US10385036B2 - Sulfonamide-substituted indole modulators of RORC2 and methods of use thereof - Google Patents

Sulfonamide-substituted indole modulators of RORC2 and methods of use thereof Download PDF

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US10385036B2
US10385036B2 US15/547,228 US201615547228A US10385036B2 US 10385036 B2 US10385036 B2 US 10385036B2 US 201615547228 A US201615547228 A US 201615547228A US 10385036 B2 US10385036 B2 US 10385036B2
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compounds
compound
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methyl
certain embodiments
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US20180273504A1 (en
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Mark Edward Schnute
Andrew Christopher Flick
Peter Jones
Neelu Kaila
Scot Richard Mente
John David Trzupek
Michael L. Vazquez
Goran Mattias Wennerstal
Li Xing
Edouard Zamaratski
Liying Zhang
Rayomand J. Unwalla
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Pfizer Corp SRL
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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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • Retinoid-related orphan receptors are reported to have an important role in numerous biological processes. Scientific investigations relating to each of retinoid-related orphan receptors ROR ⁇ , ROR ⁇ , and ROR ⁇ have been described in the literature. Continuing research in this field is spurred by the promise of developing new therapeutic agents to treat medical disorders associated with retinoid-related orphan receptor activity.
  • ROR ⁇ has been reported to be expressed in high concentration in various tissues, such as thymus, kidney, liver, muscle, and certain fat tissue.
  • Two isoforms of ROR ⁇ have been identified and are referred to as ⁇ 1 and ⁇ 2 (also referred to as ROR ⁇ t).
  • Expression of the ⁇ 2 isoform has been reported to appear in, for example, double-positive thymocytes.
  • Compounds capable of modulating RORyt activity are contemplated to provide a therapeutic benefit in the treatment of multiple medical disorders, including immune and inflammatory disorders.
  • Psoriasis is a T cell-mediated inflammatory disease that affects approximately 2% to 3% of adults and has a substantial adverse impact on the quality of life for patients suffering from this disorder. Plaques resulting from psoriasis can be painful and are visually unappealing.
  • Various therapeutics have been developed in an attempt to treat psoriasis. However, the traditional therapies for psoriasis often have toxic adverse effects. Accordingly, a need exists for improved treatments for psoriasis as well as other immune and inflammatory disorders.
  • the present invention provides compounds, pharmaceutical compositions, methods of inhibiting ROR ⁇ activity and/or reducing the amount of IL-17 in a subject, and methods of treating various medical disorders using such compounds.
  • one aspect of the invention relates to compounds represented by Formula I:
  • R 1 , X and W are as defined in the Detailed Description.
  • Another aspect of the invention provides a method of treating a subject suffering from a medical disorder.
  • the method comprises administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as described in the Detailed Description.
  • a large number of disorders may be treated using the compounds described herein.
  • the compounds described herein may be used to treat an immune disorder or inflammatory disorder, such as rheumatoid arthritis, psoriasis, chronic graft-versus-host disease, acute graft-versus-host disease, Crohn's disease, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren's syndrome, scleroderma, ulcerative colitis, asthma, epidermal hyperplasia, and other medical disorders described herein.
  • an immune disorder or inflammatory disorder such as rheumatoid arthritis, psoriasis, chronic graft-versus-host disease, acute graft-versus-host disease, Crohn's disease, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Celiac Sprue, idiopathic thro
  • the invention provides compounds, pharmaceutical compositions, methods of modulating ROR ⁇ activity and/or reducing the amount of IL-17 in a subject, and therapeutic uses of said compounds and pharmaceutical compositions.
  • the practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in “Comprehensive Organic Synthesis” (B. M. Trost & I. Fleming, eds., 1991-1992); “Handbook of experimental immunology” (D. M. Weir & C. C. Blackwell, eds.); “Current protocols in molecular biology” (F. M.
  • Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates.
  • ROR stands for Retinoic acid receptor-related Orphan Receptor. There are three forms of ROR, ROR- ⁇ , - ⁇ , and - ⁇ and each is encoded by a separate gene (RORA, RORB, and RORC respectively). There are two subtypes of RORC: 1 and 2. Subtype 2 is also called “t”. The human RORC gene is also called TOR; RORG; RZRG; NRIF3; and RZR-GAMMA.
  • RORC nuclear receptor ROR-gamma
  • nuclear receptor RZR-gamma nuclear receptor RZR-gamma
  • retinoic acid-binding receptor gamma retinoid-related orphan receptor gamma
  • RAR-related orphan receptor C isoform a
  • RAR-related orphan nuclear receptor variant 2 nuclear receptor subfamily 1 group F member 3.
  • ROR ⁇ and RORC2 are used interchangeably to refer to a protein from a RORC subtype 2 gene.
  • a modulator refers to a compound that alters an activity of a molecule.
  • a modulator can cause an increase or decrease in the magnitude of a certain activity of a molecule compared to the magnitude of the activity in the absence of the modulator.
  • a modulator is an inhibitor, which decreases the magnitude of one or more activities of a molecule.
  • an inhibitor completely prevents one or more activities of a molecule.
  • a modulator is an activator, which increases the magnitude of at least one activity of a molecule.
  • the presence of a modulator results in an activity that does not occur in the absence of the modulator.
  • alkyl refers to a substituent obtained by removing a hydrogen from a saturated, straight (i.e. unbranched) or branched carbon chain (or carbon), or combination thereof, which has the number of carbon atoms designated (i.e. C 1 -C 6 means one to six carbons).
  • alkyl substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, isoamyl, hexyl and the like.
  • haloalkyl is an alkyl in which at least one hydrogen on the alkyl is replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are all the same as one another. In other embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are not all the same as one another.
  • cycloalkyl refers to a substituent obtained by removing a hydrogen atom from a saturated carbocycle having the number of carbon atoms designated (i.e. C 3 -C 8 means three to eight carbons).
  • Cycloalkyl refers to both a radical of a single ring saturated carbocycle, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, as well as a radical of a two or three ring bridged, fused or spiro saturated carbocycle, such as bicyclo[4.2.0]octane and decalinyl.
  • five-membered heteroaryl is defined herein as a ring system having five ring atoms wherein at least one ring atom, alternatively 2 ring atoms, alternatively 3 ring atoms, alternatively 4 ring atoms, is a heteroatom independently selected in each instance from, unless otherwise indicated, the group consisting of nitrogen (N), oxygen (O), and sulfur (S), and wherein the ring is partially unsaturated.
  • the ring atom of the heteroaryl substituent that is bound to the group may be the at least one heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon may be in a different ring from the at least one heteroatom.
  • heteroaryl groups can be substituted.
  • the group or substituent may be bound to the heteroatom, or it may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the heteroatom(s), or where the ring carbon atom may be in a different ring from the heteroatom(s).
  • monocyclic heteroaryl rings include, but are not limited to, 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazol-2-yl, thiazol-4-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, oxazolyl, isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, and thiophen-4-yl.
  • a group of substituents are collectively described as being optionally substituted by one or more of a list of substituents, the group may include: (1) unsubstitutable substituents, (2) substitutable substituents that are not substituted by the optional substituents, and/or (3) substitutable substituents that are substituted by one or more of the optional substituents.
  • a substituent such that it “may be substituted” or as being “optionally substituted” with up to a particular number of non-hydrogen substituents, that substituent may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or by up to the maximum number of substitutable positions on the substituent, whichever is less.
  • a substituent is described as a heteroaryl optionally substituted with up to 3 non-hydrogen substituents, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen substituents as the heteroaryl has substitutable positions.
  • tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen substituent.
  • an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen substituents, then the nitrogen will be optionally substituted with up to 2 non-hydrogen substituents if the amino nitrogen is a primary nitrogen, whereas the amino nitrogen will be optionally substituted with up to only 1 non-hydrogen substituent if the amino nitrogen is a secondary nitrogen.
