WO2016198908A1 - Modulateurs des récepteurs nucléaires ror - Google Patents

Modulateurs des récepteurs nucléaires ror Download PDF

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Publication number
WO2016198908A1
WO2016198908A1 PCT/IB2015/001693 IB2015001693W WO2016198908A1 WO 2016198908 A1 WO2016198908 A1 WO 2016198908A1 IB 2015001693 W IB2015001693 W IB 2015001693W WO 2016198908 A1 WO2016198908 A1 WO 2016198908A1
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Prior art keywords
methyl
dichloro
trifluoromethyl
mmol
dimethyl
Prior art date
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Ceased
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PCT/IB2015/001693
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English (en)
Inventor
Maria A. Argiriadi
Eric BREINLINGER
Kevin P. Cusack
Adrian D. Hobson
Dominique Potin
Martine Barth
Jérôme AMAUDRUT
Olivia Poupardin
Laurent Mounier
Michael E. Kort
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AbbVie Inc
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AbbVie Inc
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Application filed by AbbVie Inc filed Critical AbbVie Inc
Priority to PCT/IB2015/001693 priority Critical patent/WO2016198908A1/fr
Priority to SI201630618T priority patent/SI3307734T1/sl
Priority to CR20170594A priority patent/CR20170594A/es
Priority to LTEP16731721.3T priority patent/LT3307734T/lt
Priority to HUE16731721A priority patent/HUE047988T2/hu
Priority to AU2016276316A priority patent/AU2016276316B2/en
Priority to US15/176,309 priority patent/US10106501B2/en
Priority to PT167317213T priority patent/PT3307734T/pt
Priority to PL16731721T priority patent/PL3307734T3/pl
Priority to PE2022000685A priority patent/PE20230683A1/es
Priority to UY0001036716A priority patent/UY36716A/es
Priority to MA051556A priority patent/MA51556A/fr
Priority to ARP160101700A priority patent/AR104934A1/es
Priority to CN201680036750.1A priority patent/CN107820494B/zh
Priority to TW110113121A priority patent/TW202128619A/zh
Priority to TW105118235A priority patent/TWI726888B/zh
Priority to RS20200097A priority patent/RS59934B1/sr
Priority to ES16731721T priority patent/ES2774517T3/es
Priority to HK18108102.8A priority patent/HK1248678B/zh
Priority to EP16731721.3A priority patent/EP3307734B1/fr
Priority to PH1/2017/502237A priority patent/PH12017502237B1/en
Priority to EP19203418.9A priority patent/EP3636643A1/fr
Priority to RU2017146835A priority patent/RU2715897C2/ru
Priority to JP2017563311A priority patent/JP6549735B2/ja
Priority to PCT/US2016/036283 priority patent/WO2016200851A1/fr
Priority to PE2017002535A priority patent/PE20181020A1/es
Priority to KR1020187000451A priority patent/KR20180014433A/ko
Priority to CA2988502A priority patent/CA2988502A1/fr
Priority to HRP20200064TT priority patent/HRP20200064T1/hr
Priority to MYPI2017704687A priority patent/MY193715A/en
Priority to UAA201713051A priority patent/UA120651C2/uk
Priority to SG10201911849SA priority patent/SG10201911849SA/en
Priority to MX2017015980A priority patent/MX372543B/es
Priority to BR112017026452-8A priority patent/BR112017026452A2/pt
Priority to DK16731721.3T priority patent/DK3307734T3/da
Publication of WO2016198908A1 publication Critical patent/WO2016198908A1/fr
Priority to IL256043A priority patent/IL256043B/en
Priority to ZA2017/08285A priority patent/ZA201708285B/en
Priority to CONC2017/0012594A priority patent/CO2017012594A2/es
Priority to DO2017000289A priority patent/DOP2017000289A/es
Priority to CL2017003147A priority patent/CL2017003147A1/es
Priority to MX2020003224A priority patent/MX2020003224A/es
Anticipated expiration legal-status Critical
Priority to ECIEPI20181225A priority patent/ECSP18001225A/es
Priority to US16/108,230 priority patent/US20190055196A1/en
Priority to JP2019118167A priority patent/JP2019178159A/ja
Priority to US16/654,141 priority patent/US20210130293A1/en
Priority to CY20201100043T priority patent/CY1122495T1/el
Priority to AU2020202584A priority patent/AU2020202584A1/en
Priority to IL274537A priority patent/IL274537A/en
Priority to JP2020135558A priority patent/JP6938737B2/ja
Priority to US17/443,264 priority patent/US20230066771A1/en
Priority to JP2021140781A priority patent/JP7235816B2/ja
Priority to AU2021232727A priority patent/AU2021232727A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • the present invention relates to novel compounds which modulate the activity of Rorc and the RORyt receptor, and their use as medicaments.
  • the retinoic acid-related orphan receptor (ROR) isoforms RORoc, RORp, and RORy are members of the steroid nuclear hormone receptor superfamily, and play prominent roles in a variety of biological processes including organ development, immunity, lipid homeostatsis and metabolism, and circadian rhythms (Jetten et al. NURSA 2009, 7, 1).
  • the ROR family members are composed of both a ligand-binding domain (LBD) and a DNA-binding domain (DBD).
  • Ligand binding causes a conformational change that modulates binding of co-regulatory proteins: agonists recruit co- activators; antagonists and inverse agonists disrupt the binding of co-activators or enhancing the binding of co-repressors thereby repressing the transcription of target genes (Fauber et al. J. Med. Chem. 2014, 57, 5871).
  • Retinoic acid-related orphan receptor ⁇ thymus (RORy, also referred to as RORc and NR1F3) is encoded by Rorc; human and mouse RORy share high sequence homology, and nearly identical binding site homology (Jin, L. et al. Mol. Endocrinol. 2010, 24, 923). Mammalian RORy exists in two distinct isoforms, RORy and RORyt, which possess indentical LBDs and differ only in their N-terminal sequences (Medvedev et al. Gene 1996, 181, 199).
  • RORyt isoform of lymphoid organs including the thymus, whereas RORy is more broadly expressed (liver, muscle, kidney), similar to ROR which is also found in brain and adipose tissue (Kurebayashi, S. et al. Proc. Natl. Acad. Sci, U.S.A. 2000, 97, 10132).
  • RORp is localized to the cerebral cortex (Hirose, T. et al. Biochem. Biophys Res. Commun. 1993, 194, 1371).
  • RORyt is critical for the development of lymph nodes and Peyer's patches and for the normal differentiation of T helper-17 (Thl7) cells, ⁇ T cells, and LTi cells (Sun et al. Science 2000, 288, 2369).
  • RORyt is an obligatory transcription factor that controls the differentiation of naive CD4 + T cells into Thl7 lineage, and regulates transcription of the effector cytokine IL-17 in Thl7 cells and cells of the innate immune response in both rodents and humans (Ivanov, I. et al. Cell 2006, 126, 1121).
  • Proinflammatory cytokines including IL-17A, IL-17F, and IL-22 produced by Thl7 cells and other RORyt + lymphocytes activate and direct the immune response to extracellular pathogens (Eberl, G. et al. Nat. Immunol. 2004, 5, 64).
  • EAE experimental autoimmune encephalomyelitis
  • Dysregulation of IL-17 transcription and secretion has been implicated multiple human autoimmune disorders including psoriasis, rheumatoid arthritis, inflammatory bowel disease (IBD), asthma, and multiple sclerosis (MS) (for example, see: Yang, X. et al. Immunity 2008, 28, 29; Pantelyushin, S. et al. J. Clin. Invest.
  • Therapeutic agents exist to treat a variety of inflammatory and autoimmune diseases, but there still remains a significant unmet medical need in these therapeutic areas.
  • IL-17 in human disease
  • RORy as targets in murine disease models
  • compounds capable of modulating RORyt activity are contemplated to provide a therapeutic benefit in the treatment of multiple immune and inflammatory disorders.
