Substituted bicyclic compounds as bromodomain inhibitors

Abstract

The invention relates to substituted bicyclic compounds, which are useful for inhibition of BET protein function by binding to bromodomains, pharmaceutical compositions comprising these compounds, and use of the compounds and compositions in therapy. ##STR00001##

Claims

1. A method for inhibiting BET proteins in a mammal, comprising administering a therapeutically effective amount of a compound of formula: ##STR00326## or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein: the A-B bicyclic ring is optionally substituted with one or more groups independently selected from deuterium, NH.sub.2, OH, alkyl(C.sub.1-C.sub.6), thioalkyl(C.sub.1-C.sub.6), and alkoxy(C.sub.1-C.sub.9); D.sub.1 is selected from isoxazole and pyrazole optionally substituted with one or more groups independently selected from deuterium, alkyl(C.sub.1-C.sub.4), OH, alkoxy(C.sub.1-C.sub.4), amino, halogen, amide, CF.sub.3, CN, OCF.sub.3, N.sub.3, ketone (C.sub.1-C.sub.4), S(O)Alkyl(C.sub.1-C.sub.4), SO.sub.2alkyl(C.sub.1-C.sub.4), -thioalkyl(C.sub.1-C.sub.4), carboxyl, and/or ester, wherein said alkyl(C.sub.1-C.sub.4), alkoxy(C.sub.1-C.sub.4), amino, amide, ketone (C.sub.1-C.sub.4), S(O)Alkyl(C.sub.1-C.sub.4), SO.sub.2alkyl(C.sub.1-C.sub.4), -thioalkyl(C.sub.1-C.sub.4), and ester may be optionally substituted with F, Cl, Br, OH, NH.sub.2, NHMe, NMe.sub.2, OMe, SMe, oxo, and/or thio-oxo; X is optionally present, and if present, is selected from (NH), O, NHCR.sub.xR.sub.y, NHSO.sub.2, CR.sub.xR.sub.yNH, or NH.sub.2 and R.sub.3 is absent; and R.sub.3 is selected from isoxazolyl, oxazolyl, pyrazolyl, pyridyl, pyridonyl, thiazolyl, isothiazolyl, pyrimidinyl, thiozolyl, pyrazinyl, pyridazinyl, azetidinyl, pyrrolidyl, piperidinyl, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, optionally substituted with one or more groups independently selected from deuterium, alkyl(C.sub.1-C.sub.4), OH, alkoxy(C.sub.1-C.sub.4), amino, halogen, amide, CF.sub.3, CN, OCF.sub.3, N.sub.3, ketone (C.sub.1-C.sub.4), S(O)Alkyl(C.sub.1-C.sub.4), SO.sub.2alkyl(C.sub.1-C.sub.4), -thioalkyl(C.sub.1-C.sub.4), carboxyl, and/or ester, wherein said alkyl(C.sub.1-C.sub.4), alkoxy(C.sub.1-C.sub.4), amino, amide, ketone (C.sub.1-C.sub.4), S(O)Alkyl(C.sub.1-C.sub.4), SO.sub.2alkyl(C.sub.i-C.sub.4), -thioalkyl(C.sub.1-C.sub.4), and ester may be optionally substituted with F, Cl, Br, OH, NH.sub.2, NHMe, NMe.sub.2, OMe, SMe, oxo, and/or thio-oxo.

2. The method of claim 1, wherein D.sub.1 is ##STR00327## and X is absent.

3. A method for inhibiting BET proteins in a mammal, comprising administering a therapeutically effective amount of a compound selected from: 4,4-(1H-benzo[d]imidazole-4,6-diyl)bis(3,5-dimethylisoxazole); 3-(6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-yl)benzonitrile; 4,4-(quinazoline-2,4-diyl)bis(3,5-dimethylisoxazole); N-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine; N-benzyl-2-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; 4,4-(2-methyl-1H-benzo[d]imidazole-4,6-diyl)bis(3,5-dimethylisoxazole); 6-(3,5-dimethylisoxazol-4-yl)-N-phenyl-1H-benzo[d]imidazol-4-amine; 4,4-(imidazo[1,2-a]pyridine-6,8-diyl)bis(3,5-dimethylisoxazole); 3,5-dimethyl-4-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 4,4-(imidazo[1,2-a]pyrazine-6,8-diyl)bis(3,5-dimethylisoxazole); 6,8-bis(3,5-dimethylisoxazol-4-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one; 2-(3,5-dimethylisoxazol-4-yl)-6,7-dimethoxy-N-phenylquinazolin-4-amine; 6,8-bis(3,5-dimethylisoxazol-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine; 3,5-dimethyl-4-(6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-4-yl)isoxazole; 6-(3,5-dimethylisoxazol-4-yl)-N-phenyl-[1,2,4]triazolo[4,3-a]pyridin-8-amine; 3,5-dimethyl-4-(4-(1-methyl-1H-pyrazol-5-O-1H-benzo[d]imidazol-6-yl)isoxazole; 4,4-([1,2,4]triazolo[1,5-a]pyridine-6,8-diyl)bis(3,5-dimethylisoxazole); 4-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 3,5-dimethyl-4-(4-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-6-yl)isoxazole; 3,5-dimethyl-4-(4-(4-methylpyridin-3-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 4,4-(1H-indazole-5,7-diyl)bis(3,5-dimethylisoxazole); 3,5-dimethyl-4-(4-(pyrimidin-5-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 3,5-dimethyl-4-(4-(1-methyl-1H-indazol-4-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; N-benzyl-6-(3,5-dimethylisoxazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-8-amine; 6-(3,5-dimethylisoxazol-4-yl)-N-(4-methoxyphenyl)-1H-benzo[d]imidazol-4-amine; 3,5-dimethyl-4-(4-(4-methylthiazol-5-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 3,5-dimethyl-4-(4-(2-methylpyridin-3-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 1-(2-(6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-yl)phenyl)-N,N-dimethylmethanamine; 3,5-dimethyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 4,6-bis(3,5-dimethylisoxazol-4-yl)-N-methyl-1H-benzo[d]imidazol-2-amine; N-benzyl-4,6-bis(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-amine; 6-(3,5-dimethylisoxazol-4-yl)-N-(3-fluorophenyl)-1H-benzo[d]imidazol-4-amine; 6-(3,5-dimethylisoxazol-4-yl)-N-(3-methoxyphenyl)-1H-benzo[d]imidazol-4-amine; 4,4-(2-(trifluoromethyl)-1H-benzo[d]imidazole-4,6-diyl)bis(3,5-dimethylisoxazole); 6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-3-ylmethyl)-1H-benzo[d]imidazol-4-amine; 3-(6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-yl)benzamide; 6-(3,5-dimethylisoxazol-4-yl)-N-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1H-benzo[d]imidazol-4-amine; 6-(3,5-dimethylisoxazol-4-yl)-N-(4-fluorobenzyl)-1H-benzo[d]imidazol-4-amine; 6-(3,5-dimethylisoxazol-4-yl)-N-((3,5-dimethylisoxazol-4-yl)methyl)-1H-benzo[d]imidazol-4-amine; N-(4-chlorophenyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine; 3,5-dimethyl-4-(2-methyl-4-(2-methylpyridin-3-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; N-(6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-yl)-3,5-dimethylisoxazol-4-amine; 6-(3,5-dimethylisoxazol-4-yl)-N-(pyrimidin-2-yl)-1H-benzo[d]imidazol-4-amine; N-(6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-yl)-4-methylisoxazol-3-amine; 4,4-(2-isopropyl-1H-benzo[d]imidazole-4,6-diyl)bis(3,5-dimethylisoxazole); 4,4)-(2-ethoxy-1H-benzo[d]imidazole-4,6-diyl)bis(3,5-dimethylisoxazole); 6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-amine; 4-(4-(2-methoxypyridin-3-yl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 3,5-dimethyl-4-(2-methyl-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 3,5-dimethyl-4-(2-methyl-4-(4-(trifluoromethyl)pyridin-3-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 4-(4-(2-methoxy-5-methylphenyl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 3,5-dimethyl-4-(2-methyl-7-(3-methylisothiazol-4-yl)-1H-benzo[d]imidazol-5-yl)isoxazole; 3,5-dimethyl-4-(2-methyl-4-(4-methylpyridin-3-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 4,4-(1-methyl-1H-indazole-5,7-diyl)bis(3,5-dimethylisoxazole); 4,4-(2-methyl-2H-indazole-5,7-diyl)bis(3,5-dimethylisoxazole); 3-(6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-yl)pyridin-2(1H)-one; 3-(6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-yl)-2-methylbenzonitrile; 3-(6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)-4-methylbenzonitrile; 3,5-dimethyl-4-(2-methyl-4-(2-trifluoromethyl)pyridin-3-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 4-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 3-(6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)isonicotinonitrile; 6-(3,5-dimethylisoxazol-4-yl)-N-(pyrazin-2-yl)-1H-benzo[d]imidazol-4-amine; 6-(3,5-dimethylisoxazol-4-yl)-2-methyl-N-(3-methylpyridin-2-yl)-1H-benzo[d]imidazol-4-amine; N-(2-(6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)phenyl)acetamide; 4,6-bis(3,5-dimethylisoxazol-4-yl)-N-(pyridin-3-ylmethyl)-1H-benzo[d]imidazol-2-amine; 4-(4-(1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 4-(5-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-7-yl)-N,3-dimethylisoxazole-5-carboxamide; 5-(6-(3,5-dimethylisoxazol-4-yl)-2-ethyl-1H-benzo[d]imidazol-4-yl)-6-methylpyridin-2-amine; 3,5-dimethyl-4-(2-methyl-4-(2-(methylsulfonyl)phenyl)-1H-benzo[d]imidazol-6-yl)isoxazole; 3,5-dimethyl-4-(7-(2-methylpyridin-3-yl)-1H-indazol-5-yl)isoxazole; 2-(6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)benzonitrile; 4-(4-(4-methoxypyridin-3-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 3-(6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-yl)-2-methylbenzamide; 3-(6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazole-4-yl)-4-methylbenzamide; 3-(6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)-4-methylbenzoic acid; 4,4-(2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-5,7-diyl)bis(3,5-dimethylisoxazole); 3,5-diethyl-4-(2-methyl-4-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)isoxazole; 3,5-dimethyl-4-(2-methyl-4-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-6-yl)isoxazole; 3,5-dimethyl-4-(2-methyl-4-(pyridin-3-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 4-(4-(5-fluoro-2-(trifluoromethyl)phenyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 4-2-ethoxy-4-(2-methylpyridin-3-yl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 3-(6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)pyridin-2-amine; 2-(6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)-6-fluorobenzonitrile; 3,5-dimethyl-4-(2-methyl-4-(3-methylpyridin-2-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 3,5-dimethyl-4-(2-methyl-4-(pyrazin-2-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 3,5-dimethyl-4-(2-methyl-4-(6-methylpyridazin-3-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 4,4-(1H-indazole-4,6-diyl)bis(3,5-dimethylisoxazole); 3,5-dimethyl-4-(2-methyl-4-phenyl-1H-benzo[d]imidazol-6-yl)isoxazole; 3,5-dimethyl-4-(2-methyl-4-O-tolyl)-1H-benzo[d]imidazol-6-yl)isoxazole; 4-(4-(4-chloro-2-methylphenyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 4-(4-(2-fluorophenyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 4-(4-(5-fluoro-2-methylphenyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 4,4-(1-methyl-1H-benzo[d]imidazole-5,7-diyl)bis(3,5-dimethylisoxazole); 2-(6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)-4-fluorobenzonitrile; 4,4-(1H-benzo[d][1,2,3]triazole-4,6-diyl)bis(3,5-dimethylisoxazole); 3,5-dimethyl-4-(2-methyl-4-(3-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)isoxazole; 4-(4-(3,5-dimethylpyridin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 4-(4-(4,6-dimethylpyrimidin-5-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 5-(6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)-4,6-dimethylpyrimidin-2-amine; 6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-4-(2-methylpyridin-3-yl)-1H-benzo[d]imidazol-2-amine; 5,7-bis(3,5-dimethylisoxazol-4-yl)-2-methylbenzo[d]oxazole; N-(6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-yl)-2-methoxybenzenesulfonamide; 4-(4-(benzo[d][1,3]dioxol-5-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 3,5-dimethyl-4-(2-methyl-4-(4-methylthiazol-5-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 4-(4-(5-chloro-2-methylphenyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 4-(4-(2-fluoro-3-methylphenyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 4-(4-(5-chloro-2-methoxyphenyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 4-(4-(2-fluoro-5-methoxyphenyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 4-(4-(2-ethoxypyridin-3-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 4-(4-(isoquinolin-8-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 3,5-dimethyl-4-(2-methyl-4-(quinolin-8-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 4-(4-(5-fluoro-2-methoxyphenyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 3,5-dimethyl-4-(2-methyl-4-(5-methylthiazol-4-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 4-(4-(2-methoxy-4-methylpyridin-3-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 3,5-dimethyl-4-(2-methyl-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 4,6-bis(3,5-dimethylisoxazol-4-yl)-N,N-dimethyl-1H-benzo[d]imidazol-2-amine; 4-(4-(2-(methoxymethyl)phenyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 4-(4-(2-methoxypyridin-3-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 3,5-dimethyl-4-(7-(4-methylpyridin-3-yl)-1H-indazol-5-yl)isoxazole; 4-(7-(1,3-dimethyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3,5-dimethylisoxazole; 1-(6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)-5-methylpyrrolidin-2-one; 1-(6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)piperidin-2-one; 3-(6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)-2-methylbenzonitrile; 4-(4-(benzo[d]thiazol-5-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 4-(4-(5-fluoro-4-methylpyridin-3-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 3-(6(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)-2-methylbenzamide; 3,5-dimethyl-4-(7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)isoxazole; 3,5-dimethyl-4-(7-(2-(trifluoromethyl)pyridin-3-yl)-1H-indazol-5-yl)isoxazole; 3,5-dimethyl-4-(7-(4-(trifluoromethyl)pyridin-3-yl)-1H-indazol-5-ylisoxazole; 4-(4-(3,5-dichloropyridin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 4-(4-(5-fluoro-2-methoxypyridin-3-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 4-(4-(3,4-difluoro-2-methylphenyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 4,6-bis(1,3-dimethyl-1H-pyrazol-4-yl)-2-methyl-1H-benzo[d]imidazole; 2-methyl-4,6-bis(1-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazole; 4-(4-(2-methoxy-6-methylpyridin-3-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 5-(6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)benzo[d]oxazole; 4-(4-(benzo[d]isothiazol-5-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 3,5-dimethyl-4-(2-methyl-4-(naphthalen-1-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 4,4-(2-methyl-1H-benzo[d]imidazole-4,6-diyl)bis(3-methylisothiazole); 4,4-(3-methyl-1H-indole-4,6-diyl)bis(3,5-dimethylisoxazole); 2-methyl-4,6-bis(4-methylthiophen-3-yl)-1H-benzo[d]imidazole; 6-(3,5-dimethylisoxazol-4-yl)-N-phenethyl-1H-benzo[d]imidazol-4-amine; 6-(3,5-dimethylisoxazol-4-yl)-2-methyl-N-(2-methylpyridin-3-yl)-1H-benzo[d]imidazol-4-amine; 4-(4-(2-chlorophenyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 4-(4-(benzo[b]thiophen-2-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 6-(3,5-dimethylisoxazol-4-yl)-2-methyl-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-4-amine; 1-(6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)azetidin-2-one; 3,5-dimethyl-4-(2-methyl-4-phenoxy-1H-benzo[d]imidazol-6-yl)isoxazole; 6,8-bis(3,5-dimethylisoxazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-((4,6-bis(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)amino)ethanol; 6-(3,5-dimethylisoxazol-4-yl)-N,N-diphenethyl-1H-benzo[d]imidazol-4-amine; 4-(4-(2-fluoro-3-methoxyphenyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 3,5-dimethyl-4-(2-methyl-4-(quinoxalin-6-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 3,5-dimethyl-4-(2-methyl-4-(3-(methylsulfonyl)phenyl)-1H-benzo[d]imidazol-6-yl)isoxazole; 3,5-dimethyl-4-(2-methyl-4-((2-methylpyridin-3-yl)oxy)-1H-benzo[d]imidazol-6-yl)isoxazole; 4-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 4-(4-(2-fluoro-5-(trifluoromethyl)phenyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; (E)-3,5-dimethyl-4-(2-methyl-4-styryl-1H-benzo[d]imidazol-6-yl)isoxazole; 4,4-(quinoxaline-5,7-diyl)bis(3,5-dimethylisoxazole); 4,6-di(furan-3-yl)-2-methyl-1H-benzo[d]imidazole; 3,5-dimethyl-4-(2-methyl-4-phenethyl-1H-benzo[d]imidazol-6-yl)isoxazole; 4-(4-(2-chloro-5-(trifluoromethyl)phenyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 3,5-dimethyl-4-(2-methyl-4-(quinolin-3-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 2-methyl-4,6-di(1H-pyrrol-3-yl)-1H-benzo[d]imidazole; N-(6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)benzamide; 3,5-dimethyl-4-(2-methyl-4-(4-methylthiophen-3-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 4,6-bis(1,4-dimethyl-1H-pyrazol-5-yl)-2-methyl-1H-benzo[d]imidazole; 5,5-(2-methyl-1H-benzo[d]imidazole-4,6-diyl)bis(2,4-dimethylthiazole); 4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 4-(4-(2,4-dimethylthiazol-5-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 4-(4-((4-methoxypyridin-3-yl)oxy)-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole; 3-((6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)oxy)-4-methylbenzonitrile; 4-(6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)morpholine; 3-((6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)oxy)-4-methylbenzamide; 3-((6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)oxy)-4-methylbenzoic acid; 4,4-(2-methyl-3H-imidazo[4,5-b]pyridine-5,7-diyl)bis(3,5-dimethylisoxazole); 4-(6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)-3-methylmorpholine; 4-(6-(1,4-dimethyl-1H-pyrazol-5-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)-3,5-dimethylisoxazole; 4,4-(3-methyl-1H-indazole-4,6-diyl)bis(3,5-dimethylisoxazole); 4-(4(3,5-dimethyl-1H-pyrazol-4-yl)-3-methyl-1H-indazol-6-yl)-3, dimethylisoxazole; 3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 3,5-dimethyl-4-(1-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-5-yl)isoxazole; 3-dimethyl-4-(2-(4-methylpiperazin-1-yl)-4-(2-methylpyridin-3-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 4-(6-(3,5-dimethylisoxazol-4-yl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-yl)morpholine; 6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylpiperidin-4-yl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine; 3-(6-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin-1H-yl)-1H-benzo[d]imidazol-4-yl)-4-methylbenzonitrile; 3,5-dimethyl-4-(2-(methylthio)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 3,5-dimethyl-4-(1-methyl-2-(methylthio)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 3-(6-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin-1H-yl)-1H-benzo[d]imidazol-4-yl)-4-methylbenzamide; 6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine; 3,5-dimethyl-4-(1-methyl-2-(methylthio)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-5-yl)isoxazole; 4,4-(7-bromo-1H-benzo[d]imidazole-4,6-diyl)bis(3,5-dimethylisoxazole); 3-(6-(3,5-dimethylisoxazol-4-yl)-2-morpholino-1H-benzo[d]imidazol-4-yl)-4-methylbenzonitrile; 3,5-dimethyl-4-(2-(methylsulfinyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-5-yl)isoxazole; 3,5-dimethyl-4-(2-(methylsulfonyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-5-yl)isoxazole; 4-(6-(3,5-dimethylisoxazol-4-yl)-4-(4-methylpyridin-3-yl)-1H-benzo[d]imidazol-2-yl)morpholine; 3-(6-(3,5-dimethylisoxazol-4-yl)-2-morpholino-1H-benzo[d]imidazol-4-yl)-4-methylbenzamide; 3-(6-(3,5-dimethylisoxazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)-1H-benzo[d]imidazol-4-yl)-4-methylbenzonitrile; 3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)-4-(4-methylpyridin-3-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 3-(6-(3,5-dimethylisoxazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)-1H-benzo[d]imidazol-4-yl)-4-methylbenzamide; 6-(3,5-dimethylisoxazol-4-yl)-4-(4-methylpyridin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-amine; 3-(6-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-4-yl)-2-methylbenzonitrile; 3-(6-(3,5-dimethylisoxazol-4-yl)-2-morpholino-1H-benzo[d]imidazol-4-yl)-2-methylbenzonitrile; 3-(6-(3,5-dimethylisoxazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)-1H-benzo[d]imidazol-4-yl)-2-methylbenzonitrile; 3-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-methylpiperidin-4-yl)amino)-1H-benzo[d]imidazol-4-yl)-4-methylbenzonitrile; 3-(6-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-4-yl)-2-methylbenzamide; 3-(6-(3,5-dimethylisoxazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)-1H-benzo[d]imidazol-4-yl)-2-methylbenzamide; 3-(6-(3,5-dimethylisoxazol-4-yl)-2-morpholino-1H-benzo[d]imidazol-4-yl)-2-methylbenzamide; 3-(2-(4-aminopiperidin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-yl)-2-methylbenzonitrile; 3-(2-(benzylamino)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-yl)-4-methylbenzonitrile; 3-(6-(3,5-dimethylisoxazol-4-yl)-2-((pyridin-3-ylmethyl)amino)-1H-benzo[d]imidazol-4-yl)-4-methylbenzonitrile; N-benzyl-6-(3,5-dimethylisoxazol-4-yl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine; 3,5-dimethyl-4-(2-(pyrrolidin-1-yl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 6-(3,5-dimethylisoxazol-4-yl)-N-methyl-4-(4-methylpyridin-3-yl)-1H-benzo[d]imidazol-2-amine; 3-(6-(3,5-dimethylisoxazol-4-yl)-2-(pyrrolidin-1H-benzo[d]imidazol-4-yl)-4-methylbenzonitrile; 3-(6-(3,5-dimethylisoxazol-4-yl)-2-((1-methylpiperidin-4-yl)amino)-1H-benzo[d]imidazol-4-yl)-2-methylbenzonitrile; 4-(2-(azetidin-1-yl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-6-yl)3,5-dimethylisoxazole; (3-(6-(3,5-dimethylisoxazol-4-yl)-2-(pyrrolidin-1-yl)-1H-benzo[d]imidazol-4-yl)-4-methylphenyl)(pyrrolidin-1-yl)methanone; 3-(6-(3,5-dimethylisoxazol-4-yl)-2-((pyridin-3-ylmethyl)amino)-1H-benzo[d]imidazol-4-yl)-4-methylbenzamide; 3-(2-(benzylamino)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-yl)-4-methylbenzamide; 6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-3-ylmethyl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine; N-benzyl-6-(3,5-dimethylisoxazol-4-yl)-4-(4-methylpyridin-3-yl)-1H-benzo[d]imidazol-2-amine; 6-(3,5-dimethylisoxazol-4-yl)-4-(4-methylpyridin-3-yl)-N-(pyridin-3-ylmethyl)-1H-benzo[d]imidazol-2-amine; 3,5-dimethyl-4-(4-(4-methylpyridin-3-yl)-2-(pyrrolidin-1-yl)-1H-benzo[d]imidazol-6-yl)isoxazole; 3-amino-5-(6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-yl)-1-methylpyridin-2(1H)-one; 4-(4,6-bis(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)morpholine; 4,4-(5-methoxy-2-methyl-1H-benzo[d]imidazole-4,6-diyl)bis(3,5-dimethylisoxazole); 4,4-(2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole-4,6-diyl)bis(3,5-dimethylisoxazole); 4,6-bis(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-amine; 3,5-dimethyl-4-(5-(1-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-7-yl)isoxazole; 4,4-(2-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazole-4,6-diyl)bis(3,5-dimethylisoxazole); 4,6-bis(3,5-dimethylisoxazol-4-yl)-N-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-amine; 4,6-bis(3,5-dimethylisoxazol-4-yl)-N-(piperidin-4-yl)-1H-benzo[d]imidazol-2-amine; and stereoisomers, tautomers, pharmaceutically acceptable salts, and hydrates thereof.

4. The method of claim 3, wherein the method further comprises treating insulin resistance diabetes.

5. The method according to claim 3, wherein the method further comprises treating a disease or disorder selected from Acute Disseminated Encephalomyelitis, Agammaglobulinemia, Allergic Disease, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Anti-phospholipid syndrome, Autoimmune aplastic anemia, Autoimmune hepatitis, Autoimmune inner ear disease, Autoimmune myocarditis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune thrombocytopenic purpura, Behcet's Disease, Bullous pemphigoid, Castleman's Disease, Celiac Disease, Churg-Strauss syndrome, Crohn's Disease, Cogan's syndrome, Dry eye syndrome, Essential mixed cryoglobulinemia, Dermatomyositis, Devic's Disease, Encephalitis, Eosinophilic esophagitis, Eosinophilic fasciitis, Erythema nodosum, Giant cell arteritis, Glomerulonephritis, Goodpasture's syndrome, Granulomatosis with Polyangiitis (Wegener's), Graves' Disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura, IgA nephropathy, Inclusion body myositis, Type I diabetes, Interstitial cystitis, Kawasaki's Disease, Leukocytoclastic vasculitis, Lichen planus, Lupus (SLE), Microscopic polyangitis, Multiple sclerosis, Myasthenia gravis, myositis, Optic neuritis, Pemphigus, POEMS syndrome, Polyarteritis nodosa, Primary biliary cirrhosis, Psoriasis, Psoriatic arthritis, Pyoderma gangrenosum, Relapsing polychondritis, Rheumatoid arthritis, Sarcoidosis, Scleroderma, Sjogren's syndrome, Takayasu's arteritis, Transverse myelitis, Ulcerative colitis, Uveitis, and Vitiligo.

6. The method of claim 3, wherein the method further comprises treating a disease or disorder selected from sinusitis, pneumonitis, osteomyelitis, gastritis, enteritis, gingivitis, appendicitis, irritable bowel syndrome, tissue graft rejection, chronic obstructive pulmonary disease (COPD), septic shock, toxic shock syndrome, SIRS, bacterial sepsis, osteoarthritis, acute gout, acute lung injury, acute renal failure, burns, Herxheimer reaction, and SIRS associated with viral infections.

7. The method of claim 3, wherein the method further comprises treating a disease or disorder selected from dyslipidemia, atherosclerosis, hypercholesterolemia, and metabolic syndrome.

8. The method of claim 3, wherein the method further comprises treating a disease or disorder selected from Alzheimer's disease, Parkinson's disease, Huntington disease, bipolar disorder, schizophrenia, Rubinstein-Taybi syndrome, and epilepsy.

9. The method of claim 3, further comprising a method of male contraception.

10. The method of claim 3, wherein the method further comprises treating a cancer selected from B-acute lymphocytic leukemia, Burkitt's lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, atypical carcinoid lung cancer, bladder cancer, breast cancer, cervix cancer, colon cancer, gastric cancer, glioblastoma, hepatocellular carcinoma, large cell neuroendocrine carcinoma, medulloblastoma, melanoma, nodular melanoma, neuroblastoma, esophageal squamous cell carcinoma, osteosarcoma, ovarian cancer, prostate cancer, renal clear cell carcinoma, retinoblastoma, rhabdomyosarcoma, small cell lung carcinoma, NUT midline carcinoma, B-cell lymphoma, non-small cell lung cancer, head and neck squamous cell carcinoma, chronic lymphocytic leukemia, follicular lymphoma, diffuse large B cell lymphoma with germinal center phenotype, Hodgkin's lymphoma, activated anaplastic large cell lymphoma, primary neuroectodermal tumor, pancreatic cancer, adenoid cystic carcinoma, T-cell prolymphocytic leukemia, malignant glioma, thyroid cancer, Barret's adenocarcinoma, hepatoma, pro-myelocytic leukemia, and mantle cell lymphoma.

11. The method of claim 3, wherein the method further comprises treating a cancer that: (a) exhibits overexpression, translocation, amplification, or rearrangement of a myc family oncoprotein; (b) results from aberrant regulation of BET proteins; (c) relies on pTEFb (Cdk9/cyclin T) and BET proteins to regulate oncogenes; (d) associated with upregulation of BET responsive genes CDK6, Bcl2, TYRO3, MYB and/or hTERT; and/or (e) is associated with a viral infection.

12. The method of claim 11, wherein: (a) the cancer exhibiting overexpression, translocation, amplification, or rearrangement of a myc family oncoprotein is selected from B-acute lymphocytic leukemia, Burkitt's lymphoma, Diffuse large cell lymphoma, Multiple myeloma, Primary plasma cell leukemia, Atypical carcinoid lung cancer, Bladder cancer, Breast cancer, Cervix cancer, Colon cancer, Gastric cancer, Glioblastoma, Hepatocellular carcinoma, Large cell neuroendocrine carcinoma, Medulloblastoma, Melanoma, nodular, Melanoma, superficial spreading, Neuroblastoma, esophageal squamous cell carcinoma, Osteosarcoma, Ovarian cancer, Prostate cancer, Renal clear cell carcinoma, Retinoblastoma, Rhabdomyosarcoma, and Small cell lung carcinoma; (b) the cancer resulting from aberrant regulation of BET proteins is selected from NUT midline carcinoma, B-cell lymphoma, non-small cell lung cancer, esophageal cancer, head and neck squamous cell carcinoma, and colon cancer; (c) the cancer relying on pTEFb (Cdk9/cyclin 7) and BET proteins to regulate oncogenes is selected from chronic lymphocytic leukemia and multiple myeloma, follicular lymphoma, diffuse large B cell lymphoma with germinal center phenotype, Burkitt's lymphoma, Hodgkin's lymphoma, anaplastic large cell lymphoma, neuroblastoma and primary neuroectodermal tumor, rhabdomyosarcoma, prostate cancer, and breast cancer; (d) the cancer associated with upregulation of BET responsive genes CDK6, Bcl2, TYRO3, MYB, and hTERT is selected from pancreatic cancer, breast cancer, colon cancer, glioblastoma, adenoid cystic carcinoma, T-cell prolymphocytic leukemia, malignant glioma, bladder cancer, medulloblastoma, thyroid cancer, melanoma, multiple myeloma, Barret's adenocarcinoma, hepatoma, prostate cancer, pro-myelocytic leukemia, chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, small cell lung cancer, and renal carcinoma; and/or (e) the viral infection is selected from Epstein-Barr Virus, hepatitis B virus, hepatitis C virus, Kaposi's sarcoma associated virus, human papilloma virus, Merkel cell polyomavirus, and human cytomegalovirus.

13. The method of claim 10, wherein the compound of Formula II is administered in combination with another anticancer agent.

14. The method of claim 13, wherein the anticancer agent is selected from ABT-737, Azacitidine (Vidaza), AZD1152 (Barasertib), AZD2281 (Olaparib), AZD6244 (Selumetinib), BEZ235, Bleomycin Sulfate, Bortezomib (Velcade), Busulfan (Myleran), Camptothecin, Cisplatin, Cyclophosphamide (Clafen), CYT387, Cytarabine (Ara-C), Dacarbazine, DAPT (GSI-IX), Decitabine, Dexamethasone, Doxorubicin (Adriamycin), Etoposide, Everolimus (RAD001), Flavopiridol (Alvocidib), Ganetespib (STA-9090), Gefitinib (Iressa), Idarubicin, Ifosfamide (Mitoxana), IFNa2a (Roferon A), Melphalan (Alkeran), Methazolastone (temozolomide), Metformin, Mitoxantrone (Novantrone), Paclitaxel, Phenformin, PKC412 (Midostaurin), PLX4032 (Vemurafenib), Pomalidomide (CC-4047), Prednisone (Deltasone), Rapamycin, Revlimid (Lenalidomide), Ruxolitinib (INCB018424), Sorafenib (Nexavar), SU11248 (Sunitnib), SU11274, Vinblastine, Vincristine (Oncovin), Vinorelbine (Navelbine), Vorinostat (SAHA), and WP1130 (Degrasyn).

Description

EXAMPLES

(1) General Methods:

(2) Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance spectra were obtained on a Bruker AVANCE 300 spectrometer at 300 MHz or Bruker AVANCE 500 spectrometer at 500 MHz. Spectra are given in ppm () and coupling constants, J values, are reported in hertz (Hz). Tetramethylsilane was used as an internal standard for .sup.1H nuclear magnetic resonance. Mass spectra analyses were performed on Waters Aquity UPLC Mass Spectrometer in ESI or APCI mode when appropriate, Agilent 6130A Mass Spectrometer in ESI, APCI, or MultiMode mode when appropriate or Applied Biosystems API-150EX Spectrometer in ESI or APCI mode when appropriate. Silica gel chromatographys were in general performed on a Teledyne Isco CombiFlash Rf 200 system or a Teledyne Isco CombiFlash Companion system.

(3) General Procedure A:

4,4-(2-methyl-1H-benzo[d]imidazole-4,6-diyl)bis(3,5-dimethylisoxazole) (Example Compound 6)

(4) ##STR00041##

(5) To a solution of 1 (250 mg, 0.86 mmol) in 1,4-dioxane (15 mL) and water (2 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (540 mg, 2.41 mmol), sodium carbonate (180 mg, 1.70 mmol) and tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.043 mmol). The reaction mixture was purged with nitrogen for 5 min and heated to 90 C. for 16 h. The mixture was diluted with methylene chloride (20 mL) and washed with brine (15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-100% ethyl acetate/hexanes) afforded Example Compound 6 (166 mg, 60%) as an off-white solid: .sup.1H NMR (300 MHz, CD.sub.3OD) 7.47 (s, 1H), 7.05 (d, J=1.5 Hz, 1H), 2.58 (s, 3H), 2.44 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H), 2.22 (s, 3H); ESI MS m/z 323 [M+H].sup.+.

(6) General Procedure B:

Preparation of N-benzyl-2-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example Compound 5)

(7) ##STR00042##

(8) Step 1:

(9) To a solution of 3 (100 mg, 0.50 mmol) in THF (2 mL) was added triethylamine (0.08 mL, 0.6 mmol) and benzylamine (53 mg, 0.50 mmol). The mixture was stirred at room temperature for 16 h, concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate/hexanes) to give 4 (122 mg, 90%) as a yellow solid: ESI m/z 270 [M+H].sup.+.

(10) Step 2:

(11) To a solution of 4 (54 mg, 0.20 mmol) in 1,4-dioxane (2 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (67 mg, 0.30 mmol), potassium phosphate (85 mg, 0.40 mmol) and tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.02 mmol). The reaction mixture was purged with nitrogen and heated at 90 C. for 16 h. The mixture was diluted with methylene chloride (30 mL) and washed with brine (210 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-100% ethyl acetate/hexanes) afforded Example Compound 5 (54 mg, 82%) as a white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 7.85 (d, J=7.5 Hz, 1H), 7.75-7.68 (m, 2H), 7.44-7.36 (m, 5H), 7.34-7.31 (m, 1H), 5.93 (s, 1H), 4.91 (d, J=5.0 Hz, 2H), 2.80 (s, 3H), 2.64 (s, 3H); ESI m/z 331 [M+H].sup.+.

(12) General Procedure C:

Preparation of N-benzyl-6-(3,5-dimethylisoxazol-4-yl)-[1,2,4]triazolo[4,3-o]pyridin-8-amine (Example Compound 24)

(13) ##STR00043##

(14) Step 1:

(15) To a solution of 5 (86 mg, 0.40 mmol) in DMF (2 mL) was added potassium carbonate (124 mg, 0.9 mmol) and benzyl bromide (68 mg, 0.40 mmol). The mixture was heated at 90 C. in a sealed tube for 16 h. After cooling to room temperature, the mixture was filtered through a celite plug, concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate/hexanes) to give 6 (41 mg, 90%) as a white solid: ESI m/z 303 [M+H].sup.+.

(16) Step 2:

(17) To a solution of 6 (36 mg, 0.20 mmol) in 1,4-dioxane (1 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (38 mg, 0.14 mmol), sodium carbonate (2.0 M in H.sub.2O, 0.1 mL, 0.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.01 mmol). The reaction mixture was purged with nitrogen and heated at 90 C. for 16 h. The mixture was diluted with methylene chloride (30 mL) and washed with brine (210 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-100% ethyl acetate/hexanes) afforded Example Compound 24 (11 mg, 29%) as a white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.30 (s, 1H), 7.88 (s, 1H), 7.40-7.34 (m, 4H), 7.31-7.28 (m, 1H), 6.12 (s, 1H), 4.55 (s, 2H), 2.28 (s, 3H), 2.10 (s, 3H); ESI m/z 320 [M+H].sup.+.

(18) General Procedure D:

Preparation of 3,5-dimethyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-6-yl)isoxazole (Example Compound 16)

(19) ##STR00044##

(20) Step 1:

(21) To a solution of 7 (1.00 g, 4.61 mmol) in 1,4-dioxane (40 ml) and water (4 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (1.23 g, 5.53 mmol), potassium carbonate (1.27 g, 9.22 mmol), and tetrakis(triphenylphosphine)palladium(0) (266 mg, 0.231 mmol). The reaction mixture was purged with nitrogen and heated at 90 C. for 16 h. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-30% ethyl acetate/hexanes) to give 8 (950 mg, 88%) as a yellow solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.02 (d, J=2.1 Hz, 1H), 7.26 (dd, J=2.1 Hz, 8.5 Hz, 1H), 6.89 (d, J=8.6 Hz, 1H), 6.14 (s, 2H), 2.40 (s, 3H), 2.26 (s, 3H); ESI m/z 234 [M+H].sup.+.