  • compounds of Formula I may be referred to as a “compound(s) of the invention.” Such terms are also defined to include all forms of the Formula I including hydrates, solvates, isomers, crystalline and non-crystalline forms, isomorphs, polymorphs, and metabolites thereof.
  • the compounds of Formula I and pharmaceutically acceptable salts thereof may exist in unsolvated and solvated forms.
  • the solvent or water When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity.
  • the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
  • a “metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • metabolized refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes, such as, oxidation reactions) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound.
  • cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyl transferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. Further information on metabolism may be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds. Both methods are well known in the art. In some embodiments, metabolites of a compound are formed by oxidative processes and correspond to the corresponding hydroxy-containing compound. In some embodiments, a compound is metabolized to pharmacologically active metabolites.
  • prodrugs refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • An example, without limitation, of a prodrug would be a compound described herein, which is administered as an ester (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
  • a further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • a prodrug upon in vivo administration, is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a pharmaceutically active compound is modified such that the active compound will be regenerated upon in vivo administration.
  • the prodrug can be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
  • Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a derivative as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not.
  • the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed.
  • the compounds of the invention may have asymmetric carbon atoms.
  • the carbon-carbon bonds of the compounds of the invention may be depicted herein using a solid line, a solid wedge or a dotted wedge.
  • the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g. specific enantiomers, racemic mixtures, etc.) at that carbon atom are included.
  • the use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of the invention may contain more than one asymmetric carbon atom.
  • a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included.
  • the compounds of the invention can exist as enantiomers and diastereomers or as racemates and mixtures thereof.
  • the use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of the invention and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.
  • Stereoisomers of compounds of the invention include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers, rotational isomers, conformational isomers, and tautomers of the compounds of the invention, including compounds exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs). Also included are acid addition or base addition salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.
  • the first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts.
  • the second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
  • the present invention also includes isotopically-labeled compounds, which are identical to those recited in Formula I herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl.
  • isotopically-labeled compounds of Formula (I) and Formula (II), for example those into which radioactive isotopes such as 3 H and 14 O are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium, i.e., 2 H can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • Isotopically-labeled compounds the invention may generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.
  • the compounds of this invention may be used in the form of salts derived from inorganic or organic acids.
  • a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil.
  • a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.
  • the salt preferably is pharmaceutically acceptable.
  • pharmaceutically acceptable salt refers to a salt prepared by combining a compound of Formula I with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption.
  • Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because of their greater aqueous solubility relative to the parent compound.
  • salts of the compounds of this invention are non-toxic “pharmaceutically acceptable salts.”
  • Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesutfonic, tartaric, and trifluoroacetic acids.
  • Suitable organic acids generally include but are not limited to aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
  • suitable organic acids include but are not limited to acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosuffonate, algenic acid, ⁇ -hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, butyrate, camphorate,
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, i.e., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quatemary ammonium salts.
  • base salts are formed from bases which form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine, tromethamine and zinc salts.
  • Organic salts may be made from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine. N,N′-benzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
  • Basic nitrogen-containing groups may be quatemized with agents such as lower alkyl (C 1 -C 6 ) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (i.e., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (i.e., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (i.e., benzyl and phenethyl bromides), and others.
  • C 1 -C 6 halides
  • dialkyl sulfates i.e., dimethyl, diethyl, dibutyl, and diamyl sulfates
  • long chain halides i.e., decyl, lau
  • hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • the compounds of the invention described herein are selective for ROR ⁇ over ROR ⁇ and/or ROR ⁇ .
  • an inhibitor compound of ROR ⁇ used in the methods described herein is identified or characterized in an in vitro assay, e.g., an acellular biochemical assay or a cellular functional assay. Such assays are useful to determine an in vitro ICS for said compounds.
  • the ROR ⁇ inhibitor compound used for the methods described herein inhibits ROR ⁇ activity with an in vitro IC 50 of less than 25 ⁇ M (e.g., less than 20 ⁇ M, less than 10 ⁇ M, less than 1 ⁇ M, less than 0.5 ⁇ M, less than 0.4 ⁇ M, less than 0.3 ⁇ M, less than 0.1, less than 0.08 ⁇ M, less than 0.06 ⁇ M, less than 0.05 ⁇ M, less than 0.04 ⁇ M, less than 0.03 ⁇ M, less than less than 0.02 ⁇ M, less than 0.01, less than 0.008 ⁇ M, less than 0.006 ⁇ M, less than 0.005 ⁇ M, less than 0.004 ⁇ M, less than 0.003 ⁇ M, less than less than 0.002 ⁇ M, less than 0.001, less than 0.00099 ⁇ M, less than 0.00098 ⁇ M, less than 0.00097 ⁇ M, less than 0.00096 ⁇ M, less than 0.00095 ⁇ M
  • Described herein are compounds of Formula I. Also described herein are pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically active metabolites, and pharmaceutically acceptable prodrugs of such compounds. Pharmaceutical compositions that include at least one such compound or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically active metabolite or pharmaceutically acceptable prodrug of such compound, are provided. In some embodiments, when compounds disclosed herein contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art. In certain embodiments, isomers and chemically protected forms of compounds having a structure represented by Formula I are also provided.
  • One aspect of the invention relates to a compound of Formula I:
  • X is phenyl or 5-membered hereroaryl, in each case optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of —CH 3 , —CF 3 , —CH 2 CH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 ,
  • R 1 is —CH 3 or —CH 2 CH 3 ;
  • R 2 is (C 1 -C 6 )alkyl, (C 3 -C 10 )cycloalkyl, phenyl or isothiazolyl, optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of —F, —Cl, —Br, —OH, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl and (C 3 -C 8 )cycloalkyl.
  • the present invention relates to any of the aforementioned compounds, wherein R 1 is —CH 3 .
  • the present invention relates to any of the aforementioned compounds, wherein R 1 is —CH 2 CH 3 .
  • the present invention relates to any of the aforementioned compounds, wherein W is
  • the present invention relates to any of the aforementioned compounds, wherein W is
  • R 1 is —CH 3 .
  • the present invention relates to any of the aforementioned compounds, wherein W is
  • the present invention relates to any of the aforementioned compounds, wherein W is
  • R 1 is —CH 3 .
  • the present invention relates to any of the aforementioned compounds, wherein W is
  • the present invention relates to any of the aforementioned compounds, wherein W is
  • the present invention relates to any of the aforementioned compounds, wherein W is
  • R 1 is —CH 3 .
  • the present invention relates to any of the aforementioned compounds, wherein W is
  • the present invention relates to any of the aforementioned compounds, wherein W is
  • R 1 is —CH 3 .
  • the present invention relates to any of the aforementioned compounds, wherein W is
  • the present invention relates to any of the aforementioned compounds, wherein W is
  • R 1 is —CH 3 .
  • the present invention relates to any of the aforementioned compounds, wherein W is
  • the present invention relates to any of the aforementioned compounds, wherein W is
  • R 1 is —CH 3 .
  • the present invention relates to any of the aforementioned compounds, wherein W is
  • the present invention relates to any of the aforementioned compounds, wherein W is
  • R 1 is —CH 3 .
  • the present invention relates to any of the aforementioned compounds, wherein W is
  • the present invention relates to any of the aforementioned compounds, wherein W is
  • the present invention relates to any of the aforementioned compounds, wherein W is
  • R 1 is —CH 3 .
  • the present invention relates to any of the aforementioned compounds, wherein W is
  • the present invention relates to any of the aforementioned compounds, wherein W is
  • R 1 is —CH 3 .
  • the present invention relates to any of the aforementioned compounds, wherein X is unsubstituted phenyl.