  • the invention provides a compound of Formula (I)
  • W is C or CR a , L 1 is connected to W or Y;
  • a and E are independently C or N provided both are not N;
  • V is CR 3 orN
  • X is CR a , NR a orN
  • Y is C, CR ⁇ NR a , N, O or S;
  • Z is CR 3 or N
  • W is N or NR a , L 1 is connected to W or Y; and A and E are independently C or N provided both are not N;
  • V is CR 3 or N
  • X is CR a , NR a or N;
  • Y is C, CR a or N
  • Z is CR 3 or N
  • Cy is a six-membered aromatic or heteroaromatic ring substituted with R 1 and R 2 ;
  • L 1 is -CH(R b ), -C(R b )( R d ), C(0) or N(R c );
  • L 2 is C(O), -0-,— C(R b )( R d ), -S-, -S(O)-, -S(0) 2 -;
  • R 1 and R 2 are independently halo, -0-(C r C 3 )alkyl, -O-cycloalkyl or (C r C 3 )alkyl;
  • each R 3 is independently H, CF 3 , CN, halo, OCF 3 , -0-(C C 3 )alkyl, -O-cycloalkyl, optionally substituted (Ci-C 3 )alkyl, optionally substituted heteoraryl or optionally substituted heterocyclyl;
  • R 4 is optionally substituted (d-C 6 )alkyl, NR 5 R 6 , optionally substituted (C 3 -C 6 )cycloalkyl or- (CH 2 ) m -optionally substituted heterocyclyl;
  • R 5 is H and R 6 is optionally substituted (Ci-C 4 )alkyl, optionally substituted (C 3 - C 6 )cycloalkyl or -(CH 2 ) m -optionally substituted heterocyclyl; or
  • R 5 and R 6 together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl
  • each R a is independently H, -C(0)CH 3 , optionally substituted (C)-C 6 )alkyl, optionally substituted (C 3 -C 6 )cycloalkyl or -S(0) 2 -phenyl;
  • each R b is independently H, F, OH, (C r C 3 )alkoxy or (C C 3 )alkyl;
  • R° is independently H or (Ci-C 3 )alkyl
  • each R d is independently H, F, or (C C 3 )alkyl; or R d and R b form a (C 3 -C 5 ) spirocycle; and m is independently 0 or 1 ;
  • G and J are independently CH or N.
  • the invention provides ahe compound according to any of the foregoing embodiments wherein the compound is a compound of Formula (la)
  • the invention provides a compound according to any of the foregoing embodiments, wherein L 1 is -CH 2 -, -C(O-), -C(H)(OH)- or -C(H)(CH 3 )-.
  • the invention provides a compound according to any of the foregoing embodiments, wherein L 2 is -C(O)-, -O- or -CH 2 -.
  • the invention provides a compound according to any of the foregoing embodiments, wherein R 1 and R 2 are independently halo, (C r C 3 )alkoxy or (Ci-C 3 )alkyl.
  • the invention provides a compound according to any of the foregoing embodiments,wherein R 3 is independently CF 3 , CN, Br, OCF 3 or (C C 3 )alkyl.
  • the invention provides a compound according to any of the foregoing embodiments wherein R 4 is optionally substituted (CVCeJalkyl, optionally substituted azepanyl, - N(H)-optionally substituted cyclohexyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted azabicyclo[3.1.0]heptanyl, optionally substituted
  • azabicyclo[2.2.1]heptanyl optionally substituted azaspiro[3.3]heptanyl, optionally substituted 2-oxa-8- azaspiro[4.5]decanyl, optionally substituted azetidinyl, optionally substituted 1 ,2-diazepanyl, optionally substituted 1 ,4-diazepanyl, optionally substituted morpholinyl, optionally substituted oxetanyl, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, or thiomorpholine 1,1 -dioxide.
  • the invention provides a compound according to any of the foregoing embodiments wherein R 4 is azaspiro[3.3]heptanyl, morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl; wherein
  • the piperazinyl is optionally substituted with one or more substituents independently selected from -C(0)OH, (C ⁇ -C 3 ) alkyl, and oxetanyl; and
  • the piperidinyl is optionally substituted with one or more substituents independently selected from OH, -C(0)OH, -CH 2 C(0)OH, -C(H)(CH 3 )C(0)OH, -CH 2 OH , (C,-C 3 ) alkyl,
  • the invention provides a compound according to any of the foregoing embodiments wherein R 1 and R 2 are both halo.
  • the invention provides a compound according to any of the foregoing embodiments wherein W is C or CH, A is C and E is C.
  • the invention provides a compound according to any of the foregoing embodiments wherein L 1 is CH 2 or C(O) and L 2 is C(O).
  • the invention provides a compound according to any of the foregoing embodiments wherein G is CH.
  • the invention provides a compound according to any of the foregoing embodiments wherein J is CH.
  • the invention provides a compound according the fourteenth embodiment wherein W is CH; X is CR a ; Y is N; A is C; E is C; V is CR 3 ; Z is CR 3 and L 1 is connected to Y.
  • the invention provides a compound according the fourteenth embodiment wherein W is C; X is N or NR a ; Y is N; A is C; E is C; V is CR 3 ; and L 1 is connected to W.
  • the invention provides a compound according the fourteenth embodiment wherein W is C; X is N or NR a ; Y is CR a ; Z is CR 3 ; A is C; V is CR 3 and L 1 is connected to W.
  • the invention provides a compound according the fourteenth embodiment wherein W is C; X is CR a ; Y is NR a ; Z is N; A is C; E is C; V is CR 3 and L 1 is connected to W.
  • the invention provides a compound according the fourteenth embodiment wherein W is CH; X is N; Y is N; Z is CR 3 ; A is C; E is C; and V is CR 3 and L 1 is connected to Y.
  • W is C; X is NR a ; Y is CR a ; Z is N; A is C; E is C; V is CR 3 and L 1 is connected to W.
  • the invention provides a compound according the fourteenth embodiment wherein W is C; X is CR a ; Y is N; A is N; E is C; Z is N; V is CR 3 and L 1 is connected to W.
  • the invention provides a compound according the fourteenth embodiment wherein W is C; X is CR a ; Y is N; Z is CR 3 ; A is N; E is C; V is CR 3 and L 1 is connected to W.
  • the invention provides a compound according the first embodiment wherein W is N; X is CR a ; Y is N; Z is CR 3 ; A is C; E is C; V is CR 3 and L 1 is connected to W.
  • the invention provides a compound according the first embodiment wherein W is N; X is CR a ; Y is N; A is C; E is C; V is CR 3 ; and Z is CR 3 and L 1 is connected to W.
  • the invention provides a compound according the fourteenth embodiment wherein W is C; X is NR a ; Y is CR a ; Z is CR 3 ; A is C; E is C; V is N; and L 1 is connected to W.
  • the invention provides a compound according the fourteenth embodiment wherein W is CR a ; X is NR a ; Y is C; Z is CR 3 ; A is C; V is C; V is CR 3 ; and L 1 is connected to Y.
  • the invention provides a compound according the fourteenth embodiment wherein W is C; X is N or NR a , Y is CR 3 ; Z is CR 3 ; A is C; V is CR 3 ; G or J is N and L 1 is connected to W.
  • the invention provides a compound according the fourteenth embodiment wherein W is C; X is N; Y is NR a ; Z is CR 3 ; A is C; E is C; V is CR 3 , G or J is N; and L 1 is connected to W.
  • the invention provides a compound according the fourteenth embodiment wherein W is C; X is NR a ; Y is CR a ; Z is N; A is C; E is C; V is CR 3 ; G or J is N; and L 1 is connected to W.
  • the invention provides a compound according the fourteenth embodiment wherein W is C; X is CR a ; Y is N; Z is N; V is CR 3 , G or J or N; and L 1 is connected to W.
  • the invention provides a compound according the fourteenth embodiment wherein W is C; X is N; Y is CR 3 ; Z is CR 3 ; A is C; E is N; V is CR 3 , G is N or J or N and L 1 is connected to W.
  • the invention provides a compound according the fourteenth embodiment wherein W is N; X is N; Y is CR 3 ; Z is CR 3 ; A is C; E is C; V is CR 3 , G or J or N and L 1 is connected to W or Y.
  • the invention provides a compound according the any of the foregoing embodiments wherein R 6 is tetrahydropyranyl or oxetanyl.
  • the invention provides a pharmaceutical composition comprising a compound of Formula (I) and one or more pharmaceutically acceptable excipients.
  • the invention provides a method of treating a disease comprising administering a therapeutically effective amount of a compound of Formula (I), wherein the disease is rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, ankylosing spondylitis, reactive arthritis, " arthritis associated with inflammatory bowel disease, undifferentiated spondyloarthritis, systemic lupus erythematosus, lupus nephritis, uveitis, atopic dermatitis, multiple sclerosis, axial spondyloarthritides or hidraenitis suppurativa.
  • a compound of Formula (I) wherein the disease is rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, Crohn's disease, inflammatory
  • the invention provides a kit comprising a packaged product comprising components with which to administer a compound according to any of the foregoing embodiments for treatment of an autoimmune disorder.
  • the invention provides a kit according to the thirty-seventh embodiment wherein the packaged product comprises a compound of claim 1 and instructions for use.
  • the invention provides a use of a compound according to any of the foregoing embodiments for the preparation of a medicament intended to treat a disease, wherein the disease is rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, ankylosing spondylitis, reactive arthritis, arthritis associated with inflammatory bowel disease, undifferentiated spondyloarthritis, systemic lupus erythematosus, lupus nephritis, uveitis, atopic dermatitis, multiple sclerosis, axial
  • the invention provides a compound according to any of the foregoing embodiments for treating a disease, wherein the disease is rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, ankylosing spondylitis, reactive arthritis, arthritis associated with inflammatory bowel disease, undifferentiated spondyloarthritis, systemic lupus erythematosus, lupus nephritis, uveitis, atopic dermatitis, multiple sclerosis, axial spondyloarthritides or hidraenitis suppurativa.
