WO2013064231A1 - Sulfonamides à sept chaînons comme modulateurs des récepteurs gamma orphelins associés à un récepteur de l'acide rétinoïque (rorγ, nr1f3) - Google Patents

Sulfonamides à sept chaînons comme modulateurs des récepteurs gamma orphelins associés à un récepteur de l'acide rétinoïque (rorγ, nr1f3) Download PDF

Info

Publication number
WO2013064231A1
WO2013064231A1 PCT/EP2012/004487 EP2012004487W WO2013064231A1 WO 2013064231 A1 WO2013064231 A1 WO 2013064231A1 EP 2012004487 W EP2012004487 W EP 2012004487W WO 2013064231 A1 WO2013064231 A1 WO 2013064231A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
halo
compound
independently selected
cycloalkyl
Prior art date
Application number
PCT/EP2012/004487
Other languages
English (en)
Inventor
Olaf Kinzel
Christian Gege
Christoph Steeneck
Gerald Kleymann
Thomas Hoffmann
Original Assignee
Phenex Pharmaceuticals Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Phenex Pharmaceuticals Ag filed Critical Phenex Pharmaceuticals Ag
Publication of WO2013064231A1 publication Critical patent/WO2013064231A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • 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
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention provides modulators for the orphan nuclear receptor RORy and methods for treating RORy mediated chronic inflammatory and autoimmune diseases by administration of these novel RORy modulators to a human or a mammal in need thereof.
  • the retinoid-receptor related orphan receptors consist of three family members, namely RORa (Beckerandre et al., Biochem. Biophys. Res. Commun. 1993, 194:1371), ROR (Andre et al., Gene 1998, 516:277) and RORy (He et al., Immunity 1998, 9:797) and constitute the NR1 F (ROR/RZR) subgroup of the nuclear receptor superfamily (Mangelsdorf et al., Cell 1995, 83:835).
  • the nuclear receptor superfamily shares common modular structural domains consisting of a hypervariable N-terminal domain, a conserved DNA binding domain (DBD), a hinge region, and a conserved ligand-binding domain (LBD).
  • the DBD targets the receptor to specific DNA sequences (nuclear hormone response elements or NREs), and the LBD functions in the recognition of endogenous or exogenous chemical ligands.
  • NREs nuclear hormone response elements
  • a constitutive transcriptional activation domain is found at the N-terminus (AF1) and a ligand regulated transcriptional activation domain is embedded within the C-terminal LBD of typical NRs.
  • the nuclear receptors can exist in a transcriptional activating or repressing state when bound to their target NREs.
  • the basic mechanism of gene activation involves ligand dependent exchange of co-regulatory proteins, namely co-activators and co-repressors (McKenna et al., Endocrine Rev. 1999, 20:321).
  • a NR in the repressing state is bound to its DNA recognition element and is associated with co-repressor proteins that recruit histone-deacetylases (HDACs).
  • HDACs histone-deacetylases
  • co-repressors are exchanged for coactivators that recruit transcription factors, which contribute to assembling of a chromatin-remodelling complex, which relieves transcriptional repression and stimulates transcriptional initiation via histone acetylation.
  • the AF-2 domain of the LBD acts as a ligand dependant molecular switch presenting interaction surfaces for co- repressor or co-activator proteins and providing with a conserved mechanism for gene activation or repression that is shared by the members of the nuclear receptor superfamily.
  • the members of the NR1 F family of nuclear receptors have been considered to be constitutively active transcription factors in the absence of known ligands, which is similar to the estrogen-related receptor alpha (Vanacker et al., Mol. Endocrinol. 1999, 13:764).
  • RORy nuclear receptors
  • 7-oxygenated oxysterols were identified to be high affinity ligands for RORa and RORy (Wang et al., J. Biol. Chem. 2010, 285:5013).
  • 7-Hydroxycholesterol is a key metabolite during the conversion of cholesterol into bile acids, but to date it is not clear whether it is a true endogenous ligand for the RORs.
  • RORy inverse agonists of RORy should reduce the transcriptional activity of RORy and influence the biological pathways controlled by RORy.
  • the RORs are expressed as isoforms arising from differential splicing or alternative transcriptional start sites. So far, isoforms have been described that differ only in their N- terminal domain (A/B-domain). In humans, four different RORo isoforms have been identified (RORa 1-4) while only two isoforms are known for both ROR (1 and 2) and RORy (1 and 2) (Andre et al., Gene 1998, 216:277; Villey et al., Eur. J. Immunol. 1999, 29:4072). RORy is used herein as a term describing both, RORyl and/or RORy2.
  • the ROR isoforms show different tissue expression patterns and regulate different target genes and physiological pathways.
  • the RORy2 also called RORyt
  • RORyt is highly restricted to CD4 + CD8 + thymocytes and to interleukin-17 (IL-17) producing T cells while other tissues express RORyl
  • IL-17 interleukin-17
  • RORs exhibit a structural architecture that is typical of nuclear receptors.
  • RORs contain four major functional domains: an amino-terminal (A/B) domain, a DNA-binding domain (DBD), a hinge domain, and a ligand-binding domain (LBD) (Evans et al., Science 1988, 240:889).
  • the DBD consists of two highly conserved zinc finger motifs involved in the recognition of ROR response elements (ROREs) which consist of the consensus motif AGGTCA preceded by an AT-rich sequence (Andre et al., Gene 1998, 216:277) which is similar to that of the nuclear receptors Rev-ErbAa and Rev-Ert$ (NR1D1 and D2, respectively) (Giguere et al., Genomics 1995, 28:596).
  • ROREs ROR response elements
  • RORa is highly expressed in different brain regions and most highly in cerebellum and thalamus.
  • RORa knock-out mice show ataxia with strong cerebellar atrophy, highly similar to the symptoms displayed in the so-called staggerer mutant mouse (RORa SQ S9 ).
  • This mouse carries mutations in RORa that results in a truncated RORa which does not contain a LBD (Hamilton et al., Nature 1996, 379:736).
  • ROR expression is mainly restricted to the brain and most abundantly found in the retina.
  • ROR3 knock-out mice display a duck-like gait and retinal degeneration which leads to blindness (Andre et al., EMBO J. 1998, 17:3867). The molecular mechanisms behind this retinal degeneration are still poorly understood.
  • RORy (particularly RORy2) null-mutant mice lack lymph nodes and Peyer ' s patches (Eberl and Littmann, Immunol. Rev. 2003, 195:81) and lymphatic tissue inducer (LTi) cells are completely absent from spleen mesentery and intestine.
  • LTi lymphatic tissue inducer
  • the size of the thymus and the number of thymocytes is greatly reduced in RORy null mice (Sun et al., Science 2000, 288:2369) due to a reduction in double-positive CD4 + CD8 + and single positive CD4 " CD8 + or CD4 + CD8 " cells suggesting a very important role of RORy2 in thymocyte development.
  • Thymocyte development follows a complex program involving coordinated cycles of proliferation, differentiation, cell death and gene recombination in cell populations dedicated by their microenvironment.
  • Pluripotent lymphocyte progenitors migrating from fetal liver or adult bone marrow to the thymus are being committed to the T-cell lineage. They develop through a series of steps from CD4 ⁇ CD8 ⁇ double negative cells to CD4 + CD8 + cells and those with low affinity towards self-MHC peptides are eliminated by negative selection. These develop further into CD4 " CD8 + (killer) or CD4 + CD8 ⁇ (helper) T-cell lineages.
  • RORy2 is not expressed in double negative and little expressed in immature single negative thymocytes (He et al., J. Immunol. 2000, 164:5668), while highly upregulated in double-positive thymocytes and downregulated during differentiation in single-positive thymocytes. RORy deficiency results in increased apoptosis in CD4 + CD8 + cells and the number of peripheral blood thymocytes is decreased by 6- fold (10-fold CD4 + and 3-fold CD8 + thymocytes).
  • T-helper cells were previously considered to consist of Th1 and Th2 cells.
  • Th17 cells which produce IL-17
  • Th17 cells were also identified as a unique class of T-cells that are considered to be pro-inflammatory. They are recognized as key players in autoimmune and inflammatory diseases since IL-17 expression has been associated with many inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosis (SLE) and allograft rejection.
  • SLE systemic lupus erythematosis
  • RORy2 is exclusively expressed in cells of the immune system and has been identified as a master regulator of Th17 cell differentiation. Expression of RORy2 is induced by TGF-beta or IL- 6 and overexpression of RORy2 results in increased Th17 cell lineage and IL-17 expression. RORy2 KG mice show very little Th17 cells in the intestinal lamina intestinal and demonstrate an attenuated response to challenges that usually lead to autoimmune disease (Ivanov et al., Cell 2006, 126:1121).
  • Inhibition of IL-17 production via inhibition of Th17 cell development may also be advantageous in atopic dermatitis and psoriasis where IL-17 is deeply involved.
  • IL-10 suppresses the expression of IL-17 secreted by both, macrophages and T-cells.
  • the expression of the Th17 transcription factor ROR72 was suppressed (Gu et al., Eur. J. Immunol. 2008, 38:1807).
  • IL-10 deficient mice provide a good model for inflammatory bowel disease (IBD) where a shift towards a Th1 type inflammatory response is frequently observed.
  • Oral IL-10 delivery poses a potential treatment option for IBD.
  • IL-17 producing Th17 cells are counteracted by another T- helper cell type, so-called regulatory T-cells or Tregs.
  • Naive T cells are differentiated into Tregs upon stimulation by TGF .
  • FoxP3 expression is suppressed and RORTt expression is induced.
  • CD4 + FoxP3 " RORyt + T- helper cells then differentiate into IL-17 producing Th17 cells, (reviewed in Awasthi and Kuchroo, Int. Immunol. 2009, 21:489, and Zhou and Littmann, Curr. Opin.
  • Th17 cells are responsible for the etiology of a whole range of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, Crohn ' s disease and other types of inflammatory bowel disease, lupus erythematosus and asthma.
  • the severity of disease seems to correlate with the presence of IL-17 + Th17 cells and it is believed that interception of RORyt by a small molecule inverse agonist or antagonist should result in a reduction of these IL-17 + Th17 cells ultimately leading to alleviation of disease symptoms and outcome (Crome et al., Clin. Exp. Immunol. 2010, 159:109).
  • retinoids including all- trans retinoid acid have been demonstrated to bind to ROR and function as partial antagonists for RORp but not RORa (Stehlin-Gaon et al., Nat. Struct. Biol. 2003, 10:820).
  • 7-oxygenated sterols such as 7-hydroxy-cholesterol and 7-keto-cholesterol were identified as highly potent modulators of RORy activity (Wang et al., J. Biol. Chem. 2010, 285:5013) in in vitro assays.
  • Modulators of the RORy receptor were recently disclosed in WO201 1/107248, WO201 1/1 12263, WO201 1/1 12264, WO201 1/1 15892, WO2012/027965, WO2012/028100, WO2012/064744, WO2012/100732, WO2012/100734, WO2012/106995 and WO2012/139775, which are based upon other structural classes.
  • JP-A-2006/056881 and WO2004/067008 describe 6 to 9-membered heterocyclic fused pyridine compounds as TGF receptor agonists for the treatment of e.g. heart failure or myocardial infarction.
  • TGF receptor agonists for the treatment of e.g. heart failure or myocardial infarction.
  • all examples in JP-A-2006/056881 and WO2004/067008 bear a cyclic structure as substituent at the atom position neighbouring the bridgehead atom "*".
  • bradykinin antagonsits of Formula (C) which contain a Chester, CH 2 -thioester or CH 2 -amide group in the 3-position of the 4,5-dihydro-1 H- benzo[e][1 ,4]diazepin-2(3H)-one core.
  • W01997/030992 describe farnesyl transferase inhibitors of general Formula (D), which have an imidazolyl residue in the 1 -position of the 7-membered cyclic ring.
  • the derivative (D1) serves as an intermediate t
  • WO2004/018432 disclosed substituted azepines as histamine H3 receptor antagonists of general Formula (F), wherein the sulfonamide residue is limited to phenyl.
  • the present invention provides RORy modulators, which can be used for treating or preventing a disease or disorder associated with the inactivation or activation of the RORy receptor.
  • the present invention relates to a RORy modulator for use in the treatment or prophylaxis of a disease or disorder associated with the inhibition or activation of RORy.