(22) Step 2:

(23) To a solution of 8 (940 mg, 4.03 mmol) in acetic acid (15 mL) at 0 C. was added N-bromosuccinimide (753 mg, 4.23 mmol). The reaction was warmed to room temperature and stirred for 16 h. The mixture was concentrated in vacuo. The residue was suspended in hot MeOH, cooled to room temperature and was basified with 10% aq. NaHCO.sub.3. The mixture was diluted with water and filtered. The solid was washed with water and dried in vacuo to afford 9 (1.10 g, 87%) as a yellow solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.04 (d, J=2.1 Hz, 1H), 7.61 (d, J=2.1 Hz, 1H), 6.69 (bs, 2H), 2.40 (s, 3H), 2.26 (s, 3H); ESI m/z 312 [M+H].sup.+.

(24) Step 3:

(25) To a solution of 9 (1.09 g, 3.49 mmol) in tetrahydrofuran (30 mL) was added sodium dithionite (4.86 g, 28.0 mmol) in water (15 mL). The reaction mixture was stirred at room temperature for 16 h and concentrated under vacuum. The residue was dissolved in MeOH/water (1:1, 150 mL) and the solid was precipitated by removing some MeOH under vacuum. The solid was filtered, washed with water and dried under vacuum to afford 10 (440 mg, 45%) as a yellow solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 6.85 (d, J=1.8 Hz, 1H), 6.51 (d, J=1.8 Hz, 1H), 4.00-3.60 (bs, 2H), 3.60-3.30 (bs, 2H), 2.36 (s, 3H), 2.23 (s, 3H); ESI m/z 282 [M+H].sup.+.

(26) Step 4:

(27) To a solution of 10 (490 mg, 1.74 mmol) in methanol (15 mL) was added trimethyl orthoformate (276 mg, 2.61 mmol) and sulfamic acid (9 mg, 0.09 mmol). The reaction was stirred at room temperature for 5 h. The reaction mixture was diluted with water (50 mL), basified with NaHCO.sub.3 and filtered. The solid was washed with water and dried in vacuo to give 11a (440 mg, 87%) as a yellow solid: .sup.1H NMR (500 MHz, DMSO-d.sub.6) 12.99 (s, 0.3H), 12.84 (s, 0.7H), 8.35 (s, 1H), 7.67 (s, 0.3H), 7.51 (s, 0.7H), 7.43 (s, 0.3H), 7.74 (s, 0.7H), 2.40 (s, 3H), 2.22 (s, 3H); ESI m/z 292 [M+H].sup.+.

(28) 11b was prepared by following the similar method as 11a using triethylorthoacetate: .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.82 (br.s, 1H), 7.42 (d, J=1.5 Hz, 1H), 7.31 (d, J=1.5 Hz, 1H), 2.52 (s, 3H), 2.40 (s, 3H), 2.24 (s, 3H).

(29) Step 5:

(30) To a solution of 11a (60 mg, 0.21 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (66 mg, 0.32 mmol), potassium carbonate (58 mg, 0.42 mmol), and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.011 mmol). The reaction mixture was purged with nitrogen and heated at 90 C. for 16 h. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-20% ethyl acetate/MeOH). It was further purified by reverse phase HPLC eluting with 10-90% CH.sub.3CN in H.sub.2O to give Example Compound 16 (49 mg, 80%) as an off-white solid: .sup.1H NMR (500 MHz, DMSO-d.sub.6) 12.90-12.40 (bs, 1H), 8.33 (s, 1H), 7.90-7.50 (m, 2H), 7.22 (s, 1H), 6.54 (d, J=1.7 Hz, 1H), 3.87 (s, 3H), 2.44 (s, 3H), 2.27 (s, 3H); ESI m/z 294 [M+H].sup.+.

(31) General Procedure E:

Preparation of 6-(3,5-dimethylisoxazol-4-yl)-N-(4-methoxyphenyl)-1H-benzo[d]imidazol-4-amine (Example Compound 25)

(32) ##STR00045##

(33) Step 1:

(34) To a suspension of 11a (1.30 g, 4.47 mmol) in DCM (40 mL) was added di-tert-butyl dicarbonate (1.17 g, 5.36 mmol) and DMAP (54 mg, 0.45 mmol). The mixture was stirred at rt for 2 h, concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate/hexanes) to give 12 (1.64 g, 94%) as a white foam: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.50 (s, 1H), 7.88 (s, 1H), 7.89 (d, J=1.5 Hz, 1H), 7.44 (d, J=1.5 Hz, 1H), 2.45 (s, 3H), 2.30 (s, 3H), 1.70 (s, 1H).

(35) Step 2:

(36) To a solution of 12 (100 mg, 0.25 mmol) in dioxane (3 mL) was added 4-methoxyaniline (61 mg, 0.50 mmol), BINAP (31 mg, 0.05 mmol), cesium carbonate (163 mg, 0.5 mmol) and palladium acetate (17 mg, 0.025 mmol). The reaction mixture was purged with nitrogen for five minutes and heated at 105 C. for 16 h. The mixture was diluted with methylene chloride (30 mL) and washed with brine (210 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-100% ethyl acetate/hexanes) afforded 13 (45 mg, 42%) as a white solid: ESI m/z 435 [M+H].sup.+.

(37) Step 3:

(38) To a solution of 13 (45 mg, 0.10 mmol) in DCM (1 mL) was added TFA (1 mL). The reaction mixture was stirred at rt for 1 h. The mixture was concentrated, neutralized with 2 N NaOH (3 mL), and extracted with methylene chloride. The extracts were dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-10% methanol/methylene chloride) afforded Example Compound 25 (8 mg, 24%) as a white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.55 (s, 1H), 7.21 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 6.74 (s, 1H), 6.73 (s, 1H), 3.20 (s, 3H), 2.36 (s, 3H), 2.22 (s, 3H); ESI m/z 335 [M+H].sup.+.

(39) General Procedure F:

Preparation of 4-(4,6-bis(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)morpholine (Example Compound 226)

(40) ##STR00046##

(41) Step 1:

(42) To a solution of 14 (2.67 g, 10.08 mmol) in 1,4-dioxane (80 mL) and water (20 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (6.69 g, 30.0 mmol), tetrakis(triphenylphosphine)palladium(0) (1.16 mg, 1.0 mmol) and sodium carbonate (4.24 g, 40.0 mmol). The reaction mixture was purged with nitrogen and was heated at 95 C. for 16 h. The mixture was diluted with methylene chloride (200 mL) and washed with brine (250 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 40-90% ethyl acetate/hexanes) afforded 15 (1.71 g, 57%) as an off-white solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6) 6.58 (d, J=2.1 Hz, 1H), 6.25 (d, J=2.1 Hz, 1H), 4.78 (s, 2H), 4.35 (s, 2H), 2.36 (s, 3H), 2.26 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H).

(43) Step 2:

(44) To a solution of 15 (1.27 g, 4.26 mmol) in 1,4-dioxane (30 mL) was added 1,1-carbonyldiimidazole (897 mg, 5.54 mmol). The reaction was heated at 65 C. for 8 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. Purification by trituration with EtOAc afforded 16 (910 mg, 66%) as a white solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6) 10.85 (s, 1H), 10.72 (s, 1H), 6.91 (s, 1H), 6.83 (d, J=1.5 Hz, 1H), 2.41 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H), 2.15 (s, 3H); ESI m/z 325 [M+H].sup.+.

(45) Step 3:

(46) A mixture of 16 (324 mg, 1.0 mmol) in POCl.sub.3 (5 mL) was heated at 110 C. for 3 h. The reaction mixture was concentrated, the residue was dissolved in CH.sub.2Cl.sub.2 (100 mL) and washed with saturated NaHCO.sub.3 (250 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to afford 17 (350 mg, 100%) as an off-white solid: ESI m/z 343 [M+H].sup.+.

(47) Step 4:

(48) To a solution of 17 (103 mg, 0.3 mmol) in THF (3 mL) was added morpholine (261 mg, 3.0 mmol). The reaction mixture was heated at 70 C. for 16 h. The reaction mixture was concentrated and purified by chromatography (silica gel, 0-5% MeOH/CH.sub.2Cl.sub.2) to afford Example Compound 226 (26 mg, 22%) as an off-white solid: .sup.1H NMR (300 MHz, MeOD) 7.21 (s, 1H), 6.88 (s, 1H), 3.82 (t, J=5.1 Hz, 4H), 3.54 (t, J=5.1 Hz, 4H), 2.43 (s, 3H), 2.38 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H); ESI m/z 394 [M+H].sup.+.

(49) General Procedure G:

Preparation of 6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine (Example Compound 4)

(50) ##STR00047##

(51) Step 1:

(52) A mixture of 18 (1.0 g 4.7 mmol), 2 (4.5 g 6.6 mmmol), K.sub.2CO.sub.3 (1.3 g, 9.4 mmol), 1,4-dioxane (48 mL) and water (3.5 mL) was degassed with nitrogen for 20 minutes followed by addition of tetrakis(triphenylphosphine)palladium(0) (550 mg, 0.94 mmol). The mixture was heated at 90 C. for 18 hours then cooled to room temperature. The crude reaction mixture was then adsorbed onto silica gel and purified by chromatography (silica gel, 0-10% methanol/dichloromethane) to provide 19 (760 mg, 68%) as an off-white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 7.98 (s, 1H), 6.74 (s, 1H), 6.40 (s, 1H), 4.45 (s, 2H), 2.38 (s, 3H), 2.25 (s, 3H); ESI m/z 229 [M+H].sup.+.

(53) Step 2:

(54) A solution of Example 30 (600 mg, 2.63 mmol), benzaldehyde (420 mg, 3.95 mmol), AcOH (1 mL) and CH.sub.2Cl.sub.2 (30 mL) was stirred at room temperature for 2 hours. NaBH(OAc).sub.3 (3.4 g, 15.8 mmol) was added portionwise over a 4 hour period. The reaction mixture was stirred 18 hours at room temperature and then diluted with CH.sub.2Cl.sub.2 (50 mL). A saturated solution of sodium bicarbonate was slowly added and the layers were separated. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by chromatography (silica gel, 0-10% methanol/dichloromethane). The product was further purified by preparative HPLC (CH.sub.3CN/H.sub.2O) to provide Example Compound 4 (218 mg, 26%) as an off-white solid: .sup.1H NMR (500 MHz, CD.sub.3OD) 8.06 (s, 1H), 7.32 (m, 2H), 7.31 (m, 2H), 7.22 (m, 1H), 6.74 (s, 1H), 6.12 (s, 1H), 4.53 (s, 2H), 2.22 (s, 3H), 2.05 (s, 3H); ESI m/z 319 [M+H].sup.+.

Preparation of 6,8-bis(3,5-dimethylisoxazol-4-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Example Compound 11)

(55) ##STR00048##

(56) Step 1:

(57) To a stirred mixture of 20 (2.13 g, 7.98 mmol) and potassium carbonate (2.76 g, 19.97 mmol) in DMF (50 ml) at 0 C. under nitrogen was added a solution of 2-chloroacetyl chloride (0.904 g, 8.00 mmol) in 1,4-dioxane (20 mL) dropwise over 30 minutes. The reaction mixture was then stirred at 0 C. for 1 h and was stirred at 70 C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (400 mL), washed with water (2350 mL) and brine (100 mL). The solution was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-100% ethyl acetate/heptane) afforded 21 (1.87 g, 76%) as a brown solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6) 10.96 (s, 1H), 7.41 (d, J=2.4 Hz, 1H), 7.02 (d, J=2.4 Hz, 1H), 4.72 (s, 2H); MM m/z 306 [M+H].sup.+.

(58) Step 2:

(59) A stirred mixture of 21 (522 mg, 1.70 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (1.25 g, 5.60 mmol) and sodium carbonate (890 mg, 8.40 mmol) in 1,4-dioxane (15 mL)/water (4 mL) was purged with nitrogen for 4 minutes. Tetrakis(triphenylphosphine)palladium(0) (236 mg, 0.204 mmol) was added and the reaction mixture stirred for 16 h at 100 C. under nitrogen atmosphere. After cooling to room temperature, the mixture was mixed with silica gel (6 g) and concentrated. The resulting residue was purified by chromatography (silica gel, 0-60% ethyl acetate/heptane) followed by trituration with methylene chloride/heptane to afford Example Compound 11 (254 mg, 44%) as a white solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6) 10.84 (s, 1H), 6.94-6.91 (m, 2H), 4.66 (s, 2H), 2.42 (s, 3H), 2.33 (s, 3H), 2.24 (s, 3H), 2.17 (s, 3H); MM m/z 340 [M+H].sup.+.

Preparation of 6,8-bis(3,5-dimethylisoxazol-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (Example Compound 13)

(60) ##STR00049##

(61) Step 1:

(62) To a stirred solution of Example Compound 11 (188 mg, 0.554 mmol) in THF (10 mL) at room temperature under nitrogen was added a solution of borane (5.00 mL, 1.0 M in THF, 5.00 mmol) dropwise over 5 minutes. The reaction mixture was then refluxed under nitrogen atmosphere for 8 h. After cooling to 0 C., the reaction was slowly quenched with methanol (25 mL), followed with aqueous hydrochloric acid (1.0 M, 10 mL). The mixture was concentrated and the resulting residue was slowly basified with saturated sodium bicarbonate (40 mL). The aqueous phase was extracted with methylene chloride (50 mL2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-90% ethyl acetate/heptane) followed by trituration with methylene chloride/hexanes to afford Example Compound 13 (145 mg, 71%) as an off-white solid: .sup.1H NMR (300 MHz, CDCl.sub.3) 6.48 (d, J=2.1 Hz, 1H), 6.35 (d, J=2.1 Hz, 1H), 4.28 (t, J=4.4 Hz, 2H), 3.95 (br s, 1H), 3.51-3.47 (m, 2H), 2.40 (s, 3H), 2.35 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H); MM m/z 326 [M+H].sup.+.

Preparation of 4,4-(2-(trifluoromethyl)-1H-benzo[d]imidazole-4,6-diyl)bis(3,5-dimethylixaole) (Example Compound 34)

(63) ##STR00050##

(64) Step 1:

(65) A mixture of 10 (75 mg, 0.27 mmol) and trifluoroacetic acid (0.53 ml) was heated at 75 C. for 5 hours. After removing the solvent in vacuo, 22 was obtained as an off-white solid (140 mg): ESI MS m/z 360, 362 [M+H].sup.+.

(66) Step 2:

(67) Using Step 5 in General Procedure D employing 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole instead afforded Example Compound 34 as an off-white solid: .sup.1H NMR (500 MHz, CD.sub.3OD) 7.65 (s, 1H), 7.27 (s, 1H), 2.47 (s, 3H), 2.40 (s, 3H), 2.31 (s, 3H), 2.25 (s, 3H); MM m/z 377 [M+H].

(68) General Procedure H:

Preparation of 4,4-(1H-indazole-4,6-diyl)bis(3,5-dimethylisoxazole) (Example Compound 70)

(69) ##STR00051##

(70) Step 1:

(71) To a solution of 23 (1.86 g, 10.0 mmol) in 1,4-dioxane (50 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (2.23 g, 12.0 mmol), 2 M Na.sub.2CO.sub.3 (7.5 mL, 15.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (577 mg, 0.5 mmol). The reaction mixture was purged with nitrogen and heated at 90 C. for 16 h. The mixture was filtered through celite and concentrated. Purification by chromatography (silica gel, 0-100% ethyl acetate/hexanes) afforded 24 (1.72 g, 85%) as a yellow oil: 1H NMR (500 MHz, CDCl.sub.3) 6.93-6.92 (m, 2H), 6.76-6.75 (m, 1H), 3.98 (br s, 2H), 2.37 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H); ESI m/z 203 [M+H].sup.+.

(72) Step 2:

(73) To a solution of 24 (315 mg, 1.56 mmol) in DCM (5 mL) was added NBS (278 mg, 1.56 mmol) in portions at room temperature. After 1 h, the reaction mixture was concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate/hexanes) to afford 25 (152 mg, 35%) as a brown solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 7.19 (d, J=1.5 Hz, 1H), 6.88 (d, J=1.5 Hz, 1H), 2.36 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H); ESI m/z 282 [M+H].sup.+.

(74) Step 3:

(75) To a solution of 25 (144 mg, 0.5 mmol) in HOAc (2 mL) was added NaNO.sub.2 (140 mg, 1.0 mmol) in portions at room temperature. After 2 h, 6 N NaOH was added to adjust to pH10. The reaction mixture was extracted with ethyl acetate, dried, concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate/hexanes) to afford 26 (96 mg, 66%) as a brown solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.22 (s, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.45 (d, J=1.5 Hz, 1H), 2.42 (s, 3H), 2.32 (s, 3H); ESI m/z 293 [M+H].sup.+.

(76) Step 4:

(77) To a solution of 26 (90 mg, 0.31 mmol) in 1,4-dioxane (3 mL) was added (2-methylpyridin-3-yl)boronic acid (110 mg, 0.46 mmol), 2 M Na.sub.2CO.sub.3 (0.31 mL, 0.62 mmol) and tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.031 mmol). The reaction mixture was purged with nitrogen and heated at 90 C. for 16 h. The mixture was diluted with methylene chloride (15 ml) and washed with brine (23 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-100% ethyl acetate/hexanes) afforded Example Compound 70 (51 mg, 52%) as a light brown solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.58-8.57 (m, 1H), 8.21 (s, 1H), 7.75-7.74 (m, 1H), 7.69 (d, J=1.5 Hz, 1H), 7.35-7.33 (m, 1H), 7.15 (d, J=1.5 Hz, 1H), 2.51 (s, 1H), 2.46 (s, 3H), 2.10 (s, 3H); ESI m/z 305 [M+H].sup.+.

(78) General Procedure I:

Preparation of 4,4-(2-isopropyl-1H-benzo[d]imidazole-4,6-diyl)bis(3,5-dimethylisoxazole) (Example Compound 45)

(79) ##STR00052##

(80) Step 1:

(81) A mixture of 10 (75 mg, 0.27 mmol) in isobutyric acid (1.0 mL) was heated at 130 C. for 5 h. The reaction mixture was concentrated under vacuum and used in the next step without purification.

(82) Step 2:

(83) To a solution of 27 (crude, 0.27 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (90 mg, 0.41 mmol), potassium carbonate (149 mg, 1.08 mmol), and tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.014 mmol). The reaction mixture was purged with nitrogen and heated at 90 C. for 16 h. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-50% ethyl acetate in hexanes). It was further purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH.sub.3CN in H.sub.2O to give Example Compound 45 (9 mg, 10%) as an off-white solid: .sup.1H NMR (500 MHz, CD.sub.3OD) 7.69 (d, J=1.4 Hz, 1H), 7.40 (d, J=1.4 Hz, 1H), 3.55-3.40 (m, 1H), 2.46 (s, 3H), 2.38 (s, 3H), 2.30 (s, 3H) 2.21 (s, 3H), 1.53 (d, J=7.0 Hz, 6H); ESI m/z 351 [M+H].sup.+.

(84) General Procedure J:

Preparation of 4,4-(2-Isopropyl-1H-benzo[d]imidazole-4,6-diyl)bis(3,5-dimethylisoxazole) (Example Compound 46)

(85) ##STR00053##

(86) Step 1:

(87) A mixture of 10 (200 mg, 0.709 mmol) in tetraethoxymethane (340 mg, 1.77 mmol) was heated at 100 C. for 4 h. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-50% ethyl acetate in hexanes) to afford 28 (177 mg, 74%) as a yellow solid: .sup.1H NMR (500 MHz, CD.sub.3OD) 7.30-7.15 (m, 2H), 4.57 (q, J=7.0 Hz, 2H), 2.39 (s, 3H), 2.23 (s, 3H), 1.47 (t, J=7.0 Hz, 3H); ESI m/z 336 [M+H].

(88) Step 2:

(89) To a solution of 28 (90, 0.27 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (90 mg, 0.41 mmol), potassium carbonate (74 mg, 0.54 mmol), and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol). The reaction mixture was purged with nitrogen and heated at 90 C. for 16 h. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-50% ethyl acetate in hexanes). It was further purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH.sub.3CN in H.sub.2O to give Example Compound 46 (27 mg, 29%) as an off-white solid: .sup.1H NMR (500 MHz, CD.sub.3OD) 7.50-7.10 (m, 1H), 6.94 (d, J=1.5 Hz, 1H), 4.53 (q, J=7.1 Hz, 2H), 2.42 (s, 3H), 2.38 (s, 3H), 2.27 (s, 3H), 2.24 (s, 3H), 1.45 (d, J=7.1 Hz, 3H); ESI m/z 353 [M+H].sup.+.

Preparation of 3,5-dimethyl-4-(6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-4-yl)isoxazole (Example Compound 14)

(90) ##STR00054##

(91) Step 1:

(92) To a solution of 4,6-dibromo-1H-benzo[d]imidazole 29 (466 mg, 1.69 mmol) in 1,4-dioxane (25 mL) and H.sub.2O (2 mL) was added 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 4.23 mmol), sodium carbonate (360 mg, 3.38 mmol) and tetrakis(triphenylphosphine)palladium(0) (195 mg, 0.17 mmol). The reaction mixture was purged with nitrogen and heated at 90 C. for 16 h. The mixture was diluted with methylene chloride (20 mL) and filtered through a layer of Celite. The filtrate was concentrated and purified by chromatography (silica gel, 0-10% CH.sub.3OH/CH.sub.2Cl.sub.2) to afford 30 (87 mg, 17%) as a yellow solid: .sup.1H NMR (300 MHz, CD.sub.3OD) 8.26 (s, 1H), 7.42 (s, 1H), 7.33 (d, J=1.2 Hz, 1H), 3.77 (s, 3H), 2.26 (s, 3H), 2.19 (s, 3H); ESI m/z 307 [M+H].sup.+.

(93) Step 2:

(94) To a solution of 4-bromo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazole 30 (87 mg, 0.29 mmol) in 1,4-dioxane (5 mL) and H.sub.2O (0.5 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (127 mg, 0.57 mmol), sodium carbonate (60 mg, 0.57 mmol) and tetrakis(triphenylphosphine)palladium(O) (33 mg, 0.029 mmol). The reaction mixture was purged with nitrogen and heated at 90 C. for 16 h. The mixture was diluted with methylene chloride (10 mL) and filtered through a layer of Celite. The filtrate was concentrated and purified by chromatography (silica gel, 0-10% CH.sub.3OH/CH.sub.2Cl.sub.2) to afford Example Compound 14 (32 mg, 35%) as a pale yellow solid: .sup.1H NMR (300 MHz, CD.sub.3OD) 8.23 (s, 1H), 7.51 (s, 1H), 7.07 (d, J=1.5 Hz, 1H), 3.80 (s, 3H), 2.40 (s, 3H), 2.32 (s, 3H), 2.25 (s, 6H); ESI m/z 322 [M+H].sup.+.

Preparation of 3,5-dimethyl-4-(6-(1-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-4-yl)isoxazole (Example Compound 230)

(95) ##STR00055##

(96) Example Compound 230 was prepared by following the similar method for the preparation of Example Compound 14 using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole affording the product as an off-white solid: .sup.1H NMR (500 MHz, CD.sub.3OD) 8.29 (s, 1H), 7.75 (br.s, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.29 (s, 1H), 6.43 (d, J=2.0 Hz, 1H), 3.92 (s, 3H), 2.38 (s, 3H), 2.23 (s, 3H); ESI m/z 294 [M+H].sup.+.

(97) General Procedure K:

Preparation of 6-(3,5-dimethylisoxazol-4-yl)-2-methyl-N-(2-methylpyridin-3-yl)-1H-benzo[d]imidazol-4-amine (Example Compound 143)

(98) ##STR00056##

(99) Step 1:

(100) To a solution of 11b (1.50 g, 5.07 mmol) in THF (100 mL) under nitrogen was added NaH (243 mg, 60% dispersion in mineral oil, 6.08 mmol) at room temperature. The mixture was stirred at room temperature for 30 min and trityl chloride (1.84 g, 6.59 mmol) was added followed by a catalytic amount of n-Bu.sub.4NI (10 mg). The mixture was stirred at room temperature for 16 h. The mixture was concentrated and purified by chromatography (silica gel, 0-50% ethyl acetate/hexanes) to give 31 (1.05 g, 38%) as a yellow solid: .sup.1H NMR (500 MHz, CD.sub.3OD) 7.35-7.41 (m, 9H), 7.30-7.35 (m, 6H), 7.28 (d, J=1.3 Hz, 1H), 5.81 (d, J=1.3 Hz, 1H), 2.10 (s, 3H), 1.96 (s, 3H), 1.94 (s, 3H).

(101) Step 2:

(102) To a solution of 31 (100 mg, 0.182 mmol) in toluene (10 mL) under nitrogen atmosphere was added 2-methylpyridin-3-amine (30 mg, 0.27 mmol), cesium carbonate (118 mg, 0.364 mmol), 2-dicyclohexylphosphino-2,4,6-tri-i-propyl-1,1-biphenyl (13 mg, 0.027 mmol), and tris(dibenzylideneacetone)dipalladium(0) (16 mg, 0.018 mmol). The reaction mixture was heated at 90 C. for 16 h, cooled to room temperature, and purified by chromatography (silica gel, 0-100% ethyl acetate/hexanes) to give 32 (78 mg, 75%) as a light brown solid: .sup.1H NMR (500 MHz, CD.sub.3OD) 8.04 (dd, J=4.8, 1.4 Hz, 1H), 7.68 (dd, J=8.1, 1.4 Hz, 1H), 7.32-7.42 (m, 15H), 7.19 (dd, J=8.1, 4.9 Hz, 1H), 6.56 (d, J=1.3 Hz, 1H), 5.44 (d, J=1.3 Hz, 1H), 2.58 (s, 3H), 2.07 (s, 3H), 1.95 (s, 3H), 1.92 (s, 3H); ESI m/z 576 [M+H].sup.+.

(103) Step 3:

(104) A mixture of 32 (78 mg, 0.14 mmol) and TFA (1 mL) were stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum. The residue was dissolved in MeOH and basified by concentrated NH.sub.4OH. The mixture was concentrated under vacuum and purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH.sub.3CN in H.sub.2O to give Example 143 (23 mg, 49%) as an off-white solid: .sup.1H NMR (500 MHz, CD.sub.3OD) 7.99 (s, 1H), 7.30-7.80 (br.s, 1H), 7.05 (s, 1H), 7.90-7.30 (br.s, 1H), 6.60-6.90 (br.s, 1H), 2.58 (s, 3H), 2.57 (s, 3H), 2.39 (s, 3H), 2.24 (s, 3H); ESI m/z 334 [M+H].sup.+.

(105) General Procedure L:

Preparation of 3,5-dimethyl-4-(2-methyl-4-(pyrazin-2-yl)-1H-benzo[d]imidazol-6-yl)isoxazole (Example Compound 85)

(106) ##STR00057##

(107) A mixture of 11b (214 mg, 0.700 mmol), potassium acetate (208 mg, 2.12 mmol) and bis(pinacolato)diboron (356 mg, 1.40 mmol) in anhydrous DMSO (5 mL) was purged with nitrogen for 5 minutes. To the mixture was added trans-dichlorobis(triphenylphosphine)palladium(II) (71 mg, 0.101 mmol). Following the addition, the mixture was purged with nitrogen for 2 minutes. The vial was capped and heated at 150 C. by microwave irradiation for 1.5 h. After cooling to room temperature, 1,4-dioxane (8 mL)/water (3 mL) was added, followed by cesium carbonate (684 mg, 2.10 mmol) and 2-chloropyrazine (120 mg, 1.05 mmol). The resulting mixture was purged with nitrogen for 5 minutes. Then dichlorobis(tri(o-tolyl)phosphine)palladium(II) was added and the mixture was heated for 16 h at 95 C. under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with water (60 mL). extracted with ethyl acetate (330 mL) and the organic extract was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 100% heptane-1% Et.sub.3N in 10% methanol/ethyl acetate), followed by trituration with methylene chloride/hexanes to afford Example 85 (77 mg, 36%) as a white solid: .sup.1H NMR (300 MHz, CD.sub.3OD) 9.36 (br s, 1H), 8.82 (br s, 1H), 8.57 (d, J=2.7 Hz, 1H), 7.87 (s, 1H), 7.60 (br s, 1H), 2.69 (s, 3H), 2.46 (s, 3H), 2.31 (s, 3H); MM m/z 306 [M+H].sup.+.

(108) General Procedure M:

Preparation of 3,5-dimethyl-4-(2-methyl-4-((2-methylpyridin-3-yl)oxy)-1H-benzo[d]imidazol-6-yl)isoxazole (Example Compound 155)

(109) ##STR00058##

(110) Step 1:

(111) A mixture of 31 (150 mg, 0.273 mmol), 2-methylpyridin-3-ol (391 mg, 0.356 mmol), picolinic acid (7 mg, 0.054 mmol) and K.sub.3PO.sub.4 (145 mg, 0.683 mmol) in DMSO (3 mL) was purged with N.sub.2 for 5 minutes. Then CuI (5 mg, 0.027 mmol) was added and the reaction mixture was heated to 90 C. for 16 h. The mixture was diluted with ethyl acetate (100 mL) and washed with brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 50-100% ethyl acetate/hexanes) to afford 33 (90 mg, 35%) as a purple sticky solid: .sup.1H NMR (300 MHz, CDCl.sub.3) 8.34 (dd, J=4.8, 1.2 Hz, 1H), 7.38-7.25 (m, 17H), 6.20 (br.s, 1H), 5.49 (s, 1H), 2.67 (s, 3H), 2.03 (s, 3H), 1.97 (s, 3H), 1.90 (s, 3H).

(112) Step 2:

(113) A solution of 33 (90 mg, 0.156 mmol) in TFA (2 mL) was stirred at rt for 1 h. The mixture was concentrated, the residue was dissolved in ethyl acetate (100 mL) and washed with saturated NaHCO.sub.3 (250 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-10% methanol/ethyl acetate) afforded Example Compound 155 (38 mg, 73%) as a pink solid: .sup.1H NMR (300 MHz, CD.sub.3OD) 8.20-8.17 (m, 1H), 7.27-7.21 (m, 3H), 6.61 (d, J=1.2 Hz, 1H), 2.60 (s, 3H), 2.58 (s, 3H), 2.37 (s, 3H), 2.21 (s, 3H); ESI m/z 335 [M+H].sup.+.

(114) General Procedure N:

Preparation of 4,4-(1-methyl-1H-benzo[d]imidazole-5,7-diyl)bis(3,5-dimethylisoxazole) (Example Compound 93)

(115) ##STR00059##

(116) Step 1:

(117) To a solution of 9 (1.00 g, 3.21 mmol) in DMF (10 mL) was added NaH (60% dispersion in mineral oil, 141 mg, 3.53 mmol) at room temperature under nitrogen. The mixture was stirred at room temperature for 30 min and iodomethane (410 mg, 2.98 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. NH.sub.4Cl/H.sub.2O (10 mL) was added, the mixture was stirred for 30 min, concentrated and purified by chromatography (silica gel, 0-25% ethyl acetate/hexanes) to give 34 (370 mg, 35%) as a orange solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 7.75 (d, I=2.1 Hz, 1H), 7.57 (d, J=2.1 Hz, 1H), 6.25 (d, J=4.6 Hz, 1H), 3.06 (d, J=5.5 Hz, 3H), 2.40 (s, 3H), 2.26 (s, 3H); ESI m/z 226 [M+H].sup.+.

(118) Step 2:

(119) To a solution of 34 (370 mg, 1.13 mmol) in tetrahydrofuran (20 mL) was added sodium dithionite (1.18 g, 6.78 mmol) in water (20 mL). The reaction mixture was stirred at room temperature for 16 h and concentrated under vacuum. The residue was dissolved in MeOH/water (1:1, 100 mL) and solid was precipitated by removing some MeOH under vacuum. The solid was filtered, washed with water, and dried under vacuum to afford 35 (180 mg, 54%) as a yellow solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 7.26 (s, 1H), 6.79 (d, J=1.9 Hz, 1H), 6.50 (d, J=1.9 Hz, 1H), 4.09 (s, 2H), 3.29 (s, 1H), 2.71 (s, 3H), 2.38 (s, 3H), 2.24 (s, 3H); ESI m/z 296 [M+H].sup.+.

(120) Step 3:

(121) To a solution of 35 (180 mg, 0.608 mmol) in methanol (5 mL) was added trimethyl orthoformate (97 mg, 0.91 mmol) and sulfamic acid (3 mg, 0.03 mmol). The reaction was stirred at room temperature for 16 h. The mixture was concentrated and then purified by chromatography (silica gel, 0-100% ethyl acetate/hexanes) to give 36 (180 mg 97%) as an off-white solid: .sup.1H NMR (500 MHz, CD.sub.3OD) 8.20 (s, 1H), 7.57 (d, J=1.4 Hz, 1H), 7.43 (d, J=1.4 Hz, 1H), 4.20 (s, 3H), 2.41 (s, 3H), 2.25 (s, 3H); ESI m/z 306 [M+H].sup.+.

(122) Step 4:

(123) To a solution of 36 (100 mg, 0.327 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (109 mg, 0.490 mmol), tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol) and potassium carbonate (90 mg, 0.65 mmol). The reaction mixture was purged with nitrogen and heated at 90 C. for 16 h. The mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-100% hexanes/ethyl acetate). It was further purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH.sub.3CN in H.sub.2O to give Example Compound 93 (41 mg, 39%) as an off-white solid: .sup.1H NMR (300 MHz, CD.sub.3OD) 8.18 (s, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.08 (d, J=1.6 Hz, 1H), 3.58 (s, 3H), 2.44 (s, 3H), 2.32 (s, 3H), 2.28 (s, 3H), 2.13 (s, 3H); ESI m/z 323 [M+H].sup.+.

Preparation of 4,4-(2-methyl-1H-benzo[d]imidazole-4,6-diyl)bis(3-methylisothiazole) (Example Compound 139)

(124) ##STR00060##

(125) Step 1:

(126) To a solution of 1 (1.00 g, 3.45 mmol) in THF (50 mL) under nitrogen was added NaH (166 mg, 60% dispersion in mineral oil, 4.14 mmol) at room temperature. The mixture was stirred at room temperature for 30 min and trityl chloride was added followed by a catalytical amount of n-Bu.sub.4NI (10 mg). The reaction was stirred at room temperature for 16 h and water and SiO.sub.2 were added. The mixture was concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate/hexanes) to give 37 (1.30 g, 71%) as an off-white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 7.44 (d, J=1.6 Hz, 1H), 7.32-7.40 (m, 9H), 7.25-7.30 (m, 6H), 5.52 (d, J=1.6 Hz, 1H), 1.93 (s, 3H).

(127) Step 2:

(128) To a solution of 37 (100 mg, 0.188 mmol) in 1,4-dioxane (10 mL) was added bis(pinacolato)diboron (105 mg, 0.414 mmol), potassium acetate (74 mg, 0.75 mmol), and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14 mg, 0.019 mmol). The reaction mixture was heated at 90 C. for 16 h under nitrogen. The reaction mixture was cooled to room temperature and the material was used in the next step without purification.

(129) Step 3:

(130) To the crude reaction mixture from Step 2 (0.188 mmol) was added water (1 mL), 4-bromo-3-methylisothiazole (100 mg, 0.564 mmol), potassium carbonate (156 mg, 1.13 mmol), and tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.019 mmol). The reaction mixture was heated at 90 C. for 16 h under nitrogen. The reaction was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate/hexanes) to give 39 (50 mg, 47%) as a yellow solid: .sup.1H NMR (500 MHz, CD.sub.3OD) 8.90 (s, 1H), 8.43 (s, 1H), 7.25-7.45 (m, 15H), 7.15 (d, J=1.4 Hz, 1H), 6.00 (d, J=1.4 Hz, 1H), 2.47 (s, 3H), 2.17 (s, 3H), 1.93 (s, 3H).

(131) Step 4:

(132) A mixture of 39 (50 mg, 0.088 mmol) and TFA (2 mL) were stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum. The residue was dissolved in MeOH and basified by Et.sub.3N. The mixture was concentrated under vacuum and purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH.sub.3CN in H.sub.2O to give Example Compound 139 (9 mg, 31%) as an off-white solid: .sup.1H NMR (500 MHz, CD.sub.3OD) 8.91 (s, 1H), 8.80 (s, 1H), 7.58 (s, 1H), 7.22 (d, J=1.5 Hz, 1H), 2.57 (s, 3H), 2.54 (s, 3H), 2.44 (s, 3H); ESI m/z 327 [M+H].sup.+.

