4-yl)-(1H-indol-3-yl)methanone (55 mg, 213.45 µmol, 100.0% purity, 1 eq) was added to the mixture. The mixture was stirred at 20 oC for 2 h. The reaction mixture was concentrated to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C 18150 * 25 mm * 5 µm; mobile phase: [water (0.05% NH3H2O+10 mM NH4HCO3)-ACN]; B%: 27%-57%, 10 min), followed by lyophilization to yield 1H-indol-3-yl-(2-methoxypyrimidin-4-yl)methanone (35.53 mg, 140.29 µmol, 65.7% yield, 100.0% purity) as a light green solid.1H NMR (500 MHz, CDCl3) δ ppm 8.94 (d, J = 3.1 Hz, 1H), 8.85-8.66 (m, 2H), 8.58 (d, J = 7.0 Hz, 1H), 7.72 (d, J = 5.0 Hz, 1H), 7.49-7.44 (m, 1H), 7.41-7.33 (m, 2H), 4.16-4.09 (m, 3H); ES-LCMS m/z 254.3 [M+H]+. I-10 and I-11
Figure imgf000069_0001
Step 1: Methyl (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-(4-formyl-2-nitro- phenoxy)tetrahydropyran-2-carboxylate
Figure imgf000069_0002
[00186] To a solution of methyl (2S,3S,4S,5R,6R)-3,4,5-triacetoxy-6-bromo-tetrahydropyran- 2-carboxylate (1.5 g, 3.78 mmol, 1 eq) and 4-hydroxy-3-nitro-benzaldehyde (631.16 mg, 3.78 mmol, 1 eq) in ACN (20 mL) was added Ag2O (4.38 g, 18.88 mmol, 5 eq) under N2 atmosphere. The mixture was stirred at 20 °C for 12 h keep in dark place. The reaction mixture was filtered, diluted with EtOAc (100 mL), washed with sat. aq. NaHCO3 (20 mL), brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield crude methyl (2S,3S,4S,5R,6S)-3,4,5- triacetoxy-6-(4-formyl-2-nitro-phenoxy)tetrahydropyran-2-carboxylate (1.5 g, 2.79 mmol, 73.9% yield, 90.0% purity) as a white solid, which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 9.99 (s, 1H), 8.32 (d, J = 2.0 Hz, 1H), 8.10 (dd, J = 2.2, 8.8 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 5.48-5.40 (m, 2H), 5.38-5.25 (m, 2H), 4.33 (d, J = 8.2 Hz, 1H), 3.72 (s, 3H), 2.14 (s, 3H), 2.09 (d, J = 3.9 Hz, 6H); ES-LCMS m/z no desired MS was found. Step 2: Methyl (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-[4-(hydroxymethyl)-2-nitro- phenoxy]tetrahydropyran-2-carboxylate
Figure imgf000070_0001
[00187] To a solution of methyl (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-(4-formyl-2-nitro- phenoxy)tetrahydropyran-2-carboxylate (1.5 g, 2.79 mmol, 90%, 1 eq) in DCM (20 mL) and i- PrOH (4 mL) was added NaBH4 (84.52 mg, 2.23 mmol, 0.8 eq) at 0 °C under N2 atmosphere. The mixture was stirred at 0 °C for 1 h. TLC (PE/EtOAc = 3/1, Rf = 0.18) indicated the starting material was consumed completely and one new spot formed. The reaction mixture was quenched by addition of water (50 mL), extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 0/1, TLC: PE/EtOAc = 1/2, Rf = 0.18) to yield methyl (2S,3S,4S,5R,6S)- 3,4,5-triacetoxy-6-[4-(hydroxymethyl)-2-nitro-phenoxy]tetrahydropyran-2-carboxylate (1.1 g, 2.08 mmol, 74.6% yield, 92.0% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 7.81 (d, J = 2.0 Hz, 1H), 7.62 (dd, J = 2.0, 8.6 Hz, 1H), 7.38 (d, J = 8.6 Hz, 1H), 5.71 (d, J = 7.8 Hz, 1H), 5.52-5.39 (m, 2H), 5.17-5.04 (m, 2H), 4.74 (d, J = 9.8 Hz, 1H), 4.51 (d, J = 5.9 Hz, 2H), 3.65 (s, 3H), 2.06-1.94 (m, 9H); ES-LCMS m/z 508.0 [M+Na]+. Step 3: [3-Nitro-4-[(2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-methoxycarbonyl-tetrahydropyran- 2-yl]oxy-phenyl]methyl 3-[6-(trifluoromethyl)pyridine-2-carbonyl]indole-1-carboxylate
Figure imgf000071_0001
[00188] To a solution of 1H-indol-3-yl-[6-(trifluoromethyl)-2-pyridyl]methanone (99.46 mg, 342.68 µmol, 100% purity, 1 eq) in THF (2 mL) was added triphosgene (110.51 mg, 372.40 µmol, 1.09 eq) and DIEA (132.86 mg, 1.03 mmol, 179.06 µL, 3 eq). The reaction mixture was stirred at 80 °C for 0.5 h. The reaction mixture was concentrated to yield 3-(6- (trifluoromethyl)picolinoyl)-1H-indole-1-carbonyl chloride (crude). Then to a solution of methyl (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-[4-(hydroxymethyl)-2-nitro-phenoxy]tetrahydropyran-2- carboxylate (200 mg, 379.07 µmol, 92% purity, 1.11 eq) in DCM (2 mL) was added 3-(6- (trifluoromethyl)picolinoyl)-1H-indole-1-carbonyl chloride (crude) in DCM (2 mL) and DIEA (132.86 mg, 1.03 mmol, 179.06 µL, 3 eq) stirred at 40 °C for 11.5 h. TLC (PE/EtOAc = 1/1, Rf = 0.60) showed starting material was consumed, and one major new spot was detected. The reaction mixture was concentrated to yield a residue which was purified by flash silica gel chromatography (from pure PE to PE/EtOAc = 3/1, TLC: PE/EtOAc = 1/1, Rf = 0.60) to yield a residue which was purified by preparative HPLC (column: Welch Xtimate C18150 * 25 mm *5 µm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 58%-88%, 10 min) and lyophilized to yield [3-nitro-4-[(2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-methoxycarbonyl-tetrahydropyran-2- yl]oxy-phenyl]methyl 3-[6-(trifluoromethyl)pyridine-2-carbonyl]indole-1-carboxylate (150 mg, 187.12 µmol, 54.6% yield, 100.0% purity) as a white solid.1H NMR (500 MHz, CDCl3) δ ppm 9.46 (s, 1H), 8.59-8.55 (m, 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.31-8.23 (m, 1H), 8.13 (t, J = 8.0 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.74 (dd, J = 2.0, 8.5 Hz, 1H), 7.50-7.44 (m, 3H), 5.50 (s, 2H), 5.41-5.31 (m, 3H), 5.26-5.23 (m, 1H), 4.24 (d, J = 8.5 Hz, 1H), 3.75 (s, 3H), 2.13 (s, 3H), 2.07 (d, J = 5.0 Hz, 6H); ES-LCMS m/z 802.0 [M+H]+. Step 4: (2S,3S,4S,5R,6S)-3,4,5-Trihydroxy-6-[2-nitro-4-[[3-[6-(trifluoromethyl)pyridine-2- carbonyl]indole-1-carbonyl]oxymethyl]phenoxy]tetrahydropyran-2-carboxylic acid
Figure imgf000072_0001
[00189] To a solution of [3-nitro-4-[(2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-methoxycarbonyl- tetrahydropyran-2-yl]oxy-phenyl]methyl 3-[6-(trifluoromethyl)pyridine-2-carbonyl]indole-1- carboxylate (50 mg, 62.37 µmol, 100% purity, 1 eq) in 1,4-dioxane (5 mL) was added HCl (2 M, 5 mL, 160.33 eq). The mixture was stirred at 50 °C for 48 h. The reaction mixture was concentrated to yield a residue which was purified by preparative HPLC (column: Welch Xtimate C18150 * 25 mm * 5 µm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 22%- 52%, 10 min) and lyophilized to yield (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-[2-nitro-4-[[3-[6- (trifluoromethyl)pyridine-2-carbonyl]indole-1-carbonyl]oxymethyl]phenoxy]tetrahydropyran-2- carboxylic acid (11.03 mg, 16.58 µmol, 26.6% yield, 99.4% purity) as a white solid.1H NMR (500 MHz, DMSO-d6) δ ppm 9.28 (s, 1H), 8.45 (d, J = 7.5 Hz, 1H), 8.41-8.37 (m, 2H), 8.25-8.17 (m, 2H), 8.11 (d, J = 2.0 Hz, 1H), 7.83 (dd, J = 2.0, 9.0 Hz, 1H), 7.52-7.44 (m, 3H), 5.55 (s, 2H), 5.31 (d, J = 4.5 Hz, 1H), 5.13 (d, J = 7.0 Hz, 1H), 5.08 (s, 1H), 3.57 (d, J = 9.5 Hz, 1H), 3.28- 3.20 (m, 3H); ES-LCMS m/z 662.2 [M+H]+. I-12
Figure imgf000072_0002
Step 1: 6-Methoxypyridine-2-carbonyl chloride
Figure imgf000072_0003
