Heterocycle -aryl compounds for inflammation and immune-related uses

Abstract

The invention relates to compounds that are useful as immunosuppressive agents and for treating and preventing inflammatory conditions, allergic disorders, and immune disorders.

1 - 31 . (canceled) 
     
     
         32 . A method of inhibiting immune cell activation comprising administering to the cell a compound selected from the group consisting of:
 2,6-difluoro-N-(4-(5-(isoxazol-5-yl)-3-methylthiophen-2-yl)phenyl)benzamide;   2,6-difluoro-N-(4-(3-methyl-5-(thiazol-2-yl)thiophen-2-yl)phenyl)benzamide;   2,6-difluoro-N-(4-(3-methyl-5-(1-methyl-1H-imidazol-5-yl)thiophen-2-yl)phenyl)benzamide;   2,6-difluoro-N-(5-(2-methyl-5-(oxazol-5-yl)thiophen-3-yl)pyrazin-2-yl)benzamide;   2,6-difluoro-N-(5-(2-methyl-5-(oxazol-5-yl)thiophen-3-yl)pyridin-2-yl)benzamide;   2,6-difluoro-N-(4-(3-methyl-5-(pyridin-3-yl)thiophen-2-yl)phenyl)benzamide;   2,6-difluoro-N-(4-(2-methyl-5-(pyridin-3-yl)thiophen-3-yl)phenyl)benzamide;   2,6-difluoro-N-(4-(2-methyl-5-(thiazol-2-yl)thiophen-3-yl)phenyl)benzamide;   2,6-difluoro-N-(4-(2-methyl-5-(1,3,4-oxadiazol-2-yl)thiophen-3-yl)phenyl)benzamide;   2,6-difluoro-N-(6-(2-methyl-5-(oxazol-5-yl)thiophen-3-yl)pyridin-3-yl)benzamide;   N-(4-(5-(1H-imidazol-5-yl)-2-methylthiophen-3-yl)phenyl)-2,6-difluorobenzamide;   2,6-difluoro-N-(4-(2-methyl-5-(4-methylpyridin-3-yl)thiophen-3-yl)phenyl)benzamide;   N-(4-(5-(5-chloro-2-methoxypyridin-3-yl)-2-methylthiophen-3-yl)phenyl)-2,6-difluorobenzamide;   2,6-difluoro-N-(5-(2-methyl-5-(thiazol-2-yl)thiophen-3-yl)pyridin-2-yl)benzamide;   2,6-difluoro-N-(5-(2-methyl-5-(thiazol-2-yl)thiophen-3-yl)pyrazin-2-yl)benzamide;   N-(5-(5-(1H-imidazol-5-yl)-2-methylthiophen-3-yl)pyridin-2-yl)-2,6-difluorobenzamide;   2,6-difluoro-N-(5-(2-methyl-5-(1-methyl-1H-imidazol-5-yl)thiophen-3-yl)pyridin-2-yl)benzamide;   3-methyl-N-(5-(2-methyl-5-(oxazol-5-yl)thiophen-3-yl)pyridin-2-yl)isonicotinamide;   N-(4-(5-(4-chloropyridin-3-yl)-2-methylthiophen-3-yl)phenyl)-2,6-difluorobenzamide;   2,6-difluoro-N-(4-(5-(4-methoxypyridin-3-yl)-2-methylthiophen-3-yl)phenyl)benzamide;   2,6-difluoro-N-(5-(2-methyl-5-(1-methyl-1H-imidazol-5-yl)thiophen-3-yl)pyrazin-2-yl)benzamide;   N-(5-(5-(1H-imidazol-5-yl)-2-methylthiophen-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide;   2,6-difluoro-N-(4-(2-methyl-5-(1-methyl-1H-imidazol-5-yl)thiophen-3-yl)phenyl)benzamide;   2,6-difluoro-N-(4-(2-methyl-5-(1-methyl-1H-imidazol-5-yl)thiophen-3-yl)phenyl)benzamide hydrochloride; and   N-(4-(5-(1-ethyl-1H-imidazol-5-yl)-2-methylthiophen-3-yl)phenyl)-2,6-difluorobenzamide; or   a pharmaceutically acceptable salt thereof.   
     
     
         33 . The method of  claim 32 , wherein immune cell activation is inhibited in a subject by administering the compound to the subject. 
     
     
         34 . The method of  claim 33 , wherein the subject is human. 
     
