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WO2007058990A2 - Therapy using cytokine inhibitors - Google Patents

Therapy using cytokine inhibitors Download PDF

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Publication number
WO2007058990A2
WO2007058990A2 PCT/US2006/043896 US2006043896W WO2007058990A2 WO 2007058990 A2 WO2007058990 A2 WO 2007058990A2 US 2006043896 W US2006043896 W US 2006043896W WO 2007058990 A2 WO2007058990 A2 WO 2007058990A2
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WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
alkyl
tert
phenyl
Prior art date
Application number
PCT/US2006/043896
Other languages
French (fr)
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WO2007058990A3 (en
Inventor
Nancy Delaet
Christopher Larson
Kent Pryor
Bonnie Hepburn
Robin Allgren
Bernard D. King
Original Assignee
Kemia, Inc.
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Application filed by Kemia, Inc. filed Critical Kemia, Inc.
Publication of WO2007058990A2 publication Critical patent/WO2007058990A2/en
Publication of WO2007058990A3 publication Critical patent/WO2007058990A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

  • the present invention relates to methods of treating, modifying and managing cytokine mediated diseases, which comprise the administration of a cytokine inhibitor alone or in combination with known therapeutics.
  • the invention also relates to pharmaceutical compositions and dosing regimens.
  • the invention relates to the use of cytokine inhibitors, optionally in conjunction with other therapies, for the treatment of autoimmune diseases, more particularly pemphigus.
  • cytokines The functioning of the immune system is finely balanced by the activities of proinflammatory and anti-inflammatory mediators or cytokines.
  • Some cytokines promote inflammation and are called proinflammatory cytokines, whereas other cytokines suppress the activity of proinflammatory cytokines and are referred to as anti-inflammatory cytokines.
  • IL-4, IL-10, and IL- 13 are potent activators of B lymphocytes, but are also potent anti -inflammatory agents. They are anti -inflammatory cytokines by virtue of their ability to suppress genes for proinflammatory cytokines such as IL-I, TNF, and chemokines (CA. Dinarello, Chest. 2000, 118: 503-508).
  • autoimmune diseases arise when immune system cells (lymphocytes, macrophages) become sensitized against the "self. Lymphocytes as well as macrophages are usually under control in this system. However, a misdirection of the system toward the body's own tissues may happen in response to still unexplained triggers.
  • lymphocytes recognize an antigen which mimics the "self and a cascade of activation of different components of the immune system takes place, ultimately leading to tissue destruction. Genetic predisposition has also been postulated to be responsible for autoimmune disorders.
  • Pemphigus is an autoimmune disorder in which the immune system produces antibodies against specific proteins in the skin and mucous membranes. These antibodies produce a reaction that leads to a separation of epidermal cells (acantholysis).
  • autoantibodies The exact cause of the development of antibodies against the body's own tissues (autoantibodies) is unknown, but the cytokines TNF-alpha (TNFa) 5 IL-6, and IL-10 can be detected at elevated levels in blister fluid from patients with pemphigus vulgaris.
  • Typical for the disease are burn-like lesions that will not heal, which result in the loss of intercellular adhesion between the keratinocytes leading to bulla (blister) formation (Sharpe, R. J.
  • Pemphigus vulgaris and pemphigus vegetans are characterized by the formation of blisters above the basal layer of the skin. In pemphigus foliaceus and pemphigus erythematosus, blisters are observed just below the stratum corneum.
  • Cicatricial Pemphigoid involves primarily the mucous membranes (Baden, L.
  • a method of treating pemphigus which comprises administering to a subject in need of such treatment a composition comprising a therapeutically effective amount of a cytokine inhibitor as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof.
  • Cytokine inhibitors of the invention may be used alone or as combinations of any two or more thereof.
  • Cytokine inhibitors useful in the invention are exemplified by Formulas IA,
  • cytokine inhibitors useful in the invention comprise: a targeting moiety comprising at least an amide group having an amide NH, the targeting moiety capable of forming one or more hydrogen bonds with a target protein, and wherein the targeting moiety is not a urea group; a pocket-expanding moiety directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non-planar hydrophobic moiety, said non-planar moiety capable of forming hydrophobic interactions with the target protein; and an orienting moiety comprising a planar hydrophobic moiety and attached to a different atom of the targeting moiety than the pocket-expanding moiety, said orienting moiety capable of forming a ⁇ - ⁇ or edge-to-face aromatic interaction with the target protein.
  • the pemphigus is pemphigus vulgaris, pemphigus vegetans, pemphigus foliaceus, pemphigus erythematosus, bullous pemphigoid, paraneoplastic pemphigus, cicatricial pemphigoid, bullous impetigo, or staphylococcal scalded-skin syndrome.
  • methods comprising administering to a subject in need thereof a combination of (i) an effective amount of a cytokine inhibitor of the invention and (ii) an effective amount of one or more therapeutic Ingredients A useful in the treatment of pemphigus as described herein, wherein the effective amount of Ingredients A is less than the effective amount of Ingredient A when used alone.
  • kits comprising administering to a subject exhibiting one or more clinical indicia of pemphigus an amount of a cytokine inhibitor of the invention effective to reduce the number and/or severity of clinical indicia of pemphigus relative to those present in the subject prior to the administration of the cytokine inhibitor, wherein the clinical indicia of pemphigus include the percentage of total body surface area (BSA) affected by pemphigus, pemphigus lesion thickness, the number of new pemphigus lesions, the number of active pemphigus lesions (including blisters and erosions), the healing time of active lesions (for example, time to 80% healing), serum anti-desmoglein-1 (DSGl) antibody levels, serum anti-DSG3 antibody levels, serum TNFa-levels, serum IL6 levels, skin TNFa- mRNA levels, skin IL6 mRNA levels, or any two or more thereof.
  • BSA total body surface area
  • DSGl serum anti-desmoglein
  • the methods additionally comprise administering to the subject an effective amount of one or more Ingredients A, useful in the treatment of pemphigus, as described herein.
  • the effective amount of Ingredients A is less than the effective amount of Ingredient A when used alone.
  • Combination therapy with therapeutic Ingredients A in the methods of the invention provides a beneficial therapeutic effect, particularly an additive or over-additive effect and/or an overall reduction of side effects of the therapy.
  • cytokine inhibitors of the invention may allow for a reduction in the amount of Ingredient A needed to produce the same therapeutic effect compared to the amount of Ingredient A used alone.
  • a variety of Ingredients A are contemplated for use in the combinations of the invention, as described herein. The beneficial effects are observed both when the cytokine inhibitors and Ingredient(s) A are administered simultaneously in a single formulation and when they are administered successively in separate formulations.
  • the methods further comprise administering to the subject an Ingredient A, wherein the Ingredient A is an antiinflammatory agent, an immunosuppressant, an anti-infective, an antibiotic, a gold salt, an alkylating agent, an immunoglobulin, or a combination of two or more thereof.
  • the Ingredient A is an antiinflammatory agent, an immunosuppressant, an anti-infective, an antibiotic, a gold salt, an alkylating agent, an immunoglobulin, or a combination of two or more thereof.
  • the anti-inflammatory may be a corticosteroid, a COX-2 inhibitor, a non-steroidal antiinflammatory drug (NSAID), a TNFa antagonist, or an IL-I antagonist.
  • the corticosteroid can be prednisone, prednisolone, or methylprednisolone.
  • Corticosteroids such as these may also be administered with either chlorambusil or mycophenylate mofetil.
  • the TNFa antagonist is infliximab, etanercept, or adalimumab.
  • the IL-I antagonist is anakinra.
  • the immunosuppressant is mycophenylate mofetil, cyclosporin, azathioprine, methotrexate, alefacept, rituximab, anti-interferon gamma, or cyclophosphamide.
  • the anti-infective is dapsone, or hydroxychloroquine.
  • the gold salt is myochrysine, or solganal.
  • the alkylating agent is lukeran.
  • the antibiotic is tetracycline, minocycline, or doxycycline.
  • the method further comprises administration of nicotinamide, or niacinamide.
  • the methods of the invention further comprise administering plasmapherisis therapy or photophoresis therapy to the subject.
  • Ingredient A is reduced by from about 10% to about 90% in comparison to the dosage used to achieve the same therapeutic effect with Ingredient A alone. In some embodiments, the dosage is reduced by at least about 10%, about 20%, about 30%, about 40%, about 50%, or about 60%.
  • Ingredient A is a corticosteroid, for example, prednisone or prednisolone. In some other embodiments, Ingredient A comprises a corticosteroid and either chlorambusil or mycophenylate mofetil.
  • the dosage of prednisone is reduced to less than about 10 mg/day, less than about 15 mg per day, less than about 20 mg/day, less than about 30 mg/day, less than about 50 mg/day or less than about 70 mg/day.
  • the cytokine inhibitor is administered orally or topically.
  • Ingredient A is a corticosteroid or antibiotic and is administered orally, topically, in a mouthwash or in a mouth spray.
  • Cytokine inhibitors contemplated for use in the methods of the invention include the compounds from List 1.
  • references to a certain element such as hydrogen or H is meant to include all isotopes of that element.
  • an R group is defined to include hydrogen or H, it also includes deuterium and tritium.
  • isotopically labeled compounds are within the scope of the invention.
  • substituted refers to an organic group as defined below (e.g., an alkyl group) in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms.
  • Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom.
  • a substituted group will be substituted with one or more substituents, unless otherwise specified.
  • a substituted group is substituted with 1, 2, 3, 4, 5, or 6 substituents.
  • substituent groups include: halogens (i.e., F, Cl, Br, and I); hydroxyls; alkoxy, alkenoxy, alkynoxy, aryloxy, aralkyloxy, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyls(oxo); carboxyls; esters; urethanes; oximes; hydroxylamines; alkoxyamines; aralkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyls; sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitro groups; nitriles (i.
  • Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups may also be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below.
  • Alkyl groups include straight chain and branched alkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8, 1 to 6, or 1 to 4 carbon atoms.
  • Alkyl groups further include cycloalkyl groups as defined below.
  • straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n- octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
  • Representative substituted alkyl groups may be substituted one or more times with substituents such as those listed above.
  • Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7.
  • Cycloalkyl groups further include mono-, bicyclic and polycyclic ring systems, such as, for example bridged cycloalkyl groups as described below, and fused rings, such as, but not limited to, decalinyl, and the like.
  • polycyclic cycloalkyl groups have three rings. Substituted cycloalkyl groups may be substituted one or more times with, non- hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups, which may be substituted with substituents such as those listed above.
  • Bridged cycloalkyl groups are cycloalkyl groups in which two or more hydrogen atoms are replaced by an alkyl ene brige, wherein the bridge can contain 2 to 6 carbon atoms if two hydrogen atoms are located on the same carbon atom, or 1 to 5 carbon atoms, if the two hydrogen atoms are located on adjacent carbon atoms, or 2 to 4 carbon atoms if the two hydrogen atoms are located on carbon atoms separated by 1 or 2 carbon atoms.
  • Bridged cycloalkyl groups can be bicyclic, such as, for example bicyclo[2.1.1]hexane, or tricyclic, such as, for example, adamantyl.
  • Representative bridged cycloalkyl groups include bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decanyl, adamantyl, noradamantyl, bornyl, or norbornyl groups.
  • Substituted bridged cycloalkyl groups may be substituted one or more times with non-hydrogen and non-carbon groups as defined above.
  • Representative substituted bridged cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted adamantyl groups, which may be substituted with substituents such as those listed above.
  • Cycloalkylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a cycloalkyl group as defined above.
  • cycloalkylalkyl groups have from 4 to 20 carbon atoms, 4 to 16 carbon atoms, and typically 4 to 10 carbon atoms.
  • Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl or both the alkyl and cycloalkyl portions of the group.
  • Representative substituted cycloalkylalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted with substituents such as those listed above.
  • Alkenyl groups include straight and branched chain and cycloalkyl groups as defined above, except that at least one double bond exists between two carbon atoms.
  • alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms.
  • alkenyl groups include cycloalkenyl groups having from 4 to 20 carbon atoms, 5 to 20 carbon atoms, 5 to 10 carbon atoms, or even 5, 6, 7, or 8 carbon atoms.
  • Representative substituted alkenyl groups may be mono- substituted or substituted more than once, such as, but not limited to, mono-, di- or tri- substituted with substituents such as those listed above.
  • Cycloalkenylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above. Substituted cycloalkylalkenyl groups may be substituted at the alkyl, the cycloalkenyl or both the alkyl and cycloalkenyl portions of the group. Representative substituted cycloalkenylalkyl groups may be substituted one or more times with substituents such as those listed above.
  • Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms.
  • Representative substituted alkynyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted with substituents such as those listed above.
  • Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
  • Aryl groups include monocyclic, bicyclic and polycyclic ring systems.
  • aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenylenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups.
  • aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6-10 carbon atoms in the ring portions of the groups.
  • aryl groups includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like), it does not include aryl groups that have other groups, such as alkyl or halo groups, bonded to one of the ring members. Rather, groups such as tolyl are referred to as substituted aryl groups. Representative substituted aryl groups may be mono-substituted or substituted more than once.
  • monosubstituted aryl groups include, but are not limited to, 2-, 3-, A-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with substituents such as those listed above.
  • Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
  • aralkyl groups contain 7 to 20 carbon atoms, 7 to 14 carbon atoms or 7 to 10 carbon atoms.
  • Substituted aralkyl groups may be substituted at the alkyl, the aryl or both the alkyl and aryl portions of the group.
  • Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4- ethyl-indanyl.
  • Representative substituted aralkyl groups may be substituted one or more times with substituents such as those listed above.
  • Heterocyclyl groups include aromatic (also referred to as heteroaryl) and non- aromatic ring compounds containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N 3 O, and S.
  • heterocyclyl groups include 3 to 20 ring members, whereas other such groups have 3 to 6, 3 to 10, 3 to 12, or 3 to 15 ring members.
  • Heterocyclyl groups encompass unsaturated, partially saturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl groups.
  • heterocyclyl group includes fused ring species including those comprising fused aromatic and non-aromatic groups, such as, for example, benzotriazolyl, 2,3-dihydrobenzo[l,4]dioxinyl, and benzo[l,3]dioxolyl.
  • the phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl.
  • the phrase does not include heterocyclyl groups that have other groups, such as alkyl, oxo or halo groups, bonded to one of the ring members. Rather, these are referred to as "substituted heterocyclyl groups".
  • Heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl,
  • substituted heterocyclyl groups may be mono- substituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed above.
  • Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridyl), indazolyl, benzimidazolyl, imidazopyridyl (azabenzimidazolyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl, benzoxazolyl, benzothi
  • heteroaryl groups includes fused ring compounds such as indolyl and 2,3-dihydro indolyl, the phrase does not include heteroaryl groups that have other groups bonded to one of the ring members, such as alkyl groups. Rather, heteroaryl groups with such substitution are referred to as "substituted heteroaryl groups.” Representative substituted heteroaryl groups may be substituted one or more times with various substituents such as those listed above.
  • Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heterocyclyl group as defined above. Substituted heterocyclylalkyl groups may be substituted at the alkyl, the heterocyclyl or both the alkyl and heterocyclyl portions of the group.
  • heterocyclyl alkyl groups include, but are not limited to, 4-ethyl-morpholinyl, 4- propylmorpholinyl, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
  • Representative substituted heterocyclylalkyl groups may be substituted one or more times with substituents such as those listed above.
  • Heteroaralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above. Substituted heteroaralkyl groups may be substituted at the alkyl, the heteroaryl or both the alkyl and heteroaryl portions of the group. Representative substituted heteroaralkyl groups may be substituted one or more times with substituents such as those listed above.
  • Alkoxy groups are hydroxyl groups (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of a substituted or unsubstituted alkyl group as defined above.
  • linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like.
  • branched alkoxy groups include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like.
  • cycloalkoxy groups include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Representative substituted alkoxy groups may be substituted one or more times with substituents such as those listed above.
  • aryloxy and arylalkoxy refer to, respectively, a substituted or unsubstituted aryl group bonded to an oxygen atom and a substituted or unsubstituted aralkyl group bonded to the oxygen atom at the alkyl. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy. Representative substituted aryloxy and arylalkoxy groups may be substituted one or more times with substituents such as those listed above.
  • Carboxylate refers to a -COOH group.
  • carboxylic ester refers to -COOR 30 groups.
  • R 30 is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
  • amide (or “amido”) includes C- and N-amide groups, i.e.,
  • R 31 and R 32 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
  • Amido groups therefore include but are not limited to carbamoyl groups (-C(O)NH 2 ) and formamide groups (-NHC(O)H).
  • Urethane groups include N- and O-urethane groups, i.e., -NR 33 C(O)OR 34 and
  • R 33 and R 34 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein.
  • amine refers to -NHR 35 and -NR 36 R 37 groups, wherein R 35 , R 36 and R 37 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
  • the amine is NH 2 , methylamino, dimethyl amino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.
  • sulfonamido includes S- and N-sulfonamide groups, i.e.,
  • R 38 and R 39 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein.
  • Sulfonamido groups therefore include but are not limited to sulfamoyl groups (-SO 2 NH 2 ).
  • thiol refers to -SH groups
  • sulfides include -SR 40 groups
  • sulfoxides include -S(O)R 41
  • sulfones include -SO 2 R 42 groups
  • sulfonyls include - SO 2 OR 43 .
  • R 40 , R 41 , R 42 , and R 43 are each independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • urea refers to -NR 44 -C(O)-NR 45 R 46 groups.
  • R 44 , R 45 , and R 46 groups are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.
  • amidine refers to -C(NR 47 )NR 48 R 49 and -NR 47 C(NR 48 )R 49 groups, wherein R 47 , R 48 , and R 49 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • guanidine refers to -NR 50 C(NR 5 ')NR 52 R 53 groups, wherein R 50 ,
  • R 51 , R 52 and R 53 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • R 54 , R 55 , R 56 and R 57 are each independently hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • imide refers to -C(O)NR 58 C(O)R 59 groups, wherein R 58 and R 59 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • the term "imine” refers to -CR 60 (NR 61 ) and -N(CR 60 R 61 ) groups, wherein R 60 and R 61 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein, with the proviso that R 60 and R 61 are not both simultaneously hydrogen.
  • protected with respect to hydroxyl groups, amine groups, carboxy groups, and sulfliydryl groups refers to forms of these functionalities which are protected from undesirable reaction by means of protecting groups.
  • Protecting groups are known to those skilled in the art and can be added or removed using well-known procedures such as those set forth in Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999).
  • Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate.
  • a reagent such as, but not limited to
  • N-Protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p- bro
  • Typical N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-b ⁇ tyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • Examples of protected sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, S-t-butylthioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
  • thioethers such as S-benzyl thioether, S-t-butylthioether, and S-4-picolyl thioether
  • substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals
  • carboxy protecting groups are Ci to Cg alkyl (e.g., methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cyclopentyl and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cyclopentylmethyl and the like; arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl (e.g., dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as
  • Tautomers refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:
  • Stereoisomers of compounds include all chiral, diastereomeric, and racemic forms and all geometric isomeric forms of a structure, unless the specific stereochemistry or isomeric form is specifically indicated.
  • compounds used in the present invention include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of the invention.
  • Certain compounds within the scope of Formulas IA 3 IB, IC and II are derivatives referred to as "prodrugs".
  • prodrug denotes a derivative of a known direct acting drug, e.g. esters and amides, which derivative has enhanced delivery characteristics and therapeutic value as compared to the drug, and is transformed into the active drug by an enzymatic or chemical process; see Notari, R.E., "Theory and Practice of Prodrug Kinetics," Methods in Enzymology 1985, 112: 309-323; Bodor, N., “Novel Approaches in Prodrug Design,” Drugs of the Future 1981, 6: 165-182; and Bundgaard, H., “Design of Prodrugs: Bioreversible-Derivatives for Various Functional Groups and Chemical Entities,” in Design of Prodrugs (H.
  • compositions are within the scope of the present invention.
  • pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid).
  • inorganic acids such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid
  • organic acids e.g., formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, male
  • the compound of the invention when it has an acidic group, such as for example, a carboxylic acid group, it can form salts with metals, such as alkali and earth alkali metals (e.g. Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+ ), ammonia, organic amines (e.g., trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e.g., arginine, lysine and ornithine).
  • alkali and earth alkali metals e.g. Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+
  • ammonia e.g., organic amines (e.g., trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e
  • a "cytokine inhibitor" within the context of this invention is a compound which at a concentration of 10 ⁇ M inhibits induced cytokine release from a cell by about 50% or greater than 50%.
  • induction of TNFa release can be achieved by, but not limited to, treatment of a cell or cell line with lipopolysaccharide (LPS) or IL-Ib and is inhibited by compounds described herein.
  • LPS lipopolysaccharide
  • IL-Ib IL-Ib
  • “Treating” within the context of the instant invention means an alleviation, in whole or in part, of symptoms associated with a disorder or disease, or a slowing or halt of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder in a subject.
  • a subject is any animal that can benefit from the administration of a cytokine inhibitor of the invention.
  • the subject is a mammal, for example, a human, a primate, a dog, a cat, a horse, a cow, a pig, a rodent, such as for example a rat or mouse.
  • the mammal is a human.
  • a "therapeutically effective amount" of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with a disorder or disease, or slows or halts of further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disease or disorder.
  • Treatment may also include administering the pharmaceutical formulations of the present invention in combination with other therapies, such as Ingredients A as defined herein.
  • the compounds of the invention can also be administered in conjunction with other anti-inflammatory agents, and other agents described herein.
  • other suitable agents which may be used in combination with the novel compounds of the invention include, but are not limited to, anti-inflammatory agents, immunosuppressants, anti-infectives, antibiotics, gold salts, immunoglobulins, alkylating agents, or a combination of two or more thereof.
  • a therapeutically effective amount of a cytokine inhibitor used in the present invention may vary depending upon the route of administration and dosage form. Effective amounts of invention compounds typically fall in the range of about 0.001 up to 100 mg/kg/day, and more typically in the range of about 0.05 up to 10 mg/kg/day. Typically, the compound or compounds used in the instant invention are selected to provide a formulation that exhibits a high therapeutic index.
  • the therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD50 and ED 5 0.
  • the LD5 0 is the dose lethal to 50% of the population and the ED 50 is the dose therapeutically effective in 50% of the population.
  • the LD 50 and ED 50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals.
  • the instant cytokine inhibitors can be used in the methods and compositions of the invention either alone or together with additional treatments or active ingredients (Ingredients A as described herein) or a combination thereof.
  • the additional active agents can act additively or, more typically, synergistically with the cytokine inhibitor.
  • a cytokine inhibitor is administered concurrently with one or more second active agents in the same pharmaceutical composition.
  • a cytokine inhibitor is administered concurrently with one or more second active agents in separate pharmaceutical compositions.
  • a cytokine inhibitor is administered prior to or subsequent to administration of a second active agent.
  • the invention contemplates administration of a cytokine inhibitor and a second active agent by the same or different routes of administration, e.g., oral and parenteral.
  • a cytokine inhibitor when administered concurrently with a second active agent that potentially produces adverse side effects including, but not limited to, toxicity, the second active agent can advantageously be administered at a dose that falls below the threshold that the adverse side effect is elicited.
  • the cytokine inhibitor is administered in an amount effective to allow for a reduction in the therapeutically effective dosage of Ingredient A compared to the effective amount of Ingredient A when used alone. This reduction in dosage is commonly referred to as Ingredient A sparing.
  • Ingredient A sparing In embodiments wherein Ingredient A is a corticosteroid, corticosteroid sparing is achieved (also called steroid sparing).
  • cytokine inhibitors or combinations of cytokine inhibitors and additional active agents may be adjusted depending on conditions of disease, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the dosage forms described below containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant invention.
  • the invention also provides for pharmaceutical compositions and medicaments which may be prepared by mixing one or more compounds of Formula IA, IB, IC, II, and optionally additional active ingredients, prodrugs thereof, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, or solvates thereof, with pharmaceutically acceptable carriers, excipients, binders, diluents or the like to treat, or prevent disorders associated with excess cytokine production.
  • the compounds and compositions of the invention may be used to prepare formulations and medicaments that prevent or treat a variety of disorders associated with excess cytokine production, e.g., autoimmune diseases and pathological conditions, such as pemphigus.
  • compositions may be administered to subjects to reduce the number and/or severity of clinical indicia of pemphigus as described herein.
  • Such compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions.
  • the instant compositions can be formulated for various routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration, or via implanted reservoir.
  • Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneally, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injections.
  • dosage forms are given by way of example and should not be construed as limiting the instant invention.
  • powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds used in the instant invention, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive such as a starch or other additive.
  • Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides.
  • oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Tablets and pills may be further treated with suitable coating materials known in the art.
  • Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water.
  • compositions and medicaments may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these.
  • a sterile liquid such as, but not limited to, an oil, water, an alcohol, and combinations of these.
  • Pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration.
  • suspensions may include oils.
  • oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil.
  • Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides.
  • Suspension formulations may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol.
  • Ethers such as but not limited to, poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water may also be used in suspension formulations.
  • Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be employed as solvents or suspending agents. Typically, the oil or fatty acid is nonvolatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.
  • the pharmaceutical formulation and/or medicament may be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates.
  • the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • the pharmaceutical formulations and medicaments may be in the form of a suppository, an ointment, an enema, a tablet or a cream for release of compound in the intestines, sigmoid flexure and/or rectum.
  • Rectal suppositories are prepared by mixing one or more compounds used in the instant invention, or pharmaceutically acceptable salts or tautomers of the compound, with acceptable vehicles, for example, cocoa butter or polyethylene glycol, which is present in a solid phase at normal storing temperatures, and present in a liquid phase at those temperatures suitable to release a drug inside the body, such as in the rectum. Oils may also be employed in the preparation of formulations of the soft gelatin type and suppositories.
  • acceptable vehicles for example, cocoa butter or polyethylene glycol
  • suspension formulations which may also contain suspending agents such as pectins, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, as well as buffers and preservatives.
  • suspending agents such as pectins, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, as well as buffers and preservatives.
  • Compounds used in the invention may be administered to the lungs by inhalation through the nose or mouth.
  • suitable pharmaceutical formulations for inhalation include solutions, sprays, dry powders, or aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • Formulations for inhalation administration contain as excipients, for example, lactose, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate.
  • Aqueous and nonaquous aerosols are typically used for delivery of inventive compounds by inhalation.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of the compound together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizes vary with the requirements of the particular compound, but typically include nonionic surfactants (T weens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • Aerosols generally are prepared from isotonic solutions.
  • a nonaqueous suspension e.g., in a fluorocarbon propellant
  • Aerosols containing compounds for use according to the present invention are conveniently delivered using an inhaler, atomizer, pressurized pack or a nebulizer and a suitable propellant, e.g., without limitation, pressurized dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, nitrogen, air, or carbon dioxide.
  • a pressurized aerosol the dosage unit may be controlled by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, for example, 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. Delivery of aerosols of the present invention using sonic nebulizers is advantageous because nebulizers minimize exposure of the agent to shear, which can result in degradation of the compound.
  • the pharmaceutical formulations and medicaments may be a spray, nasal drops or aerosol containing an appropriate solvent(s) and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • the compounds may be formulated in oily solutions or as a gel.
  • any suitable propellant may be used including compressed air, nitrogen, carbon dioxide, or a hydrocarbon based low boiling solvent.
  • Dosage forms for the topical (including buccal and sublingual) or transdermal administration of compounds used in the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches.
  • the active component may be mixed under sterile conditions with a pharmaceutically-acceptable carrier or excipient, and with any preservatives, or buffers, which may be required.
  • Powders and sprays can be prepared, for example, with excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the invention to the body. Such dosage forms can be made by dissolving or dispersing the agent in the proper medium. Absorption enhancers can also be used to increase the flux of the inventive compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Ophthalmic formulations eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
  • the compounds used in this invention can be incorporated into various types of ophthalmic formulations for delivery to the eye (e.g., topically, intracamerally, or via an implant).
  • the compounds are typically incorporated into topical ophthalmic formulations for delivery to the eye.
  • the compounds may be combined with one or more ophthalmologically acceptable preservatives, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution.
  • Ophthalmic solution formulations may be prepared by dissolving a compound in a physiologically acceptable isotonic aqueous buffer.
  • the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the compound.
  • the ophthalmic solution may contain an agent to increase viscosity, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac.
  • Gelling agents can also be used, including, but not limited to, gellan and xanthan gum.
  • sterile ophthalmic ointment formulations the compound of the invention is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum.
  • a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum.
  • Sterile ophthalmic gel formulations may be prepared by suspending the invention compound in a hydrophilic base prepared from the combination of, for example, carbopol-974, or the like, according to the published formulations for analogous ophthalmic preparations. Preservatives and tonicity agents can be optionally incorporated.
  • Intrathecal administration via bolus dosage or constant infusion, allows the local administration of a compound to a region of the spinal cord, such as the dorsal horn regions, delivering the compound directly to the subarachnoid space containing the CSF (cerebrospinal fluid).
  • a region of the spinal cord such as the dorsal horn regions
  • Central delivery to the spinal cord regions can also be performed by epidural injection to a region of the spinal cord exterior to the arachnoid membrane. Enhancing permeation of the active compound through meningeal membranes may be achieved by using hypertonic dosing solutions that increase permeability of meningeal membranes, or by addition of permeation enhancers, such as, but not limited to, liposomal encapsulation, surfactants, or ion-pairing agents.
  • excipients and carriers are generally known to those skilled in the art and are thus included in the instant invention. Such excipients and carriers are described, for example, in "Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.
  • the formulations of the invention may be designed to be short-acting, fast- releasing, long-acting, and sustained-releasing as described below.
  • the pharmaceutical formulations may also be formulated for controlled release or for slow release.
  • compositions may also comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the pharmaceutical formulations and medicaments may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants may employ known inert materials such as silicones and biodegradable polymers.
  • Administration of the cytokine inhibitors and the additional active agents to a subject can occur simultaneously or sequentially by the same or different routes of administration.
  • the suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the disease being treated.
  • a typical route of administration for cytokine inhibitors described herein is oral or topical.
  • Typical routes of administration for the additional active agents or ingredients of the invention are known to those of ordinary skill in the art [See, e.g., Physicians' Desk Reference (57 th ed., 2003)].
  • the cytokine inhibitor and the additional active agents are administrated simultaneously by coformulation.
  • the additional active agent can be administered orally, intravenously, intramuscularly, subcutaneously, mucosally, or transdermally and once or twice daily in an amount of from about 1 to about 3,500 mg, from about 5 to about 2,500 mg, from about 10 to about 500 mg, or from about 25 to about 250 mg.
  • a cytokine inhibitor and an additional active agent are administered to a subject, more typically a human, in a sequence and within a time interval such that the cytokine inhibitor can act together with the other agent to provide an increased benefit than if they were administered otherwise.
  • the additional active agents can be coadminstered by coformulation, administered at the same time or administered sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently close in time so as to provide the desired therapeutic or prophylactic effect.
  • the cytokine inhibitor and the additional active agents exert their effects at times which overlap.
  • Each additional active agent can be administered separately, in any appropriate form and by any suitable route.
  • the cytokine inhibitor is administered before, concurrently or after administration of the additional active agents.
  • the cytokine inhibitor and the additional active agents are administered less than about 1 hour apart, at about 1 hour apart, at about 1 hour to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, no more than 24 hours apart or no more than 48 hours apart.
  • the cytokine inhibitor and the additional active agents are administered concurrently.
  • the cytokine inhibitor and the additional active agents are administered concurrently by coformulation.
  • the cytokine inhibitor and the additional active agents are administered at about 2 to 4 days apart, at about 4 to 6 days apart, at about 1 week part, at about 1 to 2 weeks apart, or more than 2 weeks apart.
  • the cytokine inhibitor and optionally the additional active agents are cyclically administered to a subject. Cycling therapy involves the administration of a first agent for a period of time, followed by the administration of a second agent and/or third agent for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improve the efficacy of the treatment.
  • the cytokine inhibitor and optionally the additional active agent are administered in a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days or about once every week.
  • One cycle can comprise the administration of a cytokine inhibitor and optionally the second active agent by infusion over about 90 minutes every cycle, about 1 hour every cycle, about 45 minutes every cycle.
  • Each cycle can comprise at least 1 week of rest, at least 2 weeks of rest, at least 3 weeks of rest.
  • the number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, and more typically from about 2 to about 8 cycles.
  • the cytokine inhibitor described herein is administered in metronomic dosing regimens, either by continuous infusion or frequent administration without extended rest periods.
  • Such metronomic administration can involve dosing at constant intervals without rest periods.
  • the cytokine inhibitor is used at lower doses.
  • Such dosing regimens encompass the chronic daily administration of relatively low doses for extended periods of time. In typical examples, the use of lower doses can minimize toxic side effects and eliminate rest periods.
  • the cytokine inhibitor is delivered by chronic low-dose or continuous infusion ranging from about 24 hours to about 2 days, to about 1 week, to about 2 weeks, to about 3 weeks to about 1 month to about 2 months, to about 3 months, to about 4 months, to about 5 months, to about 6 months.
  • the scheduling of such dose regimens can be optimized by the skilled artisan.
  • Courses of treatment can be administered concurrently to a subject, i.e., individual doses of the additional active agents are administered separately yet within a time interval such that the cytokine inhibitor can work together with the additional active agents.
  • one component can be administered once per week in combination with the other components that can be administered once every two weeks or once every three weeks.
  • the dosing regimens are carried out concurrently even if the therapeutics are not administered simultaneously or during the same day.
  • cytokine inhibitors used in the instant invention are described below.