[00190] To a solution of 6-methoxypyridine-2-carboxylic acid (100 mg, 653.02 µmol, 1 eq) in DCM (5 mL) was added (COCl)2 (207.21 mg, 1.63 mmol, 142.91 µL, 2.5 eq). The mixture was stirred at 40 °C for 1 h. TLC (PE/EtOAc = 1/1, Rf = 0.75) indicated the starting material was consumed completely and one new spot formed. The reaction mixture was concentrated to yield 6-methoxypyridine-2-carbonyl chloride (300 mg, 1.66 mmol, 84.8% yield, 95.0% purity) as a white solid.1H NMR (500 MHz, DMSO-d6) δ ppm 7.85 (d, J = 7.3, 8.3 Hz, 1H), 7.67-7.62 (m, 1H), 7.07-7.02 (m, 1H), 3.90 (s, 3H). Step 2: (6-Methoxy-1H-indol-3-yl)-(6-methoxy-2-pyridyl)methanone
Figure imgf000073_0001
[00191] To a solution of 6-methoxy-1H-indole (94.12 mg, 639.49 µmol, 1.1 eq) in THF (5 mL) at 0 °C under N2 was added a solution of 6-methoxypyridine-2-carbonyl chloride (105 mg, 581.36 µmol, 1 eq) in THF (5 mL). AlCl3 (77.52 mg, 581.36 µmol, 31.77 µL, 1 eq) was added under N2. The mixture was stirred at 50 °C for 6 h under N2. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18150*25mm*5um;mobile phase: [water(0.05% NH3H2O+10 mM NH4HCO3)- ACN];B%: 36%-66%,10min), followed by lyophilization to yield (6-methoxy-1H-indol-3-yl)-(6- methoxy-2-pyridyl)methanone (16.06 mg, 55.04 µmol, 9.5% yield, 96.8% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 11.83 (s, 1H), 8.79 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 7.92 (d, J = 7.5, 8.2 Hz, 1H), 7.65 (d, J = 7.3 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 7.02 (d, J = 2.2 Hz, 1H), 6.88 (d, J = 2.3, 8.7 Hz, 1H), 4.00 (s, 3H), 3.81 (s, 3H); ES-LCMS m/z 283.2 [M+H]+. I-13
Figure imgf000073_0002
Step 1: 6-Ethoxypyridine-2-carboxylate
Figure imgf000074_0001
[00192] To a solution of 6-hydroxypyridine-2-carboxylic acid (2 g, 14.38 mmol, 1 eq) in CHCl3 (30 mL) was added Ag2CO3 (7.93 g, 28.75 mmol, 2 eq) and iodoethane (8.97 g, 57.51 mmol, 4.60 mL, 4 eq). The mixture was stirred at 80 °C for 4 h under N2 atmosphere. TLC (PE/EtOAc = 3/1, Rf = 0.80) indicated starting material was consumed completely and one new spot formed. The reaction mixture was filtered and concentrated under reduced pressure to yield ethyl 6-ethoxypyridine-2-carboxylate (2.72 g, 13.24 mmol, 92.1% yield, 95% purity) was obtained as yellow liquid.1H NMR (500 MHz, CDCl3) δ ppm 7.71-7.59 (m, 2H), 6.91-6.81 (m, 1H), 4.46-4.36 (m, 4H), 1.38 (dt, J = 3.0, 7.1 Hz, 6H) Step 2: 6-Ethoxypyridine-2-carboxylic acid
Figure imgf000074_0002
[00193] To a solution of ethyl 6-ethoxypyridine-2-carboxylate (2.7 g, 13.14 mmol, 95% purity, 1 eq) in EtOH (20 mL) was added H2O (20 mL) and NaOH (1.58 g, 39.42 mmol, 3 eq) The mixture was stirred at 20 °C for 1 hr under N2 atmosphere. TLC (PE/EtOAc = 3/1, Rf =0 ) indicated starting material was consumed completely and one new spot formed. The mixture was concentrated and then water (80 mL) and 2 N HCl was added was adjusted pH to 4-5, extracted with EtOAc (100 mL x 3). The combined organiclayers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 6-ethoxypyridine-2- carboxylic acid (2.05 g, 11.98 mmol, 91.2% yield, 97.7% purity) was obtained as white solid.1H NMR (500 MHz, CDCl3) δ ppm 8.10-7.99 (m, 2H), 7.25 (dd, J = 2.0, 7.2 Hz, 1H), 4.64 (q, J = 7.1 Hz, 2H), 1.68 (t, J = 7.0 Hz, 3H) ES-LCMS m/z 168.2 [M+H]+. Step 3: 6-Ethoxypyridine-2-carbonyl chloride
Figure imgf000075_0001
[00194] To a solution of 6-ethoxypyridine-2-carboxylic acid (300 mg, 1.75 mmol, 97.7% purity, 1 eq) in DCM (4 mL) was added oxalyl dichloride (556.38 mg, 4.38 mmol, 383.71 µL, 2.5 eq.).The mixture was stirred at 60 °C for 2 h under N2 atmosphere. TLC (PE/EtOAc = 5/1, Rf = 0.80) indicated starting material was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to 6-ethoxypyridine-2-carbonyl chloride (300 mg, 1.45 mmol, 83.0% yield, 90.0% purity) as yellow oil.1H NMR (500 MHz, CDCl3) δ ppm 8.07-7.89 (m, 2H), 7.25 (d, J = 7.0 Hz, 1H), 4.73 (q, J = 7.0 Hz, 2H), 1.68 (t, J = 7.0 Hz, 3H). Step 4: (6-Ethoxy-2-pyridyl)-(1H-indol-3-yl)methanone
Figure imgf000075_0002
[00195] To a solution of indole (239.84 mg, 2.05 mmol, 2 eq) in DCM (6 mL) was added dropwise 6-ethoxypyridine-2-carbonyl chloride (200 mg, 1.02 mmol, 95% purity, 1 eq)at 0 °C. AlCl3 (272.99 mg, 2.05 mmol, 111.88 µL, 2 eq) was added dropwise at 0 °C. The resulting mixture was stirred at 20 °C for 12 h. TLC (PE/EtOAc = 3/1, Rf = 0.50) indicated starting material was consumed completely and one new spot formed. The reaction mixture was quenched by addition of water (50mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 5/1, TLC: PE/EtOAc = 3/1, Rf = 0.50) to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18150*25mm*5um; mobile phase: [water (0.05% NH3H2O+10 mM NH4HCO3)-ACN]; B%: 41%-71%,10min). The desired fraction was lyophilized to yield (6-ethoxy-2-pyridyl)-(1H-indol-3-yl)methanone (99.07 mg, 372.03 µmol, 36.3% yield, 100.0% purity) as a white solid.1H NMR (500 MHz, CDCl3) δ ppm 8.89 (d, J = 3.1 Hz, 1H), 8.76 (s, 1H), 8.62 (d, J = 7.6 Hz, 1H), 7.83-7.78 (m, 1H), 7.78-7.68 (m, 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.37-7.28 (m, 2H), 6.92 (dd, J = 0.9, 8.1 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H); ES-LCMS m/z 267.0 [M+H]+. I-16
Figure imgf000076_0001
[00196] To a solution of 2-(trifluoromethyl)pyridine-3-carboxylic acid (3.6 g, 18.84 mmol, 1 eq) in toluene (40 mL) was added DIEA (2.92 g, 22.61 mmol, 3.94 mL, 1.2 eq) and DPPA (5.70 g, 20.72 mmol, 4.49 mL, 1.1 eq) stirred at 25 °C for 2 h. Then phenylmethanol (2.24 g, 20.72 mmol, 2.15 mL, 1.1 eq) was added and the mixture was stirred at 110 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (80mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 10/1, TLC: PE/EtOAc = 3/1, Rf =0.51) to yield benzyl N-[2-(trifluoromethyl)-3-pyridyl]carbamate (3.1 g, 10.42 mmol, 55.3% yield, 99.6% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 9.54 (s, 1H), 8.59 (d, J = 4.3 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.74 (dd, J = 4.5, 8.4 Hz, 1H), 7.43-7.29 (m, 5H), 5.16 (s, 2H); ES-LCMS m/z 297.2 [M+H]+. Step 2: Benzyl N-[1-oxido-2-(trifluoromethyl)pyridin-1-ium-3-yl]carbamate
Figure imgf000077_0001
