US20160304496A1 - Indazolones as modulators of tnf signaling - Google Patents

Indazolones as modulators of tnf signaling Download PDF

Info

Publication number
US20160304496A1
US20160304496A1 US15/130,279 US201615130279A US2016304496A1 US 20160304496 A1 US20160304496 A1 US 20160304496A1 US 201615130279 A US201615130279 A US 201615130279A US 2016304496 A1 US2016304496 A1 US 2016304496A1
Authority
US
United States
Prior art keywords
methyl
indazol
pyrimidin
difluoromethoxy
benzyl
Prior art date
Legal status (The legal status 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 status listed.)
Abandoned
Application number
US15/130,279
Other languages
English (en)
Inventor
Maria Argiriadi
Eric Breinlinger
Justin D. Dietrich
Michael Friedman
David Ihle
Michael Morytko
Kelly Mullen
Augustine Osuma
Glora Y. Lo Schiavo
Noel S. Wilson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AbbVie Inc
Original Assignee
AbbVie Inc
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 AbbVie Inc filed Critical AbbVie Inc
Priority to US15/130,279 priority Critical patent/US20160304496A1/en
Publication of US20160304496A1 publication Critical patent/US20160304496A1/en
Assigned to ABBVIE, INC. reassignment ABBVIE, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MULLEN, KELLY D., DIETRICH, Justin D., OSUMA, AUGUSTINE, WILSON, NOEL S., ARGIRIADI, MARIA A., BREINLINGER, ERIC C., FRIEDMAN, MICHAEL M., IHLE, DAVID C., LO SHIAVO, GLORIA Y., MORYTKO, MICHAEL
Priority to US15/670,708 priority patent/US10160748B2/en
Assigned to ABBVIE INC. reassignment ABBVIE INC. CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE NAME PREVIOUSLY RECORDED ON REEL 040183 FRAME 0929. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Assignors: MULLEN, KELLY D., DIETRICH, Justin D., OSUMA, AUGUSTINE, WILSON, NOEL S., ARGIRIADI, MARIA A., BREINLINGER, ERIC C., FRIEDMAN, MICHAEL M., IHLE, DAVID C., LO SHIAVO, GLORIA Y., MORYTKO, MICHAEL
Abandoned legal-status Critical Current

