Phenoxymethyl derivatives

Abstract

The invention provides novel compounds having the general formula (I) ##STR00001##
wherein R.sub.A, R.sub.B, R.sub.C, R.sub.C1 and W are as defined herein, compositions including the compounds and methods of using the compounds.

Claims

1. A compound of formula (I): ##STR00645## or a pharmaceutically acceptable salt thereof, wherein: (1) R.sub.A is selected from the group consisting of i) C.sub.1-C.sub.6-alkyl, ii) cyano-C.sub.1-C.sub.6-alkyl, iii) C.sub.3-C.sub.8-cycloalkyl, iv) halo-C.sub.1-C.sub.6-alkoxy, v) halo-C.sub.1-C.sub.6-alkyl, vi) aryl substituted with R.sub.G, R.sub.G1 and R.sub.G2, vii) heterocycloalkyl substituted with R.sub.G, R.sub.G1 and R.sub.G2, and viii) heteroaryl substituted with R.sub.G, R.sub.G1 and R.sub.G2; and R.sub.B is selected from the group consisting of i) C.sub.1-C.sub.6-alkyl, ii) C.sub.3-C.sub.8-cycloalkyl, iii) C.sub.1-C.sub.6-alkylsulfonyl, iv) C.sub.3-C.sub.8-cycloalkylsulfonyl, v) C.sub.1-C.sub.6-alkylsulfonylamino, vi) C.sub.3-C.sub.8-cycloalkylsulfonylamino, vii) aminocarbonyl, ix) halogen, x) halo-C.sub.1-C.sub.6-alkoxy, xi) halo-C.sub.1-C.sub.6-alkyl, xii) heterocycloalkyl, and xiii) heteroaryl substituted with one H, C.sub.1-C.sub.6-alkyl, or trialkylsilyl-C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl; or (2) R.sub.A is selected from the group consisting of i) cyano-C.sub.1-C.sub.6-alkyl, ii) C.sub.3-C.sub.8-cycloalkyl, iii) halo-C.sub.1-C.sub.6-alkoxy, iv) halo-C.sub.1-C.sub.6-alkyl, v) aryl substituted with R.sub.G, R.sub.G1 and R.sub.G2, vi) heterocycloalkyl substituted with R.sub.G, R.sub.G1 and R.sub.G2, and vii) heteroaryl substituted with R.sub.G, R.sub.G1 and R.sub.G2; and R.sub.B is cyano; and: R.sub.C and R.sub.C1 are independently selected from the group consisting of i) H, ii) C.sub.1-C.sub.6-alkyl, iii) C.sub.3-C.sub.8-cycloalkyl, iv) halo-C.sub.1-C.sub.6-alkoxy, v) halo-C.sub.1-C.sub.6-alkyl, and vi) halogen; or R.sub.B and R.sub.C together with the carbon atoms to which they are attached form a ring system selected from the group consisting of i) C.sub.3-C.sub.8-cycloalkyl substituted with one to two substituent independently selected from H, C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, halo-C.sub.1-C.sub.6-alkyl and C.sub.3-C.sub.8-cycloalkyl, ii) heterocycloalkyl substituted with one to two substituent independently selected from H, C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, halo-C.sub.1-C.sub.6-alkyl and C.sub.3-C.sub.8-cycloalkyl, iii) aryl substituted with one to two substituent independently selected from H, halogen, C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, halo-C.sub.1-C.sub.6-alkyl and C.sub.3-C.sub.8-cycloalkyl, and iv) heteroaryl substituted with one to two substituent independently selected from H, halogen, C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, halo-C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.8-cycloalkyl; W is ring system A: ##STR00646## R.sub.D1 is selected from the group consisting of i) H, ii) C.sub.1-C.sub.6-alkyl, iii) halo-C.sub.1-C.sub.6-alkoxy, iv) halo-C.sub.1-C.sub.6-alkyl, and v) C.sub.3-C.sub.8-cycloalkyl, R.sub.G is selected from the group consisting of i) H, ii) C.sub.1-C.sub.6-alkoxy, iii) C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkylcarbonylamino-C.sub.1-C.sub.6-alkyl, iv) C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkylcarbonyl(C.sub.1-C.sub.6-alkyl)amino-C.sub.1-C.sub.6-alkyl, v) C.sub.1-C.sub.6-alkoxycarbonyl, vi) C.sub.1-C.sub.6-alkyl, vii) C.sub.1-C.sub.6-alkylsulfonyl, viii) C.sub.3-C.sub.8-cyloalkylsulfonyl, ix) carboxy, x) cyano, xi) C.sub.3-C.sub.8-cycloalkyl, xii) C.sub.3-C.sub.8-cycloalkoxy, xiii) C.sub.3-C.sub.8-cycloalkylcarbonylamino-C.sub.1-C.sub.6-alkyl, xiv) C.sub.3-C.sub.8-cycloalkylcarbonyl(C.sub.1-C.sub.6-alkyl)amino-C.sub.1-C.sub.6-alkyl, xv) C.sub.1-C.sub.6-alkylcarbonylamino-C.sub.1-C.sub.6-alkyl, xvi) C.sub.1-C.sub.6-alkylcarbonyl(C.sub.1-C.sub.6-alkyl)amino-C.sub.1-C.sub.6-alkyl, xvii) halo-C.sub.1-C.sub.6-alkyl, xviii) halo-C.sub.1-C.sub.6-alkoxy, xix) halogen, xx) hydroxy, xxi) aminocarbonyl substituted on the nitrogen atom with RN and Ro, xxii) aminocarbonyl-C.sub.1-C.sub.6-alkoxy substituted on the nitrogen atom with RN and Ro, xxiii) heteroaryl substituted with one H, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl, alkyl, halo-C.sub.1-C.sub.6-alkoxy, benzyl or aryl, wherein benzyl and aryl are substituted with one to three substituents independently selected from H, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl, halo-C.sub.1-C.sub.6-alkyl and halo-C.sub.1-C.sub.6-alkoxy, xxiv) heterocycloalkyl-C.sub.1-C.sub.6-alkoxy substituted with one H, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl, halo-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, benzyl or aryl, wherein benzyl and aryl are substituted with one to three substituents independently selected from H, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl, halo-C.sub.1-C.sub.6-alkyl and halo-C.sub.1-C.sub.6-alkoxy, and xxv) heterocycloalkyl-C.sub.1-C.sub.6-alkyl substituted with one H, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl, halo-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, benzyl or aryl, wherein benzyl and aryl are substituted with one to three substituents independently selected from H, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl, halo-C.sub.1-C.sub.6-alkyl and halo-C.sub.1-C.sub.6-alkoxy; R.sub.G1 and R.sub.G2 are independently selected from the group consisting of i) H, ii) halogen, iii) C.sub.1-C.sub.6-alkyl, iv) C.sub.3-C.sub.8-cycloalkyl, v) halo-C.sub.1-C.sub.6-alkoxy, and vi) halo-C.sub.1-C.sub.6-alkyl; R.sub.N is selected from the group consisting of i) H, ii) C.sub.1-C.sub.6-alkoxy, iii) C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, iv) C.sub.1-C.sub.6-alkoxycarbonyl-C.sub.1-C.sub.6-alkyl, v) C.sub.1-C.sub.6-alkyl, vi) carboxy-C.sub.1-C.sub.6-alkyl, vii) C.sub.3-C.sub.8-cycloalkyl, viii) C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.6-alkyl, ix) hydroxy-C.sub.1-C.sub.6-alkyl, x) phenyl, and xi) heteroaryl-C.sub.1-C.sub.6-alkyl; and R.sub.O is selected from the group consisting of i) H, and ii) C.sub.1-C.sub.6-alkyl; or R.sub.N and R.sub.O together with the nitrogen atom to which they are attached form a heterocycloalkyl.

2. The compound of claim 1, wherein the compound is: 3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[(2-tert-butyl-4-chloro-5-fluorophenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[(3,3-dimethyl-6-propan-2-yl-1,2-dihydroinden-5-yl)oxymethyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[2-tert-butyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[(2-tert-butyl-4-[1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]phenoxy]methyl-4-methyl-1H-1,2,4-triazol-5-one; 3-[[2-tert-butyl-4-(1-methylimidazol-2-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[2-tert-butyl-4-(1,3-oxazol-2-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[(2-tert-butyl-4-morpholin-4-ylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[2-tert-butyl-4-(3-methylimidazol-4-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[2-tert-butyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[(4-chloro-2-cyclopropyl-5-methylsulfonylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[(2-tert-butyl-4-methylsulfonylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[2-tert-butyl-4-[3-(2-trimethyl silyl-ethoxymethyl)imidazol-4-yl]phenoxy]-methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[(4-chloro-2-cyclopropyl-5-methylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[(4-chloro-2-cyclohexyl-5-methylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[4-chloro-5-methyl-2-(oxan-4-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 2-chloro-4-cyclopropyl-5-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile; N-[2-chloro-4-cyclopropyl-5-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]methanesulfonamide; 4-tert-butyl-3-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzamide; 4-methyl-3-[(5-methyl-2-propan-2-ylphenoxy)methyl]-1H-1,2,4-triazol-5-one; 3-[(4-chloro-5-methyl-2-propan-2-ylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[(4-chloro-2-propan-2-ylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[(6-cyclopropyl-2-methyl-1,3-benzothiazol-5-yl)oxymethyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[(4-chloro-2-cyclobutyl-5-methylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[2-tert-butyl-4-(1H-imidazol-2-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[ [2-tert-butyl-4-(1H-imidazol-5-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[(4-chloro-5-methyl-2-phenylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[4-chloro-2-(2-chlorophenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[4-chloro-2-(3-chlorophenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[4-chloro-2-(4-chlorophenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzonitrile; 3-[[4-chloro-5-methyl-2-(3-methylsulfonylphenyl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[4-chloro-5-methyl-2-(2-methylsulfonylphenyl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[4-chloro-5-methyl-2-[3-(piperidine-1-carbonyl)phenyl]phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-cyclohexylbenzamide; 3-[[4-chloro-5-methyl-2-[3-(morpholine-4-carbonyl)phenyl]phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzamide; 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N,N-dimethylbenzamide; 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-phenylbenzamide; 3-chloro-5-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzamide; 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-cyclopropyl-4-fluorobenzamide; 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-(2-methoxyethyl)benzamide; 3-[[4-chloro-2-(2-chloropyridin-3-yl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[4-chloro-2-(6-chloropyridin-2-yl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 5-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]pyri dine-3-carboxamide; 3-[[4-chloro-2-(6-methoxypyridin-2-yl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[(4-chloro-5-methyl-2-pyrazin-2-ylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[(4-chloro-5-methyl-2-pyrimidin-2-ylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[4-chloro-5-methyl-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[4-chloro-5-methyl-2-(1,2-oxazol-5-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[4-chloro-5-methyl-2-(1,3-oxazol-5-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[4-chloro-5-methyl-2-(3-methylimidazol-4-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[4-chloro-2-(1H-imidazol-5-yl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[4-chloro-5-methyl-2-(1,3-oxazol-2-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[4-chloro-5-methyl-2-(2-methylpyrazol-3-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 2-chloro-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]-5-phenylbenzonitrile; 2-chloro-5-(4-fluorophenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile; 3-[4-chloro-5-cyano-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-methylbenzamide, 2-chloro-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]-5-[3-(1H-pyrazol-3-yl)phenyl]benzonitrile; 2-chloro-5-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile; 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-(2-hydroxyethyl)benzamide; 2-chloro-5-[3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile; 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluoro-N,N-dimethylbenzamide; 3-[4-chloro-5-cyano-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N,N-dimethylbenzamide; 3-[[4-chloro-2-[2-fluoro-5-(morpholine-4-carbonyl)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 2-chloro-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]-5-[3-(morpholine-4-carbonyl)phenyl]benzonitrile; methyl 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoate; 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoic acid; methyl 3-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoyl]amino]propanoate; 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-(2-hydroxyethyl)-N-methylbenzamide; ethyl 2-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoyl]amino]acetate; 3-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoyl]amino]propanoic acid; 2-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoyl]amino]acetic acid; methyl 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-methylbenzoate; 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-methylbenzoic acid; 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N,N,4-trimethylbenzamide; 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-(trifluoromethoxy)benzamide; 3-[[4-chloro-2-(2-methoxypyridin-3-yl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 2-chloro-5-(2-methoxypyridin-3-yl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile; 3-[[4-chloro-2-(5-ethoxy-2-fluorophenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[4-chloro-2-(2-methoxyphenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[4-chloro-2-(2-fluoro-5-propan-2-yloxyphenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[4-chloro-2-[2-fluoro-5-(2-methylpropoxy)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[4-chloro-2-[2-methoxy-5-(trifluoromethyl)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[4-chloro-2-(2-methoxy-5-propan-2-ylphenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 2-chloro-5-[2-fluoro-5-(morpholine-4-carbonyl)phenyl-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile; 3-[[4-chloro-2-[2-fluoro-5-(pyrrolidine-1-carbonyl)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-cyclopropyl-4-fluoro-N-methylbenzamide; 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluoro-N-(2-hydroxyethyl)-N-methylbenzamide; 4-[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorobenzoyl]-1-methylpiperazin-2-one; 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-cyclopentyl-4-fluoro-N-methylbenzamide; 3-[[4-chloro-2-[2-fluoro-5-(oxolan-3-ylmethoxy)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluoro-N-methyl-N-(thiophen-2-ylmethyl)benzamide; 3-[[4-chloro-2-[2-fluoro-5-(piperidine-1-carbonyl)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-(cyclopropylmethyl)-4-fluoro-N-methylbenzamide; 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluoro-N-methyl-N-(pyridin-2-ylmethyl)benzamide; 3-[[4-chloro-2-[2-fluoro-5-(oxan-4-ylmethoxy)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluoro-N-(2-methoxyethyl)-N-methylbenzamide; 3-[[4-chloro-2-[2-fluoro-5-(oxolan-2-ylmethoxy)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 2-[3[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorophenoxy]-N,N-dimethylacetamide; 1-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorophenyl]methyl]-4-methylpiperazine-2,5-dione; 7-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-6-fluoro-3-methyl-1,3-benzoxazol-2-one; N-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorophenyl]methyl]-2-methoxy-N-methyl acetamide; N-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorophenyl]methyl]cyclopropanecarboxamide; N-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorophenyl]methyl]-N-methylcyclopropanecarboxamide; 3-[[4-chloro-2-[2-fluoro-5-[(2-oxopyrrolidin-1-yl)methyl]phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 3-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorophenyl]methyl]-1,3-oxazolidin-2-one; N-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorophenyl]methyl]-2-methoxyacetamide; 2-chloro-5-(2-fluorophenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile; 2-chloro-5-(3-fluorophenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile; 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-(trifluoromethoxy)benzonitrile; 2-chloro-5-[2-fluoro-5-(oxolan-2-ylmethoxy)phenyl]-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile; 2-chloro-5-(2-fluoro-3-methoxyphenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile; 2-chloro-5-(2-fluoro-5-propan-2-yloxyphenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile; 3-[[4-chloro-2-(2-fluoro-3-methoxyphenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 2-chloro-5-(2,3-difluorophenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile; 3-[[4-chloro-2-(5-cyclopropyloxy-2-fluorophenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one; 2-chloro-5-(5-chloro-2-fluorophenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile; 2-chloro-5-(2,5-difluorophenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile; 2-chloro-5-(5-cyclopropyloxy-2-fluorophenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile; or 2-chloro-5-[2-fluoro-5-(trifluoromethyl)phenyl]-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile; or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

4. A pharmaceutical composition comprising a compound of claim 2, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is manufactured by the process comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III): ##STR00647## wherein X is halogen, mesylate or tosylate; and R.sub.A, R.sub.B, R.sub.C and W are as defined in formula (I).

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sub.A is selected from the group consisting of: C.sub.1-C.sub.6-alkyl; cyano-C.sub.1-C.sub.6-alkyl; C.sub.3-C.sub.8-cycloalkyl; aryl substituted with R.sub.G, R.sub.G1, and R.sub.G2; heterocycloalkyl substituted with R.sub.G, R.sub.G1, and R.sub.G2; and heteroaryl substituted with R.sub.G, R.sub.G1, and R.sub.G2.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sub.A is selected from the group consisting of: C.sub.1-C.sub.6-alkyl; cyano-C.sub.1-C.sub.6alkyl; C.sub.3-C.sub.8-cycloalkyl; phenyl substituted with R.sub.G, R.sub.G1, and R.sub.G2; tetrahydropyranyl substituted with R.sub.G, R.sub.G1, and R.sub.G2; and heteroaryl substituted with R.sub.G, R.sub.G1, and R.sub.G2, wherein heteroaryl is selected from benzoxazolonyl, imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, and pyrimidinyl.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sub.A is phenyl substituted with R.sub.G, R.sub.G1, and R.sub.G2.

9. The compound of claim 1, wherein the compound is of formula (Ib): ##STR00648## or a pharmaceutically acceptable salt thereof, wherein: R.sub.A is C.sub.1-C.sub.6-alkyl and R.sub.B is halogen; or R.sub.A is phenyl substituted with R.sub.G, R.sub.G1, and R.sub.G2 and R.sub.B is cyano or halogen; and R.sub.C is selected from the group consisting of H, C.sub.1-C.sub.6-alkyl, and halogen; R.sub.D1 is C.sub.1-C.sub.6-alkyl, R.sub.G is selected from the group consisting of H; C.sub.1-C.sub.6-alkoxy; C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkylcarbonyl(C.sub.1-C.sub.6-alkyl)amino-C.sub.1-C.sub.6-alkyl; halogen; aminocarbonyl substituted on the nitrogen atom with R.sub.N and R.sub.O; aminocarbonyl-C.sub.1-C.sub.6-alkoxy substituted on the nitrogen atom with R.sub.N and R.sub.O; heteroaryl substituted with one H or C.sub.1-C.sub.6-alkyl wherein the heteroaryl is isoxazolyl, oxazolyl, or pyrazolyl; and heterocycloalkyl-C.sub.1-C.sub.6-alkoxy substituted with one H or C.sub.1-C.sub.6-alkyl, wherein the heterocycloalkyl-C.sub.1-C.sub.6-alkoxy is tetrahydropyranylmethoxy or tetrahydrofuranylmethoxy; R.sub.G2 is H and R.sub.G1 is H or halogen; R.sub.N is C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl and C.sub.1-C.sub.6-alkyl; and R.sub.O is C.sub.1-C.sub.6-alkyl; or R.sub.N and R.sub.O together with the nitrogen atom to which they are attached form morpholinyl, pyrrolidinyl, or methylpiperazinonyl.

10. A pharmaceutical composition comprising a compound of claim 9, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

Description

EXAMPLES

(1) All examples and intermediates were prepared under nitrogen atmosphere if not specified otherwise.

(2) Abbreviations: aq.=aqueous; CAS: =Chemical Abstracts Service Registry Number; HPLC=high performance liquid chromatography; MS=mass spectrum; sat.=saturated; rt=room temperature; TLC=thin layer chromatography; NMR: nuclear magnetic resonance spectrum;

Intermediates A

(3) Intermediate A2:

2-tert-Butyl-4-chloro-5-fluorophenol

(4) ##STR00050##

(5) To a solution of 4-chloro-3-fluorophenol (CAS: 2713-33-9; 1.14 g) in acetic acid (6.0 mL) were added tert-butanol (1.73 g), followed by sulfuric acid (1.53 g) at rt under an argon atmosphere. The mixture was then heated to 80° C. for 17 hours. TLC showed that the reaction was not complete and thus the reaction was refluxed (88° C.) for another 30 hours. While there was still some starting material visible on TLC, the reaction mixture was cooled down to rt and poured into ice/water. The aqueous phase was then extracted two times with ethyl acetate and the combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude material was purified by flash chromatography on silica gel with a gradient of 0% to 25% EtOAc in heptane as an eluent, to provide the title compound as a brown liquid (320 mg). MS (m/z): 201.1 [M−H].sup.−.

(6) Intermediate A4:

2-tert-Butyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenol

(7) ##STR00051##

Step 1: 1-Benzyloxy-4-bromo-2-tert-butyl-benzene

(8) ##STR00052##

(9) This material which is known in the literature (CAS: 33839-12-2) was made as follows:

(10) To a solution of 4-bromo-2-tert-butyl-phenol (CAS: 10323-39-4; 8 g) in anhydrous acetonitrile (150 mL) was added Cs.sub.2CO.sub.3 (22.7 g) followed by benzyl bromide (6.26 mL) at 25° C. and the mixture was stirred at 85° C. for 3 h. The reaction mixture was cooled to 25° C., filtered and the filtrate was evaporated under reduced pressure. The resulting residue was purified by column chromatography over silica gel (gradient of 3-5% ethyl acetate in hexanes) to provide 1-benzyloxy-4-bromo-2-tert-buty-benzene (11.0 g) as an off white solid. .sup.1H-NMR (400 MHz, S, DMSO-D6): 1.32 (s, 9H), 5.14 (s, 2H), 7.04 (d, 1H), 7.28-7.50 (m, ˜7H).

Step 2: 4-Benzyloxy-3-tert-butyl-benzonitrile

(11) ##STR00053##

(12) This material which is known in the literature (CAS: 847943-59-3) was made as follows:

(13) To a solution of 1-benzyloxy-4-bromo-2-tert-butyl-benzene (4.5 g) in anhydrous DMF (100 mL) were added Zn(CN).sub.2 (3.30 g), dppf (782 mg) and Zn (229 mg) under argon atmosphere and the reaction mixture was purged with argon for 10 minutes. Then, Pd.sub.2(dba).sub.3 (645 mg) was added at 25° C. and the reaction mixture was purged again with argon for 10 min. The mixture was then stirred at 110° C. for 16 h. The mixture was cooled, filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (5-7% ethyl acetate in hexanes) to afford the title compound (3.2 g) as an off white solid. MS (m/z): 265.0 [M].sup.+.

Step 3: 4-Benzyloxy-3-tert-butyl-benzoic acid

(14) ##STR00054##

(15) This material which is known in the literature (CAS: 146852-63-3) was made as follows:

(16) To a solution of 4-benzyloxy-3-tert-butyl-benzonitrile (800 mg) in MeOH (30 mL) was added 6N aq. NaOH solution (40 mL) at 25° C. and the reaction mixture was refluxed for 16 h. The mixture was cooled to 25° C. and the solvent was evaporated under reduced pressure. The resulting residue was diluted with water, acidified with conc. HCl and extracted with EtOAc (2×50 ml). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the title compound (830 mg) as a brown solid. MS (m/z): 285.2 [M+H].sup.+.

Step 4: 4-Benzyloxy-3-tert-butyl-benzoic acid methyl ester

(17) ##STR00055##

(18) This material which is known in the literature (CAS: 146852-62-2) was made as follows:

(19) To a solution of 4-benzyloxy-3-tert-butyl-benzoic acid (830 mg) in anhydrous DMF (30 mL) at 25° C. were added Cs.sub.2CO.sub.3 (1.9 g) followed iodomethane (0.273 mL) and the reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (gradient of 3-5% ethyl acetate in hexanes) to afford the title compound (740 mg) as an off white solid. MS (m/z): 299.3 [M+H].sup.+.

Step 5: 5-(4-Benzyloxy-3-tert-butyl-phenyl)-3-methyl-[1,2,4]oxadiazole

(20) ##STR00056##

(21) To a solution of 4-benzyloxy-3-tert-butyl-benzoic acid methyl ester (740 mg) and N-hydroxyacetamidine (229.7 mg) in anhydrous DMF (30 mL) was added NaH (218 mg) in portions at 25° C. and the reaction mixture was stirred at 25° C. for 3 h. The mixture was then quenched with water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (gradient of 7-10% EtOAc in hexane) to afford the title compound (650 mg) as an off white solid. MS (m/z): 323.0 [M+H].sup.+.

Step 6: 2-tert-Butyl-4-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenol

(22) ##STR00057##

(23) To a solution of 5-(4-benzyloxy-3-tert-butyl-phenyl)-3-methyl-[1,2,4]oxadiazole (300 mg) in anhydrous DCM (30 mL) kept at −78° C. was added BBr.sub.3 (1M solution in DCM, 2.79 mL) and the reaction mixture was stirred at −78° C. for 2 h. The mixture was quenched with saturated aqueous NaHCO.sub.3 solution (20 mL) and was extracted with DCM (2×30 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (gradient of 5-20% EtOAc in hexanes) to afford the title compound (150 mg) as an off white solid. MS (m/z): 233.2 [M+H].sup.+.

(24) Intermediate A5:

2-tert-Butyl-4-[1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]phenol

(25) ##STR00058##

Step 1: 2-(4-Benzyloxy-3-tert-butyl-phenyl)-4,5-dihydro-1H-imidazole

(26) ##STR00059##

(27) To a solution of 4-benzyloxy-3-tert-butyl-benzonitrile (1.4 g), obtained in intermediate A1, Step 2, in ethylenediamine (20 mL) in a sealed tube was added P.sub.2S.sub.5 (0.985 mg) at 25° C. and the reaction mixture was kept under pressure with stirring at 120° C. for 2 h. The reaction mixture was cooled to 25° C. and was then poured into water (100 mL). The mixture was stirred for 30 minutes and the resulting precipitate was collected by filtration and dried in vacuo to afford the title compound (1.45 g) as an off white solid. MS (m/z): 308.9 [M+H].sup.+.

Step 2: 2-(4-Benzyloxy-3-tert-butyl-phenyl)-1H-imidazole

(28) ##STR00060##

(29) To a solution of 2-(4-benzyloxy-3-tert-butyl-phenyl)-4,5-dihydro-1H-imidazole (1.4 g) in DMSO (50 mL) were added potassium carbonate (690 mg) and diacetoxy-iodobenzene (1.61 g) and the reaction mixture was stirred at 25° C. for 16 h in the dark. The mixture was then diluted with water and was extracted with dichloromethane (2×40 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography over amino silica gel (gradient of 33-40% EtOAc in hexanes) to afford the title compound (805 mg) as an off white solid. MS (m/z): 306.8 [M+H].sup.+.

Step 3: 2-(4-Benzyloxy-3-tert-butyl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole

(30) ##STR00061##

(31) To a suspension of NaH (16 mg) in anhydrous DMF (10 mL) at 0° C. was added a solution of 2-(4-benzyloxy-3-tert-butyl-phenyl)-1H-imidazole (500 mg) in anhydrous DMF (5 mL) and the reaction mixture was stirred at 25° C. for 30 minutes. Then, SEM-chloride (0.087 ml) was added dropwise at 25° C. and the reaction mixture was stirred at 25° C. for 2 h. The mixture was then quenched with water and was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated in vacuo. The residue was purified by column chromatography over silica gel (gradient of 30-40% ethyl acetate in hexanes) to afford the title compound (310 mg) as a sticky, colorless liquid. MS (m/z): 436.9[M].sup.+.

Step 4: 2-tert-Butyl-4-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-phenol

(32) ##STR00062##

(33) A solution of 2-(4-benzyloxy-3-tert-butyl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (300 mg) in MeOH (20 mL) was purged with argon for 10 min and then Pd(OH).sub.2 (100 mg) was added. An atmosphere of hydrogen was introduced and the reaction mixture was stirred under H.sub.2 at 25° C. for 6 h. The mixture was filtered and the filtrate was evaporated in vacuo to afford the title compound (200 mg) as an off white solid. MS (m/z): 347.0 [M+H].sup.+.

(34) Intermediate A6

2-tert-Butyl-4-(1-methylimidazol-2-yl)phenol

(35) ##STR00063##

Step 1: 2-(4-Benzyloxy-3-tert-butyl-phenyl)-1-methyl-1H-imidazole

(36) ##STR00064##

(37) A suspension of NaH (60% in mineral oil, 31 mg) in anhydrous THF (15 mL) was cooled to 0° C. and a solution of 2-(4-benzyloxy-3-tert-butyl-phenyl)-1H-imidazole (200 mg), obtained in Intermediate A5, Step 2, in THF (20 mL) was then added at 0° C. The reaction mixture was stirred at 0° C. for 30 min and then iodomethane (0.049 mL) was added at 0° C. Stirring was continued at 0° C. for 3 h. The mixture was quenched with water and was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (gradient of 60-70% EA in hexanes) to afford the title compound (175 mg) as a sticky solid. MS (m/z): 320.8 [M+H].sup.+.

Step 2: 2-tert-Butyl-4-(1-methylimidazol-2-yl)phenol

(38) ##STR00065##

(39) The title compound was obtained from 2-(4-benzyloxy-3-tert-butyl-phenyl)-1-methyl-1H-imidazole in analogy to Intermediate 5, Step 4 as an off white solid. MS (m/z): 230.7 [M+H].sup.+.

(40) Intermediate A7

2-tert-Butyl-4-(1,3-oxazol-2-yl)phenol

(41) ##STR00066##

Step 1: 2-(3-tert-Butyl-4-methoxymethoxy-phenyl)-oxazole

(42) ##STR00067##

(43) A solution of 4-bromo-2-tert-butyl-1-methoxymethoxy-benzene (500 mg, made from 4-bromo-2-tert-butyl-phenol according to WO2013079223) and 2-tributylstannanyl-oxazole (0.92 mL) in anhydrous dioxane (10 mL) in a sealed tube was purged with argon for 10 min. Then, PdCl.sub.2(dppf).sub.2 CH.sub.2Cl.sub.2 complex (149.5 mg) was added and the reaction mixture was purged again with argon for 10 min. The mixture was then stirred at 100° C. for 4 h and was then cooled to 25° C. filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (gradient of 5-10% ethyl acetate in hexanes) to afford the title compound (350 mg) as a light brown liquid. MS (m/z): 262.8 [M+H].sup.+.

Step 2: 2-tert-Butyl-4-oxazol-2-yl-phenol

(44) ##STR00068##

(45) To a solution of 2-(3-tert-buty-4-methoxymethoxy-phenyl)-oxazole (200 mg) in anhydrous DCM (10 mL) at 0-5° C. was added 4N HCl in dioxane (2.5 mL) and the reaction mixture was stirred at 25° C. for 28 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography over silica gel (gradient of 8-15% ethyl acetate in hexanes) to afford the title compound (120 mg) as an off white solid. MS (m/z): 217.9 [M+H].sup.+.

(46) Intermediate A8

2-tert-Butyl-4-morpholin-4-ylphenol

(47) ##STR00069##

Step 1: 4-(3-tert-Butyl-4-methoxymethoxy-phenyl)-morpholine

(48) ##STR00070##

(49) To a solution of 4-bromo-2-tert-butyl-1-methoxymethoxy-benzene (900 mg, made from 4-bromo-2-tert-butyl-phenol according to WO2013079223) and morpholine (0.44 mL) in anhydrous toluene (10 mL) in a sealed tube were added NaOtBu (475 mg) and xantphos (76.2 mg) at 25° C. The tube was purged with argon for 10 min and then Pd.sub.2(dba).sub.3 (60.3 mg) was added and the tube was again purged with argon for 10 min. Then, the mixture was stirred under pressure for 16 at 110° C. and was then cooled to 25° C. and filtered. The filtrate was evaporated under reduced pressure and the resulting crude material was purified by column chromatography (gradient of 7-10% ethyl acetate in hexanes) to afford the title compound (560 mg) as a sticky liquid. .sup.1H-NMR (400 MHz, δ, CDCl.sub.3): 1.38 (s, 9H), 3.04-3.10 (m, 4H), 3.48 (s, 3H), 3.80-3.90 (m, 4H), 5.17 (s, 2H), 6.69 (dd, 1H), 6.93 (d, 1H), 7.04 (d, 1H).

Step 2: 2-tert-Butyl-4-morpholin-4-yl-phenol

(50) ##STR00071##

(51) The title compound was obtained from 4-(3-tert-butyl-4-methoxymethoxy-phenyl)-morpholine using the conditions described in Intermediate A7, Step 2, as an off white solid. MS (m/z): 235.9 [M+H].sup.+.

(52) Intermediate A9

2-tert-Butyl-4-(1-methyl-1H-imidazol-2-yl)-phenol

(53) ##STR00072##

(54) To a solution of 4-bromo-2-tert-butyl-phenol (CAS: 10323-39-4, 200 mg) and 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-imidazole (272 mg) in anhydrous DMF (10 mL) was added K.sub.2CO.sub.3 (362 mg) at 25° C. under a nitrogen atmosphere. The reaction mixture was purged with argon for 10 min, and then PdCl.sub.2(dppf).sub.2 DCM complex (14.2 mg) was added. The vessel was again purged with argon for 10 min and the reaction mixture was stirred at 120° C. for 28 h. The mixture was cooled to 25° C., filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (gradient of 2-5% MeOH in DCM) to afford the title compound (124 mg) as a brown solid. MS (m/z): 230.9 [M+H].sup.+.

(55) Intermediate A10

2-ter-butyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenol

(56) ##STR00073##

Step 1: 3-tert-Butyl-4-hydroxy-benzoic acid methyl ester

(57) ##STR00074##

(58) To a solution of 3-tert-butyl-4-hydroxy-benzoic acid (CAS: 66737-88-0, 3 g) in anhydrous MeOH (40 mL) was added dropwise conc. H.sub.2SO.sub.4 (0.4 mL) at 25° C. and the reaction mixture was stirred at reflux for 16 h. Then, the solvent was evaporated under reduced pressure. The residue was diluted with DCM (50 mL) and the solution was washed with water and brine, dried over Na.sub.2SO.sub.4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography over silica gel (gradient of 0.5-1% MeOH in DCM) to afford the title compound (2.8 g) as an off white solid. MS (m/z): 209.4 [M+H].sup.+.

Step 2: 3-tert-Butyl-4-hydroxy-benzoic acid hydrazide

(59) ##STR00075##

(60) To a solution of 3-tert-butyl-4-hydroxy-benzoic acid methyl ester (3.7 g) in anhydrous MeOH (40 mL) in a sealed tube was added hydrazine hydrate (4.36 mL) at 25° C. and the reaction mixture was heated under pressure at to 65° C. for 16 h. The mixture was then cooled to 25° C. and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (gradient of 2-4% MeOH in DCM) to afford the title compound (2.8 g, 75%) as off white solid. MS (m/z): 209.1 [M+H].sup.+.

Step 3: 2-tert-butyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenol

(61) ##STR00076##

(62) To a suspension of 3-tert-butyl-4-hydroxy-benzoic acid hydrazide (1.5 g) in triethyl orthoacetate (25 mL) was heated to reflux at 150° C. for 7 h. The reaction mixture was then cooled to 25° C. and the solvent was evaporated under reduced pressure. The residue was diluted with DCM (50 mL) and was washed with water and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered, and evaporated under reduced pressure. The crude material was purified by column chromatography over silica gel (gradient of 2-3% MeOH in DCM) to afford the title compound (1.15 g) as an off white solid. MS: 233.1 [M+H].sup.+.

(63) Intermediate A14:

4-Chloro-2-cyclopropyl-5-methylsulfonylphenol

(64) ##STR00077##

Step 1: 1-Bromo-2-chloro-5-fluoro-4-nitrobenzene

(65) ##STR00078##

(66) To a stirred solution of 2-bromo-1-chloro-4-fluorobenzene (CAS: 201849-15-2; 10 g) in sulfuric acid (95-97%; 100 mL) was gradually added potassium nitrate (5.82 g) at −5° C. The reaction mixture was stirred at −5° C. for 1.5 hours and was then poured on 400 mL ice-water. The precipitate was filtered and dried in vacuo to provide the title compound as a colorless solid (11.54 g). MS (m/z): 253 [M].sup.+.