[00197] To a solution of benzyl N-[2-(trifluoromethyl)-3-pyridyl]carbamate (2 g, 6.72 mmol, 1 eq) in DCM (40 mL) was added m-CPBA (4.35 g, 20.17 mmol, 80.0% purity, 3 eq). The mixture was stirred at 25 °C for 24 h. TLC (PE/EtOAc = 1/1, Rf = 0.17) showed the starting material was remained and one new spot was detected. The reaction mixture was quenched by aq. sat. NaHSO3 (80 mL), extracted with DCM (80 mL x 2). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 1/2, TLC: PE/EtOAc = 1/1, Rf = 0.17) to yield benzyl N-[1-oxido-2-(trifluoromethyl)pyridin-1- ium-3-yl]carbamate (1 g, 3.14 mmol, 46.7% yield, 98.0% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 9.88 (s, 1H), 8.35-8.30 (m, 1H), 7.63 (dd, J = 6.7, 8.4 Hz, 1H), 7.41- 7.33 (m, 6H), 5.16 (s, 2H); ES-LCMS m/z 313.2 [M+H]+. Step 3: Benzyl N-[6-chloro-2-(trifluoromethyl)-3-pyridyl]carbamate [00198] A mixture of benzyl N-[1-oxido-2-(trifluoromethyl)pyridin-1-ium-3-yl]carbamate (1 g, 3.14 mmol, 1 eq) in POCl3 (22.55 g, 147.07 mmol, 13.67 mL, 46.86 eq). The mixture was stirred at 25 °C for 6 h. The reaction mixture was poured into water (30 mL) slowly and adjusted to pH 8 with aq. sat NaHCO3, extracted with EtOAc (60 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 0/1, TLC: PE/EtOAc = 3/1, Rf = 0.81) to yield benzyl N-[6-chloro-2- (trifluoromethyl)-3-pyridyl]carbamate (500 mg, 1.25 mmol, 39.9% yield, 83.0% purity) as a colorless oil.1H NMR (400 MHz, CDCl3) δ ppm 8.65 (d, J = 8.6 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.45-7.35 (m, 5H), 7.10 (s, 1H), 5.24 (s, 2H); ES-LCMS m/z 331.6 [M+H]+. Step 4: Methyl 5-(benzyloxycarbonylamino)-6-(trifluoromethyl)pyridine-2-carboxylate
Figure imgf000078_0001
[00199] To a solution of benzyl N-[6-chloro-2-(trifluoromethyl)-3-pyridyl]carbamate (500 mg, 1.25 mmol, 1 eq) in MeOH (10 mL) was added TEA (380.96 mg, 3.76 mmol, 524.02 µL, 3 eq) and Pd(dppf)Cl2 (91.83 mg, 125.50 µmol, 0.1 eq). The suspension was degassed under vacuum and purged with CO several times. The mixture was stirred under CO (50 psi) at 80 °C for 24 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 5/1, TLC: PE/EtOAc = 3/1, Rf =0.57) to yield methyl 5-(benzyloxycarbonylamino)-6-(trifluoromethyl)pyridine-2-carboxylate (330 mg, 745.17 µmol, 59.4% yield, 80.0% purity) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ ppm 9.81 (s, 1H), 8.35-8.28 (m, 2H), 7.47-7.28 (m, 5H), 5.20 (s, 2H), 3.91 (s, 3H); ES-LCMS m/z 355.6 [M+H]+. Step 5: 5-(Methoxycarbonylamino)-6-(trifluoromethyl)pyridine-2-carboxylic acid
Figure imgf000078_0002
[00200] To a solution of methyl 5-(benzyloxycarbonylamino)-6-(trifluoromethyl)pyridine-2- carboxylate (330 mg, 745.17 µmol, 1 eq) in MeOH (3 mL) was added LiOH (1 M, 3.73 mL, 5 eq). The mixture was stirred at 25 °C for 2 h. The solvent was removed to yield a residue which was purified by preparative HPLC (column: Phenomenex Synergi C18150*30mm*4um; mobile phase: [water(0.05%HCl)-ACN]; B%: 24%-77%,10min), followed by lyophilization to yield 5- (methoxycarbonylamino)-6-(trifluoromethyl)pyridine-2-carboxylic acid (100 mg, 283.92 µmol, 38.1% yield, 75.0% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 9.67 (s, 1H), 9.18 (s, 1H), 8.30-8.21 (m, 2H), 3.69 (s, 3H); ES-LCMS m/z 265.2 [M+H]+. Step 6: Methyl N-[6-chlorocarbonyl-2-(trifluoromethyl)-3-pyridyl]carbamate
Figure imgf000079_0001
[00201] To a solution of 5-(methoxycarbonylamino)-6-(trifluoromethyl)pyridine-2-carboxylic acid (100 mg, 264.99 µmol, 1 eq) in DCM (3 mL) was added (COCl)2 (100.91 mg, 794.98 µmol, 69.59 µL, 3 eq). The mixture was stirred at 25 °C for 2 h. The solvent was removed to yield methyl N-[6-chlorocarbonyl-2-(trifluoromethyl)-3-pyridyl]carbamate (70 mg, crude) as a white solid. Step 7: Methyl N-[6-(1H-indole-3-carbonyl)-2-(trifluoromethyl)-3-pyridyl]carbamate
Figure imgf000079_0002
[00202] To a solution of indole (34.82 mg, 297.24 µmol, 1.2 eq) in DCM (3 mL) were added AlCl3 (33.03 mg, 247.70 µmol, 1 eq) and methyl N-[6-chlorocarbonyl-2-(trifluoromethyl)-3- pyridyl]carbamate (70 mg, 247.70 µmol, 1 eq). The mixture was stirred at 50 °C for 5 h. The solvent was removed to yield a residue which was purified by preparative HPLC (column: Phenomenex Synergi C18150*30mm*4um;mobile phase: [water(0.05%HCl)-ACN];B%: 41%- 71%,10min), followed by lyophilization to yield methyl N-[6-(1H-indole-3-carbonyl)-2- (trifluoromethyl)-3-pyridyl]carbamate (40 mg, 99.09 µmol, 40.0% yield, 90.0% purity) as a brown solid.1H NMR (400 MHz, CD3OD) δ ppm 11.70 (s, 1H), 9.01-8.98 (m, 1H), 8.53 (d, J = 8.8 Hz, 1H), 8.49-8.43 (m, 1H), 8.38 (d, J = 8.8 Hz, 1H), 7.53-7.45 (m, 1H), 7.31-7.23 (m, 2H), 3.83 (s, 3H); ES-LCMS m/z 364.1 [M+H]+. Step 8: [5-Amino-6-(trifluoromethyl)-2-pyridyl]-(1H-indol-3-yl)methanone
Figure imgf000079_0003
[00203] To a solution of methyl N-[6-(1H-indole-3-carbonyl)-2-(trifluoromethyl)-3- pyridyl]carbamate (30 mg, 74.32 µmol, 1 eq) in H2O (1 mL) and EtOH (1 mL) was added KOH (20.85 mg, 371.60 µmol, 5 eq). The mixture was stirred at 80 °C for 2 h. The solvent was removed to yield a residue which was purified by preparative TLC (PE/EtOAc = 2/1, TLC: PE/EtOAc = 2/1, Rf = 0.40), followed by lyophilization to yield [5-amino-6-(trifluoromethyl)-2- pyridyl]-(1H-indol-3-yl)methanone (14.75 mg, 48.32 µmol, 65.0% yield, 100.0% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 11.99 (s, 1H), 8.92 (d, J = 2.2 Hz, 1H), 8.42- 8.36 (m, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.53-7.47 (m, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.26-7.18 (m, 2H), 6.54 (s, 2H); ES-LCMS m/z 306.2 [M+H]+. I-18
Figure imgf000080_0001
Step 1: (E)-N,N-Dimethyl-2-(1-nitro-2-naphthyl)ethenamine
Figure imgf000080_0002
[00204] To a solution of 2-methyl-1-nitro-naphthalene (3.2 g, 17.09 mmol, 1 eq) in toluene (2 mL) was added 1-tert-butoxy-N, N, N', N'-tetramethyl-methanediamine (5.96 g, 34.19 mmol, 7.06 mL, 2 eq). The mixture was stirred at 120 °C for 3 h. The reaction mixture was quenched with PE (100 mL). The mixture was filtered, and the filter cake was rinsed with PE (30 mL x 2), dried to yield (E)-N,N-dimethyl-2-(1-nitro-2-naphthyl)ethenamine (2.9 g, 10.77 mmol, 63.0% yield, 90.0% purity) as a red solid, which was used into the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 7.73 (dd, J = 8.6, 12.5 Hz, 2H), 7.60-7.56 (m, 1H), 7.54-7.48 (m, 2H), 7.40-7.35 (m, 1H), 7.03 (d, J = 13.4 Hz, 1H), 5.15 (d, J = 13.4 Hz, 1H), 2.91 (s, 6H); ES-LCMS m/z 243.1 [M+H]+. Step 2: 1H-Benzo[g]indole
Figure imgf000081_0001
[00205] To a solution of (E)-N,N-dimethyl-2-(1-nitro-2-naphthyl)ethenamine (2.8 g, 10.40 mmol, 90%, 1 eq) in EtOH (40 mL) and H2O (5 mL) was added Fe (2.90 g, 52.01 mmol, 5 eq) and NH4Cl (5.56 g, 104.02 mmol, 10 eq). The mixture was stirred at 80 °C for 6 h. The mixture was filtered, and the filter cake was rinsed with PE (10 mL x 2), dried to yield a residue. The reaction mixture was quenched by addition of water (100 mL), extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 5/1, TLC: PE/EtOAc = 5/1, Rf = 0.79) to yield 1H- benzo[g]indole (1.5 g, 8.97 mmol, 86.2% yield, 100.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.90 (s, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.58-7.51 (m, 2H), 7.48-7.41 (m, 1H), 7.30 (t, J = 2.7 Hz, 1H), 6.72 (t, J = 2.4 Hz, 1H); ES-LCMS m/z 168.3 [M+H]+. Step 3: 1H-Benzo[g]indole-3-carbaldehyde
Figure imgf000081_0002