  • the disease is rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, ankylosing spondylitis,
  • a method for treating a disease or disorder selected from an autoimmune disease or disorder, psoriasis, psoriatic arthritis, asthma, an allergic disease or disorder, a metabolic disease or disorder, and cancer in a subject comprises administering to the subject a therapeutically effective amount of compound according to formula (I), stereoisomeric form, N-oxide, pharmaceutically acceptable salt, solvate, hydrate or pharmaceutical composition as described herein.
  • the autoimmune disease or disorder is selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, uveitis, graft-versus-host disease, and lupus.
  • the allergic disease or disorder is selected from atopic dermatitis, allergic rhinitis, asthma, or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the metabolic disease or disorder is selected from obesity, obesity-induced insulin resistance, atherosclerosis, and type II diabetes.
  • the oncology disease or disorder is is melanoma.
  • the disease or disorder is psoriasis or psoriatic arthritis.
  • psoriasis or psoriatic arthritis See for example: Pantelyushin, S. et al. "RORyt + innate lymphocytes and ⁇ T cells initiate psoriasiform plaque formation in mice” J. Clin. Invest. 2012, 122, 2252; and Raychaudhuri, S. et al. "Role of EL-17 in psoriasis and psoriatic arthritis," Clin. Rev. Allergy Immunol. 2013, 44, 183.
  • the disease or disorder is atopic dermatitis.
  • atopic dermatitis See for example: Ma, L. et al. "The imbalance of Thl7 cells and CD4 + CD25highFoxp3 + Treg cells in patients with atopic dermatitis" J. Eur. Acad. Dermatol. Venereol. 2014, 28, 1079; and Peiser, M. "Role of Thl7 cells in skin inflammation of allergic contact dermatitis" Clin. Dev. Immunol. 2013, 261037.
  • the disease or disorder is rheumatoid arthritis.
  • rheumatoid arthritis See for example: Park, T.- Y. et al. "RORyt-specific transcriptional interactomic inhibition suppresses autoimmunity associated with TH17 cells” Proc. Natl. Acad. Sci. USA 2014, 111, 18673; and Solt, L. et al. "Action of RORs and their ligands in (pathophysiology" Trends Endocrinol. Metab. 2012, 23, 619; and Chang, M. et al. "Pharmacologic repression of retinoic acid receptor-related orphan nuclear receptor ⁇ is therapeutic in the collagen-induced arthritis experimental model" Arthritis Rheumatol. 2014, 66, 579.
  • the disease or disorder is ankylosing spondylitis. See for example: Bidad, K. et al "Effect of all-transretinoic acid on Thl7 and T regulatory cell subsets in patients with ankylosing spondylitis" J. Rheumatol. 2013, 40, 476; and Toussirot, E. et al. "The IL-23/Thl7 pathway as a therapeutic target in chronic inflammatory diseases," Inflamm. Allergy Drug Targets 2012, 1, 159.
  • the disease or disorder is multiple sclerosis. See for example: Martinez, N. et al. "RORyt, but not T-bet, overexpression exacerbates an autoimmune model for multiple sclerosis” J. Neuroimmunol. 2014, 11, 105/1; and Codarri, L. et al., “RORyt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of, autoimmune neuroinflammation” Nat. Immunol. 2011 12, 560.
  • the disease or disorder is inflammatory bowel disease.
  • inflammatory bowel disease See for example: Troncone, E. et al. "Thl7 cytokines in inflammatory bowel diseases: discerning the good from the bad” Intl. Rev. Immunol. 2013, 32, 526; and Leppkes, M. et al. "RORgamma-expressing Thl7 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F" Gastroenterology 2009, 136, 257-67.
  • the diseases or disorders are ulcerative colitis or Crohn's disease. See for example: Dong, Z. et al. "Aberrant expression of circulating Thl 7, Thl and Tel cells in patients with active and inactive ulcerative colitis” Intl. J. Mol. Med. 2013, 31, 989; and Kumawat, A. et al. "Microscopic colitis patients demonstrate a mixed Thl7/Tcl7 and Thl /Tel mucosal cytokine profile" Mol Immunol. 2013, 55, 355.
  • the disease or disorder is autoimmune uveitis. See for example: Horai, R. et al. "Cytokines in autoimmune uveitis" J. Interferon Cytokine Res. 2011 31, 733.
  • the disease or disorder is lupus. See for example: Yoh, K. et al. "Overexpression of RORyt under control of the CD2 promoter induces polyclonal plasmacytosis and autoantibody production in transgenic mice” Eur. J. Immunol. 2012, 42, 1999.
  • the disease or disorder is graft-versus-host disease (GVHD).
  • GVHD graft-versus-host disease
  • the disease or disorder is atherosclerosis. See for example: Erbel, C. et al. "IL-17A influences essential functions of the monocyte/macrophage lineage and is involved in advanced murine and human atherosclerosis" J. Immunol. 2014, 193, 4344.
  • the diseases or disorders are allergic rhinitis, asthma, or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the diseases or disorders are obesity, and/or insulin resistance, and/or type II diabetes.
  • the diseases or disorders are obesity, and/or insulin resistance, and/or type II diabetes.
  • Solt, L. et al. “ROR inverse agonist suppresses insulitis and prevents hyperglycemia in a mouse model of type 1 diabetes” Endocrinology 2015, 156, 869; and Meissburger, B. et al. "Adipogenesis and insulin sensitivity in obesity are regulated by retinoid-related orphan receptor gamma” EMBO Mol. Med. 2011, 3, 637; and Solt, L. "Ligand regulation of retinoic acid receptor-related orphan receptors: implications for development of novel therapeutics” Curr. Opin. Lipidology 2010, 21 , 204.
  • the disease or disorder is melanoma. See for example: Purwar, R. et al. "Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells” Nat. Med. 2012, 18, 1248.
  • the combinations which are to be included within this invention are those combinations useful for their intended purpose.
  • the agents set forth below are illustrative for purposes and not intended to be limited.
  • the combinations, which are part of this invention can be the compounds of the present invention and at least one additional agent selected from the lists below.
  • the combination can also include more than one additional agent, e.g., two or three additional agents if the combination is such that the formed composition can perform its intended function.
  • Preferred combinations are non-steroidal anti-inflammatory drug(s) also referred to as NSAIDS which include drugs like ibuprofen.
  • Other preferred combinations are corticosteroids including prednisolone; the well known side-effects of steroid use can be reduced or even eliminated by tapering the steroid dose required when treating patients in combination with the compounds of this invention.
  • Non-limiting examples of therapeutic agents for rheumatoid arthritis with which a compound of Formula (I) of the invention can be combined include the following: cytokine suppressive anti-inflammatory drug(s) (CSATDs); antibodies to or antagonists of other human cytokines or growth factors, for example, LT, IL-1, JL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-12, IL- 15, IL-16, IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF, MMP-13 and PDGF.
  • CSATDs cytokine suppressive anti-inflammatory drug
  • Compounds of the invention can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligands including CD154 (gp39 or CD40L).
  • cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligands including CD154 (gp39 or CD40L).
  • Preferred combinations of therapeutic agents may interfere at different points in the autoimmune and subsequent inflammatory cascade; preferred examples include IL-1 inhibitors (Interleukin-1 -converting enzyme inhibitors, IL-IRA etc.) may be effective for the same reason. Other preferred combinations include Interleukin 11. Yet other preferred combinations are the other key players of the autoimmune response which may act parallel to, dependent on or in concert with IL-18 function; especially preferred are IL-12 antagonists including IL-12 antibodies or soluble IL-12 receptors, or IL-12 binding proteins. It has been shown that IL-12 and IL-18 have overlapping but distinct functions and a combination of antagonists to both may be most effective. Yet another preferred combination is non-depleting anti-CD4 inhibitors. Yet other preferred combinations include antagonists of the co-stimulatory pathway CD80 (B7.1) or CD86 (B7.2) including antibodies, soluble receptors or antagonistic ligands.
  • IL-1 inhibitors Interleukin-1 -converting enzyme inhibitors, IL-IRA etc.