Step 2: 1-Bromo-2-chloro-5-methoxy-4-nitrobenzene

(67) ##STR00079##

(68) To a solution of 1-bromo-2-chloro-5-fluoro-4-nitrobenzene (11.0 g) in methanol (110 mL) was slowly added sodium methoxide (2.45 g) at 0° C. and the reaction mixture was stirred at 0° C. for 1.5 hours. The suspension was poured on water and was extracted with EtOAc. The combined organic extracts were dried with MgSO.sub.4, filtered and concentrated in vacuo to provide the title compound as a yellow solid (11.2 g). MS (m/z): 265[M].sup.+.

Step 3: 1-Chloro-4-methoxy-2-methylsulfonyl-5-nitrobenzene

(69) ##STR00080##

(70) To a solution of L-proline (61.3 mg) in DMSO (2 mL) was added sodium hydroxide (24.0 mg) and the mixture was stirred at rt for 30 minutes. Copper(I)iodide (114 mg), 1-bromo-2-chloro-5-methoxy-4-nitrobenzene (0.20 g) and sodium methanesulfinate (173 mg) were added. The reaction mixture was heated to 60° C. to give a turbid blue solution. After 5 hours, the reaction was allowed to cool down to room temperature. The mixture was poured on 50 mL 10% aqueous NaHCO.sub.3 solution and 50 mL EtOAc and the layers were filtered to remove any precipitates. The filtrated layers were then separated. The aqueous layer was extracted a second time with 50 mL EtOAc and the organic layers were washed with 50 mL brine, dried over MgSO.sub.4, filtered and concentrated in vacuo to give the title compound as a yellow solid (122 mg). MS (m/z): 265 [M].sup.+.

Step 4: 5-Chloro-2-methoxy-4-methylsulfonylaniline

(71) ##STR00081##

(72) To a mixture of ethanol (2.00 mL) and water (2.00 mL) was added acetic acid (140 μL) and this mixture was stirred under reflux for 10 minutes. To the solution thus obtained was added iron (163 mg) and 1-chloro-4-methoxy-2-methylsulfonyl-5-nitrobenzene (200 mg) and the mixture was stirred for additional 20 minutes. After cooling, 20 mL of acetone was added and the iron was filtered off through a pad of dicalite and washed with 20 mL of acetone. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with a gradient of n-heptane in ethyl acetate (100/0 to 50/50). This provided the title compound as white crystals (177 mg). MS (m/z): 235 [M].sup.+.

Step 5: 1-Chloro-5-iodo-4-methoxy-2-methylsulfonylbenzene

(73) ##STR00082##

(74) To a suspension of 5-chloro-2-methoxy-4-methylsulfonylaniline (1.50 g) in semi-concentrated HCl (18.5%, 15.1 g) was added dropwise at 0-5° C. a solution of sodium nitrite (461 mg) in water (3.66 mL). The initial suspension gradually cleared and turned nearly into a solution. This mixture was stirred for 1 hour at 0° C. and was then added dropwise to a stirred suspension of potassium iodide (3.17 g) in aq. HBr (48%, 21.0 mL) at rt. Stirring was continued for 30 minutes at rt. The reaction mixture was poured on 100 mL 2M aqueous Na.sub.2CO.sub.3 solution and 50 mL EtOAc and the layers were separated. The aqueous layer was extracted and a second time with 100 mL EtOAc. The organic layers were washed with Na.sub.2S.sub.2O.sub.3 and brine (50 mL), dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of n-heptane in ethyl acetate (100/0 to 50/50) to provide the title compound as a light yellow solid (950 mg). MS (m/z): 346 [M].sup.+.

Step 6: 4-Chloro-2-iodo-5-methylsulfonylphenol

(75) ##STR00083##

(76) To a solution of 1-chloro-5-iodo-4-methoxy-2-methylsulfonylbenzene (750 mg) in AcOH (15.6 g) was added aqueous HBr (48%, 4.7 ml) and the clear, colorless solution was stirred at reflux for 4 days in a sealed tube. The reaction mixture was cooled, poured on 100 mL water and 100 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 100 mL EtOAc. The organic layers were washed with 100 mL brine, dried over MgSO.sub.4, filtered and concentrated in vacuo. The compound was purified by silica gel chromatography, eluting with a gradient of n-heptane in ethyl acetate (100/0 to 60/40) to give the title compound as a light yellow solid (625 mg). MS (m/z): 330.87 [M−H].sup.−.

Step 7: 4-Chloro-2-cyclopropyl-5-methylsulfonylphenol

(77) ##STR00084##

(78) To a suspension of 4-chloro-2-iodo-5-methylsulfonylphenol (200 mg) in toluene (3 mL) were added under argon potassium cyclopropyltrifluoroborate (178 mg), water (0.21 mL), cesium carbonate (490 mg), palladium (II) acetate (6.75 mg) and butyldi-1-adamantylphosphine (21.6 mg) and the mixture was stirred in a sealed tube at 125° C. for 66 hours. The reaction mixture was cooled and poured on sat. aqueous NH.sub.4Cl solution and ethyl acetate and the layers were separated. The aqueous layer was extracted twice with additional ethyl acetate. The organic layers were dried over MgSO.sub.4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography, eluting with a gradient of n-heptane in ethyl acetate (100/0 to 50/50) to provide the title compound as a colorless solid (72 mg). MS (m/z): 245 [M].sup.+.

(79) Intermediate A15:

2-tert-Butyl-4-methylsulfonylphenol

(80) ##STR00085##

Step 1: 4-Bromo-2-tert-butyl-1-phenylmethoxybenzene

(81) ##STR00086##

(82) To a solution of 4-bromo-2-tert-butylphenol (CAS: 10323-39-4; 500 mg) in DMF (5 mL) was added NaH (114 mg) and the reaction mixture was stirred for 10 minutes at rt. Then, benzylchloride (290 mg) was added and the reaction mixture was stirred for 2 hours at rt. The mixture was poured on 30 mL 10% aqueous NH.sub.4Cl solution and 30 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed with 30 mL brine, dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of n-heptane in ethyl acetate (100/0 to 80/20) to give the title compound as a colorless solid (583 mg. MS (m/z): 318 [M].sup.+.

Step 2: 2-tert-Butyl-4-methylsulfonyl-1-phenylmethoxybenzene

(83) ##STR00087##

(84) To a solution of L-proline (88.3 mg) in DMSO (10 mL) was added sodium hydroxide (34.6 mg) and the mixture was stirred at room temperature for 30 minutes. Copper(I)iodide (165 mg), 4-bromo-2-tert-butyl-1-phenylmethoxybenzene (345 mg) and sodium methanesulfinate (249 mg) were added. The reaction mixture was heated to 60° C. to give a turbid blue solution and then the reaction was stirred for 2 hours at 60° C. TLC and LC-MS showed no conversion. Again, sodium methanesulfinate (249 mg) was added and the reaction mixture was stirred for 2 hours at 60° C. TLC and LS-MS showed again no conversion. The reaction mixture was transferred into a sealed tube and stirred at 135° C. over night. TLC and LC-MS showed complete conversion and LC-MS showed the presence of the desired mass. The reaction mixture was poured on 50 mL 10% aqueous NH.sub.4Cl solution and 50 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 50 mL EtOAc. The organic layers were washed with brine (50 mL), dried over MgSO.sub.4, filtered and concentrated in vacuo. The compound was purified by silica gel chromatography, eluting with a gradient of n-heptane in ethyl acetate (100/0 to 60/40) to provide the title compound as a colorless solid (278 mg). MS (m/z): 317.12 [M−H].sup.−.

Step 3: 2-tert-Butyl-4-methylsulfonylphenol

(85) ##STR00088##

(86) To a solution of 2-tert-butyl-4-methylsulfonyl-1-phenylmethoxybenzene (250 mg) in MeOH (3 mL) and ethyl acetate (3 mL) was added Pd on charcoal (10% Pd, 25 mg) under an argon atmosphere. The reaction was evacuated and purged with hydrogen. The reaction was stirred for 18 hours at 1.7 bar under H.sub.2-atmosphere. The reaction mixture was then filtered through a filter aid (dicalite) and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of n-heptane in ethyl acetate (100/0 to 50/50) to provide the title compound as colorless solid (140 mg). MS (m/z): 227.08 [M−H].sup.−.

(87) Intermediate A16:

5-tert-Butyl-4-hydroxy-2-methylbenzonitrile

(88) ##STR00089##

(89) To a solution of 4-bromo-2-tert-butyl-5-methylphenol (CAS: 51345-97-2, 0.45 g), made from 4-bromo-3-methylphenol according to WO2005058798 or WO2008059026, in DMF (4 mL) under argon were added water (40 μL), 1,1′-bis(diphenylphosphino)ferrocene (30.8 mg), zinc cyanide (120 mg), zinc (4.84 mg), zinc acetate (13.6 mg) and tris(dibenzylideneacetone)-dipalladium (0) (16.9 mg). The reaction mixture was capped and heated in a microwave oven for 30 minutes at 180° C. The reaction mixture was then poured into saturated aqueous NH.sub.4Cl solution containing a small volume of water, and ethyl acetate, and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were dried over MgSO.sub.4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography eluting with a gradient of n-heptane in ethyl acetate (100/0 to 75/25) to give the title compound (160 mg) as a light brown solid. MS (m/z): 188.11 [M−H].sup.−.

(90) Intermediate A17:

4-tert-butyl-5-hydroxy-2-methylbenzonitrile

(91) ##STR00090##

(92) This material was made in analogy to Intermediate A16 from 5-bromo-2-tert-butyl-4-methylphenol (CAS 1237614-78-6), made from 3-bromo-4-methylphenol according to WO2005058798 or WO2008059026), as a light yellow solid. MS (m/z): 188.11 [M−H].sup.−.

(93) Intermediate A18:

2-ter-Butyl-4-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-phenol

(94) ##STR00091##

Step 1: 144-Benzyloxy-3-tert-butyl-phenyl)-ethanone

(95) ##STR00092##

(96) To a solution of 1-benzyloxy-4-bromo-2-tert-butyl-benzene (Intermediate A15, Step 1, 5.0 g) in DMF (40 mL) and water (4 mL) were added n-butylvinylether (8.1 mL), 1.3-bis(diphenylphosphino)propane (1.61 g), K.sub.2CO.sub.3 (2.60 g) and Pd(OAc).sub.2 (351 mg) at 25° C. Then, the mixture was purged with argon and was stirred at 150° C. for 5 h. The mixture was cooled to 25° C., diluted with aq 2N HCl (25 mL) and stirred at 25° C. for 2 h. The mixture was extracted with EtOAc (2×100 mL) and the combined organic layers were washed with sat aq. NaHCO.sub.3 solution. The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (5% ethyl acetate in hexanes) to afford the title compound (1.6 g) as a brown liquid. MS (m/z): 283.2 [M+H].sup.+.

Step 2: 1-(4-Benzyloxy-3-tert-butyl-phenyl)-2-bromo-ethanone

(97) ##STR00093##

(98) To a solution of 1-(4-benzyloxy-3-tert-butyl-phenyl)-ethanone (1.0 g) in anhydrous THF (20 mL) and MeOH (10 mL) was added a solution of Bu.sub.4NBr.sub.3 (1.71 g) in THF (10 mL) at 25° C. and the reaction mixture was stirred at 50° C. for 5 h. The mixture was cooled to 25° C. and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (5% ethyl acetate in hexane) to afford the title compound (800 mg) as colorless liquid that was used without further characterization.

Step 3: 5-(4-Benzyloxy-3-tert-butyl-phenyl)-1H-imidazole

(99) ##STR00094##

(100) A solution of 1-(4-benzyloxy-3-tert-butyl-phenyl)-2-bromo-ethanone (800 mg) in formamide (30 mL) was stirred at 160-170° C. for 4 h. The reaction mixture was then cooled to 25° C. and was diluted with EtOAc (30 mL) and water (30 mL). The organic layer was separated and the aqueous layer was extracted with more EtOAc (2×30 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over amine silica gel (gradient of 5-10% MeOH in DCM) to afford the title compound (330 mg) as light yellow solid. MS (m/z): 306.9 [M+H].sup.+.

Step 4: 5-(4-Benzyloxy-3-tert-butyl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole

(101) ##STR00095##

(102) To a suspension of NaH (51 mg) in anhydrous THF (20 mL) was added dropwise a solution of 5-(4-benzyloxy-3-tert-butyl-phenyl)-1H-imidazole (330 mg) in anhydrous THF (10 mL) at 25° C. The reaction mixture was stirred at 25° C. for 30 min and then (2-chloromethoxy-ethyl)-trimethyl-silane (0.287 ml) was added dropwise at 25° C. The reaction mixture was stirred at 25° C. for 3 h, was then quenched with water and was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (40% ethyl acetate in hexanes) to get the title compound (310 mg) as an off white solid. MS (m/z): 436.9 [M+H].sup.+.

Step 5: 2-tert-Butyl-4-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-phenol

(103) ##STR00096##

(104) To a solution of 5-(4-benzyloxy-3-tert-butyl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (170 mg) in MeOH (20 mL) was purged with argon for 10 min and then Pd(OH).sub.2 (100 mg) was added at 25° C. The reaction mixture was stirred at 25° C. for 4 h under a H.sub.2 atmosphere. The mixture was then filtered and the filtrate was evaporated under reduced pressure to afford the title compound (170 mg) as an off white solid. MS (m/z): 347.0 [M+H].sup.+.

(105) Intermediate A19

4-chloro-2-cyclopropyl-5-methylphenol

(106) ##STR00097##

Step 1: 5-Chloro-2-methoxy-4-methyl-phenylamine

(107) ##STR00098##

(108) To a solution of 1-chloro-4-methoxy-2-methyl-5-nitro-benzene (CAS: 101080-03-9, 10.64 g) in MeOH (250 mL) and water (125 mL) were added Zn dust (24.15 g) and NH.sub.4Cl (31.05 g) at 25° C. and the reaction mixture was stirred for 2 h at 25° C. The mixture was filtered through a celite pad and the filtrate was evaporated, diluted with DCM (300 mL) and washed with water (2×200 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to provide the title compound (8.99 g) as a light brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 2.25 (3H, s), 3.80 (3H, s), 6.60 (1H, s), 6.68 (1H, s).

Step 2: 1-Chloro-5-iodo-4-methoxy-2-methyl-benzene

(109) ##STR00099##

(110) To a suspension of 5-chloro-2-methoxy-4-methyl-phenylamine (8.98 g) in conc. HCl (37%, 84 mL) was added a solution of NaNO.sub.2 (7.22 g) in water (70 mL) at 0° C. After stirring the reaction mixture for 30 min at 0° C., a solution of KI (34.74 g) in water (176 mL) was added and the reaction mixture was then stirred at 25° C. for 16 h. The reaction mixture was diluted with ethyl acetate (250 mL) and the organic layer was separated, washed with water (100 mL), saturated sodium thiosulfate solution (100 mL) and brine (50 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to get a crude material which was purified by flash chromatography over silica gel (hexanes) to afford the title compound (11.9 g) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 2.32 (3H, s), 3.84 (3H, s), 6.65 (1H, s), 7.68 (1H, s).

Step 3: 4-Chloro-2-iodo-5-methyl-phenol

(111) ##STR00100##

(112) To a stirred solution of 1-chloro-5-iodo-4-methoxy-2-methyl-benzene (3.13 g) in anhydrous DCM (20 mL) at 0° C. was added a solution of 1M boron tribromide in DCM (44.4 ml) and the resulting solution was stirred for 2 h at 25° C. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and was diluted with DCM (20 mL). The organic layer was separated and washed with water (25 mL) and brine (25 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (gradient of 5-10% ethyl acetate in hexanes) to afford the title compound as a brown solid (2.89 g). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 2.30 (3H, s), 5.12 (1H, s), 6.86 (1H, s), 7.57 (1H, s).

Step 4: 4-Chloro-2-cyclopropyl-5-methyl-phenol

(113) ##STR00101##

(114) To a solution of 4-chloro-2-iodo-5-methyl-phenol (500 mg) in toluene (8.5 mL) and water (0.5 mL) were added cyclopropylboronic acid (416 mg), K.sub.3PO.sub.4 (1.31 g), Pd(OAc).sub.2 (33 mg) and tricyclohexylphosphine (94 mg) and the reaction mixture was heated at 100° C. for 16 h. The mixture was filtered through celite and the filtrate was washed with brine. The organic layer was dried over Na.sub.2SO.sub.4 and was vaporated in vacuo. The residue was purified by flash chromatography over silica gel (gradient of 2-5% ethyl acetate in hexanes) to afford the title compound (210 mg) as a brown liquid. .sup.1H NMR (400 MHz, CDCl.sub.3): 0.59-0.62 (2H, m), 0.92-0.96 (2H, m), 1.69-1.76 (1H, m), 5.29 (1H, s), 6.86 (1H, s), 7.57 (1H, s).

(115) Intermediates A19A and A19B

(116) The following Intermediates were synthesized from 4-chloro-2-iodo-5-methyl-phenol and the suitable boronate building block in analogy to Intermediate A19, Step 4:

(117) TABLE-US-00002 Intermediate Systematic Name Building block Analytics A19A 02 cyclohexene-1-boronic acid pinacol ester Rƒ. 0.4 (10% ethyl acetate in hexanes) A19B 03 3,5-dihydro-2H-pyran- 4-boronic acid pinacol ester .sup.1H NMR (400 MHz, CDCl.sub.3): 2.29 (3H, s), 2.38-2.40 (2H, m), 3.92 (2H, t, J = 4), 4.28-4.29 (2H, m), 5.33 (1H, s), 5.92 (1H, s) 6.77 (1H, s), 7.05 (1H, s).
Intermediate A20:

4-Chloro-2-cyclohexyl-5-methyl-phenol

(118) ##STR00104##

(119) To a solution of 4-chloro-2-cyclohex-1-enyl-5-methyl-phenol (Intermediate A19A, 202 mg) in methanol (10 mL) was added Pd on carbon (10% Pd, 25 mg) and the reaction mixture was stirred at 25° C. under hydrogen atmosphere for 45 min. The mixture was then filtered through celite and the filtrate was evaporated under reduced pressure to afford the title compound (190 mg) as a colorless liquid. R.sub.f=0.3 (10% ethyl acetate in hexane) The following Intermediate was synthesized from the corresponding precursor in analogy to Intermediate A20:

(120) TABLE-US-00003 Intermediate Systematic Name Building block Analytics A21 05 4-Chloro-2-(3,6- dihydro-2H-pyran-4- yl)-5-methyl-phenol Intermediate A19B .sup.1H NMR (400 MHz, CDCl.sub.3): 1.72-1.78 (4H, m), 2.27 (3H, s), 3.01- 3.05 (1H, m), 3.51-3.57 (2H, m), 4.05-4.07 (2H, m), 5.33 (1H, s), 4.73 (1H, s) 6.60 (1H, s), 7.09 (1H, s).
Intermediate A22

2-Chloro-4-cyclopropyl-5-hydroxy-benzonitrile

(121) ##STR00106##

Step 1: 5-Amino-2-bromo-4-chloro-phenol

(122) ##STR00107##

(123) To a solution of 4-bromo-2-chloro-5-methoxy-phenylamine (CAS: 98446-54-9, 2.05 g) in anhydrous DCM (40 mL) at 0° C. was added a solution of BBr.sub.3 in DCM (1M, 86.7 mL) and the reaction mixture was stirred at 25° C. for 12 h. The mixture was quenched with saturated aqueous NaHCO.sub.3 solution (40 mL) and was extracted with DCM (2×60 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and were evaporated under reduced pressure to afford the title compound (1.9 g) as a brown solid. .sup.1H NMR (400 MHz, DMSO-D6): 5.36 (2H, s), 6.41 (1H, s), 7.21 (1H, s), 9.94 (1H, s).

Step 2: Carbonic acid 2-bromo-5-(di tert-butoxycarbonyl)amino-4-chloro-phenyl ester tert-butyl ester

(124) ##STR00108##

(125) To a stirred solution of 5-amino-2-bromo-4-chloro-phenol (1.9 g) in anhydrous THF (40 mL) at 25° C. were added di-tert-butyldicarbonate (“Boc anhydride”, 10.96 mL), Et.sub.3N (7.12 mL) and DMAP (10 mg) and the reaction mixture was refluxed for 12 h. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography over silica gel (gradient of 2-5% ethyl acetate/in hexanes) to afford the desired compound (3.82 g) as a white solid. MS (m/z): 522.1 [M].sup.+.

Step 3: Carbonic acid 5-(di tert-butoxycarbonyl)amino-4-chloro-2-cyclopropyl-phenyl ester tert-butyl ester

(126) ##STR00109##

(127) The title compound was obtained in analogy to intermediate A19, Step 4, from carbonic acid 2-bromo-5-(di tert-butoxycarbonyl)amino-4-chloro-phenyl ester tert-butyl ester and cyclopropylboronic acid as a colorless, sticky liquid. MS (m/z): 484.0 [M].sup.+.

Step 4: 5-Amino-4-chloro-2-cyclopropyl-phenol

(128) ##STR00110##

(129) To a solution of carbonic acid 5-(di tert-butoxycarbonyl)amino-4-chloro-2-cyclopropyl-phenyl ester tert-butyl ester (1.05 g) in DCM (20 mL) was added TFA (6.45 mL) and the reaction mixture was stirred at 25° C. for 2 h. The solvent was evaporated under reduced pressure and the residue was diluted with DCM (50 mL). The solution was washed with saturated aqueous NaHCO.sub.3 solution (30 mL) and water (20 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated to afford the title compound (397 mg) as a brown solid. .sup.1H NMR (400 MHz, DMSO-D.sub.6) δ: 0.42-0.46 (2H, m), 0.70-0.74 (2H, m), 1.80-1.87 (1H, m), 4.94 (2H, s), 6.26 (1H, s), 6.51 (1H, s), 9.11 (1H, s).

Step 5: 4-Chloro-2-cyclopropyl-5-iodo-phenol

(130) ##STR00111##

(131) To a suspension of 5-amino-4-chloro-2-cyclopropyl-phenol (395 mg) in water (1 mL) at 0° C. was added slowly conc. H.sub.2SO.sub.4 (1.29 mL), followed by a solution of NaNO.sub.2 (148 mg) in water (5.5 mL) at 0° C. After stirring the reaction mixture for 10 more minutes, a solution of KI (714 mg) in water (1 mL) was added and reaction mixture was heated at 60° C. for 2 h. The mixture was cooled to 25° C. and extracted with DCM (2×30 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified by flash chromatography over silica gel (gradient of 2-5% ethyl acetate in hexanes) to afford the title compound (241 mg) as a yellow liquid. MS (m/z): 292.8 [M−H].sup.−.

Step 6: 2-Chloro-4-cyclopropyl-5-hydroxy-benzonitrile

(132) ##STR00112##

(133) To a solution of 4-chloro-2-cyclopropyl-5-iodo-phenol (238 mg) in anhydrous DMF (5 mL) was added CuCN (145 mg) and the reaction mixture was heated at 100° C. for 24 h. The solvent was evaporated in vacuo and the residue was purified by flash chromatography over silica gel (gradient of 5-10% ethyl acetate in hexanes) to afford the title compound (120 mg) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 0.68-0.72 (2H, m), 1.06-1.10 (2H, m), 1.86-1.89 (1H, m), 5.64 (1H, s), 7.09 (1H, s), 7.10 (1H, s).

(134) Intermediate A23

N-(2-Chloro-4-cyclopropyl-5-hydroxy-phenyl)-methanesulfonamide

(135) ##STR00113##

(136) To a solution of 5-amino-4-chloro-2-cyclopropyl-phenol (78 mg), obtained in Intermediate A22, Step 4, in DCM (5 mL) were added pyridine (0.04 mL) and methanesulfonyl chloride (0.03 mL) at 0° C. and the reaction mixture was then stirred at 25° C. for 12 h. The mixture was quenched with 6N aqueous NaOH solution (5 mL) and water (10 mL). The organic layer was separated and the aqueous phase was extracted with additional DCM (20 mL). The aqueous layer was cooled to 0° C., acidified with conc. HCl and extracted with ethyl acetate (2×20 mL). The combined organic ethyl acetate extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel (gradient of 5-20% ethyl acetate in hexanes) to provide the title compound (58 mg) as a brown solid. .sup.1H NMR (400 MHz, DMSO-D): 0.62-0.65 (2H, m), 0.84-0.89 (2H, m), 1.97-2.05 (1H, m), 2.95 (3H, s), 6.80 (1H, s), 6.91 (1H, s), 9.19 (1H, s), 9.80 (1H, s).

(137) Intermediate A24:

4-tert-Butyl-3-hydroxy-benzonitrile

(138) ##STR00114##

Step 1: 4-tert-Butyl-3-methoxy-benzamide

(139) ##STR00115##

(140) A solution of 4-tert-butyl-3-methoxy-benzoic acid (CAS: 79822-46-1: 2 g) in SOCl.sub.2 (5 mL) was refluxed for 2 h. Excess SOCl.sub.2 was evaporated in vacuo and the residue was dissolved in THF (5 mL) and conc. aqueous NH.sub.3 solution (2 mL) was added dropwise at 0° C. The reaction mixture was stirred at rt for 1 h and was then extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4 and were evaporated under reduced pressure to afford the title compound (1.95 g) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 1.36 (9H, s), 3.88 (3H, s), 6.0 (2H, bs), 7.20 (1H, dd, J=4 Hz, 12 Hz), 7.30 (I H, d, J=12 Hz), 7.42 (1H, d, J=4 Hz).

Step 2: 4-tert-Butyl-3-methoxy-benzonitrile

(141) ##STR00116##

(142) A solution of 4-tert-butyl-3-methoxy-benzamide (500 mg, 2.41 mmol) in POCl.sub.13 (5 mL) was refluxed for 6 h. Excess POCl.sub.13 was evaporated in vacuo and the residue was dissolved in ethyl acetate (30 mL) and washed with saturated aqueous NaHCO.sub.3 solution (25 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered, and was then evaporated under reduced pressure. The crude material was purified by flash chromatography over silica gel (5% ethyl acetate in hexane) to provide the title compound (360 mg) as a colorless liquid. MS (M/z): 189.0 [M].sup.+.

Step 3: 4-tert-Butyl-3-hydroxy-benzonitrile

(143) ##STR00117##

(144) The title compound was obtained in analogy to intermediate A22, Step 1, from 4-tert-butyl-3-methoxy-benzonitrile by treatment with BBr.sub.3 as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): 1.39 (9H, s), 5.41 (1H, s), 6.93 (1H, d, J=4 Hz), 7.17 (1H, dd, J=4 Hz, 12 Hz), 7.33 (1H, d, J=8 Hz).

(145) The following Intermediate was synthesized from the corresponding precursor in analogy to Intermediate A24, Step 3:

(146) TABLE-US-00004 Intermediate Systematic Name Building block Analytics A25 4-tert-butyl-3- methoxybenzamide Intermediate A24, Step 1 .sup.1H NMR (400 MHz, CDCl.sub.3): 1.55 (9H, s), 5.73 (1H, s), 7.16 (1H, dd, J = 4 Hz, 12 Hz), 7.30 (1H, d, J = 12 Hz), 7.34 (1H, d, J = 4 Hz).
Intermediate A30:

6-Cyclopropyl-2-methylbenzo[d]thiazol-5-ol

(147) ##STR00119##

Step 1: 6-Iodo-5-methoxy-2-methylbenzo[d]thiazole

(148) ##STR00120##

(149) A solution of 5-methoxy-2-methylbenzo[d]thiazol-6-amine (CAS: 89976-71-6; 1.0 g) in water (2.6 mL) and conc. hydrochloric acid (2.54 mL) was cooled down to 0° C. Then, a solution of sodium nitrite (373 mg) in water (2.6 mL) was added dropwise over 3 minutes. The brown solution was stirred at 0° C. for 5 minutes and was then added dropwise to a vigorously stirred suspension of potassium iodide (2.56 g) in HBr solution (48% in water, 12.2 mL) over 5 minutes at rt. Stirring at rt was continued for 20 minutes. The reaction mixture was poured into 2M aqueous Na.sub.2CO.sub.3 solution (60 mL) and ethyl acetate (50 mL) and the layers were separated. The aqueous layer was extracted twice with ethyl acetate (30 mL, each). The organic layers were washed once with aqueous Na.sub.2S.sub.2O.sub.3 solution (50 mL) and once with brine (20 mL), dried over MgSO.sub.4, filtered, treated with silica gel and evaporated. The compound was purified twice by silica gel chromatography on a 50 g column using an MPLC system eluting with a gradient of n-heptane/ethyl acetate (1000 to 50/50) to provide the title compound as a slightly impure, light brown solid (0.66 g). MS (m/z): 306.4 [M+H].sup.+.

Step 2: 6-Iodo-2-methylbenzo[d]thiazol-5-ol

(150) ##STR00121##

(151) To a solution of 6-iodo-5-methoxy-2-methylbenzo[d]thiazole (0.625 g) in dichloromethane (4 mL) in a sealed tube under argon at room temperature was added dropwise tribromoborane (1M in DCM: 2.25 mL) and the light brown suspension was stirred at reflux (oil bath at 60° C.) for 1.5 hours. No product was detected at this point. More DCM (4.00 mL) and tribromoborane (1M in dichloromethane; 2.25 mL) were added after 3 hours and stirring was continued at 60° C. over the weekend. The reaction mixture was poured into water and DCM (containing a small volume of methanol) and the layers were separated. The aqueous layer was extracted twice with DCM. The organic layers were washed once with brine, dried over MgSO.sub.4, filtered and evaporated. The residue was taken up in ethyl acetate and dichloromethane and was partially evaporated until a suspension formed. This suspension was filtered, washed with a small amount of ethyl acetate and dried in vacuo to provide the title compound as a light brown solid (455 mg). MS (m/z): 292.3 [M+H].sup.+.

Step 3: 6-cyclopropyl-2-methyl-1,3-benzothiazol-5-ol

(152) ##STR00122##

(153) To a suspension of 6-iodo-2-methylbenzo[d]thiazol-5-ol (0.15 g) in toluene (3 mL) were added under argon potassium cyclopropyltrifluoroborate (152 mg), water (0.21 mL), cesium carbonate (420 mg), palladium (1) acetate (5.78 mg) and butyldi-1-adamantylphosphine (18.5 mg) and the mixture was stirred in a sealed tube at 125° C. for 66 hours. The reaction mixture was poured into saturated aqueous NH.sub.4Cl solution and ethyl acetate and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over MgSO.sub.4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC system eluting with a gradient of n-heptane in ethyl acetate (100/0 to 0/100) to provide the title compound as alight brown solid. MS (m/z): 206.06 [M+H].sup.+.

(154) According to LC-MS, the material contains some 2-methylbenzo[d]thiazol-5-ol as an impurity.

(155) Intermediate A31

4-Chloro-2-cyclobutyl-5-methyl-phenol

(156) ##STR00123##

Step 1: 1-(5-Chloro-2-methoxy-4-methyl-phenyl)-cyclobutanol

(157) ##STR00124##

(158) To a solution of 1-chloro-5-iodo-4-methoxy-2-methyl-benzene (1 g). Intermediate A19, Step 2, in anhydrous THF (20 mL) was added dropwise isopropyl magnesium chloride (2M in THF, 2.12 mL) at −40° C. under a nitrogen atmosphere and the reaction mixture was stirred at −40° C. for 1 h. Then, a solution of cyclobutanone (298 mg) in anhydrous THF (3 mL) was added dropwise to the reaction mixture at −40° C. and stirring was continued at 25° C. for 11 h. The reaction mixture was quenched with saturated aqueous NH.sub.4Cl solution and was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography over silica gel (gradient of 5-15% ethyl acetate in hexanes) to afford the title compound (431 mg) as a colorless liquid. .sup.1H NMR (400 MHz, CDCl.sub.3): 1.55-1.66 (1H, m), 1.96-2.06 (1H, m), 2.31-2.41 (5H, m), 2.43-2.48 (2H, m) 3.48 (1H, s), 3.85 (3H, s), 6.75 (1H, s), 7.23 (1H, s).

Step 2: 1-Chloro-5-cyclobutyl-4-methoxy-2-methyl-benzene

(159) ##STR00125##

(160) To a mixture of 1-(5-chloro-2-methoxy-4-methyl-phenyl)-cyclobutanol (428 mg) and triethyl silane (0.362 mL) in anhydrous DCM (20 mL) at −78° C. under argon atmosphere was added dropwise boron trifluoride etherate (0.237 mL) and the reaction mixture was allowed to warm to −40° C. within a period of 3 h. Stirring was then continued at −40° C. for another 2 h. The reaction mixture was then poured into 10% aqueous KHCO.sub.3 solution (30 mL) and was extracted with DCM (3×30 mL). The combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and evaporated. The residue was purified by column chromatography over silica gel (gradient of 0-5% ethyl acetate in hexanes) to provide the title compound (370 mg) as a colorless liquid. .sup.1H NMR (400 MHz, CDCl.sub.3): 1.78-1.81 (1H, m), 1.91-2.06 (3H, m), 2.24-2.32 (5H, m), 3.62-3.75 (I H, m), 3.38 (3H, s), 6.63 (1H, s), 7.12 (1H, s).

Step 3: 4-Chloro-2-cyclobutyl-5-methyl-phenol

(161) ##STR00126##

(162) The title compound was obtained in analogy to Intermediate A19, Step 3, from 4-chloro-2-cyclobutyl-5-methyl-phenol by treatment with BBr.sub.3 in DCM as a brown solid (327 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 1.82-1.89 (1H, m), 1.98-2.16 (3H, m), 2.27 (3H, s), 2.31-2.42 (2H, m) 3.53-3.59 (1H, m), 4.50 (1H, s), 6.61 (1H, s), 7.09 (1H, s).

(163) Intermediate A34

4-(tert-Butyl)-2-chloro-5-hydroxy benzonitrile

(164) ##STR00127##

Step 1: 5-Bromo-2-(tert-butyl)-4-chlorophenol

(165) ##STR00128##

(166) To a solution of 3-bromo-4-chlorophenol (2.0 g, CAS: 13659-24-0) in acetic acid (6.0 mL) were added tert-butanol (1.07 g, 1.36 mL) followed by sulfuric acid (946 mg, 517 μL) at room temperature under an argon atmosphere. The mixture was heated to 70° C. for 80 hours. More tert-butanol (715 mg, 905 μL) and sulfuric acid (756 mg, 413 μL) were added and the mixture was heated to 90° C. for another 24 hours. The reaction mixture was cooled to room temperature and was then poured into ice/water. The aqueous layer was extracted twice with ethyl acetate. The organic layers were washed once with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. Residual tert-butanol was removed by evaporation from toluene (200 mL) to dryness. The crude material was purified by flash chromatography (0% to 20% ethyl acetate in heptane) to give the title compound as a light brown liquid (506 mg, 19%). MS (ESI): m/z=263.11 [M−H].sup.−.

Step 2; 4-(tert-Butyl)-2-chloro-5-hydroxybenzonitrile

(167) ##STR00129##

(168) 5-Bromo-2-(tert-butyl)-4-chlorophenol (501 mg), 1,1′-bis(diphenylphosphino)-ferrocene (31.6 mg), zinc granules (4.97 mg), zinc cyanide (123 mg), zinc acetate (14 mg), tris(dibenzylidene-acetone)dipalladium(0) (17.4 mg) were dissolved in dimethylformamide (5.0 mL) and water (50 μL) at room temperature. The mixture was then subjected to microwave irradiation for 30 minutes at 180° C. The reaction mixture was cooled to room temperature and was then poured then into ice/water. The aqueous layer was acidified with sat. NH.sub.4Cl solution and was extracted twice with ethyl acetate. The organic layers were washed once with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. Residual DMF was removed by evaporation from toluene (150 mL) to dryness. The crude material was purified by flash chromatography (0% to 20% ethyl acetate in heptane) to give the title compound as a light yellow solid (71 mg, 18%). MS (ESI): m/z=208.1 [M−H].sup.−.