     
         35 . A method of inhibiting cytokine production in a cell, comprising administering to the cell a compound selected from the group consisting of:
 2,6-difluoro-N-(4-(5-(isoxazol-5-yl)-3-methylthiophen-2-yl)phenyl)benzamide;   2,6-difluoro-N-(4-(3-methyl-5-(thiazol-2-yl)thiophen-2-yl)phenyl)benzamide;   2,6-difluoro-N-(4-(3-methyl-5-(1-methyl-1H-imidazol-5-yl)thiophen-2-yl)phenyl)benzamide;   2,6-difluoro-N-(5-(2-methyl-5-(oxazol-5-yl)thiophen-3-yl)pyrazin-2-yl)benzamide;   2,6-difluoro-N-(5-(2-methyl-5-(oxazol-5-yl)thiophen-3-yl)pyridin-2-yl)benzamide;   2,6-difluoro-N-(4-(3-methyl-5-(pyridin-3-yl)thiophen-2-yl)phenyl)benzamide;   2,6-difluoro-N-(4-(2-methyl-5-(pyridin-3-yl)thiophen-3-yl)phenyl)benzamide;   2,6-difluoro-N-(4-(2-methyl-5-(thiazol-2-yl)thiophen-3-yl)phenyl)benzamide;   2,6-difluoro-N-(4-(2-methyl-5-(1,3,4-oxadiazol-2-yl)thiophen-3-yl)phenyl)benzamide;   2,6-difluoro-N-(6-(2-methyl-5-(oxazol-5-yl)thiophen-3-yl)pyridin-3-yl)benzamide;   N-(4-(5-(1H-imidazol-5-yl)-2-methylthiophen-3-yl)phenyl)-2,6-difluorobenzamide;   2,6-difluoro-N-(4-(2-methyl-5-(4-methylpyridin-3-yl)thiophen-3-yl)phenyl)benzamide;   N-(4-(5-(5-chloro-2-methoxypyridin-3-yl)-2-methylthiophen-3-yl)phenyl)-2,6-difluorobenzamide;   2,6-difluoro-N-(5-(2-methyl-5-(thiazol-2-yl)thiophen-3-yl)pyridin-2-yl)benzamide;   2,6-difluoro-N-(5-(2-methyl-5-(thiazol-2-yl)thiophen-3-yl)pyrazin-2-yl)benzamide;   N-(5-(5-(1H-imidazol-5-yl)-2-methylthiophen-3-yl)pyridin-2-yl)-2,6-difluorobenzamide;   2,6-difluoro-N-(5-(2-methyl-5-(1-methyl-1H-imidazol-5-yl)thiophen-3-yl)pyridin-2-yl)benzamide;   3-methyl-N-(5-(2-methyl-5-(oxazol-5-yl)thiophen-3-yl)pyridin-2-yl)isonicotinamide;   N-(4-(5-(4-chloropyridin-3-yl)-2-methylthiophen-3-yl)phenyl)-2,6-difluorobenzamide;   2,6-difluoro-N-(4-(5-(4-methoxypyridin-3-yl)-2-methylthiophen-3-yl)phenyl)benzamide;   2,6-difluoro-N-(5-(2-methyl-5-(1-methyl-1H-imidazol-5-yl)thiophen-3-yl)pyrazin-2-yl)benzamide;   N-(5-(5-(1H-imidazol-5-yl)-2-methylthiophen-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide;   2,6-difluoro-N-(4-(2-methyl-5-(1-methyl-1H-imidazol-5-yl)thiophen-3-yl)phenyl)benzamide;   2,6-difluoro-N-(4-(2-methyl-5-(1-methyl-1H-imidazol-5-yl)thiophen-3-yl)phenyl)benzamide hydrochloride; and   N-(4-(5-(1-ethyl-1H-imidazol-5-yl)-2-methylthiophen-3-yl)phenyl)-2,6-difluorobenzamide; or   a pharmaceutically acceptable salt thereof.   
     
     
         36 . The method of  claim 35 , wherein cytokine production is inhibited in a subject by administering the compound to the subject. 
     
     
         37 . The method of  claim 36 , wherein the subject is human. 
     
     
         38 . The method of  claim 36 , wherein the cytokine is selected from the group consisting of IL-2, IL-4, IL-5, IL-13, GM-CSF, IFN-γ, TNF-α, and combinations thereof. 
     
     
         39 . The method of  claim 38 , wherein the cytokine is IL-2. 
     