  • a first group of compounds are represented by Formula IA,
  • G is a C3-10 carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8-11 membered bicyclic heterocyclyl containing 1 or more heteroatoms selected from O, N or S; wherein G is substituted with one or more R 1 , R 2 or R 3 ;
  • X is C(O), C(S) or CH 2 ;
  • Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, C 6 _io aryl, -(C1- 3 alkyl)-(C6-io aryl), -(Y)-(Co -3 alkyl)-(C 6 .
  • L is a covalent bond or a saturated or unsaturated branched or unbranched Ci. 10 carbon chain, wherein one or more carbon atoms such as methylene groups are optionally independently replaced by heteroatoms selected from O, NR or S(O) m ; and wherein L is optionally substituted with 1-2 oxo groups and/or one or more of F, Cl, Br, or I;
  • Q is hydrogen, -NR'R', cycloalkyl, aryl, heterocyclyl, Ci -6 alkoxy, C] -6 alkyl-S(O) m , or phenyl-S(O) m , wherein the cycloalkyl, aryl, heterocyclyl, Ci -6 alkoxy, Ci -6 alkyl-S(O) m , or phenyl-S(O) m is each optionally substituted with one or more R 27 ; each m is independently 0, 1 or 2; each R is independently hydrogen or substituted or unsubstituted Ci -6 alkyl; each R' is independently hydrogen, substituted or unsubstituted Ci -8 alkyl, substituted or unsubstituted (C0-4 alkyl)-(C6-io aryl) or substituted or unsubstituted (Co ⁇ alkyl)-(5-l 0 member heterocyclyl); each R 1 is independently F, Cl, Br
  • R 20 is substituted or unsubstituted Cj -I0 alkyl, substituted or unsubstituted C 0 - 6 alkyl-phenyl, substituted or unsubstituted Co_ 6 alkyl-heterocyclyl, OR' or NR' 2 ;
  • R 21 is hydrogen or Ci -4 branched or unbranched alkyl optionally partially or fully halogenated; each R 22 , R 23 and R 24 is independently hydrogen, substituted or unsubstituted Ci-io alkyl, wherein the Ci. io alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted C 0 .
  • each R 26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C 0 ⁇ alkyl)amino, wherein the C 0-4 alkyl is optionally partially or fully halogenated; each R 27 is independently F, Cl, Br 5 1, cyano, -C(O)R', -C(O)NR' 2 , -C(O)OR', -OR', -NR'R', -SiR' 3 , - S(O) m R', substituted or unsubstituted Ci-I 0 alkyl, substituted or unsubstituted C 2 - 10 alken
  • the compound at a concentration of 10 ⁇ M inhibits induced TNFa-release from a cell by about 50% or greater than 50%.
  • Ar is -(Y)-(Co-Io aryl) and G is N-(substituted or unsubstituted phenyl)-pyrazolyl, the pyrazolyl is additionally substituted with one or more R 1 , R 2 or R 3 .
  • IA is not N-(5- tert-butyl-2-phenyl-2H-pyrazol-3-yl)-2-(4-chloro-phenyl)-acetamide.
  • G is phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, benzofuran-3-one; pyrazolyl, pyrrolyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzo
  • G is phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, or benzofuran-3-one.
  • G is pyrazolyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl,
  • G is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, isoxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomo ⁇ holinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl.
  • G is phenyl, naphthyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, or pyridinyl.
  • Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, or C ⁇ -io aryl.
  • Ar is substituted with at least one R 4 or R 5 .
  • Ar is indazolyl, isoindolyl, pyrazolyl, pyrrolinyl, phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl or imidazolyl.
  • Ar is indazolyl, phenyl, tetrahydronapthyl or naphthyl.
  • Ar is -(Ci- 3 alkyl)-
  • Ar is substituted with at least one R or R .
  • Y is -CZ 2 - and each Z is independently F, -OR or -CHR.
  • Y is -CF 2 -.
  • Y is -CHR or -CHZ- and Z is -OR.
  • Y is -CHOH-.
  • Y is -O- or -CH 2 -.
  • the C ⁇ -io aryl is phenyl or naphthyl, and/or the 5-10 member heteroaryl is quinolinyl, isoquinolinyl, phthalazinyl, or quinazolinyl.
  • Ar is -(Ci -3 alkyl)-(C 6 -io aryl).
  • one or more methylene groups of L are independently replaced by hetero atoms selected from O, NR or S(O)m.
  • L is a covalent bond, a Cj-Cg alkoxy, -C(O)O-, -NH- or -O-.
  • R 27 hi certain embodiments of the first group of compounds of Formula IA Q is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrrolidinyl, benzimidazolyl, furanyl, thienyl, pyranyl, naphthylpyridinyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolo[3,4-b]pyrimidinyl 5 purinyl, pyrrolo[2,3- b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5-b]pyridinyl, or imidazo[4,5- bjpyridinyl, tetrahydropyranyl, tetrahydro furanyl, 1,
  • R 27 is Cj- ⁇ alkyl, d. 6 alkoxy, hydroxy amino, substituted or unsubstituted 5-10 member heterocyclyl, mono- or di-(Ci- 3 alkyl)amino, mono- or di-(phenyl-Ci -3 alkyl)amino, Ci.
  • Q is hydrogen, phenyl, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinonyl, oxazepinyl, diazepinonyl, imidazolyl, pyridinyl or morpholino.
  • Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl.
  • R 27 is -C(O)OR', -NR'R', substituted or unsubstituted straight or branched C ⁇ 1O alkyl, substituted or unsubstituted C 7-20 aralkyl, or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1 , 2, 3, or 4 heteroatoms independently selected from N, O, or S(O) n ,.
  • Q is pyrimidinyl and R 27 is -NR'R' or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S(O) m .
  • Q is pyridinyl, and R 27 is —NR'R', substituted or unsubstituted Ci- 6 alkyl, or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1 , 2, 3, or 4 heteroatoms independently selected from N, O, or S(O) m .
  • R 4 and R 5 are absent, -L-Q is not -H.
  • each R 1 is independently
  • C 3 . 10 branched or unbranched alkenyl optionally partially or fully halogenated, and optionally substituted with one to three Ci-S branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl; each of the aforementioned being optionally, partially or fully halogenated, Cj.
  • each R 1 is independently C 3 -io branched or unbranched alkyl optionally partially or fully halogenated, and optionally substituted with one to three C 3 .10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, or isothiazolyl; each of which is optionally substituted with 1 to 5 halogen, Ci -6 branched or unbranched alkyl which is optionally partially or fully halogenated, C 3-8 cycloalkyl, Cs -8 cycloalkenyl, hydroxy, cyano, Ci -3 alkoxy which is optionally partially or fully halogenated and NH 2 C(O) or mono- or
  • each R 2 is independently -OR', -OR 6 , -C(O)R', -C(O)OR', -C(O)NR' 2 , -NR' 2 , -NO 2 , -S(O) m R", -NR 3 SO 2 R", -NR'C(O)NR'R ⁇ -NR'C(S)NR'R', -NR 5 C(O)OR' or -SO 2 NR' 2 .
  • each R 2 is independently -NR' 2 , -NO 2 , -C(O)NR' 2 , -NR 5 SO 2 R", -NR 5 C(O)NR 5 R', - NR 1 C(S)NR 1 R 5 , -NR 5 C(O)OR' or -SO 2 NR' 2 .
  • each R 3 is independently phenyl, naphthyl, or heterocyclyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisooxazolyl, benzpyrazolyl,
  • a fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocycle selected from cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclopentanoindole, cyclohexanoindole, cyclobenzimidazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclic ring is optionally
  • R 20 C(O)N(R 21 )-, R 22 O-, R 23 R 24 NC(O)-, R 26 (CH 2 ) ra C(O)N(R 21 )- or R 26 C(O)(CH 2 ) m N(R 21 )-;
  • R 18 is independently hydrogen or Ci-4 branched or unbranched alkyl optionally independently substituted with oxo or R 25 .
  • each R 3 is independently phenyl, naphthyl, or heterocyclyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisooxazolyl, benzpyrazolyl, benzothiofuranyl, 1-3 of phenyl, naph
  • each R 3 is independently phenyl, pyridazinyl or pyridyl, each of which is optionally partially or fully halogenated and optionally substituted with Ci -6 branched or unbranched alkyl which is optionally partially or fully halogenated, hydroxy, oxo, cyano, C 1 - 3 alkoxy optionally partially or fully halogenated, nitro, amino, mono- or di-(Ci- 3 alkyl)amino; C ]-6 alkyl or Ci -6 alkoxy, each optionally partially or fully halogenated or optionally substituted with R 17 , amino, OR 18 , C ]-5 mono- or di-alkylamino optionally substituted with R 19 ; R 20 C(O)N(R 21 )-, R 22 O-, R 23 R 24 NC(O)-, R 26 (CH 2 ) m C(O)N(R 21 )- or R 26 C(O)(CH 2 ) m N(
  • a second group of cytokine inhibitors having Formula IA, stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein the variables G, L, m, Q, R, R', R", R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 1S , R 16 ,R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , and R 27 are as defined for the first group of compounds of Formula IA; and wherein:
  • X is C(O)or C(S);
  • Ar is -(Y)-(C 0-3 alkyl)-(bicyclic aryl), or -(Y)-(Co -3 alkyl)-(bicyclic heteroaryl), wherein the bicyclic heteroaryl is indazolyl, isoindolyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, dihydrobenzoisoxoazolyl, dihydroisoindolyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl, or benzoisothiazolyl dioxide, and wherein Ar is optionally substituted with one or more R 4 or R 5 ; and
  • Y is -C(O)-, -C(N(NRC(O)OR))-, -C(N(NRR))-, -C(N(NC(O)NRR))- or -C(N(OR))-.
  • Ar is -(Y)-(Co O alkyl)-(bicyclic aryl), and the bicyclic aryl is naphthyl, tetrahydronaphthyl, dihydronaphthyl, indenyl, indanyl or azulenyl.
  • Ar is substituted with at least one R 4 or R 5 .
  • Y is -C(O)-, -C(N(NRC(O)OR))- or -C(N(OR))-.
  • Ar is -C(O)-(bicyclic aryl) or -C(NOR)-(bicyclic aryl) and the bicyclic aryl can be naphthyl, dihydronapthyl, tetrahydronaphthyl, indanyl, indenyl or azulenyl.
  • Ar is -(Y)-(Co -3 alkyl)-(bicyclic heteroaryl). In some such embodiments, Ar is substituted with at least one R 4 or R 5 .
  • Y is -C(O)-, -C(N(NRC(O)OR))- or -C(N(OR))-.
  • Ar is -C(O)-(bicyclic heteroaryl) or -C(NOR)-(bicyclic heteroaryl).
  • the bicyclic heteroaryl is quinolinyl, isoquinolinyl, phthalazinyl, or quinazolinyl.
  • each R 1 is independently a substituted or unsubstituted straight or branched C 1- ,o alkyl and each R 3 can be independently R 23 R 24 N-C(O)-, R 20 -C(O)-NR 21 -, or OR 22 .
  • each R 2 is independently -NR 1 SO 2 R", -Cl, -Br, -F, -C(O)-NR' 2 , substituted or unsubstituted straight or branched Ci -6 alkyl, -NR' 2 , or -OR'.
  • each R 1 is independently a substituted or unsubstituted straight or branched Ci-io alkyl
  • each R 3 can be independently phenyl or pyridinyl, optionally substituted with one, two, or three -F, -Cl, substituted or unsubstituted Ci-6 branched or unbranched alkyl or substituted or unsubstituted Ci -4 alkoxy.
  • a third group of compounds having Formula IA, stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof wherein the variables L, m, Q, R, R', R", R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R I6 ,R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , and R 27 are as defined for the first group of compounds of Formula IA; and wherein:
  • G is a C 3-5 cycloalkyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyrrolinyl, pyridazinyl, pyrrolyl, imidazolyl, imidazolonyl, isoxazolyl, furanyl, thienyl, pyridonyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazoly
  • X is C(O)Or C(S);
  • Ar is -(Y)-(Co- 3 alkyl)-(phenyl), or -(Y)-(Co -3 alkyl)-(monocyclic heteroaryl), wherein Ar is optionally substituted with one or more R 4 or R 5 ;
  • Y is -C(O)-, -C(N(NRC(O)OR))-, -C(N(NRR))-, -C(N(NC(O)NRR))- or -C(N(OR))-.
  • R 4 and R 5 are absent, -L-Q is not -H.
  • the pyrazolyl is additionally substituted with one or more R 1 , R 2 or R 3 .
  • G is cyclopropyl, cyclobutyl or cyclopentyl.
  • G is cyclopropyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, or thienyl.
  • Ar is substituted by at least one R 4 or R 5 . In others, Ar is -C(O)-(phenyl).
  • Ar is -(Y)-(Co -3 alkyl)-(monocyclic heteroaryl), and the monocyclic heteroaryl is pyrazolyl, imidazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyrimidinyl or pyridazinyl.
  • Ar is substituted by at least one R 4 or R 5 .
  • Y is -C(O)-, -C(N(NRC(O)OR))- or -C(N(OR))-.
  • Ar is -C(O)- (monocyclic heteroaryl) or -C(N(OR))-(monocyclic heteroaryl).
  • the monocyclic heteroaryl can be pyrazolyl, imidazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyrimidyl, or pyridazinyl.
  • each R 1 is independently a substituted or unsubstituted straight or branched C MO alkyl.
  • each R 3 can be independently phenyl or pyridinyl, optionally substituted with one, two, or three -F, -Cl, substituted or unsubstituted C I -6 branched or unbranched alkyl or substituted or unsubstituted Ci -4 alkoxy.
  • R 4 and R 5 are absent, -L-Q is not -H.
  • Ar is substituted with at least one R 4 or R 5 .
  • Y is -CHR or -CHZ- and Z is -OR.
  • Y is -CH 2 -.
  • the C ⁇ -io aryl is phenyl or naphthyl or the 5-10 member heteroaryl is quinolinyl, isoquinolinyl, phthalazinyl, or quinazolinyl.
  • Ar is -(Ci -3 alkylMCe-io 81 YO-
  • a second group of compounds having Formula IB, stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof wherein the variables L, m, Q, R, R', R", R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 5 R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 ,R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , and R 27 are as defined for the first group of compounds of Formula IA; and wherein:
  • G is a G'-(Y)- wherein G' is a C 3-I o carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8-11 membered bicyclic heterocyclyl other than indolyl containing 1 or more heteroatoms selected from O, N or S, wherein G' is substituted by one or more R 1 , R 2 or R 3 ;
  • X is C(O) or C(S);
  • Ar is bicyclic aryl or 8-1 1 membered bicyclic heteroaryl containing 1 or more heteroatoms selected from O 5 N or S, wherein Ar is optionally substituted with one or more R 4 or R s ;
  • Y is independently -C(O)-, -C(N(NRC(O)OR))-, -C(N(NRR))-, -C(N(NC(O)NRR)) or -C(N(OR))-.
  • R 4 and R 5 are absent, -L-Q is not -H.
  • G' is phenyl, naphthyl, cyclopropyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, benzofuran- 3 -one; pyrazolyl, pyrrolyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl
  • G' is phenyl, naphthyl, cyclopropyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, or benzofuran-3-one.
  • G' is pyrazolyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolonyl, benzo[l,4]oxazin-3-onyl, benzodioxolyl, benzo[l,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, or phthalimi
  • G' is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, isoxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl.
  • G' is phenyl, naphthyl, pyrazolyl, cyclopropyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, or pyridinyl.
  • Y is -C(O)-, -C(N(NRC(O)OR))- or -C(N(OR))-.
  • Ar is naphthyl, dihydronapthyl, tetrahydronaphtyl, indenyl or azulenyl.
  • Ar is indazolyl, isoindolyl, quinolinyl, isoquinolinyl, phthalazinyl, indolyl, dihydroindolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, dihydrobenzoisoxoazolyl, dihydroisoindolyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl or benzoisothiazolyl dioxide.
  • Ar is naphthyl
  • G is C-(Y)-
  • G' is selected from phenyl, pyridinyl, pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl or thienyl.
  • Ar is naphthyl
  • G is G'-(Y)-
  • G' is phenyl or pyridinyl, substituted by one or more R 1 , R 2 or R 3 .
  • each R 1 is independently a substituted or unsubstituted straight or branched C MO alkyl.
  • each R 3 can be independently R 23 R 24 N-C(O)-, R 20 -C(O)-NR 21 -, or OR 22 .
  • each R 2 is independently -NR 5 SO 2 R", -Cl, -Br, -F, -C(O)-NR' 2 , substituted or unsubstituted straight or branched Ci -6 alkyl, -NR'2, or —OR'.
  • each R 1 is independently a substituted or unsubstituted straight or branched C 1- 10 alkyl.
  • each R 3 can be independently substituted or unsubstituted Cj -6 alkyl, pyridinyl or phenyl, optionally substituted with one to three -F, -Cl, substituted or unsubstituted Ci -6 branched or unbranched alkyl, or substituted or unsubstituted Ci- 3 alkoxy.
  • a third group of compounds having Formula IB, stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof wherein the variables L 5 m, Q, R, R', R", R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R I6 ,R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , and R 27 are as defined for the first group of compounds of Formula IA; and wherein:
  • G is a G'-(Y)- wherein G' is a C3-10 cycloalkyl, phenyl, naphthyl, tetrahydronaphthyl other than l,l,4,4-tetramethyl-l,2,3,4-tetrahydronaphthyl, pyrazolyl, thiazolyl, pyridinyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, imidazolyl, furanyl other than furan-2-yl, thienyl other than thien-2-yl, dihydronaphthyl, indanyl, indenyl, quinolinyl.
  • X is C(O) or C(S);
  • Ar is phenyl, pyrimidinyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, pyrrolinyl, pyridazinyl, pyrrolyl, imidazolyl, furanyl, thienyl, pyrimidinyl, pyrazinyl; wherein Ar is optionally substituted with one or more R 4 or R s ; and
  • Y is independently -C(O)-, -C(N(NRC(O)OR))-, -C(N(NRR))-, -C(N(NC(O)NRR))- or -C(N(OR))-.
  • R 4 and R 5 are absent, -L-Q is not -H.
  • Ar-L-Q is -N-(substituted or unsubstituted phenyl)-pyrazolyl and G is phenyl, naphthyl, indane or tetrahydronaphthyl
  • the pyrazolyl is additionally substituted with one or more R 4 or R 5 .
  • the third group of compounds of Formula IB 5 G' is phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydronaphthyl, pyrazolyl, thiazolyl, pyridinyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, imidazolyl, furanyl, thienyl, dihydronaphthyl, indanyl, indenyl, quinolinyl, isoquinolinyl, pyrimidinyl, or pyrazinyl.
  • G' is phenyl, naphthyl, pyrazolyl, cyclopropyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, or pyridinyl.
  • Ar is phenyl, pyrazoly, imidazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, or pyrimidinyl.
  • Ar is phenyl
  • G is G'-(Y)-
  • G' is selected from phenyl, pyridinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl or thienyl.
  • Ar is phenyl
  • G is G '-(Y)-
  • G' is phenyl or pyridinyl, substituted by one or more R 1 , R 2 or R 3 .
  • each R 1 is independently a substituted or unsubstituted straight or branched Cj. i 0 alkyl.
  • each R 3 can be independently R 23 R 24 N-C(O)-, R 20 -C(O)-NR 21 -, or OR 22 .
  • each R 2 is independently -NR 1 SO 2 R", -Cl, -Br, -F, -C(O)-NR * 2 , substituted or unsubstituted straight or branched Ci -6 alkyl, -NR' 2 , or-OR ⁇
  • each R 1 is independently a substituted or unsubstituted straight or branched Ci- io alkyl.
  • each R 3 can be independently substituted or unsubstituted Cue alkyl, pyridinyl or phenyl, optionally substituted with one to three -F, -Cl, substituted or unsubstituted Ci -6 branched or unbranched alkyl, or substituted or unsubstituted Q. 3 alkoxy.
  • Ring is maleimide, succinimide, imidazolidinone, imidazolidine-dione, imidazolidine-trione, triazolidin-dione, or triazine-dione; and
  • G is a C 3-I o carbocyclyl, C 4- i 2 carbocyclylalkyl, 5-8 membered monocyclic heterocyclyl or heterocyclylalkyl, 8-11 membered bicyclic heterocyclyl or heterocyclylalkyl, wherein the heterocyclyl rings contain 1 or more heteroatoms selected from O, N or S; and G is substituted by one or more R 1 , R 2 or R 3 .
  • G is phenyl, naphthyl, cyclopropyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, or benzofuran-3-one.
  • G is phenyl, naphthyl, cyclopropyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, or pyridinyl.
  • Ring is maleimide, succinimide or triazine-dione.
  • Ring is succinimid-1 ,4-diyl, maleimide-1 ,4-diyl, imidazolidin-2-one-l s 3-diyl 5 imidazolidine-2,4 3 5-trione-l 5 3-diyl, [l,2,4]triazolidine-3,5- dione-l,4-diyl, or 2H-[l,2,4]triazine-3,5-dione-4,6-diyl.
  • Ar is phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl, indole, or the structure -(Y')-(Co-3 alkyl)-(C6-io aryl), each being optionally substituted with one or more R 4 groups;
  • Y' is absent or is -O- or -NH-; and each R 3 is independently H, substituted or unsubstituted C ⁇ -io aryl * substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S(O) n ,, substituted or unsubstituted C 3-12 cycloalkyl, substituted or unsubstituted C 5-12 cycloalkenyl, substituted or unsubstituted C 7-2O aralkyl, substituted or unsubstituted straight or branched Ci -8 alkyl, R 20 C(O)N(R 21 )-, R 22 O-, R 23 R 24 NC(O)-, R 26 (CH 2 ) m C(O)N(R 21 )-, R 26 C(O)(CH 2 ) m N(R 21 )-, substituted or unsub
  • Ar is indazolyl, isoindolyl, pyrazolyl, imidazolyl, or imidazolonyl. In some such embodiments, Ar is substituted with at least one R 4 . Alternatively, Ar is indazolyl, optionally substituted with one or more R 4 . In yet other embodiments, Ar is phenyl or naphthyl. In some such embodiments, Ar is substituted with at least one R 4 .
  • Ar is -(Y')-(Co-3 alkyl)-(C 6 -io aryl).
  • Ar is substituted with at least one R 4 .
  • the C 6- ] O aryl is phenyl or naphthyl.
  • Y' is -NH-.
  • each R 3 is independently hydrogen or phenyl, naphthyl, or heterocyclyl, each of which is optionally partially or fully halo genated and optionally substituted with 1-3 of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisooxazolyl, benzpyrazolyl, be
  • R 20 C(O)N(R 21 )-, R 22 -, R 23 R 24 NC(O)-, R 26 (CH 2 ) m C(O)N(R 21 )- or R 26 C(O)(CH 2 ) m N(R 21 )-;
  • C2-6 alkynyl branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH and S(O) m or S and wherein said alkynyl group is optionally independently substituted with 0-2 oxo groups, pyrrolidinyl, pyrrolyl, one or more C 1-4 branched or unbranched alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or CM branched or unbranched alkylamino optionally substituted by one or more halogen atoms; or benzoyl or naphthoyl.
  • Table 2 sets forth various combinations of substituents from all groups of compounds of Formulas IA, IB, IC and II.
  • combination 1477 describes those embodiments in which L is -O- and Q is heterocyclyl.
  • substituents that result in a chemically stable compound are possible and will understand how to select such combinations.
  • any combination from Table 1, describing Ar and G may be combined with any combination from Table 2, describing L and Q.
  • combination 1045 from Table 1 and combination 1509 from Table 2 describe those embodiments of Formula IA in which Ar is pyrazolyl, G is naphthyl, L is-O-(CH2) 2 -, and Q is heterocyclyl.
  • Ar is pyrazolyl
  • G is naphthyl
  • L is-O-(CH2) 2 -
  • Q is heterocyclyl.
  • Each Ar, G, L, and Q group in the tables is understood to be optionally substituted as described herein.
  • each value of X (C(O), C(S), CH 2 ) may be combined with any combination from Table 1 or Table 2 or any pair of combinations from the two tables.
  • combination 1004 describes those embodiments in which X is C(O), Ar is indolyl and G is phenyl, as well as those where X is CH 2 , Ar is indolyl and G is phenyl, etc.
  • Table 3 illustrates combinations of Ar and G for the second group of compounds having Formula IA.
  • Table 2 above illustrates combinations of L and Q, which can be employed for the second group of compounds having Formula IA. Any combination from Table 3 may be combined with any combination from Table 2, as all such combinations are within the scope of the invention.
  • Table 4 illustrates combinations of Ar and G for the third group of compounds having Formula IA.
  • Table 2 above illustrates combinations of L and Q that may be employed for the third group of compounds having Formula IA.
  • TABLE 4 Exemplary Combinations of Ar and G for the Third Group of Compounds of Formula IA
  • cytokine inhibitors useful in the invention comprising: a targeting moiety comprising at least an amide group having an amide NH, the targeting moiety capable of forming one or more hydrogen bonds with a target protein, and wherein the targeting moiety is not a urea group; a pocket-expanding moiety directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non-planar hydrophobic moiety, said non-planar moiety forming hydrophobic interactions with the target protein; an orienting moiety comprising a planar hydrophobic moiety and attached to a different atom of the targeting moiety than the pocket-expanding moiety, said orienting moiety capable of forming a ⁇ - ⁇ or edge-to-face aromatic interaction with the target protein.
  • the cytokine inhibitors have the structure
  • PEM-TM-OM At a concentration of 10 ⁇ M such compounds typically inhibit induced TNFa-release from a cell by about 50% or greater than 50%.
  • the targeting moiety can hydrogen bond to residues at the binding site of the target protein and may further include additional hydrogen bond donor or acceptor groups that also form hydrogen bonds to the target protein.
  • Targeting moieties include amide and thioamide groups, methyl amide and thioamide groups, carbamates, hydroxymethyl amides, alpha-ketoamides, diamides, and the like. Cyclic targeting moieties are also contemplated such as imidazolinone, imidazoline dione and trione.
  • the pocket-expanding moiety is of sufficient size to force a conformational change in the target protein, resulting in an expanded binding pocket therein.
  • Such moieties include, for example, pyrazolyl, oxazolyl, phenyl or the like, each substituted with bulky moieties.
  • Bulky moieties fill a large volume of space in comparison to, for example, a methyl group and include groups such as t-butyl, norbornyl, and the like.
  • the orienting moiety by binding to a hydrophobic pocket on the target protein, provides the proper orientation of the targeting moiety and pocket-expanding moiety for binding of the cytokine inhibitor to its target protein.
  • the planar hydrophobic moieties which make up the orienting moiety have either few or no polar groups. Such moieties include, for example, phenyl, naphthyl, indazolyl, and the like.
  • the cytokine inhibitors further comprise a hydrophilic moiety having at least one functionality selected from the group consisting of a hydrogen- bond donor, hydrogen-bond acceptor, basic heteroatom, or acidic heteroatom, wherein the hydrophilic moiety is indirectly attached to the hydrophobic orienting moiety and is capable of forming a hydrogen bond with the backbone of the protein.
  • the hydrophilic moiety is attached to the orienting moiety by a linker chain of atoms of from about 2 to about 10 angstroms in length.
  • the hydrophilic moiety binds in or near an ATP -binding pocket on the target protein, forming at least one hydrogen bond with a residue of the ATP-binding pocket.
  • Hydrophilic moieties include morpholinyl, piperazinyl, and pyrimidinyl groups, among others. Such moieties may be attached to the orienting moiety by, for example, oxy, ethylene, methyleneoxy and ethyleneoxy chains.
  • the pocket- expanding moiety is not a substituted 5-member heterocyclyl ring if the cytokine inhibitor is PEM-CHR"C(O)NH-OM, wherein R" is H or C] -6 alkyl, optionally partially or fully halogenated.
  • the targeting moiety is not a substituted tricyclic heterocyclyl ring having a nitrogen atom ring member bonded to the amide carbonyl of the targeting moiety.
  • Cytokine inhibitors of the invention may be readily synthesized by techniques well known to those of skill in the art, as described in U.S. Application No. 10/939,324, filed September 10, 2004, U.S. Application No. 60/656,196, filed February 24, 2005, and International Application No. PCT/US2006/006682, filed February 23, 2006.
  • THP-I cells (ATCC TIB 202, American Type Culture Collection, Rockville, MD) are maintained at 37°C, 5% CO 2 in RPMI 1640 media with 10% fetal bovine serum, 10 mM Hepes, 1 mM sodium pyruvate, 4.5 g/L glucose and 0.05 mM 2-mercaptoethanol as suggested by ATCC.
  • the cells and compounds are diluted in the media above having 1% fetal bovine serum (assay media).
  • Test compound stocks in DMSO are diluted into assay media to 6x the final assay concentration, with a final DMSO concentration of less than 0.3% in the assay.
  • THP-I cells are plated at lX10 5 /well in 96 well tissue culture plates. Diluted compounds (or DMSO control) are added and allowed to preincubate with the cells at 37 0 C, 5% CO 2 for 30 minutes prior to the addition of LPS (Sigma) to a final concentration of 1 ⁇ g/ml. Cells are then incubated 18-20 hours at 37°C/5% CO 2 . The assay is terminated by centrifuging the plates for 10 min at room temperature.
  • IC 50 is the concentration of the test compound that causes a 50% decrease in the maximal TNFa production.
  • the effectiveness of the compounds of the invention or its derivatives or salts in the treatment of any of the forms of pemphigus described above can be evaluated by one or more of the following methods: (a) in an established organ culture model where the degree of acantholysis can be measured, after introduction of exogenous pemphigus antibody; (b) in a neonatal mouse model where disease can be induced, and evidence of clearing can be monitored; and/or (c) in humans with pemphigus. (See for example, Berkowitz et al, J. Biol.
  • purification regimens can include protein-A or protein-G binding and elution, and various chromatography schemes that exploit differences in the size and charge of the IgG 5 as known to those skilled in the art.
  • the fractions are concentrated and sterilized via filtration.
  • the pemphigus anti-body titer in the serum is then measured.
  • PV IgG Pemphigus (PV) sera (mucocutaneous) have been described (Ding et al. J. Invest. Dermatol. 1997, 109: 592-596).
  • the PV IgG are purified from PV patient sera by ammonium sulfate precipitation followed by affinity chromatography on Protein G (HiTrap; Amersham Pharmacia, Piscataway, NJ). IgG fractions are dialyzed against PBS and sterile filtered. Purity is confirmed by SDS/PAGE, and activity is assayed by indirect immunofluoresence (IF) on sectioned monkey esophagus and ELISA. Control IgG (no activity by indirect IF) are prepared in parallel from normal human sera.
  • IF indirect immunofluoresence
  • the culture medium should contain approximately 7 mg/ml of pemphigus IgG with or without the test compounds. After each culture period, the skin explants are examined by routine histologic (hemotoxylin and eosin staining) methods. The final concentration of test compound should range from 0.1 to 20 mg/ml. The skin can be preincubated (1-24 hours) with the test compound prior to addition of pemphigus IgG. Acantholysis is evaluated on a scale of (-), (+), (++), or (+++), where (-) is no acantholysis, (+) is positive on 10-30%, (++) is positive on 30-70%, and (+++) is positive on 70-100% of the epidermis in the histologic section.
  • Normal primary human keratinocytes are passaged and expanded as described (Hu, et al., J. Investig.Dermatol. 1997, 117: 1059-1067).
  • Third passage keratinocytes are grown to 80- 90% confluence when DSG3, but not DSGl, was detected by Western blot of cell extracts using DSG3- and DSGl -specific monoclonal antibodies, respectively.
  • [ 32 P]HsPO 4 is added to the culture medium (5 mCi/ml). The cells are incubated for 2 hr and either control IgG, PV IgG, or an equivalent volume of buffer is added (to concentrations of 5, 10, or 25 ⁇ M).
  • IEF lysis buffer 8 M urea, 4% CHAPS, 2.5 mM dithiothreitol, 40 mM Tris, 10 ⁇ M pepstatin, 100 ⁇ M leupeptin, 10 ⁇ M E-64, 1 mM phenylmethylsulfonyl fluoride. Protein concentration is by modified Bradford as described (Hu, et al., J. Investig.Dermatol. 1997, 117: 1059- 1067). IPG buffer (pH 3—10, non linear; Amersham Biosciences) is added to each sample to a final concentration of 0.5% prior to isoelectric focusing.
  • keratinocytes are preincubated for 60 min at 37°C with the cytokine inhibitor, after which PV IgG is added to a final concentration of 25 ⁇ M and the cells are incubated for 30 min at 37°C and harvested in IEF lysis buffer.
  • Neonatal Mouse Model for Pemphigus General protocol. The ability of the test compounds to reduce the symptoms of pemphigus in vivo can be evaluated in a neonatal mice model (Anhalt, et al., N. Engl. J. Med. 1982, 306:. 1189-96 or Berkowitz et al., Proc. Nat. Acad. Sci., 2006, 103(34), 12855-12860). Purified IgG fractions are injected i.p. into neonatal mice using a 30 gauge needle in a single administration of IgG per gram body weight according to an established model (Takahashi, et al., J. Invest. Dermatol. 1985, 84: 41-46).
  • Skin and serum samples are obtained from animals receiving injections of either normal human IgG (control) or human pemphigus IgG. Skin samples from the flank region, where lesions most often occur are processed for direct immunofluorescence. Human pemphigus antibodies are also monitored in the animals' serum, to confirm transfer of the pemphigus antibodies.
  • One group of mice is treated with administration of the test compound and monitored for disease improvement by sampling the skin and assessing its appearance by histology and/or by clinical appearance.