  • the activity of said receptor is preferably reduced.
  • the disease or disorder is selected from the group consisting of autoimmune diseases.
  • Autoimmune diseases comprise a group of diseases with a similar etiology of an overshooting immune response against endogenous targets resulting in chronic inflammation and physical disabilities or other severe symptoms.
  • Autoimmune diseases comprise e.g. rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, psoriasis, atopic eczema, inflammatory bowel diseases such as Crohn ' s disease, asthma, multiple sclerosis, type 1 diabetes and amyotrophic lateral sclerosis.
  • the present invention provides a compound of Formula (1)
  • R 1 is hydrogen, C -12 -alkyl, C 2 -i 2-alkenyl, C 2 -i 2-alkynyl, C 3 .i 0 -cycloalkyl, C 3 .i 0 -heterocycloalkyl, a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, or a 6-10 membered mono- or bicyclic aromatic ring system,
  • alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl groups are unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, oxo, halogen, halo-Ci. 6 -alkyl, 0-Ci. 6 -alkyl or CHhalo- ⁇ -e-alkyl),
  • heteroaromatic and aromatic ring systems are independently from each other unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, oxo, halogen, cyano, C 1-6 -alkyl, C 3 . 6 -cycloalkyl, C 3 .i 0 -heterocycloalkyl, 0-Ci. 6 -alkyl, a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, or a 6-10 membered mono- or bicyclic aromatic ring system,
  • R 2 is a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, or a 6-10 membered mono- or bicyclic aromatic ring system
  • heteroaromatic and aromatic ring systems are independently from each other unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from oxo, halogen, cyano, Ci- 6 -alkyl, halo-C M 2 -alkyl, C 3 . 6 -cycloalkyl, C 3 . 6 -heterocycloalkyl, C 0 . e-alkylene-OR 16 , COOH, COO-(d. 6 -alkyl), CO-N(R 10 )(R 11 ), SO 2 -N(R 10 )(R 11 ), SO y -(d. 6 - alkyl), or SO y -(halo-d-6-alkyl); or
  • heteroaromatic and the aromatic ring systems are fused with a saturated 5-8 membered carbocycle or a saturated 5-8 membered heterocycle containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, and the fused ring system is unsubstituted or substituted by 1 , 2, 3 or 4 substituents independently selected from OH, oxo, halogen, cyano, Ci. 6 -alkyl, halo-d-e-alkyl, C 3 . 6 -cycIoalkyl, C 3 . 6 -heterocycloalkyl, O- Ci. 6 -alkyl or 0-(halo-Ci -6 -alkyl);
  • R 10 is independently in each instance selected from H, d-10-alkyl, C 2 .i 0 -alkenyl, C 2 -io-alkynyl, C 0 - 6 -alkylene-C 3 .io-cycloalkyl, C 0 -6-alkylene-C 3 .i 0 -heterocycloalkyl or C 0 -6-alkylene-5-membered heteroaromatic ring system containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl and 5-membered heteroaromatic ring system are unsubstituted or substituted with 1 to 6 substituents independently selected from OH, oxo, CN, O-C ⁇ -alkyl, O-halo-d-e-alkyl, d- 6 -alkyl, halogen,
  • R 11 is independently in each instance selected from H, d-e-alkyl, halo-d-e-alkyl or C 3 . 6 -cycloalkyl; or
  • R 10 and R 1 when taken together with the nitrogen to which they are attached form a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S, S(O), S(0 2 ) or N(R 7 ), wherein said ring is unsubstituted or substituted with one or more halogen, OH, oxo or d. 6 -alkyl;
  • L is -(CR 6 2 ) X -, -(CR 6 2 ) X -NR 7 -, -(CR 6 2 ) x -0- or -(CR 6 2 ) x -0-(CR 6 2 ) x -;
  • R 6 is independently in each instance H, F, d-e-alkyl, C 3 - 6 -cycloalkyl, halo-d-e-alkyl or halo-C 3 _6-cycloalkyl;
  • R 7 is independently in each instance H, C e-alkyl, C 3 . 6 -cycloalkyl, halo-Ci- 6 -alkyl, halo-C 3 . 6-cycloalkyl or hydroxy-C 2 . 6 -alkyl;
  • R 12 , R 3 and R 14 are independently of one another selected from H, F, d. 6 -alkyl or halo-d-e- alkyl;
  • Y is selected from C or N;
  • Z is selected from C or N; wherein at least one of Y and Z is C;
  • Ar together with Y and Z is a 5-6 membered monocyclic heteroaromatic ring system containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, or a 6 membered monocyclic aromatic ring system
  • heteroaromatic and aromatic ring system is unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, halogen, halo-C - 6 -alkyl, Chalky!, C 3 - 6 -cycloalkyl, 0-Ci. 6 -alkyl or 0-(halo-Ci. 6 -alkyl);
  • X 1 is selected from C or N;
  • X 2 is selected from C or N;
  • R 16 is independently in each instance selected from H, Ci -6 -alkyl or halo-d. 6 -alkyl;
  • R 17 is independently in each instance selected from H, OH, F, C 1-6 -alkyl, C 3 . 6 -cycloalkyl, O-Ci-6-alkyl, 0-C 3 . 6 -cycloalkyl, halo-C ! -e-alkyl or O-halo-d-e-alkyl;
  • R 18 and R 19 together with X 1 and X 2 form a 5-membered ring containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, said 5-membered ring being unsubstituted or substituted by 1 or 2 substituents independently selected from OH, oxo, halogen, CN, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 3 . 6 -cycloalkyl, 0-Ci- 6 -alkyl, 0-(halo-Ci. 6 -alkyl), COOH, C0 2 N(R 16 ) 2 or N(R 16 ) 2 ;
  • each of R 22 and R 23 is independently of one another selected from H, F, Ci. 6 -alkyl or halo-Ci-6-alkyl;
  • x is independently selected from 1 , 2, 3 or 4;
  • y is independently selected from 0, 1 or 2;
  • Ar together with Y and Z is a 6-membered aromatic or heteroaromatic ring system containing 1 or 2 nitrogen atoms, said heteroaromatic or aromatic ring system being unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, halogen, Ci. 6 -alkyl, halo- d-e-alkyl, C 3 . 6 -cycloalkyl, O-d-e-alkyl or 0-(halo-d. 6 -alkyl), more preferably being unsubstituted.
  • Ar together with Y and Z is a 5-membered heteroaromatic ring system containing 1 , 2 or 3 nitrogen atoms, in particular 2 or 3 nitrogen atoms, said heteroaromatic ring system being unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, halogen, d-e-alkyl, halo-d-e-alkyl, C 3 . 6 -cycloalkyl, O-C ⁇ -alkyl or 0-(halo-Ci. 6 -alkyl).
  • said heteroaromatic ring system is unsubstituted or substituted by 1 or 2 substituents independently selected from C 1-6 -alkyl.
  • Ar is selected from the group consisting of
  • Ar is selected from the group consisting of
  • R 1 is hydrogen, C -12 -alkyl, C 3 .i 0 -cycloalkyl, C 3-10 -heterocycloalkyl, a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, or a 6-10 membered mono- or bicyclic aromatic ring system,
  • alkyl, cycloalkyl and heterocycloalkyl groups are unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, oxo, halogen, halo-Ci-6-alkyl, O-d-e-alkyl or O-ihalo-d-e-alkyl),
  • heteroaromatic and aromatic ring systems are independently from each other unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, oxo, halogen, cyano, C 1-6 -alkyl, C 3 . 6 -cycloalkyl, C 3 .i 0 -heterocycloalkyl, O-d-e-alkyl, a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, or a 6-10 membered mono- or bicyclic aromatic ring system, wherein each of the Ci. 6 -alkyl, C 3 .
  • L is -(CR 6 2 ) X -, -(CR 6 2 ) x -0- or -(CR 6 2 ) x -0-(CR 6 2 ) x -;
  • R 6 is independently H, F or Ci. 6 -alkyl
  • x is independently selected from 1 or 2.
  • R is hydrogen, d. ⁇ -alkyl, C 3 -i 0 -cycloalkyl, C 3 .i 0 -heterocycloalkyl, a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, or a 6-10 membered mono- or bicyclic aromatic ring system,
  • alkyl, cycloalkyl and heterocycloalkyl groups are unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, oxo, halogen, halo-d-e-alkyl, 0-d. 6 -alkyl or O-ihalo-C ! -e-alkyl),
  • heteroaromatic and aromatic ring systems are independently from each other unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, oxo, halogen, cyano, C 1-6 -alkyl, C 3 . 6 -cycloalkyl, C 3 . 10 -heterocycloalkyl, 0-Ci- 6 -alkyl, a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, or a 6-10 membered mono- or bicyclic aromatic ring system,
  • R 1 is hydrogen, C - 6 -alkyl, C 3 . 6 -cycloalkyl, C 4 . 8 -heterocycloalkyl, a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2, or 3 heteroatoms independently selected from N or O, or a 6-10 membered mono- or bicyclic aromatic ring system,
  • alkyl, cycloalkyl and heterocycloalkyl groups are unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, oxo, halogen, halo-d-e-alkyl, 0-Ci- 6 -alkyl or O-Chalo-C t -e-alkyl), in particular unsubstituted, wherein said heteroaromatic and aromatic ring systems are independently from each other unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from Ci-e-alkyl, 0-Ci- 6 -alkyl or a 6-membered aromatic ring system, in particular unsubstituted, wherein each of the C 1-6 -alkyl, O-d-e-alkyl, and the 6-membered mono- or bicyclic aromatic ring system is independently of one another unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, d
  • R 1 is hydrogen, Ci. 6 -alkyl, C 5 . 6 -cycloalkyl, C 6 -heterocycloalkyl, a 6-10 membered mono- or bicyclic aromatic ring system,
  • alkyl, cycloalkyl and heterocycloalkyl groups are unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from OH, oxo, halogen, halo-Ci-e-alkyl, 0-Ci. 6 -alkyl or 0-(halo-d.6-alkyl), in particular unsubstituted,
  • aromatic ring system is unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from C 1-6 -alkyl, 0-Ci. 6 -alkyl or a 6-membered aromatic ring system, in particular unsubstituted,
  • each of the Ci. 6 -alkyl, 0-C 1-6 -alkyl, and the 6-10 membered mono- or bicyclic aromatic ring system is independently of one another unsubstituted or substituted by 1 , 2 or 3 substituents selected from halogen, Ci- 6 -alkyl, halo-Ci. 6 - alkyl, 0-d. 6 -alkyl or 0-(halo-Ci. 6 -alkyl).
  • R 1 is hydrogen, C 3 . 6 -cycloalkyl, C 4 . 8 -heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O, or a 6-membered monocyclic aromatic ring system which is unsubstituted or substituted by d. 6 -alkyl or 0-Ci -6 -alkyl, said Ci-e-alkyl or 0-d. 6 -alkyl being unsubstituted or substituted by 1 , 2 or 3 halogen atoms.
  • R 2 is a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, or a 6 membered monocyclic aromatic ring system,
  • heteroaromatic and aromatic ring systems are independently from each other unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from oxo, halogen, cyano, d. 6 -alkyl, halo-Ci-i 2 -alkyl, C 3 . 6 -cycloalkyl, C 3 . 6 -heterocycloalkyl, C 0 . 6-alkylene-OR 6 , COOH, COO-(Ci-e-alkyl), CO-N(R 0 )(R 11 ), SO 2 -N(R 10 )(R 11 ), SO y -(d. 6 - alkyl) or SO y -(halo-d. 6 -alkyl);
  • the heteroaromatic and the aromatic ring systems are fused with a saturated 5-8 membered carbocycle or a saturated 5-8 membered heterocycle containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, and the fused ring system is unsubstituted or substituted by 1 , 2, 3 or 4 substituents independently selected from OH, oxo, halogen, cyano, Ci -6 -alkyl, halo- ⁇ -e-alkyl, C 3 - 6 -cycloalkyl, C 3 . 6 -heterocycloalkyl, O- d-e-alkyl or 0-(halo-Ci. 6 -alkyl).
  • R 2 is a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, or a 6 membered monocyclic aromatic ring system,
  • heteroaromatic and aromatic ring systems are independently from each other unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from oxo, halogen, cyano, C 1-6 -alkyl, halo-C ⁇ -alkyl, C 3 - 6 -cycloalkyl, C 3 . 6 -heterocycloalkyl, C 0 . 6-alkylene-OR 16 , COOH, COO-(d-6-alkyl), CO-N(R 10 )(R 11 ), SO 2 -N(R 0 )(R 11 ), SO y -(d- 6 - alkyl), or SO y -(halo-d-6-alkyl); or
  • heteroaromatic and the aromatic ring systems are fused with a saturated 5-8 membered carbocycle or a saturated 5-8 membered heterocycle containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, and the fused ring system is unsubstituted or substituted by 1 , 2, 3 or 4 substituents independently selected from OH, oxo, halogen, cyano, C 1-6 -alkyl, halo-d-e-alkyl, C 3 . 6 -cycloalkyl, C 3 . 6 -heterocycloalkyl, O- Ci-e-alkyl or 0-(halo-Ci. 6 -alkyl).
  • R 2 is a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1 , 2 or 3 heteroatoms independently selected from N or O, or a 6 membered monocyclic aromatic ring system,
  • heteroaromatic and aromatic ring systems are independently from each other unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from halogen, cyano, C e-alkyl, halo-Ci-e-alkyl, C 3 . 6 -cycloalkyl, C 3 - 6 -heterocycloalkyl, C 0 - 6 - alkylene-OR 16 , COOH, COO-(d. 6 -alkyl), CO-N(R 0 )(R 11 ), SO 2 -N(R 0 )(R 11 ), SO y -(d r alkyl), or SO y -(halo-d. 6 -alkyl); or
  • heteroaromatic and the aromatic ring systems are fused with a saturated 5-6 membered carbocycle or a saturated 5-6 membered heterocycle containing 1 , 2 or 3 heteroatoms independently selected from N or O, and the fused ring system is unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from halogen, cyano, C e-alkyl, halo-d- 6 -alkyl, C 3 . 6 -cycloalkyl, C 3 . 6 -heterocycloalkyl, O-d-e- alkyl or 0-(halo-d. 6 -alkyl).