[00206] A solution of POCl3 (660.26 mg, 4.31 mmol, 400.16 µL, 1.2 eq) was added to DMF (2 mL) at 0 °C. Then a solution of 1H-benzo[g]indole (600 mg, 3.59 mmol, 100%, 1 eq) in DMF (0.7 mL) was added to the stirred mixture. The mixture was stirred at 80 °C for 1 h. The reaction mixture was quenched by addition of water (50 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.23) to yield 1H- benzo[g]indole-3-carbaldehyde (570 mg, 2.92 mmol, 81.3% yield, 100.0% purity) as yellow oil. 1H NMR (400MHz, CDCl3) δ ppm 10.18 (s, 1H), 9.63 (s, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 3.2 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.64- 7.57 (m, 1H), 7.56-7.50 (m, 1H); ES-LCMS m/z 196.0 [M+H]+. Step 4: 1-(2-Trimethylsilylethoxymethyl)benzo[g]indole-3-carbaldehyde
Figure imgf000082_0001
[00207] To a solution of 1H-benzo[g]indole-3-carbaldehyde (570 mg, 2.92 mmol, 100%, 1 eq) in THF (10 mL) was added NaH (291.96 mg, 7.30 mmol, 60%, 2.5 eq) at 0 °C. After stirring 30 min, SEM-Cl (973.60 mg, 5.84 mmol, 1.03 mL, 2 eq) was added to the above mixture dropwise and stirred at 0 °C for 1 h. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (50 mL x3). The combined organic layers were dried over Na2SO4, filtered and concentrated which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.65) to yield 1-(2- trimethylsilylethoxymethyl)benzo[g]indole-3-carbaldehyde (790 mg, 2.33 mmol, 79.8% yield, 96.0% purity) as a white solid.1H NMR (400MHz, CDCl3) δ ppm 10.15 (s, 1H), 8.55 (d, J = 8.6 Hz, 1H), 8.41 (d, J = 8.6 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.81-7.73 (m, 2H), 7.65-7.59 (m, 1H), 7.56-7.50 (m, 1H), 5.87 (s, 2H), 3.68 (t, J = 8.1 Hz, 2H), 0.97 (t, J = 8.1 Hz, 2H), -0.04 (s, 9H); ES-LCMS m/z 326.7 [M+H]+. Step 5: Methyl 5-(benzhydrylideneamino)-2-[hydroxy-[1-(2- trimethylsilylethoxymethyl)benzo[g]indol-3-yl]methyl]thiazole-4-carboxylate
Figure imgf000083_0001
[00208] To a solution of methyl 5-(benzhydrylideneamino)thiazole-4-carboxylate (834.65 mg, 2.33 mmol, 90%, 1 eq) and 1-(2-trimethylsilylethoxymethyl)benzo[g]indole-3-carbaldehyde (790 mg, 2.33 mmol, 96%, 1 eq) in THF (30 mL) was added LDA (1 M, 4.66 mL, 2 eq) at -70 °C. The mixture was stirred at -70 °C for 30 min under N2. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (50 mL x3). The combined organic layers were dried over Na2SO4, filtered and concentrated which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.23) to yield methyl 5- (benzhydrylideneamino)-2-[hydroxy-[1-(2-trimethylsilylethoxymethyl)benzo[g]indol-3- yl]methyl]thiazole-4-carboxylate (1 g, 864.39 µmol, 37.1% yield, 56.0% purity) as a yellow solid which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 8.55 (d, J = 8.8 Hz, 1H), 8.35 (s, 1H), 8.05 (s, 2H), 7.96 (d, J = 8.3 Hz, 2H), 7.62 ( s, 4H), 7.53 (s, 5H), 7.40-7.36 (m, 3H), 5.74 (s, 2H), 3.88 (s, 3H), 3.67-3.59 (m, 2H), 0.97-0.93 (m, 2H), -0.04 (s, 9H); ES-LCMS m/z 648.2 [M+H]+. Step 6: Methyl 5-(benzhydrylideneamino)-2-[1-(2- trimethylsilylethoxymethyl)benzo[g]indole-3-carbonyl]thiazole-4-carboxylate
Figure imgf000083_0002
[00209] To a solution of methyl 5-(benzhydrylideneamino)-2-[hydroxy-[1-(2- trimethylsilylethoxymethyl)benzo[g]indol-3-yl]methyl]thiazole-4-carboxylate (1 g, 864.39 µmol, 56%, 1 eq) in 1,2-dichlorethane (15 mL) was added MnO2 (1.50 g, 17.29 mmol, 20 eq). The mixture was stirred at 80 °C for 1 h. The mixture was filtered, and the filter cake was rinsed with PE (10 mL x 2), dried to yield a residue. The reaction mixture was quenched by addition of water (50 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.58) to yield methyl 5-(benzhydrylideneamino)-2-[1-(2- trimethylsilylethoxymethyl)benzo[g]indole-3-carbonyl]thiazole-4-carboxylate (520 mg, 724.64 µmol, 83.8% yield, 90.0% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 9.01 (s, 1H), 8.51 (d, J = 8.8 Hz, 1H), 8.42 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.68-7.45 (m, 12H), 6.05 (s, 2H), 3.82 (s, 3H), 3.66 (t, J = 7.9 Hz, 2H), 0.90 (t, J = 7.9 Hz, 2H), -0.12 (s, 9H); ES-LCMS m/z 464.2 [M+H]+. Step 7: Methyl 5-amino-2-(1H-benzo[g]indole-3-carbonyl)thiazole-4-carboxylate
Figure imgf000084_0001
[00210] To a solution of methyl 5-(benzhydrylideneamino)-2-[1-(2- trimethylsilylethoxymethyl)benzo[g]indole-3-carbonyl]thiazole-4-carboxylate (480 mg, 668.90 µmol, 90%, 1 eq) in DCM (10 mL) was added TFA (2.22 g, 19.45 mmol, 1.44 mL, 29.08 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated at 25 °C to yield a residue. The mixture was concentrated to yield a residue which was dissolved in THF (10 mL) .The mixture was adjusted pH to 9 by saturated KOH (112.59 mg, 2.01 mmol, 3 eq) solution then stirred at 25 °C for 1 h. The reaction mixture was quenched by addition of water (50 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Welch Xtimate C18150*25mm*5µm; mobile phase: [water(10 mM NH4HCO3)-ACN]; B%: 39%-69%, 10 min), followed by lyophilization to yield methyl 5-amino-2-(1H-benzo[g]indole-3-carbonyl)thiazole-4-carboxylate (30 mg, 81.96 µmol, 12.2% yield, 96.0% purity) as a yellow solid.1H NMR (400MHz, DMSO- d6) δ ppm 12.99 (s, 1H), 8.97 (d, J = 2.4 Hz, 1H), 8.43-8.34 (m, 2H), 8.04 (s, 2H), 8.01 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.55-7.48 (m, 1H), 3.86 (s, 3H); ES-LCMS m/z 352.0 [M+H]+. I-19
Figure imgf000085_0001
Step 1: 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde
Figure imgf000085_0002
[00211] To a mixture of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (2.3 g, 15.74 mmol, 1 eq) in THF (30 mL) was added NaH (1.26 g, 31.48 mmol, 60% purity, 2.0 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. SEM-Cl (3.94 g, 23.61 mmol, 4.18 mL, 1.5 eq) was added into the mixture at 0 °C. The mixture was stirred under N2 atmosphere at 30 °C for 15.5 h. TLC (PE/EtOAc = 3/1, Rf = 0.6) showed the reaction was completed. The mixture was added water (30 mL) which was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na2SO4, filtered and concentrated to yield a residue which was purified by silica gel column chromatography (from PE/EtOAc = 5/1 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.6) to yield 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3- b]pyridine-3-carbaldehyde (1.8 g, 5.86 mmol, 37.2% yield, 90.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 10.08-9.99 (m, 1H), 8.58 (dd, J = 1.5, 7.8 Hz, 1H), 8.45 (dd, J = 1.6, 4.8 Hz, 1H), 8.01 (s, 1H), 7.30 (dd, J = 4.6, 7.8 Hz, 1H), 5.75 (s, 2H), 3.68-3.52 (m, 2H), 1.05-0.87 (m, 2H), -0.05 (s, 9H); ES-LCMS m/z 277.7 [M+H]+. Step 2: Methyl 5-((diphenylmethylene)amino)-2-(hydroxy(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)thiazole-4- carboxylate
Figure imgf000086_0001