  • Neonatal mice 24 — 36 hr old with body weights between 1.4 and 1.6 g were used for passive transfer experiments. Neonates were injected i.d. with a sterile solution of either control IgG or PV IgG as described (Proc. Nat. Acad. Sci.,2006, 103(34): 12855-12860 (and refs. 1, 34, 35 therein)).
  • the cytokine inhibitor of the invention was administered i.d. in two doses.
  • mice were injected with PV IgG or control
  • IgG at 1.5 mg/g body weight in a total volume of 50 ⁇ l of PBS. This dose of PV IgG resulted in gross sloughing of the skin.
  • PV IgG 1.0 mg/g body weight in 50 ⁇ l of PBS
  • the animals were euthanized, and skin and serum specimens were obtained for routine histological examination using light microscopy (hematoxylin/eosin staining).
  • a multiple week study e.g., a 12 week or 26 week study, of steroid sparing can be conducted as follows. At study entry, all patients will be taking a stable dose of prednisone (or an equivalent corticosteroid) of 20 to 120 mg/day for at least 2 weeks. Patients will be randomly assigned to several study arms. The treatment arms will receive the cytokine inhibitor of the invention, and the control arm will receive placebo. Drug administration will take place daily. Prednisone doses may be tapered (for example, by 15% every 2 weeks) during the study at the investigator's discretion. There will be several study visits until the end of the study (typically Week 12 or Week 26).
  • Each study visit will include a physical exam, vital signs measurement, medical and medication history, a review of the disease activity log and adverse events experienced since the last visit, skin assessments, and blood collection. Patients will be asked to complete quality of life questionnaires at study entry and at several time points during the study. Skin biopsies of unaffected skin will be done at study entry and at several time points during the study; if patients have PV-associated lesions, additional skin biopsies of affected skin will be done as deemed necessary by investigator.
  • patients will be monitored for some or all of the following outcomes: disease activity; modified responder status, defined as achieving prednisone dosage less than or equal to 25% of the initial starting dose or a dosage of less than 10 mg prednisone/day (whichever is greater) at the end of the study (e.g., week 26 in a 26 week study), regardless of new blister formation; time to cessation of new blisters; time to 80% healing (as determined by the reduction in surface area or volume) of erosions or ulcerations existing at the time of enrollment total prednisone dosage required to achieve cessation of new blisters and to achieve 80% healing of existing erosions; quality of life (SF-36) changes from baseline through the end of the study; dermatology-related quality of life changes from baseline through the end of the study; change in serum anti-DSGl antibody levels from baseline through the end of the study; change in serum anti-DSG3 antibody levels from baseline through the end of the study; change in serum TNF-alpha and IL-6 levels from baseline through the end of the
  • test compounds in humans with oral lesions.
  • the effectiveness of treatment of patients with oral lesions resulting from lichen planus, bullous pemphigoid, cicatricial pemphigoid, pemphigus or canker sores (aphthous uclers) with test compounds can be evaluated as described generally for treatment of lichen planus by Eisen, Ellis, Duell, Griffiths and Voorhees, in N. Engl. J. Med. 1990, Vol. 323, pp. 290-4.
  • patients with symptomatic oral lichen planus are given either placebo or a test compound formulation containing 1 to 50% test compound. The solutions are swished for several minutes and expectorated or swallowed several times daily.
  • Clinical evaluations are performed by the same physician for the duration of the experiment. Each patient's disease is measured on a scale of 1 to 4, with 1 indicating minimal disease, and 4 indicating severe lesions. The degree of erosion, erythema, and reticulation of each lesion is separately scaled over time for a period ranging from 1 day to 6 months, as desired. In addition, the patients evaluate lesion discomfort on a scale of 1 to 4.
  • the compounds of the invention can be assayed by one or more of the above methods and have or are expected to have activity in one or more of the above assays.
  • a range includes each individual member.
  • a group having 1-3 atoms refers to groups having 1, 2, or 3 atoms.
  • a group having 1-5 atoms refers to groups having 1, 2, 3, 4, or 5 atoms, and so forth.

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Abstract

The present invention relates to methods of treating autoimmune diseases, which comprise the administration of a cytokine inhibitor alone or in combination with known therapeutics or treatments. The invention also relates to pharmaceutical compositions and dosing Tegimens. In particular, the invention relates to the use of cytokine inhibitors, optionally in conjunction with other therapies, for the treatment of autoimmune diseases, more particularly pemphigus.

Description

THERAPY USING CYTOKINE INHIBITORS
FIELD OF THE INVENTION
[0001] The present invention relates to methods of treating, modifying and managing cytokine mediated diseases, which comprise the administration of a cytokine inhibitor alone or in combination with known therapeutics. The invention also relates to pharmaceutical compositions and dosing regimens. In particular, the invention relates to the use of cytokine inhibitors, optionally in conjunction with other therapies, for the treatment of autoimmune diseases, more particularly pemphigus.
BACKGROUND OF THE INVENTION
[0002] - The functioning of the immune system is finely balanced by the activities of proinflammatory and anti-inflammatory mediators or cytokines. Some cytokines promote inflammation and are called proinflammatory cytokines, whereas other cytokines suppress the activity of proinflammatory cytokines and are referred to as anti-inflammatory cytokines. For example, IL-4, IL-10, and IL- 13 are potent activators of B lymphocytes, but are also potent anti -inflammatory agents. They are anti -inflammatory cytokines by virtue of their ability to suppress genes for proinflammatory cytokines such as IL-I, TNF, and chemokines (CA. Dinarello, Chest. 2000, 118: 503-508).
[0003] Unregulated activities of these mediators can lead to the development of serious inflammatory conditions. For example, autoimmune diseases arise when immune system cells (lymphocytes, macrophages) become sensitized against the "self. Lymphocytes as well as macrophages are usually under control in this system. However, a misdirection of the system toward the body's own tissues may happen in response to still unexplained triggers. One hypothesis is that lymphocytes recognize an antigen which mimics the "self and a cascade of activation of different components of the immune system takes place, ultimately leading to tissue destruction. Genetic predisposition has also been postulated to be responsible for autoimmune disorders. [0004] Pemphigus is an autoimmune disorder in which the immune system produces antibodies against specific proteins in the skin and mucous membranes. These antibodies produce a reaction that leads to a separation of epidermal cells (acantholysis). The exact cause of the development of antibodies against the body's own tissues (autoantibodies) is unknown, but the cytokines TNF-alpha (TNFa)5 IL-6, and IL-10 can be detected at elevated levels in blister fluid from patients with pemphigus vulgaris. Typical for the disease are burn-like lesions that will not heal, which result in the loss of intercellular adhesion between the keratinocytes leading to bulla (blister) formation (Sharpe, R. J. in Manual of Clinical Problems in Dermatology, Olbricht, Bigby and Arndt eds., Little Brown & Co., Boston, 1992, pp. 56-60). Pemphigus vulgaris and pemphigus vegetans are characterized by the formation of blisters above the basal layer of the skin. In pemphigus foliaceus and pemphigus erythematosus, blisters are observed just below the stratum corneum. (For a review, see Ruocco E, et al, Precautions and suggestions for pemphigus patients, Dermatology 2001, 203(3): 201-7 and Hertl M, Veldman C, Pemphigus-paradigm of autoantibody-mediated autoimmunity, Int. J. Fertil. Womens Med. 2001, 46(4): 190-205).
[0005] Bullous pemphigoid is more prevalent in elderly patients and includes large tense blisters, on erythematous or non-erythematous skin or on urticarial plaques. A mortality rate of 10 to 20 percent is reported for the disease, largely due to side-effects from the use of systemic steroid therapy.
[0006] Cicatricial Pemphigoid involves primarily the mucous membranes (Baden, L.
A., Manual of Clinical Problems in Dermatology, Little, Brown & Co., Boston, 1992, pp. 54). In many cases, this disorder involves desquamative gingivitis and ultimately leads to blindness. Current treatments have been reported as unsatisfactory (Bleicher, P. A. in Manual of Clinical Problems in Dermatology, Olbricht, Bigby and Arndt, eds., 1992, Little, Brown & Co., Boston, pp. 85-89; Arndt, K. in Fitzpatrick, Eisen, Wolff, Freedberg and Austen, Dermatology in General Medicine, 1987, Vol. 1, McGraw-Hill, Inc., New York, pp. 582-584). [0007] Current treatments of pemphigus include corticosteroids and immunosuppressive agents such as cyclophosphamide, azathioprine, methotrexate and cyclosporine-A (Lever, J. Am. Acad. Dermatol. 1979, 1, pp. 2-31). Antibiotics can also be used in combination with high dose corticosteroids. However, the severity of symptoms and the high mortality associated with pemphigus often lead to hospitalization. In addition, clinically significant bone loss occurs in the vast majority of patients exposed to corticosteroids causing a very high risk for vertebral fracture (see Adachi J D, Cortico steroid- induced osteoporosis, Acta Derm. Venereol 1999, 79(5): 351-5).
SUMMARY OF THE INVENTION
[0008] In one aspect of the invention, there is provided a method of treating pemphigus, which comprises administering to a subject in need of such treatment a composition comprising a therapeutically effective amount of a cytokine inhibitor as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. Cytokine inhibitors of the invention may be used alone or as combinations of any two or more thereof.
[0009] Cytokine inhibitors useful in the invention are exemplified by Formulas IA,
IB, IC and II and are described in US application 10/939,324, filed September 10, 2004, U.S. Application No. 60/656,196, filed February 24, 2005, International Application No. PCT/US2006/006682, filed February 23, 2006, U.S. Provisional Application No. 60/736,621, filed 11/14/2005 and U.S. Provisional Application No. 60/785,943, filed 3/24/2006.
Figure imgf000004_0001
Q
IA IB IC
Figure imgf000004_0002
π, wherein the variables G, X, Ar, L, Q, Ring and X' are as defined in the Detailed Description of the Invention.
[0010] Other cytokine inhibitors useful in the invention comprise: a targeting moiety comprising at least an amide group having an amide NH, the targeting moiety capable of forming one or more hydrogen bonds with a target protein, and wherein the targeting moiety is not a urea group; a pocket-expanding moiety directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non-planar hydrophobic moiety, said non-planar moiety capable of forming hydrophobic interactions with the target protein; and an orienting moiety comprising a planar hydrophobic moiety and attached to a different atom of the targeting moiety than the pocket-expanding moiety, said orienting moiety capable of forming a π-π or edge-to-face aromatic interaction with the target protein.
[0011] In some embodiments of methods of treating pemphigus, the pemphigus is pemphigus vulgaris, pemphigus vegetans, pemphigus foliaceus, pemphigus erythematosus, bullous pemphigoid, paraneoplastic pemphigus, cicatricial pemphigoid, bullous impetigo, or staphylococcal scalded-skin syndrome.
[0012] In another aspect, there are provided methods comprising administering to a subject in need thereof a combination of (i) an effective amount of a cytokine inhibitor of the invention and (ii) an effective amount of one or more therapeutic Ingredients A useful in the treatment of pemphigus as described herein, wherein the effective amount of Ingredients A is less than the effective amount of Ingredient A when used alone.
[0013] Also provided are methods comprising administering to a subject exhibiting one or more clinical indicia of pemphigus an amount of a cytokine inhibitor of the invention effective to reduce the number and/or severity of clinical indicia of pemphigus relative to those present in the subject prior to the administration of the cytokine inhibitor, wherein the clinical indicia of pemphigus include the percentage of total body surface area (BSA) affected by pemphigus, pemphigus lesion thickness, the number of new pemphigus lesions, the number of active pemphigus lesions (including blisters and erosions), the healing time of active lesions (for example, time to 80% healing), serum anti-desmoglein-1 (DSGl) antibody levels, serum anti-DSG3 antibody levels, serum TNFa-levels, serum IL6 levels, skin TNFa- mRNA levels, skin IL6 mRNA levels, or any two or more thereof. In some embodiments of the invention, the methods additionally comprise administering to the subject an effective amount of one or more Ingredients A, useful in the treatment of pemphigus, as described herein. In some such embodiments, the effective amount of Ingredients A is less than the effective amount of Ingredient A when used alone.
[0014] Combination therapy with therapeutic Ingredients A in the methods of the invention provides a beneficial therapeutic effect, particularly an additive or over-additive effect and/or an overall reduction of side effects of the therapy. Thus, the use of cytokine inhibitors of the invention may allow for a reduction in the amount of Ingredient A needed to produce the same therapeutic effect compared to the amount of Ingredient A used alone. A variety of Ingredients A are contemplated for use in the combinations of the invention, as described herein. The beneficial effects are observed both when the cytokine inhibitors and Ingredient(s) A are administered simultaneously in a single formulation and when they are administered successively in separate formulations.
[0015] In some embodiments of the methods of the invention, the methods further comprise administering to the subject an Ingredient A, wherein the Ingredient A is an antiinflammatory agent, an immunosuppressant, an anti-infective, an antibiotic, a gold salt, an alkylating agent, an immunoglobulin, or a combination of two or more thereof.
[0016] In some embodiments in which Ingredient A is an anti-inflammatory agent, the anti-inflammatory may be a corticosteroid, a COX-2 inhibitor, a non-steroidal antiinflammatory drug (NSAID), a TNFa antagonist, or an IL-I antagonist. For example, the corticosteroid can be prednisone, prednisolone, or methylprednisolone. Corticosteroids such as these may also be administered with either chlorambusil or mycophenylate mofetil. In some embodiments, the TNFa antagonist is infliximab, etanercept, or adalimumab. In others, the IL-I antagonist is anakinra.
[0017] In other embodiments, the immunosuppressant is mycophenylate mofetil, cyclosporin, azathioprine, methotrexate, alefacept, rituximab, anti-interferon gamma, or cyclophosphamide.
[0018] In some other embodiments, the anti-infective is dapsone, or hydroxychloroquine.
[0019] In some embodiments, the gold salt is myochrysine, or solganal.
[0020] In some embodiments, the alkylating agent is lukeran.
[0021] In some embodiments, the antibiotic is tetracycline, minocycline, or doxycycline. In some such embodiments, the method further comprises administration of nicotinamide, or niacinamide.
[0022] In other embodiments of the methods of the invention, the methods of the invention further comprise administering plasmapherisis therapy or photophoresis therapy to the subject.
[0023] In some embodiments of the methods of the invention, the dosage of
Ingredient A is reduced by from about 10% to about 90% in comparison to the dosage used to achieve the same therapeutic effect with Ingredient A alone. In some embodiments, the dosage is reduced by at least about 10%, about 20%, about 30%, about 40%, about 50%, or about 60%. In some embodiments, Ingredient A is a corticosteroid, for example, prednisone or prednisolone. In some other embodiments, Ingredient A comprises a corticosteroid and either chlorambusil or mycophenylate mofetil. hi some embodiments, the dosage of prednisone is reduced to less than about 10 mg/day, less than about 15 mg per day, less than about 20 mg/day, less than about 30 mg/day, less than about 50 mg/day or less than about 70 mg/day. [0024] In yet other embodiments, the cytokine inhibitor is administered orally or topically.
[0025] In some embodiments, Ingredient A is a corticosteroid or antibiotic and is administered orally, topically, in a mouthwash or in a mouth spray.
[0026] Cytokine inhibitors contemplated for use in the methods of the invention include the compounds from List 1.
LIST l
1 H-Indazole-3-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-amide;
3-tert-Butyl-5-phenyl- 1 -p-tolyl- 1 ,6-dihydro-imidazo[4,5-c]pyrazole;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-
2-oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-moφholin-4-yl- ethoxy)-naphthalen- 1 -yl] -2-oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl- pyrimidin-4-yloxy)-naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-hydroxy-3-moφholin-4-ylmethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-hydroxy-3-methyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-methoxy-3-methyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl]-2-oxo-acetamide;
N-(5-tert-Butyl-3-chloro-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl] -2-oxo-acetamide;
N-(5-tert-Butyl-2-methoxy-3-trifluoromethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[7-chloro-4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide; 5-tert-Butyl-N-cyclopropyl-2-methoxy-3- {2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen- 1 -yl]-
2-oxo-acetylamino} -benzamide;
N-[5-tert-Butyl-2-methoxy-3-(piperidine-l-carbonyl)-phenyl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthal en- 1 -yl ] -2 -oxo-acetamide;
5-tert-Butyl-2-hydroxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino} -benzoic acid;
N-(2-Benzenesυlfonyl-5-tert-butyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-1 -yl]-2-oxo-acetamide; .
2-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-
2-oxo-acetamide; l-Bicyclo[2.2.1]hept-2-yl-5-phenylamino-3-p-tolyl-l,3-dihydro-imidazo[4,5-b]ρyridin-2-one;
3-p-Tolyl-5-p-tolylamino-l,3-dihydro-imidazo[4,5-b]pyridin-2-one;
1 -Bicyclo[2.2.1 ]hept-2-yl-3-p-tolyl-5-p-tolylamino-l ,3-dihydro-imidazo[4,5-b]pyridin-2-one;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2,2-difluoro-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-N'-naphthalen-l-yl-oxalamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[(Z)-methoxyimino]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl]-acetamide;
2-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -ylamino)- 1 -[4-(2-morpholin-4-yl-ethoxy)-naphthalen- l-yl]-ethanol; l-(3-tert-Butyl-phenyl)-4-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-[l,2i4]triazolidine-
3,5-dione;
4-(3-tert-Butyl-phenyl)-l-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-[l,2,4]triazolidine-
3,5-dione;
(E)-3-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-3-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-l-yl]-acrylic acid methyl ester;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2,5-dioxo-
2,5-dihydro-pyrrol- 1 -yl} -phenyl)-methanesulfonamide; N-(5-tert-Butyl-2-methoxy-3-{3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2,5-dioxo- pyrrolidin-l-yl}-phenyl)-methanesulfonamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl]-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-oxo-2-[4-(2-piperidin-l-yl- pyrimidin-4-yloxy)-naphthalen- 1 -yl]-acetamide;
3-tert-Butyl-l-p-tolyl-5-(3-trifluoromethyl-phenyl)-l,6-dihydro-iraidazo[4,5-c]pyrazole;
1 -(2-Morpholin-4-yl-ethyl)-l H-indazole-3-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-arnide;
N-[4-(2-Moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-2-(2,436-trimethyl-phenyl)- acetamide;
1 -Phenyl-cyclopropanecarboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-amide;
N-[5-tert-Butyl-2-(2,5-difluoro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetamide;
N-(5-tert-Butyl-3 -methanesulfonyl amino-2-methoxy-phenyl)-2-(4-methoxy-naphthalen- 1 - yl)-2-oxo-acetamide;
N-[5-tert-Butyl-2-(3-chloro-benzoyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-1 -yl]-2-oxo-acetamide;
N-[5-tert-Butyl-2-(3-methanesulfonyl-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2-oxo-acetaτnide;
4-[(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylcarbamoyl)-methyl]-piperidine- 1 -carboxylic acid tert-butyl ester;
N-[3-(Benzenesulfonyl-carbamoylmethyl-amino)-5-tert-butyl-2-methoxy-phenyl]-2- naphthal en- 1 -yl-2-oxo-acetamide;
N-(3-tert-Butyl-isoxazol-5-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetamide;
N-(5-tert-Butyl-3-ethanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-1 -yl]-succinamic acid methyl ester; 2-(2-Benzyl-5-tert-butyl-2H-pyrazol-3-yl)-N-[4-(2-morρholin-4-yl-ethoxy)-naphthalen-l-yl]-
2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-pyrimidin-4-ylamino)- naphthalen-l-yl]-2-oxo-acetamide;
5-tert-Butyl-2-(3-chloro-phenyl)-2H-pyrazole-3-carboxylic acid [4-(2-morpholin-4-yl- ethoxy)-naphthalen-l -yl]-amide;
2-(3-Bromo-4-methoxy-phenyl)-N-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[3-fluoro-4-(2-morpholin-4-yl-ethoxy)-phenyl]- acetamide;
(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-(2,2-dimethyl-propyl)-amine;
2-(4-Benzyloxy-phenyl)-N-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-hydroxy-2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen- 1 -yl] -acetamide;
N-[5-tert-Butyl-2-(4-sulfamoyl-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide;
5-tert-Butyl-2-methoxy-3 -(I -naphthalen- 1 -yl-3,5-dioxo-[ 1 ,2,4]triazolidin-4-yl)-benzamide;
2-(4-Bromo-naphthalen-l-yl)-N-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-2-oxo-acetamide;
5-tert-Butyl-2-hydroxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino } -benzamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-hydroxy-2-(4-methoxy-naphthalen-l-yl)- acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(6-morpholin-4-ylmethyl- pyridin-3 -yl)-naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-[4-(2-methylamino-pyrimidin-4-ylamino)-naphthalen-
1 -yl] -2-oxo-acetamide;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-[4-(2-dimethylamino-pyrimidin-4-ylamino)- naphthalen- 1 -yl] -2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-oxo-2-{4-[2-(l-oxo-lλ4-thiomorpholin-4-yl)- ethoxy]-naphthalen- 1 -yl} -acetamide; 5-tert-Butyl-3-{2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]- acetylamino}-thioρhene-2-carboxylic acid methyl ester;
N-[5-tert-Butyl-2-(3-methanesulfonyl-phenyl)-2H-pyrazol-3-yl]-2-hydroxy-2-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-l-yl]-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-{4-[2-((2R,6R)-2,6-dimethyl-morpholin-4-yl)- ethoxy] -naphthalen- 1 -yl } -2-oxo-acetamide;
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[7-chloro-4-(2-moφholin-4- yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[(Z)-hydroxyimino]-2-[4-(2- morpholin-4-yl-ethoxy)-naphthalen- 1 -yl] -acetamide;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-
1 -yl]-2-oxo-acetamide;
5-tert-Butyl-N-cyclopropyl-2-methoxy-3-[2-(4-methoxy-naphthalen-l-yl)-2-oxo- acetylamino]-benzamide;
4-tert-Butyl-N-[4-(2-piperidin- 1 -yl-ethoxy)-naphthalen- 1 -yl]-benzamide;
N-(2-Acetyl-5-tert-butyl-2H-pyrazol-3-yl)-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-
2-oxo-acetamide;
5-tert-Butyl-N-cyclopropyl-3-{2-hydrazono-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l- yl]-acetylamino}-2-methoxy-benzamide;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-hydroxy-2-(4-methoxy-naphthalen-l-yl)- propionamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-oxo-2-phenyl-acetamide;
N-(5-tert-Bυtyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-hydrazono-2-[4-(2- moφholin-4-yl-ethoxy)-naphthalen- 1 -yl] -acetamide;
2,3-Dihydro-indole-l -carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-amide;
N-(3 ,4-Dimethyl-phenyl)-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-cyclohexyl-2H-pyrazol-3-yl)-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-
1 -yl]-2-oxo-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(3,5-difluoro-phenyl)-acetamide;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-oxo-2-(4-pyridin-3-yl-naphthalen-l-yl)-acetamide;
N-(5-tert-Butyl-isoxazol-3-yl)-2-[(Z)-hydroxyimino]-2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen- 1 -yl]-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-diethylamino-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-oxo-2-{4-[2-(3-oxo-[l,4]diazepan-l-yl)-ethyl]- naphthalen- 1 -yl } -acetamide;
5-tert-Butyl-N-ethyl-2-methoxy-3-[2-(4-methoxy-naphthalen-l-yl)-2-oxo-acetylamino]- benzamide;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-oxo-2-{4-[6-(tetrahydro-pyran-4-ylamino)-pyridin-3- yl] -naphthalen- 1 -yl} -acetamide;
5-tert-Butyl-3-ethanesulfonylamino-2-methoxy-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-
1 -yl]-benzamide;
2-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-oxo-N-m-tolyl-acetamide;
N-(2,5-Dimethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
Pyrrolidine- 1 -carboxyli c acid (5-tert-butyl-2-methoxy-3 - {2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetylamino} -phenyl)-amide;
2-(4-Bromo-phenyl)-N-(5-tert-butyl-2-methoxy-phenyl)-acetamide;
N-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-2-oxo-2-{4-[2-((S)-l-phenyl-ethylamino)- pyrimidin-4-yl amino] -naphthalen- 1 -yl } -acetamide;
5-tert-Butyl-3-[l-(2,3-dimethyl-phenyl)-3,5-dioxo-[l,2,4]triazolidin-4-yl]-2-methoxy- benzamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-naphthalen-2-yl-acetamide;
5-tert-Butyl-2-methoxy-3- {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo- acetyl amino } -benzamide ;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-methoxy-2-(4-methoxy-naphthalen-l-yl)- propionamide;
5-tert-Butyl-2-methoxy-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-ylmethyl]-3-nitro- benzamide; N-(5-tert-Butyl-2-methoxy-3-{2-[4-(2-rnorpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino}-phenyl)-benzamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(2,5-difluoro-phenyl)-acetamide;
N-(3,5-Di-tert-butyl-2-methoxy-phenyl)-2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl] -acetamide;
N'-[l-(5-tert-Butyl-2-methyl-2H-pyrazol-3-ylcarbamoyl)-l-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-meth-(E)-ylidene]-hydrazinecarboxamide;
N-[2-(4-Amino-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-2-hydroxy-2-[4-(2-morpholin-4-yl- ethoxy)-naphthal en- 1 -yl] -acetamide;
5-tert-Butyl-3-{2-[(Z)-methoxyimino]-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]- acetylamino}-thiophene-2-carboxylic acid amide;
Ethanesulfonic acid (5-tert-butyl-2-methoxy-3- {3-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-
1 -yl]-2,5-dioxo-2,5-dihydro-pyrrol-l -yl}-phenyl)-amide;
5-tert-Butyl-N-cyclopropylmethyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetylamino} -benzamide;
5-Fluoro-l H-indazole-3-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-amide;
N-[5-tert-Bυtyl-2-methoxy-3-(2-methoxy-acetylamino)-phenyl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl] -2-oxo-acetamide;
7-Bicyclo[2.2.1]hept-2-yl-9-p-tolyl-2-p-tolylamino-7,9-dihydro-purin-8-one;
N-(5-tert-Butyl-2-isopropoxy-3-methanesulfonylamino-phenyl)-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl] -2-oxo-acetamide;
N-[5-tert-Butyl-2-(3,4-dimethyl-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
3-tert-Butyl-l-(3,4-dichloro-phenyl)-5-phenyl-l,6-dihydro-imidazo[4,5-c]pyrazole;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-oxo-2-[4-(2-thiomorpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-acetamide;
5-Nitro- 1 H-pyrazole-3-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-amide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-dimethylamino- pyrimidin-4-ylamino)-naphthalen-l-yl]-2-oxo-acetamide; l-(2-Amino-4-tert-butyl-6-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino } -phenyl)-pyridinium;
N-(5-tert-Butyl-2-isoproρoxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetamide;
N-[4-(2-Morpholin-4-yl-ethoxy)-naρhthalen-l-yl]-2,5-bis-trifluoromethyl-benzamide;
2-(tert-Butyl-dimethyl-silanyloxy)-N-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(4-methoxy- phenyl)-acetamide;
N-(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3-yl)-2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-acetamide;
5-tert-Butyl-2-methoxy-3-[2-(4-methoxy-naphthalen-l-yl)-2-oxo-acetylamino]-benzamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-oxo-2-phenyl-acetamide;
5-tert-Butyl-2-methoxy-N-(2-methoxy-ethyl)-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-
1 -yl]-2-oxo-acetylamino} -benzamide;
(E)-3-(5-tert-Butyl-3-ethanesulfonylamino-2-methoxy-phenylcarbamoyl)-3-[4-(2-morpholin-
4-yl-ethoxy)-naphthalen-l-yl]-acrylic acid methyl ester; l-Isopropyl-3-phenyl-5-phenylamino-l,3-dihydro-imidazo[4,5-b]pyridin-2-one;
N-(5-tert-Butyl-isoxazol-3-yl)-2-[4-(2-moφholin-4-yl-pyrimidin-4-ylamino)-naphthalen-l- yl]-2-oxo-acetamide;
2-(2-Benzyl-5-tert-butyl-2H-pyrazol-3-yl)-2-[(Z)-hydroxyimino]-N-[4-(2-moφholin-4-yl- ethoxy)-naphthalen-l-yl]-acetamide;
2-(5-tert-Butyl-2-methoxy-phenyl)-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(2,4-dimethoxy-phenyl)-acetamide;
(5-tert-Butyl-2-methoxy-3- {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo- acetylamino}-phenyl)-carbamic acid methyl ester;
3-tert-Butyl-5-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetylamino}- pyrazole-1-carboxylic acid adamantan-1-ylamide;
3-tert-Butyl-5-phenyl-l-(4-trifluoromethyl-phenyl)-l,6-dihydro-imidazo[4,5-c]pyrazole;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2,4,5-trioxo- imidazolidin- 1 -yl} -phenyl)-methanesulfonamide; 3-tert-Butyl-l-(3-chloro-phenyl)-5-phenyl-l,6-dihydro-imidazo[4,5-c]pyτazole;
5-tert-Butyl-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetylamino}- thiophene-2-carboxylic acid amide;
2-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-hydroxy-N-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-{4-[2-(2,6-dimethyl-morpholin-4-yl)-ethyl]- naphthalen- 1 -yl} -2-oxo-acetamide;
N-(5-tert-Butyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetamide;
N-[5-tert-Butyl-2-methoxy-3-(propane-l-sulfonylamino)-phenyl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-acetamide;
3-tert-Butyl-5-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetylamino}- pyrazole-1-carboxylic acid tert-butylamide;
1 -(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-(2,3-dichlorophenyl)-3'-(carbamic acid ethyl ester)-urea ;
2-(3,5-Difluoro-phenyl)-N-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
3-tert-Butyl-5-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetylamino}- pyrazole-1-carboxylic acid amide;
N-Allyl-5-tert-butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino}-benzamide;
N-(5-tert-Butyl-isoxazol-3-yl)-2-[(Z)-methoxyimino]-2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen- 1 -yl]-acetamide;
3-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-l-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]- pytτole-2,5-dione;
2-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-[(Z)-hydroxyimino]-N-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl]-acetamide;
3-tert-Butyl-5-o-tolyl-l-p-tolyl-l,6-dihydro-imidazo[4,5-c]pyrazole;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[(E)-hydroxyimino]-2-phenyl-acetamide;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-hydroxy-2-phenyl-acetamide; N-(3-Acetylamino-5-tert-butyl-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide;
1 H-Indazole-3-carboxylic acid (5-tert-butyl-3-memanesulfonylamino-2-methoxy-phenyl)- amide;
5-tert-Butyl-2-methoxy-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-3-nitro-benzamide;
5-tert-Butyl-3-{2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy)- naphthalen-l-yl]-acetylamino}-thiophene-2-carboxylic acid amide;
N-[3-(4-Acetyl-piperazine-l-carbonyl)-5-tert-butyl-2-methoxy-phenyl]-2-[4-(2-morpholin-4- yl-ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;
2-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-N-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy)- naphthalen- 1 -yl] -2-oxo-acetamide;
N-(5-tert-Butyl-4-methyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[(Z)-hydroxyimino]-2-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-l-yl]-acetamide;
2-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen- 1 -yl] -2-oxo-N-(2-phenyl-cyclopropyl)- acetamide;
N-(5-tert-Butyl-isoxazol-3-yl)-2-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-
2-oxo-acetamide;
N-(5-tert-Butyl-2,3-dimethoxy-phenyl)-2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthal en- 1 -yl] -acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(2-chloro-phenyl)-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2- {4-[2-(4-methyl-piperazin- 1 -yl)-ethyl]- naphthalen- 1 -yl } -2-oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-(lH-indol-3-yl)-2-oxo- acetamide;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-[4-(2-moφholin-4-yl-pyridin-4-ylamino)-naphthalen-
1 -yl] -2-oxo-acetamide;
N-(4-tert-Butyl-6-trifluoromethyl-pyrimidin-2-yl)-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-o-tolyl-acetamide; 5-tert-Butyl-3-{2-[(Z)-hydroxyimino]-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]- acetylamino}-thiophene-2-carboxylic acid methylamide;
N-[5-tert-Butyl-2-(3,5-dichloro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-{4-[2-((2RJ6S)-2,6-dimethyl-moφholin-4-yl)- ethoxy] -naphthalen- 1 -yl } -2-oxo-acetamide;
3-tert-Butyl-l,5-diphenyl-l,6-dihydro-imidazo[4,5-c]pyrazole;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-imidazol-l-yl-ethyl)-naphthalen-l-yl]-2- oxo-acetamide;
S-tert-Butyl-S-^-chloro-phenyty-l-p-tolyl-l.β-dihydro-imidazol^S-clpyrazole;
N-(5-tert-Butyl-2-methoxy-3-phenylmethanesulfonylamino-phenyl)-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l -yl] -2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-oxo-2-[4-(2-pyridin-4-yl-ethoxy)-naphthalen-l- yl]-acetamide; l-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{2-[(pyridin-2-ylmethyl)-amino]-pyrimidin-4- yloxy}-naphthalen-l-yl)-imidazolidine-2,4,5-trione;
N-[5-tert-Butyl-2-(3-chloro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
5-Methoxy- 1 H-indazole-3-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-amide;
N-[5-tert-Butyl-2-(6-chloro-pyridazin-3-yl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3-yl)-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l- yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(2-methoxy-phenyl)-acetamide;