(169) Intermediate A35

5-tert-butyl-2-chloro-4-hydroxy-benzonitrile

(170) ##STR00130##

Step 1: 4-bromo-2-tert-butyl-5-chloro-phenol

(171) ##STR00131##

(172) To a sealable vessel containing 4-bromo-3-chlorophenol (23 g, 111 mmol) was added acetic acid (115 mL), tBuOH (48 mL, 499 mmol), and sulfuric acid (30 mL, 333 mmol). The vessel was sealed and heated to 90° C. with vigorous stirring. After 18 h, an additional charge of tBuOH (48 mL, 499 mmol), and sulfuric acid (30 mL, 333 mmol) was added, and heating was continued at 90° C. After 5 h, the reaction was cooled to room temperature then partitioned between ethylacetate and water. The layers were separated, and the aqueous phase washed again with ethylacetate. The combined organic phases were washed twice with water, once with brine, dried over MgSO.sub.4, filtered and concentrated. The resulting crude mixture was purified on SiO.sub.2, eluting first with 100% hexanes, then ramping to 25% ethylacetate in hexanes to yield 9.76 g of the title compound which was used in the next step without further purification (60% pure, measured by NMR).

Step 2: 5-tert-butyl-2-chloro-4-hydroxy-benzonitrile

(173) ##STR00132##

(174) To 4-bromo-2-tert-butyl-5-chloro-phenol (9.76 g, 60% pure, 22.2 mmol) was added DMF (80 mL) then CuCN (4 g, 44.7 mmol). The resulting mixture was heated to 170° C. for 8 h Upon reaction completion, the mixture was cooled then partitioned between ethylacetate and water. The resulting suspension was filtered over celite and rinsed with ethylacetate. The layers were separated, and the aqueous phase washed again with ethylacetate. The combined organic phases were washed with water, brine, dried over MgSO.sub.4, filtered and concentrated. The resulting crude mixture was purified on SiO2, eluting with 0-60% ethylacetate in hexanes to yield 2.59 g of the title compound (56% yield).

(175) Intermediate A36

5-tert-butyl-2-fluoro-4-hydroxy-benzonitrile

(176) ##STR00133##

Step 1: 2-tert-butyl-4-chloro-5-fluoro-phenol

(177) ##STR00134##

(178) The title compound was prepared in analogy to intermediate A35, step 1, from 4-chloro-3-fluorophenol (5 g) and was obtained (4.4 g, 64%).

Step 2: 5-tert-butyl-2-fluoro-4-hydroxy-benzonitrile

(179) ##STR00135##

(180) To 2-tert-butyl-4-chloro-5-fluoro-phenol (108 mg, 0.53 mmol) was added dioxane/water (1:1, 2 mL), potassium acetate (10 mg, 0.11 mmol), and K.sub.4[Fe(CN).sub.6].3H.sub.2O (113 mg, 0.27 mmol). Nitrogen gas was bubbled through for 20 minutes. 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (11 mg, 0.027 mmol) and [(2-Di-tert-butylphosphino-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-amino-1,1-biphenyl)] palladium(II) methanesulfonate (21 mg, 0.027 mmol) were added and the mixture was heated to 100° C. for 3 h. Upon reaction completion, the mixture was cooled then partitioned between ethylacetate and brine. The resulting suspension was filtered over celite and rinsed with ethylacetate. The layers were separated, the organic phases were washed twice with brine, dried over magnesiumsulfate, filtered and concentrated. The resulting crude mixture was purified on SiO2 eluting with 0-100% ethylacetate in hexanes) to yield 61.3 mg of the title compound (60% yield).

Intermediates B

(181) Intermediate B1:

4-Chloro-5-methyl-2-phenylphenol

(182) ##STR00136##

Step 1: 5-Chloro-2-methoxy-4-methylaniline

(183) ##STR00137##

(184) To a solution of 1-chloro-4-methoxy-2-methyl-5-nitrobenzene (0.15 g, prepared as described in WO2011/141716) in THF (0.22 mL) were added Fe(acac).sub.3 (52.6 mg, CAS: 14024-18-1) and 1,1,3,3-tetramethyldisiloxane (300 mg, CAS: 3277-26-7) and the reaction mixture was stirred at reflux in a sealed tube for 15 hours. The reaction mixture was allowed to cool to rt, treated with EtOAc (5 mL) and extracted with aqueous 25% HCl solution (2 mL). The aqueous layer was extracted once more with EtOAc (5 mL). The aqueous layer was then adjusted to approx. pH 8 to 9 using solid NaHCO.sub.3 and was then extracted three times with EtOAc. The combined organic layers were dried over MgSO.sub.4, filtered and evaporated to give the title compound as a brown solid (0.1 g: 78%). MS (ESI): m/z=172.4 [M+H].sup.+.

Step 2: 1-Chloro-5-iodo-4-methoxy-2-methylbenzene

(185) ##STR00138##

(186) To conc. aqueous HCl (127 μL) at 0° C. was added NaNO.sub.2 (57.5 mg, CAS: 7632-00-0).

(187) To this mixture was added dropwise over 7 minutes a solution of 5-chloro-2-methoxy-4-methylaniline (0.13 g) in AcOH (1.5 mL) and the resulting mixture was stirred at rt for 30 minutes. This mixture was added dropwise via syringe to a stirred solution of KI (377 mg, CAS: 7681-11-0) in 48% aqueous HBr (2 mL) at room temperature. The brown mixture was stirred at rt for another 2 hours. The reaction mixture was poured on 2M aqueous Na.sub.2CO.sub.3 solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed once with brine, dried over MgSO.sub.4, filtered and evaporated. The residue was purified by silica gel chromatography on a 10 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane in EtOAc (100/0 to 50/50) to give the title compound as a light brown solid (0.134 g; 63%). MS (EI): m/z=282[M].

Step 3: 4-Chloro-2-iodo-5-methylphenol

(188) ##STR00139##

(189) To a solution of I-chloro-5-iodo-4-methoxy-2-methylbenzene (1.13 g) in DCM (20 mL) was added dropwise at 0° C. tribromoborane 1M in DCM (4.2 mL, CAS: 10294-334) over 15 minutes. The reaction mixture was stirred for 4 hours at rt. The reaction mixture was poured on H.sub.2O (60 mL) and DCM (60 mL) and the layers were separated. The aqueous layer was extracted a second time with DCM (60 mL). The organic layers were washed with brine (60 mL), dried over MgSO.sub.4, filtered and concentrated in vacuo to give the title compound as a light yellow solid (1.023 g, 95%). MS (ESI): m/z=266.907 [M−H].sup.−.

Step 4: 4-Chloro-5-methyl-2-phenylphenol

(190) ##STR00140##

(191) To a solution of 4-chloro-2-iodo-5-methylphenol (100 mg) in DME (2 mL) was added phenylboronic acid (45.4 mg, CAS: 98-80-6) and 2M aqueous Na.sub.2CO.sub.3 (1 mL). The reaction mixture was stirred for 15 minutes under argon atmosphere. Pd(II)acetate (4.18 mg, CAS: 3375-31-3) and triphenyphosphine (9.77 mg, CAS: 603-35-0) were added. The reaction mixture was stirred for 2 hours at 90° C. The reaction mixture was poured on 10% aqueous NaHCO.sub.3 solution (30 mL) and EtOAc (30 mL) and the layers were separated. The aqueous layer was extracted a second time with EtOAc (30 mL). The organic layers were washed with brine (30 mL), dried over MgSO.sub.4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane in EtOAc (100/0 to 70/40) to give the title compound as alight yellow oil (0.077 g, 95%). MS (EI): m/z=218 [M].sup.+.

(192) The following intermediates were made in analogy to intermediate B1, step 4, from 4-chloro-2-iodo-5-methylphenol (intermediate B1, step 3) and the corresponding aryl boronic acid or aryl borolane building block as indicated in the following table:

(193) TABLE-US-00005 Inter- Building block/ mediate Systematic Name intermediate MS, m/z  B2 2-chlorophenylboronic acid CAS: 3900-89-8 MS (EI): 252.0 [M].sup.+  B3 3-chlorophenylboronic acid CAS: 63503-60-6 MS (ESI): 251.003 [M − H].sup.−  B4 4-chlorophenylboronic acid CAS: 1679-18-1 MS (ESI): 251.003 [M − H].sup.−  B5 3-cyanophenylboronic acid CAS: 150255-96-2 MS (ESI): 242.048 [M − H].sup.−  B6 3-(methylsulfonyl)phenyl- boronic acid CAS: 373384-18-0 MS (ESI): 295.020 [M − H].sup.−  B7 2-(methylsulfonyl)phenyl- boronic acid CAS: 330804-03-0 MS (EI): 296.0 [M].sup.+  B8 3-(piperidine-1- carbonyl)phenylboronic acid CAS: 850568-34-2 MS (ESI): 330.127 [M + H].sup.+  B9 3-(cyclohexylcarbamoyl) phenylboronic acid CAS: 850567-25-8 MS (ESI): 344.143 [M + H].sup.+ B10 3-(morpholine-4- carbonyl)phenylboronic acid CAS: 723281-55-8 MS (ESI): 332.104 [M + H].sup.+ B11 0 3-carbamoylphenylboronic acid CAS: 351422-73-6 MS (ESI): 260.047 [M − H].sup.− B12 3-(dimethylcarbamoyl)- phenylboronic acid CAS: 373384-14-6 MS (ESI): 290.095 [M + H].sup.+ B13 3-(phenylcarbamoyl)- phenylboronic acid CAS: 397843-71-9 MS (ESI): 338.09 [M + H].sup.+ B14 3-carbamoyl-5- chlorophenylboronic acid CAS: 957120-53-5 MS (ESI): 294.01 [M − H].sup.− B15 5-(cyclopropylcarbamoyl)- 2-fluorophenylboronic acid CAS: 874289-54-0 MS (ESI): 320.08 [M + H].sup.+ B17 N-(2-methoxyethyl)-3- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)benzamide ( CAS: 1073353-64-6 MS (ESI): 320.11 [M + H].sup.+ B18 2-chloropyridin-3- ylboronic acid CAS: 381248-04-0 MS (ESI): 254.01 [M + H].sup.+ B19 6-chloropyridine-2-boronic acid pinacol ester CAS: 652148-92-0 MS (ESI): 224.998 [M + H].sup.+ B20 5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)nicotinamide CAS: 1169402-51-0 MS (ESI): 263.06 [M + H].sup.+ B21 6-methoxypyridin-2- ylboronic acid CAS: 372963-51-4 MS (ESI): 250.06 [M + H].sup.+ B36 0 N-(2-hydroxyethyl)-3- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)benzamide CAS: 943911-66-8 MS (ESI): 306.1 [M + H].sup.+ B38 5-(dimethylcarbamoyl)-2- fluorophenylboronic acid CAS: 874289-46-0 MS (ESI): 308.1 [M + H].sup.+ B40 2-fluoro-5-(morpholine-4- carbonyl)phenylboronic acid CAS: 1072951-41-7 MS (ESI): 350.1 [M + H].sup.+ B42 3-(methoxycarbonyl)- phenylboronic acid CAS: 99769-19-4 MS (ESI): 275.2 [M − H].sup.− B44 3-(3-methoxy-3- oxopropylcarbamoyl)- phenylboronic acid CAS: 957034-72-9 MS (ESI): 348.2 [M + H].sup.+ B46 3-(2-ethoxy-2- oxoethylcarbamoyl)phenyl boronic acid CAS: 1072945-97-1 MS (ESI): 348.1 [M + H].sup.+ B49 5-(methoxycarbonyl)-2- methylphenylboronic acid CAS: 876189-18-3 MS (ESI): 289.2 [M − H].sup.− B52 5-carbamoyl-2- (trifluoromethoxy)phenyl- boronic acid eMolecules #BB-4033 MS (ESI): 346.1 [M + H].sup.+ B53 2-methoxypyridin-3- ylboronic acid CAS: 163105-90-6 MS (ESI): 250.1 [M + H].sup.+
Intermediate B16:

6-Hydroxy-biphenyl-3-carbonitrile

(194) ##STR00169##

Step 1: 4-Hydroxy-3-iodo-benzonitrile

(195) ##STR00170##

(196) To a solution of 4-hydroxy-benzonitrile (5 g, CAS: 767-00-0) in NH.sub.4OH (225 mL) was added a solution of KI (34.14 g, CAS: 7681-11-0) and 12 (10.65 g, CAS: 7553-56-2) in H.sub.2O (50 mL). The reaction mixture was stirred at rt for 16 hours. The reaction mixture was filtered and the filtrate was evaporated. The residue was dissolved in DCM (250 mL) and was washed with H.sub.2O (2×150 mL), saturated aqueous NaS.sub.2O.sub.3 solution (100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (8.44 g, 82%) that was used in the next step without further purification. LC-MS: (ESI): m/z=244.0 [M−H].sup.−.

Step 2: 6-Hydroxy-biphenyl-3-carbonitrile

(197) ##STR00171##

(198) The title compound was obtained in analogy to intermediate B1, step 4, from 4-hydroxy-3-iodo-benzonitrile and phenylboronic acid (CAS: 98-80-6) as a colorless solid (0.580 g, 73%). .sup.1H NMR (400 MHz, CDCl.sub.3): 5.72 (1H, s), 7.03-7.07 (1H, d, J=4), 7.40-7.42 (2H, d, J=8), 7.44-7.56 (5H, m).

(199) Intermediate B26:

4-Chloro-5-methyl-2-oxazol-5-yl-phenol

(200) ##STR00172##

Step 1: 5-Chloro-2-methoxy-4-methyl-benzaldehyde

(201) ##STR00173##

(202) To a solution of 1-chloro-5-iodo-4-methoxy-2-methylbenzene (1.0 g, intermediate B1, step 2) in anhydrous THF (25 mL) was added n-BuLi (1.7 mL, 2.5M solution in hexane) dropwise at −78° C. under nitrogen atmosphere and the reaction mixture was stirred at −78° C. for 2 hours. Then, DMF (0.329 mL) dissolved in anhydrous THF (2 mL) was added dropwise to the reaction mixture at −78° C. and the solution was stirred at −78° C. for 2 hours. The reaction mixture was quenched with saturated aqueous NH.sub.4Cl solution and was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to give the title compound as yellow solid (0.685 g, 76%). Rf=0.6 (10% EtOAc/hexane).

Step 2: 5-(5-Chloro-2-methoxy-4-methyl-phenyl)-oxazole

(203) ##STR00174##

(204) To a stirred solution of 5-chloro-2-methoxy-4-methyl-benzaldehyde (500 mg) in MeOH (20 mL) was added tosylmethyl isocyanide (582 mg, CAS: 36635-61-7), followed by K.sub.2CO.sub.3 (561 mg) and the resulting mixture was refluxed for 3 hours. Then, MeOH was evaporated and the residue was purified by flash chromatography over silica gel (5-10% EtOAc/hexane) to give the title compound as an off white solid (294 mg, 49%). MS (ESI): m/z=224.0 [M+H].sup.+.

Step 3: 4-Chloro-5-methyl-2-oxazol-5-yl-phenol

(205) ##STR00175##

(206) The title compound was obtained in analogy to intermediate B1, step 3, from 5-(5-chloro-2-methoxy-4-methyl-phenyl)-oxazole (292 mg) as a brown solid (0.266 g, 97%). MS (ESI): m/z=210.2 [M+H].sup.+.

(207) Intermediate B30:

4-Chloro-5-methyl-2-(2-methyl-2H-pyrazol-3-yl)-phenol

(208) ##STR00176##

Step 1: 5-(5-Chloro-2-methoxy-4-methyl-phenyl)-1-methyl-1H-pyrazole

(209) ##STR00177##

(210) To a mixture of 1-chloro-5-iodo-4-methoxy-2-methyl-benzene (500 mg, intermediate B1, step 2), 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (442 mg, CAS: 847818-74-0) and K.sub.2CO.sub.3 (733 mg) in dioxane (12 ml) and water (4 ml) was added PdCl.sub.2(PPh.sub.3).sub.2—CH.sub.2Cl.sub.2 (25 mg) and the reaction mixture was heated to 110° C. for 16 h. The reaction mixture was diluted with ethyl acetate (50 ml), filtered through celite and the filtrate was evaporated. The resulting residue was purified by column chromatography over silica gel (0-20% EtOAc/hexane) to obtain 5-(5-chloro-2-methoxy-4-methyl-phenyl)-1-methyl-1H-pyrazole (365 mg, 87%) as brown sticky solid. MS (ESI): m/z=236.7 [M+H].sup.+.

Step 2: 4-Chloro-5-methyl-2-(2-methyl-2H-pyrazol-3-yl)-phenol

(211) ##STR00178##

(212) To a solution of 5-(5-chloro-2-methoxy-4-methyl-phenyl)-1-methyl-1H-pyrazole (355 mg) in DCM (20 ml) at 0° C. was added BBr.sub.3 (1M solution in DCM, 3 mL) and the reaction mixture was stirred at 25° C. for 3 h. All volatiles were then removed in vacuo and the remaining residue was dissolved in DCM (50 ml) and washed with 10% aqueous NaHCO.sub.3 solution and brine. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The resulting crude material was purified by column chromatography over silica gel (0-30% EtOAc/hexane) to afford 4-chloro-5-methyl-2-(2-methyl-2H-pyrazol-3-yl)-phenol (138 mg, 41%) as yellow solid. MS (ESI): m/z=223 [M+H].sup.+.

(213) Intermediate B31:

4-Chloro-6-hydroxy-biphenyl-3-carbonitrile

(214) ##STR00179##
Method A:

Step 1: 5-Bromo-2-chloro-4-hydroxy-benzonitrile

(215) ##STR00180##

(216) To a solution of 2-chloro-4-hydroxy-benzonitrile (4.0 g, CAS: 3336-16-1) in anhydrous acetonitrile (80 ml) was added TfOH (2.53 ml) drop wise at −30° C. and the reaction mixture was stirred at −30° C. for 10 min. Then NBS (6.49 g) was added and the mixture was stirred at −30° C. for 5 min. The reaction mixture was then allowed to warm to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was quenched with saturated aqueous sodium bisulfite solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and filtered. The filtrate was evaporated under reduced pressure and the resulting residue was purified by column chromatography over silica gel (2-6% EtOAc/hexane) to afford 5-bromo-2-chloro-4-hydroxy-benzonitrile (1.2 g, 20%) as an off white solid. MS (ESI): m/z=231.6 [M+H].sup.+.

Step 2: 5-Bromo-2-chloro-4-methoxymethoxy-benzonitrile

(217) ##STR00181##

(218) To a suspension of NaH (62 mg, 60% in mineral oil) in anhydrous THF (10 mL) at 0° C. was added a solution of 5-bromo-2-chloro-4-hydroxy-benzonitrile (300 mg) in anhydrous THF (5 mL) and the reaction mixture was stirred at 25° C. for 30 min. Then MOM-Cl (0.147 ml) was added dropwise and the reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was quenched with water and was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure. The resulting crude material was purified by column chromatography over silica gel (0-3% EtOAc/hexane) to afford 5-bromo-2-chloro-4-methoxymethoxy-benzonitrile (315 mg, 88%) as an off white solid. .sup.1H-NMR (δ, CDCl.sub.3): 3.51 (s, 3H), 5.30 (s, 2H), 7.28 (s, 1H), 7.81 (s, 1H).

Step 3: 4-Chloro-6-hydroxy-biphenyl-3-carbonitrile

(219) ##STR00182##

(220) To a mixture of 5-bromo-2-chloro-4-methoxymethoxy-benzonitrile (100 mg) and phenyl boronic acid (132.3 mg, CAS: 98-80-6) in anhydrous DMF (50 mL) in a sealed tube was added K.sub.2CO.sub.3 (149.7 mg) at 25° C. and the reaction mixture was purged with argon for 10 min. Then Pd(dppf)Cl.sub.2—CH.sub.2Cl.sub.2 complex (8.85 mg) was added and the mixture was again purged with argon for 10 min and then heated to 120° C. for 16 h. The reaction mixture was cooled to 25° C. and filtered. The filtrate was evaporated under reduced pressure and the resulting residue was purified by column chromatography over silica gel (5-7% EtOAc/hexane) to afford 4-chloro-6-hydroxy-biphenyl-3-carbonitrile (43 mg, 44%) as off white solid. .sup.1H-NMR (δ, CDCl.sub.3): 5.91 (s, 1H), 7.13 (s, 1H), 7.39 (dd, 2H), 7.44-7.56 (m, 4H).

(221) Method B:

Step 1: 5-iodo-2-chloro-4-hydroxy-benzonitrile

(222) ##STR00183##

(223) To a solution of 2-chloro-4-hydroxybenzonitrile (1.18 g, CAS: 3336-16-1) in acetic acid (10 mL) and DCM (10 mL) was added concentrated sulfuric acid (100 μL) and then N-iodosuccinimide (1.66 g) in one portion at rt under an argon atmosphere. The mixture was stirred at rt for 16 hours. The reaction mixture was then poured into ice/water and was extracted two times with ethyl acetate. The organic layers were washed once with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude material was adsorbed onto silica gel and was then purified by flash chromatography (ISCO, 100 g silica gel cartridge, gradient of 0% to 20% EtOAc in heptane). The fractions containing the desired product along with some di-iodinated side products were combined, evaporated and dried at high vacuum. The residue (1.42 g) was further purified by preparative HPLC (Column: Gemini NX 3u 50×4.6 mm; Eluent: 2% formic acid, 98% CH.sub.3CN) to provide the title compound (770 mg) as an off white solid. MS (ESI.sup.−): m/z=278.0 [M−H].sup.−.

Step 2: 4-Chloro-6-hydroxy-biphenyl-3-carbonitrile

(224) ##STR00184##

(225) 2-Chloro-4-hydroxy-5-iodobenzonitrile (350 mg), phenylboronic acid (160 mg) and sodium carbonate (398 mg) were combined with DMF (13.0 mL) and water (2.0 mL) at rt under an argon atmosphere. Ten, [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with DCM (133 mg) was added to the orange suspension. The reaction mixture was three times evaporated and purged with argon and then heated to 80° C. for 3.5 hours. The mixture was cooled to room temperature, poured into ice/water and was then acidified with saturated NH.sub.4Cl solution. The aqueous layer was extracted twice with ethyl acetate. The organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude material was purified by flash chromatography (ISCO, silica gel, 40 g cartridge, 100% CH.sub.2Cl.sub.2 and then CH.sub.2Cl.sub.2/CH.sub.3CN=96/4). The appropriate fractions were combined and evaporated to provide the title compound (150 mg) as an off white solid.

(226) MS (ESI.sup.−): m/z=228.1 [M−H].sup.−. NMR complies with the material described above from method A.

(227) The following Intermediates were prepared in analogy to intermediate B31, either via method A from 5-bromo-2-chloro-4-hydroxy-benzonitrile (intermediate B31, step 1), or via method B from 5-iodo-2-chloro-4-hydroxy-benzonitrile, and the boronic acid precursors as indicated in the table below:

(228) TABLE-US-00006 Inter- Building block/ mediate Systematic Name intermediate MS, m/z B32 4-Chloro-4′-fluoro-6- hydroxy-biphenyl-3- carbonitrile 4-fluoro phenyl boronic acid CAS: 1765-93-1 Method A MS (ESI): 245.6 [M + H].sup.+ B33 4′-Chloro-5′-cyano-2′- hydroxy-biphenyl-3- carboxylic acid methylamide 3-(N- methylarninocarbonyl) phenylboronic acid CAS: 832695-88-2 Method A MS (ESI): 287.1 [M + H].sup.+ B84 2-chloro-5-(2- fluorophenyl)- 4-hydroxybenzonitrile 2-fluoro phenyl boronic acid CAS: 1993-03-9 Method B MS(ESI): 248.1 [M + H].sup.+ B85 2-ch1oro-5-(3- f1uorophenyl)- 4-hydroxybenzonitrile 3-fluoro phenyl boronic acid CAS: 768-35-4 Method B MS(ESI): 246.1 [M − H].sup.− B89 2-chloro-5-(2-fluoro-5- propan-2-yloxypbenyl)- 4-hydroxybenzonitrile (2-fluoro-5-propan-2- yloxyphenyl) boronic acid CAS: 849062-30-2 Method B MS(ESI): 304.2 [M − H].sup.−
Intermediate 835:

4-Chloro-6-hydroxy-3′-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-3-carbonitrile

(229) ##STR00190##

Step 1: 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile

(230) ##STR00191##

(231) To a solution of 3-cyanophenyl boronic acid (2.5 g, CAS: 150255-96-2) in anhydrous THF (150 ml) under an atmosphere of nitrogen were added pinacol (2.95 g) and Na.sub.2SO.sub.4 (10 g) at 25° C. The reaction mixture was stirred for 12 h at 25° C. under an atmosphere of nitrogen. Then, Na.sub.2SO.sub.4 was filtered off and all volatiles were evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was then separated, dried over Na.sub.2SO.sub.4 and concentrated to afford the title compound (4.72 g) as off white solid which was directly used in the next reaction step without further characterization.

Step 2: N-Hydroxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamidine

(232) ##STR00192##

(233) To a solution of -(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (4.65 g) in ethanol (150 ml) were added DIPEA (7.15 mL) and hydroxyl amine hydrochloride (3.53 g) at 25° C. The reaction mixture was then refluxed for 3 h. All volatiles were evaporated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over Na.sub.2SO.sub.4 and concentrated to afford N-hydroxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamidine along with some impurities (5.7 g) as an off white, sticky solid. MS (ESI): m/z=262.8 [M+H].sup.+.

Step 3: 5-Methyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-[1,2,4]oxadiazole

(234) ##STR00193##

(235) A solution of N-hydroxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamidine (5.7 g) in acetic anhydride (100 mL) was refluxed for 3 h. Acetic anhydride was evaporated and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed with aqueous NaHCO.sub.3 solution, water and brine and dried over Na.sub.2SO.sub.4 and concentrated. The crude product was purified by column chromatography over silica gel (0-5% EtOAc/hexane) to afford the title compound (3.5 g) as an off white solid. MS (EST): m/z=287.0 [M+H].sup.+.

Step 4: 4-Chloro-6-hydroxy-3′-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-3-carbonitrile

(236) ##STR00194##

(237) The title compound was prepared in analogy to Intermediate B31, step 3, from 5-bromo-2-chloro-4-methoxymethoxy-benzonitrile (Intermediate B32, step 2) (300 mg) and 5-methyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-[1,2,4]oxadiazole (932 mg) and was obtained as off white solid (190 mg, 56%). MS (ESI): m/z=310.2 [M−H].sup.−.

(238) Intermediate B37:

4-Chloro-6-hydroxy-3′-(5-methyl-[1,3,4]oxadiazol-2-yl)-biphenyl-3-carbonitrile

(239) ##STR00195##

Step 1: 4′-Chloro-5′-cyano-2′-hydroxy-biphenyl-3-carboxylic acid methyl ester

(240) ##STR00196##

(241) The title compound was prepared in analogy to Intermediate B31, step 3, from 5-bromo-2-chloro-4-methoxymethoxy-benzonitrile (Intermediate B31, step 2) (1.0 g) and 3-methoxycabonyl phenyl boronic acid (973 mg, CAS: 99769-19-4) and was obtained as off white solid (430 mg, 41%). MS (ESI): m/z=286 [M−H].sup.−.

Step 2: 4′-Chloro-5′-cyano-2′-methoxy-biphenyl-3-carboxylic acid methyl ester

(242) ##STR00197##

(243) To a solution of 4′-chloro-5′-cyano-2′-hydroxy-biphenyl-3-carboxylic acid methyl ester (650 mg) in anhydrous DMF (30 mL) were added Cs.sub.2CO.sub.3 (1.10 g) and methyliodide (0.169 mL) at 25° C. The reaction mixture was stirred at 25° C. for 16 h and then filtered. The filtrate was evaporated under reduced pressure and the remaining residue was purified by column chromatography over silica gel (10-15% EtOAc/hexane) to afford the title compound (490 mg, 71%) as an off white solid that was used without further characterization.

Step 3: 4′-Chloro-5′-cyano-2′-methoxy-biphenyl-3-carboxylic acid

(244) ##STR00198##

(245) To a solution of 4′-chloro-5′-cyano-2′-methoxy-biphenyl-3-carboxylic acid methyl ester (490 mg) in mixture of THF and water (45 mL) was added LiOH—H.sub.2O (136.6 mg) at 25° C. and the reaction mixture was stirred at rt for 12 h. The reaction mixture was then diluted with EtOAc (20 mL) and the layers were separated. The aqueous layer was acidified by addition of 6N HCl and was extracted with EtOAc. The combined extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to obtain the title compound (410 mg, 88%) as an off white solid. MS (ESI): m/z=286.1 [M−H].sup.−.

Step 4: 4′-Chloro-5′-cyano-2′-methoxy-biphenyl-3-carboxylic acid N′-acetyl-hydrazide

(246) ##STR00199##

(247) To a solution of 4′-chloro-5′-cyano-2′-methoxy-biphenyl-3-carboxylic acid (410 mg) in anhydrous DMF (30 mL) were added HBTU (812.1 mg) and DIPEA (0.76 mL) at 25° C. The reaction mixture was stirred for 10 min and then acetic acid hydrazide (211.42 mg) was added and stirring was continued for 16 h. The solvent was evaporated and to the remaining residue were added EtOAc and water. The organic layer was separated, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography over silica gel (2-3% MeOH/DCM) to afford the title compound (470 mg, 96%) as an off white solid. MS (ESI): m/z=344.2 [M+H].sup.+.

Step 5: 4-Chloro-6-methoxy-3′-(5-methyl-[1,3,4]oxadiazol-2-yl)-biphenyl-3-carbonitrile

(248) ##STR00200##

(249) A solution of 4′-chloro-5′-cyano-2′-methoxy-biphenyl-3-carboxylic acid N′-acetyl-hydrazide (400 mg) in POCl.sub.3 (10 mL) was heated to 110° C. for 6 h. The reaction mixture was then cooled to 25° C. and all volatiles were removed under reduced pressure. To the remaining residue was added sat. NaHCO.sub.3 solution (15 mL) and the mixture was extracted with EtOAc. The combined extracts were dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography over silica gel (10-15% EtOAc/hexane) to afford the title compound (130 mg, 34%) as an off white solid. MS (ESI): m/z=326.2 [M+H].sup.+.

Step 6: 4-Chloro-6-hydroxy-3′-(5-methyl-[1,3,4]oxadiazol-2-yl)-biphenyl-3-carbonitrile

(250) ##STR00201##

(251) To a solution of 4-chloro-6-methoxy-3′-(5-methyl-[1,3,4]oxadiazol-2-yl)-biphenyl-3-carbonitrile (110 mg) in anhydrous DCM (10 mL) was added BBr.sub.3 (0.4 mL) at 0° C. The reaction mixture was stirred at 25° C. for 28 h. Again BBr.sub.3 (0.5 mL) was added and reaction mixture was stirred for another 16 h. All volatiles were removed under reduced pressure and the residue was purified by column chromatography over silica gel (30-45% EtOAc/hexane) to afford the title compound (80 mg, 76%) as an off white solid. MS (EST): m/z=310.2 [M−H].sup.−.

(252) Intermediate B39:

3-(4-Chloro-5-cyano-2-hydroxy-phenyl)-N,N-dimethyl-benzamide

(253) ##STR00202##

Step 1: 3-[4-Chloro-5-cyano-2-(methoxymethoxy)phenyl]-N,N-dimethyl-benzamide

(254) ##STR00203##

(255) The title compound was prepared in analogy to Intermediate B31, step 3, from 5-bromo-2-chloro-4-methoxymethoxy-benzonitrile (Intermediate B31, step 2) (48.9 mg) and 3-(dimethylcarbamoyl)phenylboronic acid (40.9 mg, CAS: 373384-14-6) and was obtained as light yellow gum (43 mg, 71%). MS (ESI): m/z=698.3 [2M+H].sup.+.

Step 2: 3-(4-Chloro-5-cyano-2-hydroxy-phenyl)-N,N-dimethyl-benzamide

(256) ##STR00204##

(257) To solution of 3-[4-chloro-5-cyano-2-(methoxymethoxy)phenyl]-N,N-dimethyl-benzamide (40.0 mg) in dioxane (1 mL) was added dropwise 4N HCl in dioxane (150 μl) at 0° C. The reaction mixture was then stirred at rt for 4 h. Additional 4N HCl in dioxane (100 μl) was added and the resulting suspension was stirred at rt overnight. The reaction mixture was concentrated to dryness and then co-evaporated from DCM three times. The resulting off white solid (34 mg, 97%) was used in the next reaction step without further purification. MS (ESI): m/z=301.1 [M+H].sup.+.

(258) Intermediate B41:

2-Chloro-4-hydroxy-5-[3-(morpholine-4-carbonyl)phenyl]benzonitrile

(259) ##STR00205##

Step 1: 2-Chloro-4-(methoxymethoxy)-5-[3-(morpholine-4-carbonyl)phenyl]benzonitrile

(260) ##STR00206##

(261) The title compound was prepared in analogy to Intermediate B31, step 3, from 5-bromo-2-chloro-4-methoxymethoxy-benzonitrile (Intermediate B31, step 2) (50.0 mg) and 3-(morpholine-4-carbonyl)phenylboronic acid (51.0 mg, CAS: 723281-55-8) and was obtained as white solid (53 mg, 76%). MS (ESI): m/z=387.2 [M+H].sup.+.

Step 2: 2-Chloro-4-hydroxy-5-[3-(morpholine-4-carbonyl)phenyl]benzonitrile

(262) ##STR00207##

(263) The title compound was prepared in analogy to Intermediate B39, step 2, from 2-chloro-4-(methoxymethoxy)-5-[3-(morpholine-4-carbonyl)phenyl]benzonitrile (49.9 mg) and was obtained as off white solid (44 mg, 99%). MS (ESI): m/z=343.11 [M+H].sup.+.

(264) Intermediate B54:

2-Chloro-4-hydroxy-5-(2-methoxy-3-pyridyl)benzonitrile

(265) ##STR00208##

Step 1: 2-Chloro-4-(methoxymethoxy-5-(2-methoxy-3-pyridyl)benzonitrile

(266) ##STR00209##

(267) The title compound was prepared in analogy to Intermediate B31, step 3, from 5-bromo-2-chloro-4-methoxymethoxy-benzonitrile (intermediate B31, step 2) (50.0 mg) and 2-methoxypyridin-3-ylboronic acid (33.2 mg, eMolecules #BB-4033) and was obtained as a white solid (43 mg, 78%). MS (ESI): m/z=305.1 [M+H].sup.+.

Step 2: 2-Chloro-4-hydroxy-5-(2-methoxy-3-pyridyl)benzonitrile

(268) ##STR00210##

(269) The title compound was prepared in analogy to Intermediate B39, step 2, from 2-chloro-4-(methoxymethoxy)-5-(2-methoxy-3-pyridyl)benzonitrile (41.1 mg) and was obtained as an off white solid (35.2 mg, 100%). MS (ESI): m/z=261.1 [M+H].sup.+.

(270) Intermediate B58

4-Chloro-2-[2-fluoro-5-(2-methylpropoxy)phenyl]-5-methylphenol

(271) ##STR00211##

(272) 4-Chloro-2-iodo-5-methylphenol (intermediate B1, step 3, (80 mg), (2-fluoro-5-isobutoxyphenyl)boronic acid (75.8 mg, CAS: 1217500-65-6) and sodium carbonate (94.7 mg) were combined with DMF (5.0 mL) and water (0.85 mL) at rt under an argon atmosphere. Then, [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (31.6 mg, CAS: 95464-05-4) was added to the orange suspension. The reaction mixture was heated to 80° C. for 3 hours and was then cooled and kept at rt for 64 hours. The reaction mixture was poured into ice/water and was acidified with saturated NH.sub.4Cl solution. The aqueous layer was extracted twice with ethyl acetate. The organic layers were washed once with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The crude material was purified by flash chromatography (0% to 50% ethyl acetate in heptane) to give the title compound as a light yellow liquid (62 mg, 65%). MS (ESI): m/z=307.3 [M−H].sup.−.