     
         40 . A method for treating an immune disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound selected from the group consisting of:
 2,6-difluoro-N-(4-(5-(isoxazol-5-yl)-3-methylthiophen-2-yl)phenyl)benzamide;   2,6-difluoro-N-(4-(3-methyl-5-(thiazol-2-yl)thiophen-2-yl)phenyl)benzamide;   2,6-difluoro-N-(4-(3-methyl-5-(1-methyl-1H-imidazol-5-yl)thiophen-2-yl)phenyl)benzamide;   2,6-difluoro-N-(5-(2-methyl-5-(oxazol-5-yl)thiophen-3-yl)pyrazin-2-yl)benzamide;   2,6-difluoro-N-(5-(2-methyl-5-(oxazol-5-yl)thiophen-3-yl)pyridin-2-yl)benzamide;   2,6-difluoro-N-(4-(3-methyl-5-(pyridin-3-yl)thiophen-2-yl)phenyl)benzamide;   2,6-difluoro-N-(4-(2-methyl-5-(pyridin-3-yl)thiophen-3-yl)phenyl)benzamide;   2,6-difluoro-N-(4-(2-methyl-5-(thiazol-2-yl)thiophen-3-yl)phenyl)benzamide;   2,6-difluoro-N-(4-(2-methyl-5-(1,3,4-oxadiazol-2-yl)thiophen-3-yl)phenyl)benzamide;   2,6-difluoro-N-(6-(2-methyl-5-(oxazol-5-yl)thiophen-3-yl)pyridin-3-yl)benzamide;   N-(4-(5-(1H-imidazol-5-yl)-2-methylthiophen-3-yl)phenyl)-2,6-difluorobenzamide;   2,6-difluoro-N-(4-(2-methyl-5-(4-methylpyridin-3-yl)thiophen-3-yl)phenyl)benzamide;   N-(4-(5-(5-chloro-2-methoxypyridin-3-yl)-2-methylthiophen-3-yl)phenyl)-2,6-difluorobenzamide;   2,6-difluoro-N-(5-(2-methyl-5-(thiazol-2-yl)thiophen-3-yl)pyridin-2-yl)benzamide;   2,6-difluoro-N-(5-(2-methyl-5-(thiazol-2-yl)thiophen-3-yl)pyrazin-2-yl)benzamide;   N-(5-(5-(1H-imidazol-5-yl)-2-methylthiophen-3-yl)pyridin-2-yl)-2,6-difluorobenzamide;   2,6-difluoro-N-(5-(2-methyl-5-(1-methyl-1H-imidazol-5-yl)thiophen-3-yl)pyridin-2-yl)benzamide;   3-methyl-N-(5-(2-methyl-5-(oxazol-5-yl)thiophen-3-yl)pyridin-2-yl)isonicotinamide;   N-(4-(5-(4-chloropyridin-3-yl)-2-methylthiophen-3-yl)phenyl)-2,6-difluorobenzamide;   2,6-difluoro-N-(4-(5-(4-methoxypyridin-3-yl)-2-methylthiophen-3-yl)phenyl)benzamide;   2,6-difluoro-N-(5-(2-methyl-5-(1-methyl-1H-imidazol-5-yl)thiophen-3-yl)pyrazin-2-yl)benzamide;   N-(5-(5-(1H-imidazol-5-yl)-2-methylthiophen-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide;   2,6-difluoro-N-(4-(2-methyl-5-(1-methyl-1H-imidazol-5-yl)thiophen-3-yl)phenyl)benzamide;   2,6-difluoro-N-(4-(2-methyl-5-(1-methyl-1H-imidazol-5-yl)thiophen-3-yl)phenyl)benzamide hydrochloride; and   N-(4-(5-(1-ethyl-1H-imidazol-5-yl)-2-methylthiophen-3-yl)phenyl)-2,6-difluorobenzamide; or   a pharmaceutically acceptable salt thereof.   
     
     
         41 . The method of  claim 40 , wherein the disorder is selected from the group consisting of multiple sclerosis, myasthenia gravis, Guillain-Barre, autoimmune uveitis, autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia, temporal arteritis, anti-phospholipid syndrome, vasculitides such as Wegener's granulomatosis, Behcet's disease, psoriasis, dermatitis herpetiformis, pemphigus vulgaris, vitiligo, Crohn's disease, ulcerative colitis, primary biliary cirrhosis, autoimmune hepatitis, Type 1 or immune-mediated diabetes mellitus, Grave's disease, Hashimoto's thyroiditis, autoimmune oophoritis and orchitis, autoimmune disorder of the adrenal gland, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, ankylosing spondylitis, and Sjogren's syndrome.