[00212] To a stirred solution of DIPA (593.24 mg, 5.86 mmol, 828.55 µL, 3 eq) in THF (60 mL) was added n-BuLi (2.5 M, 2.35 mL, 3 eq) dropwise under N2 atmosphere at -75 °C. The reaction mixture was stirred under N2 atmosphere at -75 °C for 30 min, which was dropwise into the mixture of 1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-3-carbaldehyde (540.16 mg, 1.76 mmol, 90% purity, 0.9 eq) and methyl 5-(benzhydrylideneamino)thiazole-4-carboxylate (700 mg, 1.95 mmol, 90% purity, 1 eq) in THF (60 mL). The mixture was stirred under N2 atmosphere at -75 °C for 2 h. TLC (PE/EtOAc = 2/1, Rf = 0.35) showed the reaction was completed. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 2/1, TLC: PE/EtOAc = 2/1, Rf = 0.35) to yield methyl 5- ((diphenylmethylene)amino)-2-(hydroxy(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3- b]pyridin-3-yl)methyl)thiazole-4-carboxylate (500 mg, 751.52 µmol, 38.5% yield, 90.0% purity). 1H NMR (400 MHz, CDCl3) δ ppm 8.34 (dd, J = 1.6, 4.7 Hz, 1H), 7.72 (dd, J = 1.6, 7.8 Hz, 2H), 7.39 (s, 7H), 7.30-7.26 (m, 3H), 7.05 (dd, J = 4.7, 7.8 Hz, 1H), 6.16 (d, J = 3.5 Hz, 1H), 5.66- 5.58 (m, 2H), 3.87 (s, 3H), 3.60-3.50 (m, 2H), 3.16 (d, J = 3.9 Hz, 1H), 0.95-0.89 (m, 2H), -0.06 (s, 9H); ES-LCMS m/z 599.4, [M+H]+. Step 3: Methyl 5-((diphenylmethylene)amino)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridine-3-carbonyl)thiazole-4-carboxylate
Figure imgf000087_0001
[00213] To a solution of methyl 5-(benzhydrylideneamino)-2-[hydroxy-[1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-3-yl]methyl]thiazole-4-carboxylate (500 mg, 751.52 µmol, 90.0% purity, 1 eq) in CHCl3 (10 mL) was added MnO2 (1.96 g, 22.55 mmol, 30 eq). The mixture was stirred under N2 atmosphere at 70 °C for 1 h. The mixture was filtered, washed with DCM (20 mL x 2). The filtrate was concentrated to yield a residue which was purified by silica gel column chromatography (from PE/EtOAc = 5/1 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.5) to yield methyl5-((diphenylmethylene)amino)-2-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)thiazole-4-carboxylate (400 mg, 603.25 µmol, 80.3% yield, 90.0% purity) as yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 9.18 (s, 1H), 8.69 (dd, J = 1.6, 7.8 Hz, 1H), 8.42 (dd, J = 1.6, 4.7 Hz, 1H), 7.68-7.37 (m, 10H), 7.32-7.28 (m, 1H), 5.78 (s, 2H), 3.92 (s, 3H), 3.68-3.59 (m, 2H), 1.00-0.90 (m, 2H), -0.05 (s, 9H); ES-LCMS m/z 597.6, [M+H]+. Step 4: Methyl 5-amino-2-(1-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridine-3- carbonyl)thiazole-4-carboxylate
Figure imgf000088_0001
[00214] To a solution of methyl 5-(benzhydrylideneamino)-2-[1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-3-carbonyl]thiazole-4-carboxylate (400 mg, 603.25 µmol, 90% purity, 1 eq) in DCM (1 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 22.39 eq) at 23 °C. The mixture was stirred under N2 atmosphere at 23 °C for 1 h. The mixture was neutralized with 2 N NaHCO3 to pH = 7, concentrated, diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to yield methyl 5-amino-2-(1- (hydroxymethyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)thiazole-4-carboxylate (200 mg, 601.80 µmol, 99.8% yield, N/A purity) as yellow oil, which was used in the next step without further purification. ES-LCMS m/z 333.2 [M+H]+. Step 5: Methyl 5-amino-2-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)thiazole-4-carboxylate
Figure imgf000088_0002
[00215] To a solution of methyl 5-amino-2-[1-(hydroxymethyl)pyrrolo[2,3-b]pyridine-3- carbonyl]thiazole-4-carboxylate (200 mg, 601.80 µmol, N/A purity, 1 eq) in THF (100 mL) was added KOH (5 M, 120.36 µL, 1 eq). The mixture was stirred under N2 atmosphere at 25 °C for 0.1 h. The mixture was adjusted pH to 7 with 1 N HCl and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to yield a residue which was purified by preparative HPLC ( [water ( 0.05% NH3H2O+10mM NH4HCO3)-ACN]; B%: 25%-55%), followed by lyophilization to yield methyl 5-amino-2-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)thiazole-4-carboxylate (11 mg, 36.39 µmol, 6.1% yield, 100.0% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 8.99 (s, 1H), 8.55 (d, J = 7.4 Hz, 1H), 8.36 (dd, J = 1.6, 4.7 Hz, 1H), 7.29 (dd, J = 4.7, 7.8 Hz, 1H), 3.84 (s, 3H); ES-LCMS m/z 303.2 [M+H]+. I-21
Figure imgf000089_0001
Step 1: Methyl 3-(4-isopropylthiazole-2-carbonyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxylate
Figure imgf000089_0002
[00216] To a solution of 4-isopropylthiazole-2-carbonyl chloride (172.25 mg, 908.20 µmol, 1 eq) in DCM (5 mL) was added AlCl3 (605.50 mg, 4.54 mmol, 5 eq) and methyl 1H-pyrrolo[2,3- b]pyridine-6-carboxylate (160 mg, 908.20 µmol, 1 eq). The mixture was stirred at 75 °C for 12 h. The reaction mixture was quenched by addition of MeOH (50 mL) slowly at 0 °C, concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from EtOAc/MeOH = 10/1, TLC: EtOAc/MeOH = 10/1, Rf = 0.20) first and by preparative HPLC (column: Boston Prime C18150*30mm*5µm; mobile phase: [water (0.05% NH3H2O+10mM NH4HCO3)-ACN]; B%: 58%-88%, 10 min), followed by lyophilization to yield methyl 3-(4-isopropylthiazole-2-carbonyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (8 mg, 22.88 µmol, 2.5% yield, 94.2% purity) as a white solid.1H NMR (500 MHz, DMSO-d6) δ ppm 9.37 (s, 1H), 8.74 (d, J = 8.1 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.80 (s, 1H), 3.92 (s, 3H), 3.22 (td, J = 6.8, 13.8 Hz, 1H), 1.37 (d, J = 6.9 Hz, 6H); ES-LCMS m/z 330.0 [M+H]+. I-22
Figure imgf000089_0003
Step 1: 3-[(E)-[3-(4-Isopropylthiazole-2-carbonyl)-1H-indol-4-yl]azo]benzoic acid
Figure imgf000090_0001
[00217] To a solution of (4-amino-1H-indol-3-yl)-(4-isopropylthiazol-2-yl)methanone (400 mg, 1.09 mmol, 1 eq) in toluene (2 mL) and H2O (8 mL) was added methyl 3-nitrosobenzoate (722.24 mg, 4.37 mmol, 100.0%, 4 eq) and NaOH (437.34 mg, 10.93 mmol, 10 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The aqueous layer was concentrated in vacuum to yield a residue which was purified by preparative HPLC (column: Boston Prime C18150*30 mm*5 µm; mobile phase: [water (0.05% NH3·H2O+10 mM NH4HCO3)-ACN]; B%: 19%-49%, 10 min), followed by lyophilization to yield 3-[(E)-[3-(4- isopropylthiazole-2-carbonyl)-1H-indol-4-yl]azo]benzoic acid (9.02 mg, 19.85 µmol, 1.8% yield, 92.1% purity) as a yellow solid.1H NMR (500 MHz, CD3OD) δ ppm 8.57 (s, 1H), 8.42 (s, 1H), 8.09 (d, J = 7.5 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.55 (d, J = 7.6 Hz, 2H), 7.44-7.41 (m, 1H), 7.32 (s, 1H), 3.06-3.01 (m, 1H), 1.24 (d, J = 7.0 Hz, 6H); ES-LCMS m/z 731.4 [M+H]+. I-25
Figure imgf000090_0002
Step 1: 1-(2-Trimethylsilylethoxymethyl)indazole-3-carbaldehyde
Figure imgf000091_0001