  • Other preferred combinations include Interleukin
  • a compound of Formula (I) of the invention may also be combined with agents, such as methotrexate, 6-mercaptopurine, azathioprine sulphasalazine, mesalazine, olsalazine chloroquinine/hydroxychloroquine, pencillamine, aurothiomalate (intramuscular and oral), azathioprine, cochicine, corticosteroids (oral, inhaled and local injection), beta-2 adrenoreceptor agonists (salbutamol, terbutaline, salmeteral), xanthines (theophylline, aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSATDs, for example, ibuprofen, corticosteroids such as prednisolone,
  • cytokines e.g. IL- 4, IL-10, IL-11 , IL-13
  • celecoxib folic acid, hydroxychloroquine sulfate, rofecoxib, naproxen, valdecoxib, sulfasalazine, methylprednisolone, meloxicam, methylprednisolone acetate, gold sodium thiomalate, aspirin, triamcinolone acetonide, propoxyphene napsylate/apap, folate, nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone HC1, hydrocodone bitartrate/apap, diclofenac sodium/misoprostol, fentanyl, anakinra, trama
  • Non-limiting examples of therapeutic agents for inflammatory bowel disease with which a compound of Formula (I) of the invention can be combined include the following: budenoside; epidermal growth factor; corticosteroids; cyclosporin, sulfasalazine; aminosalicylates; 6- mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide; antioxidants; thromboxane inhibitors; IL-1 receptor antagonists; anti-IL- ⁇ monoclonal antibodies; anti-IL-6 monoclonal antibodies; growth factors; elastase inhibitors; pyridinyl-imidazole compounds; antibodies to or antagonists of other human cytokines or growth factors, for example, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP-I
  • IL- ⁇ converting enzyme inhibitors T-cell signalling inhibitors such as kinase inhibitors; metalloproteinase inhibitors; sulfasalazine; azathioprine; 6-mercaptopurines; angiotensin converting enzyme inhibitors; soluble cytokine receptors and derivatives thereof (e.g. sIL-lRI, sIL- 1RII, sIL-6R) and antiinflammatory cytokines (e.g. IL-4, IL-10, IL-11, IL-13).
  • Preferred examples of therapeutic agents for Crohn's disease with which a compound of Formula (I) can be combined include PDE4 inhibitors.
  • a compound of Formula (I) can be combined with corticosteroids, for example, budenoside and dexamethasone; sulfasalazine, 5-aminosalicylic acid; olsalazine; and agents which interfere with synthesis or action of proinflammatory cytokines such as IL-1, for example, IL- ⁇ converting enzyme inhibitors and IL-lra; T cell signaling inhibitors, for example, tyrosine kinase inhibitors; 6-mercaptopurine; IL-11; mesalamine; prednisone; azathioprine; mercaptopurine; infliximab; methylprednisolone sodium succinate; diphenoxylate/atrop sulfate; loperamide hydrochloride; methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water; hydrocodone bitartrate/apap; tetracycline hydrochloride;
  • Non-limiting examples of therapeutic agents for multiple sclerosis with which a compound of Formula (I) can be combined include the following: corticosteroids; prednisolone; methylprednisolone; azathioprine; cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine; tizanidine; interferon-pia (AVONEX®; Biogen); interferon-pib (BETASERON®; Chiron/Berlex); interferon a-n3) (Interferon Sciences Fujimoto), interferon-a (Alfa Wassermann/J&J), interferon ⁇ - IF (Serono/Inhale Therapeutics), Peginterferon a 2b (Enzon/Schering-Plough), Copolymer 1 (Cop-1; COPAXONE®; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen; intravenous immunoglobulin; cladribine; antibodies to or antagonists of other
  • a compound of Formula (I) can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands.
  • cell surface molecules such as CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands.
  • a compound of Formula (I) may also be combined with agents such as methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, an S1P1 agonist, NSAIDs, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents which interfere with signalling by proinflammatory cytokines such as IL-1 (e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1 ⁇ converting enzyme inhibitors, TACE inhibitors, T-cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptor
  • interferon- ⁇ for example, IFNpia and IFNpib
  • Copaxone corticosteroids
  • caspase inhibitors for example inhibitors of caspase-1, IL-1 inhibitors, and antibodies to CD40 ligand and CD80.
  • a compound of Formula (I) may also be combined with agents, such as alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol, a-immunokine NNS03, ABR-215062, AnergiX.MS, chemokine receptor antagonists, BBR-2778, calagualine, CPI-1189, LEM (liposome encapsulated mitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidone allotrap 1258 (RDP-1258), sTNF-Rl, talampanel, teriflunomide, TGF-beta2, tiplimotide, VLA-4 antagonists (
  • Non-limiting examples of therapeutic agents for ankylosing spondylitis wit which a compound of Formula (I) can be combined include the following: ibuprofen, diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine, minocyclin, and prednisone
  • Non-limiting examples of therapeutic agents for psoriasis with which a compound of Formula (I) can be combined include the following: calcipotriene, clobetasol propionate, triamcinolone acetonide, halobetasol propionate, tazarotene, methotrexate, fluocinonide, betamethasone diprop augmented, fluocinolone acetonide, acitretin, tar shampoo, betamethasone valerate, mometasone furoate, ketoconazole, pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide, urea, betamethasone, clobetasol propionate/emoll, fluticasone propionate, azithromycin, hydrocortisone, moisturizing formula, folic acid, desonide, pimecrolimus, coal tar, diflorasone diacetate, etanercept fo
  • Non-limiting examples of therapeutic agents for psoriatic arthritis with which a compound of Formula (I) can be combined include the following: methotrexate, etanercept, rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac, betamethasone diprop augmented, infliximab, methotrexate, folate, triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenac sodium/misoprostol, fluocinonide, glu
  • Non-limiting examples of therapeutic agents for restenosis with which a compound of Formula (I) can be combined include the following: sirolimus, paclitaxel, everolimus, tacrolimus, ABT-578, and acetaminophen.
  • Preferred examples of therapeutic agents for SLE (Lupus) with which a compound of Formula (I) can be combined include the following: NSAIDS, for example, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin; COX2 inhibitors, for example, celecoxib, rofecoxib, valdecoxib; antimalarials, for example, hydroxychloroquine; steroids, for example, prednisone, prednisolone, budenoside, dexamethasone; cytotoxics, for example, azathioprine, cyclophosphamide, mycophenolate mofetil, methotrexate; inhibitors of PDE4 or purine synthesis inhibitor, for example Cellceptd ) .
  • NSAIDS for example, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin
  • COX2 inhibitors for example, celecoxib
  • a compound of Formula (I) may also be combined with agents such as sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran® and agents which interfere with synthesis, production or action of proinflammatory cytokines such as IL-1, for example, caspase inhibitors like IL- ⁇ converting enzyme inhibitors and IL-lra.
  • agents such as sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran® and agents which interfere with synthesis, production or action of proinflammatory cytokines such as IL-1, for example, caspase inhibitors like IL- ⁇ converting enzyme inhibitors and IL-lra.
  • a compound of Formula (I) may also be used with T cell signaling inhibitors, for example, tyrosine kinase inhibitors; or molecules that target T cell activation molecules, for example, CTLA-4-IgG or anti-B7 family antibodies, anti-PD-1 family
  • a compound of Formula (I) can be combined with EL- 11 or anti-cytokine antibodies, for example, fonotolizumab (anti-IFNg antibody), or anti-receptor receptor antibodies, for example, anti-IL-6 receptor antibody and antibodies to B-cell surface molecules.
  • a compound of Formula (I) may also be used with LJP 394 (abetimus), agents that deplete or inactivate B-cells, for example, Rituximab (anti-CD20 antibody), and lymphostat-B (anti-BlyS antibody).
  • a “therapeutically effective amount” is an amount of a compound of Formula (I) or a combination of two or more such compounds, which inhibits, totally or partially, the progression of the condition or alleviates, at least partially, one or more symptoms of the condition.
  • a therapeutically effective amount can also be an amount which is prophylactically effective. The amount which is therapeutically effective will depend upon the patient's size and gender, the condition to be treated, the severity of the condition and the result sought. For a given patient, a therapeutically effective amount can be determined by methods known to those of skill in the art.
  • “Pharmaceutically acceptable salts” refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid or organic acids such as sulfonic acid, carboxylic acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, lactic acid, tartaric acid (e.g. (+) or (-)-tartaric acid or mixtures thereof), amino acids (e.g. (+) or (-)-amino acids or mixtures thereof), and the like.
  • These salts can be prepared by methods known to those skilled in the art.
  • Certain compounds of Formula (I) which have acidic substituents may exist as salts with pharmaceutically acceptable bases.
  • the present invention includes such salts.
  • Examples of such salts include sodium salts, potassium salts, lysine salts and arginine salts. These salts may be prepared by methods known to those skilled in the art.
  • Certain compounds of Formula (I) and their salts may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof.
  • Certain compounds of Formula (I) and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.
  • Certain compounds of Formula (I) may contain one or more chiral centers, and exist in different optically active forms.
  • compounds of Formula (I) may contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as racemic mixtures.
