Amino-pyrimidine compounds as inhibitors of ikk epsilon and/or tbk1

A method of treating inflammation, RA, SLE, diseases associated with aberrant accumulation of cytosolic nucleic acids (including Sjögrens syndrome, Aicardi-Goutières syndrome, subtypes of SLE, chilblain lupus, and RVCL), systemic sclerosis, myositis (including dermatomyositis and polymyositis), psoriasis, COPD, IBD, obesity, insulin resistance, NIDDM, metabolic syndrome and cancer, and complications associated with these diseases and disorders, in a human patient, comprising identifying a patient in need of such treatment and administering to said patient a therapeutically effective amount of a compound having a structure according to Formula I:

• and pharmaceutically acceptable salts thereof, wherein:
• R1, R2, R3, and R5 are independently chosen from the following groups:
• alkyl, alkylene, alkenyl, alkenylene, alkynyl, carbocycle, cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl, halo, hydro, hydroxyl, alkoxy, alkynyloxy, cycloalkyloxy, heterocycloxy, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, mercapto, alkylthio, arylthio, cycloalkylthio, arylalkyl, heteroarylalkyl, heteroarylalkenyl, arylalkynyl, haloalkyl, aldehyde, thiocarbonyl, O-carboxy, C-carboxy, carboxylic acid, ester, C-carboxy salt, carboxyalkyl, carboxyalkenylene, carboxyalkyl salt, carboxyalkoxy, carboxyalkoxyalkanoyl, amino, aminoalkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, aminothiocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, cyano, nitrile, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, sulfonamide, aminosulfonyl, aminosulfonyloxy, sulfonamidecarbonyl, alkanoylaminosulfonyl, trihalomethylsulfonyl, or trihalomethylsulfonamide,
• wherein any of the foregoing groups are optionally substituted at least once with alkyl, alkylene, alkenyl, alkenylene, alkynyl, carbocycle, cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl, halo, hydro, hydroxyl, alkoxy, alkynyloxy, cycloalkyloxy, heterocycloxy, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, mercapto, alkylthio, arylthio, cycloalkylthio, arylalkyl, heteroarylalkyl, heteroarylalkenyl, arylalkynyl, haloalkyl, aldehyde, thiocarbonyl, O-carboxy, C-carboxy, carboxylic acid, ester, C-carboxy salt, carboxyalkyl, carboxyalkenylene, carboxyalkyl salt, carboxyalkoxy, carboxyalkoxyalkanoyl, amino, aminoalkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, aminothiocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, cyano, nitrile, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, sulfonamide, aminosulfonyl, aminosulfonyloxy, sulfonamidecarbonyl, alkanoylaminosulfonyl, trihalomethylsulfonyl, or trihalomethylsulfonamide,
• with the proviso that R2 is not heteroaryl;
• or,
• R2 and either R1 or R3, together with the carbon atoms to which they are bound, form an optionally-substituted cycloalkyl, heterocycle, aryl, or heteroaryl;
• R4 is independently chosen from hydro, halo, and an optionally-substituted group chosen from lower alkyl, haloalkyl, alkoxy, arylalkoxy, heteroarylalkoxy, and heterocycloalkoxy;
• R6 and R7 are independently chosen from hydro, halo, and lower alkyl;
• or
• R6, taken together with R7, form an aryl or heteroaryl ring;
• and,
• with the proviso that the compound is NOT:
• 3-(2-{[3-(hydroxymethyl)-4-(morpholin-4-yl)phenyl]amino }primidin-4- benzonitrile (CAS Registry No. 1187660-52-1);
• tert-butyl 1-[5-{[4-(3-cyanophenyl)pyrimidin-2-yl]amino}-2-(morpholin-4-yl)benzyl]-L-prolinate (CAS Registry No. 1187660-08-7);
• 2-hydroxy-5-(2-{[4-(morpholin-4-yl)phenyl]amino}pyrimidin-4-yl)benzonitrile (CAS Registry No. 1056634-86-6);
• 2-fluoro-5-{2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}benzonitrile (CAS Registry No. 1056634-82-2);
• 2-fluoro-5-(2-{[4-(morpholin-4-yl)phenyl]amino}pyrimidin-4-yl)benzonitrile (CAS Registry No. 1056634-78-6);
• 3-(2-{[4-(morpholin-4-yl)phenyl]amino}pyrimidin-4-yl)benzonitrile (CAS Registry No. 1056634-74-2);
• 3-{2-[(4-{[4-hydroxy-4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]sulfonyl}phenyl)amino]pyrimidin-4-yl}benzonitrile (CAS Registry No. 1049105-08-9);
• 3-(2-{[4-(morpholin-4-yl)phenyl]amino}-9H-purin-6-yl)benzonitrile (CAS Registry No. 1042916-08-4);
• 3-{2-[4-methoxyphenyl)amino]pyrimidin-4-yl}benzonitrile (CAS Registry No. 902502-38-9);
• 3-{2-[4-hydroxyphenyl)amino]pyrimidin-4-yl}benzonitrile (CAS Registry No. 839727-81-0);
• 3-{2-[(3-hydroxyphenyl)amino]pyrimidin-4-yl}benzonitrile (CAS Registry No. 839727-80-9);
• 5-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-2-ethoxybenzonitrile (CAS Registry No. 691895-41-7);
• 3-[2-(phenylamino)pyrimidin-4-yl]benzonitrile (CAS Registry No. 663611-44-7);
• or
• 3-(2-{[4-(1,1,2,2-tetrafluoroethoxy)phenyl]amino}pyrimidin-4-yl)benzonitrile (CAS Registry No. 170141-17-0).