[00218] To a solution of 1H-indazole-3-carbaldehyde (1 g, 6.84 mmol, 1 eq) in THF (20 mL) was added NaH (301.07 mg, 7.53 mmol, 60%, 1.1 eq) at 0 °C under N2. After being stirred for 30 min, SEM-Cl (1.37 g, 8.21 mmol, 1.45 mL, 1.2 eq) was added. The mixture was stirred at 25 °C for 12 h. TLC (PE/EtOAc = 5/1, Rf = 0.72) indicated the starting material was consumed completely and two new spots formed. The reaction mixture was quenched by addition of water (100 mL), extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue. The residue was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 10/1, TLC: PE/EtOAc = 5/1, Rf = 0.72) to yield 1-(2-trimethylsilylethoxymethyl)indazole-3- carbaldehyde (1.1 g, 3.78 mmol, 55.2% yield, 95.0% purity) as colorless oil.1H NMR (500 MHz, CDCl3) δ ppm 10.27 (s, 1H), 8.33 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.44-7.37 (m, 1H), 5.84 (s, 2H), 3.65-3.54 (m, 2H), 0.97-0.84 (m, 2H), -0.05 (s, 9H); ES-LCMS m/z 277.2 [M+H]+. Step 2: 2-Isopropyl-N,N-dimethyl-imidazole-1-sulfonamide
Figure imgf000091_0002
[00219] To a solution of 2-isopropyl-1H-imidazole (2 g, 18.16 mmol, 1 eq) in DMF (20 mL) was added NaH (2.18 g, 54.47 mmol, 60%, 3 eq). After being stirred for 30 min, N,N- dimethylsulfamoyl chloride (3.39 g, 23.60 mmol, 2.53 mL, 1.3 eq) was added at 0 °C under N2. The mixture was stirred at 25 °C for 1 h. TLC (PE/EtOAc = 3/1, Rf = 0.73) indicated the starting material was consumed completely and one new spot formed. The reaction mixture was quenched by addition of water (50 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue. The residue was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.73) to yield 2- isopropyl-N,N-dimethyl-imidazole-1-sulfonamide (2.5 g, 11.26 mmol, 62.0% yield, 97.9% purity) as colorless oil.1H NMR (500 MHz, CDCl3) δ ppm 7.26 (d, J = 1.5 Hz, 1H), 7.04 (d, J = 1.5 Hz, 1H), 3.58 (td, J = 6.8, 13.6 Hz, 1H), 2.96 (s, 6H), 1.45-1.41 (m, 6H); ES-LCMS m/z 218.2 [M+H]+. Step 3: 5-[Hydroxy-[1-(2-trimethylsilylethoxymethyl)indazol-3-yl]methyl]-2-isopropyl-N,N- dimethyl-imidazole-1-sulfonamide
Figure imgf000092_0001
[00220] To a solution of 2-isopropyl-N,N-dimethyl-imidazole-1-sulfonamide (495.84 mg, 2.23 mmol, 97.9%, 1.3 eq) in THF (20 mL) was added n-BuLi (2.5 M, 2.06 mL, 3 eq) at -70 °C under N2. After being stirred for 30 min, the solution was warmed to 0 °C, left stirred another 30 min. The solution was cooled to -70 °C again, added dropwise a solution of 1-(2- trimethylsilylethoxymethyl)indazole-3-carbaldehyde (500 mg, 1.72 mmol, 95% purity, 1 eq) in THF ( 1 mL). The mixture was stirred at -70 °C for 2 h. TLC (PE/EtOAc = 3/1, Rf = 0.22) indicated about half of the starting material was remained and one new spot formed. The reaction mixture was quenched by addition of NH4Cl (30 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 2/1, TLC: PE/EtOAc = 3/1, Rf = 0.22) to yield 5- [hydroxy-[1-(2-trimethylsilylethoxymethyl)indazol-3-yl]methyl]-2-isopropyl-N,N-dimethyl- imidazole-1-sulfonamide (90 mg, 169.36 µmol, 9.8% yield, 92.9% purity) as colorless oil. ES- LCMS m/z 494.6 [M+H]+. Step 4: 2-Isopropyl-N,N-dimethyl-5-[1-(2-trimethylsilylethoxymethyl)indazole-3- carbonyl]imidazole-1-sulfonamide
Figure imgf000093_0001
[00221] To a solution of 5-[hydroxy-[1-(2-trimethylsilylethoxymethyl)indazol-3-yl]methyl]-2- isopropyl-N,N-dimethyl-imidazole-1-sulfonamide (90 mg, 169.36 µmol, 92.9%, 1 eq) in DCE (5 mL) was added MnO2 (220.86 mg, 2.54 mmol, 15 eq) under N2. The mixture was stirred at 80 °C for 2 h. The mixture was filtered, and the cake was rinsed with EtOAc (10 mL x 2). The filtrate was concentrated under reduced pressure to yield 2-isopropyl-N,N-dimethyl-5-[1-(2- trimethylsilylethoxymethyl)indazole-3-carbonyl]imidazole-1-sulfonamide (75 mg, crude) as colorless oil, which was used in the next step without further purification.1H NMR (500 MHz, DMSO-d6) δ ppm 8.41 (d, J = 8.1 Hz, 1H), 7.70-7.64 (m, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.43- 7.36 (m, 1H), 5.82 (s, 2H), 3.70 (td, J = 6.8, 13.5 Hz, 1H), 3.60 (t, J = 8.1 Hz, 2H), 3.10 (s, 6H), 1.43 (d, J = 6.7 Hz, 6H), 0.92-0.88 (m, 2H), -0.06 (s, 9H); ES-LCMS m/z 492.1 [M+H]+. Step 5: (2-Isopropyl-1H-imidazol-5-yl)-[1-(2-trimethylsilylethoxymethyl)indazol-3- yl]methanone
Figure imgf000093_0002
[00222] To a solution of 2-isopropyl-N,N-dimethyl-5-[1-(2- trimethylsilylethoxymethyl)indazole-3-carbonyl]imidazole-1-sulfonamide (75 mg, 152.54 µmol, 1 eq) in THF (5 mL) was added conc. HCl (12 M, 1 mL, 78.67 eq) under N2. The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated to yield (2-isopropyl-1H- imidazol-5-yl)-[1-(2-trimethylsilylethoxymethyl)indazol-3-yl]methanone (58 mg, crude) as a white solid, which was used in the next step without further purification. ES-LCMS m/z 385.1 [M+H]+. Step 6: 1H-Indazol-3-yl-(2-isopropyl-1H-imidazol-5-yl)methanone
Figure imgf000094_0001
[00223] To a solution of (2-isopropyl-1H-imidazol-5-yl)-[1-(2- trimethylsilylethoxymethyl)indazol-3-yl]methanone (52 mg, 135.22 µmol, 1 eq) in DCM (10 mL) was added TFA (4.62 g, 40.52 mmol, 3 mL, 299.64 eq) under N2. The mixture was stirred at 20 °C for 12 h. The mixture was concentrated under reduced pressure to yield a residue, which was dissolved in MeCN (5 mL), added NH3·H2O (16.93 mg, 135.22 µmol, 18.60 µL, 28%, 1 eq). The resulting mixture was stirred for 2 h at 20 °C. The reaction mixture was concentrated to yield a residue which was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5µm; mobile phase: [water (0.05% NH3H2O+10mM NH4HCO3)-ACN]; B%: 25%- 55%, 10 min), followed by lyophilization to yield 1H-indazol-3-yl-(2-isopropyl-1H-imidazol-5- yl)methanone (15.75 mg, 61.94 µmol, 45.8% yield, 100% purity) as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 8.36 (d, J = 8.2 Hz, 1H), 8.33 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.35-7.28 (m, 1H), 3.17 (td, J = 7.0, 14.1 Hz, 1H), 1.38 (d, J = 7.0 Hz, 6H); ES- LCMS m/z 255.1 [M+H]+. Example 2. In Vitro Assay DRE-Luciferase Reporter Assay [00224] AHR binds to Dioxin Responsive Elements (DRE) upstream of genes that it activates. One measure of AHR activity is activation of a reporter gene, such as luciferase, downstream of one or multiple DRE elements. Luciferase activity will reflect activation and inhibition of AHR in the cells expressing this reporter. [00225] Murine Hepa1-6 or Hepa-1c1c7 or other murine cell line with a DRE-luciferase reporter either stably or transiently transfected are plated in media in plates (96-well, 384-well or other plates) and incubated overnight at 37C in a CO2 incubator. Likewise, human HepG2 or other human cell line with a DRE-luciferase reporter either stably or transiently transfected are plated in media in plates (96-well, 384-well or other plates) and incubated overnight at 37C in a CO2 incubator. [00226] The next day, an AHR agonist compound is added. Cells are incubated for 6, 16 or 24 hours or another time point and then lysed for determination of luciferase activity as a read-out of the AHR activation. Luciferase can be measured with a commercial kit such as the Promega Luciferase kit or any kit or reagents that provide the luciferin substrate for measuring luciferase activity. The level of luciferase with only activating ligand (e.g. such as TCDD, kynurenine, ITE (2-(1H-indole-3-ylcarbonyl)-4-thiazolecarboxylic methyl ester), VAF347, BNF (beta- naphthoflavone), ICZ (6-formylindolo(3,2-b) carbazole or other AHR ligands) added is the maximum signal while the luciferase with no ligand is the minimum signal. EC50s can be determined as the concentration which activates half of the maximum luciferase activity. [00227] In some embodiments, compounds have an EC50 > 1 μM. In some embodiments, compounds have an EC50 < 1 μM. In some embodiments, compounds have an EC50 < 0.1 μM. In some embodiments, compounds have an EC50 < 0.01 μM. P450 CYP1A1 Luciferase Assay [00228] AHR binds to Dioxin Responsive Elements (DRE) upstream of genes that it activates. One measure of AHR activity is P450 CYP1A1 protein levels determined by measuring CYP1A1 enzyme activity using a luminogenic CYP1A1 luciferin-based substrate. Luciferase activity will reflect CYP1A1 activity resulting from activation of AHR in the cells. [00229] Murine Hepa1-6 or Hepa-1c1c7 or other murine cell line, human HepG2 or other human cell line are plated in media (96-well, 384-well or other plates) and incubated overnight at 37C in a CO2 incubator. [00230] The next day, an AHR agonist compound is added. Cells are incubated for 6, 16 or 24 hours or another time point and then lysed and incubated with a CYP1A1 luciferase-based substrate (e.g., Luciferin-CEE) for 3, 6, or 12 hours of another time point. Determination of luciferase activity as a read-out of CYP1A1 enzyme activity can be measured with a commercial kit such as the Promega P450 Glo CYP1A1 detection reagent or any kit or reagents that provide for measuring luciferase activity. The level of luciferase with only activating ligand (e.g., such as TCDD, kynurenine, ITE (2-(1H-indole-3-ylcarbonyl)-4-thiazolecarboxylic methyl ester), VAF347, BNF (beta-naphthoflavone), ICZ (6-formylindolo(3,2-b) carbazole or other AHR ligands) added is the maximum signal while the luciferase with no ligand is the minimum signal. EC50s can be determined as the concentration which activates half of the maximum luciferase activity. [00231] Certain compounds were tested in the assays. The data are listed in Table 2 below. A: EC50 ≤ 0.010 μM; B: 0.010 μM < EC50 ≤ 0.1 μM; C: 0.1 μM < EC50 ≤ 1.0 μM; and D: EC50 > 1.0 μM. Table 2. In vitro Data of Certain Exemplary Compounds.
Figure imgf000096_0001
Example 3. Liver and Colon Pharmacodynamics (PD) Assays and Methods [00232] C57BL/6N mice are weighed and randomized into treatment groups with group size of 3-5 mice. On study Day 1, treatment is initiated and necropsies follow on day 1 at 4 and 12 hours post-dose and on Day 2, 24 hours post-dose. [00233] On Day 1, mice are dosed orally with one dose of the AHR agonist compound(s) that are in a suspension and mixed well before dosing. At the designated time, animals are euthanized and plasma and tissue taken for compound levels (PK) and compound effect (PD) on gene expression. Liver samples and proximal colon are weighed and then frozen for subsequent RNA extraction and RT-PCR analysis. AHR activation is determined by measuring Cyp1a1 gene expression relative to a housekeeping gene, such as GAPDH or HPRT. Cyp1a1 expression levels in the liver are compared to Cyp1a1 levels in the colon to determine a colon:liver ratio, in order to assess the level of “GI-preferred” AHR activation. Example 4: DSS IBD Study Method [00234] On study day -1, C57Bl/6 mice are weighed and randomized into treatment groups based on body weight. On study day 0, treatment groups are given 2.5% DSS in drinking water and treatment is initiated on the same day, with either vehicle or AHR agonist compound(s). [00235] On study day 7, DSS drinking water is replaced with normal drinking water for the remainder of the study. Body weight is measured daily during the entire study. [00236] On study day 10, animals are anesthetized with Isoflurane and bled to exsanguination followed by cervical dislocation. The entire colon is removed and measured for length, weight, and weight per length. Overall efficacy of test AR agonist compounds is based on body weight, colon length, and colon histopathology. [00237] Histopathology data is assessed for appropriate parameters, as determined by a pathologist and the parameters for these DSS studies can include inflammation, erosion, gland loss, edema, hyperplasia, neutrophil count ,mucosal thickening, lymphoid aggregate count and lymphoid aggregate size. The different parameter scores can be added for a summed score for the study histopathology. Example 5: Th17 Assay [00238] On Day 1, naive CD62L+ human T-Cells are plated in a 96 well plate (25,000 cells in 200uL media). Cells are activated with human CD3/CD28 tetramer (12.5µL/1x106 cells) and differentiated with human Th17 cytokines (50 ng/mL IL-6, 20 ng/mL IL-1β, 10 ng/mL IL-23, 1 ng/mL TGF-β, 12 µg/mL anti-human IFN- º antibody and 10 µg/mL anti-human IL-4 antibody) for 10 days. Media containing cytokine cocktail and CD3/CD28 is refreshed every 2-3 days. [00239] On Day 10, cell supernatant is collected and frozen for cytokine analysis. Cells are stimulated with 1x Cell Stimulation Cocktail (PMA and Ionomycin) for 5 hours. After 5 hours of stimulation, cells are stained for intracellular cytokines (human CD4, IL-17A, IL-22). Samples are run on BD LSR FORTESSA and analyzed in FLOWJO software. Example 6: Treg Assay [00240] On day 0, naïve T cells from cryopreserved human derived PBMCs are isolated. These cells are plated in 48 well plate at 500,000 cells/mL concentration with human CD3/CD28 activation tetramer (12.5 µL/1x106 cells) and differentiated into regulatory T cells (Tregs) with 1 ng/mL TGF-β and 5 ng/mL human recombinant IL-2 in the presence of DMSO or different concentrations of AHR agonist compounds. [00241] On day 5, the Tregs are counted and washed. CD25- Effector T cells (Teffs) are isolated from the same human donor and labeled with Cell Trace Violet. The Tregs and Teffs are cocultured for 4 days in 96 well plate at 1:2 or 1:1 ratio with human CD3/CD28 tetramer (12.5 µL/1x106 cells). [00242] At the end of a 4 day co-culture, the cells are washed and stained with LiveDead stain. The cells are run on a flow cytometer and analyzed using FLOWJO software. Example 7: T cell Transfer IBD model [00243] On study day 0, donor Balb/C mice are terminated, and spleens obtained for CD4+CD45RBhigh cell isolation (Using a SCID IBD Cell Separation Protocol). After cells have been sorted and obtained, each recipient SCID animal receives an IP injection of, at a minimum, 4 X 105 cells (200 µl/mouse injections). [00244] Also on study day 0, SCID mice are weighed and randomized into treatment groups based on body weight. On study day 14, AHR agonist compound treatments are initiated and dosed orally daily; the control group receiving anti-IL12 (0.5 mg/mouse) is