(273) The following intermediates were prepared in analogy to intermediate B58 from 4-chloro-2-iodo-5-methylphenol (Intermediate B1, step 3) and the corresponding building blocks indicated in the table below:

(274) TABLE-US-00007 Inter- Building block/ mediate Systematic Name intermediate MS, m/z B55 4-Chloro-2-(5-ethoxy-2- fluorophenyl)-5- methylphenol 5-ethoxy-2- fluorophenylboroni acid CAS: 900174-60-9 MS (ESI): 279.2 [M − H].sup.− B56 4-Chloro-2-(2- methoxyphenyl)-5- methylphenol (2-methoxyphenyl) boronic acid CAS: 5720-06-9 MS (ESI): 249.2 [M + H].sup.+ B57 4-Chloro-2-(2-fluoro-5- propan-2-yloxyphenyl)-5- methylphenol (2-fluoro-5- isopropoxyphenyt) boronic acid CAS: 849062-30-2 MS (ESI): 293.2 [M − H].sup.− B59 4-Ch1oro-2-[2-methoxy-5- (trifluoromethyl)phenyl]-5- methylphenol (2-methoxy-5- (trifluoromethyl)phenyl) boronic acid CAS: 240139-82-6) MS (ESI): 315.2 [M − H].sup.− B60 4-Chloro-2-(2-methoxy-5- propan-2-ylphenyl)-5- methylphenol (5-isopropyl-2- methoxyphenyl) boronic acid CAS: 216393-63-4) MS (ESI): 289.3 [M − H].sup.−
Intermediate 361

2-Chloro-5-[2-fluoro-5-(morpholine-4-carbonyl)phenyl]-4-hydroxybenzonitrile

(275) ##STR00217##

Step 1: 2-Chloro-5-[2-fluoro-5-(morpholine-4-carbonyl)phenyl]-4-(methoxymethoxy)benzonitrile

(276) ##STR00218##

(277) The title compound was prepared in analogy to Intermediate B58 from 5-bromo-2-chloro-4-methoxymethoxy-benzonitrile (intermediate B32, step 2) (100 mg) and (2-fluoro-5-(morpholine-4-carbonyl)phenyl)boronic acid (110 mg, CAS: 1072951-41-7) and was obtained as a light yellow foam (24 mg, 15%). MS (ESI): m/z=405.2 [M+H].sup.+.

Step 2: 2-Chloro-5-[2-fluoro-5-(morpholine-4-carbonyl)phenyl]-4-hydroxybenzonitrile

(278) ##STR00219##

(279) The title compound was prepared in analogy to Intermediate B39, step 2 from 2-chloro-5-[2-fluoro-5-(morpholine-4-carbonyl)phenyl]-4-(methoxymethoxy)benzonitrile (29 mg) and was obtained as an off-white solid (14 mg, 54%). MS (ESI): m/z=361.1 [M+H].sup.+.

(280) Intermediate B63

3-(5-Chloro-2-hydroxy-4-methylphenyl)-N-cyclopropyl-4-fluoro-N-methylbenzamide

(281) ##STR00220##

Step 1: 3-(5-Chloro-2-methoxy-4-methylphenyl)-N-cyclopropyl-4-fluorobenzamide

(282) ##STR00221##

(283) The title compound was prepared in analogy to Intermediate B58 from 1-chloro-5-iodo-4-methoxy-2-methylbenzene (intermediate B1, step 2) (265 mg) and (5-(cyclopropylcarbamoyl)-2-fluorophenyl)boronic acid (251 mg, CAS: 874289-54-0) and was obtained as a yellow solid (163 mg, 52%). MS (ESI): m/z=334.1 [M+H].sup.+.

Step 2: 3-(5-Chloro-2-methoxy-4-methylphenyl)-N-cyclopropyl-4-fluoro-N-methylbenzamide

(284) ##STR00222##

(285) Sodium hydride 60% dispersion in mineral oil (37.9 mg) was added to a solution of 3-(5-chloro-2-methoxy-4-methylphenyl)-N-cyclopropyl-4-fluorobenzamide (158 mg) in DMF (4.0 mL) at rt under an argon atmosphere. The mixture was stirred at rt for 45 minutes. Then, iodomethane (87.3 mg) was added dropwise over a period of 2 minutes and the mixture was stirred at rt for 3 hours. The reaction mixture was then poured into ice/water. The aqueous layer was extracted twice with ethyl acetate. The organic layers were washed once with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The crude material was purified by flash chromatography (0% to 50% ethyl acetate in heptane) to give the title compound as a white foam (154 mg, 93%). MS (ESI): m/z=348.2 [M+H].sup.+.

Step 3: 3-(5-Chloro-2-hydroxy-4-methylphenyl)-N-cyclopropyl-4-fluoro-N-methylbenzamide

(286) ##STR00223##

(287) The title compound was prepared in analogy to Intermediate B1, step 3, from 3-(5-chloro-2-methoxy-4-methylphenyl)-N-cyclopropyl-4-fluoro-N-methylbenzamide (151 mg) and was obtained as an off-white foam (157 mg, 98%). MS (ESI): m/z=334.1 [M+H].sup.+.

(288) Intermediate B62

[3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluorophenyl]-pyrrolidin-1-ylmethanone

(289) ##STR00224##

Step 1: Methyl 3-(5-chloro-2-methoxy-4-methylphenyl)-4-fluorobenzoate

(290) ##STR00225##

(291) Methyl 3-bromo-4-fluorobenzoate (3.75 g) was dissolved in cyclopentylmethylether (70 mL) at room temperature under an argon atmosphere. Then, potassium acetate (6.32 g), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (5.72 g) and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (526 mg CAS: 95464-05-4) were added to the mixture. The reaction mixture was heated to 95° C. for 4 hours and was then cooled down to rt for another hour. To the mixture was added sodium carbonate solution (15%, 26.2 mL), 1-chloro-5-iodo-4-methoxy-2-methylbenzene (intermediate B1, step 2) (6.06 g) and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with DCM (526 mg, CAS: 95464-05-4). The mixture was heated again to 85° C. for 18 hours. Then, the reaction mixture was cooled to rt and poured into ice/water. The aqueous layer was extracted twice with cyclopentylmethylether. The organic layers were washed once with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The crude material was purified by flash chromatography (0% to 50% ethyl acetate in heptane) to give the title compound as a light yellow solid (4.46 g, 67%). .sup.1H NMR (400 MHz, CDCl.sub.3): 2.43 (3H, s), 3.76 (3H, s), 3.91 (3H, s), 6.85 (1H, s), 7.14-7.18 (1H, t), 7.24 (1H, s), 8.0-8.07 (2H, m).

Step 2: 3-(5-Chloro-2-methoxy-4-methylphenyl)-4-fluorobenzoic acid

(292) ##STR00226##

(293) LiOH 1M solution (2.51 mL) was added to a solution of methyl 3-(5-chloro-2-methoxy-4-methylphenyl)-4-fluorobenzoate (310 mg) in THF (6.0 mL) at room temperature. The mixture was stirred at rt for 18 hours. The reaction mixture was poured into ice/water and was acidified with HCl 1M solution to pH=1. The aqueous layer was extracted twice with ethyl acetate. The organic layers were washed once with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness to give the title compound as a white solid (309 mg, 99%). MS (ESI): m/z=293.2 [M−H].sup.−.

Step 3: [3-(5-Chloro-2-methoxy-4-methylphenyl)-4-fluorophenyl]-pyrrolidin-1-ylmethanone

(294) ##STR00227##

(295) 3-(5-Chloro-2-methoxy-4-methylphenyl)-4-fluorobenzoic acid (100 mg), pyrrolidine (36.2 mg, CAS: 123-75-1) and 4-methylmorpholine (51.5 mg) were dissolved in DMF (4.0 mL) at rt under an argon atmosphere. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (97.6 mg) and 1-hydroxybenzotriazole hydrate (68.8 mg) were added to the light yellow solution. The mixture was stirred at rt for 2.5 hours. The reaction mixture was poured then into ice/water and was basified with 2M Na.sub.2CO.sub.3 solution. The aqueous layer was extracted twice with ethyl acetate. The organic layers were washed once with 1M HCl solution and once with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The crude material was purified by flash chromatography (0% to 70% ethyl acetate in heptane) to give the title compound as a white solid (78 mg, 65%). MS (ESI): m/z=348.1 [M+H].sup.+.

Step 4: [3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluorophenyl]-pyrrolidin-1-ylmethanone

(296) ##STR00228##

(297) The title compound was prepared in analogy to Intermediate B, step 3 from [3-(5-chloro-2-methoxy-4-methylphenyl)-4-fluorophenyl]-pyrrolidin-1-ylmethanone (74 mg) and was obtained as an off-white solid (83 mg, 99%). MS (ESI): m/z=334.2 [M+H].sup.+.

(298) The following intermediates were obtained in analogy to Intermediate B62, by replacing pyrrolidine with the appropriate amine building block in Step 3 as indicated in the table below:

(299) TABLE-US-00008 Inter- Building block/ mediate Systematic Name intermediate MS, m/z B64 3-(5-Chloro-2-hydroxy-4- methylphenyl)-4-fluoro-N-(2- hydroxyethyl)-N- methytbenzamide 2-(methylamino)ethanol CAS: 109-83-1 MS (ESI): 338.1 [M + H].sup.+ B65 4-[3-(5-Chloro-2-hydroxy-4- methylphenyl)-4- fluorobenzoyl]-1- methylpiperazin-2-one 0 1-methylpiperazin-2-one CAS: 59702-07-7 MS (ESI): 377.2 [M + H].sup.+ B66 4-[3-(5-Chloro-2-hydroxy-4- methylphenyl)-4- fluorobenzoyl]-1- methylpiperazin-2-one N-methylcyclopentan- amine CAS: 2439-56-7 MS (ESI): 362.2 [M + H].sup.+ B68 3-(5-Chloro-2-hydroxy-4- methylphenyl)-4-fluoro-N- methyl-N-(thiophen-2- ylmethyl)benzamide N-methyl-1-(thiophen-2- yl)methanamine CAS: 58255-18-8 MS (ESI): 390.1 [M + H].sup.+ B69 [3-(5-Chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]-piperidin-1- ylmethanone piperidine CAS: 110-89-4 MS (ESI): 348.2 [M + H].sup.+. B70 3-(5-Chloro-2-hydroxy-4- methylphenyl)-N- (cyclopropylmethyl)-4-fluoro- N-methylbenzamide 1-cyclopropyl-N- methylmethanamine CAS: 18977-45-2 MS (ESI): 348.1 [M + H].sup.+ B71 3-(5-Ch1oro-2-hydroxy-4- methylphenyl)-4-fluoro-N- methyl-N-(pyridin-2- ylmethyl)benzamide N-methyl-1-(pyridin-2- yl)methanamine CAS: 21035-59-6 MS (ESI): 385.1 [M + H].sup.+
Intermediate B67

4-Chloro-2-[2-fluoro-5-(oxolan-3-ylmethoxy)phenyl]-5-methylphenol

(300) ##STR00236##

Step 1: 3-[(3-Bromo-4-fluorophenoxy)methyl]oxolane

(301) ##STR00237##

(302) Diisopropylazodicarboxylate (1.22 g) was added dropwise over a period of 5 minutes to a solution of 3-bromo-4-fluorophenol (1.05 g, CAS: 27407-11-0), (tetrahydrofuran-3-yl)methanol (674 mg, CAS: 15833-61-1) and triphenylphosphine (1.87 g) in THF (12 mL) at 0° C. under an argon atmosphere. The yellow solution was warmed up to rt and kept at this temperature for 4.5 hours. The reaction mixture was poured into ice/water and was basified with 2M NaOH solution to achieve pH=10. The aqueous layer was extracted twice with ethyl acetate. The organic layers were washed once with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The crude material was purified by flash chromatography (0% to 60% ethyl acetate in heptane) to give the title compound as a light yellow liquid (1.26 g, 79%). MS (E): m/z=274.0 [M].sup.+.

Step 2: 2-[2-Fluoro-5-(oxolan-3-ylmethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

(303) ##STR00238##

(304) A mixture of 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (129 mg), 3-[(3-bromo-4-fluorophenoxy)methyl]oxolane (100 mg), potassium acetate (107 mg) and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (14.8 mg, CAS: 95464-05-4) in 1,4-dioxane (4.0 mL) were purged three times with argon and was then heated to 85° C. for 20 hours under an argon atmosphere. The reaction mixture was cooled down to rt and poured then into ice/water. The aqueous layer was extracted twice with ethyl acetate. The organic layers were washed once with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The crude material was purified by flash chromatography (0% to 20% ethyl acetate in heptane) to give the title compound as a colorless liquid (90 mg, 62%, purity approx. 80%). MS (EI): m/z=322.0 [M].sup.+.

Step 3: 4-Chloro-2-[2-fluoro-5-(oxolan-3-ylmethoxy)phenyl]-5-methylphenol

(305) ##STR00239##

(306) The title compound was prepared in analogy to Intermediate B58 from 4-chloro-2-iodo-5-methylphenol (Intermediate B1, step 3) (58 mg) and 2-[2-fluoro-5-(oxolan-3-ylmethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (83.5 mg) and was obtained as alight yellow oil (29 mg, 39%). MS (ESI): m/z=337.11 [M+H].sup.+.

(307) The following intermediates were obtained in analogy to Intermediate B67, by replacing (tetrahydrofuran-3-yl)methanol in step 1 with the appropriate alcohol building block as indicated in the table below:

(308) TABLE-US-00009 Inter- Building block/ mediate Systematic Name intermediate MS, m/z B72 4-Chloro-2-[2-fluoro-5-(oxan- 4-ylmethoxy)phenyl]-5- methylphenol 0 (tetrahydro-2H- pyran-4- yl)methanol CAS: 14774-37-9 MS (ESI): 351.1 [M + H].sup.+ B74 4-Chloro-2-[2-fluoro-5-(oxan- 4-ylmethoxy)phenyl]-5- methylphenol (tetrahydrofuran-2- ylmethanol CAS: 97-99-4 MS (ESI): 335.2 [M − H].sup.−
Intermediate B75

2-[3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluorophenoxy]-N,N-dimethylacetamide

(309) ##STR00242##

Step 1: 2-(3-Bromo-4-fluorophenoxy)-N,N-dimethylacetamide

(310) ##STR00243##

(311) 3-Bromo-4-fluorophenol (500 mg, CAS 27407-11-0), 2-chloro-N,N-dimethylacetamide (573 mg) and potassium carbonate (832 mg) were combined with acetone (15 mL) at rt under an argon atmosphere. The mixture was heated to reflux for 18 hours and was then kept at rt for 1 hour. The reaction mixture was poured then into ice/water and the aqueous layer was extracted twice with ethyl acetate. The organic layers were washed once with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The crude material was purified by flash chromatography (0% to 80% ethyl acetate in heptane) to give the title compound as alight yellow liquid (934 mg, 91%, purity approx. 70%). MS (ESI): m/z=278.1 [M+H].sup.+.

Step 2: 2-[4-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxyl]-N,N-dimethylacetamide

(312) ##STR00244##

(313) The title compound was prepared in analogy to Intermediate B67, step 2 from 2-(3-bromo-4-fluorophenoxy)-N,N-dimethylacetamide (930 mg) and was obtained as a colorless oil (188 mg, 18%, purity 70%). MS (ESI): m/z=324.2 [M+H].sup.+.

Step 3: 2-[3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluorophenoxy]-N,N-dimethylacetamide

(314) ##STR00245##

(315) The title compound was prepared in analogy to Intermediate B58 from 4-chloro-2-iodo-5-methylphenol (intermediate B1, step 3) (108 mg) and 2-[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-N,N-dimethylacetamide (186 mg, purity 70%) and was obtained as a light brown foam (63 mg, 46%). MS (ESI): m/z=338.1 [M+H].sup.+.

(316) Intermediate B73

3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluoro-N-(2-methoxyethyl)-N-methylbenzamide

(317) ##STR00246##

Step 1: 3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluorobenzoic acid

(318) ##STR00247##

(319) 3-(5-Chloro-2-methoxy-4-methylphenyl)-4-fluorobenzoic acid (Intermediate B62, step 2) (145 mg) was combined with dichloromethane (5.0 mL) at 0° C. under an argon atmosphere. Then, boron tribromide 1M solution in dichloromethane (1.23 mL) was added dropwise over a period of 2 minutes. The resulting yellow solution was then kept at rt for 6 hours. The reaction mixture was poured then into ice/water and the aqueous layer was extracted twice with ethyl acetate. The organic layers were washed once with brine, dried over Na—SO.sub.4, filtered and evaporated to dryness to give the title compound as a light brown solid (146 mg, 100%). MS (ESI): m/z=559.21 [2M−H].sup.−.

Step 2: 3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluoro-N-(2-methoxyethyl)-N-methylbenzamide

(320) ##STR00248##

(321) The title compound was obtained in analogy to Intermediate B62, step 3 from 3-(5-chloro-2-hydroxy-4-methylphenyl)-4-fluorobenzoic acid (50 mg) using 2-methoxy-N-methylethanamine (24 mg, CAS: 38256-93-8) in place of pyrrolidine and was obtained as a white foam (40 mg, 63%). MS (EST): m/z=352.1 [M+H].sup.+.

(322) Intermediate B76

1-[[3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluorophenyl]methyl]-4-methylpiperazine-2,5-dione

(323) ##STR00249##

Step 1: 2-Bromo-4-(bromomethyl)-1-fluorobenzene

(324) ##STR00250##

(325) Tetrabromomethane (7.28 g) was added to a solution of 3-bromo-4-fluorophenyl)methanol (3.0 g, CAS: 77771-03-0) in THF (50 mL) at 0° C. under an argon atmosphere. Then, a solution of triphenylphosphine (5.76 g) in THF (30 mL) was added dropwise over a period of 40 minutes. The mixture was warmed up to rt and kept at this temperature for 65 hours. The reaction mixture was poured then into ice/water and was extracted two times with ethyl acetate. The organic layers were washed once with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The crude material was purified by flash chromatography (0% to 10% ethyl acetate in heptane) to give the title compound as a light yellow liquid (5.10 g, 95%, purity 70%). MS (EI): m/z=267.9 [M].sup.+.

Step 2: 1-[(3-Bromo-4-fluorophenyl)methyl]-4-methylpiperazine-2,5-dione

(326) ##STR00251##

(327) 1-Methylpiperazine-2,5-dione (150 mg, CAS: 5625-52-5) was dissolved in DMF (5.0 mL) at rt under an argon atmosphere. The mixture was cooled down to 0° C. and sodium hydride 60% dispersion in mineral oil (103 mg) was added in one portion. The suspension was stirred at 0° C. for 10 minutes and then warmed up to rt for 45 minutes. Then, 2-bromo-4-(bromomethyl)-1-fluorobenzene (627 mg) was added dropwise over a period of 5 minutes. The mixture was stirred at rt for 16 hours. The reaction mixture was poured then into ice/water and the aqueous layer was extracted twice with ethyl acetate. The organic layers were washed once with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The crude material was purified by flash chromatography (0% to 10% methanol in dichloromethane) to give the title compound as a light brown gum (121 mg, 32%). MS (ESI): m/z=315.0 [M+H].sup.+.

Step 3: 1-[[4-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-4-methylpiperazine-2,5-dione

(328) ##STR00252##

(329) The title compound was prepared in analogy to Intermediate B67, step 2, from 1-[(3-bromo-4-fluorophenyl)methyl]-4-methylpiperazine-2,5-dione (120 mg) and was obtained as a light brown gum (102 mg, 52%, purity 70%). MS (ESI): m/z=363.2 [M+H].sup.+.

Step 4: 1-[[3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluorophenyl]methyl]-4-methylpiperazine-2,5-dione

(330) ##STR00253##

(331) The title compound was prepared in analogy to Intermediate B58 from 4-chloro-2-iodo-5-methylphenol (intermediate B1, step 3) (52 mg) and 1-[[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-4-methylpiperazine-2,5-dione (100 mg, purity ˜70%) and was obtained as a light brown foam (28 mg, 37%). MS (ESI): m/z=377.1 [M+H].sup.+.

(332) The following intermediates were obtained in analogy to intermediate B76, by replacing 1-methylpiperazine-2,5-dione in Step 2 with the appropriate amide building block as indicated in the table below:

(333) TABLE-US-00010 Inter- Building block/ mediate Systematic Name intermediate MS, m/z B81 1-[[3-(5-Chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]methyl] pyrrolidin-2-one pyrrolidin-2-one CAS: 616-45-5 MS (ESI): 334.0 [M + H].sup.+ B82 3-[[3-(5-Chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]methyl]-1,3- oxazolidin-2-one oxazolidin-2-one CAS: 497-25-6 MS (EST): 334.1 [M − H].sup.−
Intermediate 878

N-[[3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluorophenyl]methyl]-2-methoxy-N-methylacetamide

(334) ##STR00256##

Step 1: N-[(3-Bromo-4-fluorophenyl)methyl]-2-methoxyacetamide

(335) ##STR00257##

(336) 2-Methoxyacetic acid (165 mg, CAS: 625-45-6), (3-bromo-4-fluorophenyl)-methanamine hydrochloride (529 mg, CAS: 202865-68-7) and 4-methylmorpholine (741 mg) were dissolved in DMF (6.0 mL) at rt under an argon atmosphere. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (527 mg) and 1-hydroxybenzotriazole hydrate (371 mg) were added to the light yellow solution. The mixture was stirred at rt for 16 hours. The reaction mixture was poured then into ice/water and was basified with 2M Na.sub.2CO.sub.3 solution. The aqueous layer was extracted twice with ethyl acetate. The organic layers were washed once with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The crude material was purified by flash chromatography (0% to 80% ethyl acetate in heptane) to give the title compound as a white solid (503 mg, 98%). MS (ESI): m/z=278.01 [M+H].sup.+.

Step 2: N-[(3-Bromo-4-fluorophenyl)methyl]-2-methoxy-N-methylacetamide

(337) ##STR00258##

(338) The title compound was prepared in analogy to Intermediate B63, step 2, from N-[(3-bromo-4-fluorophenyl)methyl]-2-methoxyacetamide (290 mg) and was obtained as a colorless liquid (198 mg, 62%). MS (ESI): m/z=290.0 [M+H].sup.+.

Step 3: N-[[4-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-2-methoxy-N-methylacetamide

(339) ##STR00259##

(340) The title compound was prepared in analogy to Intermediate B67, step 2, from N-[(3-bromo-4-fluorophenyl)methyl]-2-methoxy-N-methylacetamide (199 mg) and was obtained as a light yellow liquid (262 mg, 57%, purity ˜50%). MS (ESI): m/z=338.2 [M+H].sup.+.

Step 4: N-[[3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluorophenyl]methyl]-2-methoxy-N-methylacetamide

(341) ##STR00260##

(342) The title compound was prepared in analogy to Intermediate B58 from 4-chloro-2-iodo-5-methylphenol (intermediate B1, step 3) (102 mg) and N-[[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-2-methoxy-N-methylacetamide (256 mg, purity ˜50%) and was obtained as a yellow gum (106 mg, 64%, purity ˜80%). MS (ESI): m/z=352.1 [M+H].sup.+.

(343) The following intermediates were obtained in analogy to intermediate B78, by replacing 2-methoxyacetic acid in Step 1 with the appropriate carboxylic acid building block as indicated in the table below:

(344) TABLE-US-00011 Inter- Building block/ mediate Systematic Name intermediate MS, m/z B80 N-[[3-(5-Chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]methyl]-N- methylcyclopropane carboxamide cyclopropanecarboxylic acid CAS: 1759-53-1 MS (EST): 348.1 [M + H].sup.+
Intermediate B79

N-[[3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluorophenyl]methyl]cyclopropanecarboxamide

(345) ##STR00262##

Step 1: N-[(3-Bromo-4-fluorophenyl)methyl]cyclopropanecarboxamide

(346) ##STR00263##

(347) The title compound was prepared in analogy to Intermediate B78, step 1, from cyclopropanecarboxylic acid (127 mg, CAS: 1759-53-1) and was obtained as a white powder (444 mg, 100%). MS (ESI): m/z=272.0 [M+H].sup.+.

Step 2: N-[[4-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-cyclopropanecarboxamide

(348) ##STR00264##

(349) The title compound was prepared in analogy to Intermediate B67, step 2, from N-[(3-bromo-4-fluorophenyl)methyl]cyclopropanecarboxamide (217 mg) and was obtained as a light yellow oil (257 mg, 61%, purity 60%). MS (ESI): m/z=320.2 [M+H].sup.+.

Step 3: N-[[3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluorophenyl]methyl]cyclopropanecarboxamide

(350) ##STR00265##

(351) The title compound was prepared in analogy to intermediate B58 from 4-chloro-2-iodo-5-methylphenol (intermediate B1, step 3) (119 mg) and N-[[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-cyclopropanecarboxamide (236 mg, purity ˜60%) and was obtained as a light yellow foam (63 mg, 42%). MS (ESI): m/z=334.1 [M+H].sup.+.

(352) The following intermediates were obtained in analogy to intermediate B79, by replacing cyclopropanecarboxylic acid in step 1 with the appropriate carboxylic acid building block as indicated in the table below:

(353) TABLE-US-00012 Inter- Building block/ mediate Systematic Name intermediate MS, m/z B83 N-[[3-(5-Chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]methyl]-2- methoxyacetamide 2-methoxyacetic acid CAS: 625-45-6 MS (ESI): 336.1 [M − H].sup.−
Intermediate B77

7-(5-Chloro-2-hydroxy-4-methylphenyl)-6-fluoro-3-methyl-1,3-benzoxazol-2-one

(354) ##STR00267##

Step 1: 7-Bromo-6-fluoro-3H-1,3-benzoxazol-2-one

(355) ##STR00268##

(356) A solution of 1,1′-carbonyldiimidazole (378 mg) in tetrahydrofuran (6.0 mL) was added to a suspension of 6-amino-2-bromo-3-fluorophenol (400 mg, CAS: 1257535-00-4) in THF (5.0 mL) at rt under an argon atmosphere. The mixture was stirred at rt for 4 hours. The reaction mixture was poured then into ice/water and the aqueous layer was extracted twice with ethyl acetate. The organic layers were washed once with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The crude material was purified by flash chromatography (0% to 100% ethyl acetate in heptane) to give the title compound as an orange solid (298 mg, 65%). MS (ESI): m/z=230.0 [M−H].sup.−.

Step 2: 7-Bromo-6-fluoro-3-methyl-1,3-benzoxazol-2-one

(357) ##STR00269##

(358) The title compound was prepared in analogy to Intermediate B63, step 2, from 7-bromo-6-fluoro-3H-1,3-benzoxazol-2-one (290 mg) and was obtained as a light brown foam (263 mg, 84%). MS (EI): m/z=245.0 [M].sup.+.

Step 3: 2-(5-Chloro-2-methoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

(359) ##STR00270##

(360) The title compound was prepared in analogy to Intermediate B67, step 2, from 1-chloro-5-iodo-4-methoxy-2-methylbenzene (Intermediate B1, step 2) (300 mg) and was obtained as an off-white solid (75 mg, 21%, purity ˜80%). MS (ESI): m/z=311.1 [M+H].sup.+.

Step 4: 7-(5-Chloro-2-methoxy-4-methylphenyl)-6-fluoro-3-methyl-1,3-benzoxazol-2-one

(361) ##STR00271##

(362) The title compound was prepared in analogy to Intermediate B58 from 7-bromo-6-fluoro-3-methyl-1,3-benzoxazol-2-one (Intermediate B77, step 2) (38 mg) and 2-(5-chloro-2-methoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (71 mg, purity ˜80%) and was obtained as an off-white solid (18 mg, 36%). MS (ESI): m/z=322.0 [M+H].sup.+.

Step 5: 7-(5-Chloro-2-hydroxy-4-methylphenyl)-6-fluoro-3-methyl-1,3-benzoxazol-2-one

(363) ##STR00272##

(364) The title compound was prepared in analogy to Intermediate B1, step 3, from 7-(5-chloro-2-methoxy-4-methylphenyl)-6-fluoro-3-methyl-1,3-benzoxazol-2-one (18 mg) and was obtained as a light brown solid (15 mg, 79%, purity 90%). MS (ESI): m/z=306.1 [M−H].sup.−.

(365) Intermediate B86

3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-(trifluoromethoxy)benzonitrile

(366) ##STR00273##

(367) Cyclopentyl methyl ether (5 mL) was purged three times with argon and was then combined with 3-bromo-4-(trifluoromethoxy)benzonitrile (130 mg, CAS: 191602-89-8), potassium acetate (144 mg), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (130 mg) and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) DCM complex (20 mg). The mixture was heated to 95° C. for 4 hours under an argon atmosphere. The reaction mixture was allowed to cool to rt and was then combined with argon-purged sodium carbonate solution (15% in water, 600 μL), 4-chloro-2-iodo-5-methylphenol (131 mg, obtained in Intermediate B1, step 3) and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(I) DCM complex (20 mg). The reaction mixture was again heated to 86° C. for 18 hours. The reaction mixture was cooled to rt and was poured then into ice/water. The aqueous layer was extracted twice with ethylacetate and the organic layers were washed once with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified by flash chromatography (silica gel, 20 g cartridge, gradient of 0% to 20% ethyl acetate in heptane) to provide the title compound as alight yellow solid (48 mg). MS (ESI.sup.−): m/z=326.3 [M−H].sup.−.

(368) The following intermediates were made in analogy to Intermediate B86 by replacing 3-bromo-4-(trifluoromethoxy)benzonitrile with the corresponding aryl-bromide and, if appropriate, 4-chloro-2-iodo-5-methylphenol with the corresponding aryl-iodide as described in the following table:

(369) TABLE-US-00013 Inter- Building block/ mediate Systematic Name intermediate MS, m/z B88 2-chloro-5-(2-fluoro-3- methoxyphenyl)-4- hydroxybenzonitrile 1-bromo-2-fluoro-3- methoxybenzene (CAS: 95970-22-2) and 2-chloro-4-hydroxy-5- iodobenzonitrile (Intermediate B31, Method B, step 1) MS (ESI): 278.1 [M + H].sup.+ B90 4-chloro-2-(2-fluoro-3- methoxyphenyl)-5- methylphenol 1-bromo-2-fluoro-3- methoxybenzene (CAS: 95970-22-2) and 4-chloro-2-iodo-5- methylphenol (Intermediate B1, step 3) MS (ESI): 267.1 [M + H].sup.+ B91 2-chloro-5-(2,3- difluorophenyl)-4- hydroxybenzonitrile 1-bromo-2,3- difluorobenzene (CAS: 38573-88-5) and 2-chloro-4-hydroxy-5- iodobenzonitrile (Intermediate B31, Method B. step 1) MS (ESI.sup.−): 264.1 [M − H].sup.− B92 4-chloro-2-(5- cyclopropyloxy-2- fluorophenyl)-5-methylphenol 2-bromo-4- cyclopropyloxy-1- fluorobenzene (CAS: 1243469-64-8) and 4-chloro-2-iodo-5- methylphenol (Intermediate B1, step 3) MS (ESI): 293.1 [M + H].sup.+ B93 2-chloro-5-(5-chloro-2- fluorophenyl)-4- hydroxybenzonitrile 2-bromo-4-chloro-1- fluorobenzene (CAS: 1996-30-1) and 2-chloro-4-hydroxy-5- iodobenzonitrile (Intermediate B31, Method B, step 1) MS (ESI.sup.−): 280.1 [M − H].sup.− B94 2-chloro-5-(2,5- difluorophenyl)-4- hydroxybenzonitrile 2-bromo-1,4- difluorobenzene (CAS: 399-94-0) and 2-chloro-4-hydroxy-5- iodobenzonitrile (Intermediate B31, Method B. step 1) MS (ESI.sup.−): 264.1 [M + H].sup.− B95 2-chloro-5-(5- cyclopropyloxy-2- fluorophenyl)-4- hydroxybenzonitrile 0 2-bromo-4- cyclopropyloxy-1- fluorobenzene (CAS: 1243469-64-8) and 2-chloro-4-hydroxy-5- iodobenzonitrile (Intermediate B31, Method B, step 1) MS (ESI.sup.−): 302.2 [M − H].sup.− B96 2-chloro-5-[2-fluoro-5- (trifluoromethyl)phenyl]-4- hydroxybenzonitrile 2-bromo-1-fluoro-4- trifluoromethyl)benzene (CAS: 68322-84-9) and 2-chloro-4-hydroxy-5- iodobenzonitrile (Intermediate B31, Method B, step 1) MS (ESI.sup.−): 314.2 [M − H].sup.−
Intermediate B87

2-Chloro-5-[2-fluoro-5-(oxolan-2-ylmethoxy)phenyl]-4-hydroxybenzonitrile

(370) ##STR00282##

(371) This material was prepared in analogy to Intermediate B67, steps 1-3, by replacing in step 1 (tetrahydrofuran-3-yl)methanol with (tetrahydrofuran-2-yl)methanol (CAS: 97-99-4), and in step 3 4-chloro-2-iodo-5-methylphenol with 2-chloro-4-hydroxy-5-iodobenzonitrile (made in Intermediate B31, Method B, step 1). Light brown oil: MS (ESI): 348.11 [M+H].sup.+.

(372) Intermediate B97

2-Chloro-5-[2-fluoro-5-(trifluoromethoxy)phenyl]-4-hydroxybenzonitrile

(373) ##STR00283##

(374) This material was made in analogy to Intermediate B86 from 2-bromo-1-fluoro-4-(trifluoromethoxy)benzene (210 mg, CAS: 286932-57-8) and 2-chloro-4-hydroxy-5-iodobenzonitrile (204 mg, Intermediate B31, Method B, Step 1) to provide the title compound as a colorless solid (130 mg, 47%). MS (m/z): 330.1 [M−H].sup.−.

(375) Intermediate B98

2-Chloro-5-[2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl]-4-hydroxybenzonitrile

(376) ##STR00284##

Step 1: 2-Bromo-1-fluoro-4-(2,2,2-trifluoroethoxy)benzene

(377) ##STR00285##

(378) 3-Bromo-4-fluorophenol (500 mg. CAS: 27407-11-0), 1,1,1-trifluoro-2-iodoethane (824 mg, CAS: 353-83-3) and potassium carbonate (1.09 g) were combined with DMF (10.0 mL) at room temperature under an argon atmosphere. The mixture was heated to 80° C. for 2 hours and then at 60° C. for another 16 hours. TLC showed a lot of starting material. More 1,1,1-trifluoro-2-iodoethane (824 mg) and potassium carbonate (724 mg) were added and the mixture was heated again at 80° C. for 64 hours. The reaction mixture was then cooled and poured into ice/water. The aqueous layer was basified with sat. Na.sub.2CO.sub.3 solution and was extracted twice with ethyl acetate. The organic layers were washed once with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. Residual DMF was removed by co-evaporation with toluene. The crude material was purified by flash chromatography (ISCO, silica gel, 25 g cartridge, 0% to 20% ethyl acetate in heptane) to give the title compound as a light yellow liquid (601 mg, 80%). MS (EI, m/z): 272.0 [M].sup.+.