Links

Classifications

    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • the present disclosure relates to a class of indazolone derivatives, and to their use in therapy. More particularly, this disclosure is concerned with pharmacologically active substituted indazolone derivatives. These compounds are modulators of the signaling of TNF ⁇ , and are accordingly of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory and autoimmune disorders, neurological and neurodegenerative disorders, pain and nociceptive disorders, cardiovascular disorders, metabolic disorders, ocular disorders, and oncological disorders.
  • TNF ⁇ is the prototypical member of the Tumor Necrosis Factor (TNF) superfamily of proteins that share a primary function of regulating cell survival and cell death.
  • TNF Tumor Necrosis Factor
  • One structural feature common to all known members of the TNF superfamily is the formation of trimeric complexes that bind to, and activate, specific TNF superfamily receptors.
  • TNF ⁇ exists in soluble and transmembrane forms and signals through two receptors, known as TNFR1 and TNFR2, with distinct functional endpoints.
  • TNF ⁇ inhibitors include anti-TNF ⁇ antibodies and soluble TNF ⁇ receptor fusion proteins.
  • anti-TNF ⁇ antibodies examples include fully human antibodies such as adalimumab (Humira®) and golimumab (Simponi®), chimeric antibodies such as infliximab (Remicade®), and pegylated Fab′ fragments such as certulizumab pegol (Cimzia®).
  • An example of a commercially available soluble TNF ⁇ receptor fusion protein is etanercept (Enbrel®).
  • TNF superfamily members including TNF ⁇ itself, are implicated in a variety of physiological and pathological functions that are believed to play a part in a range of conditions of significant medical importance (see, for example, M. G. Tansey & D. E. Szymkowski, Drug Discovery Today, 2009, 14, 1082-1088; and F. S. Carneiro et al., J. sexual Medicine, 2010, 7, 3823-3834).
  • the compounds in accordance with the present disclosure may be beneficial in the treatment and/or prevention of various human ailments. These include autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.
  • the compounds in accordance with the present disclosure may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • the compounds of this disclosure may be useful as radioligands in assays for detecting pharmacologically active compounds.
  • certain compounds of this disclosure may be useful for coupling to a fluorophore to provide fluorescent conjugates that can be utilized in assays (e.g., a fluorescence polarization assay) for detecting pharmacologically active compounds.
  • the compounds in accordance with the present disclosure potently neutralize the activity of TNF ⁇ using the TNF ⁇ fluorescence polarization competitive binding assay.
  • the compounds of the present disclosure exhibit an IC 50 value of 50 ⁇ M or less, generally of 10 ⁇ M or less, usually of 5 ⁇ M or less, typically of 1 ⁇ M or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (the skilled person will appreciate that a lower IC 50 figure denotes a more active compound).
  • the present disclosure provides a compound of Formula (I),
  • X, Y and Z are independently CR 4 or N;
  • L is a bond, optionally substituted (C 1 -C 3 )alkylene or —C(O)—;
  • R 1 is H, CD 3 , optionally substituted (C 1 -C 3 )alkyl, optionally substituted (C 3 -C 6 )cycloalkyl, —(CH 2 ) q -optionally substituted (C 3 -C 6 )aryl, or —(CH 2 ) q -optionally substituted (C 3 -C 6 )heteroaryl;
  • R 2 is optionally substituted aryl or optionally substituted heteroaryl
  • R 3 is —R 3a -R 3b , wherein:
  • R 4 is independently H, Cl, CN, F, CF 3 methoxy, or optionally substituted (C 1 -C 3 )alkyl;
  • n 0 or 1
  • p 0, 1 or 2;
  • q 0 or 1.
  • the disclosure provides a compound according to the first embodiment wherein the compound is a compound of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id) or Formula (Ie)
  • the disclosure provides a compound according to any of the foregoing embodiments wherein R 1 is optionally substituted (C1-C3)alkyl or optionally substituted cyclopropyl.
  • the disclosure provides a compound according to any of the foregoing embodiments wherein R 2 is optionally substituted heteroaryl, or optionally substituted phenyl.
  • the disclosure provides a compound according to any of the foregoing embodiments wherein R 3a is optionally substituted 1,2,4-oxadiazolyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substituted 1,2,4-thiadiazolyl.
  • the disclosure provides a compound according to any of the foregoing embodiments wherein R 3b is —N(R a )(R b ), —O(R a ), optionally substituted (C 1 -C 3 )alkyl, —(CH 2 ) p -optionally substituted 2-oxa-6-azaspiro[3.3]heptanyl, —(CH 2 ) p -optionally substituted 2-azaspiro[3.3]heptanyl, —(CH 2 ) p -optionally substituted 5-azaspiro[2.3]hexanyl, —(CH 2 ) p -optionally substituted azetidinyl, —(CH 2 ) p -optionally substituted morpholinyl, —(CH 2 ) p -optionally substituted oxetanyl, —(CH 2 ) p -optionally substituted piperazinyl, —(CH 2 )
  • the disclosure provides a compound according to any of the foregoing embodiments wherein L is a bond or optionally substituted (C 1 -C 2 )alkylene.
  • the disclosure provides a compound according to any of the foregoing embodiments wherein R 2 is phenyl, pyridinyl or pyrimidinyl, and R 2 is optionally substituted by one or more substituents independently selected from halogen, CN, haloalkoxy, CF 3 , or optionally substituted (C 1 -C 3 )alkyl.
  • the disclosure provides a compound according to any of the foregoing embodiments wherein R 3b is —N(H)CH 2 -optionally substituted pyrrolidinyl, —O(R a ), —N(H)-optionally substituted oxetanyl, optionally substituted (C 1 -C 3 )alkyl, optionally substituted 2-oxa-6-azaspiro[3.3]heptanyl, optionally substituted 5-azaspiro[2.3]hexanyl, optionally substituted azetidinyl, optionally substituted morpholinyl, —(CH 2 ) p -optionally substituted oxetanyl, optionally substituted piperazinyl, optionally substituted piperidinyl, —(CH 2 ) p -optionally substituted pyrrolidinyl, or optionally substituted tetrahydropyranyl; wherein R a is selected from H, optionally substituted (C 1 ), optionally substitute
  • the disclosure provides a compound according to any of the foregoing embodiments wherein R 3b is optionally substituted by one or more substituents independently selected from halogen, CN, —C(O)OH, —C(O)CH 3 , —C(O)NH 2 , NH 2 , ⁇ O, —OH, optionally substituted (C 1 -C 3 )alkyl, optionally substituted (C 1 -C 3 )alkoxy and optionally substituted oxetanyl.
  • substituents independently selected from halogen, CN, —C(O)OH, —C(O)CH 3 , —C(O)NH 2 , NH 2 , ⁇ O, —OH, optionally substituted (C 1 -C 3 )alkyl, optionally substituted (C 1 -C 3 )alkoxy and optionally substituted oxetanyl.
  • the disclosure provides a compound according to any of the foregoing embodiments wherein Y is CR 4 .
  • the disclosure provides a compound according to any of the foregoing embodiments wherein Z is CR 4 .
  • the disclosure provides a compound according to any of the foregoing embodiments wherein the compound is:
  • the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein
  • X, Y and Z are independently CR 4 or N;
  • L is a bond, optionally substituted (C 1 -C 3 )alkylene or —C(O)—;
  • R 1 is H, CD 3 , CN, optionally substituted (C 1 -C 3 )alkyl, —(CH 2 ) n -optionally substituted phenyl, —(CH 2 ) n -optionally substituted heteroaryl or —(CH 2 ) n -optionally substituted heterocyclyl;
  • R 2 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl or optionally substituted cycloalkyl;
  • R 3 is —R 3a -R 3b , wherein:
  • R 4 is independently H, Cl, CN, F, CF 3 , optionally substituted (C 1 -C 3 )alkyl or optionally substituted (C 1 -C 3 ) alkoxy;
  • n 0 or 1
  • p 0, 1 or 2.
  • the disclosure provides a compound according to any of the foregoing embodiments wherein R 1 is H, CD 3 , optionally substituted (C 1 -C 3 )alkyl or —CH 2 -pyrimidinyl.
  • the disclosure provides a compound according to any of the foregoing embodiments wherein R 2 is optionally substituted heteroaryl, optionally substituted heterocyclyl or optionally substituted phenyl.
  • the disclosure provides a compound according to any of the foregoing embodiments wherein R 3a is optionally substituted dihydropyranyl, optionally substituted imidazo[1,2-b]pyridazinyl, optionally substituted 1,2,4-oxadiazolyl, optionally substituted pyrazolyl, optionally substituted 3,6-dihydro-2H-pyranyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substituted 1,2,4-thiadiazolyl.
  • R 3a is optionally substituted dihydropyranyl, optionally substituted imidazo[1,2-b]pyridazinyl, optionally substituted 1,2,4-oxadiazolyl, optionally substituted pyrazolyl, optionally substituted 3,6-dihydro-2H-pyranyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazin
  • the disclosure provides a compound according to any of the foregoing embodiments wherein R 3b is —N(R a )(R b ), —O(R a ), optionally substituted (C 1 -C 3 )alkyl, —(CH 2 ) p -optionally substituted imidazo[1,2-b]pyridazinyl, —(CH 2 ) p -optionally substituted morpholinyl, —(CH 2 ) p -optionally substituted piperazinyl, —(CH 2 ) p -optionally substituted piperidinyl, —(CH 2 ) p -optionally substituted pyrrolidinyl, —(CH 2 ) p -optionally substituted tetrahydropyranyl, —(CH 2 ) p -optionally substituted tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5
  • the disclosure provides a compound according to any of the foregoing embodiments wherein L is a bond or optionally substituted (C 1 -C 2 )alkylene.
  • the disclosure provides a compound according to any of the foregoing embodiments wherein R 2 is 4,5-dihydrobenzo[f][1,5]thiazepin-3(2 h)-one, 1.3-dihydroisobenzofuranyl, phenyl, pyridinyl, pyrimidinyl or pyrrolyl, and R 2 is optionally substituted by one or more substituents independently selected from halogen, CN, haloalkoxy, CF 3 , —SCHF 2 , optionally substituted (C 1 -C 3 )alkyl, optionally substituted (C 3 -C 6 )cycloalkyl, —CH 2 OC(O)C(H)NH 2 CH 3 , —CH 2 NHC(O)OCH 3 , —CH 2 -pyridinyl, —CH 2 -pyrrolyl, —CH 2 -optionally substituted pyrazolyl, —CH 2 -trifluoride,
  • the disclosure provides a compound according to any of the foregoing embodiments wherein R 3b is —N(H)-optionally substituted oxetanyl, —N(H)-optionally substituted piperidin-2-one, —N(H)-optionally substituted tetrahydropyranyl, —O-tetrahydropyranyl, optionally substituted (C 1 -C 3 )alkyl, optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, -optionally substituted tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one —(CH 2 ) p -optionally substituted hexahydroimidazo[1,5-a]pyrazin-3(2H)-one, or optionally substituted tetrahydropyranyl.
  • the disclosure provides a compound according to any of the foregoing embodiments wherein R 3b is optionally substituted by one or more substituents independently selected from halogen, —CHO, CN, —C(O)OH, —C(O)CH 3 , —C(O)CH 2 CN, —C(O)CH 2 OH, —C(O)CH 2 NH 2 , C(O)CH 2 OCH 3 , —C(O)C(H)(CH 3 )NH 2 , —C(O)C(H)(OH)CH 2 OH, —C(O)C(H)(OH)CH 2 C(O)OH, —C(O)C(H)(OH)CH 2 NH 2 , —C(O)CH 2 OC(O)C(H)(NH 2 )CH(CH 3 ) 2 , —C(O)NH 2 , —C(O)OCH 3 , —C(O)NH 2 , —C
  • the disclosure provides a compound according to any of the foregoing embodiments wherein Y is CR 4 and R 4 is H.
  • the disclosure provides a compound according to any of the foregoing embodiments wherein Z is CR 4 and R 4 is H or F.
  • the disclosure provides a compound according to any of the foregoing embodiments wherein the compound is:
  • the disclosure provides a pharmaceutical composition comprising a compound according to any of the foregoing embodiments and one or more pharmaceutically acceptable excipients.
  • the disclosure provides a method of treating a disease comprising administering a therapeutically effective amount of a compound or pharmaceutical composition according to any of the foregoing embodiments.
  • the disclosure provides a method of the twenty-seventh embodiment, wherein the disease is rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, psoriatic arthritis, psoriasis, ankylosing spondylitis, systemic lupus erythematosus, lupus nephritis, multiple sclerosis, uveitis or hidraenitis suppurativa.
  • the disease is rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, psoriatic arthritis, psoriasis, ankylosing spondylitis, systemic lupus erythematosus, lupus neph