  • the enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent.
  • enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
  • a compound of Formula (I) When a compound of Formula (I) contains more than one chiral center, it may exist in diastereoisomeric forms.
  • the diastereoisomeric compounds may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers may be separated as described above.
  • the present invention includes each diastereoisomer of compounds of Formula (I) (and mixtures thereof.
  • Certain compounds of Formula (I) may exist in different tautomeric forms or as different geometric isomers, and the present invention includes each tautomer and/or geometric isomer of compounds of Formula (I) and mixtures thereof.
  • Certain compounds of Formula (I) may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
  • the present invention includes each conformational isomer of compounds of Formula (I) and mixtures thereof.
  • Certain compounds of Formula (I) may exist in zwitterionic form and the present invention includes each zwitterionic form of compounds of Formula (I) (and mixtures thereof.
  • pro-drug refers to an agent which is converted into the parent drug in vivo by some physiological chemical process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form).
  • Pro-drugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • the pro-drug may also have improved solubility in pharmacological compositions over the parent drug.
  • pro-drug a compound of the present invention wherein it is administered as an ester (the "pro-drug") to facilitate transmittal across a cell membrane where water solubility is not beneficial, but then it is metabolically hydrolyzed to the carboxylic acid once inside the cell where water solubility is beneficial.
  • Pro-drugs have many useful properties. For example, a pro-drug may be more water soluble than the ultimate drug, thereby facilitating intravenous administration of the drug. A pro-drug may also have a higher level of oral bioavailability than the ultimate drug. After administration, the prodrug is enzymatically or chemically cleaved to deliver the ultimate drug in the blood or tissue.
  • Exemplary pro-drugs upon cleavage release the corresponding free acid, and such hydrolyzable ester-forming residues of the compounds of this invention include but are not limited to carboxylic acid substituents wherein the free hydrogen is replaced by (Q- Ci 2 )alkanoyloxymethyl, (C 4 -C 9 )l-(alkanoyloxy)ethyl, 1 -methyl- 1 -(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1 -(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, l-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atom
  • exemplary pro-drugs release an alcohol of Formula (I) wherein the free hydrogen of the hydroxyl substituent (e.g., R 1 contains hydroxyl) is replaced by (C C 6 )alkanoyloxymethyl, l-((Ci- C6)alkanoyloxy)ethyl, l-methyl-l-((Ci-C 6 )alkanoyloxy)ethyl, (Ci-Ci 2 )alkoxycarbonyloxymethyl, ⁇ - (C r C6)alkoxycarbonylamino-methyl, succinoyl, (C]-C 6 )alkanoyl, a-amino(Ci-C 4 )alkanoyl, arylactyl and a-aminoacyl, or ⁇ -aminoacyl-a-aminoacyl wherein said a-aminoacyl moieties are independently any of the naturally occurring L-amino acids found in proteins, P(0)(OH) 2
  • heterocyclic include non- aromatic, ring systems, including, but not limited to, monocyclic, bicyclic, tricyclic and spirocyclic rings, which can be completely saturated or which can contain one or more units of unsaturation, for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system) and have 5 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur.
  • heterocyclic rings azepinyl, azetidinyl, indolinyl, isoindolinyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, quinucludinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydroindolyl, thiomorpholinyl and tropanyl.
  • heteroaryl or “heteroarylene” as used herein, include aromatic ring systems, including, but not limited to, monocyclic, bicyclic and tricyclic rings, and have 5 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur.
  • azaindolyl benzo(6)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3- i ]pyrimidinyl, pyrazolo[3,4-i/]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl,
  • alkyl As used herein, “alkyl,” “alkylene” or notations such as “(C C 8 )” include straight chained or branched hydrocarbons which are completely saturated. Examples of alkyls are methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and isomers thereof.
  • alkenyl As used herein, “alkenyl,” “alkenylene,” “alkynylene” and “alkynyl” means C 2 -C 8 and includes straight chained or branched hydrocarbons which contain one or more units of unsaturation, one or more double bonds for alkenyl and one or more triple bonds for alkynyl.
  • aromatic groups include aromatic carbocyclic ring systems (e.g. phenyl) and fused polycyclic aromatic ring systems (e.g. naphthyl, biphenyl and 1,2,3,4-tetrahydronaphthyl).
  • cycloalkyl or “cycloalkylene” means C 3 -Ci 2 monocyclic or multicyclic (e.g., bicyclic, tricyclic, spirocyclic, etc.) hydrocarbons that is completely saturated.
  • Examples of a cycloalkyl group are cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[l.l.l]pentyl, and cyclohexyl.
  • cycloalkenyl means C 3 -C 12 monocyclic or multicyclic (e.g., bicyclic, tricyclic, spirocyclic, etc.) hydrocarbons that has one or more unsaturated bonds but does not amount to an aromatic group.
  • Examples of a cycloalklenyl group are cyclopentenyl and cyclohexenyl.
  • kit refers to a packaged product comprising components with which to administer a compound of Formula (I) of the invention for treatment of an autoimmune disorder.
  • the kit preferably comprises a box or container that holds the components of the kit.
  • the box or container is affixed with a label or a Food and Drug Administration approved protocol.
  • the box or container holds components of the invention which are preferably contained within plastic, polyethylene, polypropylene, ethylene, or propylene vessels.
  • the vessels can be capped-tubes or bottles.
  • the kit can also include instructions for administering a compound of Formula (I).
  • One or more compounds of this invention can be administered to a human patient by themselves or in pharmaceutical compositions where they are mixed with biologically suitable carriers or excipient(s) at doses to treat or ameliorate a disease or condition as described herein. Mixtures of these compounds can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions.
  • a therapeutically effective dose refers to that amount of the compound or compounds sufficient to result in the prevention or attenuation of a disease or condition as described herein.
  • Suitable routes of administration may, for example, include oral, eyedrop, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
  • compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for use in accordance with the present invention thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture With filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds can be formulated for parenteral administration by injection, e.g. bolus injection or continuous infusion.
  • Formulations for injection may be presented in ⁇ dosage form, e.g. in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation.
  • Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly or by intramuscular injection).
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • An example of a pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the cosolvent system may be the VPD co-solvent system.
  • VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD co-solvent system (VPD:5W) consists of VPD diluted 1:1 with a 5% dextrose in water solution.
  • This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • identity of the co-solvent components may be varied: for example, other low -toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethysulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • compositions also may comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • salts may be provided as salts with pharmaceutically compatible counter ions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms.
  • compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated. Determination of the effective amounts is well within the capability of those skilled in the art.
  • the therapeutically effective dose can be estimated initially from cellular assays.
  • a dose can be formulated in cellular and animal models to achieve a circulating concentration range that includes the IC 50 as determined in cellular assays (e.g., the concentration of the test compound which achieves a half-maximal inhibition of a given protein kinase activity).
  • IC 50 as determined in cellular assays
  • serum albumin Such information can be used to more accurately determine useful doses in humans.
  • the most preferred compounds for systemic administration effectively inhibit protein kinase signaling in intact cells at levels that are safely achievable in plasma.
  • a therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms in a patient.
  • Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) and the ED 50 (effective dose for 50% maximal response).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between MTD and ED 50 .
  • Compounds which exhibit high therapeutic indices are preferred.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition (see, e.g., Fingl et al., 1975, in The Pharmacological Basis of Therapeutics, Ch. 1, p. 1).
  • the administration of an acute bolus or an infusion approaching the MTD may be required to obtain a rapid response.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the kinase modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data; e.g. the concentration necessary to achieve 50-90% inhibition of protein kinase using the assays described herein. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using the MEC value.
  • Compounds should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90% until the desired amelioration of symptoms is achieved.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labelled for treatment of an indicated condition.
  • the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
  • active compound denotes any compound of the invention but particularly any compound which is the final product of one of the following Examples.
  • capsules 10 parts by weight of active compound and 240 parts by weight of lactose can be de-aggregated and blended. The mixture can be filled into hard gelatin capsules, each capsule containing a unit dose or part of a unit dose of active compound.
  • Tablets can be prepared, for example, from the following ingredients.
  • the active compound, the lactose and some of the starch can be de-aggregated, blended and the resulting mixture can be granulated with a solution of the polyvinylpyrrolidone in ethanol.
  • the dry granulate can be blended with the magnesium stearate and the rest of the starch.
  • the mixture is then compressed in a tabletting machine to give tablets each containing a unit dose or a part of a unit dose of active compound.
  • Tablets can be prepared by the method described in (b) above.
  • the tablets can be enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanolrdichloromethane (1:1).
  • suppositories for example, 100 parts by weight of active compound can be incorporated in 1300 parts by weight of triglyceride suppository base and the mixture formed into suppositories each containing a therapeutically effective amount of active ingredient.