dosed IP once a week. [00245] On study day 49, animals are anesthetized with Isoflurane and bled to exsanguination followed by cervical dislocation. The entire colon is removed, measured, and weighed. Overall efficacy of AHR agonist compounds are based on a ratio of colon weight to length, and colon histopathology and colon cytokines (Th17 panel). Example 8: IBD ex vivo treat methods [00246] The studies described herein are to assess the effect of various AHR agonist compounds in human Crohn’s and ulcerative colitis tissue cultures ex vivo. Following this culture, the resulting culture supernatant samples are collected for analysis of cytokine release. Briefly, Crohn’s Disease or ulcerative colitis donor samples are obtained with full ethical consent from patients undergoing therapeutic resection for Crohn’s disease or ulcerative colitis. A minimum of 18 x 5 mm2 mucosal biopsies are taken using a scalpel. Three baseline biopsy samples are collected at time 0, and a minimum of 9 biopsies are incubated in 12 well culture plates. Tissues are placed apical (mucosal) side facing upwards on a Netwell filter. The biopsies are then cultured in either control media or media fortified with the appropriate AHR agonist compound in an incubator at 37 °C and high O2 atmospheric conditions (95% O2/5% CO2). To minimize variation, the biopsies are cultured in the presence of the inflammatory stimulant Staphylococcal Enterotoxin B (SEB) to normalize cytokine levels. The positive control BIRB796 (Selleck Chemicals catalogue No: S1574) is purchased as a powder. A 1 mM stock solution is prepared in DMSO and used at 1 μM. At approximately 18 hours post-culture start, media samples are collected, protease inhibitor is added and samples are stored at -80 °C. Supernatant is collected at the 18-hour timepoint and divided into aliquots for cytokine analysis: analysis of cytokines, such as TNF- ^, IFN- º, IL-1β, IL17- ^, IL-22, and IL-10) are performed in duplicate after completion of each set of 3 donors. [00247] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the application and appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

CLAIMS What is claimed is: 1. A compound of Formula (I):
Figure imgf000100_0001
or a pharmaceutically acceptable salt thereof, wherein: Ring A is an optionally substituted 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S, or an optionally substituted 6-10 membered bicyclic or bridged bicyclic saturated or partially unsaturated carbocyclic ring; Ring B is selected from
Figure imgf000100_0002
Figure imgf000100_0003
wherein X is N or CR6; Y is N or CR2; Z is N or CR4; and W is NR1, O, or S; each of R1, R2, R3, R4, and R6 is independently halogen, -CN, -NO2, RW, -C(O)-RW, -C(=NRW)- RW, -N(RW)-C(O)-RW, -N(RW)-C(=NRW)-RW, -OC(O)-RW, -OC(=NRW)-RW, -S(O)2-RW, - N(RW)-S(O)2-RW, -OS(O)2-RW, -S(O)-RW, -N(RW)-S(O)-RW, or -OS(O)-RW; R5 is -R, -C(O)-RW, -C(=NRW)-RW, -S(O)2-RW, or -S(O)-RW; RW is -R, -N(R)2, -NR-OR, -N(R)-N(R)2, -N(OR)-N(R)2, -N(R)-N(OR)R, -OR, -O-N(R)2, -N=NR, or –SR; and R is hydrogen, optionally substituted C1-6 aliphatic, or an optionally substituted ring selected from a 3-7 membered carbocyclic ring, a 3-7 membered heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, phenyl, and a 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S, or two R’s together with the nitrogen to which they attach form an optionally substituted 4-7 membered heterocyclic ring having 0-2 heteroatoms independently selected from N, O, or S in addition to the nitrogen to which the two R’s attach, provided that, when Ring A is an optionally substituted 5-membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S, at least one of X, Y, and Z of is N, and with the proviso that the compound is not
Figure imgf000101_0001
. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is
Figure imgf000101_0002
, wherein each of R7 and R8 is independently halogen, -CN, -NO2, RW, -C(O)-RW, -C(=NRW)-RW, -N(RW)-C(O)-RW, -N(RW)-C(=NRW)-RW, -OC(O)-RW, -OC(=NRW)-RW, -S(O)2- RW, -N(RW)-S(O)2-RW, -OS(O)2-RW, -S(O)-RW, -N(RW)-S(O)-RW, or -OS(O)-RW. 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is
Figure imgf000101_0003
wherein each of R7 and R8 is independently halogen, -CN, -NO2, RW, -C(O)-RW, -C(=NRW)-RW, -N(RW)-C(O)-RW, -N(RW)-C(=NRW)-RW, -OC(O)-RW, - OC(=NRW)-RW, -S(O)2-RW, -N(RW)-S(O)2-RW, -OS(O)2-RW, -S(O)-RW, -N(RW)-S(O)-RW, or - OS(O)-RW.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A
Figure imgf000102_0002
. 7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof,
Figure imgf000102_0001
8. The compound of claim 1, wherein the compound is a compound selected from Formulas (II-a) to (II-p):
Figure imgf000103_0001
(II-j) (II-k) (II-l)
Figure imgf000104_0001
(II-o) (II-p) , or a pharmaceutically acceptable salt thereof, wherein each of R7, R8, and R12 is independently halogen, -CN, -NO2, RW, -C(O)-RW, -C(=NRW)-RW, -N(RW)-C(O)-RW, -N(RW)-C(=NRW)-RW, - OC(O)-RW, -OC(=NRW)-RW, -S(O)2-RW, -N(RW)-S(O)2-RW, -OS(O)2-RW, -S(O)-RW, -N(RW)- S(O)-RW, or -OS(O)-RW. 9. The compound of claim 1, wherein the compound is a compound selected from Formulas (III-a) to (III-l):
Figure imgf000104_0002
Figure imgf000105_0001
, (III-j) (III-k) (III-l) , or a pharmaceutically acceptable salt thereof, wherein each of R7 and R8 is independently halogen, -CN, -NO2, RW, -C(O)-RW, -C(=NRW)-RW, -N(RW)-C(O)-RW, -N(RW)-C(=NRW)-RW, -OC(O)- RW, -OC(=NRW)-RW, -S(O)2-RW, -N(RW)-S(O)2-RW, -OS(O)2-RW, -S(O)-RW, -N(RW)-S(O)-RW, or -OS(O)-RW. 10. The compound of claim 1, wherein the compound is a compound of Formula (IV-a) or (IV-b):
Figure imgf000105_0002
(IV-a) (IV-b) , or a pharmaceutically acceptable salt thereof, wherein each of R7 and R8 is independently halogen, -CN, -NO2, RW, -C(O)-RW, -C(=NRW)-RW, -N(RW)-C(O)-RW, -N(RW)-C(=NRW)-RW, -OC(O)- RW, -OC(=NRW)-RW, -S(O)2-RW, -N(RW)-S(O)2-RW, -OS(O)2-RW, -S(O)-RW, -N(RW)-S(O)-RW, or -OS(O)-RW. 11. A compound selected from those listed Table 1, or a pharmaceutically acceptable salt thereof. 12. A pharmaceutical composition comprising the compound of any one of the claims 1-11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 13. A method for treating or preventing or reducing the risk of an angiogenesis implicated disorder in a patient comprising administering to the patient the compound of any one of the claims 1-11, or a pharmaceutically acceptable salt thereof. 14. The method of claim 13, wherein the angiogenesis implicated disorder is retinopathy, psoriasis, rheumatoid arthritis, obesity, or cancer. 15. A method for treating or preventing or reducing the risk of an inflammatory disorder in a patient comprising administering to the patient the compound of any one of the claims 1-11, or a pharmaceutically acceptable salt thereof.
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