  • the present invention relates to any of the aforementioned compounds, wherein X is phenyl substituted with one, two, three, four or five substituents independently selected from the group consisting of —CH 3 , —CF 3 , —CH 2 CH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 ,
  • the present invention relates to any of the aforementioned compounds, wherein X is phenyl substituted with one substituent selected from the group consisting of with —CH 3 , —CF 3 , —CH 2 CH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 ,
  • the present invention relates to any of the aforementioned compounds, wherein X is phenyl substituted with two substituents independently selected from the group consisting of —CH 3 , —CF 3 , —CH 2 CH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 , W,
  • the present invention relates to any of the aforementioned compounds, wherein X is phenyl substituted with three substituents independently selected from the group consisting of —CH 3 , —CF 3 , —CH 2 CH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 , —F, —Cl, —Br and —CN.
  • the present invention relates to any of the aforementioned compounds, wherein X is phenyl substituted with four substituents independently selected from the group consisting of —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 ,
  • the present invention relates to any of the aforementioned compounds, wherein X is phenyl substituted with five substituents independently selected from the group consisting of —CH 3 , —CF 3 , —CH 2 CH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 ,
  • the present invention relates to any of the aforementioned compounds, wherein X is phenyl substituted with —F and optionally substituted with one or two substituents independently selected from the group consisting of —CH 3 , —CF 3 , —CH 2 CH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 ,
  • the present invention relates to any of the aforementioned compounds, wherein X is phenyl optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of —CH 3 , —CF 3 , —CH 2 CH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 H, —OCH 2 CH 2 OCH 3 ,
  • the present invention relates to any of the aforementioned compounds, wherein X is
  • the present invention relates to any of the aforementioned compounds, wherein X is
  • the present invention relates to any of the aforementioned compounds, wherein X is,
  • the present invention relates to any of the aforementioned compounds, wherein X is 5-membered hereroaryl optionally substituted with one, two, three, or four substituents independently selected from the group consisting of —CH 3 , —CF 3 , —CH 2 CH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 ,
  • the present invention relates to any of the aforementioned compounds, wherein X is isoxazolyl or pyrazolyl, in each case optionally substituted with one, two or three, substituents independently selected from the group consisting of —CH 3 , —CF 3 , —CH 2 CH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 ,
  • the present invention relates to any of the aforementioned compounds, wherein X is
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is (C 1 -C 6 )alkyl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of —F, —Cl, —Br, —OH, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl and (C 3 -C 10 )cycloalkyl.
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is unsubstituted (C 1 -C 6 )alkyl. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R 2 is unsubstituted branched (C 1 -C 6 )alkyl.
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is (C 1 -C 3 )alkyl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of —F, —Cl, —Br, —OH, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl and (C 3 -C 10 )cycloalkyl.
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is methyl optionally substituted with one, two or three substitutents independently selected for each occurrence from the group consisting of —F, —Cl, —Br, —OH, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl and (C 3 -C 10 )cycloalkyl.
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is ethyl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of —F, —Cl, —Br, —OH, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl and (C 3 -C 10 )cycloalkyl.
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is n-propyl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of —F, —Cl, —Br, —OH, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl and (C 3 -C 10 )cycloalkyl.
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is i-propyl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of —F, —Cl, —Br, —OH, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl and (C 3 -C 10 )cycloalkyl.
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is methyl substituted with (C 3 -C 6 )cycloalkyl.
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is propyl substituted with —CF 3 .
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is ethyl substituted with (C 3 -C 6 )cycloalkyl.
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is ethyl substituted with bicyclo[1.1.1]pentanyl.
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is (C 3 -C 10 )cycloalkyl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of —F, —Cl, —Br, —OH, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl and (C 3 -C 10 )cycloalkyl.
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is unsubstituted (C 3 -C 10 )cycloalkyl.
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is cyclopropyl optionally substituted with one, two, three or four substitutents independently selected for each occurrence from the group consisting of —F, —Cl, —Br, —OH, (C 1 -C 3 )alkyl. (C 1 -C 3 )haloalkyl and (C 3 -C 10 )cycloalkyl.
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is cyclobutyl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of —F, —Cl, —Br, —OH, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl and (C 3 -C 10 )cycloalkyl.
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is cyclopentyl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of —F, —Cl, —Br, —OH, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl and (C 3 -C 10 )cycloalkyl.
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is cyclohexyl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of —F, —Cl, —Br, —OH, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl and (C 3 -C 10 )cycloalkyl.
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is unsubstituted phenyl.
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is phenyl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of —F, —Cl, —Br, —OH, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl and (C 3 -C 10 )cycloalkyl.
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is phenyl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of —F, —Cl, —Br, —OH and —CH 3 .
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is unsubstituted isothiazolyl.
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is isothiazolyl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of —F, —Cl, —Br, —OH, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl and (C 3 -C 10 )cycloalkyl.
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is isothiazolyl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of —F, —Cl, —Br, —OH and —CH 3 .
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is,
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is
  • Another embodiment of the invention is a compound selected from the group consisting of the compounds of Examples 1-35 and pharmaceutically acceptable salts thereof.
  • one aspect of the invention provides a method of treating a disorder selected from the group consisting of an immune disorder or inflammatory disorder.
  • the method comprises administering a therapeutically effective amount of a compound of Formula I to a subject in need thereof to ameliorate a symptom of the disorder, wherein Formula I are as described above.
  • the particular compound of Formula I is a compound defined by one of the embodiments described above.
  • the disorder is an immune disorder. In certain other embodiments, the disorder is an inflammatory disorder. In certain other embodiments, the disorder is an autoimmune disorder. In certain other embodiments, the disorder is rheumatoid arthritis, psoriasis, chronic graft-versus-host disease, acute graft-versus-host disease, Crohn's disease, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren's syndrome, scleroderma, ulcerative colitis, asthma, or epidermal hyperplasia.
  • the disorder is cartilage inflammation, bone degradation, arthritis, juvenile arthritis, juvenile rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile reactive arthritis, juvenile Reter's Syndrome, SEA Syndrome, juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, pauciarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic onset rheumatoid arthritis, ankylosing spondylitis, enteropathic arthritis, reactive arthritis, Reter's Syndrome, dermatomyositis, psoriatic arthritis, vasculitis, myositis, polymyositis, osteoarthriti
  • the psoriasis is plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, or erythrodermic psoriasis.
  • the disorder is noninfectious uveitis, Behcet's disease or Vogt-Koyanagi-Harada syndrome.
  • Another aspect of the invention provides for the use of a compound of Formula I in the manufacture of a medicament.
  • the medicament is for treating a disorder described herein.
  • Another aspect of the invention provides for the use of a compound of Formula I for treating a medical disorder, such a medical disorder described herein.
  • compounds of Formula I can inhibit the activity of ROR ⁇ .
  • another aspect of the invention provides a method of inhibiting the activity of ROR ⁇ . The method comprises exposing a ROR ⁇ to an effective amount of a compound of Formula I to inhibit said ROR ⁇ , wherein Formula I is as described above.
  • the particular compounds of Formula I are the compound defined by one of the embodiments described herein.
  • compounds of Formula I can reduce the amount of interleukin-17 (IL-17) in a subject.
  • IL-17 is a cytokine that affects numerous biological functions, including inducing and mediating pro-inflammatory responses.
  • another aspect of the invention provides a method of reducing the amount of IL-17 in a subject. The method comprises administering to a subject an effective amount of a compound of I to reduce the amount of IL-17 in the subject, wherein Formula I is as described above.
  • the particular compounds of Formula I are the compounds defined by one of the embodiments described herein.
  • the subject is a human.
  • administering the compound reduces the amount of IL-17 produced by Th-17 cells in the subject.
  • a change in the amount of IL-17 produced by, for example, Th-17 cells can be measured using procedures described in the literature, such as an ELISA assay or intracellular staining assay.