  • R 2 is a 6 membered heteroaromatic ring system containing 1 or 2 heteroatoms independently selected from N and O, a 9-10 membered bicyclic heteroaromatic ring system containing 1 or 2 heteroatoms independently selected from N and O, or a 6 membered aromatic ring system wherein said heteroaromatic and aromatic ring systems are independently from each other unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from halogen, cyano, C 1-6 -alkyl, halo-Ci- 6 -alkyl, C 3 . 6 -cycloalkyl, C 3 .
  • heteroaromatic and the aromatic ring systems are fused with a saturated 5-6 membered carbocycle or a saturated 5-6 membered heterocycle containing 1 , 2 or 3 heteroatoms independently selected from N or O, and the fused ring system is unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from halogen, cyano, C alkyl, halo-C 1-6 -alkyl, C 3 . 6 -cycloalkyl, C 3 . 6 -heterocycloalkyl, 0-Ci- 6 - alkyl or 0-(halo-Ci. 6 -alkyl).
  • R 2 is a 6 membered aromatic ring system
  • aromatic ring system is substituted in ortho-position by a substituent selected from with Ci-3-alkyl, fluoro-C 1-3 -alkyl, 0-C 1-3 -alkyl or fluoro-Ci- 3 -alkyl; and
  • aromatic ring system is optionally unsubstituted or substituted by 1 or 2 substituents independently selected from halogen, cyano, C n-3 -aikyl, halo-Ci. 3 -alkyl, C 3 . 4 - cycloalkyl or C 0 . 3 -alkylene-OR 16 ;
  • R 2 is selected from
  • R 2 is not 4-methylphenyl. In another preferred embodiment in combination with any of the above or below embodiments, R 2 is not phenyl substituted by alkyl.
  • X is selected from -NR 16 -CO-, -C(R 22 )(R 23 )-C(R 22 )(R 17 )-, -0-C(R 22 )(R 23 )- or -X (R 18 )-X 2 (R 19 )-, wherein R 18 and R 9 together with the atoms to which they are connected form a 5-membered ring containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, said 5-membered ring being unsubstituted or substituted by 1 or 2 substituents independently selected from OH, oxo, halogen, CN, Ci -6 -alkyl, halo-Ci.
  • X is selected from -NR 16 -CO-, -C(R 22 )(R 23 )-C(R 22 )(R 17 )-, -0-C(R 22 )(R 23 )- or -X (R 18 )-X 2 (R 19 )-, wherein R 18 and R 19 together with the atoms to which they are connected form a 5-membered ring containing 1 or 2 heteroatoms independently selected from N or O, said 5-membered ring being unsubstituted or substituted by 1 or 2 substituents independently selected from halogen, CN, Ci.
  • R 12 is selected from H, F, d-e-alkyl or halo-Ci. 6 -alkyl, more preferably from H or Ci. 3 -alkyl, in particular H or methyl.
  • R 13 is selected from H, F, C ⁇ -alkyl or halo-d-e-alkyl, more preferably from H or C 1-3 -alkyl, in particular H or methyl.
  • R 14 is selected from H, F, Ci. 6 -alkyl or halo-Ci. 6 -alkyl, more preferably from H or Ci. 3 -alkyl, in particular H or methyl.
  • one or R 13 and R 4 is hydrogen and the other of R 13 and R 4 is C 1-3 -alkyl.
  • each of R 12 , R 13 and R 14 is hydrogen.
  • R 22 is selected from H, F, Ci_ 6 -alkyl or halo-d-e-alkyl, more preferably from H or C -3 -alkyl, in particular H or methyl.
  • R is selected from H, F, C 1-6 -alkyl or halo-Ci. 6 -alkyl, more preferably from H or C ⁇ -alkyl, in particular H or methyl.
  • L is - (CR 6 2 ) X -, -(CR 6 2 ) x -0- or -(CR 6 2 ) x -0-(CR 6 2 ) x -.
  • L-R 1 is selected from the group consisting of
  • R 6 is independently in each instance H, F, OH, C 1-6 -alkyl, C 3 . 6 -cycloalkyl, halo-C ⁇ -alkyl or halo- C 3 . 6 -cycloalkyl, or two R 6 at the same carbon atom to which they are attached together are oxo, more preferably H.
  • R 7 is independently in each instance H, C -6 -alkyl, C 3 . 6 -cycloalkyl, halo-Ci. 6 -alkyl, halo-C 3 . 6 - cycloalkyl or hydroxy-C 2 . 6 -alkyl, more preferably H or C 1 . 6 -alkyl.
  • R 10 is selected from H, Ci-i 0 -alkyl, C 2 -i 0 -alkenyl, C 2 . 10 -alkynyl, C 0 - 6 -alkylene-C 3 .i 0 -cycloalkyl, C 0 - 6 - alkylene-C 3 _io-heterocycloalkyl or C 0 - 6 -alkylene-5-membered heteroaromatic ring system containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyi, heterocycloalkyi and 5-membered heteroaromatic ring system are unsubstituted or substituted with 1 to 6 substituents independently selected from OH, oxo, CN, O-d-e-alkyl, 0-halo-Ci.
  • R 0 is selected from H, C M0 - alkyl, C 2 .
  • R 11 is independently selected from H, d- 6 -alkyl, halo-Ci. 6 -alkyl or C 3 . 6 -cycloalkyl, more preferably H or Ci. 6 -alkyl.
  • R 0 and R 11 when taken together with the nitrogen to which they are attached form a 3- to 8- membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S, S(O), S(0) 2 or N(R 7 ), wherein said ring is unsubstituted or substituted with one or more halogen, OH, oxo or C 1-6 -alkyl.
  • each R 16 is independently in each instance selected from H, C 1-6 -alkyl or halo-Ci. 6 -alkyl, more preferably from H, d-4-alkyl or fluoro-C ⁇ -alkyl.
  • each R 17 is independently in each instance selected from H, OH, F, C 1-6 -alkyl, C 3 . 6 -cycloalkyl, O- Ci-e-alkyl, 0-C 3 . 6 -cycloalkyl, halo-C 1 . 6 -alkyl or 0-halo-Ci -6 -alkyl, more preferably H or Ci. 4 -alkyl.
  • R 18 and R 19 together with X 1 and X 2 form a 5-membered ring containing 1 , 2 or 3 heteroatoms independently selected from N, O or S, said 5-membered ring being unsubstituted or substituted by 1 or 2 substituents independently selected from OH, oxo, halogen, CN, d-e-alkyl, halo-Ci -6 - alkyl, C 3 .
  • x is independently selected from 1 , 2, 3 or 4, in particular 1 or 2.
  • y is independently selected from 0, 1 or 2.
  • the compound is selected from the group consisting of
  • the invention also provides the compound of the invention for use as a medicament.
  • diseases or disorders which are Th17 mediated tissue inflammation or of autoimmune etiology or which are a skin disease with associated symptoms such as pain, itching or excoriations.
  • diseases or disorders are rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, psoriasis, atopic eczema, inflammatory bowel diseases such as Crohn ' s disease or ulcerative colitis, asthma, multiple sclerosis, type 1 diabetes and amyotrophic lateral sclerosis.
  • the invention further relates to the compound of the invention for use in the treatment or prophylaxis of a disease or disorder associated with the inhibition or activation of the RORy receptor.
  • composition comprising the compound of the invention and a pharmaceutically acceptable carrier.
  • d-12-alkyl means a saturated alkyl chain having 1 to 12 carbon atoms, i.e, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, which may be straight chained or branched.
  • Examples of Ci. 12 -alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.
  • halo-C ⁇ -alkyl means that one or more hydrogen atoms in the alkyl chain are replaced by a halogen.
  • halo-C ⁇ -alkyl is selected from CF 3 , CH 2 CF 3 or CH 2 CH 2 F.
  • C 2 _i 2 -alkenyl means an alkyl chain having 2 to 12 carbon atoms, i.e, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, which may be straight chained or branched, containing at least one carbon to carbon double bond. Examples thereof include ethenyl, propenyl, dodecenyl, 2- methylenehexyl and (2E,4£)-hexa-2,4-dienyl.
  • C 2 -i 2 -alkynyl means an alkyl chain having 2 to 12, i.e.
  • carbon atoms which may be straight chained or branched, containing at least one carbon to carbon triple bond. Examples thereof include ethynyl, propynyl and dodecynyl.
  • Coupled residue means that the respective group is divalent and connects the attached residue with the remaining part of the molecule. Moreover, in the context of the present invention, "C 0 - alkylene” is meant to represent a bond.
  • a C 3 .io-cycloalkyl group means a saturated mono-, bi- or multicyclic ring system comprising 3 to 10 carbon atoms, i.e, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, pentacyclo[4.2.0.0 2 ' 5 .0 38 .0 4 ' 7 ]octyl and adamantyl.
  • a C 3 .io-heterocycloalkyl group means a saturated or partially unsaturated 3, 4, 5, 6, 7, 8, 9 or 10 membered carbon mono-, bi- or multicyclic ring wherein 1 , 2 or 3 carbon atoms are replaced by 1 , 2 or 3 heteroatoms, respectively, said heteroatoms being independently selected from N, O and S.
  • the substitution can be at the carbon atoms of the cycle or at the nitrogen or sulfur heteroatom(s) of the cycle. Examples of the substituted S or N atom are SO, S0 2 or N-Ci- 6 -alkyl.
  • Examples of the C 3 .i 0 -heterocycloalkyl include epoxidyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, ,4-dioxanyl, morpholinyl, 4-quinuclidinyl, 1 ,4-dihydropyridinyl and 3,6- dihydro-2H-thiopyranyl.
  • a 5-10 membered mono- or bicyclic heteroaromatic ring system containing up to 4 heteroatoms means a monocyclic heteroaromatic ring (such as pyrrolyl, imidazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl and thiadiazolyl), or a bicyclic ring system wherein the heteroatom(s) may be present in one or both rings including the bridgehead atoms, respectively.
  • a monocyclic heteroaromatic ring such as pyrrolyl, imidazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl and
  • bicyclic heteroaromatic ring system examples include quinolinyl, isoquinolinyl, quinoxalinyl, benzimidazolyl, benzisoxazolyl, benzodioxanyl, benzofuranyl, benzoxazolyl, indolyl, indolizinyl and pyrazolo[1 ,5-a]pyrimidinyl.
  • a 6-10 membered mono- or bicyclic aromatic ring system means an aromatic carbon cycle containing 6, 7, 8, 9 or 10 carbon atoms. Examples thereof are phenyl or naphthalenyl.
  • Halogen is selected from fluorine, chlorine, bromine and iodine.
  • the compounds of the present invention are optical isomers.
  • the stereoisomer of Formula (V) with the following structure is preferred:
  • the compounds of the present invention are partly subject to tautomerism.
  • tautomerism For example, if a heteroaromatic group containing a nitrogen atom in the ring is substituted with a hydroxy group on the carbon atom adjacent to the nitrogen atom, the following tautomerism can appear:
  • the compounds of the present invention can be in the form of a pharmaceutically acceptable salt or a solvate.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.
  • the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts.
  • the compounds of the present invention which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or ammonium salts.
  • salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.
  • the compounds of the present invention which contain one or more basic groups, i.e. groups which can be protonated, can be used according to the invention in the form of their addition salts with inorganic or organic acids.
  • acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art.
  • the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
  • inner salts or betaines zwitterions
  • the respective salts can be obtained by customary methods which are known to the person skilled in the art like, for example, by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
  • the compounds of the present invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • oral liquid preparations such as, for example, suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparation
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally as, for example, liquid drops or spray.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • the compounds of the present invention may also be administered parenterally.
  • Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
  • oral, rectal, topical, parenteral (including intravenous), ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compounds of the present invention are administered orally.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • the compounds of Formula (1) When treating or preventing RORy-mediated conditions with the compounds of Formula (1), generally satisfactory results are obtained when the compounds are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of mammal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 1.0 milligram to about 1000 milligrams, preferably from about 1 milligram to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the present invention describes modulators, in the following also referred to as ligands, which bind to the RORy receptor. Surprisingly, it has been found that compounds of Formula (1) act as modulators of the RORy receptor.
  • the RORy receptor is considered to be involved in thymocyte development, thus the modulators described herein may be useful in the treatment of inflammatory skin diseases such as atopic eczema and psoriasis. It is further suggested that down-modulation of RORy transcriptional activity with a ligand could result in a shift of the immune response towards a Th2 type response which could be beneficial in the treatment of certain allergic inflammatory conditions such as rheumatoid arthritis, systemic lupus erythomatosis, inflammatory bowel disease (Crohn ' s Disease) and multiple sclerosis (Tesmer et. al., Immunol. Rev. 2008, 223:97).