Preparation of 4,4-(3-methyl-1H-indole-4,6-diyl)bis(3,5-dimethylisoxazole) (Example Compound 140)

(133) ##STR00061##

(134) Step 1:

(135) To a solution of 40 (1.00 g 3.98 mmol) in concentrated HCl (8 mL) at 0 C. was added dropwise a solution of sodium nitrite (275 mg, 3.98 mmol) in water (1 mL). The mixture was stirred at 0 C. for 1 h. Tin (II) chloride (1.50 g, 7.96 mmol) in concentrated HCl (20 mL) was slowly added. The mixture was warmed to room temperature and stirred for 16 h. The solid was filtered, washed with EtOH, and dried under vacuum at 50 C. to give 41 (1.05 g, 87%) as a light brown solid: .sup.1H NMR (500 MHz, CD.sub.3OD) 7.36 (s, 1H), 7.12 (s, 2H).

(136) Step 2:

(137) To a solution of 41 (200 mg, 0.661 mmol) in ethanol (5 mL) was added propionaldehyde (58 mg, 0.99 mmol) at room temperature. The mixture was heated at 80 C. for 30 min and then cooled to room temperature. Concentrated hydrochloric acid (0.1 mL) was added and the reaction was heated at 80 C. for 5 h. The mixture was concentrated under vacuum. The residue was dissolved in MeOH and basified with sodium carbonate (20% in water). The mixture was concentrated and purified by chromatography (silica gel, 0-10% ethyl acetate/hexanes) to give 42 (45 mg, 23%) as an orange oil: .sup.1H NMR (500 MHz, CD.sub.3OD) 7.44 (d, J=1.6 Hz, 1H), 7.24 (d, J=1.6 Hz, 1H), 7.04 (d, J=1.0 Hz, 1H), 2.48 (d, J=1.0 Hz, 3H).

(138) Step 3:

(139) To a solution of 42 (170 mg, 0.588 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (525 mg, 2.35 mmol), potassium carbonate (487 mg, 3.53 mmol), and tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.059 mmol). The reaction mixture was purged with nitrogen and heated at 90 C. for 16 h. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-30% ethyl acetate/hexanes). It was further purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH.sub.3CN in H.sub.2O to give Example Compound 140 (63 mg, 33%) as an off-white solid: .sup.1H NMR (500 MHz, CD.sub.3OD) 7.33 (d, J=1.4 Hz, 1H), 7.09 (d, J=0.9 Hz, 1H), 6.72 (d, J=1.5 Hz, 1H), 2.43 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H), 2.08 (s, 3H), 1.93 (d, J=0.9 Hz, 3H); ESI m/z 322 [M+H].sup.+.

Preparation of 4,4-(1H-indazole-4,6-diyl)bis(3,5-dimethylisoxazole) (Example Compound 87)

(140) ##STR00062##

(141) Step 1:

(142) To a solution of 43 (0.75 g, 2.95 mmol) in anhydrous THF (15 mL) under N.sub.2 at 78 C. was added LDA (2 M in THF, 1.77 mL, 3.54 mmol) slowly. After the reaction mixture was stirred at this temperature for 2 h, DMF (438 mg, 6 mmol) was added slowly. The reaction temperature was allowed to rise to room temperature over 30 min and stirred for additional 30 min. The reaction was quenched by addition of water (5 mL) at 0 C. The mixture was diluted with ether (50 mL) and washed with brine (210 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-100% ethyl acetate/hexanes) afforded 44 as a yellow solid (309 mg, 37%): .sup.1H NMR (500 MHz, CDCl.sub.3) 10.29 (d, J=0.5 Hz, 1H), 7.69-7.68 (m, 1H); 7.37-7.34 (m, 1H).

(143) Step 2:

(144) To a solution of 44 (110 mg, 0.39 mmol) in DMF (1 mL) was added hydrazine monohydrate (1 mL). The reaction mixture was heated at 90 C. for 16 h, concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate/hexanes) to give 45 as a white solid (110 mg, 70%): ESI m/z 276 [M+H].sup.+.

(145) Step 3:

(146) To a solution of 45 (49 mg, 0.18 mmol) in 1,4-dioxane (2 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (120 mg, 0.54 mmol), 2 M Na.sub.2CO.sub.3 (0.18 mL, 0.36 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.018 mmol). The reaction mixture was purged with nitrogen and heated at 90 C. for 16 h. The mixture was diluted with methylene chloride (30 mL) and washed with brine (210 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-100% ethyl acetate/hexanes) afforded Example Compound 87 (9 mg, 16%) as a white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 7.94 (s, 1H), 7.44 (s, 1H), 6.92 (d, J=1.0 Hz, 1H), 2.48 (s, 1H), 2.41 (s, 3H), 2.33 (s, 3H), 2.27 (s, 3H); ESI m/z 309 [M+H].sup.+.

Preparation of 4,4-(1-methyl-1H-indazole-5,7-diyl)bis(3,5-dimethylisoxazole) (Example Compound 54) and 4,4-(2-methyl-2H-indazole-5,7-diyl)bis(3,5-dimethylisoxazole) (Example Compound 55)

(147) ##STR00063##

(148) Step 1:

(149) To a solution of 46 (191 mg, 0.69 mmol) in anhydrous THF (2 mL) at 0 C. was added NaH (60% dispersion in mineral oil, 30 mg, 0.76 mmol) in portions. The reaction mixture was stirred at room temperature for 30 min, followed by addition of iodomethane (392 mg, 2.76 mmol). The reaction mixture was stirred for 2 h, concentrated, and purified by chromatography (silica gel, 0-100% ethyl acetate/hexanes) to afford two products 47 (49 mg, 25%): .sup.1H NMR (500 MHz, CDCl.sub.3) 7.89 (s, 1H), 7.79 (d, J=1.5 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 4.40 (s, 3H); .sup.13C NMR (125 MHz, DMSO-d.sub.6) 135.7, 132.2, 132.1, 127.2, 123.1, 112.3, 103.5, 40.0; and 48 (110 mg, 56%): .sup.1H NMR (500 MHz, CDCl.sub.3) 7.94 (s, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 4.25 (s, 3H); .sup.13C NMR (125 MHz, DMSO-d.sub.6) 145.0, 130.1, 126.3, 123.0, 122.5, 112.5, 111.2, 40.3.

(150) Step 2:

(151) To a solution of 47 (44 mg, 0.15 mmol) in 1,4-dioxane (2 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (102 mg, 0.46 mmol), 2 M Na.sub.2CO.sub.3 (0.15 mL, 0.45 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.018 mmol). The reaction mixture was purged with nitrogen for 5 min and heated at 90 C. for 16 h. The mixture was diluted with methylene chloride (20 mL) and washed with brine (25 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-100% ethyl acetate/hexanes) afforded Example 54 (34 mg, 71%) as a white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.08 (s, 1H), 7.64 (d, J=1.5 Hz, 1H), 7.0 (d, J=1.5 Hz, 1H), 3.80 (s, 3H), 2.44 (s, 3H), 2.34 (s, 3H), 2.30 (s, 3H), 2.16 (s, 3H); ESI m/z 323 [M+H].sup.+.

(152) Example Compound 55 was synthesized in the same manner as Example Compound 54 as a white solid (67%): .sup.1H NMR (500 MHz, CDCl.sub.3) 8.01 (s, 1H), 7.53 (d, J=1.5 Hz, 1H), 6.98 (d, J=1.5 Hz, 1H), 4.26 (s, 3H), 2.45 (s, 3H), 2.44 (s, 3H), 2.31 (s, 6H); ESI m/z 323 [M+H].sup.+.

Preparation of 4,4-(quinoxaline-5,7-diyl)bis(3,5-dimethylisoxazole) (Example Compound 159)

(153) ##STR00064##

(154) Step 1:

(155) Glyoxal (40%, 354 mg, 2.44 mmol) was added to a solution of 3,5-dibromobenzene-1,2-diamine (15, 500 mg, 1.88 mmol) and ethanol (10 mL) at room temperature. The solution was then heated at reflux for 3 hours and then cooled to room temperature. The solvent was removed under reduced pressure to provide a tan solid (173 mg, 32%) that was used without further purification: .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.08 (d, J=2.0 Hz, 1H), 9.05 (d, J=1.5 Hz, 1H), 8.46 (d, J=2.5 Hz, 1H), 8.40 (d, J=2.0 Hz, 1H).

(156) Step 2:

(157) Example Compound 159 was synthesized according to General Procedure A affording an 84% yield as a white solid: .sup.1H NMR (500 MHz, CD.sub.3OD) 8.95 (d, J=2.0 Hz, 1H), 8.92 (d, J=1.5 Hz, 1H), 8.13 (d, J=2.0 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 2.54 (s, 3H), 2.39 (s, 3H), 2.35 (s, 3H), 2.17 (s, 3H); ESI m/z 321 [M+H].sup.+.

Preparation of 4,4-(1H-benzo[d][1,2,3]triazole-4,6-diyl)bis(3,5-dimethylisoxazole) (Example Compound 95)

(158) ##STR00065##

(159) A solution of 16 (55 mg, 0.18 mmol) in water (2 mL), concentrated HCl (47 L) and absolute ethanol (0.62 mL) was cooled to 0 C. and a solution of sodium nitrite (20 mg, 0.29 mmol) in water (1 mL) was added. The reaction was allowed to warm to room temperature over 0.5 h and stirred at room temperature for 1 h. The precipitated solid was filtered and washed with hexanes (5 mL). The remaining material was dissolved in acetonitrile (3 mL) and was purified on the preparative HPLC. This afforded Example 95 (16 mg, 28%) as a white solid: .sup.1H NMR (500 MHz, CD.sub.3OD) 7.83 (s, 1H), 7.34 (s, 1H), 2.48 (s, 3H), 2.43 (s, 3H), 2.32 (s, 3H), 2.27 (s, 3H); ESI m/z 308 [MH].sup..

Preparation of 5,7-bis(3,5-dimethylisoxazol-4-yl)-2-methylbenzo[d]oxazole (Example Compound 101)

(160) ##STR00066##

(161) Step 1: 50 (2.00 g, 6.80 mmol) and a solution of 7 N ammonia in methanol (4.76 mL, 33.3 mmol) were combined and stirred. After adding methanol (10 mL), the reaction stirred at room temperature for 1 h. The precipitate was filtered, washed with hexanes (20 mL) and air dried for 2 h, affording 51 as a yellow solid (1.95 g, 98%): .sup.1H NMR (500 MHz, DMSO-d.sub.6): 14.8 (s, 1H), 10.8 (s, 1H), 7.73 (d, J=2.5 Hz, 1H), 7.61 (d, J=2.5 Hz, 1H).

(162) Step 2:

(163) A solution of 51 (1.00 g, 3.40 mmol) in isopropanol (10 mL) was cooled to 0 C. under nitrogen, a solution of aqueous sodium hypochlorite (12.5%, 6.12 mL, 10.2 mmol) was added dropwise keeping the internal temperature<10 C. The reaction mixture was allowed to warm to room temperature over 0.5 h and water was added (20 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated. The resulting solid residue was purified by flash chromatography (silica gel, 0-10% ethyl acetate/hexanes) affording 52 as a white solid (381 mg, 38%): .sup.1H NMR (500 MHz, CDCl.sub.3) 7.72 (d, J=1.5 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 2.67 (s, 3H).

(164) Step 3:

(165) To a sealed tube was added 52 (200 mg, 0.68 mmol), potassium carbonate (380 mg, 2.75 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (460 mg, 2.06 mmol), water (1.5 mL) and 1,4-dioxane (7 mL). The mixture was sparged with nitrogen for 5 minutes and tetrakis(triphenylphosphine)palladium(0) (80 mg, 0.067 mmol) was added. The tube was sealed and the mixture heated at 90 C. for 16 h. The reaction mixture was concentrated to dryness and the residue was purified by flash chromatography (silica gel, 0-30% ethyl acetate/hexanes). Further purification on a preparative HPLC using a 10:90 acetonitrile:water to 100% acetonitrile over a 30 min gradient afforded Example Compound 101 as a white solid (125 mg, 56%): .sup.1H NMR (500 MHz, CD.sub.3OD) 7.61 (d, J=1.5 Hz, 1H), 7.26 (d, J=1.5 Hz, 1H), 2.67 (s, 3H), 2.45 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H), 2.28 (s, 3H); ESI m/z 324 [M+H].sup.+.

Preparation of 2-methyl-4,6-di(1H-pyrrol-3-yl)-1H-benzo[d]imidazole (Example Compound 164)

(166) ##STR00067##

(167) Step 1:

(168) Compound 53 was synthesized according to General Procedure A affording a 40% yield as a beige solid: .sup.1H NMR (500 MHz, CD.sub.3OD) 7.51 (br s, 1H), 7.26 (br s), 7.25 (d, J=2.0 Hz, 1H), 7.07 (t, J=2.0 Hz, 1H), 6.89 (s, 1H), 6.67 (d, J=2.0 Hz, 1H), 6.78 (br s, 1H), 6.66 (d, J=2.0 Hz, 1H), 2.61 (s, 3H), 1.54-1.46 (m, 6H), 1.15 (d, J=7.5 Hz, 18H), 1.13 (d, J=7.5 Hz, 18H).

(169) Step 2:

(170) To a stirred solution of 53 (160 mg, 0.28 mmol) in anhydrous THF (5 mL) under nitrogen was added 1.0 M tetrabutylammonium fluoride in THF (0.556 mL, 0.556 mmol). The reaction was stirred at room temperature for 2 h and then was concentrated to dryness. After adding methanol (10 mL) and silica gel (10 g) the mixture was concentrated and chromatographed on silica gel eluting with 0-90% ethyl acetate in hexanes to afford the crude product. The material was further purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH.sub.3CN in H.sub.2O to give Example 164 (26 mg, 35%) as a white solid: .sup.1H NMR (500 MHz, CD.sub.3OD) 7.50 (d, J=1.0 Hz, 1H), 7.52-7.20 (m, 2H), 7.09 (t, J=2.0 Hz, 1H), 6.83 (s, 1H), 6.77 (dd, J=2.5, 2.0 Hz, 1H), 6.60 (br s, 1H), 6.47 (dd, J=2.5, 1.5 Hz, 1H), 2.56 (s, 3H); ESI m/z 263 [M+H].sup.+.

Preparation of 6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-4-(2-methylpyridin-3-yl)-1H-benzo[d]imidazol-2-amine (Example Compound 100)

(171) ##STR00068##

(172) Step 1:

(173) A solution of 10 (300 mg, 1.06 mmol) and ethyl isothiocyanate (184 mg, 2.12 mmol) in ethyl acetate (5 mL) was heated at 70 C. for 3 h. The reaction mixture was concentrated, the residue was dissolved in ethyl acetate (10 mL), EDCI (305 mg, 1.59 mmol) was added and the mixture was heated at 70 C. for 1 h. The mixture was diluted with CH.sub.2Cl.sub.2 (100 mL), washed with brine (100 mL) and the organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 30-100% ethyl acetate/hexanes) to afford 54 (125 mg, 35%) as a white sticky solid: .sup.1H NMR (300 MHz, CDCl.sub.3) 7.07 (br.s, 2H), 3.44 (q, J=7.2 Hz, 2H), 2.40 (s, 3H), 2.24 (s, 3H), 1.29 (t, J=7.2 Hz, 3H).

(174) Step 2:

(175) To a solution of 54 (125 mg, 0.373 mmol) in 1,4-dioxane (8 mL) was added 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (163 mg, 0.746 mmol), 2 M aq. sodium carbonate (0.56 mL, 1.12 mmol) and tetrakis(triphenylphosphine)palladium(0) (43 mg, 0.037 mmol). The reaction mixture was purged with nitrogen and heated at 80 C. for 16 h. The mixture was diluted with ethyl acetate (100 mL) and washed with brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-8% methanol/ethyl acetate) followed by trituration with ethyl acetate afforded Example Compound 100 (72 mg, 56%) as a white solid: .sup.1H NMR (300 MHz, CD.sub.3OD) 8.45 (dd, J=5.1, 1.5 Hz, 1H), 7.78 (dd, J=7.8, 1.5 Hz, 1H), 7.38 (dd, J=7.8, 4.8 Hz, 1H), 7.19 (d, J=1.2 Hz, 1H), 6.79 (d, J=1.5 Hz, 1H), 3.40 (q, J=7.2 Hz, 2H), 2.44 (s, 3H), 2.43 (s, 3H), 2.28 (s, 3H), 1.26 (t, J=7.2 Hz, 3H); ESI m/z 348 [M+H].sup.+.

Preparation of 3-((6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)oxy)-4-methylbenzamide (Example Compound 174) and 3-((6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)oxy)-4-methylbenzoic acid (Example Compound 175)

(176) ##STR00069##

(177) To a solution of Example 172 (50 mg, 0.14 mmol) in EtOH (4 ml) was added 2 N NaOH (0.7 ml, 1.4 mmol). The reaction mixture was heated to reflux for 8 h. The reaction mixture was adjusted to pH 7 using 2 N HCl, then extracted with i-PrOH/CHCl.sub.3 (1/9) (250 ml). The organic layer was concentrated, and the residue was purified by chromatography (silica gel, 3-10% MeOH/CH.sub.2Cl.sub.2) to afford Example 174 (32 mg, 60%) as a white solid and Example Compound 175 (11 mg, 21%) as a white solid; Example 174: .sup.1H NMR (300 MHz, CD.sub.3OD) 7.61 (dd, J=7.5, 1.2 Hz, 1H), 7.46 (d, J=1.2 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.19 (br.s, 1H), 6.42 (s, 1H), 2.60 (s, 3H), 2.38 (s, 3H), 2.34 (s, 3H), 2.17 (s, 3H); APCI m/z 377 [M+H].sup.+; Example 175: .sup.1H NMR (300 MHz, CD.sub.3OD) 7.73 (dd, J=7.8, 1.2 Hz, 1H), 7.48 (d, J=1.2 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.23 (s, 1H), 6.49 (d, J=1.2 Hz, 1H), 2.60 (s, 3H), 2.41 (s, 3H), 2.35 (s, 3H), 2.18 (s, 3H); APCI m/z 378 [M+H].sup.+.

Preparation of N-(6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-yl)-2-methoxybenzenesulfonamide (Example Compound 102)

(178) ##STR00070##

(179) A mixture of Example 30 (83 mg, 0.25 mmol), NEt.sub.3 (51 mg, 0.5 mmol), 2-methoxybenzene-1-sulfonyl chloride (63 mg, 0.3 mmol) and DMAP (10 mg, 0.08 mmol) in 1,4-dioxane (4 mL) was stirred at room temperature for 48 h. TFA (1 mL) was then added to the reaction mixture and the solution was stirred at room temperature for 2 h. After concentration, the resulting oil was dissolved in CH.sub.2Cl.sub.2 and Na.sub.2CO.sub.3 was added to the solution to reach pH 7. The mixture was filtered, concentrated and purified on silica gel to afford Example 102 as an off-white solid (25 mg, 25%). .sup.1H NMR (300 MHz, CD.sub.3OD) 8.73 (s, 1H), 7.72 (dd, J=7.8, 1.5 Hz, 1H), 7.59-7.53 (m, 1H), 7.38 (d, J=0.9 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H), 6.98 (td, J=7.8, 0.9 Hz, 1H), 6.89 (d, J=1.5 Hz, 1H), 3.93 (s, 3H), 2.22 (s, 3H), 2.05 (s, 3H); ESI MS m/z 399 [M+H].sup.+.

Preparation of 3,5-dimethyl-4-(2-methyl-4-phenethyl-1H-benzo[d]imidazol-6-yl)isoxazole (Example Compound 161)

(180) ##STR00071##

(181) A mixture of Example 158 (66 mg, 0.2 mmol), aqueous hydrazine (500 mg, 10 mmol) and H.sub.2O.sub.2(1.13 g, 10 mmol) in EtOH (2 ml) was stirred at room temperature for 64 h. The reaction mixture was concentrated and purified on silica gel to afford Example Compound 161 as an off-white solid (14 mg, 21%). .sup.1H NMR (300 MHz, CD.sub.3OD) 1217.24-7.13 (m, 6H), 6.74 (s, 1H), 3.33-3.31 (m, 2H), 3.08-3.03 (m, 2H), 2.62 (s, 3H), 2.29 (s, 3H), 2.13 (s, 3H); ESI MS m/z 332 [M+H].sup.+.

Preparation of 3-(6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)-2-methylbenzamide (Example Compound 126)

(182) ##STR00072##

(183) To a solution of Example 123 (100 mg, 0.29 mmol) in ethanol (3 mL), was added 2 N NaOH (2.9 mL). The reaction mixture was heated to 80 C. and stirred for 16 h. The reaction was neutralized with acetic acid (1 mL), and concentrated. The residue was purified by chromatography (silica gel, 0-10% methanol/methylene chloride) to afford Example Compound 126 as an off-white solid (56 mg, 54%): .sup.1H NMR (500 MHz, CD.sub.3OD) 7.48 (d, J=7.3 Hz, 2H), 7.40 (d, J=6.6 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H), 6.99 (s, 1H), 2.55 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H), 2.23 (s, 3H); ESI m/z 361 [M+H].sup.+.

Preparation of 1-(6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)-5-methylpyrrolidin-2-one (Example Compound 121)

(184) ##STR00073##

(185) Tert-butyl 4-bromo-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazole-1-carboxylate (55) was synthesized using the same method as in Step 1 of General Procedure E instead using 4-(4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole (1).

(186) Step 1:

(187) A mixture of 55 (50 mg, 0.12 mmol), 5-methylpyrrolidin-2-one (14 mg, 0.14 mmol), xantphos (4 mg, 0.01 mmol), tris(dibenzylideneacetone)dipalladium (0) (2 mg, 0.003 mmol) and Cs.sub.2CO.sub.3 (55 mg, 0.17 mmol) in toluene (3 mL) was heated at 100 C. for 16 hours. The solvent was removed and the residue was purified by silica gel chromatography (eluting with 0 to 50% CMA (80% CH.sub.2Cl.sub.2, 18% methanol, 2% NH.sub.4OH) in CH.sub.2Cl.sub.2) to provide 56 (48 mg, 94%) as a white solid: .sup.1H NMR (500 MHz, CD.sub.3OD) 7.62 (s, 1H), 7.21 (s, 1H), 4.81-4.79 (m, 1H), 2.85 (s, 3H), 2.58-2.44 (m, 3H), 2.34 (s, 3H), 2.25 (s, 3H), 2.03-1.84 (m, 1H), 1.21 (s, 3H), 1.12 (s, 9H); ESI m/z 425 [M+H].sup.+.

(188) Step 2:

(189) To a solution of 56 (48 mg, 0.11 mmol) in CH.sub.2Cl.sub.2 (2 mL) was added TFA (1 mL) at room temperature. The solution was stirred for 16 hours and the solvent was removed under reduced pressure. The residue was treated with a solution of saturated sodium bicarbonate and extracted with CH.sub.2Cl.sub.2. The organic layer was dried over sodium sulfate and filtered. The residue was purified by passing through a plug of silica gel (eluting with 10% MeOH in CH.sub.2Cl.sub.2) followed by semi-preparative HPLC to provide Example Compound 121 (12 ma 33%) as a white solid: .sup.1H NMR (300 MHz, CD.sub.3OD) 7.63 (s, 1H), 7.39 (s, 1H), 4.62-4.43 (m, 1H), 2.88 (s, 3H), 2.70-2.65 (m, 3H), 2.44 (s, 3H), 2.28 (s, 3H), 2.31-1.84 (m, 1H), 1.23 (d, J=6.2 Hz, 3H); ESI m/z 325 [M+H].sup.+.

Preparation of 1-(6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)piperidin-2-one (Example Compound 122)

(190) ##STR00074##

(191) Step 1:

(192) A mixture 55 (50 mg, 0.12 mmol), piperidin-2-one (14 mg, 0.14 mmol), Cs.sub.2CO.sub.3 (55 mg, 0.17 mmol), xantphos (4 mg, 0.01 mmol) and tris(dibenzylideneacetone)dipalladium(0) (2 mg, 0.003 mmol) in toluene (3 mL) was heated at 100 C. for 16 hours. The solvent was removed and the residue was purified by combiflash (eluting with 0 to 50% CMA (80% CH.sub.2Cl.sub.2, 18% methanol, 2% NH.sub.4OH) in CH.sub.2Cl.sub.2) to provide 57 (22 mg, 44%) as a white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 7.77 (s, 1H), 7.47 (s, 1H), 3.85-3.83 (m, 2H), 2.81 (s, 3H), 2.71-2.63 (m, 2H), 2.44 (s, 3H), 2.27 (s, 3H), 2.09-2.04 (m, 4H), 1.68 (s, 9H).

(193) Step 2:

(194) To a solution of 57 (22 mg, 0.05 mmol) and CH.sub.2Cl.sub.2 (2 mL) was added TFA (0.5 mL) at room temperature. The solution was stirred for 16 hours and the solvent was removed under reduced pressure. The residue was treated with saturated sodium bicarbonate solution and extracted into CH.sub.2Cl.sub.2. The organic layer was dried over sodium sulfate and filtered. The residue was purified by passing through a plug of silica gel (eluting with 10% MeOH in CH.sub.2Cl.sub.2) followed by semi-preparative HPLC to provide Example Compound 122 (4 mg, 25%): .sup.1H NMR (300 MHz, CD.sub.3OD) 7.62 (s, 1H), 7.48 (s, 1H), 3.90-3.81 (m, 2H), 2.87 (s, 3H), 2.69-2.61 (m, 2H), 2.44 (s, 3H), 2.28 (s, 3H), 2.07-2.05 (m, 4H); ESI m/z 325 [M+H].sup.+.

Preparation of 4,4-(5-methoxy-2-methyl-1H-benzo[d]imidazole-4,6-diyl)bis(3,5-dimethylisoxazole) (Example Compound 227)

(195) ##STR00075##

(196) Step 1:

(197) To a suspension of 58 (760 mg, 308 mmol) and NaOAc (379 mg, 4.62 mmol) in acetic acid (10 mL) was added bromine (0.237 mL, 4.62 mmol) dropwise. The reaction was stirred at room temperature for 3h. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with saturated NaHCO.sub.3 (250 mL), saturated Na.sub.7S.sub.2O.sub.3 (350 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in THF (50 mL) and water (40 mL), sodium dithionite (2.90 g, 16.68 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. 1N HCl (10 mL) was added and the mixture was heated to reflux for 30 minutes, then cooled to room temperature. Saturated NaHCO.sub.3 (100 mL) was added slowly. The mixture was extracted with EtOAc (150 mL), the organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in MeOH (25 mL), and triethyl orthoacetate (666 mg, 4.11 mmol) and sulfamic acid (14 mg, 0.14 mmol) were added. The reaction was stirred at room temperature for 5 h. The reaction mixture was concentrated, the residue was suspended in EtOAc (100 mL) and washed with brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give 59 (880 mg, 90%) as a light brown solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.65 (s, 0.3H), 12.60 (s, 0.7H), 7.76 (s, 0.3H), 7.69 (s, 0.7H), 3.79 (s, 3H), 2.50 (s, 3H).

(198) Step 2:

(199) To a solution of 59 (550 mg, 1.72 mmol) in 1,4-dioxane (10 mL) and water (3 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (1.15 g, 5.16 mmol), Na.sub.2CO.sub.3 (729 mg, 6.88 mmol) and tetrakis(triphenylphosphine)palladium(0) (398 mg, 0.34 mmol). The reaction mixture was purged with nitrogen and heated at 90 C. overnight. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-5% MeOH/CH.sub.2Cl.sub.2) to give Example Compound 227 (49 mg, 80%) as a white solid: .sup.1H NMR (300 MHz, CD.sub.3OD) 7.40 (s, 1H), 3.17 (s, 3H), 2.55 (s, 3H), 2.39 (s, 3H), 2.34 (s, 3H), 2.22 (s, 3H), 2.20 (s, 3H); ESI m/z 353 [M+H].sup.+.

Preparation of 4,4-(2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole-4,6-dyl)bis(3,5-dimethylisoxazole) (Example Compound 228)

(200) ##STR00076##

(201) To a solution of 16 (100 mg, 0.335 mmol) and tetrahydro-2H-pyran-4-carboxylic acid (47 mg, 0.369 mmol) in CH.sub.2Cl.sub.2 was added EDC (97 mg, 0.503 mmol). The reaction was stirred at rt for 16 h. The mixture was diluted with EtOAc (100 mL), washed with brine (50 mL) and saturated NaHCO.sub.3 (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in AcOH (2 mL) and heated to reflux for 5 h. The mixture was concentrated, the residue was dissolved in EtOAc (100 mL), washed with saturated NaHCO.sub.3 (250 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-5% MeOH/EtOAc) to give Example Compound 228 (50 mg, 38%) as an off-white solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.49 (s, 0.7H), 12.18 (s, 0.3H), 7.60 (s, 0.3H), 7.41 (s, 0.7H), 7.06 (s, 1H), 3.96-3.93 (m, 2H), 3.51-3.45 (m, 2H), 3.21-3.01 (m, 1H), 2.44-2.33 (m, 6H), 2.28-2.17 (m, 6H), 1.93-1.82 (m, 4H); ESI m/z 393 [M+H].sup.+.

Preparation of 4,4-(2-methyl-3H-imidazo[4,5-b]pyridine-5,7-diyl)bis(3,5-dimethylisoxazole) (Example Compound 176)

(202) ##STR00077##

(203) Step 1:

(204) To a solution of 60 (1.00 g, 4.59 mmol) in 1,4-dioxane (40 mL) and water (4 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (1.53 g, 6.88 mmol), tetrakis(triphenylphosphine)palladium(0) (265 mg, 0.229 mmol) and potassium carbonate (1.27 g, 9.18 mmol). The reaction mixture was purged with nitrogen and heated at 90 C. for 16 h. The mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-100% hexanes/ethyl acetate) to give 61 (1.01 g, 94%) as a yellow solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 7.47 (d, J=8.5 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H), 5.95 (s, 2H), 2.62 (s, 3H), 2.47 (s, 3H).

(205) Step 2:

(206) To a solution of 61 (500 mg, 2.14 mmol) in tetrahydrofuran (10 mL) was added sodium dithionite (2.23 g, 12.8 mmol) in water (10 mL). The reaction mixture was stirred at room temperature for 16 h and concentrated. The residue was suspended in MeOH and the solid was filtered, washed with MeOH, and the filtrate was concentrated. To the residue was added 2 N HCl and the mixture was heated to reflux for 10 minutes. The mixture was cooled to room temperature and concentrated. The residue was dissolved in MeOH and basified by 10% NaHCO.sub.3. The mixture was concentrated, and the residue was purified by chromatography (silica gel, 0-100% hexanes/ethyl acetate) to afford 62 (335 mg, 77%) as an off-white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 6.95 (d, J=7.7 Hz, 1H), 6.64 (d, J=7.7 Hz, 1H), 4.25 (s, 2H), 3.34 (s, 2H), 2.50 (s, 3H), 2.37 (s, 3H); ESI m/z 205 [M+H].sup.+.

(207) Step 3:

(208) To a solution of 62 (330 mg, 1.62 mmol) in ethanol (5 mL) was added triethylorthoacetate (228 mg, 1.78 mmol) and sulfamic acid (3 mg, 0.03 mmol). The reaction was heated in a sealed tube at 90 C. for 16 h. The mixture was concentrated, and the residue was purified by chromatography (silica gel, 0-30% ethyl acetate in hexanes) to give 63 (340 mg, 92%) as a yellow solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 10.92 (s, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H), 2.56 (s, 3H), 2.51 (s, 3H), 2.42 (s, 3H); ESI m/z 229 [M+H].sup.+.

(209) Step 4:

(210) To a solution of 63 (191 mg, 0.838 mmol) in dichloromethane (5 mL) was added m-CPBA (375 mg, 1.68 mmol). The reaction mixture was stirred for 1 h, then additional m-CPBA (375 mg, 1.68 mmol) was added. The mixture was stirred for 1 h, concentrated, and the residue was purified by chromatography (silica gel, 0-20% methanol in ethyl acetate) to give 64 (128 mg, 62%) as an off-white solid: .sup.1H NMR (500 MHz, CD.sub.3OD) 7.71 (d, J=7.8 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H), 2.66 (s, 3H), 2.40 (s, 3H), 2.26 (s, 3H); ESI m/z 245 [M+H].sup.+.

(211) Step 5:

(212) To a mixture of POBr.sub.3 (422 mg, 1.48 mmol) in DMF (5 mL) was added a solution of 64 (120 mg, 0.492 mmol) in DMF (3 mL). The reaction mixture was stirred for 2 h, methanol (5 mL) was added slowly, and the mixture was basified by NaHCO.sub.3 (10%). The mixture was concentrated, and the residue was purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give 65 (75 mg, 50%) as an off-white solid: .sup.1H NMR (500 MHz, CD.sub.3OD) 7.54 (s, 1H), 2.63 (s, 3H), 2.57 (s, 3H), 2.41 (s, 3H); ESI m/z 307 [M+H].sup.+.

(213) Step 6:

(214) To a solution of 65 (60 mg, 0.20 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (134 mg, 0.60 mmol), tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.02 mmol) and potassium carbonate (110 mg, 0.80 mmol). The reaction mixture was purged with nitrogen and heated at 90 C. for 20 h. The mixture was cooled to room temperature, concentrated and the residue was purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes and then to 20% methanol in ethyl acetate). The desired product was further purified by reverse phase HPLC on a Polaris C.sub.18 column eluting with 10-90% CH.sub.3CN in H.sub.2O to give Example Compound 176 (40 mg, 62%) as an off-white solid: .sup.1H NMR (300 MHz, CD.sub.3OD) 8.18 (s, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.08 (d, J=1.6 Hz, 1H), 3.58 (s, 3H), 2.44 (s, 3H), 2.32 (s, 3H), 2.28 (s, 3H), 2.13 (s, 3H); ESI m/z 323 [M+H].sup.+.

Preparation of 4-(6-(1,4-dimethyl-1H-pyrazol-5-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)-3,5-dimethylisoxazole (Example Compound 178)

(215) ##STR00078##

(216) Step 1:

(217) To a degassed solution of 2-bromo-6-nitroaniline (10 g, 46.1 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (13.4 g, 59.9 mmol) and K.sub.2CO.sub.3 (19.1 g, 138 mmol) in 1,4-dioxane (200 mL) and water (70 mL) was added Pd(PPh.sub.3).sub.4(7.9 g, 6.9 mmol) and the mixture was degassed again. The reaction was heated at 90 C. for 20 h under N.sub.2. The reaction was cooled to rt, filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL) and washed with water (200 mL). The aqueous phase was extracted with additional ethyl acetate and the combined organics were dried over Na.sub.2SO.sub.4 and concentrated. The residue was triturated with diethyl ether to give 67 (8.2 g, 76%) as an orange solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.22 (dd, J=8.8 Hz, 1.2 Hz, 1H), 7.23 (dd, J=7.6 Hz, 1.6 Hz, 1H), 6.78 (dd, J=8.8 Hz, 1.6 Hz, 1H), 6.14 (br.s, 2H), 2.32 (s, 3H), 2.16 (s, 3H); ESI MS m/z 232 [MH].sup..

(218) Step 2:

(219) To a solution of 67 (8.2 g, 35.2 mmol) in acetic acid (90 mL) was added dropwise a solution of bromine (1.7 mL, 32.2 mmol) in acetic acid (10 mL) at 50 SC. After the addition was complete the reaction was stirred an additional 2h. The reaction was carefully poured into crushed ice and stirred for 20 min. The resulting precipitate was collected by filtration, the filter cake was washed with water (250 mL) and dried at 50 C. under vacuum to give 68 (8.9 g, 81%) as a yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.37 (d, J=2.4 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 6.17 (b.s, 2H), 2.34 (s, 3H), 2.17 (s, 3H); ESI MS m/z 312 [M+H].sup.+.

(220) Step 3:

(221) Granular tin (10.3 g, 86.5 mmol) was added to a solution of 68 (9.0 g, 28.8 mmol) in ethanol (150 mL). To the resulting suspension, concentrated HCl (15 mL) was added dropwise over a period of 30 min. After the addition was complete the reaction was stirred at rt for 18 h. The reaction was concentrated under reduced pressure and the resulting residue treated with water (100 mL), cooled on an ice-water bath and neutralized with 3 N NaOH solution. Then aqueous saturated NaHCO.sub.3 solution (150 mL) was added to adjust to pH 8-9. Dichloromethane (100 mL) and methanol (50 mL) were added and the mixture was stirred for 30 min at rt. The resulting emulsion was filtered, the organic phase was separated, washed with water (500 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 1-5% methanol/dichloromethane) to afford 69 (7.6 g, 93%) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 6.89 (d, J=2.0 Hz, 1H), 6.67 (d, J=2.4 Hz, 1H), 3.49 (br.s. 2H), 3.32 (br.s, 2H), 2.30 (s, 3H), 2.16 (s, 3H); ESI MS m/z 282 [M+H].sup.+.