  • compounds of Formula I may inhibit the synthesis of IL-17 in a subject.
  • another aspect of the invention provides a method of inhibiting the synthesis IL-17 in a subject. The method comprises administering to a subject an effective amount of a compound of Formula I to inhibit the synthesis IL-17 in the subject, wherein Formula I is as described above.
  • the particular compounds of Formula I are the compounds defined by one of the embodiments described herein.
  • the compounds of Formula I or their pharmaceutically acceptable salts may be used in combination with additional therapeutic agents to treat medical disorders, such as medical disorders associated with inappropriate IL-17 pathway activity.
  • additional therapeutic agents include, for example, (1) a TNF-a inhibitor; (2) a non-selective COX-I/COX-2 inhibitor; (3) a selective COX-2 inhibitor, such as celecoxib and rofecoxib; (4) other agents for treating inflammatory disease and autoimmune disease including, for example, methotrexate, leflunomide, sulfasalazine, azathioprine, penicillamine, bucillamine, actarit, mizoribine, lobenzarit, hydroxychloroquine, d-penicillamine, aurothiomalate, auranofin, parenteral gold, oral gold, cyclophosphamide, Lymphostat-B, a BAFF/APRIL inhibitor, CTLA-4-Ig,
  • the additional therapeutic agent is selected from the group consisting of corticosteroids, vitamin D3, anthralin and retinoids. In certain embodiments, the additional therapeutic agent is a corticosteroid. In certain embodiments, the additional therapeutic agent is vitamin D3. In certain embodiments, the additional therapeutic agent is anthralin. In certain embodiments, the additional therapeutic agent is a retinoid.
  • the amount of the compounds of Formula I and additional therapeutic agent and the relative timing of administration may be selected in order to achieve a desired combined therapeutic effect.
  • the therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising the therapeutic agents may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like.
  • a compound of Formula I may be administered during a time when the additional therapeutic agent(s) exerts its prophylactic or therapeutic effect, or vice versa.
  • the doses and dosage regimen of the active ingredients used in the combination therapy may be determined by an attending clinician.
  • the compound of Formula I and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating the disorder.
  • the compound of Formula I and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating the disorder.
  • a compound of Formula I and the additional therapeutic agent(s) are present in the same composition, which is suitable for oral administration.
  • the compound of Formula I and the additional therapeutic agent(s) may act additively or synergistically.
  • a synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy.
  • a lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy.
  • kits comprising a therapeutically effective amount of a compound of Formula I, a pharmaceutically acceptable carrier, vehicle or diluent, and optionally at least one additional therapeutic agent listed above.
  • a compound of the invention is administered in an amount effective to treat a condition as described herein.
  • the compounds of the invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • Therapeutically effective doses of the compounds required to treat the progress of the medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts.
  • the term “therapeutically effective amount” as used herein refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as “treating” is defined immediately above.
  • treating also includes adjuvant and neo-adjuvant treatment of a subject.
  • the invention provides pharmaceutical compositions, which comprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • the pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention.
  • an aforementioned formulation renders orally bioavailable a compound of the present invention.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxa
  • pharmaceutically-acceptable carriers such as sodium citrate or dicalcium phosphate
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include 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, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl 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, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the invention also includes pharmaceutical compositions utilizing one or more of the present compounds along with one or more pharmaceutically acceptable carriers, excipients, vehicles, etc.
  • Topical formulations of the presently disclosed compounds may be administered topically, (intra)dermally, or transdermally to the skin or mucosa.
  • Topical administration using such preparations encompasses all conventional methods of administration across the surface of the body and the inner linings of body passages including epithelial and mucosal tissues, including transdermal, epidermal, buccal, pulmonary, ophthalmic, intranasal, vaginal and rectal modes of administration.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, colloid, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions.
  • Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Such topical formulations may be prepared in combination with additional pharmaceutically acceptable excipients.
  • a penetration enhancer may be used.
  • penetration enhancers include, for example, saturated C10-C18 fatty alcohols (such as decyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol and stearyl alcohol), cis-unsaturated C10-C18 fatty alcohols (such as oleyl alcohol, linoleyl alcohol, ⁇ -linolenyl alcohol and linolenyl alcohol), C10-C18 fatty acids (which when saturated may include capric acid, lauric acid, myristic acid, palmitic acid, stearic acid and arachidic acid), cis-unsaturated fatty acids (such as palmitoleic acid (cis-9-hexadecenoic acid), oleic acid (cis-9-octadecenoic acid), cis-vaccenic acid (cis-11-octadecenoic acid), linoleic acid (cis-9
  • topical formulations which contain one or more compounds of the invention in therapeutically effective amounts that may be given in daily or twice daily doses to patients in need.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients which enhance the stability of the formulations include aldehyde scavengers, such as glycerine and propylene glycol, and antioxidants, such as butyl hydroxyanisole (BHA), butyl hydroxytoluene (BHT), propyl gallate, ascorbic acid (Vitamin C), polyphenols, tocopherols (Vitamin E), and their derivatives.
  • aldehyde scavengers such as glycerine and propylene glycol
  • antioxidants such as butyl hydroxyanisole (BHA), butyl hydroxytoluene (BHT), propyl gallate, ascorbic acid (Vitamin C), polyphenols, tocopherols (Vitamin E), and their derivatives.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this invention is dissolved or suspended in a suitable carrier.
  • a typical formulation suitable for ocular or aural administration may be in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline.
  • formulations suitable for ocular and aural administration include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant.
  • Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone; as a mixture, for example, in a dry blend with lactose; or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the compounds are administered at about 0.01 mg/kg to about 200 mg/kg, more preferably at about 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5 mg/kg to about 50 mg/kg.
  • the effective amount may be less than when the agent is used alone.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • preferred dosing is one administration per day.
  • the invention further provides a unit dosage form (such as a tablet or capsule) comprising a compound of Formula I or a specific compound described herein, or pharmaceutically acceptable salts thereof, in a therapeutically effective amount for the treatment of an immune or inflammatory disorder, such as one of the particular immune disorders or inflammatory disorders described herein.
  • a unit dosage form such as a tablet or capsule
  • an immune or inflammatory disorder such as one of the particular immune disorders or inflammatory disorders described herein.
  • the compounds of Formula I may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and derivatizations that are familiar to those of ordinary skill in the art.
  • the starting materials used herein are commercially available or may be prepared by routine methods known in the art (such as those methods disclosed in standard reference books such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI (published by Wiley-Interscience)). Preferred methods include, but are not limited to, those described below.
  • any of the following synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991, and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, which are hereby incorporated by reference.
  • conventional protecting groups such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991, and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999
  • Compounds of Formula I may be prepared as single enantiomer or as a mixture of individual enantiomers which includes racemic mixtures.
  • Methods to obtain preferentially a single enantiomer from a mixture of individual enantiomers or a racemic mixture are well known to those ordinarily skilled in the art of organic chemistry. Such methods include but are not limited to preferential crystallization of diastereomeric salts (e.g. tartrate or camphor sulfonate), covalent derivatization by a chiral, non-racemic reagent followed by separation of the resulting diastereomers by common methods (e.g.
  • the compounds of the invention or any intermediates to the compounds of the invention which bear a stereogenic center may be transiently reacted with an achiral reagent, separated, and then reverted to scalemic compound by standard synthetic techniques.
  • Compounds of Formula A-6 can be prepared as described in Scheme A.
  • Aryl halides A-1 can be converted to boronates of Formula A-2.
  • Boronates A-2 can be coupled with vinyl triflate B-3 (prepared as described in Scheme B) to afford compounds of the Formula A-3.
  • the resulting amine of compounds of Formula A-4 can be transformed to the corresponding sulfonamides by the reaction with sulfonyl chlorides in the presence of base to afford compounds of Formula A-5.