  • the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.
  • the compounds of this invention can be administered in combination with another therapeutic agent that is known to treat a disease or condition described herein.
  • the compounds of the invention can be administered prior to, subsequent to or simultaneously with the additional pharmaceutical agent, whichever course of administration is appropriate.
  • the additional pharmaceutical agents include, but are not limited to, anti-edemic steroids, NSAIDS, ras inhibitors, anti-ILl agents, antihistamines, PAF-antagonists, COX- 1 inhibitors, COX-2 inhibitors, NO synthase inhibitors, Akt PTB inhibitors, IGF-1R inhibitors, PKC inhibitors, PI3 kinase inhibitors, calcineurin inhibitors and immunosuppressants.
  • the compounds of the invention and the additional pharmaceutical agents act either additively or synergistically.
  • the present invention also comprises the use of a compound of Formula (I) as a medicament.
  • the present invention also provides a method of treating rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, ankylosing spondylitis, reactive arthritis, arthritis associated with inflammatory bowel disease, undifferentiated spondyloarthritis, systemic lupus erythematosus, lupus nephritis, uveitis, atopic dermatitis, multiple sclerosis, axial spondyloarthritides or hidraenitis suppurativa and/or other disorders of the immune system which comprises the administration of a therapeutically effective amount of a compound of Formula (I) to a mammal, particularly a human being, in need thereof.
  • Scheme X General methods for preparing 2,4-dichloro-3-((l-methyl-lH-pyrrolo[2,3-6]pyridin-2- yl)methyl)benzamide compounds of the invention are illustrated in Scheme X, and are further described in Examples CL and CM :
  • Scheme XIV General methods for preparing 2,4-dichloro-3-((l-methyl-3,4-dihydroisoquinolin- 2(lH)-yl)methyl)benzamide compounds of the invention are illustrated in Scheme XIV, and are further
  • Scheme XXIV General methods for preparing 2,4-dichloro-3-(lH-indol-l-yl)methyl) benzamide compounds of the invention are illustrated in Scheme XXIV, and further described in Examples J, DH, DI, DJ, DK, DL, DM and DN:
  • UV detection DAD 210-260 nm. MS detection (ESI positive and negative).
  • UV detection DAD 210-260 nm. MS detection (ESI positive and negative).
  • Detection methods are diode array (DAD) and
  • ELSD evaporative light scattering
  • Step B methyl 3-(bromomethyl)-2,4-dichlorobenzoate:
  • Step D methyl 2,4-dichloro-3-(l-hydroxyprop-2-yn-l-yl)benzoate
  • Step B methyl 2,4-dichloro-3-(2-oxoeth l)benzoate
  • Step B 2,6-dichloro-3-(morphoIine-4-carbon l)benzaldehyde
  • Step C (2,4-dichloro-3-(l-hydroxypro -2-yn-l-yI)phenyl)(morpholino)methanone:
  • Dimethoxyethane was evaporated and the residue was diluted with water and washed with ethyl acetate.
  • the aqueous layer was acidified by IN HC1 solution (pH 1) and extracted with dichloromethane, dried over magnesium sulfate and concentrated under reduced pressure to give 3- formyl-2,4-dimethylbenzoic acid (150 mg, 69%) as a white powder.
  • Step D (3-(l-hydroxyprop-2-yn-l-yI)- morpholino)methanone:
  • methyl 3,5-dichloro-4-(l- hydroxyprop-2-yn-l-yl)benzoate (1 g, 60%) was prepared from methyl 3,5-dichloro-4-formylbenzoate (described in WO2013/149997) (1.5 g, 6.44 mmol).
  • Step D 2-(2,6-dichloro-3-(morpholine-4-carbonyI)phenyl)acetic acid
  • Step B 2-(3-(methoxycarbonyl)-2,6-dimethylphenyl)acetic acid
  • Step B (2,4-dichloro-3-(hydroxymeth l)phenyl)(morpholino)methanone
  • Step C (2,4-dichloro-3-(chlorometh I)phenyI)(morphoIino)methanone
  • Step B methyl 2,4-dichloro-3-(2-oxobutyl)benzoate
  • Step C methyl 3-(3-bromo-2-oxobutyl)-2,4-dichlorobenzoate
  • Step B l-(3,5-dichloro-2-methoxypyridin-4- l)prop-2-yn-l-ol
  • Step B ⁇ -( -iodo-S-methyl-S-itrifluoromethy ⁇ phenylJbenzenesulfonamide
  • N-(2-iodo-4-methyl-5- (trifluoromethyl)phenyl)benzenesulfonamide (3 g, 100%) was prepared from 2-iodo-4-methyl-5- (trifluoromethyl)aniline (described in WO2006/002342) (2 g, 6.64 mmol).
  • Step D ⁇ -(S-cyano-l-iodo-S-methylphenylJbenzenesulfonainide
  • N-(5-cyano-2-iodo-3- methylphenyl)benzenesulfonamide 9.43 g, 91%) was obtained as an orange solid from 3-amino-4- iodo-5-methylbenzonitrile (6.7 g, 26 mmol).
  • LC/MS (Method k) R, 2.68 min.; MS m/z: 397 [M-H] ⁇ .
  • N-(4-cyano-2- iodophenyl)benzenesulfonamide (3.7 g, 100%) was obtained as an orange solid from 4-amino-3- iodobenzonitrile (2 g, 8.20 mmol).
  • LC/MS (Method h) R, 2.41 min.; MS m/z: 383 [M-H] "
  • Step A A r -(2-methyl-4-(trifluoromethyl)phenyl)acetamide
  • Acetic anhydride (8.08 niL, 86 mmol) was added to 2-methyl-4-(trifluoromethyl)aniline (5 g, 28.5 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for 20 minutes. The solid formed was crushed with mortar, put in suspension in water and neutralized with ammonia. The precipitate was filtered and dry under vacuum to give N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide (5.91 g, 95%) as a beige solid.
  • Step B 7V-(2-methyl-6-nitro-4-(trifluoromethyl)phenyl)acetamide
  • N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide 5.9 g, 27.2 mmol
  • sulfuric acid 20 mL, 375 mmol
  • nitric acid dropwise 20 mL, 448 mmol
  • the reaction mixture was stirred at 0°C for 2 hours and at room temperature overnight.
  • the reaction mixture was diluted in water and extracted with ethyl acetate. The layers were separated and the organic layer was washed with NaHC0 3 saturated aqueous solution and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give N-(2-methyl-6-nitro-4-(trifluoromethyl)phenyl)acetamide (6.6 g, 93%).
  • Step E ethyl (2-amino-3-methyl-5-(trifluoromethyI)phenyl)carbamate
  • Step F A'-ljSjS-trimethylbenzene-lj -diamine
  • 6-chloro-N2,4- dimethylpyridine-2,3 -diamine (90 mg, 51%) was prepared from 6-chloro-N,4-dimethyl-3-nitropyridin- 2-amine (200 mg, 0.992 mmol).
  • LC/MS (Method h) R, 1.40 min.; MS m/z: 172 [M+H] + .
  • Step B ⁇ -( -bromo-S-itrifluoromethylJpyridin-S-y benzenesulfonamide
  • N-(2-bromo-5- (trifluoromethyl)pyridin-3-yl)benzenesulfonamide 954 m g, 50%
  • 2-bromo-5- (trifluoromethyl)pyridin-3 -amine 1.2 g, 4.98 mmol
  • LC/MS (Method h) R, 2.52 min.; MS m/r. 381 [M+H] + .
  • N-(5-iodo-2- (trifluoromethyl)pyridin-4-yl)benzenesulfonamide (13.32 g, 52%) was prepared from 5-iodo-2- (trifluoromethyl)pyridin-4-amine (described in WO2010/091310) (17.3 g, 60.1 mmol)
  • LC/MS (Method h) R t 2.57 min.; MS m/z: 429 [M+H] + .
  • Step B l-fluoro-3-methyI-2-nitro-4-(trifluoromethyI)benzene
  • Step D 7Vl,3-dimethyl-4-(trifluoromethyl)benzene-l,2-diamine
  • Step A 4-bromo-A r ,3-dimethyl-2-nitroaniline
  • reaction mixture was partitioned between diethyl ether and IN HC1 solution.
  • the aqueous layer was extracted with diethyl ether, the organic layer was dried over magnesium sulfate, and concentrated.
  • the residue was purified by column chromatography on silica gel (eluting with 5-10% ethyl acetate in cyclohexane) to give tert-butyl 2,4-dichloro-3-formylbenzoate (10.6g, 71%) as a yellow oil.
  • Step C tert-butyl 2,4-dichloro-3-(l-h droxyprop-2-yn-l-yI)benzoate
  • N-(2-iodo-6-mefhyl-4- (trifluoromethyl)phenyl)benzenesulfonamide (2.73 g, 32%) was prepared from 2-iodo-6-methyl-4- (trifluoromethyl)aniline (5.8 g, 19.3 mmol).