  • the disclosure provides a kit comprising a packaged product comprising components with which to adminster a compound or composition of any of the foregoing embodiments for the treatment of an autoimmune disorder.
  • the disclosure provides a kit according to the twenty-ninth embodiment, wherein the packaged product comprises a compound or pharmaceutical composition of any of the foregoing embodiments and instructions for use.
  • 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.
  • 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 disclosure 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.
  • heterocycle 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(b)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-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl,
  • alkyl As used herein, “alkyl,” “alkylene” or notations such as “(C 1 -C 8 )” include straight chained or branched hydrocarbons which are completely saturated.
  • An alkyl is a monovalent radical while an alkylene is a bivalent radical.
  • alkyls are methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and isomers thereof.
  • alkylenes include methylene (—CH 2 —), ethylene (—CH 2 CH 2 —), propylene (—CH 2 CH 2 CH 2 —), isopropylene (—CH(CH 3 )CH 2 —) and the like.
  • alkenyl 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.
  • alkoxy refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy.
  • alkoxyalkyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, and methoxypropyl.
  • 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 -C 12 monocyclic or multicyclic (e.g., bicyclic, tricyclic, spirocyclic, etc.) hydrocarbons that are completely saturated.
  • Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]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.
  • cycloalkenyl groups are cyclopentenyl and cyclohexenyl.
  • groups that are substituents are: (C 1 -C 8 )alkyl groups optionally substituted with —OH, (C 2 -C 8 )alkenyl groups, (C 2 -C 8 )alkynyl groups, (C 3 -C 10 )cycloalkyl groups optionally substituted with —CN, halogen (F, Cl, Br or I), halogenated (C 1 -C 8 )alkyl groups (for example but not limited to —CF 3 ), —O—(C 1 -C 8 )alkyl groups, —(C 1 -C 6 )alkyl-C(O)OH, ⁇ O, ⁇ CH 2 , —OH, —CH 2 OH, —CH 2 NH 2 , (C 1 -C 4 )alkyl-OH, —CH 2 CH 2 OCH 2 CH 3 , —S—
  • kit refers to a packaged product comprising components with which to administer a compound of Formula (I) of the disclosure 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 disclosure 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).
  • Compounds of this disclosure include compounds of Formula (I), which include compounds of Formula (Ia), (Ib), (Ic), (Id) and (Ie) as described herein.
  • compounds of the disclosure include compounds of Formula (I),
  • X, Y and Z are independently CR 4 or N;
  • L is a bond, optionally substituted (C 1 -C 3 )alkylene or —C(O)—;
  • R 1 is H, CD 3 , optionally substituted (C 1 -C 3 )alkyl or optionally substituted (C 3 -C 6 )cycloalkyl;
  • R 2 is optionally substituted aryl or optionally substituted heteroaryl
  • R 3 is —R 3a -R 3b , wherein:
  • R 4 is independently H, Cl, CN, F, CF 3 , or optionally substituted (C 1 -C 3 )alkyl;
  • p 0, 1 or 2.
  • the compound of Formula (I) may be a compound of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id) or Formula (Ie):
  • any reference to a compound of Formula (I) includes references to compounds of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id) and Formula (Ie).
  • R 1 is optionally substituted (C 1 -C 3 )alkyl (e.g., —CH 3 ) or optionally substituted cyclopropyl (e.g., unsubstituted cyclopropyl).
  • R 2 is optionally substituted heteroaryl, or optionally substituted phenyl.
  • R 2 is unsubstituted phenyl, unsubstituted pyridinyl, or unsubstituted pyrimidinyl.
  • R 2 is phenyl, pyridinyl or pyrimidinyl that is substituted by one or more substituents (e.g., one substituent or two substituents) independently selected from halogen (e.g., F or Cl), CN, haloalkoxy (e.g., —OCHF 2 ), CF 3 , an optionally substituted (C 1 -C 3 )alkyl (e.g., —CH 3 or —CH 2 OH).
  • substituents e.g., one substituent or two substituents
  • substituents e.g., one substituent or two substituents
  • substituents e.g., one substituent or two substituents
  • substituents e.g., one substituent or two substituents
  • substituents e.g., one substituent or two substituents
  • substituents e.g., one substituent or two substituents
  • halogen e.g., F or Cl
  • R 3a is optionally substituted 1,2,4-oxadiazolyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substituted 1,2,4-thiadiazolyl.
  • R 3a may be 1,2,4-oxadiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or 1,2,4-thiadiazolyl.
  • R 3a may be substituted 1,2,4-oxadiazolyl, substituted pyrazolyl, substituted pyridinyl, substituted pyrimidinyl, substituted pyrazinyl, or substituted 1,2,4-thiadiazolyl; for example, R 3a may be substituted with one or more substituents (e.g., one substituent or two substituents) such as halogen (e.g., Cl).
  • substituents e.g., one substituent or two substituents
  • halogen e.g., Cl
  • R 3b is —N(R a )(R b ), —O(R a ), optionally substituted (C 1 -C 3 )alkyl, —(CH 2 ) p -optionally substituted 2-oxa-6-azaspiro[3.3]heptanyl, —(CH 2 ) p -optionally substituted 2-azaspiro[3.3]heptanyl, —(CH 2 ) p -optionally substituted 5-azaspiro[2.3]hexanyl, —(CH 2 ) p -optionally substituted azetidinyl, —(CH 2 ) p -optionally substituted morpholinyl, —(CH 2 ) p -optionally substituted oxetanyl, —(CH 2 ) p -optionally substituted piperazinyl, —(CH 2 ) p -optionally substituted piperidinyl, —(CH 2 )
  • R 3b may be —N(H)CH 2 -optionally substituted pyrrolidinyl, —O(R a ), —N(H)-optionally substituted oxetanyl, optionally substituted (C 1 -C 3 )alkyl, optionally substituted 2-oxa-6-azaspiro[3.3]heptanyl, optionally substituted 5-azaspiro[2.3]hexanyl, optionally substituted azetidinyl, optionally substituted morpholinyl, —(CH 2 ) p -optionally substituted oxetanyl, optionally substituted piperazinyl, optionally substituted piperidinyl, —(CH 2 ) p -optionally substituted pyrrolidinyl, or optionally substituted tetrahydropyranyl.
  • R 3b may be optionally substituted by one or more substituents independently selected from halogen, CN, —C(O)OH, —C(O)CH 3 , —C(O)NH 2 , NH 2 , ⁇ O, —OH, optionally substituted (C 1 -C 3 )alkyl, optionally substituted (C 1 -C 3 )alkoxy and optionally substituted oxetanyl.
  • L is a bond or optionally substituted (C 1 -C 2 )alkylene (e.g., —CH 2 —, —CH 2 CH 2 —, —CH(CH 3 )—, —C(O)—).
  • X is CR 4 .
  • Y is CR 4 .
  • Z is CR 4 .
  • Exemplary compounds of Formula (I) include:
  • compounds of the disclosure include compounds of Formula (I), wherein X, Y and Z are independently CR 4 or N;
  • L is a bond, optionally substituted (C 1 -C 3 )alkylene or —C(O)—;
  • R 1 is H, CD 3 , CN, optionally substituted (C 1 -C 3 )alkyl, —(CH 2 ) n -optionally substituted phenyl, —(CH 2 ) n -optionally substituted heteroaryl or —(CH 2 ) n -optionally substituted heterocyclyl;
  • R 2 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl or optionally substituted cycloalkyl;
  • R 3 is —R 3a -R 3b , wherein:
  • R 4 is independently H, Cl, CN, F, CF 3 , optionally substituted (C 1 -C 3 )alkyl or optionally substituted (C 1 -C 3 ) alkoxy;
  • n 0 or 1
  • p 0, 1 or 2.
  • Certain compounds of Formula (I) which have acidic substituents may exist as salts with pharmaceutically acceptable bases.
  • the present disclosure 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 disclosure 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 disclosure 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 disclosure 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 disclosure 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 disclosure 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 disclosure 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 disclosure includes each zwitterionic form of compounds of Formula (I) (and mixtures thereof.
  • Certain compounds of Formula (I) may further be in the form of a pro-drug.
  • Pro-drugs have many useful properties.
  • 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 disclosure include but are not limited to carboxylic acid substituents wherein the free hydrogen is replaced by (C 1 -C 4 )alkyl, (C 1 -C 12 )alkanoyloxymethyl, (C 4 -C 9 )1-(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, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4
  • 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 1 -C 6 )alkanoyloxymethyl, 1-((C 1 -C 6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1 -C 6 )alkanoyloxy)ethyl, (C 1 -C 12 )alkoxycarbonyloxymethyl, N—(C 1 -C 6 )alkoxycarbonylamino-methyl, succinoyl, (C 1 -C 6 )alkanoyl, ⁇ -amino(C 1 -C 4 )alkanoyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ -aminoacyl wherein said ⁇ -aminoacyl moieties are independently any of the naturally occurring L-amino acids found in proteins, P(
  • Compounds of Formula (I) also include compounds with one or more isotopic substitutions.
  • H may be in any isotopic form, including 1 H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 12 C, 13 C, and 14 C; O may be in any isotopic form, including 16 O and 18 O; and the like.
  • autoimmune diseases and disease associated with chronic inflammation, as well as acute responses have been linked to excessive or unregulated production or activity of one or more cytokines.
  • the compounds of the disclosure are also useful in the treatment of rheumatoid arthritis, asthma, allergic asthma, osteoarthritis, juvenile arthritis, ankylosing spondylitis, hidradenitis supportive, ulcerative colitis. Crohn's disease, and inflammatory bowel disease.
  • Compounds of Formula (I) of the disclosure can be used alone or in combination with an additional agent, e.g., a therapeutic agent, said additional agent being selected by the skilled artisan for its intended purpose.
  • the additional agent can be a therapeutic agent art-recognized as being useful to treat the disease or condition being treated by the compound of the present disclosure.
  • the additional agent also can be an agent that imparts a beneficial attribute to the therapeutic composition e.g., an agent that affects the viscosity of the composition.
  • the combinations which are to be included within this disclosure 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 disclosure can be the compounds of the present disclosure 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 disclosure.
  • Non-limiting examples of therapeutic agents for rheumatoid arthritis with which a compound of Formula (I) of the disclosure can be combined include the following: cytokine suppressive anti-inflammatory drug(s) (CSAIDs); antibodies to or antagonists of other human cytokines or growth factors, for example, LT, IL-1, IL-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.
  • CSAIDs cytokine suppressive anti-inflammatory drug
  • Compounds of the disclosure 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-1RA 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-1RA etc.
  • Other preferred combinations include Interleukin 11.
  • a compound of Formula (I) of the disclosure 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, NSAIDs, for example, ibuprofen, corticosteroids such as prednisolone,
  • Non-limiting examples of therapeutic agents for inflammatory bowel disease with which a compound of Formula (I) of the disclosure 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-1 ⁇ 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-II
  • 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-1 ⁇ converting enzyme inhibitors and IL-1ra; T cell signaling inhibitors, for example, tyrosine kinase inhibitors; 6-mercaptopurine; IL-11; mesalamine; prednisone; azathioprine; mercaptopurine; infliximab; methylprednisolone sodium succinate; diphenoxylate/atropine sulfate; loperamide hydrochloride; methotrexate; omeprazole; folate; cip
  • 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- ⁇ 1a (AVONEX®; Biogen); interferon- ⁇ 1b (BETASERON®; Chiron/Berlex); interferon ⁇ -n3) (Interferon Sciences/Fujimoto), interferon- ⁇ (Alfa Wassermann/J&J), interferon ⁇ 1A-IF (Serono/Inhale Therapeutics), Peginterferon ⁇ 2b (Enzon/Schering-Plough), Copolymer 1 (Cop-1; COPAXONE®; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen; intravenous immunoglobulin; cladribine; antibodies to