  • the compounds of Formula (1) show antagonistic activity, with respect to the dose dependent modulation of the constitutive interaction of the RORy ligand binding domain with peptides derived from the co-activators such as SRC-1 , TRAP 220 or TIF-2.
  • the identification of high affinity ligands for RORy with agonistic and antagonistic properties is the basis to enable experts knowledgeable in the field to establish assays for the identification of novel agonistic and antagonistic RORy ligands from libraries of small molecules.
  • the identification of ligands which bind to and modulate the activity of RORyl and RORy2 is the first mandatory step to develop new small molecule based medicines with a potential to be developed for the treatment of diseases which are directly or indirectly controlled by the activity of RORyl or RORy2.
  • Such diseases include but are not restricted to inflammatory diseases, asthma, rheumatoid arthritis, autoimmune diseases or diseases with an autoimmune component such as systemic lupus erythomatosis, inflammatory bowel disease (Crohn ' s disease), ulcerative colitis, inflammatory skin diseases such as atopic eczema or psoriasis, multiple sclerosis or similar diseases.
  • the compounds of the present invention can be prepared by a combination of methods known in the art including the procedures described in Schemes I to X below.
  • Oxazepines with a free secondary amino function and the general structure as shown in Scheme I can be transformed into sulfonamides by reaction with sulfonyl chlorides in the presence of suitable base and solvent.
  • the lactam amide bond of the 1 ,4-diazepin-2-ones of the compounds of the present invention can be transformed into 5-membered heterocycles as shown in Schemes III. Transformation of the lactam into a thiolactam by use of Lawesson's reagent and subsequent treatment with acylhydrazides affords annulated 2-substituted triazoles.
  • the thiolactam can be S- alkylated and heated with 2,2-dimethoxyethanamine.
  • the resulting amidine can be treated with acid to afford annulated imidazoles.
  • the methyl iminothioester can be oxidized to a methyl sulfone functionality in order to facilitate the reaction with 2,2-dimethoxyethanamine or other reagents.
  • the 4- amino group of the 1 ,4-diazepin-2-ones can be protected e.g. as a Boc-group, which can be cleaved of after the formation of the annulated 5-membered heterocycles.
  • the free secondary amino group of the diazepinone core can be transformed into sulfonamides by reaction with sulfonyl chlorides in the presence of a suitable base and solvent.
  • annulated 2-azepines with a 4-subsituent of the present invention can be prepared as depicted in Scheme V.
  • Ortho methyl-substituted aromatic carboxylic acids or oxazolidines can be reacted with /V-protected 2-amino aldehydes under strongly basic conditions at low temperature to afford annulated 6-membered lactones I or the corresponding hydroxy-carboxylic acids la, similar as described in J. Chem. Soc, Chem. Commun. 1991 , 708.
  • the lactones can isomerize under basic conditions to 4-hydroxy-2,3,4,5-tetrahydro- 1 H-benzo[c]azepin-1-ones (II).
  • sulfonamides can be obatined by reaction with sulfonyl chlorides.
  • the free hydroxyl group can be alkylated or oxidized to the ketone by standard methods.
  • the /V-protected 4-hydroxy- 2,3,4,5-tetrahydro-1 H-benzo[c7azepin-1-ones (II) can be first alkylated, then reduced to the amine and the protecting group removed. Finally, the free secondary amino group can be transformed into sulfonamides by reaction with sulfonyl chlorides.
  • R alkyl, haloalkyl or cycloalkyl
  • R 1 -L 2.
  • 1 ,4-Thiazepines and its corresponding 1 ,1 -dioxides (sulfones) that are compounds of the present invention can be prepared as shown in Scheme IX.
  • a 2-mercaptobenzoic acid is converted to the ester followed by S-alkylation with a suitable, /V-protected 2-amino-1-bromo derivative obtained from an amino alkohol through /V-protection and halogenation.
  • the resulting thioether is saponified and A/-deprotected to give an amino carboxylic acid intermediate that can be lactamised using amide coupling reagents.
  • Reduction leads to the 1 ,4-thiazepine derivative that can be sulfonylated.
  • a reaction sequence of AAprotection, sulfide oxidation, deprotection and sulfonylation leads to the corresponding 1 ,1 -dioxides.
  • ,4-oxazepines can be prepared by derivatisation of a 3-hydroxymethylene scaffold IV as shown in Scheme X: A suitable protected serine derivative is reduced to the alcohol followed by Mitsunobu reaction with a 2-hydroxy aryl carboxylic acid ester. Reduction of the ester to the benzylic alcohol and conversion to bromide is followed by ⁇ deprotection and cyclisation using a suitable base like potassium carbonate. O-deprotection leads to the hydroxy compound IV, which can be further derivatised by O-alkylation or mesylation followed by nucleophilic subsitution with an amine and a suitable base.
  • the compounds described in the present invention are usually single enantiomers, however racemates can be prepared as well.
  • the stereoisomer of Formula (1") with the following structure usually shows a higher biological activity:
  • Step 1 3-Benzyl-4-(2-methoxyphenylsulfonvn-2,3,4,5-tetrahvdrobenzorflri,41oxazepine (1)
  • Step 2 (ff)-3-Benzyl-4,5-dihvdro-1 H-benzofeiri .41diazeoin-2(3/-/)-one (2b)
  • Step 3 (fl)-3-Benzyl-4-(quinolin-8-ylsulfonyl)-4,5-dihvdro-1 H-benzoiein ,41diazepin-2(3H)-one
  • Step 4 (R)-3-Benzyl-1-methyl-4-(auinolin-8-ylsulfonyl)-4.5-dihvdro-1 H-benzofelH ,41diazepin- 2(3H)-one (3)
  • Step 1 Methyl 2-(((benzyloxy)carbonyl)amino)-3-(methoxymethoxy)propanoate (4a)
  • Step 4 3-((Methoxymethoxy)methyl)-4.5-dihvdro- H-benzofe1f1,41diazepin-2(3 - )-one (4d)
  • Step 5 3-((Methoxymethoxy)methyl)-4-(2-(trifluoromethoxy)phenylsulfonyl)-4,5-dihvdro-1 H- benzofein ,41diazepin-2(3/- )-one (4e)
  • Step 7 3-(Hvdroxymethyl)-1-methyl-4-(2-(trifluoromethoxy)phenylsulfonyl)-4.5-dihvdro-1 H- benzofein ,41diazepin-2(3H)-one (4q)
  • Step 8 (1-Methyl-2-oxo-4- 2-(trifluoromethoxy)phenylsulfonyl)-2,3,4,5-tetrahvdro-1 /7-benzo- Tein ,41diazepin-3-yl)methyl methanesulfonate (4h)
  • Step 9 1 -Methyl-3-(3-methylbenzvn-1 H-benzorelf1.41diazepin-2(5 -ft-one (4i)
  • Step 10 1-Methyl-3-(3-methylbenzyl)-4.5-dihvdro-1 H-benzoreiri .41diazepin-2(3H)-one (41)
  • MeOH MeOH
  • NaBH 4 50 mg, 1.3 mmol
  • the solution was stirred at rt for 1 d. It was concentrated and to the residue was added 2M KOH.
  • the mixture was extracted with EA. The organic layer was washed with brine, dried over NaS0 4 , filtered and concentrated under reduced pressure to give compound 4j (50 mg, 99%) as a yellow oil.
  • Step 1 1 1 -Methyl-3-(3-methylbenzyl)-4-(2-(trifluoromethoxy)phenylsulfonyl)-4.5-dihvdro-1 H- benzoiein ,41diazepin-2(3H)-one (4)
  • Step 1 3-Benzyl-5-methyl-1 H-benzorein .4ldiazeDin-2(3H)-one (5a)
  • Step 2 3-Benzyl-5-methyl-4,5-dihvdro-1 /-/-benzofeiri .4ldiazepin-2(3H)-one (5b)
  • Step 3 3-Benzyl-5-methyl-4-(2-(trifluoromethoxy)phenylsulfonyl)-4.5-dihvdro-1 H- benzofelH ,41diazepin-2(3H)-one (5c)
  • a mixture of compound 5b (100 mg, 0.38 mmol), 2-(trifluoromethoxy)benzene-1 -sulfonyl chloride (127 mg, 0.49 mmol) and pyridine (2 mL) in a sealed tube was irradiated in a microwave oven at 80°C overnight. The resulting mixture was concentrated under reduced pressure and purified by CC (PE/EA 8/1 ) to give compound 5c (55 mg, 30%) as a yellow solid.
  • Step 4 3-Benzyl-1 ,5-dimethyl-4-(2-(trifluoromethoxy)phenylsulfonyl)-4,5-dihvdro-1 H- benzofelM ,41diazepin-2(3 -/)-one (5 and 5', diastereomers)
  • Step 1 3-Benzyl-5-methyl-4-(2-(trifluoromethoxy)phenylsulfonyl)-4.5-dihvdro-1 H-benzofel- [1 ,41diazepine-2(3HHhione (6a)
  • Step 3 3-Benzyl-5-methyl-2-(methylsulfonyl)-4-(2-(trifluoromethoxy)phenylsulfonyl)-4.5-dihvdro- 3/- -benzoreiri .41diazepine (6c)
  • Step 4 (Z)-/V-(3-Benzyl-5-methyl-4-(2-(trifluoromethoxy)phenylsulfonyl)-4.5-dihvdro-1 H- benzoreiri ,41diazepin-2(3H)-ylidene)-2,2-dimethoxyethanamine (6d)
  • Step 5 4-Benzyl-6-methyl-5-(2-(trifluoromethoxy)phenylsulfonyl)-5.6-dihvdro-4 -/-benzo- rflimidazoH ,2-alH ,41diazepine (6)
  • Example 6/1 was prepared from compound 2 similar as described for Example 6.
  • Example 6/2 was prepared from 10f similar as in described in Example 6.
  • Example 6/3 was prepared from BB1 respectively similar as in described in the Example 10 (10b to 10f) and after formation of the seven-membered ring as described in Example 6: Structure Analytical data
  • Step 1 terf-Butyl 5-(hvdroxymethyl)thiazol-4-ylcarbamate (BB1a)
  • Step 1 (F?)-2-(2-(Dibenzylamino)-1 -hvclroxy-3-phenylpropyl)nicotinic acid (7a)
  • n-Butyllithium (2M, 85.4 mL, 213 mmol) was added to a solution of diisopropylamine (35.9 mL, 255 mmol) in dry THF at -70°C, and the mixture stirred under N 2 for 40 min.
  • 2-Methyl-nicotinic acid (9.74 g, 71 mmol) was added quickly and after stirring for 20 min, a solution of (H)-2- (dibenzylamino)-3-phenylpropanal (19.5 g, 0.059 mol) in anhydrous THF (170 mL) was added dropwise at -70°C. The resulting mixture was stirred at -70°C for 20 min. Sat.
  • Step 2 (ff)-7-(1-(Dibenzylamino)-2-phenylethyl)-7.8-dihvdro-5 -/-pyranor4,3-- lPyridin-5-one (7b)
  • Step 7 (ff)-7-Benzyl-8-methoxy-6-(2-(trifluoromethoxy)phenylsulfonyl)-6.7.8.9-tetrahvdro-5 - - pyridof3,2-c1azepine (7)
  • Step 1 (fl)-3-Benzyl-4-(guinolin-8-ylsulfonyl)-4,5-dihvdro-1 H-benzofelH ,41diazepine-2(3H)- thione (8a)
  • Example 8 The following Examples were prepared similar as described in Example 8 using the corresponding substituted aminoesters and sulfonyl chlorides as building blocks.
  • Example 8/6 was prepared using 2,2,2-trifluoroacetohydrazide in place of formohydrazide in the last step:
  • Step 1 fert-Butyl pyridin-2-ylcarbamate (9a)
  • Step 3 Methyl 2-((2-(re/ -butoxycarbonylamino)pyridin-3-yl)methylamino)-3-phenylpropa-noate (9c)
  • Step 6 terf-Butyl 3-benzyl-2-oxo-2,3-dihvdro-1 A7-pyridof2,3-e1M .41diazepine-4(5/-fl-carboxylate i£f]
  • Step 7 terf-Butyl 3-benzyl-2-thioxo-2.3-dihvdro-1 --pyridof2.3-eiri.4ldiazepine-4(5/-/)- carboxylate (9q)
  • Step 8 terf-Butyl 3-benzyl-2-(methylthio)-3H-pyridor2.3-eiri.41diazepine-4(5 -/)-carboxylate (9h)
  • Step 10 terf-Butyl 7-benzyl-5H-imidazori .2-alpyridof3,2-riri .41diazepine-6(7H)-carboxylate (9i)
  • Step 11 7-Benzyl-6.7-dihvdro-5/-/-imidazori .2-alPyridof3,2- iri,4ldiazepine hydrochloride (9k)
  • Step 12 7-Benzyl-6-(auinolin-8-ylsulfonyl)-6,7-dihvdro-5/-/-imidazori ,2-alpyridor3,2- flH ,41diazepine (9)
  • Step 5 3-Benzyl-4,5-dihvdro-1 H-pyridor3.2-eiri,41diazepin-2(3H)-one (10e) To a solution of NaH (1.6 g, 40 mmol) in anhydrous DMF (20 mL) was added a solution of compound lOd (1.9 g, 6.6 mmol) in anhydrous DMF (20 mL) at 0°C under N 2 atmosphere and the solution was stirred at rt for 2 h. Water was added for quenching and EA was added to extract three times.
  • Step 6 3-Benzyl-4-(2-(trifluoromethoxy)phenylsulfonyl)-4,5-dihvdro-1 H-pyrido[3,2- ein ,41diazepin-2(3H)-one dot)
  • Step 7 3-Benzyl-1 -methyl-4-(2-(trifluoromethoxy)phenylsulfonyl)-4,5-dihvdro-1 H-pyridof3,2- e1f1 ,41diazepin-2(3H)-one (10)
  • Example 10b The following Example was prepared from 10b and methyl 2-amino-2-methyl-3- phenylpropanoate similar as described in Example 10:
  • Step 1 Benzyl (f?)-1 -((f?)-1 -oxoisochroman-3-yl)-2-phenylethylcarbamate (11 a) and benzyl (R)- 1 -((S)-1 -oxoisochroman-3-yl)-2-phenylethylcarbamate (11 a')
  • Step 4 (3fl.4ff)-3-Benzyl-2-(guinolin-8-ylsulfonyl)-2.3.4.5-tetrahvdro-1 H-benzoiclazepin-4-ol ill)
  • Step 4a (3ff.4/ : ?)-3-Benzyl-4-methoxy-2-(auinolin-8-ylsulfonyl)-2.3.4.5-tetrahvdro-1 H- benzofclazepine (12)
  • Step 4b (ff)-3-Benzyl-2-(quinolin-8-ylsulfonyl)-2.3-dihvdro-1 -/-benzorc1azepin-4(5H)-one (13)
  • Step 5 (3ff,4S)-3-Benzyl-2-(quinolin-8-ylsulfonyl)-2,3,4.5-tetrahvdro-1 -/-benzofdazepin-4-ol
  • Example 11 ' was prepared from 11a' similar as described for 11.
  • H-NMR 400 MHz, CD 3 OD
  • ⁇ 2.85-2.91 m, 1 H
  • 3.06-3.16 m, 2H
  • 3.39-3.43 m, 1 H
  • 3.92-3.95 m, 1 H
  • 4.61-4.65 m, 1 H
  • 4.70-4.72 m, 1 H
  • 4.95-4.99 m, 1 H
  • Example 12' was prepared from 11 " similar as described for Example 12.
  • Step 1 (fl)-3-((terf-Butoxycarbonyl)amino)-4-phenylbutanoic acid (14a)
  • Step 5 (f?)-/V-(1-Cvano-3-phenylpropan-2-yl)-2-(trifluoromethoxy)benzenesulfonamide (14e)
  • Step 6 (fl)-Ethyl 2-(A/-(1-cvano-3-phenylpropan-2-yl)-2- (trif luoromethoxy)phenylsulfonamido)acetate (14f)
  • Step 7 (ffl-Ethyl 2-(/V-(4-amino-1-phenylbutan-2-yl)-2- (trifluoromethoxy)phenylsulfonamido)acetate TFA salt(14q)
  • Step 8 (fll-Ethyl 2-(/V-(4-((tetf-butoxycarbonyl)amino)-1-phenylbutan-2-yl)-2- (trifluoromethoxy)phenylsulfonamido)acetate (14h)