Step 2: 2-Chloro-5-[2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl]-4-hydroxybenzonitrile

(379) ##STR00286##

(380) This material was made in analogy to Intermediate B86 from 2-bromo-1-fluoro-4-(2,2,2-trifluoroethoxy)benzene (220 mg) and 2-chloro-4-hydroxy-5-iodobenzonitrile (203 mg, Intermediate B31, Method B, Step 1) to provide the title compound as an off-white solid (8 mg, 3%). (MS (m/z): 346.1 [M+H].sup.+.

Intermediates C

(381) Intermediate C3

4-Chloro-5-fluoro-2-isopropyl-phenol

(382) ##STR00287##

Step 1: 4-Chloro-5-fluoro-2-isopropenyl-phenol

(383) ##STR00288##

(384) To a solution of 4-chloro-5-fluoro-2-iodo-phenol (500 mg, CAS: 1235407-15-4) in DMF (8 mL) were added isopropenylboronic acid pinacol ester (771 mg, CAS: 126726-62-3) and K.sub.2CO.sub.3 (761 mg) and the reaction mixture was purged with argon for 30 min. Then Pd(dppf)Cl.sub.2 DCM complex (45 mg, CAS: 14221-01-3) was added and the reaction mixture was stirred at 90° C. for 16 hours. The solvent was evaporated, the residue was diluted with H.sub.2O (40 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography over silica gel (2-4% EtOAc/hexane) to give the title compound as a colorless liquid (263 mg, 76%). .sup.1H-NMR (400 MHz, CDCl.sub.3) 2.07 (3H, s), 5.15 (1H, s), 5.42 (1H, s), 5.73 (1H, bs), 6.73 (1H, d, J=8), 7.12 (1H, d, J=8).

Step 2: 4-Chloro-5-fluoro-2-isopropyl-phenol

(385) ##STR00289##

(386) A solution of 4-chloro-5-fluoro-2-isopropenyl-phenol (524 mg) in MeOH (30 mL) was purged with argon for 15 min. Then, 10% palladium on carbon (130 mg, CAS: 7440-05-3) was added and the reaction mixture was purged with argon for another 5 min. The reaction mixture was stirred under hydrogen (balloon) for 16 hours at rt. The reaction mixture was filtered through a celite bed, the celite bed was washed with EtOAc (20 mL) and the filtrate was evaporated to give the title compound as a green liquid (513 mg, 97%). .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.25 (6H, m), 3.07-3.14 (1H, m), 4.99 (1H, s), 6.58 (1H, d, J=12), 7.13 (1H, d, J=8).

(387) Intermediate C4:

(388) ##STR00290##

5-Chloro-2-isopropyl-4-methyl-phenol

Step 1: 1-Chloro-4-iodo-5-methoxy-2-methyl-benzene

(389) ##STR00291##

(390) The title compound was obtained in analogy to Intermediate A14, step 5, from 4-chloro-2-methoxy-5-methyl-phenylamine (CAS: 62492-42-6) as a brown liquid. .sup.1H-NMR (400 MHz, CDCl.sub.3): 2.25 (3H, s), 3.83 (3H, s), 6.79 (1H, s), 7.60 (1H, s).

Step 2: 5-Chloro-2-iodo-4-methyl-phenol

(391) ##STR00292##

(392) The title compound was obtained in analogy to Intermediate B1, step 3, from 1-chloro-4-iodo-5-methoxy-2-methyl-benzene as a yellow liquid. .sup.1H-NMR (400 MHz, CDCl.sub.3): 2.25 (3H, s), 5.17 (1H, s), 6.99 (1H, s), 7.49 (1H, s).

Step 3: 5-Chloro-2-isopropenyl-4-methyl-phenol

(393) ##STR00293##

(394) The title compound was obtained in analogy to Intermediate C3, step 1, from 5-chloro-2-iodo-4-methyl-phenol and isopropenylboronic acid pinacol ester (CAS: 126726-62-3) as a yellow liquid. .sup.1H-NMR (400 MHz, CDCl.sub.3): 2.20 (3H, s), 2.26 (3H, s) 5.10 (1H, s), 5.38 (1H, s), 6.93 (1H, s), 6.94 (1H, s).

Step 4: 5-Chloro-2-isopropyl-4-methyl-phenol

(395) ##STR00294##

(396) The title compound was obtained in analogy to Intermediate C3, step 2, from 5-chloro-2-isopropenyl-4-methyl-phenol by hydrogenation as a colorless liquid. .sup.1H-NMR (400 MHz CDCl.sub.3) 1.22 (6H, m), 2.27 (3H, s), 3.08-3.11 (1H, m), 4.63 (1H, s), 6.75 (1H, s), 6.93 (1H, s).

(397) Intermediate C9:

2-(5-Chloro-2-hydroxy-4-methyl-phenyl)-2-methyl-propionitrile

(398) ##STR00295##

Step 1: 4-Chloro-2-fluoro-5-methyl-phenol

(399) ##STR00296##

(400) To a solution of 2-fluoro-5-methyl-phenol (5.0 g, CAS: 63762-79-8) in AcOH (50 mL) were added NCS (5.82 g, CAS: 128-09-6) and triflic acid (1.76 mL, CAS: 1493-13-6) and the reaction mixture was refluxed for 24 hours. The solvent was evaporated under reduced pressure and the compound was purified by flash chromatography over silica gel (40-50% EtOAc/hexane) to get the title compound as a colorless liquid (3.5 g, 55%). .sup.1H-NMR (400 MHz, CDCl.sub.3): 2.26 (3H, s), 6.85 (1H, d, J=8), 7.07 (1H, d, J=8).

Step 2: 1-Benzyloxy-4-chloro-2-fluoro-5-methyl-benzene

(401) ##STR00297##

(402) To a stirred solution of 4-chloro-2-fluoro-5-methyl-phenol (3.25 g) in CH.sub.3CN (50 mL) were added Cs.sub.2CO.sub.3 (13.19 g, CAS: 534-17-8) and benzyl bromide (2.66 mL, CAS: 100-39-0) and the reaction mixture was refluxed for 2 hours. The reaction mixture was filtered through a celite bed and the filtrate was evaporated. The compound was purified by column chromatography (10% EtOAc/hexane) to give the title compound as a white solid (3.94 g, 78%). .sup.1H-NMR (400 MHz, CDCl.sub.3): 2.27 (3H, s), 5.09 (2H, s), 6.85 (1H, d, J=8), 7.09 (1H, d, J=12), 7.30-7.42 (5H, m).

Step 3: 2-(2-Benzyloxy-5-chloro-4-methyl-phenyl)-2-methyl-propionitrile

(403) ##STR00298##

(404) To a stirred solution of 1-benzyloxy-4-chloro-2-fluoro-5-methyl-benzene (1.0 g) in anhydrous toluene (10 mL) in a sealed tube were added isobutyronitrile (1.43 mL, CAS: 78-82-0) and KHMDS (6 mL, CAS: 40949-94-8, 1M solution in toluene) and the reaction mixture was stirred at 60° C. for 12 hours. The reaction mixture was poured into H.sub.2O (20 mL) and extracted with EtOAc (2×30 mL). The combined organic extract was dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure. The compound was purified by flash chromatography over silica gel (3-20% EtOAc/hexane) to give the title compound as a brown solid (167 mg, 14%). .sup.1H-NMR (400 MHz, CDCl.sub.3): 1.74 (6H, s), 2.32 (3H, s), 5.15 (2H, s), 6.85 (1H, s), 7.28 (1H, s), 7.31-7.51 (5H, m).

Step 4: 2-(5-Chloro-2-hydroxy-4-methyl-phenyl)-2-methyl-propionitrile

(405) ##STR00299##

(406) To a stirred solution of 2-(2-benzyloxy-5-chloro-4-methyl-phenyl)-2-methyl-propionitrile (420 mg) in dry DCM (20 mL) at −78° C. was added BCl.sub.3 (2.8 mL, 1M solution in DCM, CAS: 10294-34-5) and the reaction mixture was stirred at 25° C. for 4 hours. The reaction mixture was quenched with saturated aqueous Na.sub.2CO.sub.3 solution and was extracted with DCM (2×20 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography over silica gel (0-10% EtOAc/hexane) to give the title product as a brown solid (50 mg, some impurities). .sup.1H-NMR (400 MHz, CDCl.sub.3): 1.76 (6H, s), 2.28 (3H, s), 6.57 (1H, s), 7.29 (1H, s).

(407) Intermediate C1-A:

3-Chloro-6-[(4-chloro-2-isopropyl-5-methyl-phenoxy)methyl]pyridazine

(408) ##STR00300##

(409) To a solution of 3-chloro-6-chloromethyl-pyridazine (81 mg, CAS: 120276-59-7) in acetone (5 mL) was added 4-chloro-2-isopropyl-5-methyl-phenol (92 mg, CAS: 89-68-9) and K.sub.2CO.sub.3 (104 mg) and the reaction mixture was heated at reflux for 16 hours. The reaction mixture was poured into H.sub.2O (50 mL) and EtOAc (75 mL) and the layers were separated. The organic layer was washed with H.sub.2O (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound as a light yellow solid (0.072 g, 46%). MS (EST): m/z=311.07 [M].sup.+.

(410) Intermediate C2-A:

3-Chloro-6-(4-chloro-2-cyclopropyl-5-methyl-phenoxymethyl)-pyridazine

(411) ##STR00301##

(412) To a solution of 3-chloro-6-chloromethyl-pyridazine (200 mg, CAS: 120276-59-7) in CH.sub.3CN (10 mL) were added 4-chloro-2-cyclopropyl-5-methyl-phenol (82 mg, Intermediate A19), K.sub.2CO.sub.3 (109 mg. CAS: 584-08-7) and tetrabutylammonium iodide (16 mg, CAS: 311-28-4) and the reaction mixture was heated to reflux for 16 hours. The solvent was evaporated under reduced pressure and the product was purified by flash chromatography over silica gel (30-40% EtOAc/hexane) to give the title compound as a yellow solid (48 mg, 35%). .sup.1H-NMR (400 MHz, CDCl.sub.3): 0.61-0.65 (2H, m), 0.90-0.95 (2H, m), 2.07-2.09 (1n, m), 2.28 (3H, s), 5.41 (2H, s), 6.73 (1H, s), 6.83 (1H, s), 7.56 (1H, d, J=8), 7.74 (1H, d, J=8). The following intermediates were made in analogy to Intermediate C2-A from commercial 3-chloro-6-chloromethyl-pyridazine (CAS: 120276-59-7) and the proper phenol building block as indicated in the following table:

(413) TABLE-US-00014 Inter- Building block/ mediate Systematic Name intermediate Analytical data C3-A 3-Chloro-6-(4-chloro-5-fluoro- 2-isopropyl-phenoxymethyl)- pyridazine 02 4-Chloro-5-fluoro-2- isopropyl-phenol Intermediate C3 .sup.1H-NMR (400 MHz, CDCl.sub.3): 1.22 (6H, m), 3.26-3.29 (1H, m), 5.36 (2H, s), 6.73 (1H, d, J = 8), 7.20 (1H, d, J = 8), 7.58 (1H, d, J = 8), 7.65 (1H, d, J = 8). C4-A 3-Chloro-6-(5-chloro-2- isopropyl-4-methyl- phenoxymethyl)-pyridazine 03 5-Chloro-2-isopropyl-4- methyl-phenol Intermediate C4 .sup.1H-NMR (400 MHz, CDCl.sub.3): 1.22 (6H, m), 2.25 (3H, s), 3.08-3.13 (1H, m), 4.65 (2H, s), 4.62 (d, J = 16), 4.76 (d, J = 8), 6.93 (1H, s), 6.99 (1H, s) C5-A 3-Chloro-6-(4-chloro-2- cyclobutyl-5-methyl- phenoxymethyl)-pyridazine 04 4-chloro-2-cyclobutyl- 5-methyl-phenol Intermediate A31 .sup.1H-NMR (400 MHz, CDCl.sub.3): 1.82-1.86 (1H, m), 1.98-2.16 (4H, m), 3.66-3.72 (5H, m), 5.35 (2H, s), 6.70 (1H, s), 7.17 (1H, s), 7.56 (1H, d, J = 8), 7.65 (1H, d, J = 8) C6-A 3-Chloro-6-(4-chloro-2- cyclohexyl-5-methyl- phenoxymethyl)-pyridazine 05 4-chloro-2-cyclohexyl- 5-methyl-phenol Intermediate A20 .sup.1H-NMR (400 MHz, CDCl.sub.3): 1.24-1.42 (7H, m), 1,82-1.83 (3H, m), 2.88-2.92 (1H, m), 5.38 (2H, s) , 6.72 (1H, s), 7.15 (1H, s), 7.57 (1H, d, J = 8), 7.67 (1H, d, J = 8). C7-A 3-Chloro-6-[4-chloro-5- methyl-2-(tetrahydro-pyran-4- yl)-phenoxymethyl]-pyridazine 06 4-chloro-5-methyl-2- tetrahydro-pyran-4-yl)- phenol Intermediate A21 .sup.1H-NMR (400 MHz, CDCl.sub.3): 1.70-1.84 (4H, m), 2.30 (3H, s), 3.11- 3.16 (1H, m), 3.48-3.54 (2H, m), 4.05-4.08 (2H, 5.40 (2H, s), 6.75 (1H, s), 7.57-7.62 (3H, m). C8-A 3-(2-tert-Butyl-4-chloro-5- methyl-phenoxymethyl)-6- chloro-pyridazine 07 2-tert-butyl-4-chloro-5- methyl-phenol CAS: 30894-16-7 .sup.1H-NMR (400 MHz, CDCl.sub.3): 1.37 (9H, s), 2.28 (3H, s), 5.43 (2H, s), 6.74 (1H, s), 7.24 (1H, s), 7.56 (IH, d, J = 8), 7,68 (1H, d, J = 8). C9-A 2-[5-Chloro-2-(6-chloro- pyridazin-3-ylmethoxy)-4- methyl-phenyl]-2-methyl- propionitrile 08 2-(5-chloro-2-hydroxy- 4-methyl-phenyl)-2- methyl-propionitrile Intermediate C9 MS (EI): m/z = 337.5 [M + H].sup.+

(414) The following intermediates of type C were made in analogy to Intermediate C2-A from commercial 3-chloro-6-chloromethyl-pyridazine (CAS: 120276-59-7) and the proper phenol building block as indicated in the following table:

(415) TABLE-US-00015 Inter- Building block/ mediate Systematic Name intermediate Analytical data C10-A 3-chloro-6-[[4-chloro-2-(2- methoxypyridin-3-yl)-5- methylphenoxy]methyl]- pyridazine 09 4-chloro-2-(2- methoxypyridin-3-yl)- 5-methylphenol Intermediate B53 MS (ESI, m/z): 376.1 [M + H].sup.+ C12-A 2-chloro-4-[(6-chloropyridazin- 3-yl)methoxy]-5- phenylbenzonitrile 0 2-chloro-4-hydroxy-5- phenylbenzonitrile Intermediate B31 MS (ESI, m/z): 356.1 [M + H].sup.+ C13-A 4-tert-butyl-5-[(6-chloro- pyridazin-3-yl)methoxyl-2- methyl-benzonitrile 4-teri-butyl-5-hvdroxy- 2-methylbenzonitrile Intermediate A17 MS (ESI, m/z): 316.2 [M + H].sup.+ C14-A 2-chloro-4-[(6-chloropyridazin- 3-yl)methoxy]-5-(5-cyclo- propyloxy-2-fluorophenyl)- benzonitrile 2-chloro-5-(5- cyclopropyloxy-2- fluorophenyl)-4- hydroxybenzonitrile Intermediate B95 MS (ESI, m/z): 430.1 [M + H].sup.+

Intermediates D

(416) Intermediate D9:

2-tert-Butyl-5-methyl-4-methylsulfonyl-phenol

(417) ##STR00313##

Step 1: 4-Bromo-2-tert-butyl-5-methyl-phenol

(418) ##STR00314##

(419) To a solution of 2-tert-butyl-5-methylphenol (1.0 g, CAS: 88-60-8) was added N-bromosuccinimide (1.19 g) and the reaction mixture was stirred for 15 h. The reaction mixture was then poured onto saturated NH.sub.4Cl solution and was extracted with EtOAc. The combined organic layers were dried over Na.sub.2SO.sub.4 and were concentrated in vacuo. The residue was purified by chromatography (silica gel, 20 g, gradient of EtOAc in heptane) to give the title compound (1.4 g, 93%) as a yellow oil. MS (ESI): m/z=244.2 [M+H].sup.+.

Step 2: 1-Benzyloxy-4-bromo-2-tert-butyl-5-methyl-benzene

(420) ##STR00315##

(421) To a solution of 4-bromo-2-tert-butyl-5-methyl-phenol (1.4 g, in DMF (15 mL) was slowly added NaH (302 mg, 55% in mineral oil) and the reaction mixture was stirred for 30 minutes at rt. Then, benzylchloride (765 mg, 696 μL) was added and the reaction mixture was stirred for 2 h. The reaction mixture was poured onto saturated NH.sub.4Cl solution and was extracted with EtOAc. The combined organic layers were dried over Na.sub.2SO.sub.4 and were concentrated in vacuo to afford the title compound (1.9 g, 97%) as white powder which was used in the next reaction step without further characterization.

Step 3: 1-Benzyloxy-2-tert-butyl-5-methyl-4-methylsulfonyl-benzene

(422) ##STR00316##

(423) To a mixture of 1-benzyloxy-4-bromo-2-tert-butyl-5-methyl-benzene (1.9 g), L-proline (525 mg) and copper(I)iodide (869 mg) in DMF (10 mL) were added sodium hydroxide (182 mg) and sodium methanesulfinate (1.16 g) and the reaction mixture was heated to 135° C. in a sealed tube for 15 h. The reaction mixture was poured onto saturated NH.sub.4Cl solution and was extracted with EtOAc. The combined organic layers were dried over Na.sub.2SO.sub.4 and were concentrated in vacuo.

(424) The residue was purified by chromatography (silica gel, 20 g, 0% to 50% EtOAc in heptane) to obtain the title compound (1.33 g, 69%) as a white solid. MS (ESI): m/z=331.13 [M−H].sup.−.

Step 4: 2-tert-Butyl-5-methyl-4-methylsulfonyl-phenol

(425) ##STR00317##

(426) To a solution of 1-benzyloxy-2-tert-butyl-5-methyl-4-methylsulfonyl-benzene (1.2 g) in a mixture of MeOH (100 mL) and EtOAc (100 mL) was added Pd(C) (10% on charcoal, 200 mg) under an atmosphere of argon. The reaction vessel was then evacuated and purged with hydrogen and the reaction mixture was stirred for 18 h. The reaction mixture was filtered over dicalite and the filtrate was concentrated in vacuo to give the title compound (865 mg, 99%) as a white solid. MS (ESI): m/z=241.09 [M−H].sup.−.

(427) Intermediate D26-B:

3-Bromomethyl-1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine

(428) ##STR00318##

Step 1: 4-Hydrazino-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester

(429) ##STR00319##

(430) To a solution of hydrazine hydrate (6.28 mL) in ethanol (100 mL) was added drop wise a solution of 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (10 g, CAS: 5909-24-0) in ethanol (250 mL) at 0° C. and the reaction mixture was stirred at 25° C. for 1 h. All volatiles were removed under reduced pressure to afford the title compound (12.0 g) as an off white solid which was used in the next reaction step without additional purification. MS (ESI): m/z=229.5 [M+H].sup.+.

Step 2: 6-Methylsulfanyl-1,2-dihydro-pyrazolo[3,4-d]pyrimidin-3-one

(431) ##STR00320##

(432) A solution of 4-hydrazino-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (12.0 g) in 10% aqueous KOH solution (300 mL) was refluxed for 15 min. The reaction mixture was then cooled to 0° C. and was acidified with 25% aq. AcOH. The resulting precipitate was filtered off, dried under reduced pressure and co-evaporated with toluene to afford the title compound (6.3 g, 66%) as off white solid. MS (ESI): m/z=183.2 [M+H].sup.+.

Step 3: 3-Bromo-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine

(433) ##STR00321##

(434) A mixture of 6-methylsulfanyl-1,2-dihydro-pyrazolo[3,4-d]pyrimidin-3-one (4.5 g) and POBr.sub.3 (21.21 g) was heated in a sealed tube to 170° C. for 8 h. The reaction mixture was cooled to 25° C., diluted with water and basified with 25% aq. ammonia solution and was then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to afford the title compound (2.41 g, 40%) as a light brown solid. MS (ESI): m/z=245.1 [M+H].sup.+.

Step 4: 3-Bromo-1-(4-methoxy-benzyl)-6-methylsulfanyl-1I-pyrazolo[3,4-d]pyrimidine

(435) ##STR00322##

(436) To a solution of 3-bromo-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (3.6 g) in anhydrous DMF (100 mL) was added Cs.sub.2CO.sub.3 (7.16 g) at 25° C. and the reaction mixture was stirred at 25° C. for 15 min. Then, 1-(chloromethyl)-4-methoxy-benzene (2.39 mL) was added dropwise at 25° C. and the reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was filtered and the filtrate was diluted with water and extracted with EtOAc. The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (3-6% EtOAc in hexane) to afford the title compound (4 g, 75%) as an off white solid. MS (ESI): m/z=367.1 [M+H].sup.+.

Step 5: 1-(4-Methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid methyl ester

(437) ##STR00323##

(438) To a solution of 3-bromo-1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (2.0 g) in a mixture of anhydrous DMF (30 mL) and MeOH (25 mL) were added Pd(OAc).sub.2 (98 mg), DPPP (135 mg) followed by Et.sub.3N (2.34 mL) at 25° C. The reaction mixture was stirred under an atmosphere of carbon monoxide at 70 PSI and at 70° C. for 16 h. The reaction mixture was filtered through celite and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (15-20% EtOAc in hexane) to afford the title compound (1.38 g, 73%) as off white solid. MS (ESI): m/z=345.3 [M+H].sup.+.

Step 6: [1-(4-Methoxy-benzyl)-6-methylsulfanyl-4,7-dihydro-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-methanol

(439) ##STR00324##

(440) A suspension of NaBH.sub.4 (2.64 g) and CaCl.sub.2) (3.87 g) in a mixture of THF (90 mL) and EtOH (90 mL) was cooled to 0° C. and a solution of -(4-methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid methyl ester (3.0 g) in anhydrous THF (60 mL) was added drop wise. The reaction mixture was stirred at 0° C. for 2 h and was then quenched by slow addition of water at 0° C., followed by dilution with EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the title compound (2.67 g, 97%) as an off white solid. MS (ESI): m/z=319.2 [M+H].sup.+.

Step 7: [1-(4-Methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-methanol

(441) ##STR00325##

(442) A suspension of [1-(4-methoxy-benzyl)-6-methylsulfanyl-4,7-dihydro-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-methanol (2.67 g) and chloranil (2.064 g) in anhydrous toluene (100 mL) was refluxed for 2 h. The reaction mixture was cooled to 25° C. and EtOAc and water were added. The organic layer was separated, washed with brine, dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure. The resulting residue was purified by column chromatography over silica gel (50-70% EtOAc in hexane) to afford the title compound (2.2 g, 83%) as an off white solid. MS (ESI): m/z=317.0 [M+H].sup.+.

Step 8: 3-Bromomethyl-1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine

(443) ##STR00326##

(444) To a solution of [1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-methanol (1.5 g) in anhydrous acetonitrile (100 mL) was added PBr.sub.3 (0.586 mL) dropwise at 25° C. and the reaction mixture was stirred at 25° C. for 2 h. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO.sub.3 solution and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The resulting residue was purified by column chromatography over silica gel (10-14% EtOAc in hexane) to afford the title compound (1.26 g, 70%) as an off white solid. MS (ESI): m/z=381.0 [M+H].sup.+.

(445) Intermediate D3-A:

tert-Butyl 3-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]pyrazolo[3,4-b]pyridine-1-carboxylate

(446) ##STR00327##

(447) A suspension of 2-tert-butyl-4-chloro-5-methyl-phenol (61.0 mg. CAS: 30894-16-7), tert-butyl 3-(bromomethyl)pyrazolo[3,4-b]pyridine-1-carboxylate (95.8 mg, CAS: 174180-76-8, prepared according to WO200876223A1) and potassium carbonate (106 mg) in acetone (2.5 mL) was heated to 50° C. for 3 h. Acetone was removed in vacuo and the residue was diluted with saturated NH.sub.4Cl solution. The mixture was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by chromatography (20 g silica gel; heptane/EtOAc 90:10-75:25) to obtain the title compound as white solid (89 mg, 67%). MS (ESI): m/z=428.4 [M−H].sup.−.

(448) The following intermediates were synthesized from suitable building blocks in analogy to Intermediate D3-A:

(449) TABLE-US-00016 Inter. Systematic Name Building blocks MS, m/z D4-A tert-Butyl 3-[(2-tert-butyl-4-cyano-5- methyl- phenoxy)methyl]pyrazolo[3,4- b]pyridine-1-carboxylate tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS: 174180-76-8) and Intermediate A16 321.2 [M − CO.sub.2tBu + H].sup.+ D5-A tert-Butyl 3-[(4-chloro-2-isoxazol-5- yl-5-methyl- phenoxy)methyl]pyrazolo[3,4- b]pyridine-1-carboxylate tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS: 174180-76-8) and 4-chloro-2-(5-isoxazolyl)-5- methylphenol (CAS: 213690-32-5) 441.3 [M + H].sup.+ D6-A tert-Butyl 3-[(2-tert-butyl-4-chloro- 5-methyl-phenoxy)methyl]-6-fluoro- pyrazolo[3,4-b]pyridine-1- carboxylate 0 tert-butyl 3-(bromomethyl)-6- fluoro-pyrazolo[3-4-b]pyridine- 1-carboxylate (CAS: 920036-30-2, prepared according to J. Med. Chem. 2008, 51, 6503-6511) and 2-tert-butyl-4-chloro-5-methyl- phenol (CAS: 30894-16-7) 348.2 [M − CO.sub.2tBu + H].sup.+ D9-A tert-Butyl 3-[(2-tert-butyl-5-methyl- 4-methylsulfonyl- phenoxy)methyl]pyrazolo[3,4- b]pyridine-1-carboxylate tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS: 174180-76-8) and Intermediate D9 474.3 [M + H].sup.+ D10-A tert-Butyl 3-[(2-tert-butyl-5-methyl- 4-methylsulfonyl- phenoxy)methyl]indazole-1- carboxylate tert-butyl 3-(bromomethyl)- 1H-indazole-1-carboxylate (CAS 174180-42-8) and Intermediate D9 373.2 [M − CO.sub.2tBu + H].sup.+ D12-A tert-Butyl 3-[(2-tert-butyl-4-chloro- 5-fluoro-phenoxy)methyl]-6-fluoro- pyrazolo[3,4-b]pyridine-1- carboxylate tert-butyl 3-(bromomethyl)-6- fluoro-pyrazolo[3,4-b]pyridine- 1-carboxylate (CAS: 920036-30-2) and Intermediate A2 450.2 [M − H].sup.− D16-A tert-Butyl 3-[[4-chloro-2-[3-(2- methoxyethylcarbamoyl)phenyl]-5- methyl- phenoxy]methyl]pyrazolo[3,4- b]pyridine-1-carboxylate tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS: 174180-76-8) and Intermediate B17 451.2 [M + H].sup.+ D18-A tert-Butyl 3-[[4-chloro-2-[3- (dimethylcarbamoyl)phenyl]-5- methyl- phenoxy]methyl]pyrazolo[3,4- b]pyridine-1-carboxylate tert-butyl 3- (bromomethyl)pyrazolo[3,4- blpyridine-1-carboxylate (CAS: 174180-76-8) and Intermediate B12 421.2 [M + H].sup.+ D39-A tert-Butyl 3-[[4-chloro-2-[2-fluoro-5- (4-methyl-3-oxo-piperazine-1- carbonyl)phenyl]-5-methyl- phenoxy]methyl]pyrazolo[3,4- b]pyridine-1-carboxylate tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS: 174180-76-8) and Intermediate B65 508.2 [M − CO.sub.2tBu + H].sup.+ D40-A tert-Butyl 3-[[4-chloro-2-[2-fluoro-5- [2-methoxyethyl(methyl)carbamoyl]- phenyl]-5-methyl- phenoxy]methyl]pyrazolo[3,4- b]pyridine-1-carboxylate tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS: 174180-76-8) and Intermediate B73 584.3 [M + H].sup.+ D41-A tert-Butyl 3-[[4-chloro-2-[2-fluoro-5-[ (4-methyl-3-oxo-piperazine-1- carbonyl)phenyl]-5-methyl- phenoxy]methyl]indazole-1- carboxylate tert-butyl 3-(bromomethyl)- 1H-indazole-1-carboxylate (CAS 174180-42-8) and Intermediate B65 507.2 [M − CO.sub.2tBu +H].sup.+ D42-A tert-Butyl 3-[[4-chloro-2-[2-fluoro-5- (pyrrolidine-1-carbonyl)phenyl]-5- methyl- phenoxy]methy]pyrazolo[3,4- b]pyridine-1-carboxylate tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS: 174180-76-8) and Intermediate B62 565.2 [M + H].sup.+ D43-A tert-Butyl 3-[[5-chloro-4-cyano-2-[2- fluoro-5-(pyrrolidine-1- carbonyl)phenyl]phenoxy]methyl] pyrazolo[3,4-b]pyridine-1- carboxylate 0 tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS: 174180-76-8) and Intermediate D43 576.18 [M + H].sup.+ D45-A tert-Butyl 3-[(2-tert-butyl-4- methylsulfonyl- phenoxy)methyl]pyrazolo[3,4- b]pyridine-1-carboxylate tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS: 174180-76-8) and Intermediate A15 360.1 [M − CO.sub.2tBu + H].sup.+
Intermediate D43:

2-Chloro-5-[2-fluoro-5-(pyrrolidine-1-carbonyl)phenyl]-4-hydroxy-benzonitrile

(450) ##STR00342##

Step 1: 2-Chloro-5-[2-fluoro-5-(pyrrolidine-1-carbonyl)phenyl]-4-(methoxymethoxy)benzonitrile

(451) ##STR00343##

(452) The title compound was prepared in analogy to Intermediate B31, step 3, from 5-bromo-2-chloro-4-methoxymethoxy-benzonitrile (Intermediate B31, step 2) (80 mg) and (2-fluoro-5-(pyrrolidine-1-carbonyl)phenyl)boronic acid (82.3 mg, CAS: 874289-42-6) and was obtained as a white foam (60 mg, 52%). MS (ESI): m/z=389.2 [M+H].sup.+.

Step 2: 2-Chloro-5-[2-fluoro-5-(pyrrolidine-1-carbonyl)phenyl]-4-hydroxy-benzonitrile

(453) ##STR00344##

(454) To a suspension of 4-chloro-2′-fluoro-6-(methoxymethoxy)-5′-(pyrrolidine-1-carbonyl)-[1,1′-biphenyl]-3-carbonitrile (50 mg) in dioxane (3 mL) was added 4M HCl in dioxane (257 μL) dropwise over a period of 2 minutes at rt. The resulting solution was stirred at rt for 2 h. Then again, 4M HCl in dioxane (129 μL) was added and stirring was continued for 5 h. The reaction mixture was evaporated to dryness and the residue was purified by recrystallization from DCM and heptane to afford the title compound (40 mg, 88%) as a white solid. MS (ESI): m/z=386.2 [M+CH.sub.3CN+H].sup.+.

(455) Intermediate D44-B:

3-(Chloromethyl)-1-tritylpyrazolo[3,4-c]pyridine

(456) ##STR00345##

Step 1: Ethyl 1-tritylpyrazolo[3,4-c]pyridine-3-carboxylate

(457) ##STR00346##

(458) In a 20 mL round-bottomed flask, ethyl 1H-pyrazolo[3,4-c]pyridine-3-carboxylate (CAS: 1053656-33-9, 500 mg) was combined with DMF (3 mL). Triethylamine (397 mg) was added to give a light brown solution. The mixture was cooled at 0° C. and then [chloro(diphenyl)methyl]-benzene (802 mg) was slowly added. The reaction mixture was stirred for 4 h. The reaction mixture was poured into 20 mL ethyl acetate and the organic solution was washed with H.sub.2O (2×10 mL). The aqueous washings were re-extracted with ethyl acetate. The organic layers were combined, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Residual DMF was removed by addition of toluene followed by evaporation in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, gradient of 0% to 60% ethyl acetate in heptane) to give the title compound as a colorless foam (700 mg). MS (m/z): 434.18 [M+H].sup.+.

Step 2: (1-Tritylpyrazolo[3,4-c]pyridin-3-yl)methanol

(459) ##STR00347##

(460) In a 20 mL round-bottomed flask, ethyl 1-trityl-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (700 mg) was combined with CH.sub.2Cl.sub.2 (3 mL) and was then cooled to −78° C. Diisobutylalumnium hydride solution (1 M in CH.sub.2CL.sub.2, 3.2 mL) was added slowly and the mixture was allowed to stir at −78° C. for 2 h. The reaction mixture was poured into 20 mL ethyl acetate and Rochelle salt solution (10 mL) and was extracted with ethyl acetate (2×10 mL). The organic layers were combined, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give a white foam (500 mg), that was used without further purification. MS (m/z): 392.17 [M+H].sup.+.

Step 3: 3-(Chloromethyl)-1-tritylpyrazolo[3,4-c]pyridine

(461) ##STR00348##

(462) In a 20 mL round-bottomed flask, (1-trityl-1H-pyrazolo[3,4-c]pyridin-3-yl)methanol (55 mg) was combined with CH.sub.2Cl.sub.2 (3 mL) and the mixture was cooled to 0° C. Thionyl chloride (20.4 μL) was then added dropwise. The ice bath was removed and the reaction was allowed to stir at rt for 1 hr. The mixture was quenched with aq. sodium bicarbonate solution and the organic layer was separated, washed with brine and dried over Na.sub.2SO.sub.4. The solution was concentrated in vacuo to provide the title compound as a colorless foam (53 mg). MS (m/z): 410.14 [M+H].sup.+.

(463) Intermediate D54-B

3-(Chloromethyl)-1-tritylpyrazolo[4,3-c]pyridine

(464) ##STR00349##

Step 1: Ethyl 1H-pyrazolo[4,3-c]pyridine-3-carboxylate

(465) ##STR00350##

(466) Under an argon atmosphere, thionyl chloride (241 mg, 147 μl) was added to a solution of 1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (300 mg, CAS: 932702-11-9) in ethanol (20 mL). The mixture was then heated to reflux and was allowed to stir for 2 hours. The mixture was cooled to room temperature and was quenched with sat. Na.sub.2CO.sub.3 solution. The aqueous layer was extracted twice with ethyl acetate (80 mL). The organic layers were washed once with brine, dried over Na.sub.2SO.sub.4, filtered, evaporated and dried at high vacuum to provide the title compound as a light yellow powder (228 mg, 62%). MS (m/z): 192.1 [M+H].sup.+.

Steps 2-4: 3-(Chloromethyl)-1-tritylpyrazolo[4,3-c]pyridine

(467) ##STR00351##

(468) This material was obtained as a solid in exact analogy to Intermediate D44-B, Steps 1-3, from ethyl 1H-pyrazolo[4,3-c]pyridine-3-carboxylate (obtained above in Step 1) first by tritylation, then reduction to the hydroxymethyl derivative, and finally chlorination. MS (m/z): 410.2 [M+H].sup.+.