  • 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 signaling 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 receptors
  • interferon- ⁇ for example, IFN ⁇ 1a and IFN ⁇ 1b
  • 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, ⁇ -immunokine NNSO3, 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-R1, talampanel, teriflunomide, TGF-beta2, tiplimotide, VLA-4 antagonists (for
  • Non-limiting examples of therapeutic agents for ankylosing spondylitis with 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 asthma with which a compound of Formula (I) can be combined include the following: albuterol, salmeterol/fluticasone, montelukast sodium, fluticasone propionate, budesonide, prednisone, salmeterol xinafoate, levalbuterol HCl, albuterol sulfate/ipratropium, prednisolone sodium phosphate, triamcinolone acetonide, beclomethasone dipropionate, ipratropium bromide, azithromycin, pirbuterol acetate, prednisolone, theophylline anhydrous, methylprednisolone sodium succinate, clarithromycin, zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillin trihydrate, flunisolide, allergy injection, cromolyn sodium, fexofenadine hydrochloride, flunisolide/ment
  • Non-limiting examples of therapeutic agents for COPD with which a compound of Formula (I) can be combined include the following: albuterol sulfate/ipratropium, ipratropium bromide, salmeterol/fluticasone, albuterol, salmeterol xinafoate, fluticasone propionate, prednisone, theophylline anhydrous, methylprednisolone sodium succinate, montelukast sodium, budesonide, formoterol fumarate, triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin, beclomethasone dipropionate, levalbuterol HCl, flunisolide, ceftriaxone sodium, amoxicillin trihydrate, gatifloxacin, zafirlukast, amoxicillin/clavulanate, flunisolide/menthol, chlorpheniramine/hydrocodone, metaproter
  • Non-limiting examples of therapeutic agents for Idiopathic Pulmonary Fibrosis with which a compound of Formula (I) (can be combined include the following: prednisone, azathioprine, albuterol, colchicine, albuterol sulfate, digoxin, gamma interferon, methylprednisolone sodium succinate, lorazepam, furosemide, lisinopril, nitroglycerin, spironolactone, cyclophosphamide, ipratropium bromide, actinomycin d, alteplase, fluticasone propionate, levofloxacin, metaproterenol sulfate, morphine sulfate, oxycodone HCl, potassium chloride, triamcinolone acetonide, tacrolimus anhydrous, calcium, interferon-alpha, methotrexate, mycophenolate mofetil and interferon-gamma
  • 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 dipropionate augmented, fluocinolone acetonide, acitretin, tar shampoo, betamethasone valerate, mometasone furoate, ketoconazole, pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide, urea, betamethasone, clobetasol propionate/emollient, fluticasone propionate, azithromycin, hydrocortisone, moisturizing formula, folic acid, desonide, pimecrolimus, coal tar, diflorasone diacetate, eta
  • 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 dipropionate augmented, infliximab, methotrexate, folate, triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenac sodium/misoprostol, fluocinonide,
  • 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; anti-malarials, 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 Cellcept®.
  • 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-1 ⁇ converting enzyme inhibitors and IL-1ra.
  • 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-1 ⁇ converting enzyme inhibitors and IL-1ra.
  • 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 antibodies.
  • a compound of Formula (I) can be combined with IL-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 UP 394 (abetimus), agents that deplete or inactivate B-cells, for example, Rituximab (anti-CD20 antibody), and lymphostat-B (anti-BlyS antibody).
  • One or more compounds of this disclosure 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.
  • Techniques for formulation and administration of the compounds of the instant application may be found in references well known to one of ordinary skill in the art, such as “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa., latest edition.
  • Suitable routes of administration may, for example, include oral, eye drop, 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 disclosure 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 disclosure 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 disclosure 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 disclosure 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 disclosure are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, 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.
  • 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 disclosure 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 disclosure 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 disclosure formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • the compounds of the present disclosure in the form of particles of very small size, for example as obtained by fluid energy milling.
  • active compound denotes any compound of the disclosure 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.
  • Active compound 10 Lactose 190 Maize starch 22 Polyvinylpyrrolidone 10 Magnesium stearate 3
  • 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 ethanol:dichloromethane (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 disclosure can be administered in combination with another therapeutic agent that is known to treat a disease or condition described herein.
  • additional pharmaceutical agents that inhibit or prevent the production of VEGF or angiopoietins, attenuate intracellular responses to VEGF or angiopoietins, block intracellular signal transduction, inhibit vascular hyperpermeability, reduce inflammation, or inhibit or prevent the formation of edema or neovascularization.
  • the compounds of the disclosure 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-IL1 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 disclosure and the additional pharmaceutical agents act either additively or synergistically.
  • the administration of such a combination of substances that inhibit angiogenesis, vascular hyperpermeability and/or inhibit the formation of edema can provide greater relief from the deleterious effects of a hyperproliferative disorder, angiogenesis, vascular hyperpermeability or edema than the administration of either substance alone.
  • combinations with antiproliferative or cytotoxic chemotherapies or radiation are included in the scope of the present disclosure.
  • the present disclosure also comprises the use of a compound of Formula (I) as a medicament.
  • a further aspect of the present disclosure provides the use of a compound of Formula (I) or a salt thereof in the manufacture of a medicament for treating vascular hyperpermeability, angiogenesis-dependent disorders, proliferative diseases and/or disorders of the immune system in mammals, particularly human beings.
  • the present disclosure also provides a method of treating vascular hyperpermeability, inappropriate neovascularization, proliferative diseases and/or 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.
  • Compounds are serially diluted 1:3 with DMSO in columns 2-12 or 14-24. Compound solutions are dispensed into replicate assay plates at 410 nL per well. Plates stored at 4° C.
  • Step 1 Methyl 4-(isoquinolin-8-yl)-3-(4-(isoquinolin-8-yl)phenethoxy)benzoate
  • Cyanomethylenetributylphosphorane (0.90 mL, 3.4 mmol) was added to a mixture of methyl 3-hydroxy-4-(isoquinolin-8-yl)benzoate (800 mg, 2.86 mmol), 2-(4-(isoquinolin-8-yl)phenyl)ethanol (714 mg, 2.86 mmol), and toluene (30 mL). After stirring for about 4 h at about 100° C., the reaction mixture was allowed to cool to rt.
  • Lithium aluminum hydride (1 M solution in THF, 0.4 mL, 0.4 mmol) was added to a solution of methyl 4-(isoquinolin-8-yl)phenethoxy)benzoate (204 mg, 0.400 mmol) and THF (3.6 mL) under N 2 at about 0° C. After about 1 h, 10% aqueous sodium potassium tartrate (6 mL) was added. The reaction was allowed to warm to rt. After about 10 min at rt, EtOAc (10 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (10 mL). The combined organics were washed with sat. aq.
  • Step 3 2-(2-(2-((4-(Isoquinolin-8-yl)-3-(4-(isoquinolin-8-yl)phenethoxy)benzyl)oxy)ethoxy)ethoxy)ethanamine
  • Step 4 2′,7′-difluoro-3′,6′-dihydroxy-N-(2-(2-(2(4-(Isoquinolin-8-yl)-3-(4-(isoquinolin-8-yl)phenethoxy)benzyl)oxy)ethoxy)ethoxy)ethyl)-3-oxo-3H-spiro[isobenzofuran-1,9′-xanthene]-5-carboxamide
  • the column used for the chromatography is 250 ⁇ 21.1 mm Hypersil HS C18 (8 ⁇ m particles). Detection method is UV (245 nm) d HPLC: The gradient was 20-100% B over 25 min (21 mL/min flow rate).
  • mobile phase B was HPLC grade MeCN.
  • the column used for the chromatography is 250 ⁇ 21.1 mm Hypersil HS C18 (8 ⁇ m particles).
  • Detection method is UV (360 nm) e LC/MS: The gradient was 5-60% B in 1.50 min then 60-95% B to 2.5 min with a hold at 95% B for 1.2 min (1.3 mL/min flow rate). Mobile phase A was 10 mM NH 4 OAc, mobile phase B was HPLC grade MeCN. The column used for the chromatography was a 4.6 ⁇ 50 mm MAC-MOD Halo C8 column (2.7 ⁇ m particles), Detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive/negative electrospray ionization.
  • DAD diode array
  • ELSD evaporative light scattering
  • HPLC The gradient was 5-45% B in 9.5 min then 45-95% B to 10 min with a hold at 95% B for 2 min (25 mL/min flow rate).
  • Mobile phase A was 0.1% formic acid in water
  • mobile phase B was HPLC grade MeCN.
  • the column used for the chromatography is a 19 ⁇ 50 mm Waters Atlantis C18 column (5 ⁇ m particles). Detection methods are diode array (DAD) and positive/negative APCI ionization.
  • g HPLC The gradient was 10-100% B over 25 min (21 mL/min flow rate).
  • the column used for the chromatography is 250 ⁇ 21.1 mm Hypersil HS C18 (8 ⁇ m particles). Detection method is UV (280 nm) h LC/MS: The gradient was 5-60% B in 1.6 min then 60-95% B to 2.2 min with a hold at 95% B for 0.1 min (1.0 mL/min flow rate). Mobile phase A was 10 mM NH 4 OAc, mobile phase B was HPLC grade MeCN.
  • the column used for the chromatography is a 2.1 ⁇ 30 mm Waters Cortecs C18 column (1.6 ⁇ m particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive/negative electrospray ionization.
  • DAD diode array
  • ELSD evaporative light scattering
  • Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive/negative electrospray ionization.
  • j LC/MS Halo-2 C8 monitoring method: The gradient was 5-60% B in 1.6 min then 60-95% B to 2.2 min with a hold at 95% B for 0.1 min (1.0 mL/min flow rate). Mobile phase A was 10 mM NH 4 OAc, mobile phase B was HPLC grade MeCN. The column used for the chromatography is a 2.1 ⁇ 30 mm Halo-2 C8 column (2 ⁇ m particles).
  • Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive/negative electrospray ionization.
  • k LC/MS The gradient was 25-95% B in 1.6 min then a hold at 95% B for 1.2 min (1.0 mL/min flow rate).
  • Mobile phase A was 10 mM NH 4 OAc, mobile phase B was HPLC grade MeCN.
  • the column used for the chromatography is a 2.1 ⁇ 30 mm Waters Cortecs C18 column (1.6 ⁇ m particles).
  • Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive/negative electrospray ionization.
  • the column used for the chromatography used a Daicel ADH column (20 ⁇ 250 mm, 5 ⁇ m particles).
  • c Gradient separation method wherein mobile phase B was 50% EtOH (200 proof)/MeOH, mobile phase A was HPLC grade heptane with 0.2% diethylamine added. Flow rate was 20 mL/min. Gradient was 10-35% B in 0.5 min then 35-70% B over 24.5 min then hold at 70% for 10 min.
  • the column used for the chromatography was a Daicel ID column (20 ⁇ 250 mm, 5 ⁇ m particles).
  • the chromatography used a YMC-SA, 20 ⁇ 250 mm column (5 ⁇ m particles). e 27% 80:20 isopropanol:MeCN (0.2% diethylamine modifier) in CO 2 (65 mL/min, 140 bar, 35° C.). Cycle time was 6 min, with single run time of 12 min. HPLC grade isopropanol and MeCN were used with SFC grade CO 2 .