5-tert-Butyl-N-cyclopropyl-2-methoxy-3-{2-[4-(2-moφholin-4-yl-pyrimidin-4-ylamino)- naphthalen- l-yl]-2-oxo-acetylamino}-benzamide;
[(5-tert-Butyl-2-methoxy-3-{2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino}-phenyl)-methanesulfonyl-amino]-acetic acid ethyl ester;
N-(5-tert-Butyl-4-methyl-2-m-tolyl-2H-pyrazol-3-yl)-2-[(Z)-hydroxyimino]-2-[4-(2- moφholin-4-yl-ethoxy)-naphthalen-l-yl]-acetamide; N-[5-tert-Butyl-2-(2,5-dichloro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-[l,4]oxazepan-4-yl-ethoxy)-naphthalen-l- yl]-2-oxo-acetamide; l-(5-tert-Butyl-2-methoxy-3-benzamide)-3-(4-methoxy-phenyl)-3'-(carbaτnic acid ethyl ester)-urea;
N-[5-tert-Butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-2-(4-methoxy-naphthalen-l-yl)- acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazoi-3-yl)-4-chloro-benzamide;
N-(2-Bromo-5-trifluoromethyl-phenyl)-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetamide;
3-Isopropyl-5-phenyl-l-p-tolyl-l,6-dihydro-imidazo[4,5-c]pyrazole;
3 ,5-Di-tert-butyl- 1 -p~tolyl- 1 ,6-dihydro-imidazo[4,5-c]pyrazole;
5-tert-Butyl-N-cyclopentyl-2-methoxy-3-{2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-
2-oxo-acetyl amino} -benz amide;
2-[5-tert-Butyl-2-(3-fluoro-4-methyl-phenyl)-2H-pyrazol-3-yl]-N-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(4-methoxy-phenyl)-2-oxo-acetamide;
1 ,3-Di-tert-butyl-5-phenyl-l ,6-dihydro-imidazo[4,5-c]pyrazole;
4-(4-Bromo-naphthalen-l-yl)-l-(3-tert-butyl-phenyl)-[l,2,4]triazolidine-3,5-dione;
N-[5-tert-Butyl-2-(morpholine-4-carbonyl)-thiophen-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide;
3-tert-Butyl-5-(3-methoxy-phenyl)-l-p-tolyl-l,6-dihydro-imidazo[4,5-c]pyrazole;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy)-naphthalen-
1 -yl]-2-oxo-acetamide;
1 -tert-Butyl-5-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l -ylamino]-3-p-tolyl-l ,3-dihydro- imidazo[4,5-b]pyridin-2-one;
2-[5-tert-Butyl-2-(3-fluoro-ρhenyl)-2H-pyrazol-3-yl]-2-[(Z)-hydroxyimino]-N-[4-(2- moφholin-4-yl-ethoxy)-naphthalen- 1 -yl]-acetamide; 5-tert-Butyl-2-p-tolyl-2H-pyrazole-3-carboxylic acid [4-(2-morρholin-4-yl-ethoxy)- naphthalen-1 -ylmethyl]-amide;
2-[5-tert-Butyl-2-(3-fluoro-phenyl)-2H-pyrazol-3-yl]-N-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
5-tert-Butyl-N-cyclopropylmethyl-2-methoxy-3 -[2-(4-methoxy-naphthalen- 1 -yl)-2-oxo- acetylamino]-benzamide;
N-[5-tert-Butyl-3-(3,3-diethyl-ureido)-2-methoxy-phenyl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
N-[5-tert-Butyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -2-oxo-acetamide;
N-(2-Benzyl-5-tert-butyl-2H-pyrazol-3 -yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-
2-oxo-acetamide;
N-(5-tert-Butyl-3-τnethanesulfonylamino-2-methoxy-phenyl)-2-oxo-2-[4-(2-piperazin-l-yl- ethoxy)-naphthalen- 1 -yl]-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-moφholin-4-yl- pyridin-4-ylamino)-naphthalen- 1 -yl]-2-oxo-acetamide;
(5-tert-Butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylarnino}-phenyl)-carbamic acid isopropyl ester; l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-dimethylamino-pyrimidin-4-yloxy)-naphthalen-l- yl]-imidazolidine-2,4,5-trione;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-moφholin-4-yl- pyrimidin-4-ylamino)-naphthalen-l-yl]-2-oxo-acetamide;
4-(3-tert-Butyl-l-p-tolyl-l,6-dihydro-imidazo[4,5-c]pyrazol-5-yl)-2-methoxy-phenol;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(3,4-dichloro-phenyl)-acetamide;
N-[3-(3-Allyl-ureido)-5-tert-butyl-2-methoxy-phenyl]-2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen- 1 -yl] -2-oxo-acetamide;
5-tert-Butyl-N,N-diethyl-2-methoxy-3-{2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetylamino } -benzamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-[l,4]oxazepan-4-yl- ethoxy)-naphthalen-l-yl]-2-oxo-acetamide; N-(3-tert-Butyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
5-tert-Butyl-N-ethyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]- acetylamino } -benzamide;
N-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -2-oxo-acetamide;
N-[5-tert-Butyl-2-(4-ureido-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-τn-tolyl-2H-pyrazol-3-yl)-2-[4-(2-dimethylamino-ethoxy)-naphthalen-l- yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-oxo-2- [4-(2-piperidin- 1 -yl-pyrimidiri-4-yloxy)- naphthalen- 1 -yl] -acetamide;
N-[5-tert-Butyl-2-(3-fluoro-4-methyl-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl] -2-oxo-acetamide;
Indazole-1 -carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-amide;
N-[3,5-Bis-(l,l-dimethyl-propyl)-2-methoxy-phenyl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide; l-Benzyl-3-tert-butyl-5-phenyl-l,6-dihydro-imidazo[4,5-c]pyrazole;
2-(5-tert-Butyl-2-methoxy-3-nitro-phenyl)-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-
2-oxo-acetamide;
4-{2-[4-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylaminooxalyl)-naphthalen- l-yloxy]-ethyl}-piperazine-l-carboxylic acid ethyl ester;
2-Hydroxy-N-(i5-isopropyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -acetamide;
1 -Bicyclo[2.2.1 ]hept-2-yl-3-phenyl-5-phenylamino- 1 ,3 -dihydro-imidazo[4,5-b]pyridin-2- one;
N-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl-pyrimidin-4-ylamino)- naphthalen- 1 -yl]-2-oxo-acetamide;
N-[5-tert-Butyl-3-(2-dimethylamino-acetylamino)-2-methoxy-phenyl]-2-[4-(2-morpholin-4- yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetamide; N-(5-tert-Butyl-2-methoxy-3-{6-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-3,5-dioxo-
2,5-dihydro-3H-[ 1 ,2,4]triazin-4-yl} -phenyl)-methanesulfonamide;
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-
2-oxo-acetamide;
(R)-N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-hydroxy-2-phenyl-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-dimethylamino- ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
2-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-
2-oxo-acetamide;
N-[2-(3-Amino-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-2-hydroxy-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-acetamide;
2-[5-tert-Butyl-2-(3-chloro-phenyl)-2H-pyrazol-3-yl]-N-[4-(2-moφholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
1 ,5-Diphenyl-l ,6-dihydro-imidazo[4,5-c]pyrazole;
N-(5-tert-Butyl-[ 1 ,3 ,4]thiadiazol-2-yl)-2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl] -acetamide;
N-(5-tert-Butyl-3 - {2-hydroxy-2-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy)-naphthalen- 1 -yl]- ethylamino } -2-methoxy-phenyl)-methanesulfonamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-4-chloro-benzamide;
N-(5-tert-Butyl-2-ethoxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetamide;
(5-tert-Butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino}-phenyl)-carbamic acid 2-methoxy-ethyl ester;
(R)-N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-methoxy-2-phenyl-acetamide;
2-(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3-yl)-2-hydroxy-N-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -ylj-acetamide;
2-Amino-N-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-naphthalen-l-yl-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-acrylamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-imidazol-l-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetamide;
N-(4-Bromo-3-tτifluoromethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetamide;
4-(4-Benzyloxy-phenyl)- 1 -(3-tert-butyl-phenyl)-[ 1 ,2,4]triazolidine-3,5-dione;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[8-chloro-4-(2-moφholin-4- yl-ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-chloro-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide;
5-tert-Butyl-3-{2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetylamino}- thiophene-2-carboxylic acid dimethylamide;
1 -(5-tert-Butyl-isoxazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]- imidazolidine-2,4,5-trione;
N-(4-Chloro-3-trifluoromethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetamide; l-Benzoyl-3-(5-tert-butyl-2-methoxy-phenyl)-urea;
N'-[ 1 -(5-tert-Butyl-3-ethylcarbamoyl-2-methoxy-phenylcarbamoyl)-l -[4-(2-moτpholin-4-yl- ethoxy)-naphthalen-l-yl]-meth-(Z)-ylidene]-hydrazinecarboxylic acid ethyl ester;
S-tert-Butyl-S-CS-fluoro-phenyO-l-p-tolyl-ljβ-dihydro-imidazo^^-cJpyrazole;
2-[3-Bromo-4-(2-morpholin-4-yl-ethoxy)-phenyl]-N-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)- acetamide;
2-(2-Chloro-5-trifluoromethyl-phenyl)-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetamide;
N-[5-tert-Butyl-2-(3-chloro-benzenesulfonyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2 -oxo-acetamide;
(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid p-tolyl ester;
N-(5-tert-Butyl-2-diethylamino-3-methanesulfonylamino-phenyl)-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]- acetamide; N-[5-tert-Butyl-2-methoxy-3-(propane-l-sulfonylamino)-phenyl]-2-(4-methoxy-naphthalen-
1 -yl)-2-oxo-acetaτnide;
Propane-l-sulfonic acid (5-tert-butyl-2-methoxy-3-{4-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-3,5-dioxo-[l,2,4]triazolidin-l-yl}-phenyl)-amide;
3-Amino-5-tert-butyl-2-methoxy-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-ylmethyl]- benzamide;
2-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-N-(3-trifluoromethyl-phenyl)- acetamide;
4-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-6-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-
2H-[ 1 ,2,4]triazine-3 ,5-dione;
N-[5-tert-Butyl-2-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
N-[5-tert-Butyl-2-methoxy-3-(propane-l-sulfonylamino)-phenyl]-2-[4-(2-dimethylamino- pyrimidin-4-ylamino)-naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-phenyl-acetamide;
N-[5-tert-Butyl-2-methoxy-3-(propane-l-sulfonylamino)-phenyl]-2-[4-(2-morpholin-4-yl- pyrimidin-4-yloxy)-naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-3-methanesυlfonylamino-2-methoxy-phenyl)-2-{4-[2-(2,6-dimethyl- morpholin-4-yl)-ethoxy]-naphthalen-l -yl } -2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(4-methoxy-naphthalen-l-yl)-acetamide;
3-tert-Butyl-l-cyclohexyl-5-phenyl-l,6-dihydro-imidazo[4,5-c]pyrazole;
3-tert-Butyl-5-(4-fluoro-ρhenyl)-l -p-tolyl- 1 ,6-dihydro-imidazo[4,5-c]pyrazole;
N-(5-tert-Butyl-2-methoxy-3-{4-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-3,5-dioxo-
[l,2,4]triazolidin-l-yl}-phenyl)-methanesulfonamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-oxo-2-{4-[2-(3-oxo-piperazin-l-yl)-ethyl]- naphthal en- 1 -yl } -acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-oxo-2-[4-(3-pyridin-4-yl-propoxy)-naphthalen- l-yl]-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[(Z)-hydroxyimino]-2-[4-(2- morpholin-4-yl-ethoxy)-5,6,7,8-tetrahydro-naphthalen-l-yl]-acetamide; N-[5-tert-Butyl-2-(4-methanesulfonyl-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl- ethoxy)-naρhthalen-l-yl]-2-oxo-acetamide;
2-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylcarbamoyl)-2,5-dihydro-pyrrole-l-carboxylic acid tert-butyl ester;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-imidazol-l-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide;
N-[5-tert-Butyl-2-(3,5-dimethyl-ρhenyl)-2H-pyrazol-3-yl]-2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-pyridin-4-ylamino)- naphthalen- 1 -yl]-2-oxo-acetamide;
N-{5-tert-Butyl-3-[carbamoylmethyl-(propane-l-sulfonyl)-amino]-2-methoxy-phenyl}-2- naphthalen- 1 -yl-2-oxo-acetamide;
N'-[l-(5-tert-Butyl-2-methyl-2H-pyrazol-3-ylcarbamoyl)-l-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-meth-(Z)-ylidene]-hydrazinecarboxylic acid ethyl ester;
5-tert-Butyl-N-cyclopropyl-2-methoxy-3- {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]- acetylamino}-benzamide;
N-[5-tert-Butyl-2-(3-nitro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)!- naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[3-chloro-4-(2-morpholin-4-yl-ethoxy)-phenyl]-
2-oxo-acetamide;
N-(3-Benzenesulfonylamino-5-tert-butyl-2-methoxy-phenyl)-2-[4-(2-moφholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;
3-tert-Butyl-5-{2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetylamino}- pyrazole-1-carboxylic acid cyclohexylamide;
N-[5-tert-Butyl-2-methoxy-3-(2,2,2-trifluoro-ethanesulfonylamino)-phenyl]-2-[4-(2- moφholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;
N'-[l-(5-tert-Butyl-3-carbamoyl-2-methoxy-phenylcarbarnoyl)-l-[4-(2-moφholm-4-yl- ethoxy)-naphthalen-l-yl]-meth-(E)-ylidene]-hydrazinecarboxylic acid ethyl ester;
5-tert-Butyl-2-methoxy-N-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-3-(propane-l- sulfonylamino)-benzamide; N-(5-tert-Butyl-2-methoxy-phenyl)-2-hydroxy-2-(4-methoxy-naphthalen-l-yl)-acetamide;
(5-tert-Butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino}-phenyl)-carbamic acid 2-dimethylamino-ethyl ester;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[7-fluoro-4-(2-moφholin-4- yl-ethoxy)-naphthalen-l -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-isoxazol-3-yl)-2-[4-(2-morpholin-4-yl-pyridin-4-ylamino)-naphthalen-l-yl]-
2-oxo-acetamide;
3-tert-Butyl-l-(4-chloro-phenyl)-5-phenyl-l,6-dihydro-imidazo[4,5-c]pyrazole;
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(4-methoxy-naphthalen-l-yl)-2-oxo-acetamide;
2-[5-tert-Butyl-2-(3,4-dimethyl-phenyl)-2H-pyrazol-3-yl]-2-[(Z)-hydroxyimino]-N-[4-(2- moφholin-4-yl-ethoxy)-naphthalen-l-yl]-acetamide;
N-(5-tert-Butyl-isoxazol-3-yl)-2-(4-methoxy-naphthalen-l-yl)-2-oxo-acetamide;
N-[5-( 1,1 -Dimethyl -propyl)-2-p-tolyl-2H-pyrazol-3-yl]-2-hydroxy-2-[4-(2-moφholin-4-yl- ethoxy)-naphthalen-l-yl]-acetamide;
N-[5-tert-Butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-diπiethylamino-pyrimidin-4- ylamino)-naphthalen-l-yl]-2-oxo-acetamide;
N-(2-Chloro-5-trifluoromethyl-phenyl)-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[2,3-dichloro-4-(2- moφholin-4-yl-ethoxy)-phenyl]-2-oxo-acetamide;
N-(3-Methanesulfonylamino-2-methoxy-5-methyl-phenyl)-2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide;
4-{2-[4-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylaminooxalyl)-naphthalen-l-yl]-ethyl}- piperazine-1-carboxylic acid ethyl ester;
(l-Benzyl-lH-benzoimidazol-2-yl)-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-amine;
N-(3,5-Di-tert-butyl-2-hydroxy-phenyl)-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetamide;
N-(5-tert-Butyl-2-naphthalen-l-yl-2H-pyrazol-3-yl)-2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide; N-(5-tert-Butyl-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl-pyrimidin-4-ylamino)- naphthalen-l-yl]-2-oxo-acetamide;
4-{2-[4-(5-tert-Butyl-2-p-tolyl-2H-pyτazol-3-ylaminooxalyl)-naphthalen-l-yloxy]-ethyl}- piperazine-1-carboxylic acid ethyl ester;
5-tert-Butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-pyrimidin-4-ylamino)-naphthalen-l-yl]-2- oxo-acetylamino } -benzamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-metlioxy-phenyl)-2-(l-methyl-lH-indol-3-yl)-2- oxo-acetamide;
4-Phenyl-piperidine-4-carboxylic acid (5-tert-butyl-2-methoxy-phenyl)-ainide;
5-tert-Butyl-2-methoxy-3 - {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-acetylamino } - benzamide;
N-[2-(4-Acetyl-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -2-oxo-acetamide; l-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]- imidazoIidine-2,4,5-trione;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(2,3-difluoro-phenyl)-acetamide;
N-[5-tert-ButyI-3-(carbamoylmethyl-methanesulfonyl-amino)-2-methoxy-phenyl]-2- naphthalen- 1 -yl-2-oxo-acetamide;
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-[2-methyl-4-(2-morpholin-4-yl-ethoxy)- phenyl]-2 -oxo-acetamide;
N-[2-(4-Amino-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -2-oxo-acetamide;
(5-tert-Butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino}-phenyl)-carbamic acid phenyl ester;
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]- acetamide;
N-(5-tert-Butyl-2-isobutoxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetamide;
N-(4-tert-Butyl-phenyl)-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetamide; N-[5-tert-Butyl-2-(3-methyl-benzoyl)-2H-pyrazol-3-yl]-2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
5-tert-Butyl-3-{2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]- acetylamino}-thiophene-2-carboxylic acid amide; l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-chloro-pyrimidin-4-yloxy)-naphthalen-l-yl]- imidazolidine-2,4,5-trione;
(S)-N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-hydroxy-2-phenyl-acetamide;
N-[5-tert-Butyl-2-(2,3-dimethyl-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
N-[5-tert-Butyl-2-(4-nitro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
2-(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3-yl)-N-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l- yl]-2-oxo-acetamide;
2-[(Z)-Hydroxyimino]-N-(3-methanesxιlfonylamino-2-methoxy-5-methyl-phenyl)-2-[4-(2- moφholin-4-yl-ethoxy)-naphthalen- 1 -yl] -acetamide;
N-[5-tert-Butyl-2-(moφholine-4-carbonyl)-thiophen-3-yl]-2-[(Z)-hydroxyimino]-2-[4-(2- moφholin-4-yl-ethoxy)-naphthalen- 1 -yl] -acetamide;
N-(5-tert-Butyl-2-phenyl-2H-pyrazol-3-yl)-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen- 1 -yl] -
2-oxo-acetamide;
N'-[l-(5-tert-Butyl-2-methyl-2H-pyrazol-3-ylcarbamoyl)-l-[4-(2-moφholin-4-yl-ethoxy)- naphthalen-l-yl]-meth-(E)-ylidene]-hydrazinecarboxylic acid ethyl ester;
N1- [ 1 -(5-tert-Butyl-2-methyl-2H-pyrazol-3 -ylcarbamoyl)- 1 -[4-(2-mθφholin-4-yl-ethoxy)- naphthalen- 1 -yl]-meth-(Z)-ylidene] -hydrazinecaxboxamide;
N-[5-tert-Butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
5-tert-Butyl-2-methoxy-3-{2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino}-N-pyridin-2-yl-benzamide;
N-[5-tert-Butyl-3-(3,3-dimethyl-ureido)-2-methoxy-phenyl]-2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide; 5-tert-Butyl-3 - {2-[7-chIoro-4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo- acetylamino } -2-methoxy-benzamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-m-tolyl-acetamide; l-(5-tert-Butyl-2-methoxy-pheπyl)-3-[4-(2-pyrrolidin-l-yl-pyrimidin-4-yloxy)-naphthalen-l- yl]-imidazolidine-2,4,5-trione;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-hydroxy-2-phenyl-propionamide;
2-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-N-quinolin-3-yl-acetamide; l-(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]- imidazolidine-2,4,5-trione;
(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-(3-trifluoromethyl-benzyl)-amine;
N-[5-tert-Butyl-2-methoxy-3-(morpholine-4-carbonyl)-phenyl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;
N-[5-tert-Butyl-3-(3-isopropyl-ureido)-2-methoxy-phenyl]-2-[4-(2-moφholin-4-yl-etlioxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-methoxy-2-(4-methoxy-naphthalen-l-yl)- acetamide;
N-(3-Amino-5-trifluoromethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetamide;
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy)- naphthalen-l-yl]-2-oxo-acetamide;
3-Methyl- 1 ,5-diphenyl-l ,6-dihydro-imidazo[4s5-c]pyrazole;
N-(5-tert-Butyl-isoxazol-3-yl)-2-hydroxy-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]- acetamide;
N-[4-(2-Mθφholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-2-(2-phenyl-cyclopropyl)- acetamide;
2- {4-[2-(4-Acetyl-piperazin- 1 -yl)-ethoxy] -naphthalen- 1 -yl } -N~(5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-2-oxo-acetamide;
2-(lH-Indol-3-yl)-N-[4-(2-morρholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
N-[5-tert-Butyl-2-(3-fluoro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide; 2-(3-Aτnino-5-tert-bvityl-2-methoxy-phenyl)-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl]-2-oxo-acetamide;
N-[5-tert-Butyl-2-(3,4-dichloro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -2-oxo-acetamide;
N-(5-tert-Butyl-isoxazol-3-yl)-2-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy)-naphthalen-l-yl]-
2-oxo-acetamide;
N-[5-tert-Butyl-2-(2,5-dimethyl-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl- ethoxy)-5,6>7,8-tetrahydro-naphthalen-l-yl]-2-oxo-acetamide;
1 H-Indazole-3-carboxylic acid (5-tert-butyl-2-pyridin-2-yl-2H-pyrazol-3-yl)-amide;
N-(4-Chloro-3-trifluoromethyl-phenyl)-2-(4-methoxy-naphthalen-l-yl)-2-oxo-acetamide;
N-[5-(l,l-Dimethyl-butyl)-2-p-tolyl-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
1 H-Indazole-3-carboxylic acid [5-tert-butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-amide;
1 H-Indazole-3-carboxylic acid [5-tert-butyl-2-(4-hydroxy-phenyl)-2H-pyrazol-3-yl]-amide;
N'-[l-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-l-[4-(2- moφholin-4-yl-ethoxy)-naphthalen-l-yl]-meth-(E)-ylidene]-hydrazinecarboxamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-N'-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl]-oxalamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-methylamino- pyrimidin-4-ylarnino)-naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3-yl)-2-[(Z)-methoxyimino]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-acetamide;
5-tert-Butyl-N-cyclopropyl-3-[2-[(E)-hydroxyimino]-2-(4-methoxy-naphthalen-l-yl)- acetylamino]-2-methoxy-benzamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-{4-[2-(2,6-dimethyl-morpholin-4-yl)-ethoxy]- naphthalen-l-yl}-2-oxo-acetamide;
N-(5-tert-Bυtyl-3-methanesulfonylamino-2-methoxy-ρhenyl)-2-[8-fluoro-4-(2-moφholin-4- yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(3-fluoro-phenyl)-acetamide;
5-tert-Butyl-N-furan-2-ylmethyl-2-methoxy-3-{2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen- l-yl]-2-oxo-acetylamino}-benzamide;
N-[5-tert-Butyl-2-(3-trifluoromethyl-benzoyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
N-[5-tert-Butyl-2-methoxy-3-(propane-l-sulfonylamino)-phenyl]-2-[4-(2-morpholin-4-yl- pyrimidin-4-ylamino)-naphthalen-l-yl]-2-oxo-acetamide; l-(5-tert-Butyl-isoxazol-3-yl)-3-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy)-naphthalen-l-yl]- imidazolidine-2,4,5-trione; l-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-[4-(2-moφholin-4-yl-ethoxy)-naρhthalen-l-yl]-
3'-(carbamic acid ethyl ester)-urea ;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-oxo-2-{4-[2-(3-oxo- piperazin-l-yl)-ethoxy]-naphthalen-l-yl}-acetamide;
2- {4-[2-(4-Acetyl-piperazin- 1 -yl)-ethyl]-naphthalen- 1 -yl } -N-(5-tert-butyl-2-p-tolyl-2H- pyrazol-3 -yl)-2-oxo-acetamide;
N-(5-tert-Butyl-2-phenylacetyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-
1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-oxo-2-{4-[2-(3-oxo-piperazin-l-yl)-ethoxy]- naphthalen- 1 -yl } -acetamide;
2-(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3-yl)-2-[(Z)-hydroxyimino]-N-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-acetamide;
N-[5-tert-Butyl-2-(3-ureido-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[(Z)-methoxyimino]-2-[4-(2- mθφholin-4-yl-pyrimidin-4-yloxy)-naphthalen- 1 -yl]-acetamide;
N-[5-tert-Butyl-2-methoxy-3-(3-oxo-piperazine-l-carbonyl)-phenyl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl] -2-oxo-acetamide;
3-tert-Butyl-5- {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo-acetylamino}- pyrazole-1-carboxylic acid propylamide; 5-tert-Bυtyl-N-cyclopropyl-2-methoxy-3-{2-[4-(2-moφholin-4-yl-pyrimidin-4-yloxy)- naphthalen- 1 -yl]-2-oxo-acetyl amino } -benzamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2- {4-[2-(4-methyl-piperazin- 1 -yl)-ethoxy]- naphthalen- 1 -yl} -2-oxo-acetamide;
N-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-2-[4-(2-moφholin-4-yl-ρyrimidin-4-yloxy)- naphthalen-l-yl]-2-oxo-acetamide;
5-tert-Butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino } -N-propyl -benzamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-hydroxy-2-(4-methoxy-phenyl)-acetamide;
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl]-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(3-phenoxy-phenyl)-acetamide;
N-(5-Isopropyl-2-methyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetamide;
7-Isopropyl-9-phenyl-2-phenylamino-7,9-dihydro-purin-8-one;
(5-tert-Butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino}-phenyl)-carbamic acid pyridin-3-ylmethyl ester;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-ethylamino-ethoxy)- naphthalen- 1-yl] -2-oxo-acetamide;
N-(3,5-Di-tert-butyl-phenyl)-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetamide;
2-Amino-N-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-naphthalen-2-yl-acetamide;
N-[5-tert-Butyl-2-(3-fluoro-4-methyl-phenyl)-2H-pyrazol-3-yl]-2-hydroxy-2-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-l -yl] -acetamide;
2-[5-tert-Butyl-2-(3,4-difluoro-phenyl)-2H-pyrazol-3-yl]-N-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide;
N-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-2-[4-(2-methylamino-pyrimidin-4-ylamino)- naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy)- naphthalen- 1 -yl]-2-oxo-acetamide; N-[5-tert-Butyl-2-(2,3-dichloro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
N-[3 ,5-Bis-(l , 1 -dimethyl-propyl)-2-hydroxy-phenyl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
4-{2-[4-(5-tert-Butyl-3-methanesυlfonylamino-2-methoxy-phenylaminooxalyl)-naphthalen- l-yloxyj-ethy^-piperazine-l-carboxylic acid tert-butyl ester;
3-tert-Butyl- 1 -naphthalen-2-yl-5-phenyl- 1 ,6-dihydro-imidazo[4,5-c]pyrazole;
2-Biphenyl-4-yl-N-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-acetamide;
5-tert-Butyl-N-isopropyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetylamino } -benzamide;
N-(5-tert-Butyl-3-diethylaminomethyl-2-hydroxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
6-Hydroxy-nicotinic acid 3-[5-tert-butyl-2-methoxy-3-(propane-l-sulfonylamino)- phenylcarbamoyl]-lH-indazol-5-yl ester;
N-(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3-yl)-2-[4-(2-moφholin-4-yl-pyrimidin-4-ylamino)- naphthalen- 1 -yl] -2-oxo -acetami de;
N-(5-tert-Butyl-2-rnethyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-pyrimidin-4-ylarnino)- naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(4-morpholin-4-yl- pyrimidin-2-ylamino)-naphthalen- 1 -yl]-2-oxo-acetatnide;
N-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl]-2-oxo-acetamide;
1 ,3,5-Triphenyl-l ,6-dihydro-imidazo[4,5-c]pyrazole;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-cyclohexyl-acetarnide;
2-[5-tert-Butyl-2-(2-chloro-phenyl)-2H-pyrazol-3-yI]-N-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide;
7-Cyclohexylmethyl-9-phenyl-2-phenylamino-7,9-dihydro-purin-8-one;
5-tert-Butyl-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetylamino}- thiophene-2-carboxylic acid methylamide; 5-tert-Butyl-N-cyclopropylmethyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-acetylaτnino } -benzamide;
N-[5-tert-Butyl-2-(3-rnethoxy-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-pyrimidin-4- ylamino)-naphthalen- 1 -yl]-2-oxo-acetamide;
N'-[l-(5-tert-Butyl-3-carbamoyl-2-methoxy-phenylcarbamoyl)-l-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-meth-(Z)-ylidene]-hydrazinecarboxylic acid ethyl ester;
4-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-l-(2,3-dimethyl-ρhenyl)-[l,2,4]triazolidine-3,5- dione;
N-(4-Fluoro-3-trifluoromethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetamide; l-Benzyl-3-phenyl-5-phenylamino-l,3-dihydro-imidazo[4,5-b]pyridin-2-one;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-naphthalen-2-yl-acetamide;
2-[4-(2-Mθφholin-4-yl-ethoxy)-naphthalen-l -ylcarbamoy^-pyrrole-l-carboxylic acid tert- butyl ester;
N-(2,5-Di-tert-butyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetamide;
2-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo-N-((l S,2R)-2-phenyl-cyclopropyl)- acetamide;
2-Oxo-2,3-dihydro-benzoimidazole- 1 -carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3- yl)-amide;
N-(2-Methoxy-5-trifluoromethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-
2-oxo-acetamide;
N-[2-(4-Bromo-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide; l-(5-tert-Bυtyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy)-naphthalen-l- yl]-imidazolidine-234,5-trione;
5-tert-Butyl-2-methoxy-N-methyl-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetylamino}-benzamide;
N-(5-tert-Butyl-2-methoxy-3 -piperidin- 1 -ylmethyl-phenyl)-2- [4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide; N-(5-tert-Butyl-2-methoxy-phenyl)-2-naphthalen-l-yl-2-oxo-acetamide;
N-(2,5-Di-tert-butyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetamide;
(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 4-methoxy-phenyl ester;
N-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-2-naphthalen-l-yI-2 -oxo-acetamide;
5-tert-Butyl-N-ethyl-3-{2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl]-acetylamino}-2-methoxy-benzaτnide;
4-{2-[4-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylaminooxalyl)-naphthalen-l-yl]-ethyl}- piperazine-1-carboxylic acid tert-butyl ester;
5-tert-Butyl-N-ethyl-2-hydroxy-3- {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo- acetylamino } -benzamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-naphthalen-l-yl-acetamide;
N-(5-tert-Butyl-2-ethoxy-3-methanesulfonylamino-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
N'-[ 1 -(5-tert-Butyl-3 -ethylcarbamoyl-2-methoxy-phenylcarbanioyl)-l -[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-meth-(E)-ylidene]-hydrazinecarboxamide;
2- {4-[2-(4-Acetyl-piperazin- 1 -yl)-ethoxy]-naphthalen- 1 -yl } -N-(5-tert-butyl-2-p-tolyl-2H- pyrazol-3-yl)-2-oxo-acetamide;
5-tert-Butyl-N-ethyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino} -benzamide;
5-tert-Butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino} -benzoic acid;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-hydroxy-2-[4-(2-morpholin-
4-yl-ethoxy)-5,6,7,8-tetrahydro-naphthalen- 1 -yl]-acetamide;
N-(5-tert-Butyl-isoxazol-3-yl)-2-[4-(2-dimethylamino-pyrimidin-4-ylamino)-naphthalen-l- yl]-2-oxo-acetamide;
5-tert-Butyl-3-{2-[4-(2-morpholin-4-yl-pyridin-4-ylamino)-naphthalen-l-yl]-2-oxo- acetylamino} -thiophene-2-carboxylic acid amide;
2-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-N-m-tolyl-acetamide; 5-tert-Butyl-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetylamino}- thiophene-2-carboxylic acid methyl ester;
N'-[l -(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)- 1 -[4-(2- morpholin-4-yl-ethoxy)-naphthalen-l-yl]-meth-(Z)-ylidene]-hydrazinecarboxamide;
N-[5-tert-Butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-pyridin-4- ylamino)-naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-Isopropyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-
2-oxo-acetamide;
N-(5-tert-Butyl-isoxazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetamide;
N-(2-Benzoyl-5-tert-butyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl]-2-oxo-acetamide;
6-Bromo-l H-indazole-3-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-amide;
5-tert-Butyl-N-ethyl-3-{2-hydrazono-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]- acetylamino } -2-methoxy-benzamide;
N-(5-tert-Butyl-3-ethanesulfonylamino-2-methoxy-phenyl)-2-[(Z)-hydroxyimino]-2-[4-(2- morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-acetamide;
N-(3-Aπiino-5-tert-butyl-2-methoxy-phenyl)-2-[4-(2-dimethylamino-pyrimidin-4-ylamino)- naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-thiophen-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetamide;
N-[5-tert-Butyl-2-(4-chloro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide;
N'-[ 1 -(5-tert-Butyl-3 -carbaτnoyl-2-methoxy-phenylcarbamoyl)- 1 - [4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-meth-(E)-ylidene]-hydrazinecarboxamide;
N-[5-tert-Butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen- 1 -yl] -2-oxo-acetamide;
5-tert-Butyl-3-{2-[7-chloro-4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino } -N-cyclopropyl-2-methoxy-benzamide; N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2- {4-[2-(4-methyl-piperazin- 1 - yl)-ethoxy]-naphthalen- 1 -yl}-2-oxo-acetamide; l-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]- imidazolidin-2-one;
N-(5-tert-Butyl-thiophen-3-yl)-2-[(Z)-hydroxyimino]-2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen- 1 -yl]-acetamide;
5-tert-Butyl-N-cyclopropyl-3-[2-[(Z)-hydroxyimino]-2-(4-methoxy-naρhthalen-l-yl)- acetylamino]-2-methoxy-benzamide;
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-[4-(4-morpholin-4-yl-pyrimidin-2-ylamino)- naphthalen- 1 -yl]-2-oxo-acetamide;
N-[5-tert-Butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-yl]-2-[(Z)-hydroxyimino]-2-[4-(2- moφholin-4-yl-ethoxy)-naphthalen- 1 -yl]-acetamide;
N-[2-Methoxy-5-(l-methyl-l-phenyl-ethyl)-phenyl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
2-[5-tert-Butyl-2-(3,4-dimethyl-phenyl)-2H-pyrazol-3-yl]-N-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
5-tert-Butyl-3 - {2-[4-(2-morpholin-4-yl-pyrimidin-4-ylamino)-naphthalen- 1 -yl]-2-oxo- acetylamino}-thiophene-2-carboxylic acid amide;
5-tert-Butyl-N-isobutyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetyl amino } -benzamide;
2-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[(Z)-hydroxyimino]-N-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-acetamide;
3-tert-Butyl-l-(2,3-dichloro-phenyl)-5-phenyl-l,6-dihydro-imidazo[4,5-c]pyrazole;
N-(3 ,5-Di-tert-butyl-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2- oxo-acetamide;
5-tert-Butyl-3-{2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]- acetylamino}-thiophene-2-carboxylic acid dimethylamide;
N-(5-tert-Butyl-2-methoxy-3-methyl-phenyl)-2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-acetamide; N'-[l-(5-tert-Butyl-3-cyclopropylcarbamoyl-2-methoxy-phenyIcarbanioyl)-l-[4-(2- moφholin-4-yl-ethoxy)-naphthalen-l-yi]-meth-(E)-ylidene]-hydrazinecarboxylic acid ethyl ester;
N-Indan-5-yl-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
N-[5-tert-Butyl-2-(3-chloro-4-fluoro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
N-[5-tert-Butyl-3-(imidazole-l-carbonyl)-2-methoxy-phenyl]-2-[4-(2-morρholin-4-yl- ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
2-(2,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetamide;
N-[5-tert-Bxιtyl-2-(2,4-difluoro-phenyl)-2H-ρyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide;
1 H-Indazole-3-carboxylic acid (5-tert-butyl-2-methoxy-phenyl)-amide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-oxo-2-{4-[2-(5-oxo-[l,4]diazepan-l-yl)- ethoxy]-naphthalen- 1 -yl } -acetamide;
3-tert-Butyl-l-p-tolyl-5-(4-trifluoromethyl-phenyl)-l,6-dihydro-imidazo[4,5-c]pyrazole;
N-(5-tert-Butyl-3-ethanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
3-tert-Butyl-5-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetylamino}- pyrazole-1-carboxylic acid isopropylamide;
N-(5-tert-Butyl-[ 1 ,3 ,4]thiadiazol-2-yl)-2-hydroxy-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[(Z)-hydroxyimino]-2-[4-(2- morpholin-4-yl-pyrimidin-4-yloxy)-naphthalen- 1 -yl] -acetamide;
N-[2-(3-Amino-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-1 -yl]-2-oxo-acetamide;
3-tert-Butyl-5- {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l -yl]-2-oxo-acetylamino} - pyrazole-1-carboxylic acid phenylamide;
2-(5-tert-Butyl-2-rnethyl-furan-3-yl)-N-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetamάde; N-(5-tert-Butyl-2-o-tolyl-2H-pyrazol-3-yl)-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-
2-oxo-acetamide;
N-(5-tert-Butyl-isoxazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-acetaπiide;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-(3-methoxy-phenyl)-acetamide;
5-tert-Butyl-3-{2-[4-(2-morpholin-4-yl-ρyrimidin-4-yloxy)-naphthalen-l-yl]-2-oxo- acetylamino}-thiophene-2-carboxylic acid amide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-hydroxy-2-[4-(2-morpholin-