  • Step 10 (f?)-2-(A/-(4-Amino-1 -phenylbutan-2-yl)-2-(trif luoromethoxy)phenylsulfonamido)acetic acid TFA salt (14i)
  • Step 11 (ff)-5-Benzyl-4-((2-(trifluoromethoxy)phenyl)sulfonyl)-1 ,4-diazepan-2-one (14k)
  • Step 12 (ff)-5-Benzyl-4-((2-(trifluoromethoxy)phenyl)sulfonyl)-1 ,4-diazepane-2-thione (14m)
  • Step 13 (ffl-7-Benzyl-8-((2-(trifluoromethoxy)phenvhsulfonyl)-6.7,8.9-tetrahvdro-5H- imidazoM ,2-a1f1 ,4ldiazepine (14)
  • Step 1 (ff)-7-Benzyl-3-met yl-8-((2-ftrifluoromethoxy)phenyl)sulfonyl)-6.7.8.9-tetrahvdro-5H- ⁇ .2.41triazolor4.3-airi .41diazepine (15)
  • Step 1 (ff)-7-Benzyl-8-((2-(trifluoromethoxy)phenvnsulfonyl)-6.7.8,9-tetrahvdro-5/- - ⁇ .2.41triazolor4.3-airi ,41diazepine (16)
  • Step 8 Methyl 2-(3-((fert-butoxycarbonyl)amino)-4-phenylbutyl)benzoate (17h)
  • Step 11 4-(2-(Bromomethyl)phenyl)-1-phenylbutan-2-amine TFA salt (17k) To a solution of compound 17j (0.2 g, 0.48 mmol) in DCM (20 mL) was added TFA (547 mg, 4.8 mmol). The solution was stirred at rt until TLC analysis indicated the total consumption of the starting material. Then the solvent was removed to get crude compound 17k (160 mg) as a yellow oil.
  • Step 12 3-Benzyl-2,3A5-tetrahvdro-1 /-/-benzodiazepine (17m)
  • Step 13 3-Benzyl-2-(quinolin-8-ylsulfonyl)-2,3,4,5-tetrahvdro-1 -/-benzorc1azepine (17)
  • Step 2 (f?)-terf-Butyl (1-bromo-3-phenylpropan-2-yl)carbamate (18b)
  • PPh 3 46.9 g, 179 mmol
  • Step 4 (flVMethyl 2-((2-((te/ -butoxycarbonyl)amino)-3-phenylpropyl)thio)benzoate (18d)
  • Step 8 (fi)-3-Benzyl-2.3.4.5-tetrahvdrobenzorfin .41thiazepine (18h)
  • LiAIH 4 1.9 g, 50 mmol
  • Step 9 (fi)-3-Benzyl-4-(auinolin-8-ylsulfonyl)-2.3.4.5-tetrahvdrobenzor/iri,41thiazeDine (18)
  • Step 1 (flHert-Butyl 3-benzyl-2.3-dihvdrobenzor in .41thiazepine-4(5H)-carboxylate (19a)
  • Step 2 (ffl-tert-Butyl 3-benzyl-2.3-dihvdrobenzorr1f1 ,41thiazepine-4(5/-/)-carboxylate 1.1-dioxide 09bl
  • Step 3 (f?)-3-Benzyl-2.3.4,5-tetrahvdrobenzof iri .41thiazepine 1.1-dioxide hydrochloride (19c)
  • HCI/EA solution 0.9 g, 2.3 mmol
  • Et 2 0 Et 2 0 was added to the residue.
  • the formed solid was filtered off to give of compound 19c (0.5 g, 75%) as a white solid.
  • Step 4 (f?)-3-Benzyl-4-(quinolin-8-ylsulfonyl)-2,3,4.5-tetrahvdrobenzofriri .41thiazepine 1 ,1- dioxide (19)
  • Step 5 (SRert-butyl (1 -(fe/i-butoxy)-3-(2-(hvdroxymethyl)phenoxy)propan-2-yl)carbamate (20e)
  • Step 6 (SHert-Butyl (1-(2-(bromomethyl)phenoxy)-3-(feff-butoxy)propan-2-yl)carbamate (20f)
  • a solution of compound 20e (8.6 g, 24.3 mmol) in CCI 4 (50 mL) was cooled in an ice bath.
  • PBr 3 (2.8 g, 12.2 mmol) dropwise and the mixture was stirred at 0°C for 2 h.
  • the mixture was quenched with water and extracted with DCM.
  • the combined organic layers were washed with brine and concentrated.
  • the crude product 20f (6.6 g, 65%) was used in the next step without purification.
  • LCMS (m/z): AM A (MH + ).
  • Step 8 (S)-3-(te/ ⁇ -Butoxymethyl)-2.3.4.5-tetrahvdrobenzorfln .41oxazepine (20h)
  • Step 1 (S)-(4-(Quinolin-8-ylsulfonyl)-2.3,4,5-tetrahvdrobenzorriri ,41oxazepin-3-yl)methyl methanesulfonate (24a)
  • Step 2 ( ff)-3-(Morpholinomethyl)-4-(auinolin-8-ylsulfonyl)-2.3.4,5- tetrahydrobenzof f ⁇ 1 ,41oxazepine (24)
  • Step 1 Phenyl(6-((2-(trifluoromethoxy)phenyl)sulfonyl)-6,7-dihvdro-5H-imidazo[1.2-alPyridoi3,2- flf ,41diazepin-7-yl)methanol (27)
  • Example 27 If one were to use ethyl 2-amino-3-hydroxy-3-phenylpropanoate similar as described in Example 9, one would obtain Example 27.
  • Step 2 Phenyl(6-((2-(trifluoromethoxy)phenyl)sulfonyl)-6.7-dihvdro-5H-imidazori.2-alPyridor3.2- f ⁇ 1 ,41diazepin-7-yl)methanone (28) If one were to treat Example 27 with Mn0 2 or another oxidation reagent (e.g. Swern reagent) one would obtain Example 28.
  • Mn0 2 or another oxidation reagent (e.g. Swern reagent)
  • Step 3 7-(Difluoro(phenyl)methyl)-6-((2-(trifluoromethoxy)phenyl)sulfonyl)-6.7-dihvdro-5H- imidazoH ,2-alpyridor3,2-firi ,41diazepine (29)
  • Example 29 If one were to treat Example 28 with a fluorinating reagent e.g. diethylaminosulfur trifluoride or Fluolead (J. Am. Chem. Soc. 2010, 132:18199) one would obtain Example 29.
  • a fluorinating reagent e.g. diethylaminosulfur trifluoride or Fluolead (J. Am. Chem. Soc. 2010, 132:18199) one would obtain Example 29.
  • Step 4 7-(Fluoro(phenyl)methyl)-6-((2-(trifluoromethoxy)phenyl)sulfonyl)-6,7-dihvdro-5H- imidazof 1 ,2-a]Dyr ⁇ do ⁇ 3,2-f ⁇ [ 1 ,41diazepine (30)
  • Example 30 If one were to treat Example 27 with a fluorinating reagent e.g. diethylaminosulfur trifluoride or Fluolead (J. Am. Chem. Soc. 2010, 132:18199) one would obtain Example 30.
  • a fluorinating reagent e.g. diethylaminosulfur trifluoride or Fluolead (J. Am. Chem. Soc. 2010, 132:18199) one would obtain Example 30.
  • Step 1 (7ff)-7-Benzyl-10-bromo-6-((5-fluoro-2-(trifluoromethoxy)phenyl)sulfonyl)-6,7-dihydro- 5H-imidazof1 ,2-alPyrazinoF2.3- li1 ,41diazepine (31)
  • Example 31 If one were to treat the final compound from Example 9/12 with A/-bromosuccinimide similar as described in WO2007/121390 one would obtain Example 31.
  • Step 2 (7ff)-7-Benzyl-10-fluoro-6-((5-fluoro-2-(trifluoromethoxy)phenyl)sulfonyl)-6,7-dihvdro-5H- imidazoH .2-alpyrazinof2,3-flf1 ,41diazepine (32)
  • Example 32 If one were to treat the final compound from Example 31 similar as outlined in Org. Lett. 2009, 11 :2860 or J. Am. Chem. Soc. 2010, 132:12150 one would obtain Example 32.
  • Step 3 (7f?)-7-Benzyl-10-chloro-6-((5-fluoro-2-(tnfluoromethoxy)phenyl)sulfonyl)-6.7-dihvdro- 5H-imidazof 1 ,2-a1pyrazinor2,3-flH ,41diazepine (33)
  • Example 33 If one were to treat the final compound from Example 9/12 similar as described in Perkin Trans. 1 , 1990, 1645 or Bioorg. Med. Chem. Lett. 2010, 20:4045 one would obtain Example 33.
  • Step 4 (7f?)-7-benzyl-6-((5-fluoro-2-(trifluoromethoxy)phenyl)sulfonyl)-6,7-dihvdro-5 -/- imidazoH ,2-alpyrazinof2,3-f1H ,4ldiazepine-10-carbonitrile (34)
  • Step 5 (7 ⁇ -7-benzyl-6-((5-fluoro-2-(trifluoromethoxy)phenyl)sulfonyl)-6J-dihvclro-5H- irriidazori ,2-alpyrazinor2,3-/iri,41diazepine-10-carboxamide (35)
  • Example 35 If one were to treat the final compound from Example 34 with H 2 0 2 and aq. NaOH as catalyst one would obtain Example 35.
  • Step 1 (ff)-3-benzyl-4,4-difluoro-2-(quinolin-8-ylsulfonyl)-2,3,4,5-tetrahydro-1 H-benzolclazepine (36)
  • Example 36 If one were to treat the final compound from Example 13 with an fluorinating reagent e.g. diethylaminosulfur trifluoride or Fluolead (J. Am. Chem. Soc. 2010, 132:18199) one would obtain Example 36.
  • an fluorinating reagent e.g. diethylaminosulfur trifluoride or Fluolead (J. Am. Chem. Soc. 2010, 132:18199) one would obtain Example 36.
  • Protein expression and purification was done as described in WO2010/049144.
  • This method measures the ability of putative ligands to modulate the interaction between the purified bacterial expressed RORy ligand binding domain (LBD) and synthetic A/-terminally biotinylated peptides which are derived from nuclear receptor coactivator proteins such as but not limited to SRC1 (NcoA1), SRC2 (NcoA2, TIF2), SRC3 (NcoA3), PGC1a, ⁇ , CBP, GRIP1 , TRAP220, RIP140.
  • SRC1 nuclear receptor coactivator proteins
  • the LBD of RORy was expressed as fusion protein with GST in BL-21 (BL3) cells using the vector pDEST15. Cells were lysed by lysozyme-treatment and sonication, and the fusion proteins purified over glutathione sepharose (Pharmacia) according to the manufacturers instructions. For screening of compounds for their influence on the RORy-peptide interaction, the LANCE technology (Perkin Elmer) was applied. This method relies on the binding dependent energy transfer from a donor to an acceptor fluorophor attached to the binding partner of interest.
  • the potentially RORy modulating ligands were diluted.
  • protein, peptide and fluorescent acceptor and donor solutions were mixed in the Tris-based buffer system and have been added to the compound dilutions, after this addition of 'detection mix', the assay was equilibrated for one hour in the dark at rt in FIA-plates black 384 well (Corning).
  • the LANCE signal was detected by a Perkin Elmer EnVisionTM Multilabel Counter. The results were visualized by plotting the ratio between the emitted light at 665 nm and 615 nm. A basal level of RORy-peptide formation is observed in the absence of added ligand.
  • Ligands that promote the complex formation induce a concentration-dependent increase in time-resolved fluorescent signal.
  • Compounds which bind equally well to both monomeric RORy and to the RORy-peptide complex would be expected to give no change in signal, whereas ligands, which bind preferentially to the monomeric receptor would be expected to induce a concentration-dependent decrease in the observed signal.
  • IC 50 values were determined using a Ligand Sensing Assay based on Time-resolved Fluorescence Energy Transfer (TR-FRET) as described above.
  • TR-FRET Time-resolved Fluorescence Energy Transfer
  • the normalised TR-FRET assay values using the following equation: 1000 * 665 nm measurement value/615 nm measurement value, were transferred to the program GraphPad Prism to generate graphs and dose response curves using the following equation:
  • X is the logarithm of the concentration.
  • Y is the response.
  • Y starts at Bottom and goes to Top with a sigmoidal shape.
  • the IC 50 values are calculated using this equation. Examples listed below do reduce the signal in the TR-FRET assay in a dose dependent manner.
  • the Examples of the present invention usually have an inhibition activity (IC 50 FRET) ranging from below 150 nM to about 20 ⁇ , and, typically, from about 150 nM to about 2 ⁇ .
  • the RORy modulating compounds of the invention desirably have an inhibition in the TR-FRET Activity Assay ranging from below 150 nM to about 1 ⁇ .
  • Table 2 lists typical examples of compounds of the invention that have an RORy activity in the TR-FRET Activity Assay lower than 500 nM (Group A), from about 500 nM to 2 ⁇ (Group B) and above 2 ⁇ (Group C).
  • pCMV-BD (Stratagene). Expression was under control of a CMV promoter and as fusion to the DNA-binding domain of the yeast protein GAL4. The amino acid boundaries of the three proteins and the respective database entries are listed in Table 3.
  • Other vectors used were pFR-Luc (Stratagene) as regulated reporter plasmid.
  • pFR-Luc contains a synthetic promoter with five tandem repeats of the yeast GAL4 binding sites that control expression of the Photinus pyralis (American firefly) luciferase gene. In order to improve experimental accuracy the plasmid pRL-CMV was cotransfected.
  • pRL-C V contains the constitutive CMV promoter, controlling the expression of the Renilla reniformis luciferase.
  • Gal4 reporter gene assays were done in 293T cells (DSMZ (German Collection of Microorganisms and Cell Cultures), Braunschweig, Germany, ACC635) grown in Minimum Essential Medium (MEM) with Phenol Red. The medium is supplemented with 10% fetal bovine serum, 0.1 mM nonessential amino acids, 1 mM sodium pyruvate, 1% Glutamax and 100 units Penicilin/Streptavidin per mt_ at 37°C in 5% C0 2 .
  • MEM Minimum Essential Medium
  • the Examples of the present invention usually have an inhibition activity (IC 50 FF resp. IC 50 RENnorm) ranging from below 150 nM to about 20 ⁇ , and typically, from about 200 nM to about 2 ⁇ .
  • the RORy modulating compounds of the invention desirably have an inhibition in the Gal4 reporter gene assay ranging from below 150 nM to about 1 ⁇ .
  • Table 4 and 5 list typical examples of compounds of the invention that have an RORy activity in the Gal4 reporter gene assay lower than 500 nM (Group A), from about 500 nM to 2 ⁇ (Group B) and above 2 ⁇ (Group C) for firefly (FF, Table 4) and renilla normalised (RENnorm, Table 5) luciferase measurements.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des modulateurs pour le récepteur nucléaire orphelin RORγ et des procédés de traitement des maladies à médiation RORγ par administration de ces nouveaux modulateurs RORγ à un humain ou à un mammifère en ayant besoin. Plus précisément, la présente invention concerne des composés de Formule (1) et des énantiomères, diastéréoisomères, tautomères, solvates et sels pharmaceutiquement acceptables de ceux-ci ainsi que des compositions pharmaceutiques comprenant lesdits composés comme principes actifs.
PCT/EP2012/004487 2011-10-31 2012-10-26 Sulfonamides à sept chaînons comme modulateurs des récepteurs gamma orphelins associés à un récepteur de l'acide rétinoïque (rorγ, nr1f3) WO2013064231A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201161553312P 2011-10-31 2011-10-31
US61/553,312 2011-10-31
EP11008712 2011-10-31
EP11008712.9 2011-10-31