  • Step B 5-bromo-2-iodo-3-methylaniIine r
  • N-(5-bromo-2-iodo-3- methylphenyl)benzenesulfonamide (2.21 g, 95%) was prepared from 5-bromo-2-iodo-3-methylaniline (1.6 g, 5.13 mmol).
  • LC/MS (Method h) R t 2.94 min.; MS m/z: 450 [M-H] ⁇
  • Step A 5-bromo-4,6-dimethyl-2-oxo-l ,2-dihydropyridine-3-carbonitriIe
  • Step B 5-bromo-2-chloro-4,6-dimethyInicotinonitrile
  • Step E methyl 5-bromo-4,6-dimethylnicotinate
  • Step F methyl 4,6-dimethy
  • Methyl 5-bromo-4,6-dimethylnicotinate (15g, 61.5 mmol), 4,4,5,5-tetramethyl-2-vinyl-l,3,2- dioxaborolane (14.2 g, 92 mmol), Pd(PPh 3 ) 4 (7.1 g, 6.1 mmol), and KF (5.4 g, 92 mmol) were combined in DMF (20 mL) The mixture was heated to about 100 °C for about 16 h. The mixture was cooled to rt and the solvent was concentrated in vacuo.
  • Step H methyl 5-(l-hydroxyprop-2-yn-l-yl)-4,6-dimethylnicotinate
  • Step C ethyl 3,5-dichloro-4-(diethoxymethyI)picolinate
  • Step D ethyl 3,5-dichloro-4-formylpicolinate
  • Step E ethyl 3,5-dichloro-4-(l-hydroxyprop-2-yn-l-yl)picolinate
  • Step A ethyl 4,6-dichloronicotinate
  • Step B ethyl 4,6-dichloro-5-form lnicotinate
  • Step C ethyl 4,6-dichloro-5-(l-hydroxyprop-2-yn-l-yl)nicotinate
  • methyl-6- (trifluoromethyl)pyridin-4-amine (409 mg, 42%) was prepared from 2-methyl-4-nitro-6- (trifluoromethyl)pyridine (1.05 g, 5.09 mmol).
  • LC/MS (Method k) R t 2.15 min.; MS m/r. Ill [M+H] + .
  • Step D 7V-(3-iodo-2-methyl-6-(trifluoromethyl)pyridin-4-yl)benzenesulfonamide
  • N-(3-iodo-2-methyl-6- (trifluoromethyl)pyridin-4-yl)benzenesulfonamide (414 mg, 33%) was prepared from 3-iodo-2- methyl-6-(trifluoromethyl)pyridin-4-amine (740 mg, 2.45 mmol).
  • LC/MS (Method i) R t 2.24 min.; MS m/r. 443 [M+H] + .
  • Step B 7V-(6-cyano-3-iodo-2-methylpyridin-4-yl)benzenesulfonamide
  • N-(6-cyano-3-iodo-2- methylpyridin-4-yl)benzenesulfonamide 400 mg, 23%) was prepared from 4-amino-5-iodo-6- methylpicolinonitrile (1.15 g, 4.44 mmol). The compound was used directly in the next step.
  • Step A 4-bromo-6-(trifluoromethyl)pyridazin-3-amine
  • Step B 4-methyl-6-(trifluoromethyl)pyridazin-3-amine
  • the obtained aqueous layer was extracted with ethyl acetate and the obtained organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The same procedure was done three times with the obtained residue to increase conversion.
  • the residue was purified by column chromatography on silica gel (eluting with 7-60% ethyl acetate in cyclohexane) to give 4-methyl-6-(trifluoromethyl)pyridazin-3- amine (318 mg, 94%) as a beige solid.
  • Step B l-(2-fluoro-3-methyl-5-(trifluoromethyl)phenyI)ethanol
  • Step C l-(2-fluoro-3-methyl-5-(trifluoromethyl)phenyl)ethanone
  • Step A /V-allyl-2-iodo-6-methyI-4-(trifluoromethyl)aniline
  • More potassium carbonate (0.8eq), tetrabutylammonium bromide (0.05eq), potassium hydroxide (0.5eq) and allyl bromide (0.6eq) were then added.
  • the reaction mixture was stirred at 65°C for 18 hours.
  • More potassium carbonate (0.8eq), tetrabutylammonium bromide (0.05eq), potassium hydroxide (0.5eq) and allyl bromide (0.6eq) were then added.
  • the reaction mixture was stirred at 65°C for 18 hours. More potassium carbonate (0.8eq), tetrabutylammonium bromide (0.05eq), potassium hydroxide (0.5eq) and allyl bromide (0.6eq) were then added.
  • the reaction mixture was stirred at 65°C for 18 hours.
  • the aqueous layer was extracted with ethyl acetate.
  • the organic layer was washed with water, brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure.
  • Step A 3-(tert-butoxycarbonyl)-2,6-dichlorobenzoic acid
  • Step B tert-butyl 2,4-dichloro-3-(chIorocarbonyl)benzoate
  • N-(2-iodo-3-methyl-5- (trifluoromethoxy)phenyl)benzenesulfonamide (1.98 g, 100%) was prepared from 2-iodo-3-methyl-5- (trifluoromethoxy)aniline (1.36 g, 4.29 mmol).
  • Step A N-(2-methyl-4-(trifluorometh I)-6-((trimethylsilyl)ethynyl)phenyl)benzenesulfonamide
  • N-(2-iodo-6-methyl-4-(trifluoromethyl)phenyl)benzenesulfonamide (Preparation #34) (400 mg, 0.907 mmol) in tetrahydrofuran (4.5 ml) were added bis(triphenylphosphine)palladium dichloride (31.8 mg, 0.045 mmol), copper(I) iodide (17.27 mg, 0.091 mmol), trimethylsilylacetylene (351 ⁇ , 2.54 mmol) and triethylamine (4.5 ml). The reaction mixture was stirred at 65°C under microwaves for 1.5 hours. The reaction mixture was filtered, rinced with ethyl acetate and the filtrate was evaporated to give N-(2-methyl-4-(trifluoromethyl)-6-
  • Step B N-(2-ethynyl-6-methyl-4-(trifluorometh l)phenyl)benzenesulfonamide
  • Step C 7-methyI-l-(phenylsulfonyl)-5-(trifluoromethyl)-lH-indoIe
  • Step A (E)-ethyl 4-(2-ethoxy-2-oxoethylidene)-3-methylpiperidine-l-carboxylate
  • Step B ethyl 4-(2-ethoxy-2-oxoethyl)-3-methylpiperidine-l-carboxylate
  • Step D methyl 2-(3-methylpiperidin-4-yI)acetate hydrochloride
  • Step A N-(3-methyl-5-(trifluoromethyl)-2-((trimethylsilyI)ethynyl)phenyI)beiizenesulfonamide
  • Step B 4-methyl-l-(phenyIsulfonyl)-6-(trifluoromethyl)-lH-indole
  • Step D 4-methyI-6-(trifluoromethyl)-lH-indole-3-carbaldehyde
  • Step E l,4-dimethyI-6-(trifluoromethyl)-lH-indoIe-3-carbaldehyde
  • Example A (2,4-dichloro-3-((l,4-dimethyl-6-(trifluoromethyl)-lH-indol-2-yi)methyl)phenyl)(4- (2-methoxyethyl)piperazin-l-yI)methanone
  • Step 1 methyl 2,4-dichIoro-3-(hydroxy(4-methyl-l-(phenylsulfonyl)-6-(trifluoromethyl)-lH- indol-2-yl)methyl)benzoate
  • Step 2 methyl 2,4-dichloro-3-((4-methyl-l-(phenyIsuIfonyI)-6-(trifluoromethyI)-lH-indol-2- yl)methyl)benzoate
  • Step 4 methyl 2,4-dichloro-3-((l,4-dimethyl-6-(trifluoromethyl)-lH-indol-2-yI)methyl)benzoate
  • Step 5 2,4-dichloro-3-((l,4-dimethyI-6-(trifluoromethyl)-lH-indol-2-yl)methyI)benzoic acid
  • Step 6 (2,4-dichloro-3-((l,4-dimethyl-6-(trifluoromethyl)-lH-indol-2-yI)methyl)phenyl)(4-(2- methoxyethyl)piperazin-l-yl)methanone
  • Example B l-(2,4-dichloro-3-((l,4-dimethyl-6-(trifluoromethyl)-lH-indol-2- yl)methyl)benzoyl)piperidine-4-carboxylic acid
  • Example B.2 (3S,4S)-l-(2,4-dichloro-3-((l,4-dimethyl-6-(trifluoromethyl)-lH-indol-2- yl)methyl)benzoyI)-3-methylpiperidine-4-carboxylic acid and (3R,4R)-l-(2,4-dichloro-3-((l,4- dimethyl-6-(trifluoromethyl)-lH-indol-2-yI)methyl)benzoyl)-3-methylpiperidine-4-carboxylic acid
  • Example C (2,4-dichloro-3-((4-methyl-6-(trifluoromethyI)-lH-indol-2- yI)methyl)phenyl)(niorpholino)methanone
  • Step 1 (2,4-dichIoro-3-(hydroxy(4-methyl-l-(phenylsulfonyI)-6-(trifluoromethyl)-lH-indol-2- yl)methyl)phenyl)(niorpholino)methanone
  • Step 1 (2,4-dichloro-3-(hydroxy(4- methyl-l-(phenylsulfonyl)-6-(trifluoromethyl)-lH-indol-2-yl)methyl)phenyl)(mo ⁇ holino)methanone (3.7 g, 87%) was prepared from N-(2-iodo-3-methyl-5-(trifluoromethyl)phenyl)benzenesulfonamide (Preparation #16) (3 g, 6.80 mmol) and (2,4-dichloro-3-(l-hydroxyprop-2-yn-l- yl)phenyl)(mo holino)methanone (2.78 g, 8.84 mmol) (Preparation #3).