4-yl-ethoxy)-naphthalen- 1 -yl]-acetamide;
N-[5-tert-Butyl-2-(2,4-dichloro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-ButyI-isoxazol-3-yl)-2-[4-(3-hydroxy-propoxy)-naphthalen-l-yl]-2-oxo-acetamide;
N-(3-tert-Butyl-isoxazol-5-yl)-2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -acetami de;
1 H-Indole-3-carboxylic acid (5-tert-butyl-2-methoxy-phenyl)-amide;
N-[5-tert-Butyl-2-methoxy-3-(propane-l-sulfonylamino)-phenyl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
7-Bicyclo[2.2.1]hept-2-yl-9-phenyl-2-phenylamino-7,9-dihydro-purin-8-one;
N-(5-tert-Butyl-2-p-tolyl-2H-ρyrazol-3-yl)-2-(2,4-dichloro-phenyl)-acetamide;
5-tert-Butyl-2-methoxy-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-benzamide;
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-[2,3-dimethyl-4-(2-morpholin-4-yl-ethoxy)- phenyl] -2-oxo-acetamide;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-(3-fluoro-phenyl)-acetamide; l-(5-tert-Butyl-2-methoxy-3-benzamide)-3-(2,3-dimethylphenyl)-3'-(carbamic acid ethyl ester)-urea;
2-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-oxo-N-(3-trifluoromethyl-phenyl)-acetamide;
7-Benzyl-9-phenyl-2-phenylamino-7,9-dihydro-pυrin-8-one;
2,5-Dihydro-lH-pyrrole-2-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-amide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-oxo-2-{4-[2-(5-oxo-
[l,4]diazepan-l-yl)-ethoxy]-naphthalen-l-yl}-acetamide; N-[5-tert-Butyl-2-(3-cyano-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -2-oxo-acetamide;
N-(5-tert-Butyl-2-methoxy-3-phenylacetylamino-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -2-oxo-acetamide;
2-(2-Chloro-5-trifluoromethyl-phenyl)-N-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy)- naphthalen- 1 -yl] -2-oxo-acetamide;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-piperidin-l -yl-pyrimidin-4-yloxy)-naphthalen-l - yl]-imidazolidine-2,4,5-trione;
2-(2-Benzyl-5-tert-butyl-2H-pyrazol-3-yl)-2-hydroxy-N-[4-(2-moφholin-4-yl-ethoxy)- naphthalen-1 -yl]-acetamide;
5-tert-Butyl-3-{2-[4-(2-dimethylamino-pyrimidin-4-ylamino)-naphthalen-l-yl]-2-oxo- acetylamino}-thiophene-2-carboxylic acid amide;
N'-[l-(5-tert-Butyl-3-ethylcarbamoyl-2-methoxy-phenylcarbainoyl)-l-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-meth-(E)-ylidene]-hydrazinecarboxylic acid ethyl ester;
N-(3-Methanesulfonylamino-5-triflxioromethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-hydroxy-3-piperidin-l-ylmethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -2-oxo-acetamide;
2-( 1 -Methyl- 1 H-indol-3-yl)-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo- acetamide;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-oxo-2- (4-[2-((S)- 1 -phenyl-ethylamino)-pyrimidin-4- ylamino] -naphthalen- 1 -yl } -acetamide;
N-[5-tert-Butyl-2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
N'-[ 1 -(5-tert-Butyl-3-methanesυlfonylamino-2-methoxy-phenyl carbamoyl)- 1 -[4-(2- moφholin-4-yl-ethoxy)-naphthalen-l -yl]-meth-(E)-ylidene]-hydrazinecarboxylic acid ethyl ester;
N-[5-tert-Bυtyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-yl]-2-hydroxy-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-acetamide; N-(5-tert-Butyl-2-methoxy-3- {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo- acetylamino}-phenyl)-isobutyramide;
N-[5-tert-Butyl-2-(4-methyl-benzoyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
N-[5-tert-Butyl-2-(2-chloro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-moηpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
N-[5-tert-Butyl-2-(3-chloro-4-methyl-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
2-(4-Bromo-phenyl)-N-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-acetamide;
2-(5-tert-Butyl-2-methyl-furan-3-yl)-N-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl]-2-oxo-acetamide;
4-(4-{4-[2-(5-tert-Butyl-2-methyl-furan-3-yl)-2-oxo-acetylamino]-naphthalen-l-ylamino}- phenoxy)-pyridine-2-carboxylic acid methylamide;
N-[5-tert-Butyl-2-methoxy-3-(propane-l-sulfonylamino)-phenyl]-2-[4-(2-morpholin-4-yl- pyridin-4-ylamino)-naphthalen-l-yl]-2-oxo-acetamide;
5-tert-Butyl-N-cyclopropyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-pyridin-4-ylamino)- naphthalen- 1 -yl]-2-oxo-acetylamino}-benzaτnide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-oxo-2-{4-[6-(tetrahydro- pyran-4-yl amino)-ρyτidin-3 -yl] -naphthal en- 1 -yl } -acetamide;
3-[2-(4-Bromo-naphthalen-l-yl)-2-oxo-acetylamino]-5-tert-butyl-N-cyclopropyl-2-methoxy- benzamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(6-morpholin-4-yl- pyridin-3-yl)-naphthalen-l -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-oxo-2-(4-pyridin-3-yl- naphthalen- 1 -yl)-acetamide;
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-oxo-2-(4-pyridin-3-yl-naphthalen-l-yl)- acetamide; 2-(4-Chloro-3-trifluoromethyl-phenyl)-N-[4-(2-morphoHn-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetamide;
4-{4-[2-(4-Chloro-3-trifluoromethyl-phenyl)-2-oxo-acetylamino]-phenoxy}-pyridine-2- carboxylic acid methylamide;
N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2- {4-[2-(5-methoxy- 1 H-indol-
3-yl)-ethylamino]-naphthalen-l-yl}-2-oxo-acetamide;
N-[5-tert-Butyl-3-(carbamoylmethyl-methanesulfonyl-amino)-2-methoxy-phenyl]-2-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(6-dimethylamino-pyridin-
3-yl)-naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(6-methylamino-pyridin-
3-yl)-naphthalen-l-yl]-2-oxo-acetamide;
N-[5-tert-Butyl-2-methoxy-3 -(propane- 1 -sxιlfonylamino)-phenyl] -2- [4-(2-dimethylamino- pyridin-4-ylamino)-naphthalen-l-yl] -2 -oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2 -dimethyl amino-pyridiπ-
4-ylamino)-naphthalen- 1 -yl]-2-oxo-acetamide;
5-tert-Butyl-N-cyclopropyl-3-{2-[4-(2-dimethylamino-pyridin-4-ylamino)-naphthalen-l-yl]-
2-oxo-acetylamino}-2-methoxy-benzamide;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-[4-(2-dimethylamino-pyridin-4-ylamino)-naphthalen-l- yl]-2-oxo-acetamide;
5-tert-Butyl-3-{2-[4-(2-dimethylamino-pyridin-4-ylamino)-naphthalen-l-yl]-2-oxo- acetylamino}-thiophene-2-carboxylic acid amide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(3-ethyl-isoxazol-5-yl)- naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-[4-(6-methylamino-pyridin-3-yl)-naphthalen-l-yl]-2- oxo-acetamide;
5-tert-Butyl-2-methoxy-3-{2-[4-(6-methylamino-pyridin-3-yl)-naphthalen-l-yl]-2-oxo- acetylamino } -benzamide;
5-tert-Butyl-N-ethyl-2-methoxy-3-{2-[4-(6-methylamino-pyridin-3-yl)-naphthalen-l-yl]-2- oxo-acetylamino} -benzamide; 5-tert-Butyl-N-cyclopropyl-2-methoxy-3-{2-[4-(6-methylamino-pyridin-3-yl)-naphthalen-l- yl]-2-oxo-acetylamino}-benzamide;
N-[5-tert-Butyl-2-methoxy-3-(propane-l-sulfonylamino)-phenyl]-2-[4-((S)-2,3-dihydroxy- propoxy)-naphthalen-l-yl]-2-oxo-acetamide;
2-(5-tert-Butyl-2-methyl-iuran-3-yl)-N-[4-(2-chloro-pyrimidin-4-ylamino)-naplithalen-l-yl]-
2-oxo-acetamide;
2-(5-tert-Butyl-2-methyl-furan-3-yl)-2-oxo-N-[4-(pyrimidin-4-ylamino)naphthalen-l-yl]- acetamide;
N-(5-tert-Butyl-isoxazol-3-yl)-2-[4-(2,3-dihydroxy-propoxy)-naphthalen-l-yl]-2-oxo- acetamide;
2-(5-tert-Butyl-2-methyl-furan-3-yl)-2-oxo-N-[4-(pyrimidin-2-ylamino)-naphthalen- 1 -yl] - acetamide;
2-(5-tert-Butyl-2-methyl-furan-3-yl)-N-[4-(2-moη)holin-4-yl-pyriπiidin-4-yloxy)-naphthalen-
1 -yl] -2-oxo-acetamide;
2-(5-tert-Butyl-2-methyl-furan-3-yl)-N-[4-(2-morpholin-4-yl-pyrimidin-4-ylamino)- naphthalen-l-yl]-2-oxo-acetamide;
2-(5-tert-Butyl-3-methyl-furan-2-yl)-N-[4-(2-mθφholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetamide;
2-[5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-yl]-N-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -2-oxo-acetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxo-2-(4-(2-(pyrrolidin-l- yl)pyrimidin-4-ylamino)naphthalen- 1 -yl)acetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-(4-(4- moφholinophenyl)naphthalen- 1 -yl)-2-oxoacetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-(4-(6-methoxypyridin-3- yl)naphthalen-l-yl)-2-oxoacetamide;
2-(4-(2-aminopyrimidin-4-ylamino)naphthalen-l-yl)-N-(5-tert-butyl-2-methoxy-3-
(methylsulfonamido)phenyl)-2-oxoacetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxo-2-(4-(pyrimidin-4- ylamino)naphthalen- 1 -yl)acetamide; 006/043896
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxo-2-(4-(pyridin-4- ylamino)naphthalen-l-yl)acetamide; and pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0027] The following terms are used throughout as defined below.
[0028] Generally, reference to a certain element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Hence, isotopically labeled compounds are within the scope of the invention.
[0029] In general, "substituted" refers to an organic group as defined below (e.g., an alkyl group) in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Thus, a substituted group will be substituted with one or more substituents, unless otherwise specified. In some embodiments, a substituted group is substituted with 1, 2, 3, 4, 5, or 6 substituents. Examples of substituent groups include: halogens (i.e., F, Cl, Br, and I); hydroxyls; alkoxy, alkenoxy, alkynoxy, aryloxy, aralkyloxy, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyls(oxo); carboxyls; esters; urethanes; oximes; hydroxylamines; alkoxyamines; aralkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyls; sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitro groups; nitriles (i.e., CN); and the like.
[0030] Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups may also be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below. [0031] Alkyl groups include straight chain and branched alkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Alkyl groups further include cycloalkyl groups as defined below. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n- octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. Representative substituted alkyl groups may be substituted one or more times with substituents such as those listed above.
[0032] Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups further include mono-, bicyclic and polycyclic ring systems, such as, for example bridged cycloalkyl groups as described below, and fused rings, such as, but not limited to, decalinyl, and the like. In some embodiments, polycyclic cycloalkyl groups have three rings. Substituted cycloalkyl groups may be substituted one or more times with, non- hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups, which may be substituted with substituents such as those listed above.
[0033] Bridged cycloalkyl groups are cycloalkyl groups in which two or more hydrogen atoms are replaced by an alkyl ene brige, wherein the bridge can contain 2 to 6 carbon atoms if two hydrogen atoms are located on the same carbon atom, or 1 to 5 carbon atoms, if the two hydrogen atoms are located on adjacent carbon atoms, or 2 to 4 carbon atoms if the two hydrogen atoms are located on carbon atoms separated by 1 or 2 carbon atoms. Bridged cycloalkyl groups can be bicyclic, such as, for example bicyclo[2.1.1]hexane, or tricyclic, such as, for example, adamantyl. Representative bridged cycloalkyl groups include bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decanyl, adamantyl, noradamantyl, bornyl, or norbornyl groups. Substituted bridged cycloalkyl groups may be substituted one or more times with non-hydrogen and non-carbon groups as defined above. Representative substituted bridged cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted adamantyl groups, which may be substituted with substituents such as those listed above.
[0034] Cycloalkylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a cycloalkyl group as defined above. In some embodiments, cycloalkylalkyl groups have from 4 to 20 carbon atoms, 4 to 16 carbon atoms, and typically 4 to 10 carbon atoms. Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl or both the alkyl and cycloalkyl portions of the group. Representative substituted cycloalkylalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted with substituents such as those listed above.
[0035] Alkenyl groups include straight and branched chain and cycloalkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, alkenyl groups include cycloalkenyl groups having from 4 to 20 carbon atoms, 5 to 20 carbon atoms, 5 to 10 carbon atoms, or even 5, 6, 7, or 8 carbon atoms. Examples include, but are not limited to vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)^CH(CH3), -C(CH2CHs)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, , and hexadienyl, among others. Representative substituted alkenyl groups may be mono- substituted or substituted more than once, such as, but not limited to, mono-, di- or tri- substituted with substituents such as those listed above.
[0036] Cycloalkenylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above. Substituted cycloalkylalkenyl groups may be substituted at the alkyl, the cycloalkenyl or both the alkyl and cycloalkenyl portions of the group. Representative substituted cycloalkenylalkyl groups may be substituted one or more times with substituents such as those listed above.
[0037] Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. Examples include, but are not limited to -CsCH, - C=C(CH3), -C=C(CH2CH3), -CH2C≡CH, -CH2C=C(CH3), and -CH2CsC(CH2CH3), among others. Representative substituted alkynyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted with substituents such as those listed above.
[0038] Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
Aryl groups include monocyclic, bicyclic and polycyclic ring systems. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenylenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups. In some embodiments, aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6-10 carbon atoms in the ring portions of the groups. Although the phrase "aryl groups" includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like), it does not include aryl groups that have other groups, such as alkyl or halo groups, bonded to one of the ring members. Rather, groups such as tolyl are referred to as substituted aryl groups. Representative substituted aryl groups may be mono-substituted or substituted more than once. For example, monosubstituted aryl groups include, but are not limited to, 2-, 3-, A-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with substituents such as those listed above.
[0039] Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above. In some embodiments, aralkyl groups contain 7 to 20 carbon atoms, 7 to 14 carbon atoms or 7 to 10 carbon atoms. Substituted aralkyl groups may be substituted at the alkyl, the aryl or both the alkyl and aryl portions of the group. Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4- ethyl-indanyl. Representative substituted aralkyl groups may be substituted one or more times with substituents such as those listed above.
[0040] Heterocyclyl groups include aromatic (also referred to as heteroaryl) and non- aromatic ring compounds containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N3 O, and S. In some embodiments, heterocyclyl groups include 3 to 20 ring members, whereas other such groups have 3 to 6, 3 to 10, 3 to 12, or 3 to 15 ring members. Heterocyclyl groups encompass unsaturated, partially saturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl groups. The phrase "heterocyclyl group" includes fused ring species including those comprising fused aromatic and non-aromatic groups, such as, for example, benzotriazolyl, 2,3-dihydrobenzo[l,4]dioxinyl, and benzo[l,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. However, the phrase does not include heterocyclyl groups that have other groups, such as alkyl, oxo or halo groups, bonded to one of the ring members. Rather, these are referred to as "substituted heterocyclyl groups". Heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxathiane, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl, homopiperazinyl, quinuclidyl, indolyl, indolinyl, isoindolyl,azaindolyl (pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzthiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[l,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups. Representative substituted heterocyclyl groups may be mono- substituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed above.
[0041] Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridyl), indazolyl, benzimidazolyl, imidazopyridyl (azabenzimidazolyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Although the phrase "heteroaryl groups" includes fused ring compounds such as indolyl and 2,3-dihydro indolyl, the phrase does not include heteroaryl groups that have other groups bonded to one of the ring members, such as alkyl groups. Rather, heteroaryl groups with such substitution are referred to as "substituted heteroaryl groups." Representative substituted heteroaryl groups may be substituted one or more times with various substituents such as those listed above.
[0042] Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heterocyclyl group as defined above. Substituted heterocyclylalkyl groups may be substituted at the alkyl, the heterocyclyl or both the alkyl and heterocyclyl portions of the group. Representative heterocyclyl alkyl groups include, but are not limited to, 4-ethyl-morpholinyl, 4- propylmorpholinyl, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl. Representative substituted heterocyclylalkyl groups may be substituted one or more times with substituents such as those listed above.
[0043] Heteroaralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above. Substituted heteroaralkyl groups may be substituted at the alkyl, the heteroaryl or both the alkyl and heteroaryl portions of the group. Representative substituted heteroaralkyl groups may be substituted one or more times with substituents such as those listed above.
[0044] Alkoxy groups are hydroxyl groups (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of a substituted or unsubstituted alkyl group as defined above. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like. Examples of branched alkoxy groups include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like. Examples of cycloalkoxy groups include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. Representative substituted alkoxy groups may be substituted one or more times with substituents such as those listed above.
[0045] The terms "aryloxy" and "arylalkoxy" refer to, respectively, a substituted or unsubstituted aryl group bonded to an oxygen atom and a substituted or unsubstituted aralkyl group bonded to the oxygen atom at the alkyl. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy. Representative substituted aryloxy and arylalkoxy groups may be substituted one or more times with substituents such as those listed above.
[0046] The term "carboxylate" as used herein refers to a -COOH group. [0047] The term "carboxylic ester" as used herein refers to -COOR30 groups. R30 is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
[0048] The term "amide" (or "amido") includes C- and N-amide groups, i.e.,
-C(O)NR31R32, and -NR31C(O)R32 groups, respectively. R31 and R32 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. Amido groups therefore include but are not limited to carbamoyl groups (-C(O)NH2) and formamide groups (-NHC(O)H).
[0049] Urethane groups include N- and O-urethane groups, i.e., -NR33C(O)OR34 and
-OC(O)NR33R34 groups, respectively. R33 and R34 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein.
[0050] The term "amine" (or "amino") as used herein refers to -NHR35 and -NR36R37 groups, wherein R35, R36 and R37 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. In some embodiments, the amine is NH2, methylamino, dimethyl amino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.
[0051] The term "sulfonamido" includes S- and N-sulfonamide groups, i.e.,
-SO2NR38R39 and -NR38SO2R39 groups, respectively. R38 and R39 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. Sulfonamido groups therefore include but are not limited to sulfamoyl groups (-SO2NH2).
[0052] The term "thiol" refers to -SH groups, while sulfides include -SR40 groups, sulfoxides include -S(O)R41, sulfones include -SO2R42 groups, and sulfonyls include - SO2OR43. R40, R41, R42, and R43 are each independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
[0053] The term "urea" refers to -NR44-C(O)-NR45R46 groups. R44, R45, and R46 groups are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.
[0054] The term "amidine" refers to -C(NR47)NR48R49 and -NR47C(NR48)R49 groups, wherein R47, R48, and R49 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
[0055] The term "guanidine" refers to -NR50C(NR5 ')NR52R53 groups, wherein R50,
R51, R52 and R53 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
[0056] The term "enamine" refers to -C(R54)=C(R55)NR56R57 and
-NR54C(R5S)=C(R56)R57 groups, wherein R54, R55, R56 and R57 are each independently hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
[0057] The term "imide" refers to -C(O)NR58C(O)R59 groups, wherein R58 and R59 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
[0058] The term "imine" refers to -CR60(NR61) and -N(CR60R61) groups, wherein R60 and R61 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein, with the proviso that R60 and R61 are not both simultaneously hydrogen.
[0059] The term "protected" with respect to hydroxyl groups, amine groups, carboxy groups, and sulfliydryl groups refers to forms of these functionalities which are protected from undesirable reaction by means of protecting groups. Protecting groups are known to those skilled in the art and can be added or removed using well-known procedures such as those set forth in Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999). Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate.
[0060] N-Protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p- bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5- dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3 ,4,5- trimethoxybenzyloxycarbonyl, l-(p-biphenylyl)-l -methylethoxycarbonyl, oςct-dimethyl-3,5- dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Typical N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-bυtyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
[0061] Examples of protected sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, S-t-butylthioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
[0062] Representative carboxy protecting groups are Ci to Cg alkyl (e.g., methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cyclopentyl and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cyclopentylmethyl and the like; arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl (e.g., dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valerytoxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1 -(propionyloxy)- 1 -ethyl, 1 -(pivaloyloxyl)- 1 -ethyl, 1 -methyl- 1 -(propionyloxy)- 1 -ethyl, pivaloyloxymethyl, propionyloxymethyl and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexyl carbonyloxymethyl and the like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl and the like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 2-benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1-methoxycarbonyl-l -ethyl, and the like; alkoxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethylj 1 -ethoxycarbonyloxy-1 -ethyl, 1 -cyclohexyloxycarbonyloxy-1 - ethyl and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminom ethyl and the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminornethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as 4-methylpiperazinylcarbonyloxymethyl and the like; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl and the like; (5-(alkyl)-2-oxo-l,3-dioxolen-4-yl)alkyl, such as (5-t-butyl-2-oxo-l,3-dioxolen-4-yl)methyl and the like; and (5-phenyl-2-oxo-l,3-dioxolen-4- yl)alkyl, such as (5-phenyl-2-oxo-l,3-dioxolen-4-yl)methyl and the like.
[0063] Those of skill in the art will appreciate that compounds of the invention may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism and/or optical isomerism. As the formula drawings within the specification and claims can represent only one of the possible tautomeric, conformational isomeric, optical isomeric or geometric isomeric forms, it should be understood that the invention encompasses any tautomeric, conformational isomeric, optical isomeric and/or geometric isomeric forms of the compounds having one or more of the utilities described herein, as well as mixtures of these various different forms.
[0064] "Tautomers" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:
Figure imgf000055_0001
As readily understood by one skilled in the art, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of compounds of the invention, including Formulas IA, TB, IC and II, are within the scope of the present invention.
[0065] Stereoisomers of compounds include all chiral, diastereomeric, and racemic forms and all geometric isomeric forms of a structure, unless the specific stereochemistry or isomeric form is specifically indicated. Thus, compounds used in the present invention include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of the invention. [0066] Certain compounds within the scope of Formulas IA3 IB, IC and II are derivatives referred to as "prodrugs". The expression "prodrug" denotes a derivative of a known direct acting drug, e.g. esters and amides, which derivative has enhanced delivery characteristics and therapeutic value as compared to the drug, and is transformed into the active drug by an enzymatic or chemical process; see Notari, R.E., "Theory and Practice of Prodrug Kinetics," Methods in Enzymology 1985, 112: 309-323; Bodor, N., "Novel Approaches in Prodrug Design," Drugs of the Future 1981, 6: 165-182; and Bundgaard, H., "Design of Prodrugs: Bioreversible-Derivatives for Various Functional Groups and Chemical Entities," in Design of Prodrugs (H. Bundgaard, ed.), Elsevier, New York (1985), Goodman and Gilmans, The Pharmacological Basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992. The preceding references and all references listed herein are hereby incorporated in their entirety by reference.
[0067] Pharmaceutically acceptable salts of the invention compounds are within the scope of the present invention. When the compound of the invention has a basic group, such as, for example, an amino group, pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid). When the compound of the invention has an acidic group, such as for example, a carboxylic acid group, it can form salts with metals, such as alkali and earth alkali metals (e.g. Na+, Li+, K+, Ca2+, Mg2+, Zn2+), ammonia, organic amines (e.g., trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e.g., arginine, lysine and ornithine).
[0068] A "cytokine inhibitor" within the context of this invention is a compound which at a concentration of 10 μM inhibits induced cytokine release from a cell by about 50% or greater than 50%. For example, induction of TNFa release can be achieved by, but not limited to, treatment of a cell or cell line with lipopolysaccharide (LPS) or IL-Ib and is inhibited by compounds described herein. [0069] "Treating" within the context of the instant invention, means an alleviation, in whole or in part, of symptoms associated with a disorder or disease, or a slowing or halt of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder in a subject. A subject is any animal that can benefit from the administration of a cytokine inhibitor of the invention. In some embodiments, the subject is a mammal, for example, a human, a primate, a dog, a cat, a horse, a cow, a pig, a rodent, such as for example a rat or mouse. Typically, the mammal is a human. As used herein, a "therapeutically effective amount" of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with a disorder or disease, or slows or halts of further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disease or disorder. Treatment may also include administering the pharmaceutical formulations of the present invention in combination with other therapies, such as Ingredients A as defined herein. For example, the compounds of the invention can also be administered in conjunction with other anti-inflammatory agents, and other agents described herein. For the treatment of pemphigus, other suitable agents which may be used in combination with the novel compounds of the invention include, but are not limited to, anti-inflammatory agents, immunosuppressants, anti-infectives, antibiotics, gold salts, immunoglobulins, alkylating agents, or a combination of two or more thereof.
[0070] A therapeutically effective amount of a cytokine inhibitor used in the present invention may vary depending upon the route of administration and dosage form. Effective amounts of invention compounds typically fall in the range of about 0.001 up to 100 mg/kg/day, and more typically in the range of about 0.05 up to 10 mg/kg/day. Typically, the compound or compounds used in the instant invention are selected to provide a formulation that exhibits a high therapeutic index. The therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD50 and ED50. The LD50 is the dose lethal to 50% of the population and the ED50 is the dose therapeutically effective in 50% of the population. The LD50 and ED50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals. [0071] The instant cytokine inhibitors can be used in the methods and compositions of the invention either alone or together with additional treatments or active ingredients (Ingredients A as described herein) or a combination thereof. The additional active agents can act additively or, more typically, synergistically with the cytokine inhibitor. In one example, a cytokine inhibitor is administered concurrently with one or more second active agents in the same pharmaceutical composition. In another example, a cytokine inhibitor is administered concurrently with one or more second active agents in separate pharmaceutical compositions. In still another example, a cytokine inhibitor is administered prior to or subsequent to administration of a second active agent. The invention contemplates administration of a cytokine inhibitor and a second active agent by the same or different routes of administration, e.g., oral and parenteral. In certain embodiments, when a cytokine inhibitor is administered concurrently with a second active agent that potentially produces adverse side effects including, but not limited to, toxicity, the second active agent can advantageously be administered at a dose that falls below the threshold that the adverse side effect is elicited. For example, the cytokine inhibitor is administered in an amount effective to allow for a reduction in the therapeutically effective dosage of Ingredient A compared to the effective amount of Ingredient A when used alone. This reduction in dosage is commonly referred to as Ingredient A sparing. In embodiments wherein Ingredient A is a corticosteroid, corticosteroid sparing is achieved (also called steroid sparing).
[0072] Specific dosages of cytokine inhibitors or combinations of cytokine inhibitors and additional active agents (Ingredients A as described herein) may be adjusted depending on conditions of disease, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the dosage forms described below containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant invention.
[0073] The invention also provides for pharmaceutical compositions and medicaments which may be prepared by mixing one or more compounds of Formula IA, IB, IC, II, and optionally additional active ingredients, prodrugs thereof, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, or solvates thereof, with pharmaceutically acceptable carriers, excipients, binders, diluents or the like to treat, or prevent disorders associated with excess cytokine production. The compounds and compositions of the invention may be used to prepare formulations and medicaments that prevent or treat a variety of disorders associated with excess cytokine production, e.g., autoimmune diseases and pathological conditions, such as pemphigus. For example, the compositions may be administered to subjects to reduce the number and/or severity of clinical indicia of pemphigus as described herein. Such compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. The instant compositions can be formulated for various routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration, or via implanted reservoir. Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneally, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injections. The following dosage forms are given by way of example and should not be construed as limiting the instant invention.
[0074] For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds used in the instant invention, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive such as a starch or other additive. Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Optionally, oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Tablets and pills may be further treated with suitable coating materials known in the art. [0075] Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water. Pharmaceutical formulations and medicaments may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these. Pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration.
[0076] As noted above, suspensions may include oils. Such oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as but not limited to, poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water may also be used in suspension formulations.
[0077] Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be employed as solvents or suspending agents. Typically, the oil or fatty acid is nonvolatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.
[0078] For injection, the pharmaceutical formulation and/or medicament may be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these. [0079] For rectal administration, the pharmaceutical formulations and medicaments may be in the form of a suppository, an ointment, an enema, a tablet or a cream for release of compound in the intestines, sigmoid flexure and/or rectum. Rectal suppositories are prepared by mixing one or more compounds used in the instant invention, or pharmaceutically acceptable salts or tautomers of the compound, with acceptable vehicles, for example, cocoa butter or polyethylene glycol, which is present in a solid phase at normal storing temperatures, and present in a liquid phase at those temperatures suitable to release a drug inside the body, such as in the rectum. Oils may also be employed in the preparation of formulations of the soft gelatin type and suppositories. Water, saline, aqueous dextrose and related sugar solutions, and glycerols may be employed in the preparation of suspension formulations which may also contain suspending agents such as pectins, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, as well as buffers and preservatives.
[0080] Compounds used in the invention may be administered to the lungs by inhalation through the nose or mouth. Suitable pharmaceutical formulations for inhalation include solutions, sprays, dry powders, or aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. Formulations for inhalation administration contain as excipients, for example, lactose, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate. Aqueous and nonaquous aerosols are typically used for delivery of inventive compounds by inhalation.