  • the chromatography used a YMC-SA, 20 ⁇ 250 mm column (5 ⁇ m particles). f Gradient 15-28% methanol in CO 2 (55 mL/min, 140 bar, 35° C.). Cycle time and run times were 16.9 min. HPLC grade methanol was used with SFC grade CO 2 .
  • the chromatography used a YMC-SA, 20 ⁇ 250 mm column. (5 ⁇ m particles).
  • Compounds designated as salts may contain more than one molar equivalent of the salt or may contain the acid as an excipient.
  • Compounds of the disclosure where the absolute stereochemistry has been determined by the use of a commercially available enantiomerically pure starting material or a stereochemically defined intermediate or by X-ray diffraction are denoted by an asterisk after the example number. Otherwise the absolute stereochemistry is unknown and assigned randomly as drawn.
  • Compounds of the disclosure may be prepared using synthetic transformations shown herein. For groups of compounds that have been prepared in a similar fashion, a representative example is given followed by a table of these similarly prepared compounds. It should be appreciated by one skilled in the art that minor modifications to the representative example may be necessary to successfully execute these syntheses.
  • Prepared compounds may be purified by any technique or combination of techniques known to one skilled in the art. Some examples that are not limiting include column chromatography with a solid phase (i.e. silica gel, alumina, etc.) and a solvent (or combination of solvents) that elutes the desired compounds (i.e.
  • EtOAc/heptane, EtOAc/MeOH, etc. chiral LC with a solid phase and an appropriate solvent (i.e. EtOH/heptane, MeOH/heptane, IPA/heptane, etc. with or without a modifier such as diethylamine, TFA, etc.) to elute the desired compound; chiral SFC with a solid phase and CO 2 with an appropriate modifier (i.e. MeOH, EtOH, IPA with or without additional modifier such as diethylamine, TFA, etc.); precipitation from a combination of solvents (i.e. DMF/water, DMSO/DCM, EtOAc/heptane, etc.); trituration with an appropriate solvent (i.e.
  • PBr 3 (1 M in DCM, 2.9 mL, 2.9 mmol) was added to a solution of 1-(2-(difluoromethoxy)phenyl)ethanol (0.50 g, 2.7 mmol) and DCM (13.3 mL) at about ⁇ 10° C. under N 2 .
  • the reaction was allowed to warm to rt over about 1 h by thawing of the bath and then stirred at rt for about 16 h.
  • the reaction mixture was quenched at rt by careful addition of sat. aq. NaHCO 3 (2 mL) and partitioned between DCM (10 mL) and water (5 mL). After separating the layers, the organic phase was washed with sat. aq.
  • Step 2 1-(2-(Difluoromethoxy)benzyl)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3(2H)-one
  • Step 3 6-(2-Chloropyrimidin-5-yl)-1-(2-(difluoromethoxy)benzyl)-2-methyl-1H-indazol-3(2H)-one
  • Step 1 4-Bromo-N′-(2,5-dichlorophenyl)-2-iodobenzohydrazide
  • a suspension of piperidine-4-carboxylic acid (0.500 g, 3.87 mmol) in THF (10 mL) was added to a suspension of sodium hydride (60 wt % in mineral oil, 0.325 g, 8.13 mmol) in THF (5 mL) at about 0° C. After about 15 min, a solution of 2,5-dibromopyrazine (0.921 g, 3.87 mmol) and THF (5 mL) was added. The mixture was warmed to about 60° C. After about 3 h, the reaction was allowed to cool to rt. Sat. aq. NH 4 Cl (50 mL) was added.
  • Potassium carbonate (8.38 g, 60.7 mmol) was added to a solution of methyl 2-hydroxy-5-methylbenzoate (2.52 g, 15.2 mmol) and DMF (30.0 mL) under N 2 .
  • Sodium chlorodifluoroacetate (4.62 g, 30.3 mmol) was added. The mixture was warmed to about 80° C. After about 2.5 h, water (3.00 mL) was added and the mixture was warmed to about 100° C. After about 14 h, the mixture was cooled to rt and was then slowly acidified to about pH 1 using 2 N aqueous HCl (50 mL). Et 2 O (100 mL) was added.
  • Ethyl bromodifluoroacetate (7.00 mL, 54.6 mmol) was added in one portion to a mixture of methyl 5-bromosalicylate (10.0 g, 43.3 mmol), K 2 CO 3 (8.97 g, 64.9 mmol) and DMF (120 mL) under N 2 .
  • the mixture was warmed to about 80° C. for about 4 h.
  • ethyl 2-bromo-2,2-difluoroacetate (3.50 mL, 27.3 mmol) and K 2 CO 3 (3.01 g, 21.78 mmol) were added.
  • the mixture was warmed to about 80° C. for about 90 min.
  • Step 1 7-(5-Bromopyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one
  • Step 2 (S)-7-(5-Bromopyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one and (R)-7-(5-bromopyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one
  • Step 3 (((3-Bromo-4-(difluoromethoxy)benzyl)oxy)methanetriyl)tribenzene
  • N,N-Dimethylpyridin-4-amine (0.077 g, 0.63 mmol) was added to a solution of (3-bromo-4-(difluoromethoxy)phenyl)methanol (1.60 g, 6.32 mmol) and (chloromethanetriyl)tribenzene (1.76 g, 6.32 mmol) in pyridine (20 mL) at rt.
  • the reaction mixture was warmed to about 80° C. After about 2 h, the reaction was concentrated. The residue was dissolved in DCM (100 mL) and washed with sat. aq. NH 4 Cl (2 ⁇ 100 mL).
  • Step 6 (((3-(Bromomethyl)-4-(difluoromethoxy)benzyl)oxy)methanetriyl)tribenzene
  • Trethylamine (20.0 mL, 143 mmol) was added to a slurry of (R)-5-bromo-2-(3-methylpiperazin-1-yl)pyrimidine dihydrochloride (10.0 g, 30.3 mmol) (synthesized in a similar fashion to Example #3, step 1 from (R)-tert-butyl 4-(5-bromopyrimidin-2-yl)-2-methylpiperazine-1-carboxylate (synthesized in a similar fashion to Preparation #13, step 1 from (R)-1-N-Boc-2-methylpiperazine)), glycolic acid (3.52 g, 46.3 mmol) and DMF (150 mL).
  • reaction mixture was cooled to about room temperature and filtered through a pad of Celite® rinsing with EtOAc (350 mL). The solution was washed with a sat. aq. 5% NH 4 OH solution (100 mL) and sat. aq. NaCl (2 ⁇ 100 mL). The organic layer was dried over MgSO 4 , filtered and concentrated under reduced pressure. The material was purified via flash chromatography on silica gel (0-20% EtOAc/DCM).
  • NaBH 4 (0.93 g, 24.6 mmol) was added portionwise to a mixture of methyl 6-methyl-3-(trifluoromethyl)picolinate (0.912 g, 4.16 mmol)) in EtOH (40 mL) under N 2 .
  • the mixture was heated to about 50° C. for about 4 h. Additional NaBH 4 (0.35 g, 9.25 mmol) was added. After about 16 h, additional NaBH 4 (0.35 g, 9.25 mmol) and EtOH (3 mL) were added. After about 4 h. NaBH 4 (0.40 g, 10.6 mmol) was added. Additional NaBH 4 (0.945 g, 24.9 mmol) and EtOH (10 mL) were added after about 16 h.
  • the organic layer was transferred via syringe to an argon-filled flask. The solvent was removed in vacuo, and the resulting residue was dissolved in MeCN (1.7 mL) and cooled to about ⁇ 78° C. Degassed 4 M aq. potassium hydroxide (23 mL, 91 mmol) was added, followed by diethyl (bromodifluoromethyl)phosphonate (1.62 mL, 9.10 mmol) in one portion. The frozen mixture was placed in an ice bath for about 30 min, then warmed to rt for about 60 min. The reaction mixture was extracted into Et 2 O (2 ⁇ 40 mL). The organic layer was washed with water and sat. aq.
  • Step 1 tert-Butyl 6-bromo-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate
  • Step 2 tert-Butyl 2-methyl-3-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indazole-1-carboxylate
  • Step 3 tert-Butyl 6-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate
  • TFA (0.270 mL, 3.51 mmol) was added to a solution of tert-butyl 6-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate (0.135 g, 0.351 mmol) in DCM (3 mL). The reaction was stirred at rt for about 1 h. TFA (0.271 mL, 3.51 mmol) was added to the reaction which continued to stir at rt for about 5 h. The reaction was concentrated under reduced pressure. DCM (2 ⁇ 10 mL) was added to the residue and was concentrated under reduced pressure to give an off-white solid.
  • Step 1 6-Bromo-1-(2-(difluoromethoxy)-5-((trityloxy)methyl)benzyl)-2-methyl-1,2-dihydro-3H-indazol-3-one
  • Step 3 6-bromo-1-(5-(bromomethyl)-2-(difluoromethoxy)benzyl)-2-methyl-1,2-dihydro-3H-indazol-3-one
  • Step 4 2-(3-((6-Bromo-2-methyl-3-oxo-2,3-dihydro-1H-indazol-1-yl)methyl)-4-(difluoromethoxy)phenyl)acetonitrile
  • Step 1 tert-Butyl 6-(2-chloropyrimidin-5-yl)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate
  • Step 2 (R)-2-(tert-Butoxy)-1-(3-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperazin-1-yl)ethanone
  • Step 3 (R)-6-(2-(4-(2-(tert-Butoxy)acetyl)-2-methylpiperazin-1-yl)pyrimidin-5-yl)-5,7-difluoro-2-methyl-1H-indazol-3(2H)-one
  • the mixture was degassed with a stream of nitrogen and 2 nd Generation XPhos precatalyst (5 mg, 6 ⁇ mol) was added.
  • the mixture was further degassed with nitrogen for about 5 min, then the reaction was heated to about 110° C. under nitrogen for about 6 h.
  • the reaction was cooled to rt and diluted with water (5 mL) and EtOAc (10 mL).
  • the organic layer was extracted again with 1 N aq. NaOH (5 mL).
  • the combined aqueous extracts were washed once with EtOAc (10 mL), then acidified with HOAc to about pH 4.
  • the aqueous layer was extracted with EtOAc (2 ⁇ 10 mL).
  • the combined organics were dried over Na 2 SO 4 , filtered and concentrated.
  • Step 4 (R)-6-(2-(4-(2-(tert-Butoxy)acetyl)-2-methylpiperazin-1-yl)pyrimidin-5-yl)-1-(2-(difluoromethoxy)benzyl)-5,7-difluoro-2-methyl-1H-indazol-3(2H)-one
  • Step 2 (R)-2-(tert-Butoxy)-1-(2-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperazin-1-yl)ethanone
  • Step 1 6-Chloro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3(2H)-one
  • Step 2 5-Bromo-6-chloro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3(2H)-one
  • Step 3 6-Chloro-5-methoxy-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3(2H)-one
  • N-(3-Bromo-2-fluorobenzyl)-2-mercaptoacetamide (1.52 g, 5.46 mmol) was flushed with nitrogen and DMF (25 mL) was added. The reaction was cooled to about 0° C. before addition of potassium tert-butoxide (0.613 g, 5.46 mmol). After about 10 min, the mixture was warmed to ambient temperature and then to about 100° C. After about 16 h, the mixture was cooled to ambient temperature. Water (50 mL), 1 M aq. KHSO 4 (10 mL), and EtOAc (300 mL) were added. The organic layer was washed with water (2 ⁇ 50 mL), sat. aq.
  • Step 1 1-(5-(Azidomethyl)-2-(difluoromethoxy)benzyl)-6-bromo-2-methyl-1H-indazol-3(2H)-one
  • Step 2 1-(5-(Aminomethyl)-2-(difluoromethoxy)benzyl)-6-bromo-2-methyl-1H-indazol-3(2H)-one
  • Step 3 Methyl 3-((6-bromo-2-methyl-3-oxo-2,3-dihydro-1H-indazol-1-yl)methyl)-4-(difluoromethoxy)benzylcarbamate
  • Step 2 (3-((3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-chlorophenyl)amino)-1-methylpiperidin-2-one)
  • reaction was diluted with additional anhydrous THF (3 mL) and allowed to stir about 30 min while warming to rt.
  • the reaction was quenched by the addition of cold sat. aq. NH 4 Cl solution (20 mL) and extracted into EtOAc (2 ⁇ 10 mL).
  • the organic layer was washed with water (20 mL) and sat. aq. NaCl (20 mL), then dried over MgSO 4 , filtered, and concentrated in vacuo.
  • Step 1 3-((3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-chlorophenyl)amino)-1-methylpyrrolidin-2-one
  • Step 3 6-(2-Chloropyrimidin-5-yl)-2-methyl-1-((5-methyl-2-(trifluoromethyl)pyridin-3-yl)methyl)-1,2-dihydro-3H-indazol-3-one
  • Step 3 6-(2-Chloropyrimidin-5-yl)-2-methyl-1-((5-methyl-2-(trifluoromethyl)pyridin-3-yl)methyl)-1,2-dihydro-3H-indazol-3-one
  • Step 3 6-(2-Chloropyrimidin-5-yl)-2-methyl-1-(5-methyl-2-(trifluoromethyl)benzyl)-1,2-dihydro-3H-indazol-3-one
  • reaction mixture was partitioned between DCM (25 mL) and water (25 mL), the aqueous phase was extracted with DCM (10 mL). The combined organic phases were washed with 1N aq. NaOH (25 mL) and sat. aq. NaCl (50 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Step 7 1-((5-chloro-1,3-dihydroisobenzofuran-4-yl)methyl)-6-(2-chloropyrimidin-5-yl)-2-methyl-1,2-dihydro-3H-indazol-3-one
  • LiHMDS (1 M solution in hexanes, 4.80 mL, 4.80 mmol) was added over about 10 min to a solution of ethyl 2-(5-bromopyrimidin-2-yl)acetate (1.06 g, 4.33 mmol) and THF (15.0 mL) under N 2 at about ⁇ 78° C. After stirring for about 15 min, MeI (0.300 mL, 4.80 mmol) was added. The reaction was allowed to warm to rt over about 1 h. The solution was cooled to about ⁇ 78° C. LiHMDS (1 M solution in hexanes) (4.80 mL, 4.80 mmol) was added over about 10 min.
  • Diisobutylaluminum hydride (1 M solution in toluene, 11 mL, 11 mmol) was added dropwise to a solution of ethyl 2-(5-bromopyrimidin-2-yl)-2-methylpropanoate (2.0 g, 7.3 mmol) and DCM (50 mL) under N 2 at about 0° C. over about 50 min. After about 1 h, diisobutylaluminum hydride (1 M solution in toluene, 3.5 mL, 3.5 mmol) was added over about 10 min. After about 1 h, 5% aq.