Intermediates F

(469) Intermediate F1:

tert-Butyl 3-(bromomethyl)pyrazole-1-carboxylate

(470) ##STR00352##

Step 1: tert-Butyl 3-methylpyrazole-1-carboxylate

(471) ##STR00353##

(472) To a solution of 3-methyl-1H-pyrazole (500 mg) in acetonitrile (10 mL) were added di-tert-butyl dicarbonate (1.59 g, 1.7 mL) and DMAP (74.4 mg) at 0° C. The mixture was allowed to warm to rt and was stirred for 2 h. Then, EtOAc was added and the mixture was washed with 0.1 N HCl, saturated NaHCO.sub.3 solution and brine, dried with Na.sub.2SO.sub.4 and evaporated. The crude product (containing ˜15% of tert-butyl 5-methylpyrazole-1-carboxylate) was used in the next reaction step without further purification.

Step 2: tert-Butyl 3-(bromomethyl)pyrazole-1-carboxylate

(473) ##STR00354##

(474) A mixture of tert-butyl 3-methylpyrazole-1-carboxylate (1.24 g), NBS (1.7 g) and benzoyl peroxide (308 mg) in CCl.sub.4 (50 mL) was heated to reflux for 4 h. The mixture was then cooled to 0° C., filtered and evaporated. The residue was purified by column chromatography (10 g SiO.sub.2, n-heptane/EtOAc 100/0 to 90/10) to provide the title compound (481 mg, 27%) as a colorless oil. MS (ESI): m/z=161.0 [M-CO.sub.2tBu+H].sup.+.

(475) Intermediate F3:

Methyl 5-(hydroxymethyl)-2-tetrahydropyran-2-yl-pyrazole-3-carboxylate

(476) ##STR00355##

Step 1: Dimethyl 1-tetrahydropyran-2-ylpyrazole-3,5-dicarboxylate

(477) ##STR00356##

(478) TFA (74.0 mg, 50 μL) was added to a suspension of dimethyl 1H-pyrazole-3,5-dicarboxylate (1.546 g, CAS: 4077-76-3) in toluene (15 mL) and the mixture was heated to 80° C. Then, 3,4-dihydro-2H-pyran (828 mg, 900 μL) was added and the reaction mixture was refluxed overnight. The mixture was cooled to rt and the solvent was evaporated. The residue was dissolved in water and was extracted with EtOAc. The combined organic layers were washed with brine, dried with Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified by chromatography (50 g silica gel; heptane/EtOAc 100/0 to 50/50) to obtain the title compound (1.95 g, 87%) as a white solid. MS (ESI): m/z=185.1 [M-THP+H].sup.+.

Step 2: Methyl 5-(hydroxymethyl)-2-tetrahydropyran-2-yl-pyrazole-3-carboxylate

(479) ##STR00357##

(480) To a solution of dimethyl 1-tetrahydropyran-2-ylpyrazole-3,5-dicarboxylate (1.95 g) in a mixture of THF (40 mL) and diethyl ether (80 mL) was added a 1M solution of DIBAL-H in toluene (16.0 mL) dropwise at −78° C. and the mixture was stirred for 3 h at −78° C. Then, more DIBAL-H 1 M in toluene (8 mL) was added and the mixture was stirred for another hour. The mixture was warmed to 0° C. and water (15 mL) was added dropwise. The white suspension was evaporated and the remaining white cake was suspended in MeOH (120 mL), flushed with CO.sub.2 (g) for 10 minutes and then refluxed for 5.5 h. The mixture was filtered and the filtrate was concentrated. The remaining material was purified by chromatography (50 g silica gel, heptane/EtOAc 100/0 to 1/2) to obtain the title compound (810 mg, 47%) as a white solid. MS (ESI): m/z=157.0 [M-THP+H].sup.+.

Examples A: Triazolones with R.SUB.A.≠Aryl

Example A1

3-[(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one

(481) ##STR00358##

(482) 2-(tert-Butyl)-4-chloro-5-methylphenol (CAS: 30894-16-7, 250 mg), 3-(chloromethyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one (CAS: 1338226-21-3; 279 mg), potassium carbonate (348 mg) and potassium iodide (20.9 mg) were combined in acetone (10.0 mL) at rt under an argon atmosphere. The mixture was then heated to reflux for 3 hours and was then kept at rt for another 16 hours. TLC showed no residual starting material at that time. The reaction mixture was then poured into ice/water and the aqueous layer was extracted twice with ethyl acetate. The organic layers were washed once with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude material was purified by flash chromatography on silica gel with 0% to 70% ethyl acetate in heptane as an eluent to provide the title compound as a colorless solid (60 mg). MS (m/z): 310.2 [MH].sup.+.

(483) The following examples were synthesized from the suitable building blocks/intermediates and known 3-(chloromethyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one in analogy to Example A1:

(484) TABLE-US-00017 Building block/ Ex. Systematic Name intermediate MS, m/z A2 Intermediate A1 314.2 [M + H].sup.+ A3 0 6-Isopropyl-3,3-dimethyl-2,3- dihydro-1H-inden-5-ol CAS: 1588508-77-3 made according to WO2014048865 316.2 [M + H].sup.+ A4 2-tert-butyl-4-(3-methyl- 1,2,4-oxadiazol-5-yl)phenol Intermediate A4 344.2 [M + H].sup.+ A5 2-tert-butyl-4-[1-(2- trimethylsilylethoxymethyl)- imidazol-2-yl]phenol Intermediate A5 457.9 [M + H].sup.+ A6 2-tert-butyl-4-(1- methylimidazol-2-yl)phenol Intermediate A6 342.0 [M + H].sup.+ A7 2-tert-butyl-4-(1,3-oxazol-2- yl)phenol Intermediate A7 329.0 [M + H].sup.+ A8 2-tert-butyl-4-morpholin-4- ylphenol Intermediate A8 347.0 [M + H].sup.+ A9 2-tert-butyl-4-(3- methylimidazol-4-yl)phenol Intermediate A9 342.0 [M + H].sup.+ A10 2-tert-butyl-4-(5-methyl- 1,3,4-oxadiazol-2-yl)phenol Intermediate A10 344.1 [M + H].sup.+ A11 4-hydroxy-3-propan-2- ylbenzonitrile CAS: 46057-54-9 Made from 2-isopropylphenol according to WO2005023762 271.12 [M − H].sup.− A12 4-hydroxy-6-methyl-3- propan-2-ylbenzonitrile CAS: 858026-56-9 Made from 2-isopropyl-5- methlyphenol according to WO2005023762 285.14 [M − H].sup.− A13 0 3-tert-butyl-4- hydroxybenzonitrile CAS: 4910-04-7 287.15 [M + H].sup.+ A14 4-chloro-2-cyclopropyl-5- methylsulfonylphenol Intermediate A14 358.06 [M + H].sup.+ and 375.09 [M + NH.sub.4].sup.+ A15 2-tert-butyl-4- methylsulfonylphenol Intermediate A15 340.13 [M + H].sup.+ A16 5-tert-butyl-4-hydroxy-2- methylbenzonitrile Intermediate A16 301.17 [M + H].sup.+ A17 4-tert-butyl-5-hydroxy-2- methylbenzonitrile Intermediate A17 301.17 [M + H].sup.+. A18 2-tert-Butyl-4-[3-(2- trimethylsilanyl- ethoxymethyl)-3H-imidazol- 4-yl]-phenol Intermediate A18 458.10 [M + H].sup.+ A19 4-chloro-2-cyclopropyl-5- methylphenol Intermediate A19 294.0 [M + H].sup.+ A20 4-chloro-2-cyclohexyl-5- methylphenol Intermediate A20 336.0 [M + H].sup.+ A21 4-chloro-5-methyl-2-(oxan-4- yl)phenol Intermediate A21 338.0 [M + H].sup.+ A22 2-chloro-4-cyclopropyl-5- hydroxy-benzonitrile Intermediate A22 305.0 [M + H].sup.+ A23 0 N-(2-chloro-4-cyclopropyl-5- hydroxyphenyl)methane- sulfonamide Intermediate A23 373.0 [M + H].sup.+ A24 4-tert-butyl-3- hydroxybenzonitrile Intermediate A24 287.0 [M + H].sup.+ A25 4-tert-butyl-3- hydroxybenzamide Intermediate A25 305.6 [M + H].sup.+

Example A26

5-tert-Butyl-2-methyl-4-[(5-oxo-4-propan-2-yl-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile

(485) ##STR00383##

Step 1: 3-(Benzyloxymethyl)-4-isopropyl-1H-1,2,4-triazol-5(4H)-one

(486) ##STR00384##

(487) To a suspension of N-isopropylhydrazinecarboxamide hydrochloride (CAS: 35578-82-6, 1.0 g) in THF (12.5 mL) was added 2-(benzyloxy)acetyl chloride (1.2 g) and the mixture was cooled to 0° C. To the mixture was then added dropwise 5M aq. sodium hydroxide (2.67 mL) over 3 minutes and the reaction mixture was vigorously stirred at room temperature for 2.5 hours. THF was then removed by evaporation in vacuo. The remaining brown, viscous suspension was treated with 2M aq. sodium hydroxide (6.51 mL) and was heated to 95° C. (oil bath temperature) for 16 hours. After cooling, the turbid solution was adjusted to pH 4 using 25% aq. HC. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were washed with brine, dried over MgSO.sub.4, filtered, treated with silica gel and evaporated. The residue was purified by silica gel chromatography with a gradient of n-heptane in ethyl acetate (100/0 to 0/100) to provide the title compound (0.705 g). MS (m/z): 248.14 [M+H].sup.+

Step 2: 3-(Hydroxymethyl)-4-propan-2-yl-1H-1,2,4-triazol-5-one

(488) ##STR00385##

(489) To a solution of 3-(benzyloxymethyl)-4-isopropyl-1H-1,2,4-triazol-5(4H)-one (0.70 g) in ethanol (12 mL) under argon was added palladium hydroxide on carbon (20%, 298 mg) and the reaction mixture was stirred under a hydrogen atmosphere at room temperature and 0.5 bar overpressure over 18 hours. The reaction mixture was then filtered and the solid was washed with ethanol (10 mL). The filtrate was evaporated to provide the title compound as a colorless solid (0.391 g). MS (m/z): 157.0 [M].sup.+.

Step 3: 3-(Chloromethyl)-4-propan-2-yl-1H-1,2,4-triazol-5-one

(490) ##STR00386##

(491) To a suspension of 3-(hydroxymethyl)-4-isopropyl-1H-1,2,4-triazol-5(4H)-one (0.30 g) in acetonitrile (6 mL) was added thionyl chloride (261 mg) and the suspension rapidly turned into a solution. The mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated and the residue was twice treated with toluene and evaporated again to remove the remaining thionyl chloride. The residue, an off-white solid, was triturated with n-heptane in an ultrasonic bath. The suspension was then filtered, washed with n-heptane and the solid was dried in vacuo to provide the title compound (0.37 g) as a colorless solid. MS (m/z): 175.0 [M].sup.+.

Step 4: 5-tert-Butyl-2-methyl-4-[(5-oxo-4-propan-2-yl-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile

(492) This material was obtained from in analogy to Example 1 from 3-(chloromethyl)-4-propan-2-yl-1H-1,2,4-triazol-5-one and 5-tert-butyl-4-hydroxy-2-methylbenzonitrile (Intermediate A16) to provide the title compound as a light brown solid. MS (m/z): 329.20 [M+H].sup.+.

Example A27

4-Methyl-3-[(5-methyl-2-propan-2-ylphenoxy)methyl]-1H-1,2,4-triazol-5-one

(493) ##STR00387##

Step 1: 4-Methyl-3-[(5-methyl-2-propan-2-ylphenoxy)methyl]-5-methylsulfonyl-1,2,4-triazole

(494) ##STR00388##

(495) To a solution of 2-isopropyl-5-methylphenol (300 mg, CAS: 89-83-8) in acetone (20 mL) was added K.sub.2CO.sub.3 (387 mg) and 3-(iodomethyl)-4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazole (783 mg, CAS: 1068603-49-5, made according to WO2008119662). The reaction mixture was stirred over night at 60° C. and was then extracted with water (150 mL) and EtOAc (150 mL). The organic layer was washed with water (150 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude material was purified by column chromatography (gradient of up to 50% EtOAc in DCM) to provide the title compound as a yellow gum (0.241 g). MS (m/z): 324.14 [M+H].sup.+.

Step 2: 3-Methoxy-4-methyl-5-[(5-methyl-2-propan-2-ylphenoxy)methyl]-1,2,4-triazole

(496) ##STR00389##

(497) To a suspension of 4-methyl-3-[(5-methyl-2-propan-2-ylphenoxy)methyl]-5-methylsulfonyl-1,2,4-triazole (241 mg) in methanol (8 mL) was added sodium methoxide in methanol (0.6 mL, 5.4 M). The reaction mixture was heated at 85° C. under reflux. After 2 h, the reaction was stopped and cooled. The mixture was diluted with EtOAc (50 mL), washed with sat. aqueous NaHCO.sub.3 (50 mL) and sat. NaCl solution (20 mL) and was then dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The desired product was obtained as such as a light yellow solid and was used without further purification (0.2 g, containing some starting material). MS (m/z): 276.17 [M+H].sup.+.

Step 3: 4-Methyl-3-[(5-methyl-2-propan-2-ylphenoxy)methyl]-1H-1,2,4-triazol-5-one

(498) ##STR00390##

(499) To a solution of 3-methoxy-4-methyl-5-[(5-methyl-2-propan-2-ylphenoxy)methyl]-1,2,4-triazole (113 mg) in AcOH (29 mL) was added HBr (19.5 mL of a 48% solution) at rt and the reaction mixture was stirred over night. The solution was concentrated (at 50-70° C. water bath temperature) and was then diluted with DCM (50 mL) and washed with 2M KHCO.sub.3 solution (30 mL). The organic layer was dried with Na.sub.2SO.sub.4, filtered and concentrated to give the title compound as a light yellow solid (0.094 g). MS (m/z): 262.2 [M+H].sup.+.

(500) The following Examples were synthesized from the suitable building blocks/intermediates in analogy to Example A1 Steps 1-3:

(501) TABLE-US-00018 Building block/ Ex. Systematic Name intermediate MS, m/z A28 4-chloro-5-methyl-2-propan- 2-ylphenol CAS: 89-68-9 296.12 [M + H].sup.+ A29 4-chloro-2-propan-2-ylphenol CAS: 54461-05-1 282.10 [M + H].sup.+ A30 6-cyclopropyl-2- methylbenzo[d]thiazol-5-ol Intermediate A30 317.11 [M + H].sup.+ A31 4-chloro-2-cyclobutyl-5- methylphenol Intermediate A31 308.2 [M + H].sup.+

Example A32

3-[[2-tert-butyl-4-(1H-imidazol-2-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one

(502) ##STR00395##

(503) To a solution of 3-[[2-tert-butyl-4-[1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one (45 mg), obtained in Example A5, in anhydrous THF (10 mL) at 0° C. was added 2N aqueous HCl (3 mL) at 0° C. and the reaction mixture was stirred at 25° C. for 8 h. The solvent was evaporated under reduced pressure and the residue was diluted with water, basified using saturated aq. NaHCO.sub.3 solution and extracted with DCM (2×30 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure. The residue was purified column chromatography over silica gel (gradient of 3-5% MeOH in DCM) to afford the title compound (12 mg) as an off white solid. MS (m/z): 328.1 [M+H].sup.+.

(504) The following Example was synthesized from the suitable building blocks/intermediates in analogy to Example A32, with the exception that the solvent THF was replaced by DCM and that 2N HCl was replaced by trifluoroacetic acid.

(505) TABLE-US-00019 Building Ex. Systematic Name block/intermediate MS, m/z A33 Example A18 328.20 [M + H].sup.+

Example A34

4-tert-Butyl-2-chloro-5-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile

(506) ##STR00397##

(507) This material was made in analogy to Example A1 from Intermediate A34 and commercial 3-(chlormethyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one (CAS: 1338226-21-3) as a colorless solid. MS (m/z): 321.2 [M+H].sup.+.

Example A35

5-tert-butyl-2-chloro-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile

(508) ##STR00398##

(509) To 5-tert-butyl-2-chloro-4-hydroxy-benzonitrile (2.29 g, 10.9 mmol) in N-methyl-pyrrolidinone (55 mL) was added NaH (568 mg, 14.2 mmol). The mixture was stirred at room temperature for 30 min. 3-(Chloromethyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one (1.93 g, 13.11 mmol) was dissolved in N-methyl-pyrrolidinone (20 mL) and added dropwise via addition funnel over 30 min. Upon complete addition, water (160 mL) was slowly added to the reaction. After stirring until cooled to room temperature, the reaction was filtered and solids dried to give 3.15 g of the title compound as a white solid (90% yield). MS (m/z): 321.5 [M+H].sup.+.

Example A36

5-tert-butyl-2-fluoro-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile

(510) ##STR00399##

(511) The title compound was prepared in analogy to example A35, from 5-tert-butyl-2-fluoro-4-hydroxy-benzonitrile (0.118 g) and 3-(chloromethyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one (0.108 g) and was obtained (17 mg, 9%) as a white solid. MS (m/z): 305.5 [M+H].sup.+.

Examples B: Triazolones with R.SUB.A.=Aryl and Heteroaryl

Example B1

3-[(4-Chloro-5-methyl-2-phenylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one

(512) ##STR00400##

(513) To a solution of 4-chloro-5-methyl-2-phenylphenol (62.2 mg, Intermediate B1) in acetone (2 mL) was added K.sub.2CO.sub.3 (42.6 mg) and 3-(chloromethyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one (35 mg, CAS: 1338226-21-3). The reaction mixture was stirred for 2 hours at reflux. The reaction mixture was poured on 10% aqueous NH.sub.4Cl solution (30 mL) and EtOAc (30 mL) and the layers were separated. The aqueous layer was extracted a second time with EtOAc (30 mL). The organic layers were washed with brine (30 mL), dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography on a 20 g column using an Flashmaster MPLC-system eluting with a gradient of DCM:MeOH (100/0 to 50/50) to give the title compound as an off-white solid (7 mg, 9%). MS (ESI): m/z=330.100 [M+H].sup.+.

(514) The following Examples were synthesized from the suitable building blocks/intermediates and known 3-(chloromethyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one in analogy to Example B1:

(515) TABLE-US-00020 Building block/ Ex. Systematic Name intermediate MS, m/z B2 01 4-chloro-2-(2-chlorophenyl)- 5-methylphenol Intermediate B2 364.06 [M + H].sup.+ B3 02 4-chloro-2-(3-chlorophenyl)- 5-methylphenol Intermediate B3 364.06 [M + H].sup.+ B4 03 4-chloro-2-(4-chlorophenyl)- 5-methylphenol Intermediate B4 364.06 [M + H].sup.+ B5 04 3-(5-chloro-2-hydroxy-4- methylphenyl)benzonitrile Intermediate B5 355.10 [M + H].sup.+ B6 05 4-chloro-5-methyl-2-(3- methylsulfonylphenyl)phenol Intermediate B6 408.08 [M + H].sup.+ B7 06 4-chloro-5-methyl-2-(2- methylsulfonylphenyl)phenol Intermediate B7 408.08 [M + H].sup.+ B8 07 [3-(5-chloro-2-hydroxy-4- methylphenyl)phenyl]- piperidin-1-ylmethanone Intermediate B8 441.17 [M + H].sup.+ B9 08 3-(5-chloro-2-hydroxy-4- methylphenyl)-N- cyclohexylbenzamide Intermediate B9 455.19 [M + H].sup.+ B10 09 [3-(5-chloro-2-hydroxy-4- methylphenyl)phenyl]- morpholin-4-ylmethanone Intermediate B10 443.15 [M + H].sup.+ B11 0 3-(5-chloro-2-hydroxy-4- methylphenyl)benzamide Intermediate B11 373.11 [M − H].sup.− B12 3-(5-chloro-2-hydroxy-4- methylphenyl)-N,N- dimethylbenzamide Intermediate B12 401.14 [M + H].sup.+ B13 3-(5-chloro-2-hydroxy-4- methylphenyl)-N- phenylbenzamide Intermediate B13 449.14 [M + H].sup.+ B14 3-chloro-5-(5-chloro-2- hydroxy-4- methylphenyl)benzamide Intermediate B14 407.07 [M + H].sup.+ B15 3-(5-chloro-2-hydroxy-4- methylphenyl)-N- cyclopropyl-4- fluorobenzamide Intermediate B15 431.13 [M + H].sup.+ B16 6-hydroxy-biphenyl-3- carbonitrile Intermediate B16 307.2 [M + H].sup.+ B17 3-(5-chloro-2-hydroxy-4- methylphenyl)-N-(2- methoxyethyl)benzamide Intermediate B17 431.15 [M + H].sup.+ B18 4-chloro-2-(2-chloropyridin- 3-yl)-5-methylphenol Intermediate B18 365.06 [M + H].sup.+ B19 4-chloro-2-(6-chloropyridin- 2-yl)-5-methylphenol Intermediate B19 365.10 [M + H].sup.+ B20 5-(5-chloro-2-hydroxy-4- methylphenyl)pyridine-3- carboxamide Intermediate B20 (Reaction carried out in DMF at 75° C. for 2.5 hours) 374.01 [M + H].sup.+ B21 0 4-chloro-2-(6- methoxypyridin-2-yl)-5- methylphenol Intermediate B21 361.11 [M + H].sup.+ B25 4-chloro-2-(5-isoxazolyl)-5- methylphenol CAS: 213690-32-5 321.08 [M + H].sup.+ B26 4-chloro-5-methyl-2-oxazol- 5-yl-phenol Intermediate B26 321.0 [M + H].sup.+ B30 4-chloro-5-methyl-2-(2- methyl-2H-pyrazol-3-yl)- phenol Intermediate B30 333.8 [M + H].sup.+ B31 4-chloro-6-hydroxy-biphenyl- 3-carbonitrile Intermediate B31 341.1 [M + H].sup.+ B32 4-chloro-4′-fluoro-6-hydroxy- biphenyl-3-carbonitrile Intermediate B32 359.0 [M + H].sup.+ B33 4′-chloro-5′-cyano-2′- hydroxy-biphenyl-3- carboxylic acid methylamide Intermediate B33 398.3 [M + H].sup.+ B35 4-chloro-6-hydroxy-3′-(5- methyl-[1,2,4]oxadiazol-3- yl)-biphenyl-3-carbonitrile Intermediate B35 423.1 [M + H].sup.+ B36 3-(5-chloro-2-hydroxy-4- methyl-phenyl)-N-(2- hydroxyethyl)benzamide Intermediate B36 417.2 [M + H].sup.+ B37 4-chloro-6-hydroxy-3′-(5- methyl-[1,3,4]oxadiazol-2- yl)-biphenyl-3-carbonitrile Intermediate B37 423.1 [M + H].sup.+ B38 0 3-(5-chloro-2-hydroxy-4- methyl-phenyl)-4-fluoro-N,N- dimethyl-benzamide Intermediate B38 419.2 [M + H].sup.+ B39 3-(4-chloro-5-cyano-2- hydroxy-phenyl)-N,N- dimethyl-benzamide Intermediate B39 412.1 [M + H].sup.+ B40 [3-(5-chloro-2-hydroxy-4- methyl-phenyl)-4-fluoro- phenyl]-morpholino- methanone Intermediate B40 461.2 [M + H].sup.+ B41 2-chloro-4-hydroxy-5-[3- (morpholine-4- carbonyl)phenyl]benzonitrile Intermediate B41 454.2 [M + H].sup.+ B42 methyl 3-(5-chloro-2- hydroxy-4-methyl- phenyl)benzoate Intermediate B42 388.1 [M + H].sup.+ B44 methyl 3-[[3-(5-chloro-2- hydroxy-4-methyl- phenyl)benzoyl]amino]propan- oate Intermediate B44 459.2 [M + H].sup.+ B46 ethyl 2-[[3-(5-chloro-2- hydroxy-4-methyl- phenyl)benzoyl]amino]acetate Intermediate B46 459.2 [M + H].sup.+ B49 methyl 3-(5-chloro-2- hydroxy-4-methyl-phenyl)-4- methyl-benzoate Intermediate B49 402.1 [M + H].sup.+ B52 3-(5-chloro-2-hydroxy-4- methyl-phenyl)-4- (trifluoromethoxy)benzamide Intermediate B52 457.2 [M + H].sup.+ B53 4-chloro-2-(2-methoxy-3- pyridyl)-5-methyl-phenol Intermediate B53 361.1 [M + H].sup.+ B54 0 2-chloro-4-hydroxy-5-(2- methoxy-3- pyridyl)benzonitrile Intermediate B54 372.1 [M + H].sup.+ B55 4-chloro-2-(5-ethoxy-2- fluorophenyl)-5-methylphenol Intermediate B55 392.1 [M + H].sup.+ B56 4-chloro-2-(2- methoxyphenyl)-5- methylphenol Intermediate B56 306.1 [M + H].sup.+ B57 4-chloro-2-(2-fluoro-5- propan-2-yloxyphenyl)-5- methylphenol Intermediate B57 406.2 [M + H].sup.+ B58 4-chloro-2-[2-fluoro-5-(2- methylpropoxy)phenyl]-5- methylphenol Intermediate B58 420.2 [M + H].sup.+ B59 4-chloro-2-[2-methoxy-5- (trifluoromethyl)phenyl]-5- methylphenol Intermediate B59 428.2 [M + H].sup.+ B60 4-chloro-2-(2-methoxy-5- propan-2-ylphenyl)-5- methylphenol Intermediate B60 402.3 [M + H].sup.+ B61 2-chloro-5-[2-fluoro-5- (morpholine-4- carbonyl)phenyl]-4- hydroxybenzonitrile Intermediate B61 472.2 [M + H].sup.+ B62 [3-(5-chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]-pyrrolidin-1- ylmethanone Intermediate B62 445.2 [M + H].sup.+ B63 3-(5-chloro-2-hydroxy-4- methylphenyl)-N- cyclopropyl-4-fluoro-N- methylbenzamide Intermediate B63 445.3 [M + H].sup.+ B64 0 3-(5-chloro-2-hydroxy-4- methylphenyl)-4-fluoro-N-(2- hydroxyethyl)-N- methylbenzamide Intermediate B64 449.2 [M + H].sup.+ B65 4-[3-(5-Chloro-2-hydroxy-4- methylphenyl)-4- fluorobenzoyl]-1- methylpiperazin-2-one Intermediate B65 488.3 [M + H].sup.+ B66 3-(5-chloro-2-hydroxy-4- methylphenyl)-N- cyclopentyl-4-fluoro-N- methylbenzamide Intermediate B66 473.3 [M + H].sup.+ B67 4-Chloro-2-[2-fluoro-5- (oxolan-3- ylmethoxy)phenyl]-5- methylphenol Intermediate B67 448.3 [M + H].sup.+ B68 3-(5-Chloro-2-hydroxy-4- methylphenyl)-4-fluoro-N- methyl-N-(thiophen-2- ylmethyl)benzamide Intermediate B68 501.3 [M + H].sup.+ B69 [3-(5-chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]-piperidin-1- ylmethanone Intermediate B69 459.3 [M + H].sup.+ B70 3-(5-chloro-2-hydroxy-4- methylphenyl)-N- (cyclopropylmethyl)-4-fluoro- N-methylbenzamide Intermediate B70 459.3 [M + H].sup.+ B71 3-(5-chloro-2-hydroxy-4- methylphenyl)-4-fluoro-N- methyl-N-(pyridin-2- ylmethyl)benzamide Intermediate B71 496.2 [M + H].sup.+ B72 4-chloro-2-[2-fluoro-5-(oxan- 4-ylmethoxy)phenyl]-5- methylphenol Intermediate B72 462.2 [M + H].sup.+ B73 3-(5-chloro-2-hydroxy-4- methylphenyl)-4-fluoro-N-(2- methoxyethyl)-N- methylbenzamide Intermediate B73 463.2 [M + H].sup.+ B74 0 4-chloro-2-[2-fluoro-5- (oxolan-2- ylmethoxy)phenyl]-5- methylphenol Intermediate B74 448.2 [M + H].sup.+ B75 2-[3-(5-chloro-2-hydroxy-4- methylphenyl)-4- fluorophenoxy]-N,N- dimethylacetamide Intermediate B75 449.2 [M + H].sup.+ B76 1-[[3-(5-chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]methyl]-4- methylpiperazine-2,5-dione Intermediate B76 488.2 [M + H].sup.+ B77 7-(5-chloro-2-hydroxy-4- methylphenyl)-6-fluoro-3- methyl-1,3-benzoxazol-2-one Intermediate B77 419.1 [M + H].sup.+ B78 N-[[3-(5-chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]methyl]-2- methoxy-N-methylacetamide Intermediate B78 463.2 [M + H].sup.+ B79 N-[[3-(5-chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]methyl]cyclopro- pane-carboxamide Intermediate B79 445.1 [M + H].sup.+ B80 N-[[3-(5-chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]methyl]-N- methylcyclopropane- carboxamide Intermediate B80 459.2 [M + H].sup.+ B81 1-[[3-(5-chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]methyl]- pyrrolidin-2-one Intermediate B81 445.1 [M + H].sup.+ B82 3-[[3-(5-chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]methyl]-1,3- oxazolidin-2-one Intermediated B82 447.1 [M + H].sup.+ B83 N-[[3-(5-chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]methyl]-2- methoxyacetamide Intermediate B83 449.2 [M + H].sup.+ B84 0 2-chloro-5-(2-fluorophenyl)- 4-hydroxybenzonitrile Intermediate B84 359.1 [M + H].sup.+ B85 2-chloro-5-(3-fluorophenyl)- 4-hydroxybenzonitrile Intermediate B85 359.1 [M + H].sup.+ B86 3-(5-chloro-2-hydroxy-4- methylphenyl)-4-(trifluoro- methoxy)benzonitrile Intermediate B86 439.1 [M + H].sup.+ B87 2-chloro-5-[2-fluoro-5- (oxolan-2- ylmethoxy)phenyl]-4- hydroxybenzonitrile Intermediate B87 459.2 [M + H].sup.+ B88 2-chloro-5-(2-fluoro-3- methoxyphenyl)-4- hydroxybenzonitrile Intermediate B88 389.2 [M + H].sup.+ B89 2-chloro-5-(2-fluoro-5- propan-2-yloxyphenyl)-4- hydroxybenzonitrile Intermediate B89 417.3 [M + H].sup.+ B90 4-chloro-2-(2-fluoro-3- methoxyphenyl)-5- methylphenol Intermediate B90 378.1 [M + H].sup.+ B91 2-chloro-5-(2,3- difluorophenyl)-4- hydroxybenzonitrile Intermediate B91 377.1 [M + H].sup.+ B92 4-chloro-2-(5-cyclopropyl- oxy-2-fluorophenyl)-5- methylphenol Intermediate B92 404.2 [M + H].sup.+ B93 2-chloro-5-(5-chloro-2- fluorophenyl)-4- hydroxybenzonitrile Intermediate B93 393.1 [M + H].sup.+ B94 0 2-chloro-5-(2,5- difluorophenyl)-4- hydroxybenzonitrile Intermediate B94 377.1 [M + H].sup.+ B95 2-chloro-5-(5- cyclopropyloxy-2- fluorophenyl)-4- hydroxybenzonitrile Intermediate B95 415.2 [M + H].sup.+ B96 2-chloro-5-[2-fluoro-5- (trifluoromethyl)phenyl]-4- hydroxybenzonitrile Intermediate B96 427.2 [M + H].sup.+

(516) The following Examples of type B were synthesized from the suitable building blocks/intermediates and known 3-(chloromethyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one in analog to Example B1:

(517) TABLE-US-00021 Building block/ Ex. Systematic Name intermediate MS, m/z B97 2-chloro-5-[2-fluoro-5-(trifluoromethoxy)- phenyl]-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3- yl)methoxy]benzonitrile   2-chloro-5-[2-fluoro-5- (trifluorometh- oxy)phenyl]-4- hydroxybenzonitrile Intermediate B97 443.2 [M + H].sup.+ B98 2-chloro-5-[2-fluoro-5-(2,2,2-trifluoro- ethoxy)phenyl]-4-[(4-methyl-5-oxo-1H-1,2,4- triazol-3-yl)methoxy]benzonitrile   2-chloro-5-[2-fluoro-5- (2,2,2-trifluoro- ethoxy)phenyl]-4- hydroxybenzonitrile Intermediate B98 457.2 [M + H].sup.+

Example B22

3-[(4-Chloro-5-methyl-2-pyrazin-2-ylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one

(518) ##STR00485##

Step 1: 5-(4-Chloro-2-iodo-5-methyl-phenoxymethyl)-4-methyl-2,4-dihydro-[1,2,4]triazol-3-one

(519) ##STR00486##

(520) The title compound was obtained in analogy to example B from 4-chloro-2-iodo-5-methyl-phenol (900 mg, Intermediate B1, step 3) and 3-(chloromethyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one (35 mg. CAS: 1338226-21-3) as an off white solid (1.07 g, 84%). MS (ESI): m/z=380.1 [M+H].sup.+.

Step 2: 5-[(4-Chloro-2-iodo-5-methyl-phenoxy)methyl]-4-methyl-2-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-one

(521) ##STR00487##

(522) To a slurry of NaH (192 mg, 60% in mineral oil, CAS: 7646-69-7) in anhydrous DMF (10 mL) was added a solution of 5-(4-chloro-2-iodo-5-methyl-phenoxymethyl)-4-methyl-2,4-dihydro-[1,2,4]triazol-3-one (1.21 g) in anhydrous DMF (20 mL) at rt and the resulting reaction mixture was stirred at rt for 30 min. Then, 2-(trimethylsilyl)ethoxymethyl chloride (0.85 mL, CAS: 76513-69-4) was added dropwise to the reaction mixture and the mixture was stirred at rt for 16 hours. The mixture was quenched with H.sub.2O at 0° C. and the solvent was evaporated to dryness to get a residue which was dissolved in EtOAc (30 mL). The organic layer was washed with H.sub.2O (30 mL) and brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The product was purified by flash chromatography (5-25% EtOAc/hexane) to give the title compound as brown liquid (0.735 g, 45%). MS (ESI): m/z=509.8 [M+H].sup.+.

Step 3: 5-[(4-Chloro-5-methyl-2-pyrazin-2-yl-phenoxy)methyl]-4-methyl-2-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-one

(523) ##STR00488##

(524) A mixture of 5-[(4-chloro-2-iodo-5-methyl-phenoxy)methyl]-4-methyl-2-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-one (312 mg), 2-(tributylstannyl)pyrazine (339 mg, CAS: 205371-27-3) in anhydrous DMF (6 mL) was purged with argon for 30 min. Then Pd(PPh.sub.3).sub.4 (14 mg, CAS: 14221-01-3) was added and the reaction mixture was heated at 120° C. for 16 hours under an argon atmosphere. The reaction mixture was filtered through celite bed. The filtrate was evaporated to get a residue which was dissolved in EtOAc (40 mL). The organic layer was washed with H.sub.2O (40 mL) and brine (40 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography over silica gel (15-35% EtOAc/hexane) to give the title compound as light yellow oil (0.187 g, 66%). MS (ESI): m/z=461.9 [M+H].sup.+.

Step 4: 3-[(4-Chloro-5-methyl-2-pyrazin-2-ylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one

(525) ##STR00489##

(526) To a solution of 5-[(4-chloro-5-methyl-2-pyrazin-2-yl-phenoxy)methyl]-4-methyl-2-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-one (210 mg) in DCM (5 mL) was added TFA (2 mL, CAS: 76-05-1) and the mixture was stirred at 25° C. for 3 hours. The solvent was evaporated to get a residue which was dissolved in EtOAc (30 mL) and washed with saturated aqueous NaHCO.sub.3 solution (25 mL), H.sub.2O (25 mL) and brine (25 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The resulting crude product was purified by prep HPLC (NH.sub.4OAc/CH.sub.3CN) to give the title compound as a white solid (0.052 g, 35%). LC-MS: (ESI): m/z=332.1 [M+H].sup.+.