(222) Step 4:

(223) Trimethyl orthoacetate (6.5 g, 53.9 mmol) and sulfamic acid (0.523 g, 5.4 mmol) were added to a solution of 69 (7.6 g, 26.9 mmol) in methanol (150 mL). The reaction was stirred at rt for 5 h. The mixture was concentrated under reduced pressure, treated with ice cold water (150 mL) and saturated NaHCO.sub.3 solution (30 mL) and stirred for 30 min. The resulting precipitate was collected by filtration and suspended in diethyl ether (150 mL). The resulting suspension was stirred at rt for 30 min and the solids were collected by filtration. The solids were washed with additional diethyl ether and dried under vacuum to give 70 (8.1 g, 98%) as an off-white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.66 (br s, 1H), 7.19 (d, J=2.0 Hz, 1H), 2.45 (s, 3H), 2.30 (s, 3H), 2.14 (s, 3H); ESI MS m/z: 306 [M+H].sup.+.

(224) Step 5:

(225) To a degassed solution of 70 (1.0 g, 3.5 mmol), 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 4.5 mmol) and K.sub.2CO.sub.3 (0.958 g, 6.9 mmol) in 1,4-dioxane (30 mL) and water (5 mL) was added Pd(PPh.sub.3).sub.4(0.600 g, 0.5 mmol) and the mixture was degassed again. The reaction was heated at 90 C. for 16 h under N.sub.2. The reaction was cooled to rt, filtered and concentrated under reduced pressure. The residue was treated with water (50 mL) and extracted with dichloromethane (350 mL). The combined organics were dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by flash column chromatography (silica gel, 2-4% methanol/dichloromethane) to give Example Compound 178 (0.577 g, 52%) as a white solid: .sup.1H NMR (400 MHz, CD.sub.3OD) 7.51 (br.s, 1H), 7.38 (br.s, 1H), 7.08 (d, J=1.6 Hz, 1H), 3.77 (s, 3H), 2.59 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H), 2.04 (s, 3H); ESI MS m/z 322 [M+H].sup.+.

Preparation of 4,4-(3-methyl-1H-indazole-4,6-diyl)bis(3,5-dimethylisoxazole) (Example Compound 179)

(226) ##STR00079##

(227) Step 1: 71 (5.04 g, 16.0 mmol) and powdered anhydrous aluminum chloride (4.27 g, 32.0 mmol) were mixed thoroughly. Acetyl chloride (3.2 mL, 45 mmol) was added and the mixture was stirred at rt for 1 h. The temperature was increased to 90 C. and stirring was continued for 16 h. The reaction mixture was cooled to rt and quenched with ice-cold water (40 mL). The product was extracted with ethyl acetate (340 mL) and the combined organics were washed with brine (40 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10% ethyl acetate/hexanes) to give 72 (2.85 g, 50%) as an off-white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) : 7.71 (s, 2H), 2.57 (s, 3H).

(228) Step 2:

(229) Three drops of acetic acid were added to a solution of 72 (1.0 g, 2.8 mmol) and hydrazine monohydrate (0.5 mL, 10.3 mmol) in methoxyethanol (10 mL). The reaction was heated at 140 C. for 24 h. The reaction was cooled to rt and concentrated under reduced pressure. The residue was treated with ethyl acetate and stirred for 30 min. The resulting precipitate was collected by filtration and dried to give 73 (0.460 g, 57%) as an off-white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.55 (s, 1H), 7.43 (s, 1H), 2.76 (s, 3H); ESI MS m/z 289 [M+H].sup.+.

(230) Step 3:

(231) To a degassed solution of 73 (0.450 g, 1.55 mmol) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.446 g, 2.0 mmol) in dioxane (30 mL) was added Na.sub.2CO.sub.3 (0.328 g, 3.1 mmol), Pd(PPh.sub.3).sub.4 (0.185 g, 0.16 mmol) and water (3.0 ml). The reaction mixture was degassed again. The reaction was heated at 80 C. for 18 h. The reaction was cooled to rt, filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), washed with water (20 mL), brine (20 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 30-50% ethyl acetate/hexanes) followed by trituration with diethyl ether to afford Example Compound 179 (0.060 g, 12%) as an off-white solid: mp 228-230 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 10.09 (br.s, 1H), 7.36 (s, 1H), 6.79 (s, 1H), 2.47 (s, 3H), 2.33 (s, 3H), 2.32 (s, 3H), 2.26 (s, 3H), 2.15 (s, 3H); ESI MS m/z 321 [MH].sup..

Preparation of 4-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-3-methyl-1H-indazol-6-yl)-3,5-dimethylisoxazole (Example Compound 180)

(232) ##STR00080##

(233) Step 1:

(234) To a degassed solution of 73 (0.400 g, 1.38 mmol) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.260 g, 1.17 mmol) in dioxane (25 mL) was added K.sub.2CO.sub.3 (0.386 g, 2.8 mmol), Pd(PPh.sub.3).sub.4(0.080 g, 0.07 mmol) and water (2.5 mL). The reaction mixture was degassed again and then heated at 80 C. for 8 h under N.sub.2. The reaction was cooled to rt, filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (40 mL), washed with water (20 mL), brine (20 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 10-50% ethyl acetate/hexanes) followed by trituration with diethyl ether to give 74 (0.100 g, 24%) as an off-white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 10.05 (br.s, 1H), 7.23 (s, 1H), 7.19 (s, 1H), 2.81 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H); ESI MS m/z 304 [MH].sup..

(235) Step 2:

(236) To a degassed solution of 74 (0.130 g, 0.43 mmol) and 3,5-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.170 g, 0.56 mmol) In dioxane (5 mL) was added K.sub.3PO.sub.4 (0.276 g, 1.3 mmol), Pd(PPh.sub.3).sub.4(0.065 g, 0.06 mmol) and water (0.5 mL). The reaction mixture was degassed again and then heated at 100 C. for 18 h under N.sub.2. The reaction was cooled to rt, filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane (30 mL), washed with water (20 mL), brine (20 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 50-80% ethyl acetate/hexanes) to give 75 (0.060 g, 35%) as a thick gum: ESI MS m/z 404 [MH].sup..

(237) Step 3:

(238) HCl (2.0 mL, 6 N, 12 mmol) was added to a solution of 75 (0.060 g, 0.15 mmol) in methanol. The reaction was heated at 65 C. for 18 h. the reaction was cooled to rt and concentrated under reduced pressure. The residue was purified by preparative HPLC to give Example Compound 180 (0.008 g, 17%) as an off-white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.28 (d, J=1.6 Hz, 1H), 6.78 (d, J=1.6 Hz, 1H), 2.47 (s, 3H), 2.33 (s, 3H), 2.20 (s, 3H), 2.16 (s, 6H); ESI MS m/z 322 [M+H].sup.+.

(239) General Procedure O:

Preparation of 3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H benzo[d]imidazol-6-yl)isoxazole (Example Compound 181)

(240) ##STR00081## ##STR00082##

(241) Step 1:

(242) To a mixture of 9 (500 mg, 1.6 mmol), 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (454 mg, 1.92 mmol), potassium carbonate (443 mg, 3.20 mmol), water (2 ml) and 1,4-dioxane (9 mL) was added tetrakis(triphenylphosphine)palladium(0) (93 mg, 0.08 mmol). The suspension was heated at 90 C. for 17 h. After cooling to room temperature, methanol (20 ml) and silica gel (10 g) were added. The mixture was concentrated to dryness and the resulting powder was purified by flash chromatography (silica gel, 0-90% ethyl acetate/hexanes) affording 76 as a yellow solid (291 mg, 53%): .sup.1H NMR (500 MHz, CDCl.sub.3) 8.05 (d, J=2.0 Hz, 1H), 7.10 (d, J=2.5 Hz, 1H), 6.26 (br.s, 2H), 3.82 (s, 3H), 2.43 (s, 3H), 2.29 (s, 3H), 2.14 (s, 3H), 2.13 (s, 3H).

(243) Step 2:

(244) To a solution of 76 (290 mg, 0.85 mmol) in THF (20 ml) was added a solution of sodium dithionite (887 mg, 5.10 mmol) in water (20 ml). The solution stirred at room temperature for 17 h. The reaction was concentrated to dryness and methanol (30 mL) was added. The suspension stirred at room temperature for 3 h and was filtered. The filtrate was concentrated to dryness and a solution of 2N aq. HCl (20 mL) was added. The solution was brought to reflux for 5 minutes and then cooled to room temperature. The solvent was removed under reduced pressure and silica gel (10 g) and methanol (20 mL) were added. The methanol was removed and the adsorbed silica mixture was subject to flash chromatography (silica gel, 0-50% CMA (CMA: 80% CH.sub.2Cl.sub.2, 18% methanol, 2% NH.sub.4OH) in CH.sub.2Cl.sub.2) affording 77 as a light brown solid (201 mg, 76%): .sup.1H NMR (500 MHz, CDCl.sub.3) 6.59 (d, J=2.0 Hz, 1H), 6.44 (d, J=2.0 Hz, 1H), 3.80 (s, 3H), 3.48 (br.s, 4H), 2.39 (s, 3H), 2.27 (s, 3H), 2.16 (s, 3H), 2.14 (s, 3H).

(245) Step 3:

(246) To a solution of 77 (200 mg, 0.64 mmol) in anhydrous 1,4-dioxane (10 mL) at room temperature was added 1,1-carbonyldiimidazole (125 mg, 0.77 mmol). The mixture was heated at 65 C. for 17 h and then cooled to room temperature. After adding silica gel (10 g) and concentrating the mixture to dryness, the material was subject to flash chromatography (silica gel, 0-10% methanol in CH.sub.2Cl.sub.2) and the product fractions were concentrated to an off-white solid. The solid was triturated with ethyl acetate (20 mL) and the suspension was filtered. The solid collected was dried in a vacuum oven for 17 h affording 78 (140 mg, 65%) as an off-white solid: .sup.1H NMR (500 MHz, DMSO-d.sub.6) 10.7 (s, 1H), 10.4 (s 1H), 6.82 (d, J=1.5 Hz, 1H), 6.68 (d, J=1.5 Hz, 1H), 3.70 (s, 3H), 2.40 (s, 3H), 2.23 (s, 3H), 2.12 (s, 3H), 2.05 (s, 3H); ESI m/z 338 [M+H].sup.+.

(247) Step 4:

(248) A mixture of phosphorus (V) oxychloride (10 mL), 78 (1.00 g, 2.9 mmol) and N,N-dimethylaniline (4 drops) was heated at reflux for 20 h under N.sub.2. The reaction was cooled to rt and concentrated under reduced pressure. The residue was dissolved in dichloromethane and poured onto crushed ice. The pH of the aqueous solution was adjusted to between 8-9 with aqueous saturated Na.sub.2CO.sub.3 solution and extracted with dichloromethane (2100 mL). The combined organics were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 1-2% methanol/dichloromethane) 79 (0.790 g, 75%) as a light yellow solid: .sup.1H NMR (400 MHz, CD.sub.3OD) 7.44 (br.s, 1H), 7.03 (d, J=1.2 Hz, 1H), 3.80 (s, 3H), 2.44 (s, 3H), 2.28 (s, 3H), 2.19 (s, 3H), 2.14 (s, 3H); ESI MS m/z 356 [M+H]+.

(249) Step 5:

(250) To a solution of 79 (0.100 g, 0.3 mmol) in 1,4-dioxane (2 mL) was added 1-methylpiperazine (3) (0.028 g, 0.3 mmol) followed by N,N-diisopropylethylamine (0.091 g, 0.8 mmol). The reaction was stirred at 180 C. under microwave heating conditions for 4 h. The reaction was cooled to rt and concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL), washed with water (50 mL), brine (50 mL), dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure. Diethyl ether (20 mL) was added, and the resulting suspension was stirred at rt for 30 min. The solids were collected by filtration, washed with additional diethyl ether (20 mL) and dried under vacuum to give Example Compound 181 (0.078 g, 67%) as an off-white solid: m.p. 195-197 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 9.80 (br.s, 1H), 7.32 (br.s, 1H), 6.64 (br.s, 1H), 3.69-3.74 (m, 4H), 3.68 (s, 3H), 2.51-2.59 (m, 4H), 2.44 (s, 3H), 2.36 (s, 3H), 2.30 (s, 3H), 2.17 (s, 3H), 2.12 (s, 3H); ESI MS m/z 420 [M+H].sup.+.

Preparation of 3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)-4-(2-methylpyridin-3-yl)-1H-benzo[d]imidazol-6-yl)isoxazole (Example Compound 183)

(251) ##STR00083##

(252) Compound 80 was prepared starting with 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine using step 1 through 4 of General Procedure O.

(253) A solution of 80 (0.070 g, 0.207 mmol) and 1-methylpiperazine (0.09 mL, 0.828 mmol) in 1,4-dioxane (2 mL) was heated at 180 C. for 4 h under microwave heating conditions. The reaction was cooled to rt and concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL), washed with water (50 mL), brine (50 mL), dried (Na.sub.2SO.sub.4), and concentrated under reduced pressure. The residue was triturated with diethyl ether (20 mL) and the resulting suspension was stirred at rt for 30 min. The resulting precipitate was collected by filtration, washed with diethyl ether (20 mL) and dried under vacuum to give Example Compound 183 (0.071 g, 85%) as an off-white solid: mp 238-240 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 11.21 (br.s, 1H), 7.94 (d, J=3.9 Hz, 1H), 7.58 (dd, J=7.6, 1.4 Hz, 1H), 7.40 (s, 1H), 7.04 (dd, J=7.6, 4.9 Hz, 1H), 6.68 (d, J=1.6 Hz, 1H), 3.74 (br.s, 4H), 2.51 (t, J=4.7 Hz, 4H), 2.44 (s, 3H), 2.43 (s, 3H), 2.31 (s, 6H); ESI MS m/z 401 [MH].sup..

(254) General Procedure P:

Preparation of 3-(6-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-4-yl)-4-methylbenzonitrile (Example Compound 186)

(255) ##STR00084##
Compound 81 was prepared starting with 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile using step 1 through 4 of General Procedure 0.

(256) A mixture of 81 (0.110 g, 0.28 mmol) and 1-methylpiperazine (0.112 g, 1.12 mmol) in 1,4-dioxane (2 mL) was stirred at 180 C. under microwave heating conditions for 4 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL), washed with water (10 mL) and brine (10 mL), then dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, dichloromethane to 97:3 dichloromethane/methanol) to give Example Compound 186 (0.075 g, 58%) as an off-white solid: mp 133-135 C.; .sup.1H NMR (400 MHz, CD.sub.3OD) : 7.66 (s, 2H), 7.51 (d, J=7.8 Hz, 1H), 7.23 (br.s, 1H), 6.81 (br.s, 1H), 3.58 (t, J=4.9 Hz, 4H), 2.57 (t, J=4.9 Hz, 4H), 2.43 (s, 3H), 2.34 (s, 3H), 2.28 (s, 6H); ESI MS m/z 425 [MH].sup..

(257) General Procedure Q:

Preparation of 3-(6-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-4-yl)-4-methylbenzamide (Example Compound 189)

(258) ##STR00085##

(259) Potassium carbonate (0.042 g, 0.3 mmol) was added to a solution of Example 186 (0.06 g, 0.14 mmol) in DMSO (1.5 mL). The mixture was cooled to 5 C. and 0.3 mL of 30% hydrogen peroxide solution was added dropwise. After the addition was complete the reaction was stirred at 5-10 C. for 1 h. The reaction was allowed to warm to rt and stir an additional 1 h. The reaction was quenched by the addition of crushed ice (10 mL) and the resulting precipitate was collected by filtration. The crude product was dissolved in 1 N HCl (10 mL) and washed with ethyl acetate (10 mL). The aqueous layer was basified with sodium carbonate solution and extracted with CHCl.sub.3 (215 mL). The combined organics were filtered and concentrated under reduced pressure. The residue was triturated with hexane to give Example Compound 189 (0.020 g, 32%) as an off-white solid: mp 133-135 C.; .sup.1H NMR (400 MHz, CD.sub.3OD) 7.83 (s, 1H), 7.79 (d, J=7.4 Hz, 1H), 7.44 (br.s, 1H), 7.27 (br.s, 1H), 6.77 (br.s, 1H), 3.60 (br.s, 4H), 2.58 (t, J=4.7 Hz, 4H), 2.44 (s, 3H), 2.36 (s, 3H), 2.30 (s, 6H); ESI MS m/z 445 [M+H].sup.+.

(260) General Procedure R:

Preparation of 4-(6-(3,5-dimethylisoxazol-4-yl)-4-(4-methylpyridin-3-yl)-1H-benzo[d]imidazol-2-yl)morpholine (Example Compound 196)

(261) ##STR00086##

(262) Compound 82 was prepared starting with 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine using step 1 and 2 of General Procedure O.

(263) Step 1: 1,1-Thiocarbonyldlimidazole (0.267 g, 1.5 mmol) was added in one portion to a stirred suspension of 82 (0.294 g, 1.0 mmol) in anhydrous THF (10 ml). The reaction was heated at reflux with stirring for 21 h. The reaction was cooled to rt and concentrated under reduced pressure. The residue was dissolved in chloroform (20 ml), washed with water (310 mL), dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-2% methanol/chloroform) to give 83 (0.305 g, 91%) as a yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 12.58 (br.s, 1H), 11.33 (br.s, 1H), 8.45 (s, 1H), 8.23 (d, J=5.4 Hz, 1H), 7.22 (d, J=5.4 Hz, 1H), 7.15 (d, J=1.2 Hz, 1H), 6.91 (d, J=1.2 Hz, 1H), 2.41 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H); ESI MS m/z 337 [M+H].sup.+.

(264) Step 2:

(265) A solution of bromine (10.91 g, 68.3 mmol) in acetic acid (30 mL) was added drop wise to a stirred solution of 83 (6.38 g, 19 mmol) and HBr (48% aqueous solution, 4.32 g, 25.6 mmol) in acetic acid (100 mL). After the addition was complete the reaction was stirred at rt for 5 h. Then water (130 mL) was added. The reaction was stirred for an additional 1.5 h, cooled to 0 C. and the pH adjusted to 8 by using 28% aqueous NH.sub.4OH (250 mL). The mixture was extracted with chloroform (250 mL). The combined organics were washed with saturated NaHCO.sub.3 (50 mL), dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-2% methanol/chloroform) to give 84 (4.08 g, 56%) as a yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.52 (s, 1H), 8.02 (d, J=4.6 Hz, 1H), 7.65 (s, 1H), 7.20 (d, J=4.6 Hz, 1H), 7.00 (s, 1H), 2.45 (s, 3H), 2.34 (s, 3H), 2.31 (s, 3H).

(266) Step 3:

(267) A mixture of 84 (0.381 g, 0.99 mmol) and morpholine (1.55 g, 17.8 mmol) was heated at 130 C. with stirring for 19 h. The reaction was cooled to rt and diluted with diethyl ether (10 mL) and hexanes (20 mL). The resulting precipitate was collected by filtration, dissolved in chloroform (20 mL), washed with saturated NaHCO.sub.3 (10 mL), dried over MgSO.sub.4, and concentrated under reduced pressure. The crude product was triturated twice with a mixture of diethyl ether (2 mL) and hexanes (4 mL) followed by flash column chromatography (silica gel, 0-2% methanol/chloroform) to give Example Compound 196 (0.179 g, 46%) as a tan solid: m.p. 137-141 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 11.65 (br.s, 1H), 8.34 (s, 1H), 7.93 (d, J=4.8 Hz, 1H), 7.39 (s, 1H), 7.11 (d, J=4.8 Hz, 1H), 6.67 (s, 1H), 3.77 (br.s, 4H), 3.62 (br.s, 4H), 2.43 (s, 3H), 2.29 (s, 6H); ESI MS m/z 390 [M+H]+.

(268) General Procedure S:

Preparation of 3-(6-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-4-yl)-2-methylbenzonitrile (Example Compound 202)

(269) ##STR00087##

(270) Compound 85 was prepared starting with 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile using step 1 through 4 of General Procedure O.

(271) A mixture of 85 (0.500 g, 1.37 mmol) and 1-methylpiperazine (0.61 mL, 5.51 mmol) in 1,4-dioxane (2 mL) was stirred at 180 C. under microwave heating conditions for 4 h. The reaction was cooled to rt and concentrated under reduced pressure. The residue was dissolved in chloroform (50 mL), washed with water (50 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, chloroform to 97:3 chloroform/methanol, then 97:3 chloroform/7 N NH.sub.4OH in methanol) to give Example Compound 202 (0.156 g 27%) as an off-white solid: m.p. 179-182 C.; .sup.1H NMR (400 MHz, CD.sub.3OD) 7.73 (d, J=7.8 Hz, 1H), 7.61 (d, J=7.4 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.23 (br.s, 1H), 6.81 (br.s, 1H), 3.57 (t, J=4.8 Hz, 4H), 2.56 (t, J=4.8 Hz, 4H), 2.42 (s, 3H), 2.39 (s, 3H), 2.34 (s, 3H), 2.27 (s, 3H); ESI MS m/z 425 [MH].sup..

Preparation of 3,5-dimethyl-4-(2-(methylthio)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-6-yl)isoxazole (Example Compound 187), 3,5-dimethyl-4-(1-methyl-2-(methylthio)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-6-yl)isoxazole (Example Compound 188) and 3,5-dimethyl-4-(1-methyl-2-(methylthio)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-5-yl)isoxazole (Example Compound 191)

(272) ##STR00088##

(273) Step 1:

(274) A solution of 77 (2.10 g, 6.75 mmol) and 1,1-thiocarbonyldiimidazole (1.80 g, 10.12 mmol) in anhydrous THF (70 mL) was heated at reflux for 16 h under N.sub.2. The resulting precipitate was collected by filtration of the hot reaction mixture. The solid material was washed with THF (20 mL) and dried under vacuum to give 86 (1.96 g, 82%) as an off-white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.61 (s, 1H), 12.35 (s, 1H), 6.99 (d, J=1.6 Hz, 1H), 6.86 (d, J=1.6 Hz, 1H), 3.68 (s, 3H), 2.40 (s, 3H), 2.22 (s, 3H), 2.08 (s, 3H), 2.03 (s, 3H); ESI MS m/z 354 [M+H].sup.+.

(275) Step 2:

(276) To a suspension of 86 (0.354 g, 1.00 mmol) in anhydrous DMF (10 mL) was added K.sub.2CO.sub.3 (0.166 g, 1.20 mmol) followed by methyl iodide (0.075 mL, 1.20 mmol). The reaction was stirred at rt for 16 h. The reaction was concentrated under reduced pressure and the residue was treated with water (50 mL). The resulting precipitate was collected by filtration, washed with water and dried under vacuum. The crude product was purified by flash column chromatography (silica gel, 0-3% methanol/dichloromethane) to give Example Compound 187 (0.110 g, 30%), Example Compound 188 (0.087 g, 23%) and Example Compound 191 (0.067 g, 18%) as white solids. Example Compound 187: .sup.1H NMR (400 MHz, CDCl.sub.3) 11.00 (br.s, 1H), 7.55 (dd, J=1.6, 0.8 Hz, 1H), 6.83 (d, J=1.6 Hz, 1H), 3.71 (s, 3H), 2.83 (s, 3H), 2.45 (s, 3H), 2.32 (s, 3H), 2.17 (s, 3H), 2.07 (s, 3H); ESI MS m/z 368 [M+H].sup.+; Example Compound 188: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.02 (d, J=1.6 Hz, 1H), 6.91 (d, J=1.6 Hz, 1H), 3.82 (s, 3H), 3.72 (s, 3H), 2.78 (s, 3H), 2.45 (s, 3H), 2.32 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H); ESI MS m/z 382 [M+H].sup.+; Example Compound 191: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.55 (d, J=1.6 Hz, 1H), 6.76 (d, J=1.6 Hz, 1H), 3.84 (s, 3H), 3.36 (s, 3H), 2.82 (s, 3H), 2.44 (s, 3H), 2.31 (s, 3H), 2.12 (s, 3H), 2.10 (s, 3H); ESI MS m/z 382 [M+H].sup.+.

Preparation of 4,4-(7-bromo-1H-benzo[d]imidazole-4,6-diyl)bis(3,5-dimethylisoxazole) (Example Compound 192)

(277) ##STR00089##

(278) N-bromosuccinimide (0.213 g, 1.2 mmol) was added in one portion to a stirred suspension of Example Compound 1 (0.308 g, 1.0 mmol) in acetonitrile (5 mL) and THF (2 mL). The reaction was stirred at rt for 16 h and the reaction was concentrated under reduced pressure. The residue was dissolved in chloroform (10 mL), washed with saturated NaHCO.sub.3 (10 mL), dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-2% methanol/chloroform) to give Example Compound 192 (0.112 g, 29%) as a white solid: mp 133-135 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 9.90 (br.s, 1H), 8.19 (br.s, 1H), 6.99 (s, 1H), 2.44 (br.s, 3H), 2.35 (s, 3H), 2.31 (br s, 3H), 2.20 (s, 3H); ESI MS m/z 387 [M+H].sup.+.

Preparation of 3,5-dimethyl-4-(2-(methylsulfinyl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-6-yl)isoxazole (Example Compound 194)

(279) ##STR00090##

(280) To a solution of Example Compound 187 (0.368 g, 1.00 mmol) in anhydrous dichloromethane (50 mL) was added m-chloroperbenzoic acid (0.253 g, 1.10 mmol) at 10 C. in small portions. After the addition was complete the reaction was stirred at 10 C. for 30 min. The reaction was then quenched with saturated NaHCO.sub.3 solution (20 mL). The organic phase was separated, washed with water, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-6% methanol/dichloromethane) followed by trituration with diethyl ether to give Example Compound 194 (0.256 g, 67%) as a white solid: m.p. 242-244 C.; .sup.1H NMR (400 MHz, CD.sub.3OD) 7.58 (br.s, 1H), 7.13 (d, J=1.6 Hz, 1H), 3.81 (s, 3H), 3.13 (s, 3H), 2.46 (s, 3H), 2.31 (s, 3H), 2.22 (s, 3H), 2.17 (s, 3H); ESI MS m/z 382 [MH].sup..

Preparation of 3,5-dimethyl-4-(2-(methylsulfonyl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-6-yl)isoxazole (Example Compound 195)

(281) ##STR00091##

(282) Oxone (1.35 g, 2.20 mmol) was added at 0 C. to a stirred solution of Example Compound 187 (0.368 g, 1.00 mmol) in acetone (20 mL) and water (20 mL). The reaction was stirred for 30 min. The reaction was allowed to warm to rt and stirred an additional 16 h. The mixture was concentrated under reduced pressure and the residue dissolved in water (20 mL). Solid NaHCO.sub.3 was added slowly and a precipitate formed. The mixture was extracted with dichloromethane (100 mL), the organic phase was separated, washed with water, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was purified by trituration with diethyl ether to afford Example Compound 195 (0.281 g, 70%) as a white solid: mp 254-256 C.; .sup.1H NMR (400 MHz, CD.sub.3OD) 7.60 (br.s, 1H), 7.18 (d, J 1.1 Hz, 1H), 3.82 (s, 3H), 3.39 (s, 3H), 2.47 (s, 3H), 2.31 (s, 3H), 2.22 (s, 3H), 2.18 (s, 3H); ESI MS m/z 398 [MH].sup..

Preparation of 3-(6-(3,5-dimethylisoxazol-4-yl)-2-(pyrrolidin-1-yl)-1H-benzo[d]imidazol-4-yl)-4-methylbenzonitrile (Example Compound 215) and (3-(6-(3,5-dimethylisoxazol-4-yl)-2-(pyrrolidin-1-yl)-1H-benzo[d]imidazol-4-yl)-4-methylphenyl)(pyrrolidin-1-yl)methanone (Example Compound 218)

(283) ##STR00092##

(284) A mixture of 81 (0.200 g, 0.55 mmol) and pyrrolidine (0.156 g, 2.2 mmol) in 1,4-dioxane (2 mL) was stirred at 180 C. under microwave heating conditions for 4 h. The reaction was cooled to rt and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine (10 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-10% methanol/dichloromethane) to give Example Compound 215 (0.05 g, 22%) and Example Compound 218 (0.02 g, 7.7%) as off-white solids.

Example Compound 215

(285) .sup.1H NMR (400 MHz, CD.sub.3OD) 7.66 (s, 2H), 7.51 (d, J=8.2 Hz, 1H), 7.18 (br.s, 1H), 6.75 (br.s, 1H), 3.53 (t, J=6.4 Hz, 4H), 2.43 (s, 3H), 2.29 (br.s, 3H), 2.28 (s, 3H), 2.04 (t, J=6.4 Hz, 4H); ESI MS m/z 398 [M+H].sup.+; Example Compound 218: .sup.1H NMR (400 MHz, CD.sub.3OD) 7.48 (br.s, 2H), 7.38-7.45 (m, 1H), 7.16 (s, 1H), 6.74 (s, 1H), 3.58 (t, J=6.8 Hz, 4H), 3.53 (t, J=6.4 Hz, 4H), 2.42 (s, 3H), 2.27 (s, 6H), 2.03 (t, J=6.4 Hz, 4H), 1.93-2.00 (m, 2H), 1.85-1.93 (m, 2H); ESI MS m/z 470 [M+H].sup.+.