  • the Boc group within compounds of Formula A-5 could be removed through use of acid, and subsequently the piperidine nitrogen could be coupled with an appropriate acid chloride or carboxylic acid to furnish compounds of Formula A-6.
  • Carboxylic acids of the Formula R 2 CO 2 H employed in Scheme A, C, D, and F may be commercially available, prepared by procedures described in the literature, or prepared as described in Scheme F.
  • (R)-2,3,3-Trimethylbutanoic acid and (S)-2,3,3-trimethylbutanoic acid may be prepared as described by Kido, M. et al Tetrahedron: Asym. 2007, 18, 1934-1947; and thietane acid (see WO02013/7582, which is hereby incorporated by reference for the preparation of thietane acid).
  • carboxylic acids that may be prepared by Scheme F include (R)-2-cyclopentylpropanoic acid, and (S)-2-cyclopentylpropanoic acid.
  • R 2 CO 2 H according to the Formula F-4 can be prepared from acids F-1 where R may be alkyl, cycloalkyl or aryl which are reacted with an optically active chiral oxazolidinone (e.g. (R)-benzyl oxazolidinone, (R)-4-Isopropyl-2-oxazolidinone) to provide compounds of the Formula F-2.
  • Base mediated alkylation and subsequent removal of the oxazolidinone auxiliary furnishes acids of the Formula F-4 in high optical purity.
  • Chiral purity of scalemic compounds was determined by chiral SFC (super-critical fluid chromatography) employing one of the following conditions: HPLC Method A: XBridge C18, 2.1 ⁇ 50 mm, 5 um, CH3CN/H2O (0.0375% TFA), 10-100%, 0.8 mL/min, 4 min; and HPLC Method B: XBridge C18, 2.1 ⁇ 50 mm, 5 ⁇ m, CH3CN/H2O (0.0375% TFA), 1-100%, 0.8 mL/min, 4 min.
  • Method C Ultimate XB-C18, 3 ⁇ m, 3.0 ⁇ 50 mm, CH3CN/H2O (0.1% TFA), 1-5%, 1.2 mL/min, 10 min.
  • Method D Xtimate C18, 3 ⁇ m, 5.0 ⁇ 50 mm, CH3CN/H2O (0.1% TFA), 1-100%, 1.2 ml/min, 10 min.
  • Method E Ultimate XB-C18, 3 ⁇ m, 3.0 ⁇ 50 mm, CH3CN/H2O (0.1% TFA), 1-100%, 1.2 mL/min, 10 min.
  • reaction conditions length of reaction and temperature
  • reaction conditions may vary.
  • reactions were followed by thin layer chromatography or mass spectrometry, and subjected to work-up when appropriate.
  • Purifications may vary between experiments: in general, solvents and the solvent ratios used for eluants/gradients were chosen to provide appropriate RIs or retention times (RetT).
  • DCM dichloromethane
  • DEA diethylamine
  • DIPEA diisopropylethylamine
  • DME 1,2-dimethoxyethane
  • DMF dimethylformamide
  • EtOAc ethyl acetate
  • EtOH ethanol
  • HATU 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
  • MeOH methanol
  • MTBE methyl t-butyl ether
  • PE petroleum ether
  • TEA triethylamine
  • THF tetrahydrofuran.
  • Step 1 3-Bromo-1-methyl-5-nitro-1H-indole.
  • THF THF
  • 50 mL THF
  • NaH 1.9 g, 41.3 mmol, 60% w/w in mineral oil.
  • methyl iodide 6.4 mL, 103.3 mmol was added.
  • the reaction mixture was warmed to room temperature and stirred for 16 h. After completion, the reaction mixture was cooled, quenched with addition of ice-cooled water and extracted using EtOAc.
  • Step 2 1-Methyl-5-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole.
  • a solution of 3-bromo-1-methyl-5-nitro-1H-indole (3 g, 11.7 mmol) in dioxane (100 mL) was degassed using nitrogen for 10 min.
  • Step 3 tert-Butyl 3-methyl-4-oxopiperidine-1-carboxylate.
  • Boc-anhydride 8 g, 36.9 mmol
  • Pd(OH) 2 2.4 g, 40% wt of ketone
  • the reaction mixture was stirred under hydrogen atmosphere (100 psi) in autoclave for 6 h at room temperature.
  • the reaction mixture was concentrated in vacuo to obtain a crude residue which was purified by silica gel column chromatography (10-15% EtOAc in hexane) to afford the title compound (8.8 g, 78%).
  • Step 4 tert-Butyl 3-methyl-4-(((trifluoromethyl) sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate.
  • a solution of tert-Butyl 3-methyl-4-oxopiperidine-1-carboxylate (7 g, 32.8 mmol) in THF (70 mL) was added a solution of NaHMDS (66 mL, 65.7 mmol, 1M in THF) dropwise at ⁇ 78° C., stirred for 1.5 h at the same temperature, 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (23.4 g, 65.7 mmol) was added, the reaction mixture was warmed to room temperature and stirred for 16 h.
  • Step 5 tert-butyl 3-methyl-4-(1-methyl-5-nitro-1H-indol-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate.
  • Step 6 tert-butyl 4-(5-amino-1-methyl-1H-indol-3-yl)-3-methylpiperidine-1-carboxylate.
  • tert-butyl 5-methyl-4-(1-methyl-5-nitro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1 g, 2.6 mmol) in EtOH (25 mL) were added Pd(OH) 2 (1 g, 100% w/w), ammonium formate (1.7 g, 26.9 mmol) and the reaction mixture was heated at 80° C. for 4 h.
  • Step 7 tert-butyl 4-(5-((4-fluorophenyl)sulfonamido)-1-methyl-1H-indol-3-yl)-3-methylpiperidine-1-carboxylate.
  • a solution of tert-butyl 4-(5-amino-1-methyl-1H-indol-3-yl)-3-methylpiperidine-1-carboxylate (900 mg, 2.62 mmol) in DCM (25 mL) was added pyridine (0.32 mL, 3.93 mmol), followed by 4-fluorobenzenesulfonyl chloride (613 mg, 3.14 mmol) solution in DCM (25 mL) dropwise at 0-5° C.
  • reaction mixture was stirred at 0-5° C. for 30 min. After completion, the reaction mixture was basified with 10% aqueous NaHCO 3 solution and extracted using DCM. The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated to obtain the crude compound which was purified by silica gel column chromatography (1-2% MeOH in DCM) to afford the title compound (1 g, 68%).
  • Step 8 4-fluoro-N-(1-methyl-3-((3R,4R)-3-methylpiperidin-4-yl)-1H-indol-5-yl)benzenesulfonamide.
  • Step 9 4-fluoro-N-(1-methyl-3-((3R,4R)-3-methylpiperidin-4-yl)-1H-indol-5-yl)benzenesulfonamide.
  • 3R,4R)-tert-butyl 4-(5-(4-fluorophenylsulfonamido)-1-methyl-1H-indol-3-yl)-3-methylpiperidine-1-carboxylate (273 mg, 0.544 mmol) in DCM (10.9 mL, 0.05 mmol) was added 4M HCl in dioxane (2.04 mL, 8.16 mmol) at room temperature. The resulting mixture was allowed to stir for 90 min.
  • Step 10 4-fluoro-N-(1-methyl-3-((3R,4R)-3-methyl-1-((R)-2,3,3-trimethylbutanoyl)-piperidin-4-yl)-1H-indol-5-yl)benzenesulfonamide.
  • Step 1 (R)-3-(2-cyclopentylacetyl)-4-isopropyloxazolidin-2-one.