Example B23

3-[(4-Chloro-5-methyl-2-pyrimidin-2-yl-phenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one

(527) ##STR00490##

(528) To a solution of 5-(4-chloro-2-iodo-5-methyl-phenoxymethyl)-4-methyl-2,4-dihydro-[1,2,4]triazol-3-one (150 mg, example B22, step) in dioxane (5 mL) were added 2-tributylstannanyl-pyrimidine (364 mg, CAS: 153435-63-3) and Pd(PPh.sub.3).sub.4 (13 mg, CAS: 14221-01-3) and the reaction mixture was heated at 100° C. for 16 hours. The solvent was evaporated and the resulting crude product was purified by prep HPLC (NH.sub.4OAc/CH.sub.3CN) to give the title compound as a white solid (0.020 g, 15%). MS (ESI): m/z=332.3 [M+H].sup.+.

Example B24

3-[[4-Chloro-5-methyl-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]phenoxy]methyl]4-methyl-1H-1,2,4-triazol-5-one

(529) ##STR00491##

Step 1: 3-(4-Chloro-2-iodo-5-methyl-phenoxymethyl)-5-methanesulfonyl-4-methyl-4H-[1,2,4]triazole

(530) ##STR00492##

(531) The title compound was obtained in analogy to example B1 from 4-chloro-2-iodo-5-methyl-phenol (0.1 g, Intermediate B1, step 3) and 3-(iodomethyl)-4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazole (118 mg, prepared as described in US2008249151) as a colorless solid (0.145 g; 88%). MS (ESI): m/z=441.95 [M+H].sup.+.

Step 2: 3-[[4-Chloro-5-methyl-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]phenoxy]methyl]-4-methyl-5-methylsulfonyl-1,2,4-triazole

(532) ##STR00493##

(533) The title compound was obtained in analogy to Intermediate B1, step 4, from 3-(4-chloro-2-iodo-5-methyl-phenoxymethyl)-5-methanesulfonyl-4-methyl-4H-[1,2,4]triazole (0.066 g) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (0.049 g, CAS: 1025719-23-6) as a light brown gum (0.038 g: 55%). MS (ESI): m/z=464.08 [M+H].sup.+.

Step 3: 3-[[4-Chloro-5-methyl-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]phenoxy]methyl]-5-methoxy-4-methyl-1,2,4-triazole

(534) ##STR00494##

(535) To a solution of 3-[[4-chloro-5-methyl-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]phenoxy]methyl]-4-methyl-5-methylsulfonyl-1,2,4-triazole (0.084 g) in MeOH (1 mL) was added 54M sodium methoxide solution in MeOH (134 μL, CAS: 124-414) and the solution was heated at reflux for 15 minutes. The reaction mixture was poured on sat. aq. NH.sub.4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO.sub.4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 5 g column using an MPLC system eluting with a gradient of DCM:MeOH (100/0 to 90/10) to give the title compound as a colorless solid (0.054 g; 72%). MS (ESI): m/z=416.11 [M+H].sup.+.

Step 4: 3-[[4-Chloro-5-methyl-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one

(536) ##STR00495##

(537) To a solution of 3-[[4-chloro-5-methyl-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]phenoxy]methyl]-5-methoxy-4-methyl-1,2,4-triazole (0.05 g) in AcOH (826 μL) was added HBr 48% in H.sub.2O (261 μL) and the clear, colorless solution was stirred at reflux for 15 minutes. Then, the reaction mixture was evaporated. The residue was taken up in aq. sat. NaHCO.sub.3 solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO.sub.4, filtered and evaporated. The residue was purified by silica gel chromatography on a 5 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100/0 to 0/100) to give the title compound as a colorless gum (0.036 g: 75%). MS (EST): m/z=402.10 [M+H].sup.+.

Example B27

3-[[4-Chloro-5-methyl-2-(3-methylimidazol-4-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one

(538) ##STR00496##

Step 1: 5-[4-Chloro-5-methyl-2-(3-methyl-3H-imidazol-4-yl)-phenoxymethyl]-4-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,4-dihydro-[1,2,4]triazol-3-one

(539) ##STR00497##

(540) A mixture of 5-(4-chloro-2-iodo-5-methyl-phenoxymethyl)-4-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,4-dihydro-[1,2,4]triazol-3-one (220 mg, example 22, step 2), 1-methyl-1H-imidazole-5-boronic acid pinacol ester (180 mg, CAS: 942070-72-6), potassium phosphate tribasic (183 mg, CAS: 7778-53-2), tricyclohexyl phosphine (2 mg, CAS: 2622-14-2) in dioxane (4 mL) and H.sub.2O (20 mL) was purged with argon for 20 min. Then tris(dibenzylideneacetone)dipalladium(0) (4 mg. CAS: 52409-22-0) was added and the mixture was heated at 120° C. in microwave oven for 1 hour. The mixture was filtered through a celite bed. The filtrate was evaporated to get a residue which was dissolved in EtOAc (30 mL) and washed with H.sub.2O (40 mL) and brine (40 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The resulting crude material was purified by flash chromatography over silica gel (1-5% MeOH/DCM) to give the title compound as a brown liquid (180 mg, 90%). MS (ESI): m/z=464.4 [M+H].sup.+.

Step 2: 3-[[4-Chloro-5-methyl-2-(3-methylimidazol-4-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one

(541) ##STR00498##

(542) The title compound was obtained in analogy to Intermediate B22, step 4, from 5-[4-chloro-5-methyl-2-(3-methyl-3H-imidazol-4-yl)-phenoxymethyl]-4-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,4-dihydro-[1,2,4]triazol-3-one (0.160 g) as an off white solid (28 mg, 24%). MS (ESI): m/z=334.0 [M+H].sup.+.

Example B28

3-[[4-Chloro-2-(1H-imidazol-5-yl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one

(543) ##STR00499##

Step 1: 5-Iodo-1-trityl-1H-imidazole

(544) ##STR00500##

(545) To a solution of 4-iodo-1H-imidazole (2.05 g, CAS: 71759-89-2) and trityl chloride (4.4 g, CAS: 76-83-5) in DMF (35 mL) was added triethylamine (3.04 mL, CAS: 121-44-8) at 0° C. The reaction mixture was slowly warmed to rt and was stirred for 48 hours. The reaction mixture was then poured into H.sub.2O (150 mL). The solid was filtered, washed with H.sub.2O (60 mL) and dried under reduced pressure. The resulting crude material was purified by flash chromatography using silica gel (EtOAc) to give the title compound as a white solid (4.3 g, 93%). RI 0.50 (10% EtOAc/hexane).

Step 2: 5-Tributylstannanyl-1-trityl-1H-imidazole

(546) ##STR00501##

(547) To a solution of 5-iodo-1-trityl-1H-imidazole (2.02 g) in DCM (50 mL) was added ethyl magnesium bromide (1.8 mL, 3M in diethyl ether, CAS: 925-90-6). The reaction was stirred under argon atmosphere at rt for 1 hour. Tributyltin chloride (1.5 mL, CAS: 1461-22-9) was added to the reaction mixture and the resulting mixture was stirred at rt overnight. The reaction mixture was diluted with DCM (100 mL) and successively washed with saturated aqueous NH.sub.4Cl (100 mL), H.sub.2O (100 mL) and brine (100 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered and evaporated to give the title compound as a white solid (2.7 g, 97%) which was used in the next step without further purification. R.sub.f=0.60 (10% EtOAc/hexane).

Step 3: 5-[4-Chloro-5-methyl-2-(3-trityl-3H-imidazol-4-yl)-phenoxymethyl]-4-methyl-2,4-dihydro-[1,2,4]triazol-3-one

(548) ##STR00502##

(549) The title compound was obtained in analogy to example 23, from 5-(4-chloro-2-iodo-5-methyl-phenoxymethyl)-4-methyl-2,4-dihydro-[1,2,4]triazol-3-one (example 22, step 1) and 5-tributylstannanyl-1-trityl-1H-imidazole as a yellow solid. MS (EI): m/z=562.3 [M+H].sup.+.

Step 4: 3-[[4-Chloro-2-(1H-imidazol-5-yl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one

(550) ##STR00503##

(551) To a solution of 5-[4-chloro-5-methyl-2-(3-trityl-3H-imidazol-4-yl)-phenoxymethyl]-4-methyl-2,4-dihydro-[1,2,4]triazol-3-one (80 mg) in DCM (5 mL) was added HCl (0.5 mL, 4N in dioxane, CAS: 7647-01-0) at 25° C. and the resulting mixture was stirred for 4 hours. The reaction mixture was evaporated and the resulting material was purified by flash chromatography using silica gel (10% MeOH/DCM) to give the title compound as a white solid (12 mg, 26%). MS (ESI): m/z=320.2 [M+H].sup.+.

Example B29

3-[[4-Chloro-5-methyl-2-(1,3-oxazol-2-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one

(552) ##STR00504##

(553) The title compound was prepared in analogy to example B23 from 5-(4-chloro-2-iodo-5-methyl-phenoxymethyl)-4-methyl-2,4-dihydro-[1,2,4]triazol-3-one (150 mg, example B22, step 1) and 2-tributylstannanyloxazole (207 mg, CAS: 145214-05-7). The compound was obtained as white solid (9 mg, 7%). MS (ESI): m/z=320.9 [M+H].sup.+.

Example B34

2-Chloro-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]-5-[3-(H-pyrazol-3-yl)phenyl]benzonitrile

(554) ##STR00505##

Step 1: 3′-Acetyl-4-chloro-6-hydroxy-biphenyl-3-carbonitrile and 3′-acetyl-4-chloro-6-methoxymethoxy-biphenyl-3-carbonitrile

(555) ##STR00506##

(556) The title compound was prepared in analogy to Intermediate B31, step 3, from 5-bromo-2-chloro-4-methoxymethoxy-benzonitrile (Intermediate B31, step 2) (1.0 g) and 3-acetyl-phenyl boronic acid (886 mg, CAS: 204841-194)). Note that in this case the MOM-protected phenol was used as a starting material.

(557) These conditions provided the MOM protected phenol 3′-acetyl-4-chloro-6-methoxymethoxy-biphenyl-3-carbonitrile (270 mg, 24%, .sup.1H-NMR (400 MHz, DMSO-D6): 2.63 (s, 3H), 3.36 (s, 3H), 5.37 (s, 2H), 7.55 (s, 1H), 7.62 (t, 1H, J=7.6), 7.80 (d, 1H, J=7.6), 7.98 (d, 1H, J=7.6), 8.03 (s, 1H), 8.10 (s, 1H)), as well as the free phenol 3′-acetyl-4-chloro-6-hydroxy-biphenyl-3-carbonitrile (190 mg, 19%): .sup.1H-NMR (400 MHz, DMSO-D6): 2.63 (s, 3H), 7.19 (s, 1H), 7.53-7.63 (m, —1H), 7.83 (d, 1H, J=8): 7.95 (d, 1H, J=7.8), 7.97 (s, 1H), 8.11 (s, 1H), 11.48 (s, 1H).

(558) Note that depending on the reaction conditions, the MOM group may be partially lost in this reaction to give the free phenol 3′-acetyl-4-chloro-6-hydroxy-biphenyl-3-carbonitrile. This material can be subjected to step 2 below to re-introduce the MOM group. The MOM protected material from step 1 can be used directly in step 3.

Step 2: 3′-Acetyl-4-chloro-6-methoxymethoxy-biphenyl-3-carbonitrile

(559) ##STR00507##

(560) The title compound was prepared in analogy to Intermediate B31, step 2, from 3′-acetyl-4-chloro-6-hydroxy-biphenyl-3-carbonitrile (250 mg) by reaction with NaH (44 mg, 60% in mineral oil) and MOM-Cl (0.14 mL) and was obtained as an off white solid (183 mg, 63%). .sup.1H-NMR (400 MHz, DMSO-D6): 2.63 (s, 3H), 3.36 (s, 3H), 5.37 (s, 2H), 7.55 (s, 1H), 7.62 (t, 1H, J=7.6), 7.80 (d, 1H, J=7.6), 7.98 (d, 1H, J=7.6), 8.04 (s, 1H), 8.10 (s, 1H).

Step 3: 4-Chloro-3′-((E)-3-dimethylamino-acryloyl)-6-methoxymethoxy-biphenyl-3-carbonitrile

(561) ##STR00508##

(562) A solution of 3′-acetyl-4-chloro-6-methoxymethoxy-biphenyl-3-carbonitrile (180 mg) in DMF-DMA (2.5 mL) was heated to 80° C. for 16 h. The reaction mixture was cooled to 25° C. and all volatiles were evaporated under reduced pressure. The remaining residue was purified by column chromatography over silica gel (80-100% EtOAc/hexane) to afford the title compound (140 mg, 66%) as an off white solid. MS (ESI): m/z=370.9 [M+H].sup.+.

Step 4: 3′-(1-tert-Butyl-1H-pyrazol-3-yl)-4-chloro-6-methoxymethoxy-biphenyl-3-carbonitrile

(563) ##STR00509##

(564) To a solution of 4-chloro-3′-((E)-3-dimethylamino-acryloyl)-6-methoxymethoxy-biphenyl-3-carbonitrile (140 mg) in EtOH (20 mL) was added tert-butyl-hydrazine (70.37 mg, CAS: 7400-27-3) at 0° C. The reaction mixture was heated to reflux for 12 h. The mixture was then cooled to 25° C. and all volatiles were removed under reduced pressure. The residue was purified by column chromatography over silica gel (10-15% EtOAc/hexane) to obtain the title compound (110 mg, 73%) as an off white solid. MS (ESI): m/z=396.0 [M+H].sup.+.

Step 5: 3′-(1-tert-Butyl-1H-pyrazol-3-yl)-4-chloro-6-hydroxy-biphenyl-3-carbonitrile

(565) ##STR00510##

(566) To a solution of 3′-(1-tert-butyl-1H-pyrazol-3-yl)-4-chloro-6-methoxymethoxy-biphenyl-3-carbonitrile (110 mg) in anhydrous DCM (10 mL) was added HCl in dioxane (1 mL) at 0° C. and the reaction mixture was stirred at 25° C. for 32 h. The mixture was diluted with DCM (30 mL) and was washed with sat. NaHCO.sub.3 solution and brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography over silica gel (1-2% MeOH/DCM) to afford the title compound (45 mg, 46%) as an off white solid. MS (ESI): m/z=352.2 [M+H].sup.+.

Step 6: 3′-(1-tert-Butyl-1H-pyrazol-3-yl)-4-chloro-6-(4-methyl-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-ylmethoxy)-biphenyl-3-carbonitrile

(567) ##STR00511##

(568) The title compound was obtained in analogy to example B1 from 3′-(1-tert-butyl-1H-pyrazol-3-yl)-4-chloro-6-hydroxy-biphenyl-3-carbonitrile (80 mg) and 3-(chloromethyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one (34 mg) as an off white solid (45 mg, 43%). MS (ESI): m/z=463.0 [M+H].sup.+.

Step 7: 2-Chloro-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]-5-[3-(1H-pyrazol-3-yl)phenyl]benzonitrile

(569) ##STR00512##

(570) A solution of 3′-(1-tert-butyl-1H-pyrazol-3-yl)-4-chloro-6-(4-methyl-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-ylmethoxy)-biphenyl-3-carbonitrile (45 mg) in formic acid (4 mL) was heated to 85° C. for 6 h. Then, all volatiles were removed and the residue was diluted with DCM (20 mL) and washed with water and brine, dried over Na.sub.2SO.sub.4 and concentrated. The resulting material was purified by column chromatography over silica gel (2-3% MeOH/DCM) to afford the title compound (15 mg, 37%) as an off white solid. MS (ESI): m/z=407.2 [M+H].sup.+.

Example B43

3-[5-Chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoic acid

(571) ##STR00513##

(572) Methyl 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoate (36.0 mg, example B42) was suspended in THF (1.5 mL) at r. MeOH was added dropwise until everything was dissolved. Then, a solution of lithiumhydroxide monohydrate (11.7 mg) in water (280 μL) was added dropwise. A small amount of white solid precipitated. Again, MeOH was added dropwise until everything was in solution. The colorless solution was then stirred at overnight. The volatiles were removed and the remaining residue was dissolved in water. The pH was adjusted to 2 by addition of 1N HCl. The precipitate was filtered off, washed with a small amount of water and dried to obtain the title compound as white solid (31 mg, 89%). MS (ESI): m/z=374.1[M+H].sup.+.

(573) The following examples were synthesized in analogy to Example B43:

(574) TABLE-US-00022 Ex. Systematic Name Starting Material MS, m/z B47 Methyl 3-[[3-[5-chloro-4- methyl-2-[(4-methyl-5-oxo- 1H-1,2,4-triazol-3- yl)methoxy]phenyl]benzoyl]- amino]propanoate Example B44 445.2 [M + H].sup.+ B48 Ethyl 2-[[3-[5-chloro-4- methyl-2-[(4-methyl-5-oxo- 1H-1,2,4-triazol-3- yl)methoxy]phenyl]benzoyl]- amino]acetate Example B46 431.1 [M + H].sup.+ B50 Methyl 3-[5-chloro-4-methyl- 2-[(4-methyl-5-oxo-1H-1,2,4- triazol-3-yl)methoxy]phenyl]- 4-methylbenzoate Example B49 388.2 [M + H].sup.+

Example B45

3-[5-Chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-(2-hydroxyethyl)-N-methylbenzamide

(575) ##STR00517##

(576) 3-[5-Chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoic acid (23.0 mg, example B43) was dissolved in N,N-dimethylformamide (0.5 mL). Then, HATU (35.1 mg) and Hunig's base (19.9 mg, 26.9 μL) were added at rt, followed by a solution of 2-(methylamino)ethanol (6.47 mg) in N,N-dimethylformamide (0.5 mL). The light yellow solution was stirred at rt for 2 h. The reaction mixture was diluted with sat. NH.sub.4Cl solution and was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by HPLC (Gemini NX column, acetonitrile/water (containing 0.05% formic acid) 85:15) to obtain the title compound as a white solid (10 mg, 38%). MS (ESI): m/z=431.2 [M+H].sup.+.

Example B51

3-[5-Chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N,N,4-trimethylbenzamide

(577) ##STR00518##

(578) The title compound was obtained in analogy to example B47 from 3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-methylbenzoic acid (23 mg, Example B50) and dimethylamine hydrochloride (6.77 mg) as a white solid (14 mg, 57%). MS (ESI): m/z=415.2 [M+H].sup.+.

Examples C: Compounds with Pyridazinone Head Groups

Example C1

3-[(4-Chloro-5-methyl-2-propan-2-ylphenoxy)methyl]-1H-pyridazin-6-one

(579) ##STR00519##

(580) To a solution of 3-chloro-6-[(4-chloro-2-isopropyl-5-methyl-phenoxy)methyl]pyridazine (60 mg, Intermediate C1-A) in EtOH (3 mL) was added aqueous 3M NaOH (0.642 mL) and the reaction mixture was heated at reflux for 16 hours. The reaction mixture was poured into H.sub.2O and EtOAc and the layers were separated. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The material was purified by flash chromatography over silica gel (0-3% MeOH/DCM) to give to give the title compound as an off-white solid (0.005 g, 9%). MS (ESI): m/z=293.11 [M].sup.+.

Example C2

3-[(4-Chloro-2-cyclopropyl-5-methylphenoxy)methyl]-1H-pyridazin-6-one

(581) ##STR00520##

(582) A solution of 3-chloro-6-(4-chloro-2-cyclopropyl-5-methyl-phenoxymethyl)-pyridazine (45 mg, Intermediate C2-A) was refluxed in glacial acetic acid (5 mL) at 120° C. for 16 hours. Then, the solvent was removed under reduced pressure. The residue was dissolved in DCM and the organic part was washed with saturated solution of NaHCO.sub.3 and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The product was purified by prep. HPLC (NH.sub.4OAc/CH.sub.3CN) to give the title product as a white solid (30 mg, 71%). MS: (ESI): m/z=291.4 [M+H].sup.+.

(583) The following examples were synthesized from the suitable building blocks/intermediates in analogy to example C2:

(584) TABLE-US-00023 Building block/ Ex. Systematic Name intermediate MS, m/z C3 3-[(4-chloro-5-fluoro-2-propan-2- ylphenoxy)methyl]-1H-pyridazin-6-one   3-chloro-6-(4-chloro-5- fluoro-2-isopropyl- phenoxymethyl)-pyridazine Intermediate C3-A 297.2 [M + H].sup.+ C4 3-[(5-chloro-4-methyl-2-propan-2- ylphenoxy)methyl]-1H-pyridazin-6-one   3-chloro-6-(5-chloro-2- isopropyl-4-methyl- phenoxymethyl)-pyridazine Intermediate C4-A 293.2 [M + H].sup.+ C5 3-[(4-chloro-2-cyclobutyl-5- methylphenoxy)methyl]-1H-pyridazin-6-one   3-chloro-6-(4-chloro-2- cyclobutyl-5-methyl- phenoxymethyl)-pyridazine Intermediate C5-A 305.2 [M + H].sup.+ C6 3-[(4-chloro-2-cyclohexyl-5- methylphenoxy)methyl]-1H-pyridazin-6-one   3-chloro-6-(4-chloro-2- cyclohexyl-5-methyl- phenoxymethyl)-pyridazine Intermediate C6-A 333.3 [M + H].sup.+ C7 3-[[4-chloro-5-methyl-2-(oxan-4- yl)phenoxy]methyl]-1H-pyridazin-6-one   3-chloro-6-[4-chloro-5- methyl-2-(tetrahydro-pyran- 4-yl)-phenoxymethyl]- pyridazine Intermediate C7-A 335.1 [M + H].sup.+ C8 3-[(2-tert-butyl-4-chloro-5- methylphenoxy)methyl]-1H-pyridazin-6-one   3-(2-tert-butyl-4-chloro-5- methyl-phenoxymethyl)-6- chloro-pyridazine Intermediate C8-A 307.3 [M + H].sup.+ C9 2-[5-chloro-4-methyl-2-[(6-oxo-1H- pyridazin-3-yl)methoxy]phenyl]-2- methylpropanenitrile   2-[5-chloro-2-(6-chloro- pyridazin-3-ylmethoxy)-4- methyl-phenyl]-2-methyl- propionitrile Intermediate C9-A 318.0 [M + H].sup.+

(585) The following examples of type C were synthesized from the suitable building blocks/intermediates in analogy to Example C2:

(586) TABLE-US-00024 Building block/ Ex. Systematic Name intermediate MS, m/z C10 3-chloro-6-[[4-chloro-2-(2- methoxypyridin-3-yl)-5- methylphenoxy]methyl] pyridazine Intermediate C10-A 358.2 [M + H].sup.+ C11 3-chloro-6-[[4-chloro-2-(2- methoxypyridin-3-yl)-5- methylphenoxy]methyl]- pyridazine Intermediate C10-A 344.1 [M + H].sup.+ C12 0 2-chloro-4-[(6- chloropyridazin-3- yl)methoxy]-5- phenylbenzonitrile Intermediate C12-A 338.1 [M + H].sup.+ C13 4-tert-butyl-5-[(6- chloropyridazin-3- yl)methoxy]-2- methylbenzonitrile Intermediate C13-A 298.2 [M + H].sup.+ C14 2-chloro-4-[(6-chloro- pyridazin-3-yl)methoxy]-5- (5-cyclopropyloxy-2- fluorophenyl)benzonitrile Intermediate C14-A 412.1 [M + H].sup.+

Examples D: Compounds with Head Groups Related to Indazole, Aza-Indazole and Similar

Example D2

3-[(4-Chloro-5-methyl-2-propan-2-ylphenoxy)methyl]-1H-indazole

(587) ##STR00533##

(588) To a solution of 4-chloro-2-isopropyl-5-methylphenol (0.15 g, CAS: 89-68-9) in DMF (1.5 mL) was added sodium hydride (42.5 mg, 55-60% in mineral oil) and the mixture was stirred at rt for 15 minutes. A suspension of tert-butyl 3-(bromomethyl)-1H-indazole-1-carboxylate (253 mg CAS: 174180-42-8) in DMF (2.5 mL) was then added dropwise. After stirring at rt for 2.5 hours, the reaction mixture was poured on a mixture of saturated aqueous NH.sub.4Cl solution and ethyl acetate and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed twice with water and once with brine, dried over MgSO.sub.4, filtered, and evaporated. The residue was purified by silica gel chromatography using an MPLC system (eluting with a gradient of n-heptane:ethyl acetate from 100/0 to 60/40). The resulting light brown oil (0.157 g) was dissolved in dichloromethane (1.5 mL). The solution was cooled to 0° C. and trifluoroacetic acid (1.85 g, 1.25 mL) was added. After stirring at rt for 1.25 hours, the reaction mixture was poured into a mixture of saturated aqueous NaHCO.sub.3 solution and dichloromethane and the layers were separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed once with brine, dried over MgSO.sub.4, filtered and evaporated. The residue was purified by silica gel chromatography using an MPLC system (eluting with a gradient of n-heptane:ethyl acetate from 100/0 to 60/40) to afford the title compound as colorless oil (48 mg; 19%). MS (ESI): m/z=315.13 [M+H].sup.+.

Example D3

3-[(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-b]pyridine

(589) ##STR00534##

(590) To a solution of Intermediate D3-A (85.1 mg) in dioxane (3 mL) was added 4N HCl in dioxane (495 μl) and the solution was stirred at rt. A white solid precipitated and the suspension was stirred at rt overnight. Then additional 4N HCl in dioxane (495 μl) was added and after 4 h at rt again additional 4N HCl in dioxane (495 μl) was added and the mixture was stirred at rt for another 2 days. The white suspension was poured onto saturated NaHCO.sub.3 solution and the resulting mixture was extracted with DCM. The combined organic layers were dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by chromatography (10 g silica gel; heptane/EtOAc 90/10-70/30) to afford the title compound (54 mg, 83%) as a white solid. MS (ESI): m/z=330.2 [M+H].sup.+.

(591) The following examples were synthesized in analogy to example D3.

(592) TABLE-US-00025 Inter- MS, Ex. Systematic Name mediate m/z D4 Inter- mediate D4-A 321.2 [M + H].sup.+ D5 Inter- mediate D5-A 341.2 [M + H].sup.+

Example D6

3-[(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl]-6-fluoro-1H-pyrazolo[3,4-b]pyridine

(593) ##STR00537##

(594) A solution of Intermediate D6-A (55.1 mg) in a mixture of DCM (1 mL) and trifluoroacetic acid (0.4 mL) was stirred at rt for 1 h. Then, the solution was diluted with DCM and it was slowly added to saturated Na.sub.2CO.sub.3 solution. The mixture was extracted with DCM and the combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered, and evaporated. The remaining residue was purified by chromatography (5 g silica gel; DCM/MeOH 98:2) to obtain the title compound (40 mg, 94%) as a white solid. MS (ESI): m/z=348.1 [M+H].sup.+.

(595) The following examples were synthesized in analogy to example D6.

(596) TABLE-US-00026 Ex. Systematic Name Intermediate MS, m/z D9 Intermediate D9-A 374.2 [M + H].sup.+ D10 Intermediate D10-A 373.2 [M + H].sup.+ D12 0 Intermediate D12-A 352.1 [M + H].sup.+ D16 Intermediate D16-A 451.2 [M + H].sup.+ D18 Intermediate D18-A 421.2 [M + H].sup.+ D39 Intermediate D39-A 508.2 [M + H].sup.+ D40 Intermediate D40-A 483.16 [M + H].sup.+ D41 Intermediate D41-A 507.2 [M + H].sup.+ D42 Intermediate D42-A 465.14 [M + H].sup.+ D43 Intermediate D43-A 476.12 [M + H].sup.+ D45 Intermediate D45-A 360.1 [M + H].sup.+

Example D7

2-[[3-[(2-tert-Buty-4-chloro-&-methylphenoxy)methyl]-1H-pyrazolo[3,4-b]pyridin-6-yl]amino]ethanol

(597) ##STR00549##

(598) A solution of Intermediate D6-A (99.9 mg) and ethanolamine (136 mg, 135 μL) in N-methyl-2-pyrrolidinone (1.8 mL) was heated to 95° C. overnight. The solution was cooled to rt, diluted with half saturated brine and the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na.sub.2SO.sub.4 and evaporated. The crude material was purified by chromatography (20 g silica gel; DCM/MeOH 100/0-95/5) to obtain a white solid which was further purified by prep. HPLC to afford the title compound (38 mg, 44%) as a white solid. MS (ESI): m/z=389.2 [M+H].sup.+.

Example D8

2-[[3-[(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-b]pyridin-6-yl]-methylamino]ethanol

(599) ##STR00550##

(600) A solution of Intermediate D6-A (99.9 mg) and 2-(methylamino)ethanol (167 mg, 178 μl) in N-methyl-2-pyrrolidinone (1.8 mL) was heated to 50° C. for 5 h. The solution was cooled to rt, diluted with half saturated brine and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was dissolved in DCM (2 mL) and trifluoroacetic acid (0.4 mL) was added. The solution was stirred at rt for 30 min and was then poured onto saturated Na.sub.2CO.sub.3 solution and the mixture was extracted with DCM. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by column chromatography (5 g silica gel; DCM/MeOH 98/2-95/5) to afford the title compound (41 mg, 46%) as a white solid. MS (ESI): m/z=403.2 [M+H].sup.+.

(601) The following examples were synthesized in analogy to example D8.

(602) TABLE-US-00027 Ex. Systematic Name Intermediate/Amine MS, m/z D11 Intermediate D12-A and 2-aminoethanol 393.2 [M + H].sup.+ D14 Intermediate D12-A and 2-(methylamino)ethanol 407.2 [M + H].sup.+

Example D13

2-[[3-[(2-t-Butyl-4-chloro-&-methylphenoxy)methyl]-1H-pyrazolo[3,4-b]pyridin-6-yl]oxy]ethanol

(603) ##STR00553##

Step 1: 3-[(2-tert-Butyl-4-chloro-5-methyl-phenoxy)methyl]-6-fluoro-1-trityl-pyrazolo[34-b]pyridine

(604) ##STR00554##

(605) Sodium hydride (23.2 mg, 55% in mineral oil) was suspended in DMF (1 mL) and a solution of 3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-6-fluoro-1H-pyrazolo[3,4-b]pyridine (148 mg, example D6) in DMF (1 mL) was added dropwise at 0° C. The resulting brown suspension was stirred at 0° C. for 10 min and then at rt for 20 min. A solution of trityl chloride (=[chloro(diphenyl)methyl]benzene) (125 mg) in DMF (1 mL) was then added at 0° C. and the reaction mixture was stirred at rt overnight. Water was added carefully and the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by chromatography (20 g silica gel; heptane/EtOAc 98/2-90/10) to obtain the title compound (186 mg, 74%) as a white solid. .sup.1H-NMR (300 MHz, CDCl.sub.3): 1.29 (s, 9H), 2.25 (s, 3H), 5.34 (s, 2H), 6.64 (dd, 1H), 6.92 (s, 1H), 7.19 (s, 1H), 7.20-7.35 (m, ˜15H), 8.10 (dd, 1H).

Step 2: 3-[(2-tert-Butyl-4-chloro-5-methyl-phenoxy)methyl]-6-(2-tetrahydropyran-2-yloxyethoxy)-1-trityl-pyrazolo[3,4-b]pyridine

(606) ##STR00555##

(607) Sodium hydride (7.68 mg, 55% in mineral oil) was suspended in DMA (1 mL). Then, a solution of 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (25.7 mg, 23.9 μL, CAS: 2162-314) in DMA (1.5 mL) was added dropwise at 0° C. and the resulting suspension was stirred at rt for 30 min. Then, a white turbid solution of 3-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-6-fluoro-1-trityl-pyrazolo[3,4-b]pyridine (83.2 mg) in DMA (1.5 ml) was added dropwise and the reaction mixture was stirred at rt for 3 h. The mixture was carefully diluted with water and was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by flash chromatography (10 g silica gel; heptane/EtOAc 98/2-95/5) to obtain the title compound (91 mg, 90%) as a colorless oil. .sup.1H-NMR (300 MHz, CDCl.sub.3): 1.29 (s, ˜9H); 1.45-1.88 (m, ˜6H), 2.24 (s, 3H), 3.35-3.51 (m, 2H), 3.60-3.70 (m, 1H), 3.75-3.88 (m, 2H), 4.50 (m, 1H), 5.30 (s, 2H), 6.50 (d, 1H, J=8.4), 6.94 (s, 1H), 7.18 (s, 1H), 7.20-7.30 (m, ˜15H), 7.86 (d, 1H, J=8.7).

Step 3: 2-[[3-[(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-b]pyridin-6-yl]oxy]ethanol

(608) ##STR00556##

(609) To a solution of 3-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-6-(2-tetrahydropyran-2-yloxyethoxy)-1-trityl-pyrazolo[3,4-b]pyridine (83.8 mg) in DCM (1.5 mL) was added trifluoroacetic acid (0.4 mL) dropwise and the mixture was stirred at rt for 30 min. The reaction mixture was diluted with DCM and was carefully added to saturated Na.sub.2CO.sub.3 solution. The resulting mixture was extracted with DCM and the combined extracts were washed with saturated Na.sub.2CO.sub.3 solution and brine, dried over Na.sub.2SO.sub.4, and evaporated. The residue was purified by chromatography (10 g silica gel; heptane/EtOAc 90/10-50/50) to obtain the title compound (36 mg, 79%) as white solid. MS (ESI): m/z=390.2 [M+H].sup.+.

Example D15

3-[[3-[(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-b]pyridin-6-yl]oxy]propane-1,2-diol

(610) ##STR00557##

(611) The title compound was prepared from 3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-6-fluoro-1H-pyrazolo[3,4-b]pyridine (example D6) in analogy to example D13 using (2,2-dimethyl-1,3-dioxolan-4-yl)methanol instead of 2-(tetrahydro-2H-pyran-2-yloxy)ethanol in step 2 and was obtained as a white solid. MS (ESI): m/z=420.2 [M+H].sup.+.

Example D17

[3-[5-Chloro-4-methyl-2-(1H-pyrazolo[3,4-b]pyridin-3-ylmethoxy)phenyl]phenyl]-morpholin-4-ylmethanone

(612) ##STR00558##

(613) A suspension of Intermediate B10 (40.1 mg), tert-butyl 3-(bromomethyl)pyrazolo[3,4-b]pyridine-1-carboxylate (37.8 mg, CAS: 174180-76-8) and potassium carbonate (41.7 mg) in acetone (1.5 mL) was heated to 50° C. for 5.5 h. The reaction mixture was cooled to rt, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was dissolved in DCM (2 mL) and trifluoroacetic acid (0.2 mL) was added and the solution was stirred at rt for 2 h. The reaction mixture was quenched carefully by addition of saturated Na.sub.2CO.sub.3 solution and was extracted with DCM. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by chromatography (10 g silica gel, heptane/EtOAc 70/30-0/100) to obtain the title compound (40 mg, 710) as white solid. MS (ESI): m/z=463.2[M+H].sup.+.

(614) The following examples were synthesized in analogy to Example D17.