Publications (1)

Publication Number Publication Date
WO2013064231A1 true WO2013064231A1 (fr) 2013-05-10

Family

ID=48191395

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2012/004487 WO2013064231A1 (fr) 2011-10-31 2012-10-26 Sulfonamides à sept chaînons comme modulateurs des récepteurs gamma orphelins associés à un récepteur de l'acide rétinoïque (rorγ, nr1f3)

Country Status (1)

Country Link
WO (1) WO2013064231A1 (fr)

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014202741A1 (fr) * 2013-06-21 2014-12-24 F. Hoffmann-La Roche Ag Dérivés d'aryle sultame utilisés en tant que modulateurs de rorc
WO2015042212A1 (fr) * 2013-09-20 2015-03-26 Bristol-Myers Squibb Company Modulateurs de rorγ
WO2015057206A1 (fr) * 2013-10-15 2015-04-23 Janssen Pharmaceutica Nv Modulateurs d'alcool secondaire de roryt de type quinolinyle
WO2015015378A3 (fr) * 2013-08-02 2015-05-14 Pfizer Inc. Inhibiteurs de rorc2 méthodes d'utilisation associées
US9221804B2 (en) 2013-10-15 2015-12-29 Janssen Pharmaceutica Nv Secondary alcohol quinolinyl modulators of RORγt
US9266886B2 (en) 2014-02-03 2016-02-23 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9284308B2 (en) 2013-10-15 2016-03-15 Janssen Pharmaceutica Nv Methylene linked quinolinyl modulators of RORγt
US9290476B2 (en) 2012-10-16 2016-03-22 Janssen Pharmaceutica Nv Methylene linked quinolinyl modulators of RORγt
US9303015B2 (en) 2012-10-16 2016-04-05 Janssen Pharmaceutica Nv Heteroaryl linked quinolinyl modulators of RORγt
US9309222B2 (en) 2012-10-16 2016-04-12 Janssen Pharmaceutica Nv Phenyl linked quinolinyl modulators of RORγt
US9328095B2 (en) 2013-10-15 2016-05-03 Janssen Pharmaceutica Nv Heteroaryl linked quinolinyl modulators of RORgammat
US9346782B2 (en) 2013-10-15 2016-05-24 Janssen Pharmaceutica Nv Alkyl linked quinolinyl modulators of RORγt
US9403816B2 (en) 2013-10-15 2016-08-02 Janssen Pharmaceutica Nv Phenyl linked quinolinyl modulators of RORγt
CN105899507A (zh) * 2014-01-10 2016-08-24 豪夫迈·罗氏有限公司 作为RORc调节剂的芳基磺内酰胺衍生物
CN105899506A (zh) * 2014-01-10 2016-08-24 豪夫迈·罗氏有限公司 作为RORc调节剂的杂芳基磺内酰胺衍生物
CN105916852A (zh) * 2014-01-10 2016-08-31 豪夫迈·罗氏有限公司 作为RORc调节剂的芳基磺内酰胺衍生物
JP2016532715A (ja) * 2013-09-09 2016-10-20 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ ＲＯＲγ調節因子
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
WO2017002089A1 (fr) 2015-07-02 2017-01-05 Wockhardt Limited Composés bicycliques contenant de l'azote et leur utilisation dans le traitement d'infections bactériennes
JPWO2015002231A1 (ja) * 2013-07-03 2017-02-23 武田薬品工業株式会社 複素環化合物
US9624225B2 (en) 2013-10-15 2017-04-18 Janssen Pharmaceutica Nv Quinolinyl modulators of RORγt
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9670201B2 (en) 2014-09-26 2017-06-06 Pfizer Inc. Methyl- and trifluoromethyl-substituted pyrrolopyridine modulators of RORC2 and methods of use thereof
WO2017142881A1 (fr) * 2016-02-15 2017-08-24 The Regents Of The University Of Michigan 1,4-oxazepines condensées et leurs analogues associés en tant qu'inhibiteurs de bromodomaine bet
US9796710B2 (en) 2014-10-14 2017-10-24 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
WO2017213210A1 (fr) * 2016-06-10 2017-12-14 武田薬品工業株式会社 Composé hétérocyclique
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
WO2018062732A1 (fr) * 2016-09-30 2018-04-05 (주)스파크바이오파마 Nouveau composé dérivé de pyridine ou sels pharmaceutiquement acceptables de celui-ci, son procédé de production et composition pharmaceutique le comprenant
US10301261B2 (en) 2015-08-05 2019-05-28 Vitae Pharmaceuticals, Llc Substituted indoles as modulators of ROR-gamma
JP2019151624A (ja) * 2018-02-28 2019-09-12 日本たばこ産業株式会社 飽和環縮合ジヒドロピリミジノン又はジヒドロトリアジノン化合物及びその医薬用途
US10555941B2 (en) 2013-10-15 2020-02-11 Janssen Pharmaceutica Nv Alkyl linked quinolinyl modulators of RORγt
US10829481B2 (en) 2016-01-29 2020-11-10 Vitae Pharmaceuticals, Llc Benzimidazole derivatives as modulators of ROR-gamma
US10913739B2 (en) 2017-07-24 2021-02-09 Vitae Pharmaceuticals, LLC (121374) Inhibitors of RORγ
US11008340B2 (en) 2015-11-20 2021-05-18 Vitae Pharmaceuticals, Llc Modulators of ROR-gamma
WO2021092242A3 (fr) * 2019-11-05 2021-07-22 Dermira, Inc. Inhibiteurs de ror gamma t et leurs utilisations topiques
US11186573B2 (en) 2017-07-24 2021-11-30 Vitae Pharmaceuticals, Llc Inhibitors of ROR gamma