(286) TABLE-US-00002 TABLE 1 Examples prepared using the methods described above Purity Example General HPLC Compound Chemical Name Structure procedure Characterization (%) 1 4,4-(1H- benzo[d] imidazole-4,6- diyl)bis(3,5- dimethyl isoxazole) A .sup.1H NMR (300 MHz, CD.sub.3OD) 8.26 (s, 1H), 7.57 1H), 7.14 (s, 1H), 2.46 (s, 3H), 2.38 (s, 3H), 2.30 (s, 3H), 2.23 (s, 3H); ESI MS m/z 309 [M + H]+. 98.7 2 3-(6-(3,5- dimethyl isoxazol-4- yl)-1H- benzo[d] imidazol-4- yl) benzonitrile D .sup.1H NMR (300 MHz, CD.sub.3OD) 8.27 (s, 1H), 8.07-8.00 (m, 2H), 7.92 (s, 1H), 7.74-7.63 (m, 2H), 7.48 (d, J = 1.2 Hz, 1H), 2.39 (s, 3H), 2.23 (s, 3H); ESI MS m/z 315 [M + H]+ 98.0 3 4,4- (quinazoline- 2,4-diyl)bis (3,5-dimethyl isoxazole) A .sup.1H NMR (500 MHz, CDCl.sub.3) 8.09 (d, J = 8.5 Hz, 1H), 7.95- 7.91 (m, 1H), 7.75-7.74 (m, 1H), 7.62-7.59 (m, 1H), 2.88 (s, 3H), 2.71 (s, 3H), 2.43 (s, 3H), 2.31 (s, 3H); ESI MS m/z 321 [M + H]+. 96.5 4 N-benzyl-6- (3,5- dimethyl- isoxazol-4- yl)-1H- benzo[d] imidazol-4- amine G .sup.1H NMR (500 MHz, CD.sub.3OD) 8.06 (s, 1H), 7.32 (m, 2H), 7.31 (m, 2H), 7.22 (m, 1H), 6.74 (s, 1H), 6.12 (s, 1H), 4.53 (s, 2H), 2.22 (s, 3H), 2.05 (s, 3H); ESI m/z 319 [M + H]+. 98.5 5 N-benzyl-2- (3,5- dimethyl- isoxazol-4- yl)quinazolin- 4-amine B .sup.1H NMR (500 MHz, CDCl.sub.3) 7.85 (d, J = 7.5 Hz, 1H), 7.75- 7.68 (m, 2H), 7.44-7.36 (m, 5H), 7.34-7.31 (m, 1H), 5.93 (s, 1H), 4.91 (d, J = 5.0 Hz, 2H), 2.80 (s, 3H), 2.64 (s, 3H); ESI m/z 331 [M + H]+. 99.0 6 4,4-(2-methyl- 1H-benzo[d] imidazole-4,6- diyl)bis(3,5- dimethyl isoxazole) A .sup.1H NMR (300 MHz, CD.sub.3OD) 7.47 (s, 1H), 7.05 (d, J = 1.5 Hz, 1H), 2.58 (s, 3H), 2.44 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H), 2.22 (s, 3H); ESI MS m/z 323 [M + H]+ >99 7 6-(3,5- dimethyl isoxazol-4- yl)-N- phenyl-1H- benzo[d] imidazol-4- amine E .sup.1H NMR (300 MHz, CD.sub.3OD) 8.03 (s, 1H), 7.35 (s, 1H), 7.25-7.20 (m, 2H), 7.12- 7.09 (m, 2H), 6.90 (d, J = 1.8 Hz, 1H), 6.86- 6.81 (m, 1H), 2.37 (s, 3H), 2.22 (s, 3H); ESI MS m/z 305 [M + H]+ 97.6 8 4,4-(imidazo [1,2-a] pyridine- 6,8-diyl) bis(3,5- dimethyl isoxazole) 00 A .sup.1H NMR (500 MHz, CDCl.sub.3) 8.08 (d, J = 1.5 Hz, 1H), 7.73- 7.72 (m, 2H), 6.91 (d, J = 2.0 Hz, 1H), 2.47 (s, 3H), 2.46 (s, 3H), 2.32 (s, 3H), 2.31 (s, 3H); ESI m/z 309 [M + H]+. 95.4 9 3,5-dimethyl- 4-(4-(1,3,5- trimethyl-1H- pyrazol-4-yl)- 1H-benzo[d] imidazol-6- yl)isoxazole 01 D .sup.1H NMR (300 MHz, CD.sub.3OD) 8.23 (s, 1H), 7.56 (s, 1H), 7.06 (d, J = 1.2 Hz, 1H), 3.83 (s, 3H), 2.48 (s, 3H), 2.32 (s, 3H), 2.22 (s, 3H), 2.18 (s, 3H); ESI MS m/z 322 [M + H]+ >99 10 4,4-(imidazo [1,2-a] pyrazine-6,8- diyl)bis(3,5- dimethyl isoxazole) 02 A .sup.1H NMR (500 MHz, CDCl.sub.3) 8.09 (s, 1H), 7.86 (d, J = 1.1 Hz, 1H), 7.80 (d, J = 0.97 Hz, 1H), 2.62 (s, 3H), 2.60 (s, 3H), 2.44 (s, 6H); ESI MS m/z 310 [M + H]+. >99 11 6,8-bis(3,5- dimethyl- isoxazol-4- yl)-2H- benzo[b] [1,4]oxazin- 3(4H)-one 03 none .sup.1H NMR (300 MHz, DMSO-d.sub.6) 10.84 (s, 1H), 6.94-6.91 (m, 2H), 4.66 (s, 2H), 2.42 (s, 3H), 2.33 (s, 3H), 2.24 (s, 3H), 2.17 (s, 3H); MM m/z 340 [M + H]+. >99 12 2-(3,5- dimethyl- isoxazol-4- yl)-6,7- dimethoxy- N-phenyl- quinazolin- 4-amine 04 B .sup.1H NMR (500 MHz, CDCl.sub.3) 10.90 (s, 1H), 7.71 (m, 3H), 7.31 (m, 2H), 7.23 (m, 1H), 7.09 (s, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 2.61 (s, 3H), 2.31 (s, 3H); ESI MS m/z 377 [M + H]+. >99 13 6,8-bis(3,5- dimethyl- isoxazol-4- yl)-3,4- dihydro-2H- benzo[b][1,4] oxazine 05 none .sup.1H NMR (300 MHz, CDCl.sub.3) 6.48 (d, J = 2.1 Hz, 1H), 6.35 (d, J = 2.1 Hz, 1H), 4.28 (t, J = 4.4 Hz, 2H), 3.95 (br s, 1H), 3.51-3.47 (m, 2H), 2.40 (s, 3H), 2.35 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H); MM m/z 326 [M + H]+. >99 14 3,5-dimethyl- 4-(6-(1,3,5- trimethyl-1H- pyrazol-4-yl)- 1H-benzo [d]imidazol- 4-yl)isoxazole 06 none .sup.1H NMR (300 MHz, CD.sub.3OD) 8.23 (s, 1H), 7.54 (s, 1H), 7.07 (d, J = 1.5 Hz, 1H), 3.80 (s, 3H), 2.40 (s, 3H), 2.32 (s, 3H), 2.25 (s, 6H); ESI MS m/z 322 [M + H]+ 96.3 15 6-(3,5-dimethyl isoxazol-4-yl)- N-phenyl- [1,2,4] triazolo[4,3- a]pyridin-8- amine 07 C .sup.1H NMR (500 MHz, CDCl.sub.3) 8.32 (s, 1H), 7.99 (d, J = 1.0 Hz, 1H), 7.42-7.39 (m, 2H), 7.31- 7.29 (m, 2H), 7.16-7.14 (m, 1H), 7.09 (s, 1H), 6.95 (d, J = 1.5 Hz, 1H), 2.43 (s, 3H), 2.28 (s, 3H); ESI m/z 306 [M + H]+. 98.6 16 3,5-dimethyl-4- (4-(1-methyl- 1H-pyrazol-5- yl)-1H-benzo [d]imidazol-6- yl)isoxazole 08 D .sup.1H NMR (500 MHz, DMSO-d.sub.6) 12.90-12.40 (bs, 1H), 8.33 (s, 1H), 7.90-7.50 (m, 2H), 7.22 (s, 1H), 6.54 (d, J = 1.7 Hz, 1H), 3.87 (s, 3H), 2.44 (s, 3H), 2.27 (s, 3H); ESI m/z 294 [M + H]+. >99 17 4,4-([1,2,4] triazolo [1,5-a] pyridine- 6,8-diyl)bis (3,5- dimethyl- isoxazole) 09 A .sup.1H NMR (300 MHz, CDCl.sub.3) 8.56 (d, J = 1.5 Hz, 1H), 8.43 (s, 1H), 7.27 (s, 1H), 2.50 (s, 3H), 2.49 (s, 3H), 2.35 (s, 3H), 2.34 (s, 3H); ESI m/z 310 [M + H]+. >99 18 4-(4-(1,3- dimethyl- 1H-pyrazol- 4-yl)- 1H-benzo [d]imidazol- 6-yl)-3,5- dimethyl isoxazole 0 D 1H NMR (300 MHz, CD.sub.3OD) 8.31 (s, 1H), 7.92 (s, 1H), 7.50 (d, J = 1.5 Hz, 1H), 7.17 (d, J = 1.5 Hz, 1H), 3.92 (s, 3H), 2.45 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H); ESI m/z 308 [M + H]+. >99 19 3,5-dimethyl-4- (4-(2-(trifluoro methyl) phenyl)-1H- benzo[d] imidazol-6- yl)isoxazole D .sup.1H NMR (300 MHz, CD.sub.3OD) 8.18 (s, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.73-7.63 (m, 3H), 7.51 (d, J = 7.5 Hz, 1H), 7.08 (s, 1H), 2.43 (s, 3H), 2.28 (s, 3H); ESI m/z 358 [M + H]+. >99 20 3,5-dimethyl- 4-(4-(4- methyl pyridin-3- yl)-1H- benzo[d] imidazol-6- yl)isoxazole D .sup.1H NMR (300 MHz, CD.sub.3OD) 8.45 (br.s, 2H), 8.25 (s, 1H), 7.67 (br.s, 1H), 7.47 (br.s, 1H), 7.14 (s, 1H), 2.46 (s, 3H), 2.30 (s, 3H), 2.27 (s, 3H); ESI m/z 305 [M + H]+. >99 21 4,4-(1H- indazole-5,7- diyl)bis(3,5- dimethyl isoxazole) H .sup.1H NMR (300 MHz, DMSO-d.sub.6) 13.1 (s, 1H), 8.20 (s, 1H), 7.81 (s, 1H), 7.28 (s, 1H), 2.44 (s, 3H), 2.34 (s, 3H), 2.27 (s, 3H), 2.17 (s, 3H). ESI m/z 309 [M + H]+. >99 22 3,5-dimethyl- 4-(4- (pyrimidin- 5-yl)-1H- benzo[d] imidazol-6- yi)isoxazole D .sup.1H NMR (300 MHz, CD.sub.3OD) 9.38 (s, 2H), 9.19 (s, 1H), 8.34 (s, 1H), 7.63 (s, 1H), 7.46 (s, 1H), 2.46 (s, 3H), 2.31 (s, 3H); ESI MS m/z 297 [M + H]+. >99 23 3,5-dimethyl- 4-(4-(1- methyl-1H- indazol-4- yl)-1H- benzo[d] imidazol-6- yl)isoxazole D .sup.1H NMR (300 MHz, CD.sub.3OD) 8.24 (s, 1H), 7.87 (s, 1H), 7.67-7.57 (m, 3H), 7.45 (d, J = 6.0 Hz, 1H), 7.39 (s, 1H), 4.13 (s, 3H), 2.48 (s, 3H), 2.33 (s, 3H); ESI MS m/z 344 [M + H]+. 98.5 24 N-benzyl-6- (3,5- dimethyl- isoxazol-4- yl)-[1,2,4] triazolo[4,3-a] pyridin-8- amine C .sup.1H NMR (500 MHz, CDCl.sub.3) 8.30 (s, 1H), 7.88 (s, 1H), 7.40-7.34 (m, 4H), 7.31- 7.28 (m, 1H), 6.12 (s, 1H), 4.55 (s, 2H), 2.28 (s, 3H), 2.10 (s, 3H); ESI m/z 320 [M + H]+. >99 25 6-(3,5- dimethyl- isoxazol-4- yl)-N-(4- methoxy- phenyl)-1H- benzo[d] imidazol-4- amine E .sup.1H NMR (500 MHz, CDCl.sub.3) 8.52 (s, 1H), 7.21 (d, J = 1.0 Hz, 1H), 6.84-6.89 (m, 2H), 6.73 (d, J = 1.0 Hz, 1H), 3.81 (s, 3H), 2.36 (s, 3H), 2.22 (s, 3H); ESI m/z 335 [M + H]+. 95.0 26 3,5-dimethyl- 4-(4-(4- methyl thiazol-5- yl)-1H- benzo[d] imidazol-6- yl)isoxazole D .sup.1H NMR (300 MHz, CD.sub.3OD) 9.03 (s, 1H), 8.28 (s, 1H), 7.56 (s, 1H), 7.25 (d, J = 1.5 Hz, 1H), 2.46 (s, 3H), 2.42 (s, 3H), 2.30 (s, 3H); ESI MS m/z 311 [M + H]+. 95.5 27 3,5-dimethyl- 4-(4-(2- methyl pyridin-3- yl)-1H- benzo[d] imidazol-6- yl)isoxazole D .sup.1H NMR (300 MHz, CD.sub.3OD) 8.51 (d, J = 6.0 Hz, 1H), 8.24 (s, 1H), 7.83-7.80 (m, 1H), 7.63 (s, 1H), 7.43-7.41 (m, 1H), 7.14 (d, J = 1.5 Hz, 1H), 2.46 (s, 3H), 2.42 (s, 3H), 2.30 (s, 3H); ESI MS m/z 305 [M + H]+. >99 28 1-(2-(6-(3,5- dimethyl- isoxazol-4- yl)-1H- benzo[d] imidazol-4- yl)phenyl)- N,N- dimethyl methanamine 0 D .sup.1H NMR (300 MHz, CD.sub.3OD) 8.20 (s, 1H), 7.63-7.60 (m, 2H), 7.48-7.39 (m, 3H), 7.10 (d, J = 1.8 Hz, 1H), 3.45 (br.s, 2H), 2.45 (s, 3H), 2.29 (s, 3H), 2.07 (s, 6H); ESI m/z 347 [M + H]+. >99 29 3,5-dimethyl- 4-(4-(1- methyl-1H- pyrazol-4- yl)-1H- benzo[d] imidazol-6- yl)isoxazole D .sup.1H NMR (300 MHz, CD.sub.3OD) 8.39 (br.s, 1H), 8.25 (s, 1H), 8.16 (br.s, 1H), 7.37 (br.s, 2H), 3.99 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H); ESI m/z 294 [M + H]+. >99 30 4,6-bis(3,5- dimethyl- isoxazol-4- yl)-N- methyl-1H- benzo[d] imidazol-2- amine F .sup.1H NMR (300 MHz, CD.sub.3OD) 7.16 (s, 1H), 6.81 (d, J = 1.5 Hz, 1H), 2.99 (s, 3H), 2.43 (s, 3H), 2.37 (s, 3H), 2.28 (s, 3H), 2.23 (s, 3H); ESI m/z 338 [M + H]+. >99 31 N-benzyl- 4,6-bis(3,5- dimethyl isoxazol-4- yl)-1H- benzo[d] imidazol-2- amine F .sup.1H NMR (300 MHz, CD.sub.3OD) 7.40-7.24 (m, 5H), 7.16 (s, 1H), 6.81 (d, J = 1.5 Hz, 1H), 4.59 (s, 2H), 2.42 (s, 3H), 2.31 (s, 3H), 2.27 (s, 3H), 2.18 (s, 3H); ESI m/z 414 [M + H]+. 98.8 32 6-(3,5- dimethyl- isoxazol-4- yl)-N-(3- fluorophenyl)- 1H-benzo[d] imidazol-4- amine E .sup.1H NMR (500 MHz, CDCl.sub.3) 8.06 (s, 1H), 7.15-6.90 (m, 5H), 6.68 (t, J = 2.5 Hz, 1H), 2.42 (s, 3H), 2.28 (s, 3H); ESI m/z 323 [M + H]+. 95.9 33 6-(3,5- dimethyl- isoxazol-4- yl)-N-(3- methoxy- phenyl)-1H- benzo[d] imidazol-4- amine E .sup.1H NMR (500 MHz, CDCl.sub.3) 8.09 (s, 1H), 7.24 (d, J = 1.0 Hz, 1H), 7.00 (s, 1H), 6.91 (s, 1H), 6.83 (d, J = 2.5 Hz, 1H), 6.78 (s, 1H), 6.55 (d, J = 2.5 Hz, 1H), 3.81 (s, 3H), 2.36 (s, 3H), 2.22 (s, 3H); ESI m/z 335 [M + H]+. 96.9 34 4,4-(2- (trifluoro methyl)-1H- benzo[d] imidazole- 4,6-diyl)bis (3,5-dimethyl isoxazole) none .sup.1H NMR (500 MHz, CD.sub.3OD) 7.65 (s, 1H), 7.27 (s, 1H), 2.47 (s, 3H), 2.40 (s, 3H), 2.31 (s, 3H), 2.25 (s, 3H); MM m/z 377 [M + H]+. >99 35 6-(3,5- dimethyl- isoxazol-4- yl)-N- (pyridin-3- ylmethyl)- 1H-benzo[d] imidazol-4- amine G .sup.1H NMR (300 MHz, CD.sub.3OD) 8.61 (d, J = 1.5 Hz, 1H), 8.42 (dd, J = 8.0, 1.5 Hz, 1H), 8.10 (s, 1H), 7.94-7.90 (m, 1H), 7.43-7.39 (m, 1H), 6.78 (d, J = 1.2 Hz, 1H), 6.13 (d, J = 1.2 Hz, 1H), 4.63 (s, 2H), 2.24 (s, 3H), 2.07 (s, 3H); ESI MS m/z 320 [M + H]+. >99 36 3-(6-(3,5- dimethyl- isoxazol-4- yl)-1H- benzo[d] imidazol-4- yl)benzamide D .sup.1H NMR (300 MHz, CD.sub.3OD) 8.30 (d, J = 6.5 Hz, 1H), 8.27 (s, 1H), 7.98-7.96 (m, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.36 (d, J = 1.5 Hz, 1H), 2.46 (s, 3H), 2.31 (s, 3H); ESI MS m/z 333 [M + H]+. 98.7 37 6-(3,5- dimethyl- isoxazol-4- yl)-N- ((1,3,5- trimethyl-1H- pyrazol-4- yl)methyl)- 1H-benzo[d] imidazol- 4-amine G .sup.1H NMR (300 MHz, CD.sub.3OD) 8.04 (s, 1H), 6.79 (d, J = 1.2 Hz, 1H), 6.34 (d, J = 1.5 Hz, 1H), 4.22 (s, 2H), 3.71 (s, 3H), 2.40 (s, 3H), 2.27 (s, 3H), 2.25 (s, 3H), 2.21 (s, 3H), 2.01 (s, 3H); ESI MS m/z 373 [M + Na]+. 93.0 38 6-(3,5- dimethyl- isoxazol-4- yl)-N-(4- fluorobenzyl)- 1H-benzo[d] imidazol-4- amine 0 G 1H NMR (300 MHz, CD.sub.3OD) 8.07 (s, 1H), 7.46-7.42 (m, 2H), 7.08-7.02 (m, 2H), 6.76 (s, 1H), 6.12 (d, J = 0.9 Hz, 1H), 4.51 (s, 2H), 2.25 (s, 3H), 2.08 (s, 3H); ESI m/z 337 [M + H]+. >99 39 6-(3,5- dimethyl- isoxazol-4- yl)-N-((3,5- dimethyl- isoxazol-4- yl)methyl)- 1H-benzo[d] imidazol-4- amine G .sup.1H NMR (300 MHz, CD.sub.3OD) 8.07 (s, 1H), 6.81 (d, J = 1.2 Hz, 1H), 6.31 (d, J = 1.2 Hz, 1H), 4.28 (s, 2H), 2.39 (s, 3H), 2.38 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H); ESI MS m/z 338 [M + H]+. 98.0 40 N-(4- chlorophenyl)- 6-(3,5- dimethyl- isoxazol-4- yl)-1H- benzo[d] imidazol- 4-amine E .sup.1H NMR (500 MHz, CD.sub.3OD) 9.16 (s, 1H), 7.31-7.29 (m, 3H), 7.16 (s, 1H), 7.09-7.07 (m, 2H), 2.43 (s, 3H), 2.26 (s, 3H); ESI MS m/z 339 [M + H]+. >99 41 3,5-dimethyl- 4-(2- methyl-4-(2- methylpyridin- 3-yl)-1H- benzo[d] imidazol-6- yl)isoxazole D .sup.1H NMR (300 MHz, CD.sub.3OD) 8.50 (br.s, 1H), 7.80 (dd, J = 7.6, 1.3 Hz, 1H), 7.47- 7.38 (m, 2H), 7.04 (d, J = 1.4 Hz, 1H), 2.56 (s, 3H), 2.44 (s, 3H), 2.42 (s, 3H), 2.29 (s, 3H); ESI m/z 319 [M + H]+. >99 42 N-(6-(3,5- dimethyl- isoxazol-4- yl)-1H- benzo[d] imidazol-4- yl)-3,5- dimethyl- isoxazol- 4-amine E .sup.1H NMR (500 MHz, CDCl.sub.3) 8.13 (s, 1H), 6.80 (s, 1H), 6.20 (s, 1H), 6.02 (d, J = 1.0 Hz, 1H), 2.38 (s, 6H), 2.21 (s, 3H), 2.18 (s, 3H); ESI m/z 324 [M + H]+. >99 43 6-(3,5- dimethyl- isoxazol-4- yl)-N- (pyrimidin- 2-yl)-1H- benzo[d] imidazol- 4-amine E .sup.1H NMR (500 MHz, CDCl.sub.3) 8.49 (d, J = 4.5 Hz, 2H), 8.15 (s, 1H), 8.05 (s, 1H), 7.18 (s, 1H), 6.80 (t, J = 4.5 Hz, 1H), 2.47 (s, 3H), 2.34 (s, 3H); ESI m/z 307 [M + H]+. >99 44 N-(6-(3,5- dimethyl- isoxazol-4- yl)-1H- benzo[d] imidazol-4- yl)-4- methyl- isoxazol- 3-amine E .sup.1H NMR (500 MHz, CDCl.sub.3) 8.03 (s, 1H), 7.71 (s, 1H), 7.53 (s, 1H), 6.97 (s, 1H), 5.83 (s, 1H), 2.45 (s, 3H), 2.39 (s, 3H), 2.32 (s, 3H); ESI m/z 310 [M + H]+. 98.9 45 4,4-(2- isopropyl- 1H-benzo[d] imidazole-4,6- diyl)bis(3,5- dimethyl isoxazole) I .sup.1H NMR (500 MHz, CD.sub.3OD) 7.69 (d, J = 1.4 Hz, 1H), 7.40 (d, J = 1.4 Hz, 1H), 3.55-3.40 (m, 1H), 2.46 (s, 3H), 2.38 (s, 3H), 2.30 (s, 3H) 2.21 (s, 3H), 1.53 (d, J = 7.0 Hz, 6H); ESI m/z 351 [M + H]+. 99.0 46 4,4-(2- ethoxy-1H- benzo[d] imidazole- 4,6-diyl)bis (3,5-dimethyl- isoxazole) J .sup.1H NMR (500 MHz, CD.sub.3OD) 7.50-7.10 (m, 1H), 6.94 (d, J = 1.5 Hz, 1H), 4.53 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 2.38 (s, 3H), 2.27 (s, 3H), 2.24 (s, 3H), 1.45 (d, J = 7.1 Hz, 3H); ESI m/z 353 [M + H]+. 98.1 47 6-(3,5- dimethyl- isoxazol-4- yl)-N- (pyridin-2- ylmethyl)- 1H-benzo[d] imidazol- 4-amine G .sup.1H NMR (300 MHz, CD.sub.3OD) 8.53-8.51 (m, 1H), 8.10 (s, 1H), 7.77 (td, J = 7.8, 1.8 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.30 (dd, J = 6.3, 1.8 Hz, 1H), 6.77 (s, 1H), 6.06 (s, 1H), 4.65 (s, 2H), 2.23 (s, 3H), 2.06 (s, 3H); ESI MS m/z 320 [M + H]+. >99 48 4-(4-(2- methoxy- pyridin-3- yl)-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole 0 D .sup.1H NMR (300 MHz, CD.sub.3OD) 8.23 (d, J = 4.5 Hz, 1H), 8.21 (s, 1H), 7.86 (d, J = 6.0 Hz, 1H), 7.60 (s, 1H), 7.24 (s, 1H), 7.12 (dd, J = 7.2, 5.1 Hz, 1H), 3.95 (s, 3H), 2.46 (s, 3H), 2.31 (s, 3H); ESI MS m/z 321 [M + H]+. 98.4 49 3,5-dimethyl- 4-(2-methyl- 4-(1,3,5- trimethyl- 1H-pyrazol- 4-yl)-1H- benzo[d] imidazol-6- yl)isoxazole D .sup.1H NMR (300 MHz, CD.sub.3OD) 7.66 (d, J = 1.5 Hz, 1H), 7.34 (d, J = 1.5 Hz, 1H), 3.84 (s, 3H), 2.85 (s, 3H), 7.47 (s, 3H), 2.30 (s, 3H), 2.21 (s, 3H), 2.15 (s, 3H); ESI m/z 336 [M + H]+. 97.7 50 3,5-dimethyl- 4-(2- methyl-4-(4- (trifluoro- methyl) pyridin-3- yl)-1H- benzo[d] imidazol-6- yl)isoxazole D .sup.1H NMR (500 MHz, CD.sub.3OD) 9.00-8.80 (m, 1H), 8.73 (s, 1H), 7.88 (s, 1H), 7.60-7.40 (m, 1H), 7.07 (s, 1H), 2.54 (s, 3H), 2.42 (s, 3H), 2.26 (s, 3H); ESI m/z 373 [M + H]+. >99 51 4-(4-(2- methoxy-5- methyl- phenyl)- 1H-benzo[d] midazol-6- yl)-3,5- dimethyl isoxazole D .sup.1H NMR (500 MHz, DMSO-d.sub.6) 12.5-12.14 (m, 1H), 8.21-8.19 (m, 1H), 7.61 (s, 0.7H), 7.43 (d, J = 1.5 Hz, 0.56H), 7.25-7.03 (m, 3.77H), 3.71 (m, 3H), 2.44 (m, 3H), 2.31-2.26 (m, 6H); ESI m/z 334 [M + H]+. >99 52 3,5-dimethyl- 4-(2- methyl-7-(3- methyliso- thiazol-4-yl)- 1H-benzo[d] imidazol-5- yl)isoxazole L .sup.1H NMR (300 MHz, CD.sub.3OD-d.sub.4) 8.92 (s, 1H), 7.46 (s, 1H), 7.10 (d, J = 1.50 Hz, 1H), 2.57 (s, 3H), 2.44 (br s, 6H), 2.29 (s, 3H); MS m/z 325 [M + H]+. 97.6 53 3,5-dimethyl- 4-(2- methyl-4-(4- methyl- pyridin-3-yl)- 1H-benzo[d] imidazol-6- yl)isoxazole D .sup.1H NMR (300 MHz, CD.sub.3OD) 8.45 (s, 2H), 7.60- 7.40 (m, 2H), 7.04 (d, J = 1.5 Hz, 1H), 2.56 3H), 2.45 (s, 3H), 2.29 (s, 3H), 2.27 (s, 3H); ESI m/z 319 [M + H]+. >99 54 4,4-(1-methyl- 1H-indazole- 5,7-diyl)bis (3,5-dimethyl- isoxazole) none .sup.1H NMR (500 MHz, CDCl.sub.3) 8.08 (s, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.0 (d, J = 1.5 Hz, 1H), 3.80 (s, 3H), 2.44 (s, 3H), 2.34 (s, 3H), 2.30 (s, 3H), 2.16 (s, 3H); ESI m/z 323 [M + H]+. >99 55 4,4-(2-methyl- 2H-indazole- 5,7-diyl)bis (3,5-dimethyl- isoxazole) none .sup.1H NMR (500 MHz, CDCl.sub.3) 8.01 (s, 1H), 7.53 (d, J = 1.5 Hz, 1H), 6.98 (d, J = 1.5 Hz, 1H), 4.26 (s, 3H), 2.45 (s, 3H), 2.44 (s, 3H), 2.31 (s, 6H); ESI m/z 323 [M + H]+. >99 56 3-(6-(3,5- dimethyl- isoxazol-4- yl)-1H- benzo[d] imidazol-4- yl)pyridin- 2(1H)-one D .sup.1H NMR (300 MHz, CD.sub.3OD) 8.34 (s, 1H), 7.93 (dd, J = 6.6, 2.1 Hz, 1H), 7.61 (d, J = 1.5 Hz, 1H), 7.55 (dd, J = 6.6, 2.1 Hz, 1H), 7.40 (d, J = 1.5 Hz, 1H), 6.59-6.55 (m, 1H), 2.45 (s, 3H), 2.30 (s, 3H); ESI MS m/z 307 [M + H]+. >99 57 3-(6-(3,5- dimethyl- isoxazol-4- yl)-1H- benzo[d] imidazol-4- yl)-2- methyl- benzonitrile D .sup.1H NMR (300 MHz, CD.sub.3OD) 8.24 (s, 1H), 7.78 (d, J = 6.9 Hz, 1H), 7.65 (d, J = 6.9 Hz, 1H), 7.65-7.60 (m, 1H), 7.51-7.46 (m, 1H), 7.11 (s, 1H), 2.45 (s, 3H), 2.38 (s, 3H), 2.30 (s, 3H); ESI MS m/z 329 [M + H]+. >99 58 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-1H- benzo[d] imidazol-4- yl)-4- methyl- benzonitrile 0 D .sup.1H NMR (300 MHz, CD.sub.3OD) 7.70 (d, J = 7.8 Hz, 1H), 7.69 (s, 1H), 7.55 (d, J = 8.1 Hr, 1H), 7.49 (s, 1H), 7.02 (d, J = 1.5 Hz, 1H), 2.56 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H), 2.27 (s, 3H); ESI MS m/z 343 [M + H]+. >99 59 3,5-dimethyl- 4-(2- methyl-4-(2- (trifluoro- methyl) pyridin-3-yl)- 1H-benzo[d] imidazol-6- yl)isoxazole D .sup.1H NMR (300 MHz, CD.sub.3OD) 8.77 (d, J = 3.9 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.77 (dd, J = 7.8, 5.1 Hz, 1H), 7.50 (s, 1H), 7.04 (d, J = 0.9 Hz, 1H), 2.54 (s, 3H), 2.42 (s, 3H), 2.27 (s, 3H); ESI m/z 373 [M + H]+. >99 60 4-(4-(1,3- dimethyl-1H- pyrazol-4- yl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl- isoxazole D .sup.1H NMR (300 MHz, CD3OD) 7.86 (br.s, 1H), 7.35 (br.s, 1H), 7.05 (d, J = 1.2 Hz, 1H), 3.92 (s, 3H), 2.58 (s, 3H), 2.44 (s, 3H), 2.31 (s, 3H), 2.28 (s, 3H); ESI m/z 322 [M + H]+. >99 61 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-1H- benzo[d] imidazol-4- yl)isonico- tinonitrile D .sup.1H NMR (300 MHz, CD3OD) 9.67 (s, 1H), 8.79 (d, J = 5.7 Hz, 1H), 8.35 (d, J = 6.0 Hz, 1H), 8.10 (d, J = 1.2 Hz, 1H), 3.12 (s, 3H), 2.47 (s, 3H), 2.32 (s, 3H); ESI m/z 330 [M + H]+. >99 62 6-(3,5 dimethyl- isoxazol-4- yl)-N- (pyrazin-2- yl)-1H- benzo[d] imidazol-4- amine E .sup.1H NMR (500 MHz, CDCl.sub.3) 9.29 (s, 1H), 8.32 (s, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.62 (d, J = 1.1 Hz, 1H), 7.48 (s, 1H), 2.48 (s, 3H), 2.31 (s, 3H); ESI MS m/z 307 [M + H]+ >99 63 6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-N-(3- methyl pyridin-2- yl)-1H- benzo[d] imidazol-4- amine E .sup.1H NMR (500 MHz, CD.sub.3OD) 7.81 (s, 1H), 7.72 (s, 1H), 7.60 (d, J = 1.3 Hz, 1H), 7.45 (d, J = 1.3 Hz, 1H), 7.02 (s, 1H), 2.78 (s, 3H), 2.51 (s, 3H), 2.47 (s, 3H), 2.30 (s, 3H); ESI MS m/z 334 [M + H]+ >99 64 N-(2-(6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl- 1H-benzo[d] imidazol-4- yl)phenyl) acetamide D .sup.1H NMR (500 MHz, CD3OD) 7.70 (d, J = 7.0 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.48-7.42 (m, 2H), 7.37 (d, J = 7.2 Hz, 1H), 7.07 (s, 1H), 2.58 (s, 3H), 2.44 (s, 3H), 2.28 (s, 3H), 1.86 (s, 3H); ESI m/z 361 [M + H]+. >99 65 4,6-bis(3,5- dimethyl- isoxazol-4- yl)-N- (pyridin-3- ylmethyl)- 1H-benzo[d] imidazol-2- amine F .sup.1H NMR (300 MHz, CD.sub.3OD) 8.57 (d, J = 1.8 Hz, 1H), 8.43 (dd, J = 5.1, 1.5 Hz, 1H), 7.89-7.86 (m, 1H), 7.42 (dd, J = 7.8, 5.4 Hz, 1H), 7.17 (s, 1H), 6.82 (s, 1H), 4.66 (s, 2H), 2.42 (s, 3H), 2.31 (s, 3H), 2.27 (s, 3H), 2.18 (s, 3H); ESI m/z 415 [M + H]+. 98.5 66 4-(4-(1,5- dimethyl-3- (trifluoro- methyl)-1H- pyrazol-4- yl)-2-methyl- 1H-benzo[d] imidazol-6- yl)-3,5- dimethyl- isoxazole L .sup.1H NMR (300 MHz, CD.sub.3OD-d.sub.4) 7.46 (br s, 1H), 7.00 (s, 1H), 3.94 (s, 3H), 2.56 (s, 3H), 2.43 (s, 3H), 2.27 (s, 3H), 2.16 (s, 3H); MS m/z 390 [M + H]+. >99 67 4-(5-(3,5- dimethyl- isoxazol-4- yl)-2- methyl- 1H-benzo[d] imidazol-7- yl)-N,3- dimethyl isoxazole-5- carboxamide L .sup.1H NMR (300 MHz, CD.sub.3OD-d.sub.4) 7.49 (br s, 1H), 7.13 (s, 1H), 2.84 (s, 3H), 2.58 (s, 3H), 2.46 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H); MS m/z 366 [M + H]+. >99 68 5-(6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl- 1H-benzo[d] imidazol-4- yl)-6- methyl- pyridin- 2-amine 0 D .sup.1H NMR (300 MHz, CD.sub.3OD) 7.45 (d, J = 8.4 Hz, 1H), 7.42 (s, 1H), 6.97 (d, J = 1.5 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 2.55 (s, 3H), 2.43 (s, 3H), 2.28 (s, 3H), 2.23 (s, 3H); ESI m/z 334 [M + H]+. >99 69 3,5-dimethyl- 4-(2-methyl- 4-(2-(methyl- sulfonyl) phenyl)-1H- benzo[d] imidazol-6- yl)isoxazole D .sup.1H NMR (300 MHz, CD3OD) 8.24 (d, J = 6.9 Hz, 1H), 7.80- 7.72 (m, 2H), 7.53-7.50 (m, 2H), 7.14 (d, 1.5 Hz, 1H), 2.74 (s, 3H), 2.53 (s, 3H), 2.44 (s, 3H), 2.28 (s, 3H); ESI m/z 382 [M + H]+. >99 70 3,5-dimethyl- 4-(7-(2- methyl pyridin-3-yl)- 1H-indazol- 5-yl) isoxazole H .sup.1H NMR (500 MHz, CDCl.sub.3) 8.58-8.57 (m, 1H), 8.21 (s, 1H), 7.75-7.74 (m, 1H), 7.69 (d, J = 1.5 Hz, 1H), 7.35- 7.33 (m, 1H), 7.15 (d, J = 1.5 Hz, 1H), 2.51 (s, 3H), 2.46 (s, 3H), 2.10 (s, 3H); ESI m/z 305 [M + H]+. >99 71 2-(6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-1H- benzo[d] imidazol-4- yl)benzonitrile D .sup.1H NMR (300 MHz, CD.sub.3OD) 8.39 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 0.7 Hz, 1H), 7.78 (td, J = 7.8, 1.4 Hz, 1H),7.65 (t, J = 8.1 Hz, 1H), 7.58 (d, J = 0.9 Hz, 1H), 3.11 (s, 3H), 2.47 (s, 3H), 2.31 (s, 3H); ESI m/z 329 [M + H]+. 98.9 72 4-(4-(4- methoxy- pyridin-3- yl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole D .sup.1H NMR (300 MHz, CD.sub.3OD) 8.50 (d, J = 5.7 Hz, 1H), 8.45 (s, 1H), 7.49 (br.s, 1H), 7.25 (d, J = 6.0 Hz, 1H), 7.12 (d, J = 0.9 Hz, 1H), 3.92 (s, 1H), 2.57 (s, 3H), 2.45 (s, 3H), 2.29 (s, 3H); ESI m/z 335 [M + H]+. 98.6 73 3-(6-(3,5 dimethyl- isoxazol-4- yl)-1H- benzo[d] imidazol-4- yl)-2- methyl- benzamide D .sup.1H NMR (300 MHz, CD.sub.3OD) 8.23 (s, 1H), 7.62- 7,41 (m, 4H), 7.09 (s, 1H), 2.46 (s, 3H), 2.30 (s, 3H), 2.22 (s, 3H); ESI MS m/z 347 [M + H]+. >99 74 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-1H- benzo[d] imidazol-4- yl)-4-methyl benzamide D .sup.1H NMR (300 MHz, CD.sub.3OD) 7.87-7.85 (m, 2H), 7.49-7.46 (m, 2H), 7.03 (d, J = 1.5 Hz, 1H), 2.55 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H), 2.26 (s, 3H); ESI MS m/z 361 [M + H]+. >99 75 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-1H- benzo[d] imidazol-4- yl)-4- methyl benzoic acid D .sup.1H NMR (300 MHz, CD.sub.3OD) 7.99 (dd, J = 1.8, 8.1 Hz, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 1.5 Hz, 1H), 7.01 (d, J = 1.5 Hz, 1H), 2.55 (s, 3H), 2.45 (s, 3H), 2.30 (s, 3H), 2.25 (s, 3H); ESI MS m/z 362 [M + H]+. >99 76 4,4-(2-(2,2,2- trifluoro- ethyl)-1H- benzo[d] imidazole-5,7- diyl)bis(3,5- dimethyl isoxazole) I .sup.1H NMR (500 MHz, CD.sub.3OD) 7.70-7.45 (m, 1H), 7.14 (s, 3H), 3.89 (q, J = 10.4 Hz, 2H), 2.45 (s, 3H), 2.38 (s, 3H), 2.30 (s, 3H), 2.23 (s, 3H); ESI m/z 391 [M + H]+. 98.3 77 3,5-dimethyl- 4-(2- methyl-4-(2- (trifluoro- methoxy) phenyl)-1H- benzo[d] imidazol-6- yl)isoxazole D .sup.1H NMR (500 MHz, CD.sub.3OD) 7.63 (d, J = 7.2 Hz, 1H), 7.55- 7.49 (m, 4H), 7.09 (d, J = 1.6 Hz, 1H), 2.56 (s, 3H), 2.43 (s, 3H), 2.27 (s, 3H); ESI m/z 388 [M + H]+. 98.6 78 3,5-dimethyl- 4-(2- methyl-4-(2- (trifluoro methyl) phenyl)-1H- benzo[d] imidazol-6- yl)isoxazole 0 D .sup.1H NMR (500 MHz, CD.sub.3OD) 7.86 (s, 1H), 7.71 (s, 1H), 7.64 (s, 1H), 7.49 (d, J = 7.4 Hz, 2H), 6.98 (s, 1H), 2.52 (s, 3H), 2.42 (s, 3H), 2.26 (s, 3H); ESI m/z 372 [M + H]+. 98.6 79 3,5-dimethyl- 4-(2- methyl-4- (pyridin-3- yl)-1H- benzo[d] imidazol-6- yl)isoxazole D .sup.1H NMR (500 MHz, CD.sub.3OD) 9.03 (br.s, 1H), 8.58 (s, 1H), 8.31 (s, 1H), 7.59 (s, 1H), 7.45 (br.s, 1H), 7.25 (s, 1H), 2.61 (s, 3H), 2.45 (s, 3H), 2.29 (s, 3H); ESI m/z 305 [M + H]+. 97.3 80 4-(4-(5- fluoro-2- (trifluoro- methyl) phenyl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole D .sup.1H NMR (500 MHz, CD3OD) 7.92 (t, J = 6.8 Hz, 1H), 7.48 (s, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 8.3 Hz, 1H), 7.02 (s, 1H), 2.54 (s, 3H), 2.47 (s, 3H), 2.26 (s, 3H); ESI m/z 390 [M + H]+. >99 81 4-(2- ethoxy-4- (2-methyl pyridin-3- yl)-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole J .sup.1H NMR (500 MHz, CD.sub.3OD) 8.47 (s, 1H), 7.78 (d, J = 6.6 Hz, 1H), 7.45-7.20 (m, 2H), 6.93 (d, J = 1.6 Hz, 1H), 4.60-4.40 (bs, 2H), 2.43 (s, 6H), 2.28 (s, 3H), 1.55-1.35 (bs, 3H); ESI m/z 349 [M + H]+. >99 82 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-1H- benzo[d] imidazol-4- yl)pyridin- 2-amine D .sup.1H NMR (500 MHz, CD.sub.3OD) 8.03 (dd, J = 5.1, 1.8 Hz, 1H), 7.59 (dd, J = 7.5, 1.8 Hz, 1H), 7.48 (s, 1H), 7.12 (d, J = 1.3 Hz, 1H), 6.82 (dd, J = 7.2, 5.1 Hz, 1H), 2.57 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H); ESI m/z 320 [M + H]+. 