  • Step 1 6-Chloro-2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-indazole-5-carbonitrile
  • Step 2 6-Chloro-2-methyl-3-oxo-2,3-dihydro-1H-indazole-5-carbonitrile trifluoroacetic acid
  • Step 3 6-Chloro-1-(2-(difluoromethoxy)benzyl)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-5-carbonitrile
  • Toluene (215 ml) was degassed under vacuum then placed under an atmosphere of nitrogen then Pd 2 (dba) 3 (0.394 g, 0.430 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.746 g, 1.290 mmol), (R)-tert-butyl 2-methylpiperazine-1-carboxylate (4.31 g, 21.5 mmol) and 2,5-dibromopyridine (6.6 g, 27.9 mmol) were added. The mixture was stirred about 10 min then sodium tert-butoxide (3.10 g, 32.3 mmol) was added and the mixture was heated to about 100° C.
  • 6-(2-Chloropyrimidin-5-yl)-1-((3-(difluoromethoxy)-6-methylpyridin-2-yl)methyl)-2-methyl-1H-indazol-3(2H)-one was prepared in a similar fashion to Example #1, from 6-(2-chloropyrimidin-5-yl)-2-methyl-1H-indazol-3(2H)-one (Preparation #23) and 2-(bromomethyl)-3-(difluoromethoxy)-6-methylpyridine (prepared from (3-(difluoromethoxy)-6-methylpyridin-2-yl)methanol (prepared from 3-(difluoromethoxy)-6-methylpicolinaldehyde (prepared from (E)-3-(difluoromethoxy)-6-methyl-2-styrylpyridine (prepared from 2-bromo-3-(difluoromethoxy)-6-methylpyridine (prepared from 2-bromo-6-methylpyridin-3-ol in a similar
  • 6-(2-(4-Acetyl-3-methylpiperazin-1-yl)pyrimidin-5-yl)-1-(2-(difluoromethoxy)-5-methylbenzyl)-2-methyl-1H-indazol-3(2H)-one was prepared in a similar fashion to Preparation #16 using 1-(2-(difluoromethoxy)-5-methylbenzyl)-2-methyl-6-(2-(3-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-indazol-3(2H)-one, hydrochloric acid (prepared in a similar fashion to Example #3, step 1 using tert-butyl 4-(5-(1-(2-(difluoromethoxy)-5-methylbenzyl)-2-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl)pyrimidin-2-yl)-2-methylpiperazine-1-carboxylate (prepared in a similar fashion to Example #2 using 1-Bo
  • Step 1 (3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-(difluoromethoxy)benzyl)triphenylphosphonium bromide
  • Step 3 1-(3-(3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-(difluoromethoxy)benzyl)azetidin-1-yl)ethanone
  • Step 5 1-(5-((1-Acetylazetidin-3-yl)methyl)-2-(difluoromethoxy)benzyl)-6-bromo-5-fluoro-2-methyl-1H-indazol-3(2H)-one
  • Step 2 tert-Butyl 4-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate
  • Step 2 tert-Butyl (2-(5-bromopyridin-2-yl)propan-2-yl)carbamate
  • Step 2 (3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-(difluoromethoxy)phenyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methanol
  • the reaction was stirred for about 5 additional min at about ⁇ 78° C., then allowed to stir about 15 min while warming to rt.
  • the reaction was quenched via dropwise addition of water (2 mL) and diethyl ether (2 mL).
  • the aqueous layer was extracted with additional diethyl ether (5 mL), then the combined organic layers were washed with water (5 mL) and sat. aq. NaCl (5 mL).
  • the organic extract was dried over MgSO 4 , filtered, and concentrated in vacuo.
  • Step 3 (3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-(difluoromethoxy)phenyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methyl acetate
  • Step 4 4-(3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-(difluoromethoxy)benzyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole
  • Step 5 (2-(Difluoromethoxy)-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methyl)phenyl)methanol
  • Step 1 6-Bromo-2-methyl-1-((4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-3-yl)methyl)-1H-indazol-3(2H)-one
  • Example 3 The compound shown in Table 3 was synthesized in a manner similar to Example #2 from 6-(2,5-dichloropyridin-4-yl)-1-(3-fluorobenzyl)-2-methyl-1H-indazol-3(2H)-one (synthesized from 6-bromo-1H-indazol-3(2H)-one and 1-(bromomethyl)-3-fluorobenzene in a similar fashion to Example 1, alkylation with MeI in a similar fashion to Example #14, step 3, Suzuki reaction with 2,5-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in a similar fashion to Example #5) and the corresponding amine.
  • Example 4 The compound shown in Table 4 was synthesized in a manner similar to Example #2 from 6-(2,5-dichloropyridin-4-yl)-1-(2-(difluoromethoxy)benzyl)-2-methyl-1H-indazol-3(2H)-one (synthesized from 6-bromo-1-(2-(difluoromethoxy)benzyl)-2-methyl-1H-indazol-3(2H)-one (Preparation #4, step 1) and 2,5-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in a similar fashion to Example #5) and the corresponding amine.
  • Step 1 (S)-12-(Difluoromethoxy)benzyl)-2-methyl-6-(2-(pyrrolidin-3-ylamino)pyrimidin-5-yl)-1H-indazol-3(2H)-one
  • Step 2 (S)-6-(2-((1-Acetylpyrrolidin-3-yl)amino)pyrimidin-5-yl)-1-(2-(difluoromethoxy)benzyl)-2-methyl-1H-indazol-3(2H)-one
  • Step 1 5-(1-(2-(Difluoromethoxy)benzyl)-2-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl)pyrimidine-2-carbaldehyde
  • Step 2 1-((5-(1-(2-(Difluoromethoxy)benzyl)-2-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl)pyrimidin-2-yl)methyl)azetidine-3-carboxylic acid
  • 1,4-Dioxane (2 mL) and water (0.5 mL) were added to 6-bromo-1-(2-(difluoromethoxy)benzyl)-2-methyl-1H-indazol-3(2H)-one (0.060 g, 0.16 mmol) (Preparation #4, step 1), 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)morpholine (0.059 g, 0.20 mmol) and Cs 2 CO 3 (0.128 g, 0.391 mmol). The mixture was placed under N 2 . Pd(PPh 3 ) 4 (0.013 g, 11 ⁇ mol) was added.
  • the compound shown in Table 6 was synthesized in a manner similar to Example #5 from 6-bromo-1-(2-(difluoromethoxy)benzyl)-1H-indazol-3(2H)-one (prepared from 6-bromo-1H-indazol-3(2H)-one (Preparation #1) and 1-(bromomethyl)-2-(difluoromethoxy)benzene using methods similar to those described for Example #1) and the corresponding boronic acid/boronate.
  • Example 7 The compounds shown in Table 7 were synthesized in a manner similar to Example #5 from 6-bromo-1-(2,5-dichlorobenzyl)-2-methyl-1H-indazol-3(2H)-one (synthesized from 6-bromo-2-methyl-1H-indazol-3(2H)-one (Preparation #1) and 2-(bromomethyl)-1,4-dichlorobenzene in a similar fashion to Example #1) and the corresponding boronic acid/boronate.
  • the compound shown in Table 9 was synthesized in a manner similar to Example #5 from 6-bromo-1-(2,5-dichlorobenzyl)-1H-indazol-3(2H)-one (synthesized in a similar fashion to Preparation #5, step 1, from 6-bromo-1H-indazol-3(2H)-one and 2-(bromomethyl)-1,4-dichlorobenzene) and the corresponding boronic acid/boronate.
  • Example 11 The compounds shown in Table 11 were synthesized in a manner similar to Example #5 from 6-bromo-1-(3-fluorobenzyl)-2-methyl-1H-indazol-3(2H)-one (synthesized from 6-bromo-1H-indazol-3(2H)-one (Preparation #1) and 1-(bromomethyl)-3-fluorobenzene using a similar method to Preparation #5, step 1, alkylation with MeI using a similar method to Example #14, step 3) and the corresponding boronic acid/boronate.
  • Example 12 The compound shown in Table 12 was synthesized in a manner similar to Example #5 from 6-bromo-1-(2,5-dichlorophenyl)-2-methyl-1H-indazol-3(2H)-one (Preparation #6) and the corresponding boronic acid/boronate.
  • 6-bromo-1-(2-(difluoromethoxy)-5-methylbenzyl)-2-methyl-1H-indazol-3(2H)-one (0.0393 g, 0.099 mmol) (synthesized from 6-bromo-1H-indazol-3(2H)-one (Preparation #1) and 2-(bromomethyl)-1-(difluoromethoxy)-4-methylbenzene (synthesized in a similar fashion to Preparation #3, step 2 from (2-(difluoromethoxy)-5-methylphenyl)methanol (Preparation #11), Cs 2 CO 3 (0.102 g, 0.313 mmol), and bis(triphenylphosphine)palladium(II) dichloride were added in one portion.
  • Example 15 The compounds shown in Table 15 were synthesized in a manner similar to Example #8 from 6-bromo-1-(2-(difluoromethoxy)-5-methylbenzyl)-2-methyl-1H-indazol-3(2H)-one (synthesized from 6-bromo-1H-indazol-3(2H)-one (Preparation #1) and 2-(bromomethyl)-1-(difluoromethoxy)-4-methylbenzene (synthesized in a similar fashion to Preparation #3, step 2 from (2-(difluoromethoxy)-5-methylphenyl)methanol (Preparation #11)) and the corresponding halide.
  • Step 1 Methyl 4-(difluoromethoxy)-3-((2-methyl-6-(2-morpholinopyrimidin-5-yl)-3-oxo-2,3-dihydro-1H-indazol-1-yl)methyl)benzoate
  • Step 2 1-(2-(Difluoromethoxy)-5-(hydroxymethyl)benzyl)-2-methyl-6-(2-morpholinopyrimidin-5-yl)-1H-indazol-3(2H)-one
  • Lithium borohydride (0.0152 g, 0.698 mmol) was added in one portion to a mixture of methyl 4-(difluoromethoxy)-3-((2-methyl-6-(2-morpholinopyrimidin-5-yl)-3-oxo-2,3-dihydro-1H-indazol-1-yl)methyl)benzoate (0.119 g, 0.226 mmol) and THF (2.20 mL) under N 2 . After about 90 min, MeOH (5 mL) was added. The solution was left to vigorously stir for about 25 h. 5% MeOH/DCM (10 mL), sat. aq. NH 4 Cl (5 mL), and water (2 mL) were added.
  • Iodoethane (0.017 mL, 0.21 mmol) was added to a solution of 1-(2-(difluoromethoxy)benzyl)-6-(2-morpholinopyrimidin-5-yl)-1H-indazol-3(2H)-one (Example #6.1) (0.080 g, 0.18 mmol), LiOH hydrate (10 mg, 0.25 mmol), and DMF (1.8 mL).
  • the reaction mixture was heated to about 100° C. for about 1 h. After cooling to rt, the reaction was partitioned between EtOAc (15 mL) and water (2 mL).
  • Step 1 Methyl 1-(2-(difluoromethoxy)benzyl)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-6-carboxylate
  • Step 2 1-(2-(Difluoromethoxy)benzyl)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-6-carboxylic acid
  • Step 3 1-(2-(Difluoromethoxy)benzyl)-2-methyl-N-(morpholine-4-carbonothioyl)-3-oxo-2,3-dihydro-1H-indazole-6-carboxamide
  • Oxalyl dichloride (2 M solution in DCM, 0.73 mL, 1.5 mmol) was added to a solution of 1-(2-(difluoromethoxy)benzyl)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-6-carboxylic acid (253 mg, 0.726 mmol) in DCM (1.7 mL) at about 0° C. A drop of DMF was added. The ice bath was removed and reaction was allowed to warm to rt. After about 3 h, the volatiles were removed under reduced pressure. The residue was dissolved in MeCN (2.2 mL).
  • Step 4 (Z)-Methyl N-(1-(2-(difluoromethoxy)benzyl)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-6-carbonyl)morpholine-4-carbimidothioate
  • MeI (11 ⁇ L, 0.17 mmol) was added to a solution of 1-(2-(difluoromethoxy)benzyl)-2-methyl-N-(morpholine-4-carbonothioyl)-3-oxo-2,3-dihydro-1H-indazole-6-carboxamide (82 mg, 0.17 mmol) in DMF (1 mL). After about 1 h, EtOAc (30 mL) and water (10 mL) were added.
  • Step 5 1-(2-(Difluoromethoxy)benzyl)-2-methyl-6-(3-morpholino-1,2,4-oxadiazol-5-yl)-1H-indazol-3(2H)-one
  • Step 4 1-(2-(Difluoromethoxy)benzyl)-2-methyl-6-(2-morpholinopyrimidin-5-yl)-1H-pyrazolo[4,3-b]pyridin-3(2H)-one
  • 2,6-Dichloronicotinic acid (tech ⁇ 90%) (1.5 g, 7.8 mmol) in DCM (35 mL) was treated with oxalyl dichloride (0.84 mL, 9.6 mmol) and a few drops of DMF then stirred at rt for about 14 h.
  • the mixture was concentrated under reduced pressure then dissolved in DCM (35 mL).
  • the solution was added to methylhydrazine (1.1 g, 24 mmol) in DCM (35 mL) cooled to about ⁇ 50° C. keeping the reaction temp between ⁇ 40° C. and ⁇ 45° C. during the addition. After completion of addition, the mixture was allowed to warm slowly to rt.
  • Step 4 1-(2-(Difluoromethoxy)benzyl)-2-methyl-6-(2-morpholinopyrimidin-5-yl)-1H-pyrazolo[3,4-b]pyridin-3(2H)-one
  • Oxalyl dichloride (5.5 mL, 63 mmol) was added to a suspension of 4,6-dichloronicotinic acid (10.0 g, 52.1 mmol) in DCM (240 mL).
  • DMF (0.10 mL, 1.3 mmol) was added to the reaction dropwise and the reaction was stirred at rt for about 16 h.
  • the reaction was concentrated under reduced pressure.
  • the residue was dissolved in DCM (240 mL).
  • the solution was added to a solution of methylhydrazine (8.2 mL, 160 mmol) in DCM (240 mL) cooled to about ⁇ 50° C. at a rate to maintain the reaction temp between about ⁇ 40° C. and ⁇ 45° C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US15/130,279 2015-04-17 2016-04-15 Indazolones as modulators of tnf signaling Abandoned US20160304496A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US15/130,279 US20160304496A1 (en) 2015-04-17 2016-04-15 Indazolones as modulators of tnf signaling
US15/670,708 US10160748B2 (en) 2015-04-17 2017-08-07 Indazolones as modulators of tnf signaling