Citations (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994011360A1 (fr) 1992-11-09 1994-05-26 The Boots Company Plc 1,4-benzothiazepines utilisees comme agents neurologiques
WO1997030992A1 (fr) 1996-02-26 1997-08-28 Bristol-Myers Squibb Company Inhibiteurs de la farnesyl-transferase
WO1999001434A1 (fr) 1997-07-02 1999-01-14 Bristol-Myers Squibb Company Inhibiteurs de farnesyl proteine transferase
WO2001000185A2 (fr) 1999-06-24 2001-01-04 Knoll Gmbh Agents therapeutiques
WO2001081322A1 (fr) 2000-04-21 2001-11-01 Bristol-Myers Squibb Company Inhibiteurs benzodiazepine non-imidazole de la proteine farnesyl transferase
WO2004018432A1 (fr) 2002-08-20 2004-03-04 Eli Lilly And Company Azepines substituees utilisees comme antagonistes des recepteurs h3 de l'histamine, leur preparation et leurs utilisations therapeutiques
WO2004033436A1 (fr) 2002-10-10 2004-04-22 Elan Pharmaceuticals Inc Sulfonylbenzodiazepinone acetamides utilises comme antagonistes de la bradykinine
WO2004067008A1 (fr) 2003-01-28 2004-08-12 Takeda Pharmaceutical Company Limited Agonistes de recepteurs
JP2006056881A (ja) 2004-07-21 2006-03-02 Takeda Chem Ind Ltd 縮合環化合物
WO2006101496A1 (fr) 2005-03-23 2006-09-28 The Trustees Of Columbia University In The City Of New York NOUVEAUX MEDICAMENTS ANTIARYTHMIQUES ET CONTRE LA DEFAILLANCE CARDIAQUE CIBLANT LA FUITE DANS UN RECEPTEUR DE LA RYANODINE (RyR2)
WO2007121390A1 (fr) 2006-04-18 2007-10-25 Boehringer Ingelheim International Gmbh Procede de preparation de composes inhibiteurs des cytokines contenant des cycles 4- et 5-imidazolyle et leurs intermediaires
WO2010049144A2 (fr) 2008-10-28 2010-05-06 Phenex Pharmaceuticals Ag Procédés d'identification de nouveaux ligands destinés à la modulation de l'activité du récepteur orphelin gamma (nr1f3) en fonction au récepteur nucléaire orphelin du récepteur de l'acide rétinoïde (rar)
US20110172190A1 (en) 2004-01-22 2011-07-14 Andrew Robert Marks Agents for preventing and treating disorders involving modulation of the ryanodine receptors
WO2011107248A1 (fr) 2010-03-01 2011-09-09 Phenex Pharmaceuticals Ag Nouveaux composés pour modulation de l'activité récepteur gamma orphelin associé au récepteur nucléaire orphelin rar (rorγ gamma, nr1f3) et pour le traitement d'une maladie inflammatoire et auto-immune chronique
WO2011112264A1 (fr) 2010-03-11 2011-09-15 New York University Composés en tant que modulateurs de rorϒt et leurs utilisations
WO2011112263A1 (fr) 2010-03-11 2011-09-15 New York University Composés amido à titre de modulateurs rorγt et leurs utilisations
WO2011115892A1 (fr) 2010-03-15 2011-09-22 Griffin Patrick R Modulateurs des récepteurs orphelins liés au récepteur de l'acide rétinoïque
WO2012027965A1 (fr) 2010-09-01 2012-03-08 Glaxo Group Limited Nouveaux composés
WO2012028100A1 (fr) 2010-09-01 2012-03-08 Glaxo Group Limited Nouveaux composés
WO2012064744A2 (fr) 2010-11-08 2012-05-18 Lycera Corporation Tétrahydroquinoline et composés bicycliques associés pour l'inhibition de l'activité rorγ et le traitement de maladies
WO2012100732A1 (fr) 2011-01-24 2012-08-02 Glaxo Group Limited Modulateurs des récepteurs orphelins gamma apparentés au récepteur des rétinoïdes, composition les contenant et utilisations associées
WO2012100734A1 (fr) 2011-01-24 2012-08-02 Glaxo Group Limited Composés utiles en tant que modulateurs du récepteur apparenté au récepteur des rétinoïdes gamma
WO2012106995A1 (fr) 2011-02-11 2012-08-16 Merck Sharp & Dohme Corp. Inhibiteurs de rorgammat
WO2012139775A1 (fr) 2011-04-14 2012-10-18 Phenex Pharmaceuticals Ag Composés pyrrolosulfonamides pour la modulation de l'activité du récepteur orphelin gamma apparenté au récepteur nucléaire orphelin rar (ror-gamma, nr1f3) et pour le traitement de maladies inflammatoires chroniques et auto-immunes

Patent Citations (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994011360A1 (fr) 1992-11-09 1994-05-26 The Boots Company Plc 1,4-benzothiazepines utilisees comme agents neurologiques
WO1997030992A1 (fr) 1996-02-26 1997-08-28 Bristol-Myers Squibb Company Inhibiteurs de la farnesyl-transferase
WO1999001434A1 (fr) 1997-07-02 1999-01-14 Bristol-Myers Squibb Company Inhibiteurs de farnesyl proteine transferase
US6458783B1 (en) 1997-09-29 2002-10-01 Bristol-Myers Squibb Company Non-imidazole benzodiazepine inhibitors of farnesyl protein transferase
WO2001000185A2 (fr) 1999-06-24 2001-01-04 Knoll Gmbh Agents therapeutiques
WO2001081322A1 (fr) 2000-04-21 2001-11-01 Bristol-Myers Squibb Company Inhibiteurs benzodiazepine non-imidazole de la proteine farnesyl transferase
WO2004018432A1 (fr) 2002-08-20 2004-03-04 Eli Lilly And Company Azepines substituees utilisees comme antagonistes des recepteurs h3 de l'histamine, leur preparation et leurs utilisations therapeutiques
WO2004033436A1 (fr) 2002-10-10 2004-04-22 Elan Pharmaceuticals Inc Sulfonylbenzodiazepinone acetamides utilises comme antagonistes de la bradykinine
WO2004067008A1 (fr) 2003-01-28 2004-08-12 Takeda Pharmaceutical Company Limited Agonistes de recepteurs
US20110172190A1 (en) 2004-01-22 2011-07-14 Andrew Robert Marks Agents for preventing and treating disorders involving modulation of the ryanodine receptors
JP2006056881A (ja) 2004-07-21 2006-03-02 Takeda Chem Ind Ltd 縮合環化合物
WO2006101496A1 (fr) 2005-03-23 2006-09-28 The Trustees Of Columbia University In The City Of New York NOUVEAUX MEDICAMENTS ANTIARYTHMIQUES ET CONTRE LA DEFAILLANCE CARDIAQUE CIBLANT LA FUITE DANS UN RECEPTEUR DE LA RYANODINE (RyR2)
WO2007121390A1 (fr) 2006-04-18 2007-10-25 Boehringer Ingelheim International Gmbh Procede de preparation de composes inhibiteurs des cytokines contenant des cycles 4- et 5-imidazolyle et leurs intermediaires
WO2010049144A2 (fr) 2008-10-28 2010-05-06 Phenex Pharmaceuticals Ag Procédés d'identification de nouveaux ligands destinés à la modulation de l'activité du récepteur orphelin gamma (nr1f3) en fonction au récepteur nucléaire orphelin du récepteur de l'acide rétinoïde (rar)
WO2011107248A1 (fr) 2010-03-01 2011-09-09 Phenex Pharmaceuticals Ag Nouveaux composés pour modulation de l'activité récepteur gamma orphelin associé au récepteur nucléaire orphelin rar (rorγ gamma, nr1f3) et pour le traitement d'une maladie inflammatoire et auto-immune chronique
WO2011112264A1 (fr) 2010-03-11 2011-09-15 New York University Composés en tant que modulateurs de rorϒt et leurs utilisations
WO2011112263A1 (fr) 2010-03-11 2011-09-15 New York University Composés amido à titre de modulateurs rorγt et leurs utilisations
WO2011115892A1 (fr) 2010-03-15 2011-09-22 Griffin Patrick R Modulateurs des récepteurs orphelins liés au récepteur de l'acide rétinoïque
WO2012027965A1 (fr) 2010-09-01 2012-03-08 Glaxo Group Limited Nouveaux composés
WO2012028100A1 (fr) 2010-09-01 2012-03-08 Glaxo Group Limited Nouveaux composés
WO2012064744A2 (fr) 2010-11-08 2012-05-18 Lycera Corporation Tétrahydroquinoline et composés bicycliques associés pour l'inhibition de l'activité rorγ et le traitement de maladies
WO2012100732A1 (fr) 2011-01-24 2012-08-02 Glaxo Group Limited Modulateurs des récepteurs orphelins gamma apparentés au récepteur des rétinoïdes, composition les contenant et utilisations associées
WO2012100734A1 (fr) 2011-01-24 2012-08-02 Glaxo Group Limited Composés utiles en tant que modulateurs du récepteur apparenté au récepteur des rétinoïdes gamma
WO2012106995A1 (fr) 2011-02-11 2012-08-16 Merck Sharp & Dohme Corp. Inhibiteurs de rorgammat
WO2012139775A1 (fr) 2011-04-14 2012-10-18 Phenex Pharmaceuticals Ag Composés pyrrolosulfonamides pour la modulation de l'activité du récepteur orphelin gamma apparenté au récepteur nucléaire orphelin rar (ror-gamma, nr1f3) et pour le traitement de maladies inflammatoires chroniques et auto-immunes

Non-Patent Citations (44)

* Cited by examiner, † Cited by third party
Title
ANDRE ET AL., EMBO J., vol. 17, 1998, pages 3867
ANDRE ET AL., GENE, vol. 216, 1998, pages 277
ANDRE ET AL., GENE, vol. 516, 1998, pages 277
AWASTHI; KUCHROO, INT. IMMUNOL., vol. 21, 2009, pages 489
B.-C. CHEN ET AL., TETRAHEDRON LETT., vol. 42, 2001, pages 1245
BECKERANDRE ET AL., BIOCHEM. BIOPHYS. RES. COMMUN., vol. 194, 1993, pages 1371
BIOORG. MED. CHEM. LETT., vol. 20, 2010, pages 4045
CROME ET AL., CLIN. EXP. IMMUNOL., vol. 159, 2010, pages 109
DYER ET AL., ANAL. BIOCHEM., vol. 282, 2000, pages 158
EBERL ET AL., SCIENCE, vol. 305, 2004, pages 248
EBERL; LITTMANN, IMMUNOL. REV., vol. 195, 2003, pages 81
EVANS ET AL., SCIENCE, vol. 240, 1988, pages 889
GIGUERE ET AL., GENOMICS, vol. 28, 1995, pages 596
GU ET AL., EUR. J. IMMUNOL., vol. 38, 2008, pages 1807
HAMILTON ET AL., NATURE, vol. 379, 1996, pages 736
HE ET AL., IMMUNITY, vol. 9, 1998, pages 797
HOUCK ET AL., MOL. GENET. METAB., vol. 83, 2004, pages 184
IVANOV ET AL., CELL, vol. 126, 2006, pages 1121
J. AM. CHEM. SOC., vol. 132, 2010, pages 12150
J. AM. CHEM. SOC., vol. 132, 2010, pages 18199
J. CHEM. SOC., CHEM. COMMUN., 1991, pages 708
J. COMB. CHEM., vol. 9, 2007, pages 321
K. SAMANTA ET AL., BIOORG. MED. CHEM. LETT., vol. 20, 2010, pages 283
KALLEN ET AL., STRUCTURE, vol. 10, 2002, pages 1697
KUMAR ET AL., MOL. PHARMACOL., vol. 77, 2010, pages 228
LAU ET AL., J. BIOL. CHEM., vol. 283, 2008, pages 18411
MANGELSDORF ET AL., CELL, vol. 83, 1995, pages 835
MCKENNA ET AL., ENDOCRINE REV., vol. 20, 1999, pages 321
MISSBACH ET AL., J. BIOL. CHEM., vol. 271, 1998, pages 13515
MOL. CELL. ENDORINOL., vol. 338, 2011, pages 68
ORG. LETT., vol. 11, no. 2860, 2009
PERKIN TRANS., vol. 1, 1990, pages 1645
STEHLIN-GAON ET AL., NAT. STRUCT. BIOL., vol. 10, 2003, pages 820
SUN ET AL., SCIENCE, vol. 288, 2000, pages 2369
TESMER ET AL., IMMUNOL. REV., vol. 223, 2008, pages 87
TESMER, IMMUNOL. REV., vol. 223, 2008, pages 97
TILLEY ET AL., J. IMMUNOL., vol. 178, 2007, pages 3208
VANACKER ET AL., MOL. ENDOCRINOL., vol. 13, 1999, pages 764
VILLEY ET AL., EUR. J. IMMUNOL., vol. 29, 1999, pages 4072
WANG ET AL., J. BIOL. CHEM., vol. 285, 2010, pages 5013
WIESENBERG ET AL., NUCLEIC ACID RES., vol. 23, 1995, pages 327
WILSON ET AL., MOL. CELL. BIOL., vol. 13, 1993, pages 5794
XUE ET AL., BIOORG. MED. CHEM., vol. 15, 2007, pages 2156
ZHOU; LITTMANN, CURR. OPIN. IMMUNOL., vol. 21, 2009, pages 146