98.4 83 2-(6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-1H- benzo[d] imidazol-4- yl)-6- fluoro- benzonitrile D .sup.1H NMR (500 MHz, CD.sub.3OD) 7.82 (br.s, 1H), 7.58-7.38 (m, 3H), 7.23 (d, J = 1.6 Hz, 1H), 2.60 (s, 3H), 2.46 (s, 3H), 2.30 (s, 3H); ESI m/z 347 [M + H]+. 97.5 84 3,5-dimethyl- 4-(2- methyl-4-(3- methyl- pyridin-2- yl)-1H- benzo[d] imidazol-6 yl)isoxazole L .sup.1H NMR (300 MHz, CD.sub.3OD-d.sub.4) 8.48 (br s, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.52 (br s, 1H), 7.42 (dd, J1 = 8.4 Hz, J2 = 4.8 Hz, 1H), 7.13 (br s, 1H), 2.56 (s, 3H), 2.44 (s, 3H), 2.29 (br s, 6H); MS m/z 119 [M + H]+. >99 85 3,5-dimethyl- 4-(2- methyl-4- (pyrazin-2- yl)-1H- benzo[d] imidazol-6- yl)isoxazole L .sup.1H NMR (300 MHz, CD.sub.3OD-d.sub.4) 9.36 (br s, 1H), 8.82 (br s, 1H), 8.57 (d, J = 2.7 Hz, 1H), 7.87 (s, 1H), 7.60 (br s, 1H), 2.69 (s, 3H), 2.46 (s, 3H), 2.31 (s, 3H); MM m/z 306 [M + H]+. 98.0 86 3,5-dimethyl- 4-(2-methyl- 4-(6- methyl- pyridazin-3- yl)-1H- benzo[d] imidazol-6- yl)isoxazole L .sup.1H NMR (300 MHz, CD.sub.3OD-d.sub.4) 8.34 (br s, 1H), 7.78 (br s, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.62 (br s, 1H), 2.77 (s, 3H), 2.69 (s, 3H), 2.45 (s, 3H), 2.30 (s, 3H); MM m/z 320 [M + H]+. >99 87 4,4-(1H- indazole-4,6- diyl)bis(3,5- dimethyl- isoxazole) none .sup.1H NMR (500 MHz, CDCl.sub.3) 7.94 (s, 1H), 7.44 (s, 1H), 6.92 (d, J = 1.0 Hz, 1H), 2.48 (s, 3H), 2.41 (s, 3H), 2.33 (s, 3H), 2.27 (s, 3H); ESI m/z 309 [M + H]+. 97.9 88 3,5-dimethyl- 4-(2- methyl-4- phenyl-1H- benzo[d] imidazol 6- yl)isoxazole 0 D .sup.1H NMR (300 MHz, CD.sub.3OD) 7.80-7.63 (m, 2H), 7.52 (t, J = 6.6 Hz, 2H), 7.43 (d, J = 6.6 Hz, 2H), 7.17 (d, J = 1.5 Hz, 1H), 2.59 (s, 3H), 2.45 (s, 3H), 2.29 (s, 3H); ESI m/z 304 [M + H]+. >99 89 3,5-dimethyl- 4-(2-methyl- 4-(o-tolyl)- 1H-benzo[d] imidazol-6- yl)isoxazole D .sup.1H NMR (300 MHz, CD.sub.3OD) 7.44 (br.s, 1H), 7.39-7.27 (m, 4H), 6.96 (d, J = 1.2 Hz, 1H), 2.53 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H), 2.18 (s, 3H); ESI m/z 318 [M + H]+. >99 90 4-(4-(4- chloro-2- methyl- phenyl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole D .sup.1H NMR (500 MHz, CD.sub.3OD) 7.45 (s, 1H), 7.39 (s, 1H), 7.29 (s, 2H), 6.96 (d, J = 1.1 Hz, 1H), 2.54 (s, 3H), 2.43 (s, 3H), 2.28 (s, 3H), 2.18 (s, 3H); ESI m/z 352 [M + H]+. 98.5 91 4-(4-(2- fluoro- phenyl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole D .sup.1H NMR (500 MHz, CD.sub.3OD) 7.59, (t, J = 6.7 Hz, 1H), 7.47 (s, 2H), 7.34-7.26 (m, 2H), 7.14 (s, 1H), 2.58 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H); ESI m/z 322 [M + H]+. >99 92 4-(4-(5- fluoro-2- methyl- phenyl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole D .sup.1H NMR (500 MHz, CD3OD) 7.46 (s, 1H), 7.35 (s, 1H), 7.06 (d, J = 9.4 Hz, 2H), 6.98 (s, 1H), 2.55 (s, 3H), 2.44 (s, 3H), 2.28 (s, 3H), 2.15 (s, 3H); ESI m/z 336 [M + H]+. >99 93 4,4-(1- methyl-1H- benzo[d] imidazole- 5,7-diyl)bis (3,5-dimethyl isoxazole) N .sup.1H NMR (300 MHz, CD.sub.3OD) 8.18 (s, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.08 (d, J = 1.6 Hz, 1H), 3.58 (s, 3H), 2.44 (s, 3H), 2.32 (s, 3H), 2.28 (s, 3H), 2.13 (s, 3H); ESI m/z 323 [M + H]+. 99.0 94 2-(6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-1H- benzo[d] imidazol-4- yl)-4- fluoro- benzonitrile D .sup.1H NMR (300 MHz, CD.sub.3OD) 8.03-7.93 (m, 1H), 7.64-7.48 (m, 2H), 7.45- 7.31 (m, 1H), 7.25 (d, J = 1.5 Hz, 1H), 2.60 (s, 3H), 2.46 (s, 3H), 2.31 (s, 3H); ESI m/z 347 [M + H]+. >99 95 4,4-(1H- benzo[d] [1,2,3] triazole-4,6- diyl)bis(3,5- dimethyl isoxazole) none .sup.1H NMR (500 MHz, CD.sub.3OD) 7.83 (s, 1H), 7.34 (s, 1H), 2.48 (s, 3H), 2.43 (s, 3H), 2.32 (s, 3H), 2.27 (s, 3H); ESI m/z 308 [M H]. >99 96 3,5-dimethyl- 4-(2- methyl-4-(3- (trifluoro- methoxy) phenyl)-1H- benzo[d] imidazol-6- yl)isoxazole D .sup.1H NMR (500 MHz, CD.sub.3OD) 7.72 (s, 1H), 7.65 (s, 1H), 7.62-7.58 (m, 1H), 7.44 (s, 1H), 7.34 (s, 1H), 7.19 (s, 1H), 2.60 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H); ESI m/z 388 [M + H]+. HPLC > 99% >99 97 4-(4-(3,5- dimethyl- pyridin-4- yl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole L .sup.1H NMR (300 MHz, CD.sub.3OD-d.sub.4) 8.36 (s, 2H), 7.50 (s, 1H), 6.95 (d, J = 1.5 Hz, 1H), 2.54 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H), 2.06 (s, 6H); MM m/z 333 [M + H]+. 96.7 98 4-(4-(4,6- dimethyl- pyrimidin-5- yl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole 0 L .sup.1H NMR (300 MHz, CD.sub.3OD-d.sub.4) 8.94 (s, 1H), 7.53 (br s, 1H), 7.07 (d, J = 1.5 Hz, 1H), 2.56 (s, 3H), 2.45 (s, 3H), 2.29 (s, 3H), 2.28 (s, 6H); MM m/z 334 [M + H]+. 98.1 99 5-(6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-1H- benzo[d] imidazol-4- yl)-4,6- dimethyl pyrimidin-2- amine L .sup.1H NMR (300 MHz, CD.sub.3OD-d.sub.4) 7.37 (br s, 1H), 6.88 (d, J = 1.5 Hz, 1H), 2.46 (s, 3H), 2.34 (s, 3H), 2.19 (s, 3H), 1.98 (s, 6H); MM m/z 349 [M + H]+. 96.5 100 6-(3,5- dimethyl- isoxazol-4- yl)-N- ethyl-4-(2- methyl pyridin-3- yl)-1H- benzo[d] imidazol- 2-amine none .sup.1H NMR (300 MHz, CD.sub.3OD) 8.45 (dd, J = 5.1, 1.5 Hz, 1H), 7.78 (dd, J = 7.8, 1.5 Hz, 1H), 7.38 (dd, J = 7.8, 4.8 Hz, 1H), 7.19 (d, J = 1.2 Hz, 1H), 6.79 (d, J = 1.5 Hz, 1H), 3.40 (q, J = 7.2 Hz, 2H), 2.44 (s, 3H), 2.43 (s, 3H), 2.28 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H); ESI m/z 348 >99 [M + H]+. 101 5,7-bis(3,5- dimethyl- isoxazol-4- yl)-2- methyl benzo[d] oxazole a none .sup.1H NMR (500 MHz, CD.sub.3OD) 7.61 (d, J = 1.5 Hz, 1H), 7.26 (d, J = 1.5 Hz, 1H), 2.67 (s, 3H), 2.45 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H), 2.28 (s, 3H); ESI m/z 324 [M + H]+. 97.8 102 N-(6-(3,5- dimethyl- isoxazol-4- yl)-1H- benzo[d] imidazol-4- yl)-2- methoxy- benzene- sulfonamide none .sup.1H NMR (300 MHz, CD.sub.3OD) 8.73 (s, 1H), 7.72 (dd, J = 7.8, 1.5 Hz, 1H), 7.59- 7.53 (m, 1H), 7.38 (d, J = 0.9 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 6.98 (td, J = 7.8, 0.9 Hz, 1H), 6.89 (d, J = 1.5 Hz, 1H), 3.93 (s, 3 H), 2.22 (s, 3H), 2.05 (s, 3H); ESI MS m/z 399 [M + H]+. 90.0 103 4-(4- (benzo[d] [1,3]dioxol- 5-yl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole D .sup.1H NMR (300 MHz, CD.sub.3OD) 7.37 (s, 1H), 7.23- 7.19 (m, 2H), 7.12 (d, J = 1.5 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H), 6.02 (s, 2H), 2.59 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H); ESI MS m/z 348 [M + H]+. >99 104 3,5-dimethyl- 4-(2-methyl- 4-(4- methyl- thiazol-5- yl)-1H- benzo[d] imidazol-6- yl)isoxazole D .sup.1H NMR (300 MHz, CD.sub.3OD) 9.04 (s, 1H), 7.63- 7.36 (m, 1H), 7.15 (d, J = 1.5 Hz, 1H), 2.59 (s, 3H), 2.52-2.36 (m, 6H), 2.29 (s, 3H); ESI m/z 325 [M + H]+. >99 105 4-(4-(5- chloro-2- methyl- phenyl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole D .sup.1H NMR (500 MHz, CD.sub.3OD) 7.47 (br.s, 1H), 7.38-7.30 (m, 3H), 6.97 (s, 1H), 2.55 (s, 3H), 2.44 (s, 3H), 2.28 (s, 3H), 2.15 (s, 3H); ESI m/z 352 [M + H]+. 97.8 106 4-(4-(2- fluoro-3- methyl- phenyl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole D .sup.1H NMR (500 MHz, CD.sub.3OD) 7.48 (br.s, 1H), 7.10-7.29 (m, 2H), 7.23-7.16 (m, 1H), 7.12 (s, 1H), 2.58 (s, 3H), 2.44 (s, 3H), 2.38 (s, 3H), 2.29 (s, 3H); ESI m/z 336 [M + H]+. 98.7 107 4-(4-(5- chloro-2- methoxy- phenyl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole D .sup.1H NMR (300 MHz, CD.sub.3OD) 7.49-7.35 (m, 3H), 7.14 (d, J = 8.8 Hz, 1H), 7.08 (s, 1H), 3.80 (s, 3H), 2.56 (s, 3H), 2.45 (s, 3H), 2.29 (s, 3H); ESI m/z 368 [M + H]+. 97.8 108 4-(4-(2- fluoro-5- methoxy- phenyl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole 00 D .sup.1H NMR (500 MHz, CD.sub.3OD) 7.50 (br.s, 1H), 7.19-7.07 (m, 3H), 7.00 (br.s, 1H), 3.83 (s, 3H), 2.58 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H); ESI m/z 352 [M + H]+. 96.4 109 4-(4-(2- ethoxy- pyridin-3- yl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole 01 D .sup.1H NMR (300 MHz, CD.sub.3OD) 8.20 (br.s, 1H), 7.82 (d, J = 5.7 Hz, 1H), 7.48 (br.s, 1H), 7.13- 7.07 (m, 2H), 4.42 (q, J = 6.9 Hz, 2H), 2.57 (s, 3H), 2.45 (s, 3H), 2.30 (s, 3H), 1.26 (t, J = 6.9 Hz, 3H); ESI m/z 349 [M + H]+. >99 110 4-(4-(iso- quinolin-8- yl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole 02 D .sup.1H NMR (500 MHz, CD.sub.3OD) 8.95 (s, 1H), 8.46 (br.s, 1H), 8.06 (br.s, 1H), 7.94- 7.93 (m, 2H), 7.78 (d, J = 7.0 Hz, 1H), 7.61- 7.55 (m, 1H), 7.22 (s, 1H), 2.51 (s, 3H), 2.47 (s, 3H), 2.32 (s, 3H); ESI m/z 355 [M + H]+. >99 111 3,5-dimethyl- 4-(2- methyl-4- (quinolin-8- yl)-1H- benzo[d] imidazol-6- yl)isoxazole 03 D .sup.1H NMR (500 MHz, CD.sub.3OD) 8.76 (d, J = 2.2 Hz, 1H), 8.45 (d, J = 8.5 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.89 (dd, J = 7.2 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.58-7.53 (m, 2H), 7.23 (d, J = 1.3 Hz, 1H), 2.49 (s, 3H), 2.47 (s, 3H), 2.32 (s, 3H); ESI m/z 355 [M + H]+. 97.7 112 4-(4-(5- fluoro-2- methoxy- phenyl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl- isoxazole 04 D .sup.1H NMR (500 MHz, CD.sub.3OD) 7.44 (s, 1H), 7.19- 7.10 (m, 4H), 3.78 (s, 3H), 2.56 (s, 3H), 2.45 (s, 3H), 2.29 (s, 3H); ESI m/z 352 [M + H]+. >99 113 3,5-dimethyl- 4-(2- methyl-4-(5- methyl- thiazol-4- yl)-1H- benzo[d] imidazol-6- yl)isoxazole 05 L .sup.1H NMR (300 MHz, CD.sub.3OD-d.sub.4) 8.97 (s, 1H), 7.50 (br s, 1H), 7.25 (d, J = 1.2 Hz, 1H), 2.60 (s, 3H), 2.57 (br s, 3H), 2.45 (s, 3H), 2.30 (s, 3H); MM m/z 325 [M + H]+. 95.2 114 4-(4-(2- methoxy-4- methyl- pyridin-3- yl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole 06 L .sup.1H NMR (300 MHz, CD.sub.3OD-d.sub.4) 8.08 (d, J = 5.4 Hz, 1H), 7.45 (br s, 1H), 7.00 (d, J = 5.4 Hz, 1H), 6.96 (d, J = 1.5 Hz, 1H), 3.82 (s, 3H), 2.53 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H), 2.12 (s, 3H); MM m/z 349 [M + H]+. 96.4 115 3,5-dimethyl- 4-(2- methyl-4-(1- methyl-3- (trifluoro- methyl)-1H- pyrazol- 4-yl)-1H- benzo[d] imidazol-6- yl)isoxazole 07 L .sup.1H NMR (300 MHz, CD.sub.3OD-d.sub.4) 8.04 (s, 1H), 7.42 (br s, 1H), 7.09 (s, 1H), 4.04 (s, 3H), 2.58 (s, 3H), 2.42 (s, 3H), 2.27 (s, 3H); MM m/z 376 [M + H]+. >99 116 4,6-bis(3,5- dimethyl- isoxazol-4- yl)-N,N- dimethyl- 1H-benzo[d] imidazol-2- amine 08 F .sup.1H NMR (300 MHz, CD.sub.3OD) 7.34 (d, J = 1.5 Hz, 1H), 7.13 (d, J = 1.5 Hz, 1H), 2.44 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H), 2.21 (s, 3H); APCI m/z 352 [M + H]+. 97.9 117 4-(4-(2- (methoxy- methyl) phenyl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl- isoxazole 09 D .sup.1H NMR (500 MHz, CD.sub.3OD) 7.59 (d, J = 7.2 Hz, 1H), 7.47- 7.38 (m, 4H), 7.02 (d, J = 6.0 Hz, 1H), 4.31 (s, 2H), 3.17 (s, 3H), 2.53 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H); ESI m/z 348 [M + H]+. >99 118 4-(4-(2- methoxy- pyridin-3- yl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole 0 D .sup.1H NMR (500 MHz, CD.sub.3OD) 8.22 (d, J = 5.0 Hz, 1H), 7.83 (d, J = 6.7 Hz, 1H), 7.45 (s, 1H), 7.13-7.10 (m, 2H), 3.94 (s, 3H), 2.57 (s, 3H), 2.45 (s, 3H), 2.29 (s, 3H); ESI m/z 335 [M + H]+. >99 119 3,5-dimethyl- 4-(7-(4- methyl- pyridin-3- yl)-1H- indazol-5- yl)isoxazole H .sup.1H NMR (500 MHz, CDCl.sub.3) 8.56 (s, 1H), 8.44 (d, J = 4.5 Hz, 1H), 8.20 (s, 1H), 7.68 (d, J = 1.5 Hz, 1H), 7.31 (d, J = 5.0 Hz, 1H), 7.13 (d, J = 1.5 Hz, 1H), 2.45 (s, 3H), 2.32 (s, 3H), 2.29 (s, 3H); ESI m/z 305 [M + H]+. >99 120 4-(7-(1,3- dimethyl- 1H- pyrazol-4- yl)-1H- indazol-5- yl)-3,5- dimethyl isoxazole H .sup.1H NMR (500 MHz, CDCl.sub.3) 8.15 (s, 1H), 7.64 (s, 1H), 7.57 (d, J = 1.5 Hz, 1H), 7.17 (d, J = 1.5 Hz, 1H), 3.98 (s, 3H), 2.45 (s, 3H), 2.35 (s, 3H), 2.31 (s, 3H); ESI m/z 308 [M + H]+. >99 121 1-(6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-1H- benzo[d] imidazol-4- yl)-5- methyl- pyrrolidin- 2-one none .sup.1H NMR (300 MHz, CD.sub.3OD) 7.63 (s, 1H), 7.39 (s, 1H), 4.62-4.43 (m, 1H), 2.88 (s, 3H), 2.70-2.65 (m, 3H), 2.44 (s, 3H), 2.28 (s, 3H), 2.31-1.84 (m, 1H), 1.23 (d, J = 6.2 Hz, 3H); ESI m/z 325 [M + H]+. HPLC > 99% >99 122 1-(6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-1H- benzo[d] imidazol-4- yl)piperidin- 2-one none .sup.1H NMR (300 MHz, CD.sub.3OD) 7.62 (s, 1H), 7.48 (s, 1H), 3.90-3.81 (m, 2H), 2.87 (s, 3H), 2.69- G1392.61 (m, 2H), 2.44 (s, 3H), 2.28 (s, 3H), 2.07- 2.05 (m, 4H); ESI m/z 325 [M + H]+. HPLC > 99% >99 123 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-1H- benzo[d] imidazol-4- yl)-2- methyl- benzonitrile D .sup.1H NMR (300 MHz, CD.sub.3OD) 7.76 (br.s, 1H), 7.63 (d, J = 7.4 Hz, 1H), 7.50- 7.47 (m, 2H), 7.02 (s, 1H), 2.55 (s, 3H), 2.44 (s, 3H), 2.38 (s, 3H), 2.29 (s, 3H); ESI m/z 343 [M + H]+. >99 124 4-(4- (benzo[d] thiazol-5- yl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole D .sup.1H NMR (500 MHz, CD3OD) 9.31 (s, 1H), 8.45 (br.s, 1H), 8.21 (d, J = 8.1 Hz, 1H), 7.90 (br.s, 1H), 7.46 (s, 1H), 7.28 (s, 1H), 2.61 (s, 3H), 2.46 (s, 3H), 2.31 (s, 3H); ESI m/z 361 [M + H]+. >99 125 4-(4-(5- fluoro-4- methyl- pyridin-3- yl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole D .sup.1H NMR (500 MHz, CD.sub.3OD) 8.43 (s, 1H), 8.34 (s, 1H), 7.52 (br.s, 1H), 7.08 (s, 1H), 2.57 (s, 3H), 2.45 (s, 3H), 2.29 (s, 3H), 2.20 (d, J = 2.0 Hz, 3H); ESI m/z 337 [M + H]+. >99 126 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-1H- benzo[d] imidazol-4- yl)-2- methyl- benzamide none .sup.1H NMR (500 MHz, CD.sub.3OD) 7.18 (d, J = 7.3 Hz, 2H), 7.40 (d, J = 6.6 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 6.99 (s, 1H), 2.55 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H), 2.23 (s, 3H); ESI m/z 361 [M + H]+. >99 127 3,5-dimethyl- 4-(7-(1,3,5- trimethyl- 1H-pyrazol- 4-yl)-1H- indazol-5- yl)isoxazole H .sup.1H NMR (500 MHz, CDCl.sub.3) 8.16 (s, 1H), 7.60 (d, J = 1.5 Hz, 1H), 7.05 (d, J = 1.5 Hz, 1H), 3.87 (s, 3H), 2.45 (s, 3H), 2.31 (s, 3H), 2.21 (s, 3H), 2.18 (s, 3H); ESI m/z 322 [M + H]+. >99 128 3,5-dimethyl- 4-(7-(2- (trifluoro methyl) pyridin-3- yl)-1H- indazol-5- yl)isoxazole 0 H .sup.1H NMR (500 MHz, CDCl.sub.3) 8.89 (d, J = 4.0 Hz, 1H), 8.23 (s, 1H); 7.93 (d, J = 7.5 Hz, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.70-7.68 (m, 1H), 7.23 (s, 1H), 2.44 (s, 3H), 2.30 (s, 3H); ESI mz 359 [M + H]+ >99 129 3,5-dimethyl- 4-(7-(4- (trifluoro methyl) pyridin-3- yl)-1H- indazol-5- yl)isoxazole H .sup.1H NMR (500 MHz, CDCl.sub.3) 8.85-8.83 (m, 2H), 8.20 (s, 1H), 7.76-7.73 (m, 2H), 7.19 (s, 1H); 2.43 (s, 3H), 2.29 (s, 3H); ESI m/z 359 [M + H]+ >99 130 4-(4-(3,5- dichloro- pyridin-4- yl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole L .sup.1H NMR (500 MHz, CD.sub.3OD-d.sub.4) 8.68 (br s, 2H), 7.60-7.53 (m, 1H), 7.07 (br s, 1H), 2.57 (s, 3H), 2.45 (s, 3H), 2.30 (s, 3H); MM m/z 373 [M + H]+. 96.5 131 4-(4-(5- fluoro-2- methoxy- pyridin-3- yl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole L .sup.1H NMR (300 MHz, CD.sub.3OD-d4) 8.12 (d, J = 3.0 Hz, 1H), 7.75 (d, J = 6.3 Hz, 1H), 7.48 (s, 1H), 7.21 (s, 1H), 3.94 (s, 3H), 2.60 (s, 3H), 2.47 (s, 3H), 2.31 (s, 3H); MM m/z 353 [M + H]+. 95.3 132 4-(4-(3,4- difluoro-2- methyl- phenyl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole D .sup.1H NMR (500 MHz, CD.sub.3OD) 7.48 (s, 1H), 7.26-7.10 (m, 2H), 6.97 (d, J = 1.5 Hz, 1H), 2.54 (s, 3H), 2.43 (s, 3H), 2.28 (s, 3H), 2.12 (s, 3H); ESI m/z 354 [M + H]+. 98.8 133 4,6-bis(1,3- dimethyl-1H- pyrazol-4- yl)-2- methyl-1H- benzo[d] imidazole A .sup.1H NMR (500 MHz, CD.sub.3OD) 7.84 (br. s, 1H), 7.69 (s, 1H), 7.42 (br. s, 1H), 7.16 (s, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 2.56 (s, 3H), 2.38 (s, 3H), 2.31 (br s, 3H); ESI m/z 321 [M + H]+. 98.2 134 2-methyl-4,6- bis(1-methyl- 1H-pyrazol- 5-yl)-1H- benzo[d] imidazole A .sup.1H NMR (500 MHz, CDCl.sub.3) 7.74 (br.s, 1H), 7.59 (d, J = 1.7 Hz, 1H), 7.54 (d, J = 1.7 Hz, 1H), 7.29 (d, J = 1.5 Hz, 1H), 6.50 (d, J = 1.8 Hz, 1H), 6.36 (d, J = 2.0 Hz, 1H) 3.94 (s, 3H), 3.88 (s, 3H), 2.75 (s, 3H); ESI m/z 293 [M + H]+. 98.9 135 4-(4-(2- methoxy-6- methyl- pyridin-3- yl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole L .sup.1H NMR (500 MHz, CD.sub.3OD) 7.71 (d, J = 7.5 Hz, 1H), 7.45 (br s, 1H), 7.12 (s, 1H), 6.97 (d, J = 7.5 Hz, 1H), 3.95 (s, 3H), 2.58 (s, 3H), 2.53 (s, 3H), 2.47 (s, 3H), 2.32 (s, 3H); MM m/z 349 [M + H]+. 96.5 136 5-(6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-1H- benzo[d] imidazol-4- yl)benzo[d] oxazole D .sup.1H NMR (500 MHz, CD.sub.3OD) 8.52 (s, 1H), 8.11 (br s, 1H), 7.81 (s, 1H), 7.80 (s, 1H), 7.44 (s, 1H), 7.23 (s, 1H), 2.61 (s, 3H), 2.46 (s, 3H), 2.30 (s, 3H); ESI m/z 345 [M + H]+. 98.8 137 4-(4- (benzo[d] isothiazol- 5-yl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole D .sup.1H NMR (500 MHz, CD.sub.3OD) 9.07 (s, 1H), 8.75- 8.40 (m, 1H), 8.21 (s, 1H), 8.15- 7.85 (m, 1H), 7.44 (br.s, 1H), 7.30 (s, 1H), 2.62 (s, 3H), 2.46 (s, 3H), 2.31 (s, 3H); ESI m/z 361 [M + H]+. >99 138 3,5-dimethyl- 4-(2- methyl-4- (naphthalen- 1-yl)-1H- benzo[d] imidazol-6- yl)isoxazole 0 D .sup.1H NMR (500 MHz, CD.sub.3OD) 7.97 (d, J = 6.0 Hz, 2H), 7.63- 7.48 (m, 5H), 7.40 (br.s, 1H), 7.13 (s, 1H), 2.49 (s, 3H), 2.46 (s, 3H), 2.31 (s, 3H); ESI m/z 354 [M + H]+. 97.2 139 4,4-(2- methyl-1H- benzo[d] imidazole-4,6- diyl)bis(3- methyl isothiazole) none .sup.1H NMR (500 MHz, CD.sub.3OD) 8.91 (s, 1H), 8.80 (s, 1H), 7.58 (s, 1H), 7.22 (d, J = 1.5 Hz, 1H), 2.57 (s, 3H), 2.54 (s, 3H), 2.44 (s, 3H); ESI m/z 327 [M + H]+. 95.5 140 4,4-(3- methyl-1H- indole-4,6- diyl)bis(3,5- dimethyl isoxazole) none .sup.1H NMR (500 MHz, CD.sub.3OD) 7.33 (d, J = 1.4 Hz, 1H), 7.09 (d, J = 0.9 Hz, 1H), 6.72 (d, J = 1.5 Hz, 1H), 2.43 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H), 2.08 (s, 3H), 1.93 (d, J = 0.9 Hz, 3H); ESI m/z 322 [M + H]+. >99 141 2-methyl-4,6- bis(4- methyl thiophen- 3-yl)-1H- benzo[d] imidazole A .sup.1H NMR (500 MHz, CD.sub.3OD) 7.47 (s, 1H), 7.39 (d, J = 3.5 Hz, 1H), 7.25 (d, J = 4.0 Hz, 1H), 7.16 (s, 1H), 7.10 (d, J = 1.5 Hz, 1H), 7.09 (d, J = 1.5 Hz, 1H), 2.54 (s, 3H), 2.28 (s, 3H), 2.18 (s, 3H); ESI m/z 325 [M + H]+. >99 142 6-(3,5- dimethyl- isoxazol-4- yl)-N- phenethyl- 1H-benzo[d] imidazol- 4-amine G .sup.1H NMR (300 MHz, CD.sub.3OD) 8.04 (s, 1H), 7.28- 7.17 (m, 6H), 6.77 (s, 1H), 6.31 (s, 1H), 3.56 (t, J = 7.2 Hz, 2H), 3.01 (t, J = 7.2 Hz, 2H), 2.43 (s, 3H), 2.27 (s, 3H); ESI MS m/z 333 [M + H]+. 95.0 143 6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-N- (2-methyl pyridin- 3-yl)-1H- benzo[d] imidazol- 4-amine K .sup.1H NMR (500 MHz, CD.sub.3OD) 7.99 (s, 1H), 7.30- 7.80 (bs, 1H), 7.05 (s, 1H), 7.90- 7.30 (bs, 1H), 6.60-6.90 (bs, 1H), 2.58 (s, 3H), 2.57 (s, 3H), 2.39 (s, 3H), 2.24 (s, 3H); ESI m/z 334 [M + H]+. >99 144 4-(4-(2- chloro- phenyl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole D .sup.1H NMR (500 MHz, CD.sub.3OD) 7.58 (br.s, 1H), 7.51-7.39 (m, 4H), 7.05 (d, J = 1.5 Hz, 1H), 2.55 (s, 3H), 2.45 (s, 3H), 2.29 (s, 3H); ESI m/z 338 [M + H]+. 96.9 145 4-(4- (benzo[b] thiophen-2- yl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole D .sup.1H NMR (500 MHz, DMSO-d6) 12.57 and 12.44 (s, 1H), 8.56 (s, 1H), 8.04 and 7.99 (d, J = 8.0 Hz, 1H), 7.94 and 7.91 (d, J = 8.0 Hz, 1H), 7.57 and 7.49 (d, J = 1.0 Hz, 1H), 7.40 (s, 1H), 7.39-7.30 (m, 2H), 2.62 and 2.59 (s, 3H), 2.46 and 2.45 (s, 3H), 2.29 and 2.28 (s, 3H); ESI m/z 360 [M + H]+. >99 146 6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-N- (1,3,5- trimethyl- 1H-pyrazol- 4-yl)-1H- benzo[d] imidazol-4- amine K .sup.1H NMR (500 MHz, CD.sub.3OD) 6.67 (s, 1H), 5.81 (s, 1H), 3.74 (s, 3H), 2.60 (s, 3H), 2.30 (s, 3H), 2.15 (s, 3H), 2.13 (s, 3H), 2.06 (s, 3H); ESI m/z 351 [M + H]+; 98.8 147 1-(6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-1H- benzo[d] imidazol-4- yl)azetidin- 2-one K .sup.1H NMR (500 MHz, CD.sub.3OD) 6.60-7.80 (bm, 2H), 3.70-4.30 (bm, 2H), 3.20 (t, J = 4.4 Hz, 2H), 2.61 (s, 3H), 2.41 (s, 3H), 2.25 (s, 3H); ESI m/z 297 [M + H]+; 98.8 148 3,5-dimethyl- 4-(2- methyl-4- phenoxy-1H- benzo[d] imidazol-6- yl)isoxazole 0 M .sup.1H NMR (300 MHz, CD.sub.3OD) 7.40-7.34 (m, 2H), 7.21 (s, 1H), 7.15-7.05 (m, 3H), 6.58 (d, J = 1.2 Hz, 1H), 2.58 (s, 3H), 2.36 (s, 3H), 2.19 (s, 3H); ESI m/z 320 [M + H]+. 95.6 149 6,8-bis(3,5- dimethyl- isoxazol-4- yl)-[1,2,4] triazolo[4,3-a] pyridin-3(2H)- one A .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.68 (s, 1H), 7.91 (d, J = 1.58 Hz, 1H), 7.26 (d, J = 1.5 Hz, 1H), 2.45 (s, 3H), 2.42 (s, 3H), 2.27 (s, 3H), 2.25 (s, 3H); ESI m/z 326 [M + H]+. >99 150 2-((4,6- bis(3,5- dimethyl- isoxazol-4- yl)-1H- benzo[d] imidazol-2- yl)amino) ethanol F .sup.1H NMR (300 MHz, CD.sub.3OD) 7.17 (s, 1H), 6.82 (s, 1H), 3.75 (t, J = 5.4 Hz, 2H), 3.50 (t, J = 5.4 Hz, 2H), 2.43 (s, 3H), 2.37 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H); ESI MS m/z 368 [M + H]+. >99 151 6-(3,5- dimethyl- isoxazol-4- yl)-N,N- diphenethyl- 1H- benzo[d] imidazol-4- amine G .sup.1H NMR (300 MHz, DMSO-d6) 12.35 (s, 1H), 8.13 (s, 1H), 7.30-7.16 (m, 10H), 6.79 (d, J = 1.5 Hz, 1H), 6.30 (s, 1H), 3.97-3.92 (m, 4H), 2.92-2.87 (m, 4H), 2.44 (s, 3H), 2.26 (s, 3H); ESI MS m/z 437 [M + H]+. >99 152 4-(4-(2- fluoro-3- methoxy- phenyl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole D .sup.1H NMR (500 MHz, CD.sub.3OD) 7.47 (br.s, 1H), 7.23 (dd, J = 7.8, 7.5 Hz, 1H), 7.18 (dd, J = 7.8, 7.5 Hz, 1H), 7.13- 7.08 (m, 2H), 3.94 (s, 3H), 2.57 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H); ESI m/z 352 [M + H]+. >99 153 3,5-dimethyl- 4-(2- methyl-4- (quinoxalin- 6-yl)-1H- benzo[d] imidazol-6- yl)isoxazole D .sup.1H NMR (500 MHz, CD.sub.3OD) 8.92 (d, J = 11.0 Hz, 2H), 8.65- 8.15 (m, 3H), 7.49 (br.s, 1H), 7.37 (s, 1H), 2.64 (s, 3H), 2.47 (s, 3H), 2.32 (s, 3H); ESI m/z 356 [M + H]+. >99 154 3,5-dimethyl- 4-(2- methyl-4-(3- (methyl- sulfonyl) phenyl)-1H- benzo[d] imidazol-6- yl)isoxazole D .sup.1H NMR (500 MHz, CD.sub.3OD) 8.43 (br.s, 1H), 8.17 (br.s, 1H), 8.00 (br.s, 1H), 7.78 (br.s, 1H), 7.44 (br.s, 1H), 7.26 (s, 1H), 3.23 (s, 3H), 2.62 (s, 3H), 2.45 (s, 3H), 2.29 (s, 3H); ESI m/z 382 [M + H]+. >99 155 3,5-dimethyl- 4-(2-methyl- 4-((2- methyl- pyridin-3- yl)oxy)-1H- benzo[d] imidazol-6- yl)isoxazole M .sup.1H NMR (300 MHz, CD.sub.3OD) 8.50 (d, J = 5.7 Hz, 1H), 8.45 (s, 1H), 7.49 (br.s, 1H), 7.25 (d, J = 6.0 Hz, 1H), 7.12 (d, J = 0.9 Hz, 1H), 3.92 (s, 1H), 2.57 (s, 3H), 7.45 (s, 3H), 2.29 (s, 3H); ESI m/z 335 [M + H]+. 99.0 156 4-(4-([1,2,4] triazolo [4,3-a] pyridin-6- yl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole L .sup.1H NMR (300 MHz, CD.sub.3OD) 9.55 (s, 1H), 9.23 (s, 1H), 8.29- 8.19 (m, 2H), 7.84 (d, J = 1.5 Hz, 1H), 7.71 (d, J = 1.5 Hz, 1H), 2.93 (s, 3H), 2.49 (s, 3H), 2.32 (s, 3H); ESI m/z 345 [M + H]+. 93.5 157 4-(4-(2- fluoro-5- (trifluoro- methyl) phenyl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole D .sup.1H NMR (300 MHz, CD.sub.3OD) 7.91 (br.s, 1H), 7.80 (br.s, 1H), 7.48 (br.s, 2H), 7.19 (s, 1H), 2.59 (s, 3H), 2.45 (s, 3H), 2.29 (s, 3H); ESI m/z 390 [M + H]+. >99 158 (E)-3,5- dimethyl-4- (2-methyl- 4-styryl-1H- benzo[d] imidazol-6- yl)isoxazole 0 D .sup.1H NMR (300 MHz, CD.sub.3OD) 7.72-7.65 (m, 3H), 7.49-7.24 (m, 6H), 2.65 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H); ESI MS m/z 330 [M + H]+. >99 159 4,4- (quinoxaline- 5,7-diyl)bis (3,5-dimethyl isoxazole) none .sup.1H NMR (500 MHz, CD.sub.3OD) 8.95 (d, J = 2.0 Hz, 1H), 8.92 (d, J = 1.5 Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 2.54 (s, 3H), 2.39 (s, 3H), 2.35 (s, 3H), 2.17 (s, 3H); ESI m/z 321 [M + H]+ >99%. >99 160 4,6-di(furan- 3-yl)-2- methyl-1H- benzo[d] midazole A .sup.1H NMR (500 MHz, CD.sub.3OD) 8.27 (br s, 1H), 7.91 (d, J = 1.0 Hz, 1H), 7.68- 7.60 (m, 2H), 7.55 (t, J = 2.0 Hz, 1H), 7.52 (d, J = 1.0 Hz, 1H), 7.01 (br s, 1H), 6.85 (d, J = 2.0 Hz, 1H), 2.59 (s, 3H); ESI m/z 265 [M + H]+ >99 161 3,5-dimethyl- 4-(2- methyl-4- phenethyl- 1H-benzo[d] imidazol-6- yl)isoxazole none .sup.1H NMR (300 MHz, CD.sub.3OD) 7.24-7.13 (m, 6H), 6.74 (s, 1H), 3.33-3.31 (m, 2H), 3.08-3.03 (m, 2H), 2.62 (s, 3H), 2.29 (s, 3H), 2.13 (s, 3H); ESI MS m/z 332 [M + H]+. 