[0081] Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of the compound together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizes vary with the requirements of the particular compound, but typically include nonionic surfactants (T weens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions. A nonaqueous suspension (e.g., in a fluorocarbon propellant) can also be used to deliver compounds used in the invention. [0082] Aerosols containing compounds for use according to the present invention are conveniently delivered using an inhaler, atomizer, pressurized pack or a nebulizer and a suitable propellant, e.g., without limitation, pressurized dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, nitrogen, air, or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be controlled by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, 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. Delivery of aerosols of the present invention using sonic nebulizers is advantageous because nebulizers minimize exposure of the agent to shear, which can result in degradation of the compound.
[0083] For nasal administration, the pharmaceutical formulations and medicaments may be a spray, nasal drops or aerosol containing an appropriate solvent(s) and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. For administration in the form of nasal drops, the compounds may be formulated in oily solutions or as a gel. For administration of nasal aerosol, any suitable propellant may be used including compressed air, nitrogen, carbon dioxide, or a hydrocarbon based low boiling solvent.
[0084] Dosage forms for the topical (including buccal and sublingual) or transdermal administration of compounds used in the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches. The active component may be mixed under sterile conditions with a pharmaceutically-acceptable carrier or excipient, and with any preservatives, or buffers, which may be required. Powders and sprays can be prepared, for example, with excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. The ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. [0085] Transdermal patches have the added advantage of providing controlled delivery of a compound of the invention to the body. Such dosage forms can be made by dissolving or dispersing the agent in the proper medium. Absorption enhancers can also be used to increase the flux of the inventive compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
[0086] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. The compounds used in this invention can be incorporated into various types of ophthalmic formulations for delivery to the eye (e.g., topically, intracamerally, or via an implant). The compounds are typically incorporated into topical ophthalmic formulations for delivery to the eye. The compounds may be combined with one or more ophthalmologically acceptable preservatives, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution. Ophthalmic solution formulations may be prepared by dissolving a compound in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the compound. Furthermore, the ophthalmic solution may contain an agent to increase viscosity, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac. Gelling agents can also be used, including, but not limited to, gellan and xanthan gum. In order to prepare sterile ophthalmic ointment formulations, the compound of the invention is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations may be prepared by suspending the invention compound in a hydrophilic base prepared from the combination of, for example, carbopol-974, or the like, according to the published formulations for analogous ophthalmic preparations. Preservatives and tonicity agents can be optionally incorporated.
[0087] Intrathecal administration, via bolus dosage or constant infusion, allows the local administration of a compound to a region of the spinal cord, such as the dorsal horn regions, delivering the compound directly to the subarachnoid space containing the CSF (cerebrospinal fluid).
[0088] Central delivery to the spinal cord regions can also be performed by epidural injection to a region of the spinal cord exterior to the arachnoid membrane. Enhancing permeation of the active compound through meningeal membranes may be achieved by using hypertonic dosing solutions that increase permeability of meningeal membranes, or by addition of permeation enhancers, such as, but not limited to, liposomal encapsulation, surfactants, or ion-pairing agents.
[0089] Besides those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the instant invention. Such excipients and carriers are described, for example, in "Remingtons Pharmaceutical Sciences" Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.
[0090] The formulations of the invention may be designed to be short-acting, fast- releasing, long-acting, and sustained-releasing as described below. Thus, the pharmaceutical formulations may also be formulated for controlled release or for slow release.
[0091] The instant compositions may also comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the pharmaceutical formulations and medicaments may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants may employ known inert materials such as silicones and biodegradable polymers.
[0092] Administration of the cytokine inhibitors and the additional active agents to a subject can occur simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the disease being treated. A typical route of administration for cytokine inhibitors described herein is oral or topical. Typical routes of administration for the additional active agents or ingredients of the invention are known to those of ordinary skill in the art [See, e.g., Physicians' Desk Reference (57th ed., 2003)]. Alternatively, the cytokine inhibitor and the additional active agents are administrated simultaneously by coformulation.
[0093] . The additional active agent can be administered orally, intravenously, intramuscularly, subcutaneously, mucosally, or transdermally and once or twice daily in an amount of from about 1 to about 3,500 mg, from about 5 to about 2,500 mg, from about 10 to about 500 mg, or from about 25 to about 250 mg.
[0094] In one embodiment of the invention, a cytokine inhibitor and an additional active agent are administered to a subject, more typically a human, in a sequence and within a time interval such that the cytokine inhibitor can act together with the other agent to provide an increased benefit than if they were administered otherwise. For example, the additional active agents can be coadminstered by coformulation, administered at the same time or administered sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently close in time so as to provide the desired therapeutic or prophylactic effect. In one embodiment, the cytokine inhibitor and the additional active agents exert their effects at times which overlap. Each additional active agent can be administered separately, in any appropriate form and by any suitable route. In other embodiments, the cytokine inhibitor is administered before, concurrently or after administration of the additional active agents.
[0095] In various examples, the cytokine inhibitor and the additional active agents are administered less than about 1 hour apart, at about 1 hour apart, at about 1 hour to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, no more than 24 hours apart or no more than 48 hours apart. In other examples, the cytokine inhibitor and the additional active agents are administered concurrently. In yet other examples, the cytokine inhibitor and the additional active agents are administered concurrently by coformulation.
[0096] In other examples, the cytokine inhibitor and the additional active agents are administered at about 2 to 4 days apart, at about 4 to 6 days apart, at about 1 week part, at about 1 to 2 weeks apart, or more than 2 weeks apart.
[0097] In certain examples, the cytokine inhibitor and optionally the additional active agents are cyclically administered to a subject. Cycling therapy involves the administration of a first agent for a period of time, followed by the administration of a second agent and/or third agent for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improve the efficacy of the treatment.
[0098] In other examples, the cytokine inhibitor and optionally the additional active agent are administered in a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days or about once every week. One cycle can comprise the administration of a cytokine inhibitor and optionally the second active agent by infusion over about 90 minutes every cycle, about 1 hour every cycle, about 45 minutes every cycle. Each cycle can comprise at least 1 week of rest, at least 2 weeks of rest, at least 3 weeks of rest. The number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, and more typically from about 2 to about 8 cycles.
[0099] In yet other examples, the cytokine inhibitor described herein is administered in metronomic dosing regimens, either by continuous infusion or frequent administration without extended rest periods. Such metronomic administration can involve dosing at constant intervals without rest periods. Typically the cytokine inhibitor is used at lower doses. Such dosing regimens encompass the chronic daily administration of relatively low doses for extended periods of time. In typical examples, the use of lower doses can minimize toxic side effects and eliminate rest periods. In certain cases, the cytokine inhibitor is delivered by chronic low-dose or continuous infusion ranging from about 24 hours to about 2 days, to about 1 week, to about 2 weeks, to about 3 weeks to about 1 month to about 2 months, to about 3 months, to about 4 months, to about 5 months, to about 6 months. The scheduling of such dose regimens can be optimized by the skilled artisan.
[0100] Courses of treatment can be administered concurrently to a subject, i.e., individual doses of the additional active agents are administered separately yet within a time interval such that the cytokine inhibitor can work together with the additional active agents. For example, one component can be administered once per week in combination with the other components that can be administered once every two weeks or once every three weeks. In other words, the dosing regimens are carried out concurrently even if the therapeutics are not administered simultaneously or during the same day.
[0101] Examples of cytokine inhibitors used in the instant invention are described below. A first group of compounds are represented by Formula IA,
Figure imgf000067_0001
IA stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
G is a C3-10 carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8-11 membered bicyclic heterocyclyl containing 1 or more heteroatoms selected from O, N or S; wherein G is substituted with one or more R1, R2 or R3;
X is C(O), C(S) or CH2;
Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, C6_io aryl, -(C1-3 alkyl)-(C6-io aryl), -(Y)-(Co-3 alkyl)-(C6.|o aryl), or -(Y)-(Co-3 alkyl)-(5-10 member heteroaryl), each of which is optionally substituted with one or more R4 or R5;
Y is -CHZ-, -CZ2-, -CHR-, -O-, -C(=CHR)-, or -C(=C-CO2R)-; each Z is independently F, Cl, -OR, -NR2, -SR, -NHCONHR, or -NHCOR;
L is a covalent bond or a saturated or unsaturated branched or unbranched Ci. 10 carbon chain, wherein one or more carbon atoms such as methylene groups are optionally independently replaced by heteroatoms selected from O, NR or S(O)m; and wherein L is optionally substituted with 1-2 oxo groups and/or one or more of F, Cl, Br, or I;
Q is hydrogen, -NR'R', cycloalkyl, aryl, heterocyclyl, Ci-6 alkoxy, C]-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, Ci-6 alkoxy, Ci-6 alkyl-S(O)m, or phenyl-S(O)m is each optionally substituted with one or more R27; each m is independently 0, 1 or 2; each R is independently hydrogen or substituted or unsubstituted Ci-6 alkyl; each R' is independently hydrogen, substituted or unsubstituted Ci-8 alkyl, substituted or unsubstituted (C0-4 alkyl)-(C6-io aryl) or substituted or unsubstituted (Co^ alkyl)-(5-l 0 member heterocyclyl); each R1 is independently F, Cl, Br, I, cyano, -C(O)R, -C(O)NR2, -C(O)OR, -OR, -NR'R', -SiR3, - S(O)mR, substituted or unsubstituted Ci-10 alkyl, substituted or unsubstituted C2-io alkenyl, substituted or unsubstituted C2-io alkynyl, substituted or unsubstituted C3_io cycloalkyl, substituted or unsubstituted Cs-8 cycloalkenyl, substituted or unsubstituted G7.20 aralkyl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected
Figure imgf000068_0001
each R2, R4 and R5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched Ci-6 alkyl, substituted or unsubstituted Ce-io aryl, substituted or unsubstituted 5-10 member heteroaryl, -OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'2, -NR'2, -NO2, -S(O)mR", -NR5SO2R", -NR'C(O)NR'R', -NR' C(S)NR' R', -NR5C(O)OR' or -SO2NR'2; each R" is independently substituted or unsubstituted Ci_8 alkyl, substituted or unsubstituted Co-4 alkyl-C6-io aryl or substituted or unsubstituted (C0-4 alkyl)-(5- 10 member heterocyclyl); each R3 is independently substituted or unsubstituted C6-Io aryl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S(O)m, substituted or unsubstituted C3-I2 cycloalkyl, substituted or unsubstituted Cs-I2 cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted straight or branched Ci-s alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH5 or S(O)1n; each R6 is a Ci-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R26;
R20 is substituted or unsubstituted Cj-I0 alkyl, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted Co_6 alkyl-heterocyclyl, OR' or NR'2;
R21 is hydrogen or Ci-4 branched or unbranched alkyl optionally partially or fully halogenated; each R22, R23 and R24 is independently hydrogen, substituted or unsubstituted Ci-io alkyl, wherein the Ci. io alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted C0.6 alkyl-phenyl, substituted or unsubstituted Co-6 alkyl- heterocyclyl; or R23 and R24 taken together form a heterocyclic or heteroaryl ring; and each R26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C0^ alkyl)amino, wherein the C0-4 alkyl is optionally partially or fully halogenated; each R27 is independently F, Cl, Br5 1, cyano, -C(O)R', -C(O)NR'2, -C(O)OR', -OR', -NR'R', -SiR'3, - S(O)mR', substituted or unsubstituted Ci-I0 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-io alkynyl, substituted or unsubstituted C3..10 cycloalkyl, substituted or unsubstituted C5-8 cycloalkenyl, substituted or unsubstituted C7-2O aralkyl, substituted or unsubstituted 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S(O)01.
[Ol 02] In certain embodiments of the first group of Formula IA, the compound at a concentration of 10 μM inhibits induced TNFa-release from a cell by about 50% or greater than 50%. ,
[0103] In some embodiments of the first group of compounds of Formula IA, when
Ar is -(Y)-(Co-Io aryl) and G is N-(substituted or unsubstituted phenyl)-pyrazolyl, the pyrazolyl is additionally substituted with one or more R1, R2 or R3. In others, IA is not N-(5- tert-butyl-2-phenyl-2H-pyrazol-3-yl)-2-(4-chloro-phenyl)-acetamide.
[0104] In some embodiments of the first group of compounds of Formula IA, G is phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, benzofuran-3-one; pyrazolyl, pyrrolyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolonyl, 4H-benzo[l,4]oxazine-3- only, benzodioxolyl, benzo[l,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl; pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, moφholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl.
[0105] In other embodiments of the first group of compounds of Formula IA, G is phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, or benzofuran-3-one. In yet others, G is pyrazolyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl,
( isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolonyl, benzo[l,4]oxazin-3-onyl, benzodioxolyl, benzo[l,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, or phthalimidyl. Alternatively, G is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, isoxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomoφholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl. In other embodiments, G is phenyl, naphthyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, or pyridinyl.
[0106] In certain embodiments of the first group of compounds of Formula IA, Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, or Cό-io aryl. In some such embodiments, Ar is substituted with at least one R4 or R5. Alternatively, Ar is indazolyl, isoindolyl, pyrazolyl, pyrrolinyl, phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl or imidazolyl. In still other such embodiments, Ar is indazolyl, phenyl, tetrahydronapthyl or naphthyl.
[0107] In certain embodiments of compounds having Formula IA, Ar is -(Ci-3 alkyl)-
(C6-IO aryl), -(Y)-(C0-3 alkyl)-(C6-ιo aryl), or -(Y)-(C0-3 alkyl)-(5- 10 member heteroaryl). In some such embodiments, Ar is substituted with at least one R or R . In some such embodiments, Y is -CZ2- and each Z is independently F, -OR or -CHR. For example, Y is -CF2-. In others, Y is -CHR or -CHZ- and Z is -OR. Thus, for example, Y is -CHOH-. Alternatively, Y is -O- or -CH2-. In still other such embodiments, the Cβ-io aryl is phenyl or naphthyl, and/or the 5-10 member heteroaryl is quinolinyl, isoquinolinyl, phthalazinyl, or quinazolinyl. In yet other such embodiments Ar is -(Ci-3 alkyl)-(C6-io aryl).
[0108] In some embodiments of the first group of compounds of Formula IA, one or more methylene groups of L are independently replaced by hetero atoms selected from O, NR or S(O)m. In others, L is a covalent bond, a Cj-Cg alkoxy, -C(O)O-, -NH- or -O-.
[0109] As noted above, Q, other than -H or — NR'R', is optionally substituted with
R27. hi certain embodiments of the first group of compounds of Formula IA Q is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrrolidinyl, benzimidazolyl, furanyl, thienyl, pyranyl, naphthylpyridinyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolo[3,4-b]pyrimidinyl5 purinyl, pyrrolo[2,3- b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5-b]pyridinyl, or imidazo[4,5- bjpyridinyl, tetrahydropyranyl, tetrahydro furanyl, 1,3-dioxolanone, 1 ,3-dioxanone, 1,4- dioxanyl, morpholino, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinyl, piperidinyl, piperidinonyl, tetrahydropyrimidonyl, cyclohexanone, cyclohexanolol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone, Ci-6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to C 1-3 alkyl or C 1.5 alkoxyalkyl, phenylamino; Ci-6 alkyl-S(O)m or phenyl-S(O)m. In some such embodiments, R27 is Cj-β alkyl, d.6 alkoxy, hydroxy amino, substituted or unsubstituted 5-10 member heterocyclyl, mono- or di-(Ci-3 alkyl)amino, mono- or di-(phenyl-Ci-3 alkyl)amino, Ci.6 alkyl-S(O)m> phenyl-Ci-3-alkoxy or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, Cj-6 alkyl or Ci-6 alkoxy.
[0110] In some other embodiments of the first group of compounds of Formula IA, Q is hydrogen, phenyl, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinonyl, oxazepinyl, diazepinonyl, imidazolyl, pyridinyl or morpholino. In others, Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl. In some such embodiments, R27 is -C(O)OR', -NR'R', substituted or unsubstituted straight or branched C^1O alkyl, substituted or unsubstituted C7-20 aralkyl, or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1 , 2, 3, or 4 heteroatoms independently selected from N, O, or S(O)n,. Alternatively, Q is pyrimidinyl and R27 is -NR'R' or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S(O)m. In yet other such embodiments, Q is pyridinyl, and R27 is —NR'R', substituted or unsubstituted Ci-6 alkyl, or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1 , 2, 3, or 4 heteroatoms independently selected from N, O, or S(O)m.
[Ol 11] In some embodiments of the first group of compounds of Formula IA, when
R4 and R5 are absent, -L-Q is not -H.
[Ol 12] In some embodiments of the first group of compounds of Formula IA, each R1 is independently
C3-IO branched or unbranched alkyl optionally partially or fully halogenated, and optionally substituted with one to three C3-io cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, or isothiazolyl; each of which is optionally substituted with 1 to 5 halogen, Ci-β branched or unbranched alkyl which is optionally partially or fully halogenated, C3-8 cycloalkyl, Cs-g cycloalkenyl, hydroxy, cyano, C1-3 alkoxy which is optionally partially or fully halogenated and NH2C(O) or mono- or di-(Ci-3 alkyl)aminocarbonyl; cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclohexanyl, or bicycloheptanyl, which are optionally partially or fully halogenated and optionally substituted with one to three C 1.3 alkyl groups optionally partially or fully halogenated, cyano, hydroxyl Ci-3 alkyl or aryl, or an analogue of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl wherein one to three ring methylene groups are replaced independently by O, S(O)n,, CHOH, C=O, C=S or NH;
C3.10 branched or unbranched alkenyl optionally partially or fully halogenated, and optionally substituted with one to three Ci-S branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl; each of the aforementioned being optionally, partially or fully halogenated, Cj.6 branched or unbranched alkyl optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, hydroxy, cyano, C1.3 alkoxy optionally partially or fully halogenated, NH2C(O) or mono- or di-(Ci_3 alkyl)aminocarboxyl; and wherein the C3..10 branched or unbranched alkenyl is optionally interrupted by one or more O, N or S(O)ra; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three Ci-3 alkyl groups; cyano, F, Cl, Br, or I; methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl; silyl containing three C1-4 independently branched or unbranched alkyl groups optionally partially or fully halogenated;
C2-6 branched or unbranched alkyl-C(O), C2-6 branched or unbranched-S, C2-6 branched or unbranched-S(O), C2-O branched or unbranched-S(O)2;
C2-O branched or unbranched alkynyl group optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH and S(O)m and wherein said alkynyl group is optionally independently substituted with 0-2 oxo groups, pyrrolidinyl, pyrrolyl, one or more Ci-4 branched or unbranched alkyl optionally substituted with one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or Ci-4 branched or unbranched alkylamino optionally substituted with one or more halogen atoms. [0113] In other embodiments of the first group of compounds of Formula IA, each R1 is independently C3-io branched or unbranched alkyl optionally partially or fully halogenated, and optionally substituted with one to three C3.10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, or isothiazolyl; each of which is optionally substituted with 1 to 5 halogen, Ci-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-8 cycloalkyl, Cs-8 cycloalkenyl, hydroxy, cyano, Ci-3 alkoxy which is optionally partially or fully halogenated and NH2C(O) or mono- or di-(Ci_3 alkyl)aminocarbonyl. For example, each R1 is independently C3.10 branched or unbranched alkyl.
[0114] In some embodiments of the first group of compounds of Formula IA, each R2 is independently -OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'2, -NR'2, -NO2, -S(O)mR", -NR3SO2R", -NR'C(O)NR'R\ -NR'C(S)NR'R', -NR5C(O)OR' or -SO2NR'2. Alternatively, each R2 is independently -NR'2, -NO2, -C(O)NR'2, -NR5SO2R", -NR5C(O)NR5R', - NR1C(S)NR1R5, -NR5C(O)OR' or -SO2NR'2.
[0115] In some embodiments of the first group of compounds of Formula IA, each R3 is independently phenyl, naphthyl, or heterocyclyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisooxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, purinyl, indazolyl, Ci.6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl Ci-5 alkyl, naphthyl Ci-5 alkyl, hydroxy, oxo, cyano, Ci-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or di-(C]-3 alkyl)amino, phenylamino, naphthylamino, heterocyclylamino, NH2C(O), a mono- or di-(Ci-3 alkyl)aminocarbonyl, Ci-5 alkyl-C(O)-Ci_4 alkyl, amino-Ci-5 alkyl, mono- or di-(Ci.3 alkyl)amino -C1.5 alkyl, amino-S(O)2, di-(Ci-3 alkyl)amino - S(O)2, R7-Ci.5 alkyl, R8-Ci.5 alkoxy, R9-C(O)-Ci-s alkyl, R10-C,.5 alkyl(Rn)N, carboxy-mono- or di- (C1.5 alkyl)amino; a fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocycle selected from cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclopentanoindole, cyclohexanoindole, cyclobenzimidazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclic ring is optionally, independently substituted with 1 to 3 groups selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, isothiazolyl, Ci-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyano, Ci-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyl oxy, heterocyclyloxy, heteroaryloxy, nitro, amino, mono- or di-(Ci.3 alkyl)amino, phenylamino, naphthyl amino, heterocyclic or heteroaryl amino, NHsC(O), a mono- or di-(Ci_3 alkyl)aminocarbonyl, C1-4 alkyl-C(O), Ci-S alkylamino-S(0)2, mono- or di-(Ci-3 alkyl)amino-Ci-5 alkyl, R12-C,.5 alkyl, R13-C1-5 alkoxy, RI4-C(O)-C1-5 alkyl, R15-C,.5 alkyl(Rl6)N; cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, or bicycloheptanyl, which are optionally partially or fully halogenated and optionally substituted with one to three Q-3 alkyl groups optionally partially or fully halogenated, cyano, hydroxyl C1-3 alkyl or aryl; or an analogue of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl wherein one to three ring methylene groups are independently replaced by O, S(O)m, CHOH, C=O, C=S or NH; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl, bicycloheptenyl, each optionally substituted with one to three C 1.3 alkyl groups;
Ci-4 alkyl or alkylene-phenyl-C(O)-C0-4 alkyl or alkylene, Ci-4 alkyl or alkyl ene-C(0)-Co-4 alkyl or alkylene, C 1-4 alkyl or alkylene -phenyl-S(0)m-Co-4 alkyl or alkylene;
Ci-6 alkyl or C1.6 alkoxy, each optionally partially or fully halogenated or optionally substituted with R17, amino, OR18, or C1-S mono- or di-alkylamino optionally substituted with R19; cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, which are optionally partially or fully halogenated and optionally substituted with one to three Ci-3 alkyl groups optionally partially or fully halogenated wherein one to three ring methylene groups are replaced independently by O5 S(O)m, CHOH, C=O, C=S or NH;
R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)raC(O)N(R21)- or R26C(O)(CH2)mN(R21)-;
C2-6 alkenyl substituted with R23R24NC(O)-;
C2-6 alkynyl group branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O5 NH or S(O)m, and wherein said alkynyl group is optionally independently substituted with 0- 2 oxo groups, pyrrolidinyl, pyrrolyl, one or more C 1-4 branched or unbranched alkyl optionally substituted with one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or Q-4 branched or unbranched alkyl amino optionally substituted with one or more halogen atoms; or benzoyl or naphthoyl; and wherein each R7, R8, R9, R10, R12, R13, R14, R15, R17, R19, and R25 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(Co-4 alkyl)amino, wherein the Co-4 alkyl is optionally partially or fully halogenated; each R1 ' and R16 is independently hydrogen or C1-4 branched or unbranched alkyl optionally partially or fully halogenated; and
R18 is independently hydrogen or Ci-4 branched or unbranched alkyl optionally independently substituted with oxo or R25.
[0116] In some such embodiments, each R3 is independently phenyl, naphthyl, or heterocyclyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisooxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, purinyl, indazolyl, CL6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl Ci-5 alkyl, hydroxy, oxo, cyano, Ci-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or di-(C1-3 alkyl)amino, phenylamino, naphthylamino, heterocyclylamino, NH2C(O), a mono- or di-(Cι-3 alkyl)aminocarbonyl, Cj-5 alkyl-C(O)-C]-4 alkyl, amino-Ci-5 alkyl, mono- or di-(Ci-3 alkyl)amino -Ci-5 alkyl, amino-S(O)2, di-(Ci-3 alkyl)amino - S(O)2, R7-Ci.5 alkyl, R8-Ci_5 alkoxy, R9-C(O)-Ci-5 alkyl, R10-C]-5 alkyl(R' ')N, or carboxy-mono- or di-(Ci_5 alkyl)amino. In others, each R3 is independently phenyl, pyridazinyl or pyridyl, each of which is optionally partially or fully halogenated and optionally substituted with Ci-6 branched or unbranched alkyl which is optionally partially or fully halogenated, hydroxy, oxo, cyano, C1-3 alkoxy optionally partially or fully halogenated, nitro, amino, mono- or di-(Ci-3 alkyl)amino; C]-6 alkyl or Ci-6 alkoxy, each optionally partially or fully halogenated or optionally substituted with R17, amino, OR18, C]-5 mono- or di-alkylamino optionally substituted with R19; R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)- or R26C(O)(CH2)mN(R21)-. For example, R3 can be phenyl or tolyl.
[0117] In some embodiments of the first group of compounds of Formula IA, X is
C=O.
[0118] There is provided in accordance with another aspect of the invention, a second group of cytokine inhibitors having Formula IA, stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein the variables G, L, m, Q, R, R', R", R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R1S, R16,R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, and R27 are as defined for the first group of compounds of Formula IA; and wherein:
X is C(O)or C(S);
Ar is -(Y)-(C0-3 alkyl)-(bicyclic aryl), or -(Y)-(Co-3 alkyl)-(bicyclic heteroaryl), wherein the bicyclic heteroaryl is indazolyl, isoindolyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, dihydrobenzoisoxoazolyl, dihydroisoindolyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl, or benzoisothiazolyl dioxide, and wherein Ar is optionally substituted with one or more R4 or R5; and
Y is -C(O)-, -C(N(NRC(O)OR))-, -C(N(NRR))-, -C(N(NC(O)NRR))- or -C(N(OR))-.
[0119] With respect to variables that are identically defined between the first and second groups of compounds of Formula IA, all of the embodiments of the first group of compounds are also provided for the second group of compounds of Formula IA. To the extent that the variables differ between the first and second groups of compounds of Formula IA, the following additional embodiments are provided.
[0120] In some embodiments of the second group of compounds of Formula IA, when R4 and R5 are absent, -L-Q is not -H. In others, when Ar is — (Y)-(bicyclic aryl) and G is N-(substituted or unsubstituted phenyl)-pyrazolyl, the pyrazolyl is additionally substituted with one or more R1, R2 or R3.
[0121] . In some embodiments of the second group of compounds of Formula IA, Ar is -(Y)-(CoO alkyl)-(bicyclic aryl), and the bicyclic aryl is naphthyl, tetrahydronaphthyl, dihydronaphthyl, indenyl, indanyl or azulenyl. In some such embodiments, Ar is substituted with at least one R4 or R5. In others, Y is -C(O)-, -C(N(NRC(O)OR))- or -C(N(OR))-. Alternatively, Ar is -C(O)-(bicyclic aryl) or -C(NOR)-(bicyclic aryl) and the the bicyclic aryl can be naphthyl, dihydronapthyl, tetrahydronaphthyl, indanyl, indenyl or azulenyl. In other embodiments, Ar is -(Y)-(Co-3 alkyl)-(bicyclic heteroaryl). In some such embodiments, Ar is substituted with at least one R4 or R5. In others, Y is -C(O)-, -C(N(NRC(O)OR))- or -C(N(OR))-. In yet others, Ar is -C(O)-(bicyclic heteroaryl) or -C(NOR)-(bicyclic heteroaryl). For example, the bicyclic heteroaryl is quinolinyl, isoquinolinyl, phthalazinyl, or quinazolinyl.
[0122] In certain embodiments of the second group of compounds of Formula IA, Ar is -(Y)-naphthyl-, Y is -C(O)-, or -C(=NOH)- and G is selected from phenyl, pyridinyl, pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl or thienyl. In others, Ar is -(Y)-naphthyl-, Y is -C(O)-, or -C(=NOH)- and G is phenyl or pyridyl. In some such embodiments, each R1 is independently a substituted or unsubstituted straight or branched C1- ,o alkyl and each R3 can be independently R23R24N-C(O)-, R20-C(O)-NR21-, or OR22. In some such embodiments, each R2 is independently -NR1SO2R", -Cl, -Br, -F, -C(O)-NR'2, substituted or unsubstituted straight or branched Ci-6 alkyl, -NR'2, or -OR'.
[0123] In other embodiments of the second group of compounds of Formula IA, Ar is
-(Y)-naphthyl-, Y is -C(O)-, or -C(=N0H)-, and G is pyrazolyl, thienyl or isoxazolyl. In some such embodiments, each R1 is independently a substituted or unsubstituted straight or branched Ci-io alkyl each R3 can be independently phenyl or pyridinyl, optionally substituted with one, two, or three -F, -Cl, substituted or unsubstituted Ci-6 branched or unbranched alkyl or substituted or unsubstituted Ci-4 alkoxy. [0124] There is provided in accordance with another aspect of the invention, a third group of compounds having Formula IA, stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein the variables L, m, Q, R, R', R", R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, RI6,R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, and R27 are as defined for the first group of compounds of Formula IA; and wherein:
G is a C3-5 cycloalkyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyrrolinyl, pyridazinyl, pyrrolyl, imidazolyl, imidazolonyl, isoxazolyl, furanyl, thienyl, pyridonyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolonyl, 4H-benzo[l ,4]oxazine-3-onyl, benzodioxolyl, benzo[l,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl; wherein G is substituted by one or more R1, R2 or R3;
X is C(O)Or C(S);
Ar is -(Y)-(Co-3 alkyl)-(phenyl), or -(Y)-(Co-3 alkyl)-(monocyclic heteroaryl), wherein Ar is optionally substituted with one or more R4 or R5; and
Y is -C(O)-, -C(N(NRC(O)OR))-, -C(N(NRR))-, -C(N(NC(O)NRR))- or -C(N(OR))-.
[0125] As before, with respect to variables that are identically defined between the first and third groups of compounds of Formula IA, all of the embodiments of the first group of compounds are also provided for the third group of compounds of Formula IA. To the extent that the variables differ between the first and third groups of compounds of Formula IA, the following additional embodiments are provided.
[0126] In certain embodiments of the third group of compounds of Formula IA, when
R4 and R5 are absent, -L-Q is not -H. In others, when Ar is phenyl and G is N-(substituted or unsubstituted phenyl)-pyrazolyl, the pyrazolyl is additionally substituted with one or more R1, R2 or R3.
[0127] In certain embodiments of the third group of compounds of Formula IA, G is cyclopropyl, cyclobutyl or cyclopentyl. In others, G is cyclopropyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, or thienyl.
[0128] In some embodiments of the third group of compounds of Formula IA, Ar is
-(Y)-(C0-3 alkyl)-(phenyl) and Y is -C(O)-, -C(N(NRC(O)OR))- or -C(N(OR))-. In some such embodiments, Ar is substituted by at least one R4 or R5. In others, Ar is -C(O)-(phenyl). In yet other embodiments, Ar is -(Y)-(Co-3 alkyl)-(monocyclic heteroaryl), and the monocyclic heteroaryl is pyrazolyl, imidazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyrimidinyl or pyridazinyl. In some such embodiments, Ar is substituted by at least one R4 or R5. Alternatively, Y is -C(O)-, -C(N(NRC(O)OR))- or -C(N(OR))-. In yet others, Ar is -C(O)- (monocyclic heteroaryl) or -C(N(OR))-(monocyclic heteroaryl). For example, the monocyclic heteroaryl can be pyrazolyl, imidazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyrimidyl, or pyridazinyl.
[0129] In certain embodiments of the third group of compounds of Formula IA, Ar is
-(Y)-phenyl-, Y is -C(O)-, or -C(=N0H)- and G is selected from pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl or thienyl. In others, Ar is -(Y)-phenyl-, Y is -C(O)- , or -C(=NOH)-, and G is pyrazolyl, thienyl or isoxazolyl. In some such embodiments, each R1 is independently a substituted or unsubstituted straight or branched CMO alkyl. In these embodiments, each R3 can be independently phenyl or pyridinyl, optionally substituted with one, two, or three -F, -Cl, substituted or unsubstituted C I-6 branched or unbranched alkyl or substituted or unsubstituted Ci-4 alkoxy. [0130] In another aspect of the invention, there are provided cytokine inhibitors of a first group of compounds having Formula IB:
H
^X^ ^Ar-L — Q IB
stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein the variables G, X, Ar, Y, Z, L, m, Q, R, R', R", R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, RIS, R16,R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, and R27 are as defined for the first group of compounds of Formula IA.
[0131] As before, with respect to variables that are identically defined between the first groups of compounds of Formula IA and Formula IB, all of the embodiments of the first group of compounds of Formula IA are also provided for the first group of compounds of Formula IB. To the extent that the variables differ between the first groups of compounds of Formula IA and IB3 the following additional embodiments are provided.
[0132] In some embodiments of the first group of compounds of Formula IB, when
R4 and R5 are absent, -L-Q is not -H.