  • To a solution of (R)-4-isopropyloxazolidin-2-one (2.0 g, 10 mmol) in THF (55 mL) at ⁇ 78° C. was added dropwsie n-BuLi (2.5 M in hexanes, 4.92 mL, 12.3 mmol). The resulting solution was allowed to stir at the same temperature for 1 h, then cyclopentyl acetyl chloride (1.86 g, 12.3 mmol) was added. The reaction turned pale yellow rapidly and was allowed to stir at ⁇ 78° C. for 1 h.
  • Step 2 (R)-3-((R)-2-cyclopentylpropanoyl)-4-isopropyloxazolidin-2-one.
  • MeI (3.55 mL, 56.6 mmol) was added and the reaction was allowed to warm to 0° C. over 1 h and allowed to stir at 0° C. for 3 h.
  • Step 3 (R)-2-cyclopentylpropanoic acid.
  • the resulting solution was allowed to stir at room temperature overnight.
  • the reaction was quenched with 1.0 M KHSO 4 (8 mL) and extracted with EtOAc (3 ⁇ ).
  • Step 4 N-(3-((3R,4R)-1-((R)-2-cyclopentylpropanoyl)-3-methylpiperidin-4-yl)-1-methyl-1H-indol-5-yl)-4-fluorobenzenesulfonamide.
  • Example 3-5 and 32-35 were prepared analogous to Example 1 employing the appropriate sulfonyl chloride in step 7 and the appropriate carboxylic acid coupling reagent in step 10. However, chiral separation was conducted on the final product. Separation conditions: Method AA: Luxe Cellulose-4, 250 ⁇ 21.2 mm, 5 ⁇ m, 40% EtOH/CO 2 , 80.0 mL/min; Method AB: ChiralTech IC, 250 ⁇ 21.2 mm, 5 ⁇ m, 60-40% (3:1) EtOAc-MeOH/CO 2 , 80.0 mL/min.
  • Method AC ChiralPak AD-3, 50 ⁇ 4 mm, 3 ⁇ m, EtOH (0.05% DEA)/CO 2 , 4 mL/min.
  • Method AD ChiralPak AS-H, 150 ⁇ 4 mm, 5 ⁇ m, EtOH (0.05% DEA)/CO 2 , 3 mL/min.
  • Method AE ChiralPak AD-3, 50 ⁇ 4.6 mm, 3 ⁇ m, EtOH (0.05% DEA)/CO 2 , 4 mL/min.
  • Method AF ChiralPak AS-H, 150 ⁇ 4.6 mm, 5 ⁇ m. EtOH (0.05% DEA)/CO 2 , 3 mL/min.
  • Step 1 tert-butyl 4-(1-methyl-5-nitro-1H-indol-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate.
  • Step 2 tert-butyl 4-(5-amino-1-methyl-1H-indol-3-yl)piperidine-1-carboxylate.
  • dry Pd(OH) 2 /C 1600 mg
  • tert-butyl 4-(1-methyl-5-nitro-1H-indol-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate 8050 mg, 22.5 mmol
  • EtOH 500 mL
  • DCM 50 mL
  • the mixture was degassed and refilled with H 2 3 times, then the mixture was stirred under a hydrogen atmosphere (50 Psi) at 50° C.
  • Step 3 tert-butyl 4-(5-((4-fluorophenyl)sulfonamido)-1-methyl-1H-indol-3-yl)piperidine-1-carboxylate.
  • tert-butyl 4-(5-amino-1-methyl-1H-indol-3-yl)piperidine-1-carboxylate 2200 mg, 6.678 mmol
  • 4-fluorobenzensulfonyl chloride (1950 mg, 10.0 mmol)
  • pyridine 30 mL
  • Step 4 4-fluoro-N-(1-methyl-3-(piperidin-4-yl)-1H-indol-5-yl)benzenesulfonamide.
  • tert-butyl 4-(5-((4-fluorophenyl)sulfonamido)-1-methyl-1H-indol-3-yl)piperidine-1-carboxylate (1200 mg, 2.461 mmol) in DCM (15 mL) was added HCl/dioxane (7 mL, 4 M) at 0-5° C. in an ice/water bath. The brown solution was stirred at 20° C. for 2 hours. The reaction was combined with three other batches for workup.
  • Step 5 4-fluoro-N-(3-(1-(isothiazole-5-carbonyl)piperidin-4-yl)-1-methyl-1H-indol-5-yl)benzenesulfonamide.
  • the title compound was prepared in an analogous manner to Example 1, step 10 employing isothiazole-5-carboxylic acid.
  • LC/MS [M+H] + : 499; Rt 2.93 (Method A).
  • Step 1 tert-butyl 2,2-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate.
  • tert-butyl 2,2-dimethyl-4-oxopiperidine-1-carboxylate 7.76 g, 34.1 mmol
  • dry THF 130 mL
  • a solution of sodium bistrimethyldisilazide 7.51 g 41.0 mmol
  • Step 2 tert-butyl 2,2-dimethyl-4-(1-methyl-5-nitro-1H-indol-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate.
  • Step 3 tert-butyl 4-(5-amino-1-methyl-1H-indol-3-yl)-2,2-dimethylpiperidine-1-carboxylate.
  • Pd/C 200 mg
  • tert-butyl 2,2-dimethyl-4-(1-methyl-5-nitro-1H-indol-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate 1000 mg, 2.594 mmol
  • EtOH 75 mL
  • DCM 15 mL
  • the mixture was degassed and purged with H 2 for 3 times and the mixture was stirred under hydrogen atmosphere (50 Psi) at 40° C.
  • Step 4 tert-butyl 4-(5-((4-fluorophenyl)sulfonamido)-1-methyl-1H-indol-3-yl)-2,2-dimethylpiperidine-1-carboxylate.
  • tert-butyl 4-(5-amino-1-methyl-1H-indol-3-yl)-2,2-dimethylpiperidine-1-carboxylate 900 mg, 2.52 mmol
  • 4-fluorobenzenesulfonyl chloride 735 mg, 3.78 mmol
  • TEA 7.55 mmol
  • Step 5 N-(3-(2,2-dimethylpiperidin-4-yl)-1-methyl-1H-indol-5-yl)-4-fluorobenzenesulfonamide.
  • tert-butyl 4-(5-((4-fluorophenyl)sulfonamido)-1-methyl-1H-indol-3-yl)-2,2-dimethylpiperidine-1-carboxylate 900 mg, 1.75 mmol
  • DCM 25 mL
  • HCl/Dioxane 15 mL
  • the solvent was removed under reduced pressure to give the title compound (800 mg, 100%) as a white solid, which was used directly without further purification.
  • LCMS m/e 416 [M+H].
  • Step 6 4-fluoro-N-(3-(1-isobutyryl-2,2-dimethylpiperidin-4-yl)-1-methyl-1H-indol-5-yl)benzenesulfonamide.
  • N-(3-(2,2-dimethylpiperidin-4-yl)-1-methyl-1H-indol-5-yl)-4-fluorobenzenesulfonamide 400 mg, 0.885 mmol
  • DCM 25 mL
  • TEA 269 mg, 2.65 mmol
  • Step 6 (R)-4-fluoro-N-(3-(1-isobutyryl-2,2-dimethylpiperidin-4-yl)-1-methyl-1H-indol-5-yl)benzenesulfonamide.
  • the first eluting isomer (7.33 min) was arbitrarily assigned as (S)-4-fluoro-N-(3-(1-isobutyryl-2,2-dimethylpiperidin-4-yl)-1-methyl-1H-indol-5-yl)benzenesulfonamide (65 mg) as a white solid.
  • Step 1 N-(3-(1-(cyclopentanecarbonyl)-2,2-dimethylpiperidin-4-yl)-1-methyl-1H-indol-5-yl)-4-fluorobenzenesulfonamide.
  • N-(3-(2,2-dimethylpiperidin-4-yl)-1-methyl-1H-indol-5-yl)-4-fluorobenzenesulfonamide prepared as described in Example 18) (400 mg, 0.885 mmol) in DCM (25 mL) was added TEA (269 mg, 2.65 mmol) at 0° C. and the mixture was stirred until the solution turned clear.