96.2 162 4-(4-(2- chloro-5- (trifluoro- methyl) phenyl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole D .sup.1H NMR (300 MHz, CD.sub.3OD) 7.78 (br.s, 3H), 7.51 (br.s, 1H), 7.09 (d, J = 0.9 Hz, 1H), 2.57 (s, 3H), 2.45 (s, 3H), 2.29 (s, 3H); ESI m/z 406 [M + H]+. >99 163 3,5-dimethyl- 4-(2- methyl-4- (quinolin-3- yl)-1H- benzo[d] imidazol-6- yl)isoxazole D .sup.1H NMR (300 MHz, CD.sub.3OD) 9.31 (br.s, 1H), 8.77 (br.s, 1H), 8.09 (t, J = 8.4 Hz, 2H), 7.82 (dd, J = 6.9, 6.6 Hz, 1H), 7.68 (dd, J = 7.5, 7.2 Hz, 1H), 7.50 (s, 1H), 7.39 (s, 1H), 2.64 (s, 3H), 2.47 (s, 3H), 2.32 (s, 3H); ESI m/z 355 [M + H]+. >99 164 2-methyl- 4,6-di(1H- pyrrol-3- yl)-1H- benzo[d] imidazole none .sup.1H NMR (500 MHz, CD.sub.3OD) 7.50 (d, J = 1.0 Hz, 1H), 7.52- 7.20 (m, 2H), 7.09 (t, J = 2.0 Hz, 1H), 6.83 (s, 1H), 6.77 (dd, J = 2.5, 2.0 Hz, 1H), 6.60 (br s, 1H), 6.47 (dd, J = 2.5, 1.5 Hz, 1H), 2.56 (s, 3H); ESI m/z 263 [M + H]+ >99 165 N-(6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-1H- benzo[d] imidazol-4- yl)benzamide K .sup.1H NMR (500 MHz, CD.sub.3OD) 8.09 (d, J = 7.5 Hz, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.55 (t, J = 7.5 Hz, 2H), 7.00- 7.50 (br, 2H), 2.62 (s, 3H), 2.45 (s, 3H), 2.30 (s, 3H); E5I m/z 347 [M + H]+ 98.2 166 3,5-dimethyl- 4-(2- methyl-4-(4- methyl- thiophen-3- yl)-1H- benzo[d] imidazol-6- yl)isoxazole D .sup.1H NMR (300 MHz, CD.sub.3OD) 7.43 (s, 1H), 7.42 (s, 1H), 7.20 (br.s, 2H), 7.02 (d, J = 1.5 Hz, 1H); ESI m/z 324 [M + H]+. >99 167 4,6-bis(1,4- dimethyl-1H- pyrazol-5- yl)-2- methyl-1H- benzo[d] imidazole A .sup.1H NMR (500 MHz, CD.sub.3OD) 7.64-7.53 (m, 1H), 7.48-7.41 (m, 1H), 7.38 (s, 1H), 7.12 (br.s, 1H), 3.78 (s, 3H), 3.72 (s, 3H), 2.60 (s, 3H), 2.05 (s, 3H), 2.00 (s, 3H); ESI m/z 321 [M + H]+. >99 168 5,5-(2- methyl-1H- benzo[d] imidazole- 4,6-diyl) bis(2,4- dimethyl thiazole) 0 A .sup.1H NMR (300 MHz, CD.sub.3OD) 7.63-7.51 (m, 1H), 7.22 (s, 1H), 2.73 (s, 3H), 2.68 (s, 3H), 2.58 (s, 3H), 2.44 (s, 3H), 2.36-2.29 (m, 3H); ESI m/z 355 [M + H]+. >99 169 4-(4-(1,4- dimethyl- 1H-pyrazol- 5-yl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole D .sup.1H NMR (500 MHz, CD.sub.3OD) 7.60-7.49 (m, 1H), 7.47-7.42 (m, 1H), 7.12- 7.06 (m, 1H), 3.71 (s, 3H), 2.58 (s, 3H), 2.45 (s, 3H), 2.29 (s, 3H), 2.00 (br.s, 3H); ESI m/z 322 [M + H]+. >99 170 4-(4-(2,4- dimethyl- thiazol-5- yl)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole D .sup.1H NMR (500 MHz, CD.sub.3OD) 7.53-7.41 (m, 1H), 7.11 (d, J = 1.5 Hz, 1H), 2.72 (s, 3H), 2.59 (s, 3H), 2.43 (s, 3H), 2.37-2.30 (m, 3H), 2.28 (s, 3H); ESI m/z 339 [M + H]+. >99 171 4-(4-((4- methoxy- pyridin-3- yl)oxy)-2- methyl-1H- benzo[d] imidazol-6- yl)-3,5- dimethyl isoxazole M .sup.1H NMR (300 MHz, CD.sub.3OD) 8.32 (d, J = 5.7 Hz, 1H), 8.17 (s, 1H), 7.25 (d, J = 5.7 Hz, 1H), 7.17 (s, 1H), 6.35 (d, J = 1.2 Hz, 1H), 3.91 (s, 3H), 2.60 (s, 3H), 2.33 (s, 3H), 2.16 (s, 3H); ESI m/z 351 [M + H]+. >99 172 3-((6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-1H- benzo[d] imidazol-4- yl)oxy)-4- methyl benzonitrile M .sup.1H NMR (300 MHz, CD.sub.3OD) 7.49 (d, J = 4.8 Hz, 1H), 7.40 (d, J = 4.5 Hz, 1H), 7.27 (s, 1H), 7.05 (br.s, 1H), 6.59 (d, J = 0.6 Hz, 1H), 2.59 (s, 3H), 2.45 (s, 3H), 2.38 (s, 3H), 2.21(s, 3H); ESI m/z 359 [M + H]+. >99 173 4-(6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-1H- benzo[d] imidazol-4- yl) morpholine K .sup.1H NMR (500 MHz, CD.sub.3OD) 6.99 (brs, 1H), 6.53 (brs, 1H), 3.93 (t, J = 4.5 Hz, 4H), 3.20- 3.40 (m, 4H), 2.58 (s, 3H), 2.40 (s, 3H), 2.25 (s, 3H); ESI m/z 313 [M + H]+; 97.6 174 3-((6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-1H- benzo[d] imidazol-4- yl)oxy)-4- methyl benzamide none .sup.1H NMR (300 MHz, CD.sub.3OD) 7.61 (dd, J = 7.5, 1.2 Hz, 1H), 7.46 (d, J = 1.2 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.19 (br.s, 1H), 6.42 (s, 1H), 2.60 (s, 3H), 2.38 (s, 3H), 2.34 (s, 3H), 2.17 (s, 3H); APCI m/z 377 [M + H]+ >99 175 3-((6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-1H- benzo[d] imidazol-4- yl)oxy)-4- methyl benzoic acid none .sup.1H NMR (300 MHz, CD.sub.3OD) 7.73 (dd, J = 7.8, 1.2 Hz, 1H), 7.48 (d, J = 1.2 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.23 (s, 1H), 6.49 (d, J = 1.2 Hz, 1H), 2.60 (s, 3H), 2.41 (s, 3H), 2.35 (s, 3H), 2.18 (s, 3H); APCI m/z 378 [M + H]+. >99 176 4,4-(2- methyl-3H- imidazo [4,5-b] pyridine- 5,7-diyl) bis(3,5- dimethyl- isoxazole) No general proce- dure .sup.1H NMR (300 MHz, CD.sub.3OD) 8.18 (s, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.08 (d, J = 1.6 Hz, 1H), 3.58 (s, 3H), 2.44 (s, 3H), 2.32 (s, 3H), 2.28 (s, 3H), 2.13 (s, 3H); ESI m/z 321 [M + H]+. >99 177 4-(6-(3,5- dimethyl- isoxazol-4- yl)-2- methyl-1H- benzo[d] imidazol-4- yl)-3-methyl morpholine K .sup.1H NMR (500 MHz, CD.sub.3OD) 7.40-6.40 (m, 2H), 4.20-3.70 (m, 4H), 3.20- 3.40 (m, 3H), 2.58 (s, 3H), 2.41 (s, 3H), 2.25 (s, 3H), 0.95 (s, 3H); ESI m/z 327 [M + H]+. 96.7 178 4-(6-(1,4- dimethyl- 1H-pyrazol- 5-yl)-2- methyl-1H- benzo[d] imidazol-4- yl)-3,5- dimethyl isoxazole 0 No general proce- dure .sup.1H NMR (400 MHz, CD.sub.3OD) 7.51 (br s, 1H), 7.38 (br s, 1H), 7.08 (d, J = 3.6 Hz, 1H), 3.77 (s, 3H), 2.59 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H), 2.04 (s, 3H); ESI MS m/z 322 [M + H]+. 179 4,4-(3- methyl-1H- indazole- 4,6-diyl) bis(3,5- dimethyl isoxazole) No general proce- dure .sup.1H NMR (400 MHz, CDCl.sub.3) 10.09 (br s, 1H), 7.36 (s, 1H), 6.79 (s, 1H), 2.47 (s, 3H), 2.33 (s, 3H), 2.32 (s, 3H), 2.26 (s, 3H), 2.15 (s, 3H); ESI MS m/z 321 [M H]. 180 4-(4-(3,5- dimethyl- 1H-pyrazol- 4-yl)-3- methyl-1H- indazol-6- yl)-3,5- dimethyl isoxazole No general proce- dure .sup.1H NMR (400 MHz, CDCl.sub.3) 7.28 (d, J = 1.6 Hz, 1H), 6.78 (d, J = 1.6 Hz, 1H), 2.47 (s, 3H), 2.33 (s, 3H), 2.20 (s, 3H), 2.16 (s, 6H); ESI MS m/z 322 [M + H]+. 181 3,5-dimethyl- 4-(2-(4- methyl- piperazin-1- yl)-4-(1,3,5- trimethyl-1H- pyrazol-4- yl)-1H- benzo[d] imidazol-6- yl)isoxazole O .sup.1H NMR (400 MHz, CDCl.sub.3) 9.80 (br s, 1H), 7.32 (br s, 1H), 6.64 (br s, 1H), 3.69-3.74 (m, 4H), 3.68 (s, 3H), 2.51-2.59 (m, 4H), 2.44 (s, 3H), 2.36 (s, 3H), 2.30 (s, 3H), 2.17 (s, 3H), 2.12 (s, 3H); ESI MS m/z 420 [M + H]+. 182 3,5-dimethyl- 4-(1-methyl- 7-(1,3,5- trimethyl-1H- pyrazol-4- yl)-1H- benzo[d] imidazol-5- yl)isoxazole N .sup.1H NMR (400 MHz, CDCl.sub.3) 7.84 (br s, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.89 (d, J = 1.6 Hz, 1H), 3.85 (s, 3H), 3.49 (s, 3H), 2.45 (s, 3H), 2.32 (s, 3H), 2.13 (s, 3H), 2.09 (s, 3H); ESI MS m/z 336 [M + H]+. 183 3,5-dimethyl- 4-(2-(4- methyl- piperazin-1- yl)-4-(2- methyl- pyridin-3- yl)-1H- benzo[d] imidazol-6- yl)isoxazole No general proce- dure .sup.1H NMR (400 MHz, CDCl.sub.3) 11.21 (br s, 1H), 7.94 (d, J = 3.9 Hz, 1H), 7.58 (dd, J = 7.6, 1.4 Hz, 1H), 7.40 (s, 1H), 7.04 (dd, J = 7.6, 4.9 Hz, 1H), 6.68 (d, J = 1.6 Hz, 1H), 3.74 (br s, 4H), 2.51 (t, J = 4.7 Hz, 4H), 2.44 (s, 3H), 2.43 (s, 3H), 2.31 (s, 6H); ESI MS m/z 401 [M H]. 184 4-(6-(3,5- dimethyl- isoxazol-4- yl)-4-(1,3,5- trimethyl-1H- pyrazol-4- yl)-1H- benzo[d] imidazol-2- yl)morpholine O .sup.1H NMR (400 MHz, CD.sub.3OD) 7.17 (br s, 1H), 6.77 (br s, 1H), 3.78-3.82 (m, 4H), 3.79 (s, 3H), 3.51-3.53 (m, 4H), 2.43 (s, 3H), 2.28 (s, 3H), 2.19 (s, 3H), 2.16 (s, 3H); ESI MS m/z 407 [M + H]+. 185 6-(3,5- dimethyl- isoxazol-4- yl)-N-(1- methyl- piperidin-4- yl)-4-(1,3,5- trimethyl-1H- pyrazol-4- yl)-1H- benzo[d] imidazol-2- amine O .sup.1H NMR (400 MHz, CD.sub.3OD) 7.12 (br s, 1H), 6.71 (br s, 1H), 3.79 (s, 3H), 5.70 (br s, 1H), 2.88- 2.90 (m, 2H), 2.43 (s, 3H), 2.31 (s, 3H), 2.28 (s, 3H), 2.23-2.27 (m, 2H), 2.19 (s, 3H), 2.15 (s, 3H), 2.10-2.19 (m, 2H), 2.07- 2.10 (m, 2H), 1.59-1.64 (m, 2H); ESI MS m/z 434 [M + H]+. 186 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2-(4- methyl- piperazin-1- yl)-1H- benzo[d] imidazol-4- yl)-4-methyl benzonitrile P .sup.1H NMR (400 MHz, CD.sub.3OD) 7.66 (s, 2H), 7.51 (d, J = 7.8 Hz, 1H), 7.23 (br s, 1H), 6.81 (br s, 1H), 3.58 (t, J = 4.9 Hz, 4H), 2.57 (t, J = 4.9 Hz, 4H), 2.43 (s, 3H), 2.34 (s, 3H), 2.28 (s, 6H); ESI MS m/z 425 [M H]. 187 3,5-dimethyl- 4-(2- (methylthio)- 4-(1,3,5-tri methyl-1H- pyrazol-4-yl)- 1H-benzo[d] imidazol-6- yl)isoxazole No general proce- dure .sup.1H NMR (400 MHz, CDCl.sub.3) 11.00 (br s, 1H), 7.55 (dd, J = 1.6, 0.8 Hz, 1H), 6.83 (d, J = 1.6 Hz, 1H), 3.71 (s, 3H), 2.83 (s, 3H), 2.45 (s, 3H), 2.32 (s, 3H), 2.17 (s, 3H), 2.07 (s, 3H); ESI MS m/z 368 [M + H]+. 188 3,5-dimethyl- 4-(1- methyl-2- (methylthio)- 4-(1,3,5 trimethyl-1H- pyrazol-4- yl)-1H- benzo[d] imidazol-6- yl)isoxazole 0 No general proce- dure .sup.1H NMR (400 MHz, CDCl.sub.3) 7.02 (d, J = 1.6 Hz, 1H), 6.91 (d, J = 1.6 Hz, 1H), 3.82 (s, 3H), 3.72 (s, 3H), 2.78 (s, 3H), 2.45 (s, 3H), 2.32 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H); ESI MS m/z 382 [M + H]+. 189 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2-(4- methyl- piperazin-1- yl)-1H- benzo[d] imidazol-4- yl)-4-methyl benzamide Q .sup.1H NMR (400 MHz, CD.sub.3OD) 7.83 (s, 1H), 7.79 (d, J = 7.4 Hz, 1H), 7.44 (br s, 1H), 7.27 (br s, 1H), 6.77 (br s, 1H), 3.60 (br s, 4H), 2.58 (t, J = 4.7 Hz, 4H), 2.44 (s, 3H), 2.36 (s, 3H), 2.30 (s, 6H); ESI MS m/z 445 [M + H]+. 190 6-(3,5- dimethyl- isoxazol-4- yl)-N- (tetrahydro- 2H-pyran- 4-yl)-4- (1,3,5- trimethyl-1H- pyrazol-4- yl)-1H- benzo[d] imidazol-2- amine O .sup.1H NMR (400 MHz, CD.sub.3OD) 7.12 (br s, 1H), 6.71 (br s, 1H), 3.96-3.40 (m, 2H), 3.86-3.91 (m, 1H), 3.79 (s, 3H), 3.52-3.58 (m, 2H), 2.42 (s, 3H), 2.21 (s, 3H), 2.19 (s, 3H), 2.15 (s, 3H), 2.02-2.05 (m, 2H), 1.53- 1.63 (m, 2H); ESI MS m/z 421 [M + H]+. 191 3,5-dimethyl- 4-(1- methyl-2- (methylthio)- 7-(1,3,5- trimethyl-1H- pyrazol-4- yl)-1H- benzo[d] imidazol-5- yl) isoxazole No general proce- dure .sup.1H NMR (400 MHz, CDCl.sub.3) 7.55 (d, J = 1.6 Hz, 1H), 6.76 (d, J = 1.6 Hz, 1H), 3.84 (s, 3H), 3.36 (s, 3H), 2.82 (s, 3H), 2.44 (s, 3H), 2.31 (s, 3H), 2.12 (s, 3H), 2.10 (s, 3H); ESI MS m/z 382 [M + H]+. 192 4,4-(7- bromo-1H- benzo[d] imidazole- 4,6-diyl) bis(3,5- dimethyl isoxazole) No general proce- dure .sup.1H NMR (400 MHz, CDCl.sub.3) 9.90 (br s, 1H), 8.19 (br s, 1H), 6.99 (s, 1H), 2.44 (br s, 3H), 2.35 (s, 3H), 2.31 (br s, 3H), 2.20 (s, 3H); ESI MS m/z 387 [M + H]+. 192 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2- morpholino- 1H-benzo[d] imidazol-4- yl)-4- methyl benzonitrile P .sup.1H NMR (400 MHz, CD.sub.3OD) 7.63-7.69 (m, 2H), 7.51 (d, J = 8.2 Hz, 1H), 7.24 (br s, 1H), 6.82 (s, 1H), 3.76- 3.82 (m, 4H), 3.49-3.55 (m, 4H), 2.43 (s, 3H), 2.28 (s, 6H); ESI MS m/z 414 [M + H]+. 194 3,5-dimethyl- 4-(2- (methyl- sulfinyl)- 7-(1,3,5- trimethyl-1H- pyrazol-4- yl)-1H- benzo[d] imidazol-5- yl)isoxazole No general proce- dure .sup.1H NMR (400 MHz, CD.sub.3OD) 7.58 (br s, 1H), 7.13 (d, J = 1.6 Hz, 1H), 3.81 (s, 3H), 3.13 (s, 3H), 2.46 (s, 3H), 2.31 (s, 3H), 2.22 (s, 3H), 2.17 (s, 3H); ESI MS m/z 382 [M H]. 195 3,5-dimethyl- 4-(2- (methyl- sulfonyl)- 7-(1,3,5- trimethyl-1H- pyrazol-4- yl)-1H- benzo[d] imidazol-5- yl)isoxazole No general proce- dure .sup.1H NMR (400 MHz, CD.sub.3OD) 7.60 (br s, 1H), 7.18 (d, J = 1.1 Hz, 1H), 3.82 (s, 3H), 3.39 (s, 3H), 2.47 (s, 3H), 2.31 (s, 3H), 2.22 (s, 3H), 2.18 (s, 3H); ESI MS m/z 398 [M H]. 196 4-(6-(3,5- dimethyl- isoxazol-4- yl)-4-(4- methyl- pyridin-3- yl)-1H- benzo[d] imidazol-2- yl)morpholine R .sup.1H NMR (400 MHz, CDCl.sub.3) 11.65 (br s, 1H), 8.34 (s, 1H), 7.93 (d, J = 4.8 Hz, 1H), 7.39 (s, 1H), 7.11 (d, J = 4.8 Hz, 1H), 6.67 (s, 1H), 3.77 (br s, 4H), 3.62 (br s, 4H), 2.43 (s, 3H), 2.29 (s, 6H); ESI MS m/z 390 [M + H]+. 197 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2- morpholino- 1H-benzo[d] imidazol-4- yl)-4- methyl benzamide Q .sup.1H NMR (400 MHz, CD.sub.3OD) 7.80-7.86 (m, 2H), 7.43 (d, J = 7.8 Hz, 1H), 7.23 (br s, 1H), 6.83 (br s, 1H), 3.76- 3.82 (m, 4H), 3.49-3.55 (m, 4H), 2.43 (s, 3H), 2.28 (s, 3H), 2.26 (s, 3H); ESI MS m/z 432 [M + H]+. 198 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2- ((tetrahydro- 2H-pyran-4- yl)amino)- 1H-benzo[d] imidazol-4- yl)-4- methyl benzonitrile 0 P .sup.1H NMR (400 MHz, CD.sub.3OD) 7.66 (s, 2H), 7.52 (d, J = 7.8 Hz, 1H), 7.19 (br s, 1H), 6.77 (s, 1H), 3.97 (d, J = 11.3 Hz, 2H), 3.86 (br s, 1H), 3.53 (t, J = 11.3 Hz, 2H), 2.43 (s, 3H), 2.29 (s, 3H), 2.27 (s, 3H), 2.01 (d, J = 12.1 Hz, 2H), 1.58 (m, 2H); ESI MS m/z 428 [M + H]+. 199 3,5-dimethyl- 4-(2-(4- methyl piperazin- 1-yl)-4-(4- methyl pyridin-3- yl)-1H- benzo[d] imidazol-6- yl)isoxazole R .sup.1H NMR (400 MHz, CDCl.sub.3) 11.51 (br s, 1H), 8.34 (s, 1H), 7.94 (d, J = 5.0 Hz, 1H), 7.37 (d, J = 1.0 Hz, 1H), 7.10 (d, J = 5.0 Hz, 1H), 6.65 (d, J = 1.0 Hz, 1H), 3.67 (br t, J = 5.0 Hz, 4H), 2.47 (br t, J = 5.0 Hz, 4H), 2.43 (s, 3H), 2.29 (s, 9H); ESI MS m/z 403 [M + 1]+. 200 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2- ((tetrahydro- 2H-pyran- 4-yl)amino)- 1H-benzo[d] imidazol-4- yl)-4- methyl benzamide Q .sup.1H NMR (400 MHz, CD.sub.3OD) 7.80-7.87 (m, 2H), 7.45 (d, J = 7.4 Hz, 1H), 7.18 (br s, 1H), 6.79 (s, 1H), 3.97 (d, J = 11.3 Hz, 2H), 3.87 (br s, 1H), 3.53 (t, J = 11.3 Hz, 2H), 2.43 (s, 3H), 2.28 (s, 6H), 2.02 (d, J = 12.1 Hz, 2H), 1.48-1.64 (m, 2H); ESI MS m/z 446 [M + H]+. 201 6-(3,5- dimethyl- isoxazol-4- yl)-4-(4- methyl- pyridin-3- yl)-N-(tetra hydro-2H- pyran-4- yl)-1H- benzo[d] imidazol-2- amine R .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 11.40 (br s, 1H), 8.46 (s, 1H), 8.10 (br s, 1H), 7.34 (br s, 1H), 7.18 (d, J = 4.8 Hz, 1H), 6.71 (s, 1H), 4.71 (br s, 1H), 4.04 (br s, 1H), 3.95-3.92 (m, 2H), 3.44 (t, J = 10.8 Hz, 2H), 2.42 (s, 3H), 2.33 (s, 3H), 2.29 (s, 3H), 2.10-2.04 (m, 2H), 1.55- 1.45 (m, 2H). ESI MS m/z 404 [M + H]+. 202 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2-(4- methyl- piperazin-1- yl)-1H- benzo[d] imidazol-4- yl)-2-methyl benzonitrile S .sup.1H NMR (400 MHz, CD.sub.3OD) 7.73 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.23 (br s, 1H), 6.81 (br s, 1H), 3.57 (t, J = 4.8 Hz, 4H), 2.56 (t, J = 4.8 Hz, 4H), 2.42 (s, 3H), 2.39 (s, 3H), 2.34 (s, 3H), 2.27 (s, 3H); ESI MS m/z 425 [M H]. 203 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2- morpholino- 1H-benzo[d] imidazol-4- yl)-2- methyl benzonitrile S .sup.1H NMR (400 MHz, CD.sub.3OD) 7.72 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 7.2 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.24 (br s, 1H), 6.81 (br s, 1H), 3.79 (m, 4H), 3.51 (m, 4H), 2.42 (s, 3H), 2.39 (s, 3H), 2.27 (s, 3H); ESI MS m/z 414 [M + H]+. 204 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2- ((tetrahydro- 2H-pyran-4- yl)amino)- 1H-benzo[d] imidazol-4- yl)-2- methyl benzonitrile S .sup.1H NMR (400 MHz, CD.sub.3OD) 7.73 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.19 (br s, 1H), 6.76 (d, J = 1.2 Hz, 1H), 3.96 (m, 2H), 3.86 (m, 1H), 3.52 (m, 2H), 2.42 (s, 3H), 2.40 (s, 3H), 2.27 (s, 3H), 2.01 (m, 2H), 1.57 (m, 2H); ESI MS m/z: 428 [M + H]+. 205 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2-((1- methyl- piperidin-4- yl)amino)- 1H-benzo[d] imidazol-4- yl)-4- methyl benzonitrile P .sup.1H NMR (400 MHz, CD.sub.3OD) 7.66 (br s, 2H), 7.52 (d, J = 8.2 Hz, 1H), 7.18 (s, 1H), 6.77 (s, 1H), 3.67 (br s, 1H), 2.84-2.92 (m, 2H), 2.43 (s, 3H), 2.30 (br s, 3H), 2.29 (s, 3H), 2.27 (s, 3H), 2.21 (t, J = 11.5 Hz, 2H), 2.02- 2.12 (m, 2H), 1.52-1.67 (m, 2H); ESI MS m/z 441 [M + H].sup.+. 206 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2-(4- methyl- piperazin-1- yl)-1H- benzo[d] imidazol-4- yl)-2- methyl benzamide Q .sup.1H NMR (400 MHz, CD.sub.3OD) 7.42-7.50 (m, 1H), 7.37-7.42 (m, 1H), 7.29- 7.37 (m, 1H), 7.23 (br s, 1H), 6.78 (br s, 1H), 3.59 (br s, 4H), 2.56 (br s, 4H), 2.43 (s, 3H), 2.34 (s, 3H), 2.28 (s, 3H), 2.23 (s, 3H); ESI MS m/z 445 [M + H].sup.+. 207 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2- ((tetrahydro- 2H-pyran- 4-yl)amino)- 1H-benzo[d] imidazol-4- yl)-2- methyl benzamide Q .sup.1H NMR (400 MHz, CD.sub.3OD) 7.45 (d, J = 6.8 Hz, 1H), 7.37- 7.42 (m, 1H), 7.32-7.35 (m, 1H), 7.17 (br s, 1H), 6.75 (br s, 1H), 3.95-3.98 (m, 2H), 3.88 (m, 1H), 3.46- 3.56 (m, 2H), 2.42 (s, 3H), 2.27 (s, 3H), 2.25 (s, 3H), 2.01-2.04 (m, 2H), 1.52-1.62 (m, 2H); ESI MS m/z 446 [M + H].sup.+. 208 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2- morpholino- 1H-benzo[d] imidazol-4- yl)-2- methyl benzamide 00 Q .sup.1H NMR (400 MHz, CD.sub.3OD) 7.45 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 6.4 Hz, 1H), 7.32-7.35 (m, 1H), 7.23 (br s, 1H), 6.79 (br s, 1H), 3.78-3.81 (m, 4H), 3.52- 3.54 (m, 4H), 2.43 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H); ESI MS m/z 432 [M + H]+. 209 3-(2-(4- amino- piperidin-1- yl)-6-(3,5- dimethyl- isoxazol-4- yl)-1H- benzo[d] imidazol-4- yl)-2- methyl benzonitrile 01 S .sup.1H NMR (400 MHz, CD.sub.3OD) 7.73 (d, J = 7.4 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.20 (s, 1H), 6.78 (s, 1H), 4.09 (d, J = 13.3 Hz, 2H), 3.02-3.14 (m, 2H), 2.81-2.95 (m, 1H), 2.42 (s, 3H), 2.40 (s, 3H), 2.27 (s, 3H), 1.37- 1.96 (m, 2H), 1.34-1.49 (m, 2H); ESI MS m/z 425 [M H]. 210 3-(2-(benzyl amino)-6- (3,5- dimethyl- isoxazol-4- yl)-1H- benzo[d] imidazol-4- yl)-4-methyl benzonitrile 02 P .sup.1H NMR (400 MHz, CD.sub.3OD) 7.66 (s, 1H), 7.64 (br s, 1H), 7.51 (d, J = 7.4 Hz, 1H), 7.37 (d, J = 7.4 Hz, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.21-7.27 (m, 1H), 7.18 (br s, 1H), 6.78 (s, 1H), 4.57 (s, 2H), 2.42 (s, 3H), 2.27 (s, 6H); ESI MS m/z 434 [M + H]+. 211 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2- ((pyridin-3- ylmethyl) amino)- 1H-benzo[d] imidazol-4- yl)-4- methyl- benzonitrile 03 P .sup.1H NMR (400 MHz, CD.sub.3OD) 8.56 (s, 1H), 8.43 (d, J = 4.7 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.65 (br s, 2H), 7.47-7.54 (m, 1H), 7.41 (dd, J = 7.6, 4.9 Hz, 1H), 7.19 (br s, 1H), 6.78 (s, 1H), 4.64 (s, 2H), 2.41 (s, 3H), 2.26 (s, 3H), 2.25 (s, 3H); ESI MS m/z 435 [M + H]+. 212 N-benzyl-6- (3,5- dimethyl- isoxazol-4- yl)-4- (1,3,5- trimethyl-1H- pyrazol-4- yl)-1H- benzo[d] imidazol-2- amine 04 O .sup.1H NMR (400 MHz, CD.sub.3OD) 7.28-7.49 (m, 6H), 6.69 (s, 1H), 4.65 (d, J = 5.1 Hz, 2H), 3.73 (s, 3H), 2.43 (s, 3H), 2.30 (s, 3H), 2.11 (s, 3H), 2.07 (s, 3H); ESI MS m/z 427 [M + H]+. 213 3,5-dimethyl- 4-(2- (pyrrolidin-1- yl)-4-(1,3,5- trimethyl-1H- pyrazol-4- yl)-1H- benzo[d] imidazol-6- yl)isoxazole 05 O .sup.1H NMR (400 MHz, CD.sub.3OD) 7.27 (s, 1H), 6.65 (s, 1H), 3.79 (s, 3H), 3.54-3.62 (m, 4H), 2.44 (s, 3H), 2.31 (s, 3H), 2.20 (s, 6H), 2.03-2.11 (m, 4H); ESI MS m/z 389 [M H]. 214 6-(3,5- dimethyl- isoxazol-4- yl)-N- methyl-4- (4-methyl pyridin-3- yl)-1H- benzo[d] imidazol- 2-amine 06 R .sup.1H NMR (400 MHz, CD.sub.3OD) 8.49 (s, 1H), 8.24 (br s, 1H), 7.28-7.39 (m, 1H), 7.20 (d, J = 4.7 Hz, 1H), 6.73 (br s, 1H), 3.08 (d, J = 3.9 Hz, 3H), 2.43 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H); ESI MS m/z 334 [M + H]+. 215 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2- (pyrrolidin- 1-yl)-1H- benzo[d] imidazol-4- yl)-4- methyl- benzonitrile 07 P .sup.1H NMR (400 MHz, CD.sub.3OD) 7.66 (s, 2H), 7.51 (d, J = 8.2 Hz, 1H), 7.18 (br. s., 1H), 6.75 (br. s., 1H), 3.53 (t, J = 6.4 Hz, 4H), 2.43 (s, 3H), 2.29 (br.s., 3H), 2.28 (s, 3H), 2.04 (t, J = 6.4 Hz, 4H); ESI MS m/z 398 [M + H]+. 216 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2-((1- methyl- piperidin-4- yl)amino)- 1H-benzo[d] imidazol-4- yl)-2- methyl benzonitrile 08 S .sup.1H NMR (400 MHz, CD.sub.3OD) 7.73 (d, J = 7.4 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.19 (s., 1H), 6.76 (s, 1H), 3.60-3.74 (m, 1H), 2.82-2.94 (m, 2H), 2.42 (s, 3H), 2.40 (s, 3H), 2.30 (s, 3H), 2.27 (s, 3H), 2.17- 2.26 (m, 2H), 1.99-2.10 (m, 2H), 1.51-1.68 (m, 2H); ESI MS m/z 439 [M H]. 217 4-(2-(azetidin- 1-yl)-4-(1,3,5- trimethyl-1H- pyrazol-4- yl)-1H- benzo[d] imidazol-6- yl)-(3,5- dimethyl isoxazole 09 O .sup.1H NMR (400 MHz, CD.sub.3OD) 7.32 (s, 1H), 6.66 (s, 1H), 4.22 (t, J = 7.4 Hz, 4H), 3.74 (s, 3H), 2.45- 2.55 (m, 2H), 2.43 (s, 3H), 2.31 (s, 3H), 2.17 (s, 3H), 2.14 (s, 3H); ESI MS m/z 375 [M H]. 218 (3-(6-(3,5- dimethyl- isoxazol-4- yl)-2- (pyrrolidin- 1-yl)-1H- benzo[d] imidazol-4- yl)-4- methyl- phenyl) (pyrrolidin- 1-yl) methanone 0 No general proce- dure .sup.1H NMR (400 MHz, CD.sub.3OD) 7.48 (br. s., 2H), 7.38-7.45 (m, 1H), 7.16 (s, 1H), 6.74 (s, 1H), 3.58 (t, J = 6.8 Hz, 4H), 3.53 (t, J = 6.4 Hz, 4H), 2.42 (s, 3H), 2.27 (s, 6H), 2.03 (t, J = 6.4 Hz, 4H), 1.93- 2.00 (m, 2H), 1.85-1.93 (m, 2H); ESI MS m/z 470 [M + H]+. 219 3-(6-(3,5- dimethyl- isoxazol-4- yl)-2- ((pyridin-3- ylmethyl) amino)-1H- benzo[d] imidazol-4- yl)-4- methyl- benzamide Q .sup.1H NMR (400 MHz, CD.sub.3OD) 8.57 (s, 1H), 8.43 (d, J = 4.7 Hz, 1H), 7.79- 7.91 (m, 3H), 7.36-7.48 (m, 2H), 7.18 (br s, 1H), 6.81 (s, 1H), 4.65 (s, 2H), 2.42 (s, 3H), 2.27 (s, 3H), 2.24 (br s, 3H); ESI MS m/z 453 [M + H]+. 220 3-(2- (benzyl- amino)- 6-(3,5- dimethyl isoxazol-4- yl)-1H- benzo[d] imidazol-4- yl)-4- methyl- benzamide Q .sup.1H NMR (400 MHz, CD.sub.3OD) 7.79-7.90 (m, 2H), 7.21-7.49 (m, 6H), 7.18 (br s, 1H), 6.80 (s, 1H), 4.58 (s, 2H), 2.43 (s, 3H), 2.28 (s, 3H), 2.26 (s, 3H); ESI MS m/z 452 [M + H]+. 221 6-(3,5- dimethyl- isoxazol-4- yl)-N- (pyridin-3- ylmethyl)- 4-(1,3,5- trimethyl-1H- pyrazol-4- yl)-1H- benzo[d] imidazol-2- amine O .sup.1H NMR (400 MHz, CDCl.sub.3) 8.65 (br s, 1H), 8.55 (d, J = 5.1 Hz, 1H), 8.09 (s, 1H), 7.78 (d, J = 7.4 Hz, 1H), 7.27-7.34 (m, 2H), 6.71 (br s, 1H), 4.98 (br s, 1H), 4.64-4.80 (m, 2H), 3.74 (s, 3H), 2.44 (s, 3H), 2.31 (s, 3H), 2.06-2.20 (m, 6H); ESI MS m/z 426 [M H]. 222 N-benzyl-6- (3,5- dimethyl- isoxazol-4- yl)-4-(4- methyl- pyridin-3- yl)-1H- benzo[d] imidazol-2- amine R .sup.1H NMR (400 MHz, CDCl.sub.3) 8.34 (s, 1H), 8.02 (br s, 1H), 7.32-7.21 (m, 6H), 7.09 (d, J = 4.8 Hz, 1H), 6.67 (br s, 1H), 5.24 (br. s, 1H), 4.62 (s, 2H), 2.40 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H); ESI MS m/z 410 [M + H]+. 223 6-(3,5- dimethyl- isoxazol-4- yl)-4-(4- methyl- pyridin-3- yl)-N- (pyridin-3- ylmethyl)- 1H-benzo[d] imidazol-2- amine R .sup.1H NMR (400 MHz, CDCl.sub.3) 8.51 (s, 1H), 8.42-8.39 (m, 2H), 8.07 (br s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.28 (br s, 1H), 7.26-7.19 (m, 1H), 7.10 (d, J = 5.6 Hz, 1H), 6.71 (br s, 1H), 5.45 (br s, 1H), 4.67 (s, 2H), 2.40 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H). 224 3,5- dimethyl- 4-(4-(4- methyl pyridin-3- yl)-2- (pyrrolidin- 1-yl)-1H- benzo[d] imidazol-6- yl)isoxazole R .sup.1H NMR (400 MHz, CDCl.sub.3) 11.21 (br. s, 1H), 8.41 (s, 1H), 7.98 (br s, 1H), 7.35 (br. s, 1H), 7.10 (d, J = 4.8 Hz, 1H), 6.62 (s, 1H), 3.60-3.56 (m, 4H), 2.43 (s, 3H), 2.30 (s, 6H), 2.01- 1.97 (m, 4H); ESI MS m/z 374 [M + H]+. 225 3-amino- 5-(6-(3,5- dimethyl isoxazol- 4-yl)-1H- benzo[d] imidazol- 4-yl)-1- methyl- pyridin- 2(1H)-one D .sup.1H NMR (300 MHz, CD.sub.3OD) 8.27 (s, 1H), 7.68 (s, 1H), 7.49 (s, 1H), 7.23 (s, 1H), 7.22 (s, 1H), 3.70 (s, 3H), 2.45 (s, 3H), 2.29 (s, 3H); ESI MS m/z 336 [M + H]+. 94.8 226 4-(4,6- bis(3,5- dimethyl- isoxazol-4- yl)-1H- benzo[d] imidazol- 2-yl) morpholine F .sup.1H NMR (300 MHz, CD.sub.3OD) 7.21 (s, 1H), 6.88 (s, 1H), 3.82 (t, J = 5.1 Hz, 4H), 3.54 (t, J = 5.1 Hz, 4H), 2.43 (s, 3H), 2.38 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H); ESI m/z 394 [M + H]+. 98.6 227 4,4-(5- methoxy-2- methyl-1H- benzo[d] imidazole- 4,6-diyl) bis(3,5- dimethyl isoxazole) No general proce- dure .sup.1H NMR (300 MHz, CD.sub.3OD) 7.40 (s, 1H), 3.17 (s, 3H), 2.55 (s, 3H), 2.39 (s, 3H), 2.34 (s, 3H), 2.22 (s, 3H), 2.20 (s, 3H); ESI m/z 353 [M + H]+. 98.6 228 4,4-(2- (tetrahydro- 2H-pyran- 4-yl)-1H- benzo[d] imidazole- 4,6-diyl) bis(3,5- dimethyl isoxazole) 0 No general proce- dure .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.49 (s, 0.7H), 12.18 (s, 0.3H), 7.60 (s, 0.3H), 7.41 (s, 0.7H), 7.06 (s, 1H), 3.96-3.93 (m, 2H), 3.51-3.45 (m, 2H), 3.21- 3.01 (m, 1H), 2.44-2.33 (m, 6H), 2.28-2.17 (m, 6H), 1.93- 1.82 (m, 4H); ESI m/z 393 [M + H]+. 94.8 229 4,6-bis(3,5- dimethyl- isoxazol-4- yl)-N- (tetrahydro- 2H-pyran- 4-yl)-1H- benzo[d] imidazol- 2-amine F .sup.1H NMR (300 MHz, CD.sub.3OD) 7.17 (s, 1H), 6.81 (s, 1H), 4.00-3.84 (m, 3H), 3.59-3.50 (m, 2H), 2.43 (s, 3H), 2.37 (s, 3H), 2.28 (s, 3H), 2.23 (s, 3H), 2.05- 2.00 (m, 2H), 1.66-1.53 (m, 2H); ESI m/z 408 [M + H]+. >99 230 3,5-dimethyl- 4-(5-(1- methyl-1H- pyrazol-5- yl)-1H- benzo[d] imidazol- 7-yl) isoxazole No general proce- dure .sup.1H NMR (500 MHz, CD.sub.3OD) 8.29 (s, 1H), 7.75 (br.s, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.29 (s, 1H), 6.43 (d, J = 2.0 Hz, 1H), 3.92 (s, 3H), 2.38 (s, 3H), 2.23 (s, 3H); ESI m/z 294 [M + H]+. >99 231 4,4-(2-(4- methyl- piperazin- 1-yl)-1H- benzo[d] imidazole- 4,6-diyl) bis(3,5- dimethyl isoxazole) F .sup.1H NMR (300 MHz, CD.sub.3OD) 7.18 (s, 1H), 6.87 (s, 1H), 3.60 (t, J = 5.1 Hz, 4H), 2.59 (t, J = 5.1 Hz, 4H), 2.43 (s, 3H), 2.38 (s, 3H), 2.36 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H); ESI m/z 407 [M + H]+. >99 232 4,6-bis(3,5- dimethyl- isoxazol-4- yl)-N-(1- methyl- piperidin-4- yl)-1H- benzo[d] imidazol- 2-amine F .sup.1H NMR (300 MHz, CD.sub.3OD) 7.17 (s, 1H), 6.81 (s, 1H), 3.72-3.67 (m, 1H), 3.07-2.96 (m, 2H), 2.42- 2.27 (m, 11H), 2.23 (s, 3H), 2.18 (s, 3H), 2.13-2.09 (m, 2H), 1.70-1.59 (m, 2H); ESI m/z 421 [M + H]+. >99 233 4,6-bis(3,5- dimethyl- isoxazol-4- yl)-N- (piperidin- 4-yl)-1H- benzo[d] imidazol- 2-amine F .sup.1H NMR (300 MHz, CD.sub.3OD) 7.18 (s, 1H), 6.84 (s, 1H), 4.14-4.12 (m, 2H), 3.16-3.09 (m, 2H), 3.00- 2.94 (m, 1H), 2.43 (s, 3H), 2.38 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H), 1.97-1.95 (m, 2H), 1.51-1.43 (m, 2H); ESI m/z 407 [M + H]+. >99