[0133] In some embodiments of the first group of compounds of Formula IB, Ar is
-(Ci.3 alkyl)-(C6.,o aryl), -(Y)-(C0-S alkyl)-(C6.i0 aryl), or -(Y)-(C0-3 alkyl)-(5-10 member heteroaryl). In some such embodiments Ar is substituted with at least one R4 or R5. In others, Y is -CHR or -CHZ- and Z is -OR. For example, Y is -CH2-. In still other such embodiments, the Cβ-io aryl is phenyl or naphthyl or the 5-10 member heteroaryl is quinolinyl, isoquinolinyl, phthalazinyl, or quinazolinyl. Alternatively, Ar is -(Ci-3 alkylMCe-io 81YO-
[0134] There is provided in accordance with another aspect of the invention, a second group of compounds having Formula IB, stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein the variables L, m, Q, R, R', R", R1, R2, R3, R4, R5, R6, R7, R8, R9 5 R10, R11, R12, R13, R14, R15, R16,R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, and R27 are as defined for the first group of compounds of Formula IA; and wherein:
G is a G'-(Y)- wherein G' is a C3-Io carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8-11 membered bicyclic heterocyclyl other than indolyl containing 1 or more heteroatoms selected from O, N or S, wherein G' is substituted by one or more R1, R2 or R3;
X is C(O) or C(S);
Ar is bicyclic aryl or 8-1 1 membered bicyclic heteroaryl containing 1 or more heteroatoms selected from O5 N or S, wherein Ar is optionally substituted with one or more R4 or Rs; and
Y is independently -C(O)-, -C(N(NRC(O)OR))-, -C(N(NRR))-, -C(N(NC(O)NRR)) or -C(N(OR))-.
[0135] As before, with respect to variables that are identically defined between the first group of compounds of Formula IA and the second group of compounds of Formula IB, all of the embodiments of the first group of compounds of Formula IA are also provided for the second group of compounds of Formula IB. To the extent that the variables differ between the first group of compounds of Formula IA and the second group of compounds of Formula IB, the following additional embodiments are provided.
[0136] In some embodiments of the second group of compounds of Formula IB, when
R4 and R5 are absent, -L-Q is not -H.
[0137] In some embodiments of the second group of compounds of Formula IB, G' is phenyl, naphthyl, cyclopropyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, benzofuran- 3 -one; pyrazolyl, pyrrolyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolonyl, 4H-benzo[l,4]oxazine-3- only, benzodioxolyl, benzo[l,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl; pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetxamethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl.
[0138] In other embodiments of the second group of compounds of Formula IB, G' is phenyl, naphthyl, cyclopropyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, or benzofuran-3-one. In others, G' is pyrazolyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolonyl, benzo[l,4]oxazin-3-onyl, benzodioxolyl, benzo[l,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, or phthalimidyl. Alternatively, G' is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, isoxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl. In yet other embodiments, G' is phenyl, naphthyl, pyrazolyl, cyclopropyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, or pyridinyl. [0139] In certain embodiments of the second group of compounds of Formula IB5 Y is -C(O)-, -C(N(NRC(O)OR))- or -C(N(OR))-.
[0140] In certain embodiments of the second group of compounds of Formula IB, Ar is naphthyl, dihydronapthyl, tetrahydronaphtyl, indenyl or azulenyl. Alternatively, Ar is indazolyl, isoindolyl, quinolinyl, isoquinolinyl, phthalazinyl, indolyl, dihydroindolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, dihydrobenzoisoxoazolyl, dihydroisoindolyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl or benzoisothiazolyl dioxide.
[0141] In certain embodiments of the second group of compounds of Formula IB, Ar is naphthyl, G is C-(Y)-, Y is -C(O)- or -C(=NOH)- and G' is selected from phenyl, pyridinyl, pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl or thienyl. In others, Ar is naphthyl, G is G'-(Y)-, Y is -C(O)- or-C(=NOH)- and G' is phenyl or pyridinyl, substituted by one or more R1, R2 or R3. In some such embodiments, each R1 is independently a substituted or unsubstituted straight or branched CMO alkyl. In these, each R3 can be independently R23R24N-C(O)-, R20-C(O)-NR21-, or OR22. In others such embodiments each R2 is independently -NR5SO2R", -Cl, -Br, -F, -C(O)-NR'2, substituted or unsubstituted straight or branched Ci-6 alkyl, -NR'2, or —OR'.
[0142] In other embodiments of the second group of compounds of Formula IB, Ar is
-naphthyl- and G is G'-(Y)-, wherein Y is selected from -C(O)- and -C(=NOH)- and G' is pyrazolyl, isoxazolyl or furanyl, substituted by one or more R1, R2 or R3. In some such embodiments, each R1 is independently a substituted or unsubstituted straight or branched C1- 10 alkyl. In these, each R3 can be independently substituted or unsubstituted Cj-6 alkyl, pyridinyl or phenyl, optionally substituted with one to three -F, -Cl, substituted or unsubstituted Ci-6 branched or unbranched alkyl, or substituted or unsubstituted Ci-3 alkoxy.
[0143] There is provided in accordance with another aspect of the invention, a third group of compounds having Formula IB, stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein the variables L5 m, Q, R, R', R", R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, RI6,R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, and R27 are as defined for the first group of compounds of Formula IA; and wherein:
G is a G'-(Y)- wherein G' is a C3-10 cycloalkyl, phenyl, naphthyl, tetrahydronaphthyl other than l,l,4,4-tetramethyl-l,2,3,4-tetrahydronaphthyl, pyrazolyl, thiazolyl, pyridinyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, imidazolyl, furanyl other than furan-2-yl, thienyl other than thien-2-yl, dihydronaphthyl, indanyl, indenyl, quinolinyl. isoquinolinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzpyrazolyl, or homopiperidinyl; wherein G' is substituted by one or more R!, R2 or R3;
X is C(O) or C(S);
Ar is phenyl, pyrimidinyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, pyrrolinyl, pyridazinyl, pyrrolyl, imidazolyl, furanyl, thienyl, pyrimidinyl, pyrazinyl; wherein Ar is optionally substituted with one or more R4 or Rs; and
Y is independently -C(O)-, -C(N(NRC(O)OR))-, -C(N(NRR))-, -C(N(NC(O)NRR))- or -C(N(OR))-.
[0144] As before, with respect to variables that are identically defined between the first group of compounds of Formula IA and the third group of compounds of Formula IB, all of the embodiments of the first group of compounds of Formula IA are also provided for the third group of compounds of Formula IB. To the extent that the variables differ between the first group of compounds of Formula IA and the second group of compounds of Formula IB, the following additional embodiments are provided.
[0145] In some embodiments of the third group of compounds of Formula IB, when
R4 and R5 are absent, -L-Q is not -H. In others, when Ar-L-Q is -N-(substituted or unsubstituted phenyl)-pyrazolyl and G is phenyl, naphthyl, indane or tetrahydronaphthyl, the pyrazolyl is additionally substituted with one or more R4 or R5. [0146] In some embodiments of the third group of compounds of Formula IB5 G' is phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydronaphthyl, pyrazolyl, thiazolyl, pyridinyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, imidazolyl, furanyl, thienyl, dihydronaphthyl, indanyl, indenyl, quinolinyl, isoquinolinyl, pyrimidinyl, or pyrazinyl. In others, G' is phenyl, naphthyl, pyrazolyl, cyclopropyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, or pyridinyl.
[0147] In certain embodiments of the third group of compounds of Formula IB, Y is -
C(O)-, -C(N(NRC(O)OR))- or -C(N(OR))-.
[0148] In some embodiments of the third group of compounds of Formula IB, Ar is phenyl, pyrazoly, imidazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, or pyrimidinyl.
[0149] In some embodiments of the third group of compounds of Formula IB, Ar is phenyl, G is G'-(Y)-, Y is -C(O)- or -C(=NOH)- and G' is selected from phenyl, pyridinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl or thienyl. In others, Ar is phenyl, G is G '-(Y)-, Y is -C(O)- or-C(=NOH)- and G' is phenyl or pyridinyl, substituted by one or more R1, R2 or R3. In some such embodiments, each R1 is independently a substituted or unsubstituted straight or branched Cj. i0 alkyl. In these, each R3 can be independently R23R24N-C(O)-, R20-C(O)-NR21-, or OR22. Alternatively, each R2 is independently -NR1SO2R", -Cl, -Br, -F, -C(O)-NR* 2, substituted or unsubstituted straight or branched Ci-6 alkyl, -NR'2, or-OR\
[0150] In other embodiments of the third group of compounds of Formula IB, Ar is phenyl and G is G'-(Y)-, wherein Y is selected from -C(O)- and -C(=NOH)- and G' is pyrazolyl, isoxazolyl or furanyl, substituted by one or more R1, R2 or R3. In some such embodiments, each R1 is independently a substituted or unsubstituted straight or branched Ci- io alkyl. In these, each R3 can be independently substituted or unsubstituted Cue alkyl, pyridinyl or phenyl, optionally substituted with one to three -F, -Cl, substituted or unsubstituted Ci-6 branched or unbranched alkyl, or substituted or unsubstituted Q.3 alkoxy. [0151] There is provided in accordance with another aspect of the invention, compounds having Formula IC:
G — Ring — Ar — L — Q
IC
stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein the variables Ar, L3 m, Q, R3 R', R", R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Ru 3 R12, R13, R14, RIS, R16,R17, R18, R19 3 R20, R21, R22, R23, R24, R25, R26, and R27 are as defined for the first group of compounds of Formula IA; and wherein:
Ring is maleimide, succinimide, imidazolidinone, imidazolidine-dione, imidazolidine-trione, triazolidin-dione, or triazine-dione; and
G is a C3-Io carbocyclyl, C4-i2 carbocyclylalkyl, 5-8 membered monocyclic heterocyclyl or heterocyclylalkyl, 8-11 membered bicyclic heterocyclyl or heterocyclylalkyl, wherein the heterocyclyl rings contain 1 or more heteroatoms selected from O, N or S; and G is substituted by one or more R1, R2 or R3.
[0152] As before, with respect to variables that are identically defined between the first group of compounds of Formula IA and compounds of Formula IC, all of the embodiments of the first group of compounds of Formula IA are also provided for the compounds of Formula IC. To the extent that the variables differ between the first group of compounds of Formula IA and the compounds of Formula IC, the following additional embodiments are provided.
[0153] In other embodiments of compounds of Formula IC, G is phenyl, naphthyl, cyclopropyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, or benzofuran-3-one. For example, G is phenyl, naphthyl, cyclopropyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, or pyridinyl. [0154] In certain embodiments of compounds of Formula IC, Ring is maleimide, succinimide or triazine-dione. In others, Ring is succinimid-1 ,4-diyl, maleimide-1 ,4-diyl, imidazolidin-2-one-ls3-diyl5 imidazolidine-2,435-trione-l53-diyl, [l,2,4]triazolidine-3,5- dione-l,4-diyl, or 2H-[l,2,4]triazine-3,5-dione-4,6-diyl.
[0155] In another aspect of the invention there are provided compounds having
Formula II:
Figure imgf000090_0001
stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs therof, and pharmaceutically acceptable salts thereof, wherein the variables G, L, m, Q, R, R', R", R1,
R I\.2, T X?V4, P Iv6, P Cv7, P IV8, P IS.9, P IN.10 , PJLV1 1 , P IN.12 , P1V13 , PIV14 , P1V15 , PIV16 ,PIN.17 , PIN.18 , PJtV19 , PIv20 , RIv21 , RJtV22 , PJtV23 , PIv24 ,
R25, R26, and R27 are as defined for the first group of compounds of Formula IA; and wherein: X' is CR'=CR', CR'=N, NR', CR'2, O or S;
Ar is phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl, indole, or the structure -(Y')-(Co-3 alkyl)-(C6-io aryl), each being optionally substituted with one or more R4 groups;
Y' is absent or is -O- or -NH-; and each R3 is independently H, substituted or unsubstituted Cβ-io aryl* substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S(O)n,, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted C5-12 cycloalkenyl, substituted or unsubstituted C7-2O aralkyl, substituted or unsubstituted straight or branched Ci-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the Ci-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH, or S(O)n,.
[0156] As before, with respect to variables that are identically defined between the first group of compounds of Formula IA and the compounds of Formula II, all of the embodiments of the first group of compounds of Formula IA are also provided for the compounds of Formula II. To the extent that the variables differ between the first group of compounds of Formula IA and the compounds of Formula II, the following additional embodiments are provided.
[0157] In certain embodiments of compounds of Formula II, Ar is indazolyl, isoindolyl, pyrazolyl, imidazolyl, or imidazolonyl. In some such embodiments, Ar is substituted with at least one R4. Alternatively, Ar is indazolyl, optionally substituted with one or more R4. In yet other embodiments, Ar is phenyl or naphthyl. In some such embodiments, Ar is substituted with at least one R4.
[0158] In yet other embodiments of compounds of Formula II, Ar is -(Y')-(Co-3 alkyl)-(C6-io aryl). In some such embodiments, Ar is substituted with at least one R4. In others, the C6-]O aryl is phenyl or naphthyl. Alternatively, Y' is -NH-.
[0159] In certain embodiments of compounds of Formula II, each R3 is independently hydrogen or phenyl, naphthyl, or heterocyclyl, each of which is optionally partially or fully halo genated and optionally substituted with 1-3 of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisooxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, purinyl, indazolyl, C1.6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C 1.5 alkyl, naphthyl Ci-S alkyl, hydroxy, oxo, cyano, C 1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or CK-(CI-3 alkyl)amino, phenylamino, naphthylamino, heterocyclylamino, NH2C(O), a mono- or (Ji-(Ci-3 alkyl)aminocarbonyl, Ci-S alkyl-C(O)-Ci-4 alkyl, amino-Ci-5 alkyl, mono- or di-(Ci.3 alkyl)amino -Ci-5 alkyl, amino-S(O)2, CU-(Ci-3 alkyl)amino - S(O)2, R7-Ci-5 alkyl, R8-Ci_5 alkoxy, R9-C(O)-Ci.5 alkyl, R10-C,-5 alkyKR1 ')N, carboxy-mono- or di- (C1-5 alkyl)amino; a fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocycle selected from cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclopentanoindole, cyclohexanoindole, cyclobenzimidazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclic ring is optionally, independently substituted with 1 to 3 groups selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, isothiazolyl, Ci_6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyano, C 1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, heteroaryloxy, nitro, amino, mono- or di-(Ci_3 alkyl)amino, phenylamino, naphthylamino, heterocyclic or heteroaryl amino, NHaC(O), a mono- or di-(Cj. 3 alkyl)aminocarbonyl, Ci-4 alkyl-C(O), C1.5 alkylamino-S(0)2, mono- or di-(Ci-3 alkyl)amino-C.5 alkyl, R12-C,.5 alkyl, R13-C,.5 alkoxy, R14-C(O)-C,-5 alkyl, R15-C,.5 alkyl(R16)N; cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, or bi cycloheptanyl, which are optionally partially or fully halogenated and optionally substituted with one to three C 1-3 alkyl groups optionally partially or fully halogenated, cyano, hydroxyl C]_3 alkyl or aryl; or an analogue of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl wherein one to three ring methylene groups are replaced independently by O, S(O)m, CHOH, C=O, C=S or NH; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl, bicycloheptenyl, each optionally substituted with one to three Cj-3 alkyl groups;
C i-4 branched or unbranched alkyl -phenyl-C(0)-Co-4 branched or unbranched alkyl, C 1.4 branched or unbranched alkyl-C(0)-Co-4 branched or unbranched alkyl, CM branched or unbranched alkyl-phenyl-S(0)m-Co-4 branched or unbranched alkyl;
Ci_6 branched or unbranched alkyl or Q.6 branched or unbranched alkoxy each is optionally partially or fully halogenated or optionally substituted with R17;
Ci-6 branched or unbranched alkyl optionally substituted with OR18; amino or Ci -C5 branched or unbranched mono- or di-alkylamino optionally substituted with R19; cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, which are optionally partially or fully halogenated and optionally substituted with one to three Ci-3 alkyl groups optionally partially or fully halogenated wherein one to three ring methylene groups are replaced independently by O, S(O)m, CHOH, C=O, C=S or NH;
R20C(O)N(R21)-, R22-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)- or R26C(O)(CH2)mN(R21)-;
C2-6 alkenyl substituted by R23R24NC(O)-;
C2-6 alkynyl branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH and S(O)m or S and wherein said alkynyl group is optionally independently substituted with 0-2 oxo groups, pyrrolidinyl, pyrrolyl, one or more C1-4 branched or unbranched alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or CM branched or unbranched alkylamino optionally substituted by one or more halogen atoms; or benzoyl or naphthoyl.
[0160] In certain embodiments of compounds of Formula II, X' is NR', CR'=N or
CR'=CR'.
[0161] Where features or aspects of the invention are described in terms of Markush groups or other groupings of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush groups or other groupings. By way of illustration and not limitation, Table 1 sets forth various combinations of substituents from the first group of compounds of Formula IA and the first group of compounds of Formula IB as described herein. Thus, e.g., combination 1004 describes those embodiments in which Ar is indolyl and G is phenyl.
TABLE 1 — Exemplary Combinations of Ar and G for the First Group of Compounds of Form
Figure imgf000094_0001
Figure imgf000095_0001
TABLE 1 - Continued
Figure imgf000095_0002
Figure imgf000096_0001
[0162] Table 2 sets forth various combinations of substituents from all groups of compounds of Formulas IA, IB, IC and II. Thus, e.g., combination 1477 describes those embodiments in which L is -O- and Q is heterocyclyl. Further, those skilled in the art will understand that only combinations of substituents that result in a chemically stable compound are possible and will understand how to select such combinations. Those skilled in the art will further appreciate that any combination from Table 1, describing Ar and G, may be combined with any combination from Table 2, describing L and Q. For example, combination 1045 from Table 1 and combination 1509 from Table 2 describe those embodiments of Formula IA in which Ar is pyrazolyl, G is naphthyl, L is-O-(CH2)2-, and Q is heterocyclyl. Each Ar, G, L, and Q group in the tables is understood to be optionally substituted as described herein. Moreover, each value of X (C(O), C(S), CH2) may be combined with any combination from Table 1 or Table 2 or any pair of combinations from the two tables. Thus, e.g., it will be understood that combination 1004 describes those embodiments in which X is C(O), Ar is indolyl and G is phenyl, as well as those where X is CH2, Ar is indolyl and G is phenyl, etc.
TABLE 2 — Exemplary Combinations of L and Q for All Groups of Compounds of Formulas IA, IB, IC and II
Figure imgf000096_0002
Figure imgf000097_0001
[0163] Similar to Table 1 above, Table 3 illustrates combinations of Ar and G for the second group of compounds having Formula IA. Table 2 above illustrates combinations of L and Q, which can be employed for the second group of compounds having Formula IA. Any combination from Table 3 may be combined with any combination from Table 2, as all such combinations are within the scope of the invention.
TABLE 3 - Exemplary Combinations of Ar and G for the Second Group of Compounds of Formula IA, wherein Ar is -(Y)-(C0.3 alkyl)-(bicyclic aryl).
Figure imgf000097_0002
Figure imgf000098_0001
TABLE 3 -
Figure imgf000098_0002
[0164] Similar to Tables 1 and 3 above, Table 4 illustrates combinations of Ar and G for the third group of compounds having Formula IA. Table 2 above illustrates combinations of L and Q that may be employed for the third group of compounds having Formula IA. TABLE 4 - Exemplary Combinations of Ar and G for the Third Group of Compounds of Formula IA
Figure imgf000099_0001
TA
Figure imgf000099_0002
VO
Figure imgf000100_0002
Figure imgf000100_0001
Figure imgf000100_0003
Figure imgf000100_0004
I CD
O O
Figure imgf000101_0001
Figure imgf000101_0002
TABLE 4 - Continued
Figure imgf000102_0001
TABLE 4 - Continued
Figure imgf000102_0002
[0165] Similar to Tables 1, 3 and 4 above, Table 5 illustrates combinations of Ar and
G for the second group of compounds having Formula IB. Table 2 above illustrates combinations of L and Q that may also be employed for the second group of compounds having Formula IB.
TABLE 5 - Exemplary Combinations of Ar and G for the Second Group of Compounds of Formula IB
Figure imgf000103_0001
TABLE 5 - Continued
Figure imgf000104_0001
[0166] Similar to Tables 1 and 3 - 5 above, Table 6 illustrates combinations of Ar and
G for the third group of compounds having Formula IB. Table 2 above illustrates combinations of L and Q that may be employed for the third group of compounds having Formula IB.
TABLE 6 — Exemplary Combinations of Ar and G for the Third Group of compounds of Formula IB
Figure imgf000104_0002
Figure imgf000105_0001
TABLE 6 - Continued
Figure imgf000105_0002
TABLE 6 - Continued
Figure imgf000106_0001
[0167] Similar to Tables 1 and 3 - 6 above, Table 7 illustrates combinations of Ar and
G for the compounds having Formula IC. Table 2 above illustrates combinations of L and Q that may be employed for compounds having Formula IC.
TABLE 7 - Exemplary Combinations of Ar and G for the Compounds of Formula IC.
Figure imgf000107_0001
TABLE 7 - Continued
Figure imgf000108_0001
[0168] Similar to Tables 1 and 3 - 7 above, Table 8 illustrates combinations of Ar and
G for the compounds having Formula II. Table 2 above illustrates combinations of L and Q that may be employed for compounds having Formula II.
TABLE 8 - Exemplary Combinations of Ar and G for the Compounds of Formula II
Figure imgf000108_0002
Figure imgf000109_0001
[0169] In yet another aspect of the invention, there are provided cytokine inhibitors useful in the invention comprising: a targeting moiety comprising at least an amide group having an amide NH, the targeting moiety capable of forming one or more hydrogen bonds with a target protein, and wherein the targeting moiety is not a urea group; a pocket-expanding moiety directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non-planar hydrophobic moiety, said non-planar moiety forming hydrophobic interactions with the target protein; an orienting moiety comprising a planar hydrophobic moiety and attached to a different atom of the targeting moiety than the pocket-expanding moiety, said orienting moiety capable of forming a π-π or edge-to-face aromatic interaction with the target protein.
[0170] In this aspect of the invention, the cytokine inhibitors have the structure
PEM-TM-OM. At a concentration of 10 μM such compounds typically inhibit induced TNFa-release from a cell by about 50% or greater than 50%.
[0171] The targeting moiety can hydrogen bond to residues at the binding site of the target protein and may further include additional hydrogen bond donor or acceptor groups that also form hydrogen bonds to the target protein. Targeting moieties include amide and thioamide groups, methyl amide and thioamide groups, carbamates, hydroxymethyl amides, alpha-ketoamides, diamides, and the like. Cyclic targeting moieties are also contemplated such as imidazolinone, imidazoline dione and trione.
[0172] The pocket-expanding moiety is of sufficient size to force a conformational change in the target protein, resulting in an expanded binding pocket therein. Such moieties include, for example, pyrazolyl, oxazolyl, phenyl or the like, each substituted with bulky moieties. Bulky moieties fill a large volume of space in comparison to, for example, a methyl group and include groups such as t-butyl, norbornyl, and the like.
[0173] The orienting moiety, by binding to a hydrophobic pocket on the target protein, provides the proper orientation of the targeting moiety and pocket-expanding moiety for binding of the cytokine inhibitor to its target protein. The planar hydrophobic moieties which make up the orienting moiety have either few or no polar groups. Such moieties include, for example, phenyl, naphthyl, indazolyl, and the like.
[0174] In other embodiments, the cytokine inhibitors further comprise a hydrophilic moiety having at least one functionality selected from the group consisting of a hydrogen- bond donor, hydrogen-bond acceptor, basic heteroatom, or acidic heteroatom, wherein the hydrophilic moiety is indirectly attached to the hydrophobic orienting moiety and is capable of forming a hydrogen bond with the backbone of the protein. Typically the hydrophilic moiety is attached to the orienting moiety by a linker chain of atoms of from about 2 to about 10 angstroms in length. The hydrophilic moiety binds in or near an ATP -binding pocket on the target protein, forming at least one hydrogen bond with a residue of the ATP-binding pocket. Hydrophilic moieties include morpholinyl, piperazinyl, and pyrimidinyl groups, among others. Such moieties may be attached to the orienting moiety by, for example, oxy, ethylene, methyleneoxy and ethyleneoxy chains.
[0175] In certain embodiments of the cytokine inhibitors of the invention, the pocket- expanding moiety is not a substituted 5-member heterocyclyl ring if the cytokine inhibitor is PEM-CHR"C(O)NH-OM, wherein R" is H or C] -6 alkyl, optionally partially or fully halogenated. In other embodiments, the targeting moiety is not a substituted tricyclic heterocyclyl ring having a nitrogen atom ring member bonded to the amide carbonyl of the targeting moiety.
[0176] Cytokine inhibitors of the invention may be readily synthesized by techniques well known to those of skill in the art, as described in U.S. Application No. 10/939,324, filed September 10, 2004, U.S. Application No. 60/656,196, filed February 24, 2005, and International Application No. PCT/US2006/006682, filed February 23, 2006.
[0177] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document were specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.
[0178] The present invention, thus generally described, will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention. EXAMPLES
Example 1: Inhibition of TNFa production in THP cells
[0179] The inhibition of cytokine production can be observed by measuring inhibition of TNFa in lipopolysaccharide-stimulated THP-I cells (see Prichett et al. J. Inflammation, 1995, 45, 97). THP-I cells (ATCC TIB 202, American Type Culture Collection, Rockville, MD) are maintained at 37°C, 5% CO2 in RPMI 1640 media with 10% fetal bovine serum, 10 mM Hepes, 1 mM sodium pyruvate, 4.5 g/L glucose and 0.05 mM 2-mercaptoethanol as suggested by ATCC. For the assay, the cells and compounds are diluted in the media above having 1% fetal bovine serum (assay media). Test compound stocks in DMSO are diluted into assay media to 6x the final assay concentration, with a final DMSO concentration of less than 0.3% in the assay. THP-I cells are plated at lX105/well in 96 well tissue culture plates. Diluted compounds (or DMSO control) are added and allowed to preincubate with the cells at 370C, 5% CO2 for 30 minutes prior to the addition of LPS (Sigma) to a final concentration of 1 μg/ml. Cells are then incubated 18-20 hours at 37°C/5% CO2. The assay is terminated by centrifuging the plates for 10 min at room temperature. Supernatants are removed to clean culture plates and aliquots are removed for analysis for TNFa by a commercially available ELISA kit (R&D Systems #DY210, Minneapolis, MN). Data is analyzed by non-linear regression using PRISM 4 software from Graphpad Software (San Diego, CA). The calculated IC50 is the concentration of the test compound that causes a 50% decrease in the maximal TNFa production.
Example 2: Assay models for pemphigus
[0180] The effectiveness of the compounds of the invention or its derivatives or salts in the treatment of any of the forms of pemphigus described above can be evaluated by one or more of the following methods: (a) in an established organ culture model where the degree of acantholysis can be measured, after introduction of exogenous pemphigus antibody; (b) in a neonatal mouse model where disease can be induced, and evidence of clearing can be monitored; and/or (c) in humans with pemphigus. (See for example, Berkowitz et al, J. Biol.
I l l Chem., 280(25): 23778-23784; Berkowitz et al., Proc. Nat. Acad. Sci., 2006, 103(34), 12855-12860.)
[0181] Experimental procedure for purification of pemphigus antibodies from human donors. Method A. The pemphigus antibodies to be used in the analysis are purified and prepared in the following manner (Anhalt et al., J. Immunol. 1986, 137, 2835- 40). Serum is obtained from human patients with the clinical, histologic and immunologic features of pemphigus. The IgG fractions of the sera are purified by 40% ammonium sulfate precipitation, followed by ion exchange chromatography. IgG fractions prepared in this manner are free of significant protease contamination when assayed. Further or alternate purification regimens can include protein-A or protein-G binding and elution, and various chromatography schemes that exploit differences in the size and charge of the IgG5 as known to those skilled in the art. The fractions are concentrated and sterilized via filtration. The pemphigus anti-body titer in the serum is then measured.
[0182] Method B. (Berkowitz et al, J. Biol. Chem., 2005, 280(25): 23778-23784)
Pemphigus (PV) sera (mucocutaneous) have been described (Ding et al. J. Invest. Dermatol. 1997, 109: 592-596). The PV IgG are purified from PV patient sera by ammonium sulfate precipitation followed by affinity chromatography on Protein G (HiTrap; Amersham Pharmacia, Piscataway, NJ). IgG fractions are dialyzed against PBS and sterile filtered. Purity is confirmed by SDS/PAGE, and activity is assayed by indirect immunofluoresence (IF) on sectioned monkey esophagus and ELISA. Control IgG (no activity by indirect IF) are prepared in parallel from normal human sera.
[0183] Organ Culture Model for Pemphigus. Method A. Production of acantholysis in vitro can be carried out as follows (Lever, J. Am. Acad. Dermatol. 1979, 1, 2- 31). Normal human skin is maintained in organ cultures to which sera of patients with pemphigus is added. Direct IF staining of the explants with fluorescein-labeled goat anti- human IgG shows that, after incubation, binding of the pemphigus IgG occurs in the intercellular cement substance of the epidermis. Suprabasal acantholysis is observed which progresses to extensive acantholysis. Complement is not required for the in vitro production of acantholysis since heating the pemphigus sera at 560C for thirty minutes does not prevent acantholysis (Lever, J. Am. Acad. Dermatol. 1979, 1, pp. 2-31).
[0184] The ability of the compounds of the invention or its derivatives or salts to lessen or eliminate acantholysis in vitro caused by exposure to pemphigus-TgG can be evaluated as follows. Normal human skin is cultured according to the method described by Naito, et al., (Naito, Morioka, Nakajima, Ogawa, J. Invest. Dermatol. 1989, 93, 173-77). Skin is sliced into 2 x 2 mm pieces thick. The skin is then floated on top of a total volume of 1.0 ml culture medium with the assistance of paraffin edged lens paper. The cultures are kept in humid atmosphere containing CO2 in air for 24, 48 and 72 hours. The culture medium should contain approximately 7 mg/ml of pemphigus IgG with or without the test compounds. After each culture period, the skin explants are examined by routine histologic (hemotoxylin and eosin staining) methods. The final concentration of test compound should range from 0.1 to 20 mg/ml. The skin can be preincubated (1-24 hours) with the test compound prior to addition of pemphigus IgG. Acantholysis is evaluated on a scale of (-), (+), (++), or (+++), where (-) is no acantholysis, (+) is positive on 10-30%, (++) is positive on 30-70%, and (+++) is positive on 70-100% of the epidermis in the histologic section.
[0185] Method B. (Berkowitz et al, J. Biol. Chem., 2005, 280(25): 23778-23784)
Normal primary human keratinocytes are passaged and expanded as described (Hu, et al., J. Investig.Dermatol. 1997, 117: 1059-1067). Third passage keratinocytes are grown to 80- 90% confluence when DSG3, but not DSGl, was detected by Western blot of cell extracts using DSG3- and DSGl -specific monoclonal antibodies, respectively. [32P]HsPO4 is added to the culture medium (5 mCi/ml). The cells are incubated for 2 hr and either control IgG, PV IgG, or an equivalent volume of buffer is added (to concentrations of 5, 10, or 25 μM). Cells are incubated for 15, 30, 60, or 150 min and washed extensively in PBS prior to harvesting in IEF lysis buffer (8 M urea, 4% CHAPS, 2.5 mM dithiothreitol, 40 mM Tris, 10 μM pepstatin, 100 μM leupeptin, 10 μM E-64, 1 mM phenylmethylsulfonyl fluoride). Protein concentration is by modified Bradford as described (Hu, et al., J. Investig.Dermatol. 1997, 117: 1059- 1067). IPG buffer (pH 3—10, non linear; Amersham Biosciences) is added to each sample to a final concentration of 0.5% prior to isoelectric focusing. For inhibition studies, keratinocytes are preincubated for 60 min at 37°C with the cytokine inhibitor, after which PV IgG is added to a final concentration of 25 μM and the cells are incubated for 30 min at 37°C and harvested in IEF lysis buffer.
[0186] Neonatal Mouse Model for Pemphigus. General protocol. The ability of the test compounds to reduce the symptoms of pemphigus in vivo can be evaluated in a neonatal mice model (Anhalt, et al., N. Engl. J. Med. 1982, 306:. 1189-96 or Berkowitz et al., Proc. Nat. Acad. Sci., 2006, 103(34), 12855-12860). Purified IgG fractions are injected i.p. into neonatal mice using a 30 gauge needle in a single administration of IgG per gram body weight according to an established model (Takahashi, et al., J. Invest. Dermatol. 1985, 84: 41-46). Skin and serum samples are obtained from animals receiving injections of either normal human IgG (control) or human pemphigus IgG. Skin samples from the flank region, where lesions most often occur are processed for direct immunofluorescence. Human pemphigus antibodies are also monitored in the animals' serum, to confirm transfer of the pemphigus antibodies. One group of mice is treated with administration of the test compound and monitored for disease improvement by sampling the skin and assessing its appearance by histology and/or by clinical appearance.
[0187] Study details. Breeding pairs of C57BL/6J mice were purchased from The
Jackson Laboratory (Bar Harbor, ME) and maintained in accordance with International Animal Care and Use Committee protocols. Neonatal mice (24 — 36 hr old with body weights between 1.4 and 1.6 g) were used for passive transfer experiments. Neonates were injected i.d. with a sterile solution of either control IgG or PV IgG as described (Proc. Nat. Acad. Sci.,2006, 103(34): 12855-12860 (and refs. 1, 34, 35 therein)).
[0188] The cytokine inhibitor of the invention was administered i.d. in two doses.