  • Step 2 (R)—N-(3-(1-(cyclopentanecarbonyl)-2,2-dimethylpiperidin-4-yl)-1-methyl-1H-indol-5-yl)-4-fluorobenzenesulfonamide.
  • the first eluting isomer (4.99 min) was arbitrarily assigned as (S)—N-(3-(1-(cyclopentanecarbonyl)-2,2-dimethylpiperidin-4-yl)-1-methyl-1H-indol-5-yl)-4-fluorobenzenesulfonamide (92 mg, 46%) as a white solid.
  • the second eluting isomer (5.34 min) was arbitrarily assigned as (R)—N-(3-(1-(cyclopentanecarbonyl)-2,2-dimethylpiperidin-4-yl)-1-methyl-1H-indol-5-yl)-4-fluorobenzenesulfonamide (95 mg, 48%) as a white solid.
  • 1 H NMR 400 MHz, DMSO-d 8 ) ⁇ 9.78 (br.
  • Steps 1 (S)-1-(cyclopentanecarbonyl)-2-methylpiperidin-4-one.
  • a flask with a mixture of benzyl (S)-2-methyl-4-oxopiperidine-1-carboxylate (500 mg, 2.02 mmol) and Pd/C (5% by weight, 215 mg) in EtOH (10 mL) was evacuated with water aspiration and then put under hydrogen gas.
  • the mixture was stirred under 1.1 bar hydrogen over-pressure for 1 h.
  • the mixture was filtered through a Celite® plug, and the filtrate was concentrated in vacuo.
  • Step 2 (S)-1-(cyclopentanecarbonyl)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate, n-BuLi (2.5M solution in hexanes, 1.15 mL, 2.87 mmol) was added drop wise to diisopropylamine (402 ⁇ L, 2.87 mmol) in dry THF (5 mL) under nitrogen at ⁇ 78° C. The mixture was stirred at ⁇ 78° C. for 30 min, whereupon (S)-1-(cyclopentanecarbonyl)-2-methylpiperidin-4-one (300 mg, 1.43 mmol) in dry THF (4 mL) was added.
  • n-BuLi 2.5M solution in hexanes, 1.15 mL, 2.87 mmol
  • Step 3 (S)-cyclopentyl(2-methyl-4-(1-methyl-5-nitro-1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)methanone.
  • (S)-1-(cyclopentanecarbonyl)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate 119 mg, 0.35 mmol
  • K 3 PO 4 155 mg, 0.73 mmol
  • Steps 4 N-(3-((2S,4S)-1-(cyclopentanecarbonyl)-2-methylpiperidin-4-yl)-1-methyl-1H-indol-5-yl)-4-fluorobenzenesulfonamide.
  • Step 1 tert-butyl 4-(5-((4-fluoro-3-methoxyphenyl)sulfonamido)-1-methyl-1H-indol-3-yl)piperidine-1-carboxylate.
  • Step 2 4-fluoro-3-methoxy-N-(1-methyl-3-(piperidin-4-yl)-1H-indol-5-yl)benzenesulfonamide.
  • tert-butyl 4-(5-((4-fluoro-3-methoxyphenyl)sulfonamido)-1-methyl-1H-indol-3-yl)piperidine-1-carboxylate (3.9 g, 7.5 mmol) in DCM (50 mL) was added TFA (5.7 mL), and the mixture was stirred at room temperature for 1 h. The volatiles were evaporated. The residue was dissolved in DCM, and sat. NaHCO 3 was added. The phases were separated and the organic layer evaporated to provide the title compound that was used in the subsequent step without further purification.
  • LCMS m/e 418.07 [M+H] + .
  • Step 3 4-fluoro-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-1H-indol-5-yl)-3-methoxybenzenesulfonamide.
  • isobutyryl chloride 4.7 mL, 44.7 mmol.
  • the reaction mixture was stirred at room temperature for 1 h.
  • the pyridine was evaporated, and 1M HCl and DCM were added. The phases were separated and the organic layer was concentrated.
  • Examples 25-31 were prepared in an analogous manner to Example 22 employing the necessary benzenesulfonyl chloride in step 1 and the appropriate carboxylic acid in step 5.
  • the activity of compound of the invention can be determined by a co-activator recruitment by TR-FRET (time-resolved fluorescence resonance energy transfer) assay.
  • TR-FRET time-resolved fluorescence resonance energy transfer
  • the assay is based on the interaction between N-terminally Six-Histidine-tagged-RORC2 ligand binding domain (6-His-RORC2 LBD), expressed in E. coli and purified by affinity chromatography, and biotin-coactivator peptide SRC1-2 (biotin-aminohexanoic acid-CPSSHSSLTERHKILHRLLQEGSPS-NH 2 ; SEQ ID NO: 1) containing the LXXLL consensus domain which is responsible for receptor binding. This interaction is detected by addition of Europium labeled-anti-His antibody (Ex.
  • the aforementioned assay was performed as outlined below.
  • the assay was carried out in black polystyrene, 384-well plates in a total assay volume of 50.5 ⁇ L.
  • the assay buffer contained 50 mM TRIS-HCL pH 7.5, 1 mM NaCl, 2 mM MgCl 2 , 0.5 mg/mL bovine serum albumin, and 5 mM dithiothreitol.
  • the final concentration of reagents was 6.3 nM RORC2 LBD, 200 nM SRC1-2, 50 nM streptavidin APC, 1 nM Europium-labeled anti-His antibody, and varying concentrations of compounds such that final concentration of DMSO is 1% (v/v).
  • the assay steps were: (1) dispensing 500 ⁇ L compound at 100 ⁇ final concentration in DMSO (test wells) or DMSO only (control wells for no inhibition); and (2) dispensing 50 ⁇ L mixture of the other assay components including receptor (test wells) or excluding receptor (control wells for maximal inhibition).
  • TR-FRET signal was determined by calculating the ratio of 665 nm by 615 nm and ICM values of compounds of the invention (Table 1) were determined by the non-linear regression analysis of dose response curves.
  • the activity of compound of the invention can be also be determined by a luciferase reporter Gal4-RORC2 activity assay.
  • Neuro2A cells murine neuroblastoma cell line obtained from HPACC, cat #89121404
  • pM mammalian expression vector
  • Gal4-RORC2 LBD is constitutively active in the transfected Neuro2a cells, resulting in a robust luciferase response in the absence of stimulation.
  • RORC2 inhibitor Upon treatment with an RORC2 inhibitor the transcriptional response is decreased and the magnitude of the decrease in response is dose-dependently related to the intrinsic efficacy of the inhibitor.
  • the growth medium was composed by MEM EBS w/o L-glutamine, 10% (v/v) FBS, 2 mM L-glutamine and 1 ⁇ non-essential aminoacid (NEAA);
  • the seeding medium was composed by MEM EBS w/o L-glutamine, w/o phenol red, 4% (v/v) FBS, 2 mM L-glutamine, 1 ⁇ NEAA, 1% Penicillin (10,000 U/mL)/Streptomycin (10,000 ⁇ g/mL);
  • the assay medium was composed by MEM EBS w/o L-glutamine, w/o phenol red, 4% (v/v) FBS, 2 mM L-glutamine, 1 ⁇ NEAA, 1% Penicillin (10,000 U/mL)/Streptomycin (10,000 ⁇ g/mL).
  • Neuro2A cells were cultured in growth medium in humidified chambers at 37° C. and 5% CO 2 using standard tissue culture procedures.