A method of making a compound of having a structure according to Formula I:

• wherein:
• R1, R2, R3, and R5 are independently chosen from the following groups:
• alkyl, alkylene,
• alkenyl, alkenylene, alkynyl, carbocycle, cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl, halo, hydro, hydroxyl, alkoxy, alkynyloxy, cycloalkyloxy, heterocycloxy, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, mercapto, alkylthio, arylthio, cycloalkylthio, arylalkyl, heteroarylalkyl, heteroarylalkenyl, arylalkynyl, haloalkyl, aldehyde, thiocarbonyl, O-carboxy, C-carboxy, carboxylic acid, ester, C-carboxy salt, carboxyalkyl, carboxyalkenylene, carboxyalkyl salt, carboxyalkoxy, carboxyalkoxyalkanoyl, amino, aminoalkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, aminothiocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, cyano, nitrile, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, sulfonamide, aminosulfonyl, aminosulfonyloxy, sulfonamidecarbonyl, alkanoylaminosulfonyl, trihalomethylsulfonyl, or trihalomethylsulfonamide,
• wherein any of the foregoing groups are optionally substituted at least once with alkyl, alkylene, alkenyl, alkenylene, alkynyl, carbocycle, cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl, halo, hydro, hydroxyl, alkoxy, alkynyloxy, cycloalkyloxy, heterocycloxy, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, mercapto, alkylthio, arylthio, cycloalkylthio, arylalkyl, heteroarylalkyl, heteroarylalkenyl, arylalkynyl, haloalkyl, aldehyde, thiocarbonyl, O-carboxy, C-carboxy, carboxylic acid, ester, C-carboxy salt, carboxyalkyl, carboxyalkenylene, carboxyalkyl salt, carboxyalkoxy, carboxyalkoxyalkanoyl, amino, aminoalkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, aminothiocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, cyano, nitrile, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, sulfonamide, aminosulfonyl, aminosulfonyloxy, sulfonamidecarbonyl, alkanoylaminosulfonyl, trihalomethylsulfonyl, or trihalomethylsulfonamide,
• with the proviso that R2 is not heteroaryl;
• or,
• R2 and either R1 or R3, together with the carbon atoms to which they are bound, form an optionally-substituted cycloalkyl, heterocycle, aryl, or heteroaryl;
• R4 is independently chosen from hydro, halo, and an optionally-substituted group chosen from lower alkyl, haloalkyl, alkoxy, arylalkoxy, heteroarylalkoxy, and heterocycloalkoxy;
• R6 and R7 are independently chosen from hydro, halo, and lower alkyl;
• or
• R6, taken together with R7, form an aryl or heteroaryl ring, comprising following one of the synthetic schemes disclosed herein.