One injection of 6.25 μg of test compound was given 2 hr before the i.d. injection of IgG. The second dose of the same amount of inhibitor was mixed with PV IgG or control IgG and injected i.d. Each animal received a total dose of 12.5 μg of inhibitor. After 18 hr, the skin of the neonatal mice from the test and control groups was examined clinically and histologically as described (Proc. Nat. Acad. Sci., 2006, 103(34), 12855-12860 (and refs. 1, 25 therein)). [0189] For direct clinical examination, mice were injected with PV IgG or control
IgG at 1.5 mg/g body weight in a total volume of 50 μl of PBS. This dose of PV IgG resulted in gross sloughing of the skin. The skin of neonatal mice from the test and control groups was examined after the injection of IgG for the presence of Nikolsky's sign, in which gentle friction of perilesional skin causes sheet-like sloughing of the epidermis.
[0190] A second group of animals received a lower dose of PV IgG (1.0 mg/g body weight in 50 μl of PBS) to preserve the cutaneous architecture lost by epithelial sloughing at the higher dose. After clinical examination, the animals were euthanized, and skin and serum specimens were obtained for routine histological examination using light microscopy (hematoxylin/eosin staining).
[0191] Study Results. Mice injected with PV IgG developed suprabasilar acantholysis (3/3). In contrast, mice treated with the cytokine inhibitor of the invention and pathogenic PV IgG failed to develop blisters histologically (0/3). Mice injected with control IgG retained normal cutaneous architecture (3/3).
[0192] Additional models for pemphigus are described in "Animal Models of Human
Inflammatory Skin Diseases", Ed. L.S. Chan, CRC Press, 2003.
Example 3: Clinical Evaluations in humans
[0193] Steroid sparing assessment in a multiple week study. A multiple week study, e.g., a 12 week or 26 week study, of steroid sparing can be conducted as follows. At study entry, all patients will be taking a stable dose of prednisone (or an equivalent corticosteroid) of 20 to 120 mg/day for at least 2 weeks. Patients will be randomly assigned to several study arms. The treatment arms will receive the cytokine inhibitor of the invention, and the control arm will receive placebo. Drug administration will take place daily. Prednisone doses may be tapered (for example, by 15% every 2 weeks) during the study at the investigator's discretion. There will be several study visits until the end of the study (typically Week 12 or Week 26). Each study visit will include a physical exam, vital signs measurement, medical and medication history, a review of the disease activity log and adverse events experienced since the last visit, skin assessments, and blood collection. Patients will be asked to complete quality of life questionnaires at study entry and at several time points during the study. Skin biopsies of unaffected skin will be done at study entry and at several time points during the study; if patients have PV-associated lesions, additional skin biopsies of affected skin will be done as deemed necessary by investigator.
[0194] Patients will be monitored for some or all of the following outcomes: disease activity; modified responder status, defined as achieving prednisone dosage less than or equal to 25% of the initial starting dose or a dosage of less than 10 mg prednisone/day (whichever is greater) at the end of the study (e.g., week 26 in a 26 week study), regardless of new blister formation; time to cessation of new blisters; time to 80% healing (as determined by the reduction in surface area or volume) of erosions or ulcerations existing at the time of enrollment total prednisone dosage required to achieve cessation of new blisters and to achieve 80% healing of existing erosions; quality of life (SF-36) changes from baseline through the end of the study; dermatology-related quality of life changes from baseline through the end of the study; change in serum anti-DSGl antibody levels from baseline through the end of the study; change in serum anti-DSG3 antibody levels from baseline through the end of the study; change in serum TNF-alpha and IL-6 levels from baseline through the end of the study; change in skin expression of TNF-alpha and IL-6 rnRNA from baseline through the end of the study; change in number and proportion of immature B cells in circulation from baseline through the end of the study; duration of primary clinical efficacy endpoint from a predetermined time point (for example Week 18) through a second time point (for example Week 26) as measured by disease activity score and prednisone dosage.
[0195] Methods for the evaluation of test compounds in humans with oral lesions. The effectiveness of treatment of patients with oral lesions resulting from lichen planus, bullous pemphigoid, cicatricial pemphigoid, pemphigus or canker sores (aphthous uclers) with test compounds can be evaluated as described generally for treatment of lichen planus by Eisen, Ellis, Duell, Griffiths and Voorhees, in N. Engl. J. Med. 1990, Vol. 323, pp. 290-4. For example, patients with symptomatic oral lichen planus are given either placebo or a test compound formulation containing 1 to 50% test compound. The solutions are swished for several minutes and expectorated or swallowed several times daily.
[0196] Clinical evaluations are performed by the same physician for the duration of the experiment. Each patient's disease is measured on a scale of 1 to 4, with 1 indicating minimal disease, and 4 indicating severe lesions. The degree of erosion, erythema, and reticulation of each lesion is separately scaled over time for a period ranging from 1 day to 6 months, as desired. In addition, the patients evaluate lesion discomfort on a scale of 1 to 4.
[0197] The compounds of the invention can be assayed by one or more of the above methods and have or are expected to have activity in one or more of the above assays.
[0198] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as "up to," "at least," "greater than," "less than," and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 atoms refers to groups having 1, 2, or 3 atoms. Similarly, a group having 1-5 atoms refers to groups having 1, 2, 3, 4, or 5 atoms, and so forth.
[0199] Compounds are named according to standard IUPAC nomenclature using the automatic naming application Autonom 2000 (MDL Information Systems, San Leandro, CA).
[0200] While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the invention in its broader aspects as defined in the following claims.

Claims

CLAIMSWhat is claimed is:
1. A method of treating pemphigus, which comprises administering to a subject in need of such treatment a composition comprising a therapeutically effective amount of a cytokine inhibitor, wherein the cytokine inhibitor is selected from
(A) a cytokine inhibitor comprising: a targeting moiety comprising at least an amide group having an amide NH, the targeting moiety capable of forming one or more hydrogen bonds with a target protein, and wherein the targeting moiety is not a urea group; a pocket-expanding moiety directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non-planar hydrophobic moiety, said non-planar moiety capable of forming hydrophobic interactions with a target protein; and an orienting moiety comprising a planar hydrophobic moiety and attached to a different atom of the targeting moiety than the pocket-expanding moiety, said orienting moiety capable of forming a π— π or edge-to-face aromatic interaction with a target protein;
(B) a first group of compounds of Formula IA:
Figure imgf000120_0001
IA stereoisomers thereof, tautorners thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
G is a C3-Io carbocyclyl, 5-8 membered monocyclic heterocyclyl/or 8-1 1 membered bicyclic heterocyclyl containing 1 or more heteroatoms selected from O, N or S; wherein G is substituted with one or more R1, R2 or R3; X is C(O), C(S) or CH2;
Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, Cβ-io aryl, -(Cu3 βlkyl)-(C6-io aiyl), -(Y)-(Cc3 alkyl)-(C6.,0 aryl), or -(Y)-(C0-3 alkyl)-(5-10 member heteroaryl), each of which is optionally substituted with one or more R4 or R5;
Y is -CHZ-, -CZ2-, -CHR-, -O-, -C(=CHR)-, or -C(=C-CO2R)-; each Z is independently F, Cl, -OR, -NR2, -SR, -NHCONHR, or
-NHCOR;
1 L is a covalent bond or a saturated or unsaturated branched or unbranched C]-Io carbon chain, wherein one or more methylene groups are optionally independently replaced by heteroatoms selected from O3 NR or S(O)n,; and wherein L is optionally substituted with 1-2 oxo groups and/or one or more of F, Cl, Br, or I;
Q is hydrogen, -NR'R', cycloalkyl, aryl, heterocyclyl, Cj-6 alkoxy, Ci-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, C1-O alkoxy, C].6 alkyl-S(O)m, or phenyl-S(O)m is each optionally substituted with one or more R27; each m is independently O, 1 or 2; each R is independently hydrogen or substituted or unsubstituted C1-6 alkyl; each R' is independently hydrogen, substituted or unsubstituted Ci-8 alkyl, substituted or unsubstituted (C0-4 alkyl)-(C6-io aryl) or substituted or unsubstituted (C0-4 alkyl)-(5-10 member heterocyclyl); each R1 is independently F, Cl, Br, I, cyano, -C(O)R, -C(O)NR2, -C(O)OR, -OR, -NR'R', -SiR3, - S(O)mR, substituted or unsubstituted Ci-I0 alkyl, substituted or unsubstituted C2-I0 alkenyl, substituted or unsubstituted C2-10 alkynyl, substituted or unsubstituted C3-Io cycloalkyl, substituted or unsubstituted Cs-8 cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S(O)n,; each R2, R4 and R5 is independently F, Cl, Br3 1, cyano, substituted or unsubstituted straight or branched Ci-6 alkyl, substituted or unsubstituted Cβ-io aryl, substituted or unsubstituted 5-10 member heteroaryl, -OR', -OR5, -C(O)R', -C(O)OR', -C(O)NR'2> -NR'2, -NO2, -S(O)JR.", -NR1SO2R", -NR'C(O)NR'R'S -NR5C(S)NR5R', -NR5C(O)OR' or -SO2NR'2; each R" is independently substituted or unsubstituted Ci-8 alkyl, substituted or unsubstituted Co_4 alkyl-Ce-io aryl or substituted or unsubstituted (Co-4 alkyl)-(5-10 member heterocyclyl); each R3 is independently substituted or unsubstituted C6-I0 aryl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S(O)m, substituted or unsubstituted C3.12 cycloalkyl, substituted or unsubstituted C5-12 cycloalkenyl, substituted or unsubstituted C7..20 aralkyl, substituted or unsubstituted straight or branched C]-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R25C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2_s alkynyl, wherein one or more methylene groups of the Ci-S alkyl, C2-8 alkenyl, or C2.β alkynyl are optionally replaced by O, NH, or S(O)n,; each R6 is a Ci-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R26;
R20 is substituted or unsubstituted Ci_io alkyl, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl-heterocyclyl, OR5 or NR'2;
R21 is hydrogen or C^ branched or unbranched alkyl optionally partially or fully halogenated; each R22, R23 and R24 is independently hydrogen, substituted or unsubstituted CLIO alkyl, wherein the CM0 alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted Co-6 alkyl-phenyl, substituted or unsubstituted Co-6 alkyl-heterocyclyl; or R23 and R24 taken together form a heterocyclic or heteroaryl ring; and each R26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(Co-4 alkyl)amino, wherein the Co-4 alkyl is optionally partially or fully halogenated; each R27 is independently F, Cl5 Br, I, cyano, -C(O)R', -C(O)NR'2, -C(O)OR', -OR', -NR'R', -SiR'3, - S(O)raR', substituted or unsubstituted Cn0 alkyl, substituted or unsubstituted C2.io alkenyl, substituted or unsubstituted C2-io alkynyl, substituted or unsubstituted C3.10 cycloalkyl, substituted or unsubstituted C5.8 cycloalkenyl, substituted or unsubstituted C7-2O aralkyl, substituted or unsubstituted 3- 11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S(O)n,;
(C) a second group of compounds of Formula IA:
Figure imgf000123_0001
IA stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
X is C(O)or C(S);
Ar is -(Y)-(Co-3 alkyl)-(bicyclic aryl), or -(Y)-(Co-S alkyl)-(bicyclic heteroaryl), wherein the bicyclic heteroaryl is indazolyl, isoindolyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzofufanyl, benzoxazolyl, benzoisoxazolyl, dihydrobenzoisoxoazolyl, dihydroisoindolyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl, or benzoisothiazolyl dioxide, and wherein Ar is optionally substituted with one or more R4 or R5;
Y is -C(O)-, -C(N(NRC(O)OR))-, -C(N(NRR))-, -C(N(NC(O)NRR))- or -C(N(OR))-; and wherein G, L5 m, Q, R, R', R", R1, R2, R3, R4, R5, R6, R20, R21, R22, R23, R24, R26, and R27 are as defined for the first group of compounds of Formula IA;
(D) a third group of compounds of of Formula IA:
Figure imgf000124_0001
IA stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
G is a C3-5 cycloalkyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyrrolinyl, pyridazinyl, pyrrolyl, imidazolyl, imidazolonyl, isoxazolyl, furanyl, thienyl, pyridonyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolonyl, 4H-benzo[l,4]oxazine-3-onyl, benzodioxolyl, benzo[l,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl; wherein G is substituted by one or more R1, R2 or R3;
X is C(O)Or C(S); Ar is -(Y)-(Co-3 alkyl)-(phenyl), or -(Y)-(Co-3 alkyl)-(monocyclic heteroaryl), wherein Ar is optionally substituted with one or more R4 or R5;
Y is -C(O)-, -C(N(NRC(O)OR))-, -C(N(NRR))-, -C(N(NC(O)NRR))- or -C(N(OR))-; and wherein L, m, Q, R3 R', R", R1, R2, R3, R4, R5, R6, R20, R21, R22, R23, R24, R26, and R27 are as defined for the first group of compounds of Formula IA;
(E) a first group of compounds of formula IB:
Figure imgf000125_0001
IB stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
G, X, Ar, Y, Z, L, m, Q, R, R', R", R1, R2, R3, R4, R5, R6, R20, R21, R22, R23, R24, R26, and R27 are as defined for the first group of compounds of Formula IA;
(F) a second group of compounds of Formula IB:
H
X Ar-L — Q
IB stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
G is a G'-(Y)- wherein G' is a C3-1O carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8-11 membered bicyclic heterocyclyl other than indolyl containing 1 or more heteroatoms selected from O, N or S, wherein G' is substituted by one or more R1, R2 or R3;
X is C(O) or C(S); Ar is bicyclic aryl or 8-11 membered bicyclic heteroaryl containing 1 or more heteroatoms selected from O5 N or S, wherein Ar is optionally substituted with one or more R4 or R5;
Y is independently -C(O)-, -C(N(NRC(O)OR))-, -C(N(NRR))-, -C(N(NC(O)NRR)) or -C(N(OR))-; and wherein L3 m, Q, R, R', R", R1, R2, R3, R4, R5, R6, R20, R21, R22, R23, R24, R26, and R27 are as defined for the first group of compounds of Formula IA;
(G) a third group of compounds of formula IB:
H
X Ar-L — Q
IB stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
G is a C-(Y)- wherein G' is a C3-10 cycloalkyl, phenyl, naphthyl, tetrahydronaphthyl other than 1,1, 4,4- tetram ethyl- 1 ,2,3, 4-tetrahydronaphthyl, pyrazolyl, thiazolyl, pyridinyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, imidazolyl, furanyl other than furan-2-yl, thienyl other than thien-2-yl, dihydronaphthyl, indanyl, indenyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzpyrazolyl, or homopiperidinyl; wherein G' is substituted by one or more R1, R2 or R3;
X is C(O) or C(S);
Ar is phenyl, pyrimidinyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, pyrrolinyl, pyridazinyl, pyrrolyl, imidazolyl, furanyl, thienyl, pyrimidinyl, pyrazinyl; wherein Ar is optionally substituted with one or more R4 or
R5; Y is independently -C(O)-, -C(N(NRC(O)OR))-, -C(N(NRR))-, -C(N(NC(O)NRR))- or -C(N(OR))-; and wherein the variables L, m, Q, R3 R', R", R1, R2, R3, R4, Rs, R6, R20, R21, R22, R23, R24, R26, and R27 are as defined for the first group of compounds of Formula IA;
(H) a compound of Formula IC:
G — Ring — Ar — L — Q IC stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
Ring is maleimide, succinimide, imidazolidinone, imidazolidine-dione, imidazolidine-trione, triazolidin-dione, or triazine-dione;
G is a C3-Io carbocyclyl, C4-12 carbocyclylalkyl, 5-8 membered monocyclic heterocyclyl or heterocyclylalkyl, 8-11 membered bicyclic heterocyclyl or heterocyclylalkyl, wherein the heterocyclyl rings contain 1 or more heteroatoms selected from O, N or S; and G is substituted by one or more R1, R2 or R3; and wherein Ar, L, m, Q, R, R', R", R1, R2, R3, R4, R5, R6, R20, R21, R22, R23, R24, R26, and R27 are as defined for the first group of compounds of Formula IA; and
(I) a compound of Formula II:
Figure imgf000127_0001
II stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein: X' is CR'=CR\ CR'=N, NR', CR'2, O or S;
Ar is phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, pyridinyl, pyridazinyl, quinolinyl. isoquinolinyl, phthalazinyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl, indole, or the structure -(Y')-(Co-3 alkyl)-(C6-io aryl), each being optionally substituted with one or more R4 groups;
Y' is absent or is — O- or -NH-; each R3 is independently H, substituted or unsubstituted C6-Io aryl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N5 O, or S(O)m, substituted or unsubstituted C3-I2 cycloalkyl, substituted or unsubstituted C5.12 cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted straight or branched C1-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the Ci-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH, or S(O)m; and wherein G, L5 m, Q, R5 R', R", R1, R2, R4, R6, R20, R21, R22, R23, R24, R26, and R »27 are as defined for the first group of compounds of Formula IA.
2. The method of claim 1 , wherein the pemphigus is pemphigus vulgaris, pemphigus vegetans, pemphigus foliaceus, pemphigus erythematosus, bullous pemphigoid, paraneoplastic pemphigus, cicatricial pemphigoid, bullous impetigo, or staphylococcal scalded-skin syndrome.
3. The method of claim 1 , additionally comprising administering to the subject an effective amount of one or more Ingredients A useful in the treatment of pemphigus.
4. The method of claim 3, wherein the effective amount of Ingredient A is less than the effective amount of Ingredient A when used alone.
5. The method of claim 3, wherein the one or more Ingredients A is selected from anti-inflammatory agents, immunosuppressants, anti-infectives, antibiotics, gold salts, alkylating agents, or immunoglobulins.
6. The method of claim 5, wherein the anti-inflammatory is a corticosteroid, a COX-2 inhibitor, a non-steroidal anti-inflammatory drug (NSAID), a TNFa antagonist, or an IL-I antagonist.
7. The method of claim 6, wherein the corticosteroid is prednisone, prednisolone, or methylprednisolone.
8. The method of claim 3, wherein Ingredient A is a corticosteroid and either chlorambusil or mycophenylate mofetil.
9. The method of claim 6, wherein the TNFa antagonist is infliximab, etanercept, or adalimumab.
10. The method of claim 6, wherein the IL-I antagonist is anakinra.
11. The method of claim 5, wherein the immunosuppressant is mycophenylate mofetil, cyclosporin, azathioprine, methotrexate, alefacept, rituximab, anti- interferon gamma, or cyclophosphamide.
12. The method of claim 5, wherein the anti-infective is dapsone, or hydroxychloroquine.
13. The method of claim 5, wherein the gold salt is myochrysine, or solganal.
14. The method of claim 5, wherein the alkylating agent is lukeran.
15. The method of claim 5, wherein the antibiotic is tetracycline, minocycline, or doxycycline.
16. The method of claim 15, the method further comprising administration of nicotinamide, or niacinamide.
17. The method of claim 1, additionally comprising administering plasmapherisis therapy or photophoresis therapy to the subject.
18. The method of claim 4 wherein the dosage of Ingredient A is reduced by from about 10% to about 90%.
19. The method of claim 4, wherein the dosage is reduced by at least about 10%, about 20%, about 30%, about 40%, about 50%, or about 60%.
20. The method of claim 4, wherein Ingredient A is a corticosteroid.
21. The method of claim 20, wherein the corticosteroid is prednisone or prednisolone.
22. The method of claim 21 , wherein the dosage of prednisone is reduced to less than about 10 mg/day, less than about 15 nag per day, less than about 20 mg/day, less than about 30 mg/day, less than about 50 mg/day or less than about 70 mg/day.
23. A method comprising administering to a subject exhibiting one or more clinical indicia of pemphigus an amount of a cytokine inhibitor effective to reduce the number or severity of clinical indicia of pemphigus relative to those present in the subject prior to the administration of the cytokine inhibitor, wherein the clinical indicia of pemphigus are the percentage of total body surface area (BSA) affected by pemphigus, pemphigus lesion thickness, the number of new pemphigus lesions, the number of active pemphigus lesions (including blisters and erosions), the healing time of active lesions, serum anti-desmoglein-1 (DSGl) antibody levels, serum anti-DSG3 antibody levels, serum TNFa-levels, serum IL6 levels, skin TNFa-mRNA levels, skin IL6 mRNA levels, or any two or more thereof, and wherein the cytokine inhibitor is selected from:
(A) a cytokine inhibitor comprising: a targeting moiety comprising at least an amide group having an amide NH, the targeting moiety capable of forming one or more hydrogen bonds with a target protein, and wherein the targeting moiety is not a urea group; a pocket-expanding moiety directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non-planar hydrophobic moiety, said non-planar moiety capable of forming hydrophobic interactions with a target protein; and an orienting moiety comprising a planar hydrophobic moiety and attached to a different atom of the targeting moiety than the pocket-expanding moiety, said orienting moiety capable of forming a π— π or edge-to-face aromatic interaction with a target protein;
(B) a first group of compounds of Formula IA:
Figure imgf000131_0001
IA stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
G is a C3-10 carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8-11 membered bi cyclic heterocyclyl containing 1 or more heteroatoms selected from O, N or S; wherein G is substituted with one or more R1, R2 or R3;
X is C(O), C(S) or CH2;
Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, C6-ιo aryl, -(C1-3 alkyl)-(C5-io aryl), -(Y)-(C0-3 alkyl)-(C6-10 aryl), or -(Y)-(C0-3 alkyl)-(5-10 member heteroaryl), each of which is optionally substituted with one or more R4 or R5;
Y is -CHZ-, -CZ2-, -CHR-, -O-, -C(=CHR)-, or -C(=C-CO2R)-; each Z is independently F, Cl, -OR, -NR2, -SR, -NHCONHR, or -NHCOR; L is a covalent bond or a saturated or unsaturated branched or unbranched Ci-io carbon chain, wherein one or more methylene groups are optionally independently replaced by heteroatoms selected from O, NR or S(O)n,; and wherein L is optionally substituted with 1-2 oxo groups and/or one or more of F, Cl, Br, or I;
Q is hydrogen, -NR'R', cycloalkyl, aryl, heterocyclyl, Ci_6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, Ci-6 alkoxy, Cue alkyl-S(O)m, or phenyl-S(O)m is each optionally substituted with one or more R27; each m is independently 0, 1 or 2; each R is independently hydrogen or substituted or unsubstituted Ci-6 alkyl; each R' is independently hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted (Co-4 alkyl)-(C6-ιo aryl) or substituted or unsubstituted (Co-4 alkyl)-(5-10 member heterocyclyl); each R1 is independently F, Cl, Br, I5 cyano, -C(O)R, -C(O)NR2, -C(O)OR, -OR, -NR'R', -SiR3, - S(O)1nR, substituted or unsubstituted CMo alkyl, substituted or unsubstituted C2.io alkenyl, substituted or unsubstituted C2-10 alkynyl, substituted or unsubstituted C3-io cycloalkyl, substituted or unsubstituted C5.8 cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S(O)n,; each R2, R4 and R5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C1-6 alkyl, substituted or unsubstituted Cβ-io aryl, substituted or unsubstituted 5-10 member heteroaryl, -OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'2) -NR'2, -NO2, -S(O)mR", -NR1SO2R", -NR' C(O)NR5R', -NR'C(S)NR'R', -NR1C(O)OR' or -SO2NR'2; each R" is independently substituted or unsubstituted Q-s alkyl, substituted or unsubstituted Co-4 alkyl-Cδ-io aryl or substituted or unsubstituted (C0-4 alkyl)-(5-l O member heterocyclyl); each R3 is independently substituted or unsubstituted Cβ-io aryl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S(O)n,, substituted or unsubstituted C3-I2 cycloalkyl, substituted or unsubstituted C5-I2 cycloalkenyl, substituted or unsubstituted C7-2O aralkyl, substituted or unsubstituted straight or branched Cw alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-5 R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the Cj-8 alkyl, C2-8 alkenyl, or C2.g alkynyl are optionally replaced by O, NH, or S(O)1n; each R6 is a Ci-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R26;
R20 is substituted or unsubstituted d-10 alkyl, substituted or unsubstituted Co-6 alkyl-phenyl, substituted or unsubstituted Co-6 alkyl-heterocyclyl. OR' or NR! 2;
R21 is hydrogen or Ci-4 branched or unbranched alkyl optionally partially or fully halogenated; each R22, R23 and R24 is independently hydrogen, substituted or unsubstituted Cj.io alkyl, wherein the d-10 alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted Co-β alkyl-heterocyclyl; or R23 and R24 taken together form a heterocyclic or heteroaryl ring; and each R26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(Co-4 alkyl)amino, wherein the Co-4 alkyl is optionally partially or fully halogenated; each R27 is independently F, Cl, Br, I, cyano, -C(O)R', -C(O)NR'2, -C(O)OR', -OR', -NR1R', -SiR'3, - S(O)mR\ substituted or unsubstituted Ci-10 alkyl, substituted or unsubstituted C2-Io alkenyl, substituted or unsubstituted C2-io alkynyl, substituted or unsubstituted C3-10 cycloalkyl, substituted or unsubstituted C5-8 cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted 3- 11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S(O)n,;
(C) a second group of compounds of Formula IA:
Figure imgf000134_0001
IA stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
X is C(O)or C(S);
Ar is -(Y)-(Co-3 alkyl)-(bicyclic aryl), or -(Y)-(Co-3 alkyl)-(bicyclic heteroaryl), wherein the bicyclic heteroaryl is indazolyl, isoindolyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, dihydrobenzoisoxoazolyl, dihydroisoindolyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl, or benzoisothiazolyl dioxide, and wherein Ar is optionally substituted with one or more R4 or R5;
Y is -C(O)-, -C(N(NRC(O)OR))-, -C(N(NRR))-, -C(N(NC(O)NRR))- or -C(N(OR))-; and wherein G, L, m, Q, R, R', R", R1, R2, R3, R4, R5, R6, R20, R21, R22, R23, R24, R26, and R27 are as defined for the first group of compounds of Formula IA;
(D) a third group of compounds of of Formula IA:
Figure imgf000134_0002
IA stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
G is a C3-5 cycloalkyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyrrolinyl, pyridazinyl, pyrrolyl, imidazolyl, imidazolonyl, isoxazolyl, furanyl, thienyl, pyridonyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl, quinolinyl, dihydroquinolinyl, tetrahydroquiπoyl, isoquinolinyl, tetrahydroisoquinoyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolonyl, 4H-benzo[l,4]oxazine-3-onyl, benzodioxolyl, benzo[l,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl; wherein G is substituted by one or more R1, R2 or R3;
X is C(O)or C(S);
Ar is -(Y)-(Co-3 alkyl)-(phenyl), or -(Y)-(Co-3 alkyl)-(monocyclic heteroaryl), wherein Ar is optionally substituted with one or more R4 or R5;
Y is -C(O)-, -C(N(NRC(O)OR))-, -C(N(NRR))-, -C(N(NC(O)NRR))- or -C(N(OR))-; and wherein L, m, Q3 R, R\ R", R1, R2, R3, R4, R5, R6, R20, R21, R22, R23, R24, R26, and R27 are as defined for the first group of compounds of Formula IA;
(E) a first group of compounds of formula IB:
Figure imgf000135_0001
IB stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
G, X, Ar, L, m, Q, R, R', R", R1, R2, R3, R4, R5, R6, R20, R21, R22, R23, R24, R26, and R27 are as defined for the first group of compounds of Formula IA;
(F) a second group of compounds of Formula IB:
H
G ^N^
X Ar-L — Q
IB stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
G is a G'-(Y)- wherein G' is a Cs-io carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8-11 membered bicyclic heterocyclyl other than indolyl containing 1 or more heteroatoms selected from O, N or S, wherein G' is substituted by one or more R1, R2 or R3;
X is C(O) or C(S);
Ar is bicyclic aryl or 8-11 membered bicyclic heteroaryl containing 1 or more heteroatoms selected from O, N or S, wherein Ar is optionally substituted with one or more R4 Or R5;
Y is independently -C(O)-, -C(N(NRC(O)OR))-, -C(N(NRR))-, -C(N(NC(O)NRR)) or -C(N(OR))-; and wherein L5 m, Q, R, R\ R", R1, R2, R3, R4, R5, R6, R20, R21, R22, R23, R24, R26, and R27 are as defined for the first group of compounds of Formula IA;
(G) a third group of compounds of formula IB: H
^X^ ^Ar-L — Q IB stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
G is a G'-(Y)- wherein G' is a C3-10 cycloalkyl, phenyl, naphthyl, tetrahydronaphthyl other than l,l,4,4-tetramethyl-l,2,3,4-tetrahydronaphthyl, pyrazolyl, thiazolyl, pyridinyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, imidazolyl, furanyl other than furan-2-yl, thienyl other than thien-2-yl, dihydronaphthyl, indanyl, indenyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzpyrazolyl, or homopiperidinyl; wherein G' is substituted by one or more R1, R2 or R3;
X is C(O) or C(S);
Ar is phenyl, pyrimidinyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, pyrrolinyl, pyridazinyl, pyrrolyl, imidazolyl, furanyl, thienyl, pyrimidinyl, pyrazinyl; wherein Ar is optionally substituted with one or more R4 or
R5;
Y is independently -C(O)-, -C(N(NRC(O)OR))-, -C(N(NRR))-, -C(N(NC(O)NRR))- or -C(N(OR))-; and wherein the variables L, m, Q, R, R', R", R1 , R2, R3, R4, R5, R6, R20, R21, R22, R23, R24, R26, and R27 are as defined for the first group of compounds of Formula IA;
(H) a compound of Formula IC:
G — Ring — Ar — L-Q IC stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
Ring is maleimide, succinimide, imidazolidinone, imidazolidine-dione, imidazolidine-trione, triazolidin-dione, or triazine-dione;
G is a C3-J0 carbocyclyl, C442 carbocyclylalkyl, 5-8 membered monocyclic heterocyclyl or heterocyclylalkyl, 8-1 1 membered bicyclic heterocyclyl or heterocyclylalkyl, wherein the heterocyclyl rings contain 1 or more heteroatoms selected from O3 N or S; and G is substituted by one or more R1, R2 or R3; and wherein Ar, L, m, Q, R, R', R", R1, R2, R3, R4, R5, R6, R20, R21, R22, R23, R24, R26, and R27 are as defined for the first group of compounds of Formula IA; and
(I) a compound of Formula II:
Figure imgf000138_0001
stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
X' is CR'=CR', CR'=N, NR', CR'2, O or S;
Ar is phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, tetrahydroquinoline, tetrahydroiso quinoline, benzimidazole, benzofuran, indanyl, indenyl, indole, or the structure -(Y')-(Co-3 alkyl)-(C6-io aryl), each being optionally substituted with one or more R4 groups;
Y' is absent or is -O- or -NH-; each R3 is independently H, substituted or unsubstituted C6-io aryl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S(O)m, substituted or unsubstituted C3_i2 cycloalkyl, substituted or unsubstituted Cs-I2 cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted straight or branched Ci-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the Ci-S alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH, or S(O)n,; and wherein G, L, m, Q5 R, R', R", R1, R2, R4, R6, R20, R21, R22, R23, R24, R26, and R27 are as defined for the first group of compounds of Formula IA.
24. The method of claim 23, additionally comprising administering to the subject an effective amount of one or more Ingredients A useful in the treatment of pemphigus.
25. The method of claim 24, wherein the effective amount of Ingredient A is less than the effective amount of Ingredient A when used alone.
26. The method of claim 24, wherein the one or more Ingredients A is selected from anti-inflammatory agents, immunosuppressants, anti-infectives, antibiotics, gold salts, alkylating agents, or immunoglobulins. i
27. The method of claim 26 wherein the anti-inflammatory is a corticosteroid, a COX-2 inhibitor, a non-steroidal anti-inflammatory drug (NSAID), a TNFa antagonist, or an IL-I antagonist.
28. The method of claim 27, wherein the corticosteroid is prednisone, prednisolone, or methylprednisolone.
29. The method of claim 24, wherein Ingredient A is a corticosteroid and either chlorambusil or mycophenylate mofetil.
30. The method of claim 27, wherein the TNFa antagonist is infliximab, etanercept, or adalimumab.
31. The method of claim 27, wherein the IL-I antagonist is anakinra.
32. The method of claim 26, wherein the immunosuppressant is mycophenylate mofetil, cyclosporin, azathioprine, methotrexate, alefacept, rituxirnab, anti- interferon gamma, or cyclophosphamide.
33. The method of claim 26, wherein the anti-infective is dapsone, or hydroxychloroquine.
34. The method of claim 26, wherein the gold salt is myochrysine, or solganal.
35. The method of claim 26, wherein the alkylating agent is lukeran.
36. The method of claim 26, wherein the antibiotic is tetracycline, minocycline, or doxycycline.
37. The method of claim 36, the method further comprising administration of nicotinamide, or niacinamide.
38. The method of claim 23 , additionally comprising administering plasmapherisis therapy or photophoresis therapy to the subject.
39. The method of claim 25, wherein the dosage of Ingredient A is reduced by from about 10% to about 90%.
40. The method of claim 25, wherein the dosage is reduced by at least about 10%, about 20%, about 30%, about 40%, about 50%, or about 60%.
41. The method of claim 25, wherein Ingredient A is a corticosteroid.
42. The method of claim 41 , wherein the corticosteroid is prednisone or prednisolone.
43. The method of claim 42, wherein the dosage of prednisone is reduced to less than about 10 mg/day, less than about 15 mg per day, less than about 20 mg/day, less than about 30 mg/day, less than about 50 mg/day or less than about 70 mg/day.
44. The method of claim 1 or claim 23, wherein the cytokine inhibitor is administered orally or topically.
45. The method of claim 3 or claim 24, wherein Ingredient A is a corticosteroid or an antibiotic, and wherein the corticosteroid or antibiotic is administered orally, topically, in a mouthwashor in a mouth spray.
46. The method of claim 1 or claim 23, wherein the cytokine inhibitor is selected from List 1.
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