Cited By (72)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9290476B2 (en) 2012-10-16 2016-03-22 Janssen Pharmaceutica Nv Methylene linked quinolinyl modulators of RORγt
US9309222B2 (en) 2012-10-16 2016-04-12 Janssen Pharmaceutica Nv Phenyl linked quinolinyl modulators of RORγt
US9303015B2 (en) 2012-10-16 2016-04-05 Janssen Pharmaceutica Nv Heteroaryl linked quinolinyl modulators of RORγt
WO2014202741A1 (fr) * 2013-06-21 2014-12-24 F. Hoffmann-La Roche Ag Dérivés d'aryle sultame utilisés en tant que modulateurs de rorc
CN105308042A (zh) * 2013-06-21 2016-02-03 豪夫迈·罗氏有限公司 作为RORc 调节剂的芳基磺内酰胺衍生物
JP2016522240A (ja) * 2013-06-21 2016-07-28 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ ＲＯＲｃモジュレーターとしてのアリールスルタム誘導体
US10053468B2 (en) 2013-07-03 2018-08-21 Takeda Pharmaceutical Company Limited Heterocyclic compound
JPWO2015002231A1 (ja) * 2013-07-03 2017-02-23 武田薬品工業株式会社 複素環化合物
JP2016528226A (ja) * 2013-08-02 2016-09-15 ファイザー・インク Ｒｏｒｃ２阻害薬およびその使用方法
EA029499B1 (ru) * 2013-08-02 2018-04-30 Пфайзер Инк Ингибиторы rorc2 и способы их применения
EP3428160A1 (fr) * 2013-08-02 2019-01-16 Pfizer Inc Inhibiteurs de rorc2 méthodes d'utilisation associées
WO2015015378A3 (fr) * 2013-08-02 2015-05-14 Pfizer Inc. Inhibiteurs de rorc2 méthodes d'utilisation associées
JP2016532715A (ja) * 2013-09-09 2016-10-20 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ ＲＯＲγ調節因子
US9725443B2 (en) 2013-09-20 2017-08-08 Bristol-Myers Squibb Company RORγ modulators
CN105555768A (zh) * 2013-09-20 2016-05-04 百时美施贵宝公司 RORγ调节剂
WO2015042212A1 (fr) * 2013-09-20 2015-03-26 Bristol-Myers Squibb Company Modulateurs de rorγ
JP2016530213A (ja) * 2013-09-20 2016-09-29 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ ＲＯＲγ調節因子
EP3560920A1 (fr) * 2013-10-15 2019-10-30 Janssen Pharmaceutica NV Modulateurs quinolinyl d'alcool secondaire de lymphocytes t ror gamma
US9346782B2 (en) 2013-10-15 2016-05-24 Janssen Pharmaceutica Nv Alkyl linked quinolinyl modulators of RORγt
WO2015057206A1 (fr) * 2013-10-15 2015-04-23 Janssen Pharmaceutica Nv Modulateurs d'alcool secondaire de roryt de type quinolinyle
US9221804B2 (en) 2013-10-15 2015-12-29 Janssen Pharmaceutica Nv Secondary alcohol quinolinyl modulators of RORγt
US9403816B2 (en) 2013-10-15 2016-08-02 Janssen Pharmaceutica Nv Phenyl linked quinolinyl modulators of RORγt
US10555941B2 (en) 2013-10-15 2020-02-11 Janssen Pharmaceutica Nv Alkyl linked quinolinyl modulators of RORγt
JP2016534994A (ja) * 2013-10-15 2016-11-10 ヤンセン ファーマシューティカ エヌ．ベー． ＲＯＲγＴの第二級アルコールキノリニルモジュレータ
US9284308B2 (en) 2013-10-15 2016-03-15 Janssen Pharmaceutica Nv Methylene linked quinolinyl modulators of RORγt
US9328095B2 (en) 2013-10-15 2016-05-03 Janssen Pharmaceutica Nv Heteroaryl linked quinolinyl modulators of RORgammat
US10369146B2 (en) 2013-10-15 2019-08-06 Janssen Pharmaceutica Nv Phenyl linked quinolinyl modulators of RORγt
US9624225B2 (en) 2013-10-15 2017-04-18 Janssen Pharmaceutica Nv Quinolinyl modulators of RORγt
US10201546B2 (en) 2013-10-15 2019-02-12 Janssen Pharmaceutica Nv Quinolinyl modulators of RORγt
CN105916852A (zh) * 2014-01-10 2016-08-31 豪夫迈·罗氏有限公司 作为RORc调节剂的芳基磺内酰胺衍生物
CN105899507A (zh) * 2014-01-10 2016-08-24 豪夫迈·罗氏有限公司 作为RORc调节剂的芳基磺内酰胺衍生物
CN105899506A (zh) * 2014-01-10 2016-08-24 豪夫迈·罗氏有限公司 作为RORc调节剂的杂芳基磺内酰胺衍生物
US9751873B2 (en) 2014-01-10 2017-09-05 Genentech, Inc. Aryl sultam derivatives as RORc modulators
US10807980B2 (en) 2014-02-03 2020-10-20 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US10047085B2 (en) 2014-02-03 2018-08-14 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10399976B2 (en) 2014-02-03 2019-09-03 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9624217B2 (en) 2014-02-03 2017-04-18 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US11535614B2 (en) 2014-02-03 2022-12-27 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9266886B2 (en) 2014-02-03 2016-02-23 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9670201B2 (en) 2014-09-26 2017-06-06 Pfizer Inc. Methyl- and trifluoromethyl-substituted pyrrolopyridine modulators of RORC2 and methods of use thereof
US9920054B2 (en) 2014-09-26 2018-03-20 Pfizer Inc. Methyl- and trifluoromethyl-substituted pyrrolopyridine modulators of RORC2 and methods of use thereof
US10227346B2 (en) 2014-09-26 2019-03-12 Pfizer Inc. Methyl- and trifluoromethyl-substituted pyrrolopyridine modulators of RORC2 and methods of use therof
US10426135B2 (en) 2014-09-26 2019-10-01 Pfizer Inc. Methyl- and trifluromethyl-substituted pyrrolopyridine modulators of RORC2 and methods of use thereof
US10087184B2 (en) 2014-10-14 2018-10-02 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of RORγ
US9796710B2 (en) 2014-10-14 2017-10-24 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US11001583B2 (en) 2014-11-05 2021-05-11 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
WO2017002089A1 (fr) 2015-07-02 2017-01-05 Wockhardt Limited Composés bicycliques contenant de l'azote et leur utilisation dans le traitement d'infections bactériennes
US10301261B2 (en) 2015-08-05 2019-05-28 Vitae Pharmaceuticals, Llc Substituted indoles as modulators of ROR-gamma
US10829448B2 (en) 2015-08-05 2020-11-10 Vitae Pharmaceuticals, Llc Substituted benzoimidazoles as modulators of ROR-γ
US11008340B2 (en) 2015-11-20 2021-05-18 Vitae Pharmaceuticals, Llc Modulators of ROR-gamma
US10829481B2 (en) 2016-01-29 2020-11-10 Vitae Pharmaceuticals, Llc Benzimidazole derivatives as modulators of ROR-gamma
WO2017142881A1 (fr) * 2016-02-15 2017-08-24 The Regents Of The University Of Michigan 1,4-oxazepines condensées et leurs analogues associés en tant qu'inhibiteurs de bromodomaine bet
US11548899B2 (en) 2016-02-15 2023-01-10 The Regents Of The University Of Michigan Fused 1,4-oxazepines and related analogs as BET bromodomain inhibitors
JP2019507143A (ja) * 2016-02-15 2019-03-14 ザ リージェンツ オブ ザ ユニヴァシティ オブ ミシガン Ｂｅｔブロモドメイン阻害剤としての融合１，４−オキサゼピンおよび関連類似体
AU2017219627B2 (en) * 2016-02-15 2021-08-05 The Regents Of The University Of Michigan Fused 1,4-oxazepines and related analogs as BET bromodomain inhibitors
CN109071562B (zh) * 2016-02-15 2022-03-22 密执安大学评议会 作为bet溴结构域抑制剂的稠合1,4-氧氮杂䓬和相关类似物
CN109071562A (zh) * 2016-02-15 2018-12-21 密执安大学评议会 作为bet溴结构域抑制剂的稠合1,4-氧氮杂*和相关类似物
WO2017213210A1 (fr) * 2016-06-10 2017-12-14 武田薬品工業株式会社 Composé hétérocyclique
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
WO2018062732A1 (fr) * 2016-09-30 2018-04-05 (주)스파크바이오파마 Nouveau composé dérivé de pyridine ou sels pharmaceutiquement acceptables de celui-ci, son procédé de production et composition pharmaceutique le comprenant
US11535627B2 (en) 2016-09-30 2022-12-27 Spark Biopharma, Inc. Pyrimidine derivative compound, pharmaceutically acceptable salt thereof, preparation process thereof, and pharmaceutical composition using the same
US11186573B2 (en) 2017-07-24 2021-11-30 Vitae Pharmaceuticals, Llc Inhibitors of ROR gamma
US10913739B2 (en) 2017-07-24 2021-02-09 Vitae Pharmaceuticals, LLC (121374) Inhibitors of RORγ
EP3760619A4 (fr) * 2018-02-28 2021-07-07 Japan Tobacco Inc. Composé dihydropyrimidinone ou dihydrotriazinone condensé à cycle saturé, et utilisation pharmaceutique de celui-ci
CN111741948A (zh) * 2018-02-28 2020-10-02 日本烟草产业株式会社 饱和环稠合的二氢嘧啶酮或二氢三嗪酮化合物及其药物用途
JP7200005B2 (ja) 2018-02-28 2023-01-06 日本たばこ産業株式会社 飽和環縮合ジヒドロピリミジノン又はジヒドロトリアジノン化合物及びその医薬用途
JP2019151624A (ja) * 2018-02-28 2019-09-12 日本たばこ産業株式会社 飽和環縮合ジヒドロピリミジノン又はジヒドロトリアジノン化合物及びその医薬用途
CN111741948B (zh) * 2018-02-28 2023-11-10 日本烟草产业株式会社 饱和环稠合的二氢嘧啶酮或二氢三嗪酮化合物及其药物用途
US11834421B2 (en) 2018-02-28 2023-12-05 Japan Tobacco Inc. Saturated-ring-fused dihydropyrimidinone or dihydrotriazinone compounds and pharmaceutical use thereof
WO2021092242A3 (fr) * 2019-11-05 2021-07-22 Dermira, Inc. Inhibiteurs de ror gamma t et leurs utilisations topiques

Similar Documents

Publication Publication Date Title
WO2013064231A1 (fr) Sulfonamides à sept chaînons comme modulateurs des récepteurs gamma orphelins associés à un récepteur de l'acide rétinoïque (rorγ, nr1f3)
US8940722B2 (en) Compounds for modulation of orphan nuclear receptor RAR-related orphan receptor-gamma (RORγ, NR1F3) activity and for the treatment of chronic inflammatory and autoimmune disease
US10301272B2 (en) Carboxamide or sulfonamide substituted thiazoles and related derivatives as modulators for the orphan nuclear receptor ROR[γ]
TWI801372B (zh) 作為a2a抑制劑的硫胺甲酸酯衍生物以及用於癌症治療的方法
US9815851B2 (en) Pyrrolo carboxamides as modulators of orphan nuclear receptor RAR-related orphan receptor-gamma (RORγ, NR1F3) activity and for the treatment of chronic inflammatory and autoimmune diseases
EP3277670A1 (fr) Inhibiteurs de l'indoléamine 2,3-dioxygénase pour le traitement du cancer
NO20150112A1 (en) Carboxamide or sulfonamide substituted nitrogen-containing 5-membered heterocycles as modulators for the orphan nuclear receptor ROR gamma
AU2018246355B2 (en) 2-oxo-thiazole derivatives as A2A inhibitors and compounds for use in the treatment of cancers
EP2511263A1 (fr) Composés de pyrrolo sulfonamide pour la modulation d'activité de récepteur-gamma orphelin (gamme ROR, NR1F3) associée au RAR de récepteur nucléaire orphelin et pour le traitement des maladies inflammatoires et de maladies auto-immunes chroniques
WO2013096771A1 (fr) Agonistes de tgr5 non systémiques
TWI759343B (zh) 新穎萘啶酮衍生物及其於心律不整之治療的用途
TWI836960B (zh) 作為a2a抑制劑的硫胺甲酸酯衍生物以及用於癌症治療的方法
RU2774273C2 (ru) Новые производные нафтиридинона и их применение в лечении аритмии
EA038455B1 (ru) Новые производные нафтиридинона и их применение в лечении аритмии

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12780102

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12780102

Country of ref document: EP

Kind code of ref document: A1