  • LC/MS (Method k) R t 3.10 min.; MS m/z: 627[M+H] + .
  • Step 3 (2,4-dichloro-3-((4-methyl-6-(trifluoromethyI)-lH-indol-2- yl)methyl)phenyl)(morpholino)methanone
  • Step 3 (2,4-dichloro-3-((4-methyl-6- (trifluoromethyl)-lH-indol-2-yl)methyl)phenyl)(mo holino)methanone (130 mg, 59%) was prepared from (2,4-dichloro-3-((4-methyl-l-(phenylsulfonyl)-6-(trifluoromethyl)-lH-indol-2- yl)methyl)phenyl)(mo ⁇ holino)methanone (286 mg, 0.468 mmol).
  • Example D (2,4-dichIoro-3-((l,4-dimethyl-6-(trifluoromethyI)-lH-indol-2- yI)methyI)phenyl)(morphoIino)methanone
  • Step 1 (2,4-dichloro-3-(hydroxy(l-(phenylsulfonyI)-6-(trifluoromethyl)-lH-indol-2- yI)methyl)phenyl)(morpholino)methanone :
  • Step 1 (2,4-dichloro-3-(hydroxy(l- (phenylsulfonyl)-6-(trifluoromethyl)- lH-mdol-2-yl)methyl)phenyl)(mo holino)methanone (491 mg, 81%) was prepared from N-(2-iodo-5-(trifluoromethyl)phenyl)benzenesulfonamide (420 mg, 0.983 mmol) (Preparation #29) and (2,4-dichloro-3-(l-hydroxyprop-2-yn-l- yl)phenyl)(mo holino)methanone (402 mg, 1.28 mmol) (Preparation #3).
  • Step 2 (2,4-dichloro-3-((l-(phenylsulfonyl)-6-(trifluoromethyI)-lH-indol-2- yl)methyI)phenyl)(niorphoIino)methanone
  • Step 3 (2,4-dichIoro-3-((6-(trifluoromethyl)-lH-indol-2- yl)methyI)phenyl)(morpholino)methanone
  • Step 4 (2,4-dichloro-3-((l-methyl-6-(trifluoromethyl)-lH-indol-2- yl)methyl)phenyl)(morpholino)methanone
  • Example F 2-(l-(2,4-dichloro-3-((l,4-dimethyl-6-(trifluoromethyl)-lH-indol-3- yl)methyI)benzoyl)piperidin-4-yl)acetic acid
  • Step 1 tert-butyl 2,4-dichloro-3-((l,4-dimethyl-6-(trifluoromethyl)-lH-indol-3- yl)(hydroxy)methyl)benzoate
  • Step 3 methyl 2-(l-(2,4-dichloro-3-((l,4-dimethyI-6-(trifluoromethyl)-lH-indol-3- yl)methyl)benzoyl)piperidin-4-yI)acetate
  • Step 4 2-(l-(2,4-dichIoro-3-((l,4-dimethyl-6-(trifluoromethyl)-lH-indol-3- yl)methyl)benzoyl)piperidin-4-yl)acetic acid
  • Step 1 (3-(hydroxy(4-methyl-l-(phenylsulfonyI)-6-(trifluoromethyI)-lH-indol-2-yI)methyl)-2,4- dimethylphenyl)(morpholino)methanone
  • Step 1 (3-(hydroxy(4-methyl-l- (phenylsulfonyl)-6-(trifluoromethyl)-lH-indol-2-yl)methyl)-2,4- dimethylphenyl)(morpholino)methanone (374mg, 94%) was prepared from N-(2-iodo-3-methyl-5- (trifluoromethyl)phenyl)benzenesulfonamide (Preparation #16) (300 mg, 0.680 mmol) and (3-(l- hydroxyprop-2-yn-l-yl)-2,4-dimethylphenyl)(morpholino)methanone (223 mg, 0.816 mmol) (Preparation #4).
  • Step 2 (2,4-dimethyI-3-((4-methyl-l-(phenyIsulfonyl)-6-(trifluoromethyl)-lH-indol-2- yl)methyl)phenyl)(morpholino)methanone
  • Step 2 (2,4-dimethyl-3-((4-methyl-l- (phenylsulfonyl)-6-(trifluoromethyl)-lH-indol-2-yl)methyl)phenyl)(mo holino)methanone (346 mg, 95%) was prepared from (3-(hydroxy(4-methyl-l-(phenylsulfonyl)-6-(trifluoromethyl)-lH-indol-2- yl)methyl)-2,4-dimethylphenyl)(mo ⁇ holino)methanone (374 mg, 0.638 mmol).
  • Step 3 (2,4-dimethyI-3-((4-methyl-6-(trifluoromethyI)-lH-indol-2- yl)methyl)phenyl)(morpholino)methanone
  • Step 3 (2,4-dimethyl-3-((4-methyl-6- (trifluoromethyl)-lH-indol-2-yl)methyl)phenyl)(mo ⁇ holino)methanone (198 mg, 76%) was prepared from (2,4-dimethyl-3-((4-methyl-l-(phenylsulfonyl)-6-(trifluoromethyl)-lH-indol-2- yl)methyl)phenyl)(mo ⁇ holino)methanone (346 mg, 0.606 mmol).
  • Step 4 (3-((l,4-dimethyl-6-(trifluoromethyl)-lH-indol-2-yl)methyl)-2,4- dimethylphenyI)(morpholino)methanone and (2,6-dimethyl-3-(morpholine-4- carbonyI)phenyI)(l,4-dimethyl-6-(trifluoromethyl)-lH-indol-2-yI)methanone:
  • Step 4 (3-((l,4-dimethyl-6- (trifluoromethyl)-lH-indol-2-yl)methyl)-2,4-dimethylphenyl)(mo ⁇ holino)methanone (30 mg, 19%) was prepared from (2,4-dimethyl-3-((4-methyl-6-(trifluoromethyl)-lH-indol-2- yl)methyl) henyl)(mo ⁇ holino)metha one (154 mg, 0.358 mmol).
  • LC/MS (Method g) R t 1.87 min.; MS m/z: 445[ ⁇ + ⁇ ] + .
  • Step 1 2,4-dichloro-3-((4-methyl-l-(phenyIsulfonyl)-6-(trifluoromethyl)-lH-indol-2- yI)methyI)benzoic acid

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Abstract

L'invention concerne des composés de formule (I), des sels, pro-médicaments, métabolites biologiquement actifs, stéréoisomères et isomères pharmaceutiquement acceptables de ceux-ci, les variables de la formule (I) étant définies dans la description. Les composés de l'invention sont utilisés pour traiter des troubles immunologiques.
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SI201630618T SI3307734T1 (sl) 2015-06-09 2016-06-08 Modulatorji jedrnega receptorja (ROR) za zdravljenje vnetnih in avtoimunih bolezni
CR20170594A CR20170594A (es) 2015-06-09 2016-06-08 Moduladores de receptor nuclear
LTEP16731721.3T LT3307734T (lt) 2015-06-09 2016-06-08 Branduolinio receptoriaus moduliatoriai (ror), skirti uždegiminių ir autoimuninių ligų gydymui
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DK16731721.3T DK3307734T3 (da) 2015-06-09 2016-06-08 Nukleære receptormodulatorer (ror) til behandling af inflammatoriske og autoimmune sygdomme
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CN116283753A (zh) * 2023-03-20 2023-06-23 武汉朗克环境科技有限公司 一种三氟甲基吡啶酰胺衍生物及其制备方法和应用
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
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