Example 1: Inhibition of Tetra-Acetylated Histone H4 Binding Individual BET Bromodomains

(287) Proteins were cloned and overexpressed with a N-terminal 6His tag, then purified by nickel affinity followed by size exclusion chromatography. Briefly, E. coli BL21(DE3) cells were transformed with a recombinant expression vector encoding N-terminally Nickel affinity tagged bromodomains from Brd2, Brd3, Brd4. Cell cultures were incubated at 37 C. with shaking to the appropriate density and induced overnight with IPTG. The supernatant of lysed cells was loaded onto Ni-IDA column for purification. Eluted protein was pooled, concentrated and further purified by size exclusion chromatography. Fractions representing monomeric protein were pooled, concentrated, aliquoted, and frozen at 80 C. for use in subsequent experiments.

(288) Binding of tetra-acetylated histone H4 and BET bromodomains was confirmed by a Homogenous Time Resolved Fluorescence Resonance Energy Transfer (HTRF) method. N-terminally His-tagged bromodomains (200 nM) and biotinylated tetra-acetylated histone H4 peptide (25-50 nM, Millipore) were incubated in the presence of Europium Cryptate-labeled streptavidin (Cisbio Cat. #610SAKLB) and XL665-labeled monoclonal anti-His antibody (Cisbio Cat. #61HISXLB) in a white 96 well microtiter plate (Greiner). For inhibition assays, serially diluted test compound was added to these reactions in a 0.2% final concentration of DMSO. Duplicate wells were used for each concentration tested. Final buffer concentrations were 30 mM HEPES pH 7.4, 30 mM NaCl, 0.3 mM CHAPS, 20 mM phosphate pH 7.0, 320 mM KF, 0.08% BSA. After a 2 h incubation at room temperature, fluorescence was measured at 665 and 620 nm with a SynergyH4 plate reader (Biotek). The binding inhibitory activity was shown by a decrease in 665 nm relative to 620 nm fluorescence. IC.sub.50 values were determined from a dose response curve.

(289) Compounds with an IC.sub.50 value less than or equal to 0.3 M were deemed to be highly active (+++); compounds with an IC.sub.50 value between 0.3 and 3 M were deemed to be very active (++); compounds with an IC.sub.50 value between 3 and 30 M were deemed to be active (+).

(290) TABLE-US-00003 TABLE 2 Inhibition of Tetra-acetylated Histone H4 Binding to Brd4 bromodomain 1 (BRD4(1) as Measured by FRET FRET FRET FRET FRET Example activity Example activity Example activity Example activity Compound BRD4(1) Compound BRD4(1) Compound BRD4(1) Compound BRD4(1) 1 +++ 2 +++ 3 + 4 +++ 5 + 6 +++ 7 +++ 8 ++ 9 +++ 10 + 11 +++ 12 Not Active 13 +++ 14 + 15 +++ 16 +++ 17 + 18 +++ 19 ++ 20 +++ 21 +++ 22 ++ 23 +++ 24 +++ 25 ++ 26 +++ 27 +++ 28 ++ 29 +++ 30 +++ 31 +++ 32 +++ 33 +++ 34 +++ 35 +++ 36 +++ 37 +++ 38 +++ 39 +++ 40 +++ 41 +++ 42 +++ 43 +++ 44 ++ 45 +++ 46 +++ 47 +++ 48 +++ 49 +++ 50 +++ 51 +++ 52 +++ 53 +++ 54 +++ 55 +++ 56 ++ 57 +++ 58 +++ 59 +++ 60 +++ 61 Not 62 ++ 63 ++ 64 +++ active 65 +++ 66 +++ 67 +++ 68 +++ 69 +++ 70 +++ 71 + 72 +++ 73 +++ 74 +++ 75 ++ 76 +++ 77 +++ 78 ++ 79 +++ 80 +++ 81 +++ 82 ++ 83 ++ 84 ++ 85 +++ 86 ++ 87 +++ 88 +++ 89 +++ 90 ++ 91 +++ 92 +++ 93 +++ 94 +++ 95 ++ 96 +++ 97 +++ 98 +++ 99 +++ 100 +++ 101 +++ 102 ++ 103 +++ 104 +++ 105 +++ 106 +++ 107 +++ 108 +++ 109 +++ 110 +++ 111 ++ 112 +++ 113 ++ 114 ++ 115 ++ 116 ++ 117 +++ 118 +++ 119 +++ 120 +++ 121 ++ 122 ++ 123 +++ 124 +++ 125 +++ 126 +++ 127 +++ 128 ++ 129 ++ 130 +++ 131 ++ 132 ++ 133 + 134 ++ 135 +++ 136 +++ 137 +++ 138 +++ 139 ++ 140 +++ 141 Not 142 ++ 143 +++ 144 +++ Active 145 ++ 146 +++ 147 ++ 148 +++ 149 + 150 +++ 151 ++ 152 +++ 153 +++ 154 +++ 155 +++ 156 +++ 157 +++ 158 +++ 159 ++ 160 Not active 161 +++ 162 ++ 163 +++ 164 Not active 165 ++ 166 +++ 167 ++ 168 + 169 +++ 170 +++ 171 +++ 172 +++ 173 +++ 174 +++ 175 +++ 176 ++ 177 +++ 178 ++ 179 +++ 180 +++ 181 +++ 182 +++ 183 +++ 184 +++ 185 +++ 186 +++ 187 +++ 188 ++ 189 +++ 190 +++ 191 +++ 192 +++ 193 +++ 194 +++ 195 +++ 196 ++ 197 +++ 198 +++ 199 ++ 200 +++ 201 +++ 202 ++ 203 +++ 204 +++ 205 +++ 206 +++ 207 +++ 208 +++ 209 +++ 210 +++ 211 +++ 212 +++ 213 +++ 214 +++ 215 +++ 216 +++ 217 +++ 218 +++ 219 +++ 220 +++ 221 +++ 222 223 224 225 ++ 226 +++ 227 ++ 228 +++ 229 +++ 230 ++ 231 +++ 232 +++ 233 +++

Example 2: Inhibition of cMYC Expression in Cancer Cell Lines

(291) MV4-11 cells (CRL-9591) were plated at a density of 2.510.sup.4 cells per well in 96 well U-bottom plates and treated with increasing concentrations of test compound or DMSO (0.1%) in IMDM media containing 10% FBS and penicillin/streptomycin, and incubated for 3 h at 37C. Triplicate wells were used for each concentration. Cells were pelleted by centrifugation and harvested using the mRNA Catcher PLUS kit according to manufacturer's instructions. The eluted mRNA isolated was then used in a one-step quantitative real-time PCR reaction, using components of the RNA UltraSense One-Step Kit (Life Technologies) together with Applied Biosystems TaqMan primer-probes for cMYC and Cyclophilin. Real-time PCR plates were run on a ViiA7 real time PCR machine (Applied Biosystems), data was analyzed, normalizing the Ct values for cMYC to an internal control, prior to determining the fold expression of each sample, relative to the control.

(292) Compounds with an IC.sub.50 value less than or equal to 0.3 M were deemed to be highly active (+++); compounds with an IC.sub.50 value between 0.3 and 3 M were deemed to be very active (++); compounds with an IC.sub.50 value between 3 and 30 M were deemed to be active (+).

(293) TABLE-US-00004 TABLE 3 Inhibition of c-myc Activity in Human AML MV4-11 cells Example c-myc Example c-myc Example c-myc Example c-myc Compound activity Compound activity Compound activity Compound activity 1 ++ 2 ++ 4 ++ 6 ++ 7 ++ 8 Not 9 ++ 11 ++ active 13 ++ 15 + 16 ++ 18 ++ 19 ++ 20 ++ 21 ++ 22 Not active 23 ++ 24 ++ 25 ++ 26 ++ 27 ++ 28 ++ 29 ++ 32 ++ 33 ++ 34 ++ 35 ++ 36 ++ 37 ++ 38 ++ 39 ++ 40 Not active 41 ++ 42 +++ 43 Not 44 ++ active 45 ++ 46 ++ 47 ++ 48 ++ 49 +++ 50 ++ 51 ++ 52 ++ 53 ++ 54 ++ 55 ++ 56 Not Active 57 +++ 60 +++ 64 ++ 66 ++ 67 ++ 68 +++ 69 ++ 70 ++ 72 ++ 73 +++ 74 ++ 76 ++ 77 +++ 79 +++ 80 +++ 81 +++ 84 ++ 85 + 87 ++ 88 ++ 89 +++ 91 +++ 92 ++ 93 +++ 94 ++ 95 Not 97 ++ 98 ++ active 99 +++ 100 +++ 103 ++ 104 ++ 105 +++ 106 ++ 107 ++ 108 ++ 109 ++ 110 ++ 112 +++ 117 +++ 118 ++ 119 ++ 120 +++ 121 Not active 123 +++ 124 ++ 125 ++ 126 +++ 127 +++ 128 ++ 129 ++ 130 ++ 131 ++ 132 ++ 135 +++ 136 +++ 137 ++ 138 ++ 139 + 140 +++ 142 ++ 143 ++ 144 +++ 145 ++ 146 +++ 147 ++ 148 +++ 150 ++ 151 ++ 152 ++ 153 ++ 154 Not active 155 ++ 156 ++ 157 ++ 158 Not active 161 ++ 162 ++ 163 ++ 165 Not active 166 ++ 169 ++ 170 ++ 171 ++ 172 ++ 173 ++ 174 ++ 175 Not active 177 +++ 178 ++ 179 ++ 180 +++ 181 +++ 182 +++ 183 +++ 184 +++ 185 ++ 186 +++ 187 +++ 188 ++ 189 ++ 190 ++ 192 ++ 195 ++ 196 ++ 197 ++ 198 +++ 200 +++ 201 +++ 202 +++ 203 +++ 204 +++ 205 +++ 206 ++ 207 ++ 209 ++ 210 ++ 214 +++ 215 +++ 216 ++ 225 ++ 226 +++ 227 ++ 228 ++ 229 +++ 230 ++ 231 +++ 233 ++

Example 3: Inhibition of Cell Proliferation in Cancer Cell Lines

(294) MV4-11 cells (CRL-9591) were plated at a density of 510.sup.4 cells per well in 96 well flat bottom plates and treated with increasing concentrations of test compound or DMSO (0.1%) in IMDM media containing 10% FBS and penicillin/streptomycin. Triplicate wells were used for each concentration and a well containing only media was used as a control. Plates were incubated at 37 C., 5% CO.sub.2 for 72 h before adding 20 L of the CellTiter Aqueous One Solution (Promega) to each well and incubated at 37 C., 5% CO.sub.2 for an additional 3-4 h. The absorbance was read at 490 nm in a spectrophotometer and the percentage of cell titer relative to DMSO-treated cells was calculated after correcting for background by subtracting the blank well's signal. IC.sub.50 values were calculated using the GraphPad Prism software.

(295) Compounds with an IC.sub.50 value less than or equal to 0.3 M were deemed to be highly active (+++); compounds with an IC.sub.50 value between 0.3 and 3 M were deemed to be very active (++); compounds with an IC.sub.50 value between 3 and 30 M were deemed to be active (+).

(296) TABLE-US-00005 TABLE 4 Inhibition of Cell Proliferation in Human AML MV-4-11 cells Cell Cell Cell Cell Example Proliferation Example Proliferation Example Proliferation Example Proliferation Compound activity Compound activity Compound activity Compound activity 1 ++ 2 ++ 4 ++ 6 ++ 7 ++ 8 Not active 9 ++ 11 ++ 13 ++ 15 Not active 16 ++ 18 ++ 19 ++ 20 ++ 21 ++ 22 Not active 23 ++ 24 + 25 ++ 26 ++ 27 ++ 28 ++ 29 + 32 ++ 33 ++ 34 ++ 35 ++ 36 ++ 37 ++ 38 ++ 39 ++ 40 + 41 ++ 42 +++ 43 + 44 ++ 45 ++ 46 ++ 47 ++ 48 ++ 49 ++ 50 +++ 51 ++ 52 ++ 53 ++ 54 +++ 55 ++ 56 Not active 57 +++ 58 +++ 59 +++ 60 ++ 64 ++ 66 +++ 67 + 68 +++ 69 ++ 70 ++ 72 ++ 73 +++ 74 ++ 76 ++ 77 ++ 79 ++ 80 ++ 81 +++ 84 + 85 + 87 ++ 88 ++ 89 ++ 91 ++ 92 ++ 93 ++ 94 ++ 95 Not active 97 ++ 98 ++ 99 +++ 100 ++ 103 ++ 104 ++ 105 ++ 106 ++ 107 ++ 108 ++ 109 ++ 110 ++ 112 ++ 117 +++ 118 ++ 119 ++ 120 ++ 121 Not active 123 ++ 124 ++ 125 ++ 126 ++ 127 +++ 128 ++ 129 ++ 130 ++ 131 ++ 132 ++ 135 ++ 136 ++ 137 ++ 138 ++ 139 Not active 140 +++ 142 ++ 143 ++ 144 +++ 145 +++ 146 +++ 147 Not active 148 ++ 150 ++ 151 ++ 152 ++ 153 ++ 154 ++ 155 ++ 156 + 157 ++ 158 ++ 161 + 162 ++ 163 ++ 165 + 166 ++ 169 ++ 170 ++ 171 ++ 172 ++ 173 ++ 174 ++ 175 Not active 177 ++ 178 + 179 ++ 180 +++ 181 +++ 182 ++ 183 +++ 184 +++ 185 ++ 186 +++ 187 +++ 188 ++ 189 ++ 190 +++ 192 + 194 ++ 195 ++ 196 ++ 197 ++ 198 +++ 200 +++ 201 +++ 202 +++ 203 ++ 204 +++ 205 ++ 206 ++ 207 ++ 209 +++ 210 +++ 214 +++ 225 + 226 +++ 227 + 228 ++ 229 ++ 230 Not active 231 +++ 232 ++ 233 ++

Example 4: Inhibition of hIL-6 mRNA Transcription

(297) Human leukemic monocyte lymphoma U937 cells (CRL-1593.2) were plated at a density of 3.2104 cells per well in a 96-well plate in 100 L RPMI-1640 containing 10% FBS and penicillin/streptomycin, and differentiated into macrophages for 3 days in 60 ng/mL PMA (phorbol-13-myristate-12-acetate) at 37 C. in 5% CO2 prior to the addition of compound. The cells were pretreated for 1 h with increasing concentrations of test compound in 0.1% DMSO prior to stimulation with 1 ug/mL lipopolysaccharide from Escherichia coli. Triplicate wells were used for each concentration. The cells were incubated at 37 C., 5% CO2 for 3 h before the cells were harvested. At time of harvest, media was removed and cells were rinsed in 200 L PBS. Cells were harvested using the mRNA Catcher PLUS kit according to manufacturer's instructions. The eluted mRNA was then used in a one-step quantitative real-time PCR reaction using components of the RNA UltraSense One-Step Kit (Life Technologies) together with Applied Biosystems TaqMan primer-probes for hIL-6 and Cyclophilin. Real-time PCR plates were run on a ViiA7 real time PCR machine (Applied Biosystems), data was analyzed, normalizing the Ct values for hlL-6 to an internal control, prior to determining the fold expression of each sample, relative to the control.

(298) Compounds with an IC.sub.50 value less than or equal to 0.3 M were deemed to be highly active (+++); compounds with an IC.sub.50 value between 0.3 and 3 M were deemed to be very active (++); compounds with an IC.sub.50 value between 3 and 30 M were deemed to be active (+).

(299) TABLE-US-00006 TABLE 5 Inhibition of hIL-6 mRNA Transcription Example IL-6 Example IL-6 Example IL-6 Example IL-6 Compound activity Compound activity Compound activity Compound activity 1 +++ 2 ++ 4 ++ 6 ++ 7 +++ 8 Not active 9 +++ 11 ++ 13 ++ 15 + 16 +++ 18 +++ 19 ++ 20 +++ 21 ++ 22 ++ 23 +++ 24 ++ 25 ++ 26 +++ 27 +++ 28 ++ 32 ++ 33 ++ 34 ++ 35 ++ 36 ++ 37 ++ 38 ++ 41 +++ 42 +++ 43 ++ 44 ++ 49 +++ 50 +++ 51 ++ 52 ++ 53 +++ 54 ++ 55 ++ 57 +++ 58 +++ 59 +++ 60 +++ 64 +++ 66 +++ 67 Not active 68 +++ 69 ++ 70 ++ 72 ++ 73 +++ 74 ++ 76 ++ 77 ++ 79 ++ 80 ++ 81 ++ 84 ++ 85 ++ 87 ++ 88 ++ 89 ++ 91 +++ 92 +++ 93 +++ 94 ++ 95 Not active 97 +++ 98 ++ 99 +++ 104 +++ 105 +++ 106 ++ 107 ++ 108 ++ 109 +++ 110 ++ 112 +++ 114 +++ 117 +++ 118 ++ 119 +++ 120 +++ 121 ++ 123 +++ 124 ++ 127 +++ 128 +++ 129 ++ 130 +++ 131 ++ 132 ++ 135 ++ 136 ++ 137 ++ 138 +++ 139 ++ 140 +++ 142 ++ 143 ++ 144 +++ 145 ++ 146 +++ 147 ++ 148 +++ 150 ++ 151 ++ 152 +++ 153 ++ 154 +++ 155 ++ 156 + 157 ++ 158 ++ 161 ++ 162 ++ 163 ++ 165 ++ 166 ++ 169 ++ 170 ++ 171 ++ 172 ++ 173 ++ 174 ++ 175 Not active 177 ++ 178 ++ 180 +++ 181 +++ 182 +++ 201 +++ 203 +++ 204 +++ 205 ++ 206 ++ 207 ++ 208 +++ 209 ++ 210 ++ 211 ++ 212 +++ 213 +++ 214 ++ 215 ++ 216 +++ 225 + 226 +++ 227 ++ 228 ++ 229 +++ 230 + 231 +++

Example 5: Inhibition of hIL-17 mRNA Transcription

(300) Human peripheral blood mononuclear cells were plated (2.010.sup.5 cells per well) in a 96-well plate in 45 L OpTimizer T Cell expansion media (Life Technologies) containing 20 ng/ml IL-2 and penicillin/streptomycin. The cells were treated with increasing concentrations of the test compound or DMSO (0.1%), and incubated at 37 C., 5% CO2 for 1 h before addition of 10 stock OKT3 antibody at 10 ug/ml in media. Triplicate wells were used for each concentration. Cells were incubated at 37 C., 5% CO2 for 6 h before the cells were harvested. At time of harvest, cells were pelleted by centrifugation at 800 rpm for 5 min. Cells were harvested using the mRNA Catcher PLUS kit according to manufacturer's instructions. The eluted mRNA was then used in a one-step quantitative real-time PCR reaction, using components of the RNA UltraSense One-Step Kit (Life Technologies) together with Applied Biosystems TaqMan primer-probes for hIL-17 and Cyclophilin. Real-time PCR plates were run on a ViiA7 real time PCR machine (Applied Biosystems), data was analyzed, normalizing the Ct values for hIL-17 to an internal control, prior to determining the fold induction of each unknown sample, relative to the control.

(301) Compounds with an IC.sub.50 value less than or equal to 0.3 M were deemed to be highly active (+++); compounds with an IC.sub.50 value between 0.3 and 3 M were deemed to be very active (++); compounds with an IC.sub.50 value between 3 and 30 M were deemed to be active (+).

(302) TABLE-US-00007 TABLE 6 Inhibition of hIL-17 mRNA Transcription Example Example Compound IL-17 Activity compound IL-17 Activity 1 ++ 4 ++ 6 +++ 7 ++ 9 +++ 11 ++ 13 ++ 19 +++ 20 ++ 21 ++ 27 +++ 37 ++ 41 ++ 42 ++ 45 ++ 48 ++ 49 +++ 50 ++ 57 ++ 58 ++ 59 ++ 60 ++ 66 +++ 68 +++ 73 ++ 81 +++ 92 ++ 97 ++ 137 ++ 140 ++ 146 +++ 178 +++

Example 6: Inhibition of hVCAM mRNA Transcription

(303) Human umbilical vein endothelial cells (HUVECs) are plated in a 96-well plate (4.010.sup.3 cells per well) in 100 L EGM media and incubated for 24 h prior to the addition of increasing concentrations of the compound of interest or DMSO (0.1%). Triplicate wells were used for each concentration. The cells are pretreated for 1 h with the test compound prior to stimulation with tumor necrosis factor- when they are incubated for an additional 24 h before the cells are harvested. At time of harvest, the spent media is removed and HUVECs are rinsed in 200 L PBS. Cells were harvested using the mRNA Catcher PLUS kit according to manufacturer's instructions. The eluted mRNA was then used in a one-step quantitative real-time PCR reaction, using components of the RNA UltraSense One-Step Kit (Life Technologies) together with Applied Biosystems TaqMan primer-probes for hVCAM and Cyclophilin. Real-time PCR plates were run on a ViiA7 real time PCR machine (Applied Biosystems), data was analyzed, normalizing the Ct values for hVCAM to an internal control, prior to determining the fold induction of each unknown sample, relative to the control.

Example 7: Inhibition of hMCP-1 mRNA Transcription

(304) Human Peripheral Blood Mononuclear Cells are plated at a density of 1.010.sup.5 cells per well in a 96-well plate in RPMI-1640 containing 10% FBS and penicillin/streptomycin. The cells are treated with increasing concentrations of the compound or DMSO (0.1%), and incubated at 37 C., 5% CO2 for 3 h before the cells are harvested. At time of harvest, cells are transferred to V-bottom plates and pelleted by centrifugation at 800 rpm for 5 min. Cells were harvested using the mRNA Catcher PLUS kit according to manufacturer's instructions. The eluted mRNA was then used in a one-step quantitative real-time PCR reaction, using components of the RNA UltraSense One-Step Kit (Life Technologies) together with Applied Biosystems TaqMan primer-probes for hMCP-1 and Cyclophilin. Real-time PCR plates were run on a ViiA7 real time PCR machine (Applied Biosystems), data was analyzed, normalizing the Ct values for hMCP-1 to an internal control, prior to determining the fold induction of each unknown sample, relative to the control.

Example 8: Up-Regulation of hApoA-1 mRNA Transcription

(305) Huh7 cells (2.510.sup.5 per well) were plated in a 96-well plate using 100 L DMEM per well, (Gibco DMEM supplemented with penicillin/streptomycin and 10% FBS), 72 h before the addition of the compound. The cells are treated with increasing concentrations of the compound or DMSO (0.1%), and incubated at 37 C., 5% CO2 for 48 h. Spent media was removed from the Huh-7 cells and placed on ice for immediate use with the LDH cytotoxicity assay Kit II from Abcam. The cells remaining in the plate were rinsed with 100 L PBS. Cells were harvested using the mRNA Catcher PLUS kit according to manufacturer's instructions. The eluted mRNA was then used in a one-step quantitative real-time PCR reaction, using components of the RNA UltraSense One-Step Kit (Life Technologies) together with Applied Biosystems TaqMan primer-probes for hApoA-1 and Cyclophilin. Real-time PCR plates were run on a ViiA7 real time PCR machine (Applied Biosystems), data was analyzed, normalizing the Ct values for hApoA-1 to an internal control, prior to determining the fold induction of each unknown sample, relative to the control.

(306) Compounds with an EC.sub.170 value less than or equal to 0.3 M were deemed to be highly active (+++); compounds with an EC.sub.170 value between 0.3 and 3 M were deemed to be very active (++); compounds with an EC.sub.170 value between 3 and 30 M were deemed to be active (+).

(307) TABLE-US-00008 TABLE 7 Up-regulation of hApoA-1 mRNA Transcription. Example ApoA-1 Example ApoA-1 Example ApoA-1 Example ApoA-1 Compound activity Compound activity Compound activity Compound activity 1 ++ 4 + 5 +++ 37 +++ 41 +++ 49 +++ 57 +++ 60 +++ 97 +++

Examples 9: In Vivo Efficacy in Athymic Nude Mouse Strain of an Acute Myeloid Leukemia Xenograft Model Using MV4-11 Cells

(308) MV4-11 cells (ATCC) were grown under standard cell culture conditions and (NCr) nu/nu fisol strain of female mice age 6-7 weeks were injected with 510.sup.6 cells/animal in 100 L PBS+100 L Matrigel in the lower left abdominal flank. By approximately day 18-21 after MV4-11 cells injection, mice were randomized based on tumor volume (LWH)/2) of average 100-300 mm.sup.3. Mice were dosed orally with compound at 5 to 120 mg/kg b.i.d and/or q.d. on a continuous dosing schedule and at 2.5 to 85 mg/kg q.d. on a 5 day on 2 day off, 100 mg/kg q.d. on a 4 day on and 3 day off, 135 mg/kg q.d. on a 3 day on and 4 day off, 180 mg/kg on a 2 day on and 5 day off and 240 mg/kg on a 1 day on and 6 days off dosing schedules in EA006 formulation at 10 mL/kg body weight dose volume. Tumor measurements were taken with electronic micro calipers and body weights measured on alternate days beginning from dosing period. The average tumor volumes, percent Tumor Growth Inhibition (TGI) and % change in body weights were compared relative to Vehicle control animals. The means, statistical analysis and the comparison between groups were calculated using Student's t-test in Excel.

(309) TABLE-US-00009 TABLE 8 ln vivo efficacy in athymic nude mouse strain of an acute myeloid leukemia xenograft model Example In vivo activity Example Compound 1 Active Example Compound 6 Active Example Compound 9 Active Example Compound 27 Active Example Compound 41 Active Example Compound 49 Active

Example 10: In Vivo Efficacy in Athymic Nude Mouse Strain of an Acute Myeloid Leukemia Xenograft Model Using OCI-3 AML Cells

(310) OCI-3 AML cells (DMSZ) are grown under standard cell culture conditions and (NCr) nu/nu fisol strain of female mice age 6-7 weeks are injected with 1010.sup.6 cells/animal in 100 L PBS+100 L Matrigel in the lower left abdominal flank. By approximately day 18-21 after OCI-3 AML cells injection, mice are randomized based on tumor volume (LWH)/2) of average 100-300 mm.sup.3. Mice are dosed orally with compound at 30 mg/kg b.i.d on a continuous dosing schedule and at 2.5 to 45 mg/kg q.d. on a 5 day on and 2 day off dosing schedule in EA006 formulation at 10 mL/kg body weight dose volume. Tumor measurements are taken with electronic micro calipers and body weights measured on alternate days beginning from dosing period. The average tumor volumes, percent Tumor Growth Inhibition (TGI) and % change in body weights are compared relative to Vehicle control animals. The means, statistical analysis and the comparison between groups are calculated using Student's t-test in Excel.

Example 11: Evaluation of Target Engagement

(311) MV4-11 and MM1.s cells (ATCC) are grown under standard cell culture conditions and (NCr) nu/nu fisol strain of female mice age 6-7 weeks are injected with 510.sup.6 cells/animal in 100 L PBS+100 L Matrigel in the lower left abdominal flank. By approximately day 28 after MV4-11 and MM1.s cells injection, mice are randomized based on tumor volume (LWH)/2) of average 500 mm.sup.3. Mice are dosed orally with compound in EA006 formulation at 10 mL/kg body weight dose volume and tumors harvested 3, 6, 12, 24 hrs post dose for Bcl2 and c-myc gene expression analysis as PD biomarkers.

(312) TABLE-US-00010 TABLE 9 Evaluation of Target Engagement. Example Compound In vivo activity Example Compound 1 Active

Example 12: In Vivo Efficacy in Mouse Endotoxemia Model Assay

(313) Sub lethal doses of Endotoxin (E. Coli bacterial lipopolysaccharide) are administered to animals to produce a generalized inflammatory response which is monitored by increases in secreted cytokines. Compounds are administered to C57/Bl6 mice at T=4 hours orally at 75 mg/kg dose to evaluate inhibition in IL-6 and IL-17 and MCP-1 cytokines post 3-h challenge with lipopolysaccharide (LPS) at T=0 hours at 0.5 mg/kg dose intraperitoneally.

(314) TABLE-US-00011 TABLE 10 In vivo Efficacy in Mouse Endotoxemia Model Example Compound In vivo activity Example Compound 1 Active

Example 13: In Vivo Efficacy in Rat Collagen-Induced Arthritis

(315) Rat collagen-induced arthritis is an experimental model of polyarthritis that has been widely used for preclinical testing of numerous anti-arthritic agents. Following administration of collagen, this model establishes a measurable polyarticular inflammation, marked cartilage destruction in association with pannus formation and mild to moderate bone resorption and periosteal bone proliferation. In this model, collagen was administered to female Lewis strain of rats on Day 1 and 7 of study and dosed with compounds from Day 11 to Day 17. Test compounds were administered at 25 mg/kg to 120 mg/kg b.i.d and 7.5 mg/kg to 30 mg/kg q.d dose to assess the potential to inhibit the inflammation (including paw swelling), cartilage destruction and bone resorption in arthritic rats, using a model in which the treatment is administered after the disease has been established.

(316) TABLE-US-00012 TABLE 11 In Vivo Efficacy in Rat Collagen-induced Arthritis. Example Compound In vivo activity Example Compound 1 Active Example Compound 41 Active

Example 14: In Vivo Efficacy in Experimental Autoimmune Encephalomyelitis (EAE) Model of MS

(317) Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated autoimmune disease of the CNS which shares many clinical and histopathological features with human multiple sclerosis (MS). EAE is the most commonly used animal model of MS. T cells of both Th1 and Th17 lineage have been shown to induce EAE. Cytokines IL-23, IL-6 and IL-17, which are either critical for Th1 and Th17 differentiation or produced by these T cells, play a critical and non-redundant role in EAE development. Therefore, drugs targeting production of these cytokines are likely to have therapeutic potential in treatment of MS.

(318) Compounds of Formula I were administered at 50 to 125 mg/kg b.i.d. from time of immunization to EAE mice to assess anti-inflammatory activity. In this model, EAE is induced by MOG.sub.35-55/CFA immunization and pertussis toxin injection in female C57Bl/6 mice.

(319) TABLE-US-00013 TABLE 12 In Vivo Efficacy in Experimental autoimmune encephalomyelitis (EAE) Model of MS Example Compound In vivo activity Example Compound 1 Active Example Compound 6 Active

Example 15: Ex Vivo Effects on T Cell Function from Splenocyte and Lymphocyte Cultures Stimulated with External MOG Stimulation

(320) Mice were immunized with MOG/CFA and simultaneously treated with the compound for 11 days on a b.i.d regimen. Inguinal Lymph node and spleen were harvested, cultures were set up for lymphocytes and splenocytes and stimulated with external antigen (MOG) for 72 hours. Supernatants from these cultures were analyzed for TH1, Th2 and Th17 cytokines using a Cytometric Bead Array assay.

(321) TABLE-US-00014 TABLE 13 Ex Vivo effects on T cell function from Splenocyte and Lymphocyte cultures Example Compound In vivo activity Example Compound 1 Active Example Compound 6 Active

Example 16: In Vivo Efficacy in Athymic Nude Mouse Strain of Multiple Myeloma Xenograft Model Using MM1.s Cells

(322) MM1.s cells (ATCC) were grown under standard cell culture conditions and SCID-Beige strain of female mice age 6-7 weeks were injected with 1010.sup.6 cells/animal in 100 L PBS+100 L Matrigel in the lower left abdominal flank. By approximately day 21 after MM1.s cells injection, mice were randomized based on tumor volume (LWH)/2) of average 120 mm.sup.3. Mice were dosed orally with compound at 25 to 90 mg/kg b.i.d and or q.d in EA006 formulation at 10 mL/kg body weight dose volume. Tumor measurements were taken with electronic micro calipers and body weights measured on alternate days beginning from dosing period. The average tumor volumes, percent Tumor Growth Inhibition (TGI) and % change in body weights were compared relative to Vehicle control animals. The means, statistical analysis and the comparison between groups were calculated using Student's t-test in Excel.

(323) TABLE-US-00015 TABLE 14 In vivo efficacy in athymic nude mouse strain of multiple myeloma xenograft model using MM1.s cells Example Compound In vivo activity Example Compound 1 Active Example Compound 6 Active Example Compound 41 Active

(324) Other embodiments of the present disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the present disclosure disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the present disclosure being indicated by the following claims.