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201562149232P 2015-04-17 2015-04-17
US201562258651P 2015-11-23 2015-11-23
US15/130,279 US20160304496A1 (en) 2015-04-17 2016-04-15 Indazolones as modulators of tnf signaling

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US15/670,708 Continuation US10160748B2 (en) 2015-04-17 2017-08-07 Indazolones as modulators of tnf signaling

Publications (1)

Publication Number Publication Date
US20160304496A1 true US20160304496A1 (en) 2016-10-20

Family

ID=57127036

Family Applications (2)

Application Number Title Priority Date Filing Date
US15/130,279 Abandoned US20160304496A1 (en) 2015-04-17 2016-04-15 Indazolones as modulators of tnf signaling
US15/670,708 Active US10160748B2 (en) 2015-04-17 2017-08-07 Indazolones as modulators of tnf signaling

Family Applications After (1)

Application Number Title Priority Date Filing Date
US15/670,708 Active US10160748B2 (en) 2015-04-17 2017-08-07 Indazolones as modulators of tnf signaling

Country Status (5)

Country Link
US (2) US20160304496A1 (zh)
EP (1) EP3294726A1 (zh)
TW (1) TW201706258A (zh)
UY (1) UY36629A (zh)
WO (1) WO2016168633A1 (zh)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10160748B2 (en) 2015-04-17 2018-12-25 Abbvie Inc. Indazolones as modulators of tnf signaling
US10266532B2 (en) 2015-04-17 2019-04-23 Abbvie Inc. Tricyclic modulators of TNF signaling
US10273238B2 (en) 2015-04-17 2019-04-30 Abbvie Inc. Indazolones as modulators of TNF signaling

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB201510758D0 (en) 2015-06-18 2015-08-05 Ucb Biopharma Sprl Novel TNFa structure for use in therapy
GB201621907D0 (en) 2016-12-21 2017-02-01 Ucb Biopharma Sprl And Sanofi Antibody epitope
TWI770157B (zh) 2017-04-10 2022-07-11 德商拜耳廠股份有限公司 經取代之n-芳基乙基-2-胺基喹啉-4-甲醯胺及其用途
US11161838B2 (en) 2018-11-13 2021-11-02 Incyte Corporation Heterocyclic derivatives as PI3K inhibitors
WO2020102198A1 (en) 2018-11-13 2020-05-22 Incyte Corporation Heterocyclic derivatives as pi3k inhibitors
WO2020102216A1 (en) * 2018-11-13 2020-05-22 Incyte Corporation Substituted heterocyclic derivatives as pi3k inhibitors
CN113939513A (zh) * 2019-04-17 2022-01-14 阿里戈斯治疗公司 双环和三环化合物
US11845752B2 (en) 2020-10-15 2023-12-19 Aligos Therapeutics, Inc. Substituted imidazo[1,5-a]pyrazines for the treatment of hepatitis B