  • Neuro2A cells were suspended in seeding medium and mixed with plasmids and transfection reagent which was dissolved in OptiMEM I reduced serum medium (InVitrogen), and then seeded to 384-well plates (Corning, Black, Clear bottom) in 40 ⁇ L/well containing 12,500 cells, 17.25 ng Gal4-Luc3, 5.75 ng either empty pM vector (‘no receptor control’ wells) or pM-Gal4RORgamma-LBD, and 0.11 ⁇ L Lipofectamine2000.
  • OptiMEM I reduced serum medium InVitrogen
  • the cells were treated with compounds of the invention. Specifically, the treatment was started 20-24 hr after seeding and transfection of the cells.
  • Compounds of the invention were serially diluted in a 384-well polypropylene plate with assay medium containing 0.5% (v/v) DMSO at 5 ⁇ final assay concentration. 10 ⁇ L of the compounds (or 0.5% DMSO in assay medium for ‘no compound control’ wells) were transferred from the dilution plate to the 384-format cell plate such that final assay volume was 50 ⁇ L and final DMSO concentration was 0.1% (v/v), followed by incubation for 20-24 hr in humidified chambers at 37° C. and 5% CO 2
  • the activity of compound of the invention can be also be determined by an IL-17 production from human Th17 cells assay.
  • this assay measures blockade of IL-17 production, the signature cytokine of T helper 17 (Th17) cells, by compounds.
  • Purified human CD4+ T cells are stimulated with anti-CD3+anti-CD28 and incubated with a cytokine cocktail that induce their differentiation into Th17 in the absence or presence of various concentrations of compound. After 6 days, IL-17A concentration is measured in the cell culture supernatant with an ELISA kit (MSD).
  • MSD ELISA kit
  • CD4+ T cells were purified from buffy coats from healthy donors (obtained from Massachusetts General Hospital) by negative selection the following procedure: Mixing 25 mL of blood with 1 mL of Rosette Sep CD4+ T cell enrichment cocktail (StemCell Technologies) followed by application of a layer of 14 mL Ficoll Paque Plus (Amersham GE Healthcare) and subsequent centrifugation at 1200 g for 20 min at room temperature.
  • the Ficoll layer was then harvested and washed with phosphate saline buffer containing 2% (v/v) fetal bovine serum and cells were resuspended with RPMI medium containing 10% (v/v) fetal bovine serum and 10% (v/v) DMSO, frozen and kept in LN2 until used.
  • a vial containing 10 7 CD4+ T cells is thawed rapidly in 37° C. water bath, immediately transferred into 20 mL X-Vivo 15 medium (Lonza), is spun for 6 min at 300 ⁇ g, the supernatant is discarded, and the resulting pellet is re-suspended at 10 8 cells/mL in 50 mL fresh X-Vivo 15 medium, followed by storage overnight in a tissue culture vessel in a humidified chamber at 37° C. and 5% CO 2 .
  • Serial dilutions of compounds of the invention are prepared at 10 ⁇ final concentration in X-Vivo15 medium containing 3% (v/v) DMSO.
  • a 384-well tissue culture plate was coated with 10 ⁇ g/mL anti-hCD3 (eBioscience) at 50 ⁇ L/well. After 2 hr at 37° C., the supernatant is discarded and the coated plates are kept in a sterile tissue culture hood.
  • Cytokine plus anti-CD28 cocktail is prepared by mixing 25 ng/mL hIL-6 (Peprotech), 5 ng/mL hTGFbeta1 (Peprotech), 12.5 ng/mL IL-1beta (Peprotech), 25 ng/mL hIL-21, 25 ng/mL hIL-23 (R&D Systems), and 1 ug/mL anti-hCD28 (eBioscience) in X-Vivo 15 medium.
  • the cytokine plus anti-CD28 cocktail with CD4+ cells is prepared such that the cocktail is diluted 10-fold and cell density is 0.22 ⁇ 10 6 /mL. The mixture is incubated 1 hr at 37° C.
  • Superantigens are among the most powerful T cell activators.
  • Superantigens bind to the cell surface of major histocompatibilty complex (MHC) molecules, without intracellular processing. They stimulate T cells via the T cell receptor, irrespective of the antigen specificities. Therefore, bacterial superantigens are able to activate a large pool of CD4+ as well as CD8+ T cells in contrast to the low T cell frequency for conventional antigens.
  • CD4+ T cells can be classified into various subsets (Th0, Th1, Th2, Th17) based on their respective cytokine secretion profiles. Th0 cells are uncommitted na ⁇ ve precursor cells that primarily produce IL-2 upon stimulation.
  • Th0 cells upon activation can differentiate into Th1, Th2, or the Th17 subset depending on the local cytokine milieu.
  • Th1 cells mainly produce Inf- ⁇ ; Th2 cells, IL-4, IL-5, and IL-13, and Th17 cells, IL-17, and IL-22.
  • T helper subset occurs over days, or longer.
  • IL-2, IL-4, Inf- ⁇ , IL-17 the various cytokines of the different Th subsets after only 6 hr.
  • Th17 cytokine profile without affecting the cytokine profile of the other Th subsets (Th0, Th1, Th2).
  • the model uses approximately 8 week old C57BL/6, Balb/c, or C3H/HeJ mice which are dosed orally with compound 1 to 2 hr prior to superantigen injection on the day of the experiment (Day 0) based on the pharmacokinetic (PK) profile of the compound.
  • An optional dose may be given the day before superantigen injection (Day ⁇ 1) to further inhibit the response if necessary.
  • C57BL/6 and Balb/c mice will be sensitized 1 hr prior to superantigen injection with approximately 25 mg/mouse D-Galactosamine intraperitoneally (C3H/HeJ mice do not need to be sensitized). Based on the literature superantigen is typically given at 10 ⁇ g/mouse intraperitoneally. Mice will be sacrificed at 3 hr for RNA analysis or up to 6 hr for cytokine analysis.
  • 5% imiquimod (IMQ) cream (3M Pharmaceuticals) is applied to the back and right ear of each experimental mouse for two consecutive days. Control mice are treated similarly with a commercially available vehicle cream. The experimental mice are then administered with ROR ⁇ t inhibitors, and the control mice with vehicle, for 4 days. The ear thickness is measured on all days by digital micrometer (Mitutoyo). Tissues, such as ears and speens, are harvested on Day 5 for RNA analysis. Ear swelling and serum measurements are also made.
  • references describing aspects of this assay include: Van der Fits, L. et al. J. Immunol. 2009, 182(9), 5836-45; Van Belle, A. B. et al. J Immunol. 2012, 188(1), 462-9; Cai, Y. et al. Immunity 2011, 35(4), 596-610; Fanti, P. A. et al. Int. J. Dermatol. 2006, 45(12), 1464-5; Swindell, W. R. et al. PLoS One 2011, 6(4), e18266; and Roller, A. et al. J. Immunol. 2012, 189(9), 4612-20.
  • mice Ears from BALB/c mice were each injected intra-dermally every other day with 150 ng of mouse recombinant IL-23 (eBiosciences) or PBS in a total volume of 25 ⁇ l. Ear swelling was measured in triplicate using a micrometer (Mitutoyo) right before each IL-23 challenge. On Day 14, mice were euthanized and ears were collected for measurement of cytokine levels, gene expression levels and hystopathological evaluation. Mice were administered 3-100 mg/kg of an RORC2 modulator or vehicle once daily orally for the duration of the study. Alternatively, the RORC2 modulator was applied topically once or twice daily using a standard formulation (EtOH:propylene glycol:dimethyl isosorbide:DMSO, 38:30:15:15) at a concentration of 0.1% to 5.0%.
  • a standard formulation EtOH:propylene glycol:dimethyl isosorbide:DMSO, 38:30:15:15
  • references describing aspects of this assay include: Muramoto, K. et al. J. Pharmacol. Exp. Ther. 2010, 335(1), 23-31; Fridman, J. S. et al. J. Invest. Dermatol. 2011, 131(9), 1838-1844.

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