Family Cites Families (77)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8609175D0 (en) 1986-04-15 1986-05-21 Ici America Inc Heterocyclic carboxamides
GB9930750D0 (en) 1999-12-29 2000-02-16 Novartis Ag Organic compounds
EP1583745A1 (en) 2003-01-03 2005-10-12 Boehringer Ingelheim Pharmaceuticals Inc. 1-propanol and 1-propylamine derivatives and their use as glucocorticoid ligands
WO2004093872A1 (en) 2003-03-31 2004-11-04 Eli Lilly And Company 3-oxo-1, 3-dihydro-indazole-2-carboxylic acid amide derivatives as phospholipase inhibitors
US7244843B2 (en) 2003-10-07 2007-07-17 Bristol-Myers Squibb Company Modulators of serotonin receptors
ES2241496B1 (es) 2004-04-15 2006-12-01 Almirall Prodesfarma, S.A. Nuevos derivados de piridina.
GB0412741D0 (en) 2004-06-08 2004-07-07 Univ St Andrews "A multicore chemical compound library"
US20070254872A1 (en) 2004-07-08 2007-11-01 Glaxo Group Limited Antibacterial Agents
US7928107B2 (en) 2004-09-02 2011-04-19 Vertex Pharmaceuticals Incorporated Quinazolines useful as modulators of ion channels
AR051596A1 (es) 2004-10-26 2007-01-24 Irm Llc Compuestos heterociclicos condensados nitrogenados como inhibidores de la actividad del receptor canabinoide 1; composiciones farmaceuticas que los contienen y su empleo en la preparacion de medicamentos para el tratamiento de trastornos alimentarios
FR2884252B1 (fr) 2005-04-08 2007-05-18 Aventis Pharma Sa Nouveaux derives d'isoindoles, compositions les contenant, leur preparation et leurs utilisations pharmaceutiques notamment en tant qu'inhibiteurs d'activites de la proteine chaperone hsp90
KR100739118B1 (ko) 2005-07-22 2007-07-13 이제호 Ｍｓｘ1 단백질 또는 이를 코딩하는 유전자의 신규한 용도
DE102005048897A1 (de) 2005-10-12 2007-04-19 Sanofi-Aventis Deutschland Gmbh Diacylindazol-derivate als Inhibitoren von Lipasen und Phospholipasen
TW200800911A (en) 2005-10-20 2008-01-01 Biolipox Ab Pyrazoles useful in the treatment of inflammation
DE102006014688A1 (de) 2006-03-28 2007-10-04 Sanofi-Aventis Azolopyridin-3-on-derivate als Inhibitoren von Lipasen und Phospholipasen
PE20080695A1 (es) 2006-04-27 2008-06-28 Banyu Pharma Co Ltd Derivados de dihidropirazolopirimidinona como inhibidores de quinasa weel
US7906506B2 (en) 2006-07-12 2011-03-15 3M Innovative Properties Company Substituted chiral fused [1,2] imidazo [4,5-c] ring compounds and methods
ZA200902382B (en) 2006-10-19 2010-08-25 Signal Pharm Llc Heteroaryl compounds, compositions thereof, and their use as protein kinase inhibitors
EP2099450A4 (en) 2006-10-20 2011-01-26 Merck Sharp & Dohme NIACIN RECEPTOR AGONISTS, COMPOSITIONS CONTAINING THESE COMPOUNDS, AND METHODS OF TREATMENT
TW200825063A (en) 2006-10-23 2008-06-16 Astrazeneca Ab Chemical compounds
WO2008141385A1 (en) 2007-05-21 2008-11-27 Biota Scientific Management Pty Ltd Viral polymerase inhibitors
JP2009035531A (ja) 2007-07-10 2009-02-19 Osaka Prefecture Univ ヒドラジド体、および１−置換−１，２−ジヒドロインダゾール−３−オン誘導体インドール化合物の製造方法並びにヒドラジド体、および１−置換−１，２−ジヒドロインダゾール−３−オン誘導体
TW201012803A (en) 2008-06-06 2010-04-01 Organon Nv Heterocyclic derivatives
WO2010017105A1 (en) 2008-08-02 2010-02-11 Janssen Pharmaceutica N.V. Urotensin ii receptor antagonists
US8569336B2 (en) 2008-11-10 2013-10-29 Ling Tong Compounds for the treatment of inflammatory disorders
WO2010084402A2 (en) 2009-01-22 2010-07-29 Orchid Research Laboratories Ltd. Heterocyclic compounds as phosphodiesterase inhibitors
EP2396327A1 (en) 2009-02-11 2011-12-21 Sunovion Pharmaceuticals Inc. Histamine h3 inverse agonists and antagonists and methods of use thereof
US8691187B2 (en) 2009-03-23 2014-04-08 Eli Lilly And Company Imaging agents for detecting neurological disorders
MX2011010203A (es) 2009-04-02 2011-10-14 Merck Patent Gmbh Derivados de piperidina y piperazina como inhibidores de autotaxina.
WO2011062864A2 (en) 2009-11-17 2011-05-26 Emory University Inhibitors of nox enzymes and methods of use thereof
WO2011116356A2 (en) 2010-03-19 2011-09-22 Sanford-Burnham Medical Research Institute Positive allosteric modulators of group ii mglurs
TWI445696B (zh) 2010-11-29 2014-07-21 Univ Nat Yang Ming 標靶人類胸線核苷酸激酶誘導惡性腫瘤中的ｄｎａ修復毒性
WO2012088124A2 (en) 2010-12-21 2012-06-28 Albany Molecular Research, Inc. Tetrahydro-azacarboline mch-1 antagonists, methods of making, and uses thereof
US8754114B2 (en) 2010-12-22 2014-06-17 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US9938269B2 (en) 2011-06-30 2018-04-10 Abbvie Inc. Inhibitor compounds of phosphodiesterase type 10A
EP2736896B1 (en) 2011-07-26 2016-12-14 Nerviano Medical Sciences S.r.l. 3-oxo-2,3-dihydro-1h-indazole-4-carboxamide derivatives as parp-1 inhibitors
US9550737B2 (en) 2012-06-11 2017-01-24 Ucb Biopharma Sprl TNF -α modulating benzimidazoles
GB201212513D0 (en) 2012-07-13 2012-08-29 Ucb Pharma Sa Therapeutic agents
CN104619709B (zh) * 2012-07-13 2016-11-09 Ucb生物制药私人有限公司 作为tnf活性调节剂的咪唑并吡啶衍生物
US9637483B2 (en) 2013-03-28 2017-05-02 Takeda Pharmaceutical Company Limited Heterocyclic compound
GB201321732D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
GB201321734D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic Agents
RU2685234C1 (ru) 2013-12-09 2019-04-17 Юсб Байофарма Спрл Конденсированные бициклические гетероароматические производные в качестве модуляторов активности tnf
GB201321741D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
GB201321738D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic Agents
GB201321728D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
GB201321733D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
GB201321739D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
US9920052B2 (en) 2013-12-09 2018-03-20 Ucb Biopharma Sprl Imidazopyridine derivatives as modulators of TNF activity
GB201321729D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
GB201321749D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
GB201321740D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
GB201321731D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
GB201321744D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
GB201321746D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
GB201321748D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
GB201321735D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic Agents
GB201321737D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic Agents
GB201321745D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
GB201321743D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
GB201321736D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
GB201321742D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
GB201321730D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
KR20160100329A (ko) 2013-12-20 2016-08-23 3-브이 바이오사이언시스, 인코포레이티드 지질 합성의 헤테로사이클릭 조절물질 및 이들의 조합물
BR112017006669B1 (pt) 2014-10-03 2023-04-18 Ucb Biopharma Sprl Derivados de imidazol pentacíclico fundido, composição farmacêutica compreendendo os mesmos e uso dos mesmos
JP6779899B2 (ja) 2015-03-18 2020-11-04 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Ｔｎｆ阻害剤として有用なヘテロ環式化合物
EA032315B1 (ru) 2015-03-18 2019-05-31 Бристол-Маерс Сквибб Компани Замещенные трициклические гетероциклические соединения
CA2982446A1 (en) 2015-03-18 2016-09-22 Bristol-Myers Squibb Company Tricyclic heterocyclic compounds useful as inhibitors of tnf
WO2016168638A1 (en) 2015-04-17 2016-10-20 Abbvie Inc. Indazolones as modulators of tnf signaling
UY36629A (es) 2015-04-17 2016-11-30 Abbvie Inc Indazolonas como moduladores de la señalización de tnf
EP3288939A1 (en) 2015-04-17 2018-03-07 AbbVie Inc. Tricyclic modulators of tnf signaling
GB201509893D0 (en) 2015-06-08 2015-07-22 Ucb Biopharma Sprl Therapeutic agents
GB201509885D0 (en) 2015-06-08 2015-07-22 Ucb Biopharma Sprl Therapeutic agents
GB201509888D0 (en) 2015-06-08 2015-07-22 Ucb Biopharma Sprl Therapeutic agents
GB201510758D0 (en) 2015-06-18 2015-08-05 Ucb Biopharma Sprl Novel TNFa structure for use in therapy
BR112018001960A2 (pt) 2015-08-03 2018-09-18 Bristol-Myers Squibb Company compostos heterocíclicos úteis como moduladores de tnf alfa
US10335392B2 (en) 2015-08-03 2019-07-02 Bristol-Myers Squibb Company Cyclic compounds useful as modulators of TNF α

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Database CAPLUS in STN, Acc. No. 2005:1154552, VIDAL et al., WO 2005/100353 A1 (10/27/2005) (abstract). *
Database CAPLUS in STN, Acc. No. 2008:276955, CAPPELLI et al., Journal of Medicinal Chemistry (2008), 51(7), pp. 2137-2146 (abstract). *
Database CAPLUS in STN, Acc. No. 2009:1290752, VIDAL'-KHUAN et al., RU 2370496 C2 (10/20/2009) (abstract). *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10160748B2 (en) 2015-04-17 2018-12-25 Abbvie Inc. Indazolones as modulators of tnf signaling
US10266532B2 (en) 2015-04-17 2019-04-23 Abbvie Inc. Tricyclic modulators of TNF signaling
US10273238B2 (en) 2015-04-17 2019-04-30 Abbvie Inc. Indazolones as modulators of TNF signaling

Also Published As

Publication number Publication date
UY36629A (es) 2016-11-30
TW201706258A (zh) 2017-02-16
US20180086737A1 (en) 2018-03-29
WO2016168633A1 (en) 2016-10-20
US10160748B2 (en) 2018-12-25
EP3294726A1 (en) 2018-03-21

Similar Documents

Publication Publication Date Title
US10160748B2 (en) Indazolones as modulators of tnf signaling
US10280184B2 (en) Heterocyclic kinase inhibitors
JP6509838B2 (ja) Ｂｔｋ阻害薬としての一級カルボキサミド類
US8785639B2 (en) Substituted dihydropyrazolo[3,4-D]pyrrolo[2,3-B]pyridines and methods of use thereof
US7709468B2 (en) Imidazo based heterocycles
US10266532B2 (en) Tricyclic modulators of TNF signaling
US20060074102A1 (en) Kinase inhibitors as therapeutic agents
US10273238B2 (en) Indazolones as modulators of TNF signaling
US10106501B2 (en) Nuclear receptor modulators
JP2012505152A (ja) 新規な三環式化合物
US9150592B2 (en) Heterocyclic nuclear hormone receptor modulators
WO2016198908A1 (en) Ror nuclear receptor modulators
US20080249305A1 (en) Novel imidazole based heterocycles

Legal Events

Date Code Title Description
AS Assignment

Owner name: ABBVIE, INC., ILLINOIS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ARGIRIADI, MARIA A.;BREINLINGER, ERIC C.;DIETRICH, JUSTIN D.;AND OTHERS;SIGNING DATES FROM 20160922 TO 20161029;REEL/FRAME:040183/0929

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO PAY ISSUE FEE

AS Assignment

Owner name: ABBVIE INC., ILLINOIS

Free format text: CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE NAME PREVIOUSLY RECORDED ON REEL 040183 FRAME 0929. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT;ASSIGNORS:ARGIRIADI, MARIA A.;BREINLINGER, ERIC C.;DIETRICH, JUSTIN D.;AND OTHERS;SIGNING DATES FROM 20160922 TO 20161029;REEL/FRAME:043943/0480