(615) TABLE-US-00028 Ex. Systematic Name Building blocks MS, m/z D1 tert-butyl 3-(bromomethyl)- 1H-indazole-1-carboxylate (CAS 174180-42-8) and Intermediate A15 359.14 [M + H].sup.+ D19 0 tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS: 174180-76-8) and Intermediate B36 437.2 [M + H].sup.+ D20 tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS: 174180-76-8) and Intermediate B53 381.1 [M + H].sup.+ D21 tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS: 174180-76-8) and Intermediate B38 439.2 [M + H].sup.+ D22 tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS: 174180-76-8) and Intermediate B40 481.2 [M + H].sup.+ D23 tert-butyl 3- (bromomethyl)pyrazolo[4,3- b]pyridine-1-carboxylate (CAS: 194278-49-4, prepared according to J. Med. Chem. 1997, 40, 2709) and 2-tert-butyl-4-chloro-5- methyl-phenol (CAS: 30894-16-7) 330.2 [M + H].sup.+ D24 tert-butyl 3- (bromomethyl)pyrazolo[4,3- b]pyridine-1-carboxylate (CAS: 194278-49-4) and Intermediate B12 421.2 [M + H].sup.+ D25 tert-butyl 3- (bromomethyl)pyrazolo[4,3- b]pyridine-1-carboxylate (CAS: 194278-49-4) and Intermediate A2 334.2 [M + H].sup.+ D28 tert-butyl 3- (bromomethyl)pyrazolo[4,3- b]pyridine-1-carboxylate (CAS: 194278-49-4) and Intermediate B38 439.2 [M + H].sup.+ D48 tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS: 174180-76-8) and Intermediate A17 321.2 [M + H].sup.+

Example D26

2-[[3-[(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-methylamino]ethanol

(616) ##STR00569##

Step 1: 3-(2-tert-Butyl-4-chloro-5-methyl-phenoxymethyl)-1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-]pyrimidine

(617) ##STR00570##

(618) To a solution of 2-tert-butyl-4-chloro-5-methyl-phenol (851 mg, CAS: 30894-16-7) in anhydrous DMF (50 mL) were added Cs.sub.2CO.sub.3 (1.61 g) and TBAI (122 mg) at 25° C. and the reaction mixture was stirred at 25° C. for 15 min. Then, a solution of 3-bromomethyl-1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (1.26 g, Intermediate D26-B) in anhydrous DMF (10 mL) was added at 25° C. and the reaction mixture was stirred for 16 h at 25° C. The mixture was filtered and the filtrate was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (5-10% EtOAc in hexane) to afford the title compound (1.41 g, 86%) as an off white solid. MS (ESI): m/z=497.1 [M+H].sup.+.

Step 2: 3-(2-tert-Butyl-4-chloro-5-methyl-phenoxymethyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine

(619) ##STR00571##

(620) A solution of 3-(2-tert-butyl-4-chloro-5-methyl-phenoxymethyl)-1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-]pyrimidine (1.4 g) in 30% HBr in AcOH (30 mL) was heated to 80° C. for 2 h. The reaction mixture was cooled to 25° C., diluted with EtOAc and washed with saturated NaHCO.sub.3 solution and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (15-50% EtOAc in hexane) to afford the title compound (750 mg, 71%) as an off white solid. MS (ESI): m/z=377.2 [M+H].sup.+.

Step 3: 3-(2-tert-Butyl-4-chloro-5-methyl-phenoxymethyl)-6-methanesulfonyl-1H-pyrazolo[3,4-d]pyrimidine

(621) ##STR00572##

(622) To a solution of 3-(2-tert-butyl-4-chloro-5-methyl-phenoxymethyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (750 mg) in anhydrous THF (100 mL) was added m-CPBA (1.03 g) at 25° C. and the reaction mixture was stirred at 25° C. for 16 h. The mixture was diluted with EtOAc and washed with saturated aqueous sodium thiosulphate solution and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The resulting residue was purified by column chromatography over silica gel (30-50% EtOAc in hexane) to afford the title compound (580 mg, 71%) as an off white solid. MS (ESI): m/z=409.3 [M+H].sup.+.

Step 4: 2-{[3-(2-tert-Butyl-4-chloro-5-methyl-phenoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-methyl-amino}-ethanol

(623) ##STR00573##

(624) To a solution of 3-(2-tert-butyl-4-chloro-5-methyl-phenoxymethyl)-6-methanesulfonyl-1H-pyrazolo[3,4-d]pyrimidine (45 mg) in dioxane (10 mL) at 25° C. were added 2-methylaminoethanol (24.82 mg) followed by Et.sub.3N (0.03 mL) and the reaction mixture was heated to reflux for 3 h. The mixture was cooled to 25° C. and all volatiles were removed under reduced pressure. The residue was purified by column chromatography over silica gel (60-70% EtOAc in hexane) to afford the title compound (12 mg, 27%) as an off white solid. MS (ESI): m/z=404.4 [M+H].sup.+.

(625) The following examples were synthesized in analogy to example D26 from 3-(2-tert-butyl-4-chloro-5-methyl-phenoxymethyl)-6-methanesulfonyl-1H-pyrazolo[3,4-d]pyrimidine (example D26, step 3) under similar reaction conditions as described in example D26, step 4, with a suitable amine reagent:

(626) TABLE-US-00029 Ex. Systematic Name Amine reagent MS, m/z D27 3-methylamino-propane-1,2- diol 434.2 [M + H].sup.+ D29 3-(hydroxy)azetidine hydrochloride 402.3 [M + H].sup.+ D30 2-amino-ethanol 390.4 [M + H].sup.+

Example D31

2-[[3-[(2-tert-Butyl-4-chloro-&-methylphenoxy)methyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl]oxy]ethanol

(627) ##STR00577##

(628) A mixture of 3-(2-tert-butyl-4-chloro-5-methyl-phenoxymethyl)-6-methanesulfonyl-1H-pyrazolo[3,4-d]pyrimidine (150 mg, example D26, step 3), ethane-1,2-diol (1 mL) and Et.sub.3N (0.103 mL) was heated to 100° C. for 6 h. The reaction mixture was cooled to 25° C., diluted with EtOAc and washed with water and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the title compound (29 mg, 20%) as off white solid. MS (ESI): m/z=391.2 [M+H].sup.+.

Example D32

5-tert-Butyl-4-[[6-(3-hydroxyazetidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]methoxy]-2-methylbenzonitrile

(629) ##STR00578##

Step 1: 5-tert-Butyl-4-[1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy]-2-methyl-benzonitrile

(630) ##STR00579##

(631) The title compound was prepared in analogy to example D26, step 1 from 3-bromomethyl-1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (400 mg. Intermediate D26-B) and 5-tert-butyl-4-hydroxy-2-methyl-benzonitrile (259.31 mg, Intermediate A16) and was obtained as off white solid (450 mg, 87%). MS (ESI): m/z=488.5 [M+H].sup.+.

Step 2: 5-tert-Butyl-2-methyl-4-(6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy)-benzonitrile

(632) ##STR00580##

(633) The title compound was prepared in analogy to example D26, step 2 from 5-tert-butyl-4-[1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy]-2-methyl-benzonitrile (450 mg) and was obtained as an off white solid (225 mg, 66%). MS (ESI): m/z=368.2 [M+H].sup.+.

Step 3: 5-tert-Butyl-4-(6-methanesulfonyl-1-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy)-2-methyl-benzonitrile

(634) ##STR00581##

(635) The title compound was prepared in analogy to example D26, step 3, from 5-tert-butyl-2-methyl-4-(6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy)-benzonitrile (700 mg) and was obtained as an off white solid (580 mg, 76%). MS (ESI): m/z=400.2 [M+H].sup.+.

Step 4: 5-tert-Butyl-4-[[6-(3-hydroxyazetidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]methoxy]-2-methylbenzonitrile

(636) ##STR00582##

(637) The title compound was prepared in analogy to example D26, step 4, from 5-tert-butyl-4-(6-methanesulfonyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy)-2-methyl-benzonitrile (100 mg) and 3-(hydroxy)azetidine hydrochloride (82.0 mg) and was obtained as an off white solid (35 mg, 36%). MS (ESI): m/z=393.3 [M+H].sup.+.

(638) The following examples were synthesized in analogy to example D32 from 5-tert-butyl-4-(6-methanesulfonyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy)-2-methyl-benzonitrile (example D32, step 3) under similar reaction conditions as described in example D26, step 4, with a suitable amine reagent:

(639) TABLE-US-00030 Ex. Systematic Name Amine reagent MS, m/z D33 2-methylamino-ethanol 425.2 [M + H].sup.+ D35 2-amino-ethanol 381.2 [M + H].sup.+ D36 3-methylamino-propane-1,2-diol 395.4 [M + H].sup.+

Example D34

3-[[3-[(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl]oxy]propane-1,2-diol

(640) ##STR00586##

Step 1: 3-(2-tert-Butyl-4-chloro-5-methyl-phenoxymethyl)-6-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidine

(641) ##STR00587##

(642) A mixture of 3-(2-tert-butyl-4-chloro-5-methyl-phenoxymethyl)-6-methanesulfonyl-1H-pyrazolo[3,4-d]pyrimidine (150 mg, example D26, step 3), (2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (1 mL) and Et.sub.3N (0.103 mL) was heated to 100° C. for 3 h. The reaction mixture was cooled to 25° C. and all volatiles were evaporated under reduced pressure. The residue was diluted with EtOAc and the organic phase was washed water and brine. The organic layer was dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the title compound that was used in the next reaction step without further purification. MS (ESI): m/z=461.1 [M+H].sup.+.

Step 2: 3-[3-(2-tert-Butyl-4-chloro-5-methyl-phenoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yloxy]-propane-1,2-diol

(643) ##STR00588##

(644) A solution of 3-(2-tert-butyl-4-chloro-5-methyl-phenoxymethyl)-6-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidine (135 mg) in 2N aqueous HCl (15 mL) was stirred at 25° C. for 16 h. The reaction mixture was diluted with DCM and the organic layer was separated, washed with saturated aqueous NaHCO.sub.3 solution and brine, dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure. The residue was purified by HPLC to afford the title compound (36 mg, 29%) as an off white solid. MS (ESI): m/z=421.2 [M+H].sup.+.

Example D37

5-tert-Butyl-4-[[6-(2,3-dihydroxypropoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]methoxy]-2-methylbenzonitrile

(645) ##STR00589##

(646) The title compound was prepared in analogy to example D34, steps 1 and 2, from 5-tert-butyl-4-(6-methanesulfonyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy)-2-methyl-benzonitrile (150 mg, example D32, step 3) and was obtained as an off white solid (26 mg, 18%). MS (ESI): m/z=412.2 [M+H].sup.+.

Example D38

5-tert-Butyl-4-[[6-(2-hydroxyethoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]methoxy]-2-methylbenzonitrile

(647) ##STR00590##

(648) The title compound was prepared in analogy to example D31 from 5-tert-butyl-4-(6-methanesulfonyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy)-2-methyl-benzonitrile (105 mg, example D32, step 3) and was obtained as an off white solid (16 mg, 16%). MS (ESI): m/z=382.2 [M+H].sup.+.

Example D44

4-[3-[5-Chloro-4-methyl-2-(1H-pyrazolo[3,4-c]pyridin-3-ylmethoxy)phenyl]-4-fluorobenzoyl]-1-methylpiperazin-2-one

(649) ##STR00591##

Step 1: 4-[3-[5-Chloro-4-methyl-2-[(1-tritylpyrazolo[3,4-c]pyridin-3-yl)methoxy]phenyl]-4-fluorobenzoyl]-1-methylpiperazin-2-one

(650) ##STR00592##

(651) In a 20 mL round-bottomed flask, 4-(5′-chloro-6-fluoro-2′-hydroxy-4′-methyl-[1,1′-biphenyl]-3-carbonyl)-1-methylpiperazin-2-one (Intermediate B65, 50 mg), 3-(chloromethyl)-1-trityl-1H-pyrazolo[3,4-c]pyridine (Intermediate D44-B, 54.4 mg) and potassium carbonate (40.3 mg) were combined with acetone (6 mL) to give a white suspension. The mixture was then heated to 50° C. and was stirred for 4 h, but no reaction could be observed. Therefore, acetone was removed in vacuo and acetonitrile (6 mL) and cesium carbonate (95 mg) were added. The mixture was then heated again at 80° C. for 4 hours. The solvent was removed in vacuo and to the light brown residue was added saturated aqueous NH.sub.4Cl solution. The mixture was extracted 3 times with ethyl acetate and the combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give a light brown foam. The crude material was purified by flash chromatography (silica gel, 20 g, gradient of 0% to 100% ethyl acetate in heptane, followed by 0% to 10% MeOH in DCM) to afford the title compound as a colorless foam (53 mg). MS (m/z): 750.26 [M+H].sup.+.

Step 2: 4-[3-[5-Chloro-4-methyl-2-(1H-pyrazolo[3,4-c]pyridin-3-ylmethoxy)phenyl]-4-fluorobenzoyl]-1-methylpiperazin-2-one

(652) ##STR00593##

(653) In a 10 mL round-bottomed flask, 4-(5′-chloro-6-fluoro-4′-methyl-2′-((1-trityl-1H-pyrazolo[3,4-c]pyridin-3-yl)methoxy)-[1,1′-biphenyl]-3-carbonyl)-1-methylpiperazin-2-one (50 mg) was dissolved in CH.sub.2Cl.sub.2 (2.9 mL) to give a colorless solution. TFA (444 μL) was added at rt and the reaction mixture was stirred for 30 min TLC analysis confirmed the consumption of the starting material and formation of a single product. The reaction was then quenched by careful addition of sat. Na.sub.2CO.sub.3 solution. The mixture was extracted with DCM (2×25 mL) and the combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, and evaporated to provide the title compound as a colorless foam (27.0 mg). MS (m/z): 508.15 [M+H].sup.+.

(654) The following examples were synthesized from the suitable building blocks/intermediates in analogy to example D44, Steps 1-2:

(655) TABLE-US-00031 Building block/ Ex. Systematic Name intermediates MS, m/z D46 Intermediate D44-B and Intermediate B64 483.3 [M + H].sup.+ D47 Intermediate D44-B and Intermediate B53 381.2 [M + H].sup.+ D49 Intermediate D44-B and Intermediate A17 321.2 [M + H].sup.+

(656) The following additional examples of type D were synthesized from the suitable building blocks/intermediates in analogy to Example D44, Steps 1-2:

(657) TABLE-US-00032 Building block/ Ex. Systematic Name intermediates MS, m/z D50 Intermediate D44-B and Intermediate A34 341.2 [M + H].sup.+ D51 Intermediate D44-B and Intermediate B95 435.2 [M + H].sup.+ D54 Intermediate D54-B and Intermediate B97 463.1 [M + H].sup.+

(658) The following additional examples of type D were synthesized from the suitable building blocks/intermediates in analogy to Example D17:

(659) TABLE-US-00033 D52 00 tert-butyl 3-(bromomethyl)- pyrazolo[3,4-b]pyridine-1- carboxylate (CAS: 174180-76-8) and Intermediate A34 341.2 [M + H].sup.+ D53 01 tert-butyl 3-(bromomethyl)- pyrazolo[3,4-b]pyridine-1- carboxylate (CAS: 174180-76-8) and Intermediate B95 435.1 [M + H].sup.+ D55 02 tert-butyl 3-(bromomethyl)- pyrazolo[3,4-b]pyridine-1- carboxylate (CAS: 174180-76-8) and Intermediate B97 463.1 [M + H].sup.+

Examples E: Examples Related to Tetrahdro-Pyrazolopyridine Head Groups

Example E1

tert-Butyl 3-((2-tert-butyl-4-chloro-5-methylphenoxy)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

(660) ##STR00603##

Step 1: 5-tert-Butyl 3-ethyl 6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-3,5(4H)-dicarboxylate

(661) ##STR00604##

(662) Di-tert-butyl-dicarbonate (1.04 g) was added to a suspension of ethyl 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (930 mg, CAS: 926926-62-7) in diethyl ether (45 mL) at 0° C. Following addition of the reagents, the reaction mixture was stirred at rt overnight. Water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by column chromatography (50 g silica gel; heptane/EtOAc 70/30-45/55) to obtain the title compound as a white foam (1.079 g, 77%). MS (ESI): m/z=294.2 [M−H].sup.−.

Step 2: tert-Butyl 3-(hydroxymethyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

(663) ##STR00605##

(664) A solution of 5-tert-butyl 3-ethyl 6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-3,5(4H)-dicarboxylate (60.0 mg) in THF (0.5 mL) was added dropwise at 0° C. to a white suspension of calcium chloride (90.1 mg) and sodium borohydride (61.4 mg) in a mixture of EtOH (1 mL) and THF (0.5 mL). The resulting white suspension was stirred at 0° C. overnight. Then, 0.1N HCl was added carefully and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by column chromatography (5 g silica gel; DCM/MeOH 98/2-95/5) to afford the title compound as a white solid (47 mg, 92%). MS (ESI): m/z=254.2 [M+H].sup.+.

Step 3: tert-Butyl 3-(chloromethyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

(665) ##STR00606##

(666) tert-Butyl 3-(hydroxymethyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (94.0 mg) was suspended in a mixture of DCM (1 mL), acetonitrile (1 mL) and THF (1 mL). Triphenylphosphine (102 mg) and carbon tetrachloride (285 mg, 179 μL) were added to the white suspension and the mixture was stirred at rt. After awhile the reaction mixture turned into a colorless solution, which was stirred at rt for 2 d. Additional carbon tetrachloride (285 mg, 179 μL) was added and the solution was stirred for 1 more day at rt. Then, the mixture was concentrated to dryness and the residue was purified by column chromatography (20 g silica gel; DCM/MeOH 98/2-90/10) to obtain the title compound as white solid (37 mg, 35%). MS (ESI): m/z=272.2 [M+H].sup.+.

Step 4: tert-Butyl 3-((2-tert-butyl-4-chloro-5-methylphenoxy)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

(667) ##STR00607##

(668) A mixture of tert-butyl 3-(chloromethyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (45.1 mg), 2-tert-butyl-4-chloro-5-methyl-phenol (82.5 mg, CAS: 30894-16-7) and potassium carbonate (57.4 mg) in acetonitrile (2 mL) was heated to reflux for 5 h. The reaction mixture was cooled to rt and was then concentrated. The residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The remaining oil was purified by column chromatography (10 g silica gel; heptane/EtOAc 70/30-10/90) to afford the title compound as a white solid (19 mg, 26%). MS (ESI): m/z=434.3 [M+H].sup.+.

Example E2

1-(3-((2-tert-Butyl-4-chloro-5-methylphenoxy)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

(669) ##STR00608##

Step 1: 5-tert-Butyl 3-ethyl 1-trityl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate and 5-tert-Butyl 3-ethyl 2-trityl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate

(670) ##STR00609##

(671) A solution of 5-tert-butyl 3-ethyl 6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-3,5(4H)-dicarboxylate (1.17 g. example E1, step 1) in DMF (7 mL) was added dropwise to a suspension of sodium hydride (216 mg, 55% in mineral oil) in DMF (7 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min and then at rt for 30 min. The mixture was then again cooled to 0° C. and a solution of [chloro(diphenyl)methyl]benzene (1.16 g) in DMF (7 mL) was added. The resulting suspension was stirred at rt for 2 d. Water was added carefully and the mixture was extracted with EtOAc. The combined extracts were washed with water (3 times) and brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by column chromatography (120 g silica gel; heptane/EtOAc 95/5-25/75) to obtain 5-tert-butyl 3-ethyl 1-trityl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (off white solid, 790 mg, 37%. MS (ESI): m/z=560.4 [M+Na].sup.+) as well as 5-tert-butyl 3-ethyl 2-trityl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (white solid, 450 mg, 21%). MS (ESI): m/z=560.4 [M+Na].sup.+).

Step 2: tert-Butyl 3-(hydroxymethyl)-1-trityl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

(672) ##STR00610##

(673) To a solution of 5-tert-butyl 3-ethyl 1-trityl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (200 mg) in THF (3 mL) was added dropwise diisobutylaluminum hydride (818 μL, 1M in toluene) at 0° C. After the addition, the colorless solution was stirred at rt overnight. 0.5 mL MeOH were added with vigorous stirring and the resulting solution was poured into a mixture of 20 mL 10 wt % Rochelle-salt solution and 20 mL EtOAc. This mixture was stirred at rt for 1 h and the layers were then separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by column chromatography (20 g silica gel; heptane/EtOAc 80/20-50/50) to obtain the title compound as a white solid (156 mg, 85%). MS (ESI): m/z=518.4 [M+Na].sup.+).

Step 3: tert-Butyl 3-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-1-trityl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

(674) ##STR00611##

(675) To a solution of tert-butyl 3-(hydroxymethyl)-1-trityl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100 mg) in 2-methyltetrahydrofuran (1 mL) was added triethylamine (22.5 mg, 30.9 μL) at 0° C. To this mixture was added dropwise methanesulfonyl chloride (24.3 mg, 16.5 μL) and the resulting mixture was stirred at 0° C. for 1 h. A white solid precipitated which was filtered off and washed with 2-methyltetrahydrofuran. The filtrate was concentrated and the remaining colorless oil was dissolved in DMA (0.5 mL) and the resulting solution was added dropwise to a suspension of 2-tert-butyl-4-chloro-5-methyl-phenol (40.1 mg, CAS: 30894-16-7), potassium iodide (56.9 mg) and cesium fluoride (153 mg) in DMA (1 mL). The reaction mixture was stirred at rt overnight. Water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with water (3 times) and brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by column chromatography (20 g silica gel; heptane/EtOAc 98/2-50/50) to obtain the title compound as an off white solid (49 mg, 36%). MS (ESI): m/z=674.5 [M−H].sup.−.

Step 4: 3-[(2-tert-Butyl-4-chloro-5-methyl-phenoxy)methyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

(676) ##STR00612##

(677) Trifluoroacetic acid (0.2 mL) was added to a solution of tert-butyl 3-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-1-trityl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (47.0 mg) in DCM (1 mL) at rt. After 30 min, saturated Na.sub.2CO.sub.3 solution was added carefully and the mixture was extracted with DCM. The combined extracts were washed with a small amount of brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by column chromatography (5 g silica gel; DCM/MeOH 95/5-85/15) to obtain the title compound as a white solid (18 mg, 78%). MS (ESI): m/z=334.2 [M+H].sup.+.

Step 5: 1-(3-((2-tert-Butyl-4-chloro-5-methylphenoxy)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

(678) ##STR00613##

(679) A mixture of 3-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (15.0 mg), triethylamine (9.09 mg, 12.5 μL) and acetyl chloride (3.52 mg, 3.19 μL) in THF (0.5 mL) was stirred at rt overnight. Then, water was added and the mixture was extracted with EtOAc and then with DCM. The combined extracts were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by column chromatography (5 g silica gel; DCM/MeOH 19/1) to obtain the title compound as a white solid (13 mg, 77%). MS (ESI): m/z=376.2 [M+H].sup.+.

Example E3

1-(3-((2-tert-Butyl-4-chloro-5-methylphenoxy)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)-2-methoxyethanone

(680) ##STR00614##

(681) The title compound was prepared in analogy to example E2, step 5, from 3-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (15.0 mg) and 2-methoxyacetyl chloride (5.11 mg, 4.27 μL) and was obtained as a white solid (13 mg, 71%). MS (ESI): m/z=406.3 [M+H].sup.+.

Example E4

3-((2-tert-Butyl-4-chloro-5-methylphenoxy)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine

(682) ##STR00615##

Step 1: tert-Butyl 4-(1-diazo-2-ethoxy-2-oxo-ethyl)-4-hydroxy-piperidine-1-carboxylate

(683) ##STR00616##

(684) A lithium diisopropylamide solution was prepared by dropwise addition of nBuLi (19.1 mL, 1.6 M in hexane) to a solution of diisopropylamine (3.12 g, 4.4 mL) in dry THF (77 mL) at −78° C. This lithium diisopropylamide solution was then added dropwise over 1 hour to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (3.854 g) and ethyl diazoacetate (2.31 g, 2.1 mL) in dry THF (115 mL) at −78° C. The mixture was stirred for 2 hours at −78° C. Then, AcOH (5.81 g, 5.54 mL) was added at −78° C. and the mixture was then kept at rt overnight. The solvent was removed under reduced pressure to approx. 1/10 of its volume and diethyl ether (400 mL) was added. The mixture was washed with saturated NaHCO.sub.3 solution and was then dried over Na.sub.2SO.sub.4, filtered and evaporated. The remaining orange-brown viscous oil (6.46 g) was used without further analysis in the next reaction step.

Step 2: tert-Butyl 4-(1-diazo-2-ethoxy-2-oxo-ethyl)-3,6-dihydro-2H-pyridine-1-carboxylate

(685) ##STR00617##

(686) Pyridine (30.5 g, 31.2 mL) was added to a solution of tert-butyl 4-(1-diazo-2-ethoxy-2-oxo-ethyl)-4-hydroxy-cyclohexanecarboxyate (6.05 g) in MTBE (120 mL). The mixture was cooled to −10° C. and phosphorus oxychloride (5.92 g, 3.6 mL) was added dropwise over 8 minutes under vigorous stirring. The mixture was slowly warmed to rt and was stirred overnight. The mixture was cooled again to −10° C. and more phosphorus oxychloride (592 mg, 360 μL) was added dropwise. The reaction mixture was slowly warmed to rt and stirred for 3 h before 0.1M NaOH (193 mL) was added slowly. The mixture was extracted with EtOAc and the combined extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue (6.2 g) was used in the next reaction step without further purification. MS (ESI): m/z=294.2 [M−H].sup.−.

Step 3: 6-tert-Butyl 3-ethyl 1,4,5,7-tetrahydropyrazolo[3,4-c]pyridine-3,6-dicarboxylate

(687) ##STR00618##

(688) In a two-neck flask equipped with a dropping funnel and a distillation column, toluene (80 mL) was heated to reflux. A solution of tert-butyl 4-(1-diazo-2-ethoxy-2-oxo-ethyl)-3,6-dihydro-2H-pyridine-1-carboxylate (5.7 g) in a mixture of EtOAc (20 mL) and pyridine (8 mL) was added via the dropping funnel at the same rate as the rate of distillation. More toluene (7 mL) was added. The dark brown mixture was stirred for an hour and was then allowed to cool to rt. EtOAc (250 mL) was added and the mixture was washed with water (3 times) and brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude material was purified by column chromatography (50 g silica gel; heptane/EtOAc 9/1 to 1/1) to obtain the title compound as light brown solid (3.12 g, 55%). MS (ESI): m/z=294.2 [M−H].sup.−.

Step 4: 6-tert-Butyl 3-ethyl 1-trityl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-3,6-dicarboxylate and 6-tert-Butyl 3-ethyl 2-trityl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-3,6-dicarboxylate

(689) ##STR00619##

(690) In analogy to example E2, step 1, 6-tert-butyl 3-ethyl 1,4,5,7-tetrahydropyrazolo[3,4-c]pyridine-3,6-dicarboxylate (980 mg) was converted into 6-tert-butyl 3-ethyl 1-trityl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-3,6-dicarboxylate (white solid, 762 mg, 43%, MS (ESI): m/z=1097.8 [2M+Na].sup.+) and 6-tert-butyl 3-ethyl 2-trityl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-3,6-dicarboxylate (white solid, 510 mg, 290%). MS (ESI): m/z=560.4 [M+Na].sup.+).

Step 5: tert-Butyl 3-(hydroxymethyl)-1-trityl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate

(691) ##STR00620##

(692) From 6-tert-butyl 3-ethyl 1-trityl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-3,6-dicarboxylate (715 mg) the title compound was obtained in analogy to example E2, step 2, as a white solid (581 mg, 88%). MS (ESI): m/z=496.3 [M+H].sup.+.

Step 6: tert-Butyl 3-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-1-trityl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate

(693) ##STR00621##

(694) From tert-butyl 3-(hydroxymethyl)-1-trityl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (100 mg) the title compound was obtained in analogy to example E2, step 3, as a light yellow foam (58 mg, 43%). MS (ESI): m/z=698.5 [M+Na].sup.+.

Step 7: 3-((2-tert-Butyl-4-chloro-5-methylphenoxy)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine

(695) ##STR00622##

(696) From tert-butyl 3-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-1-trityl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (75.7 mg) the title compound was obtained in analogy to example E2, step 4, as a light yellow solid (29 mg, 78%). MS (ESI): m/z=334.2 [M+H].sup.+.

Example E5

1-(3-((2-tert-Butyl-4-chloro-5-methylphenoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)ethanone

(697) ##STR00623##

(698) The title compound was prepared in analogy to example E2, step 5, from 3-((2-tert-butyl-4-chloro-5-methylphenoxy)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (25.0 mg example 4) and acetyl chloride (5.88 mg, 5.33 μL) and was obtained as a white solid (19 mg, 67%). MS (ESI): m/z=376.2 [M+H].sup.+.

Example E6

1-(3-((2-tert-Butyl-4-chloro-5-methylphenoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-2-methoxyethanone

(699) ##STR00624##

(700) The title compound was prepared in analogy to example E2, step 5, from 3-((2-tert-butyl-4-chloro-5-methylphenoxy)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (22.0 mg, example 4) and 2-methoxyacetyl chloride (7.51 mg, 6.27 μL) and was obtained as a white solid (17 mg, 64%). MS (ESI): m/z=406.2 [M+H].sup.+.

Example E7

3-((4-Chloro-2-(2-methoxypyridin-3-yl)-5-methylphenoxy)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine

(701) ##STR00625##

(702) Triethylamine (26.9 mg, 37.1 μL) was added to a solution of tert-butyl 3-(hydroxymethyl)-1-trityl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (120 mg, obtained in example E4, step 5) in 2-methyltetrahydrofuran (1.5 mL) at 0° C. To the mixture was added dropwise methanesulfonyl chloride (29.1 mg, 19.7 μL) and the resulting mixture was stirred at 0° C. for 1 h. The suspension was then filtered, the filtercake was washed with 2-methyltetrahydrofuran and the filtrate was concentrated. The residue was dissolved in DMA (1.5 mL) and this solution was added dropwise to a suspension of 4-chloro-2-(2-methoxy-3-pyridyl)-5-methyl-phenol (60.4 mg. Intermediate B53), potassium iodide (68.2 mg) and cesium fluoride (184 mg) in DMA (1.5 mL) and the reaction mixture was stirred at rt overnight. Then, water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with water (3 times) and brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by column chromatography (20 g silica gel; heptane/EtOAc 90/10-50/50) to obtain a yellow foam (81 mg) that was dissolved in a mixture of DCM (2 mL) and trifluoroacetic acid (0.2 mL). This mixture was stirred at rt for 1 h. Then, saturated Na.sub.2CO.sub.3 solution was added carefully and the mixture was extracted with DCM. The combined organic layers were washed with a very small amount of brine, dried over Na.sub.2SO.sub.4 and evaporated. The remaining residue was purified by column chromatography (5 g silica gel; DCM/MeOH 95/5+DCM/MeOH/NH.sub.4OH 8/1.9/0.1) to obtain the title compound as a white foam (21 mg, 23%). MS (ESI): m/z=385.2 [M+H].sup.+.

Example E8

1-(3-((4-Chloro-2-(2-methoxypyridin-3-yl)-5-methylphenoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)ethanone

(703) ##STR00626##

(704) The title compound was prepared in analogy to example E2, step 5, from 3-((4-chloro-2-(2-methoxypyridin-3-yl)-5-methylphenoxy)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (25.0 mg, example E7) and acetyl chloride (5.88 mg, 5.33 μL) and was obtained as a white solid (8 mg, 42%). MS (ESI): m/z=427.2 [M+H].sup.+.

Examples F: Examples Related to Pyrazole Head Groups

Example F1

3-((2-tert-Butyl-4-chloro-5-methylphenoxy)methyl)-1H-pyrazole

(705) ##STR00627##

Step 1: tert-Butyl 3-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]pyrazole-1-carboxylate

(706) ##STR00628##

(707) A mixture of tert-butyl 3-(bromomethyl)pyrazole-1-carboxylate (65.8 mg, Intermediate F1), 2-tert-butyl-4-chloro-5-methyl-phenol (50 mg. CAS: 30894-16-7) and potassium carbonate (87.1 mg) in acetone (5 mL) was heated to 50° C. After 6 h and after 7.5 h, more 2-tert-butyl-4-chloro-5-methylphenol (10 mg and 22 mg, respectively) was added and heating was continued for 4 h. Sat. NH.sub.4Cl solution was added and the mixture was extracted with EtOAc. The combined extracts were washed with brine, dried with Na.sub.2SO.sub.4 and evaporated. The residue was purified by column chromatography (20 g SiO.sub.2, n-heptane/EtOAc 100/0 to 65/35) to obtain the title compound (71 mg, 74%) as colorless oil. MS (ESI): m/z=279.2 [M-CO.sub.2tBu+H].sup.+.

Step 2: 3-((2-tert-Butyl-4-chloro-5-methylphenoxy)methyl)-1H-pyrazole

(708) ##STR00629##

(709) A solution of tert-butyl 3-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]pyrazole-1-carboxylate (65 mg) in a mixture of DCM (1 mL) and TFA (1 mL) was stirred at rt for 4 h. Then, saturated NaHCO.sub.3 solution was added and the mixture was extracted with EtOAc. The combined extracts were washed with brine, dried with Na.sub.2SO.sub.4 and evaporated to provide the title compound (47 mg, 98%) as a colorless viscous oil. MS (ESI): m/z=279.2 [M+H].sup.+.

Example F2

4-((1H-Pyrazol-3-yl)methoxy)-5-tert-butyl-2-methylbenzonitrile

(710) ##STR00630##

(711) The title compound was prepared in analogy to example F1, steps 1 and 2, from tert-butyl 3-(bromomethyl)pyrazole-1-carboxylate (Intermediate F1) and 5-tert-butyl-4-hydroxy-2-methyl-benzonitrile (Intermediate A16) and was obtained as white foam. MS (ESI): m/z=270.2 [M+H].sup.+.

Example F3

Methyl 3-((2-(tert-butyl)-4-chloro-5-methylphenoxy)methyl)-1H-pyrazole-5-carboxylate

(712) ##STR00631##

Step 1: Methyl 5-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-2-tetrahydropyran-2-yl-pyrazole-3-carboxylate

(713) ##STR00632##

(714) Triethylamine (29 mg, 40 μL) was added to a solution of methyl 5-(hydroxymethyl)-2-tetrahydropyran-2-yl-pyrazole-3-carboxylate (63 mg, Intermediate F3) in 2-methyltetrahydrofuran (1.5 mL) at 0° C. Then, methanesulfonyl chloride (30.9 mg, 21 μL) was added dropwise and the reaction mixture was stirred at 0° C. for 2 h. The white precipitate was filtered off and was washed with 2-methyltetrahydrofuran. The filtrate was concentrated and the residue was suspended in DMA (2.4 mL) and added to a suspension of 2-tert-butyl-4-chloro-5-methyl-phenol (52 mg, CAS: 30894-16-7), potassium iodide (76 mg) and cesium fluoride (197 mg) in DMA (1.5 mL). The reaction mixture was stirred overnight at rt. Then, water was added and the mixture was extracted with EtOAc. The combined extracts were washed with water and brine, dried with Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified by chromatography (20 g silica gel; heptane/EtOAc 100/0 to 1/2) to provide the title compound (22 mg, 20%) as a waxy solid. MS (ESI): m/z=337.2 [M-THP+H].sup.+.

Step 2: Methyl 3-((2-(tert-butyl)-4-chloro-5-methylphenoxy)methyl)-1H-pyrazole-5-carboxylate

(715) ##STR00633##

(716) Methyl 5-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-2-tetrahydropyran-2-yl-pyrazole-3-carboxylate (22 mg) was suspended in MeOH (1 mL) and HCl (4 M in 1,4-dioxane, 70 μL) was added. The colorless solution was stirred at rt for 2 h before saturated NaHCO.sub.3 solution (5 mL) was added. The mixture was evaporated to half of its volume and was then extracted with EtOAc. The combined organic layers washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified by chromatography (10 g silica gel; heptane/EtOAc 100/0 to 70/30) to afford the title compound (16 mg, 91%) as a white powder. MS (EST): m/z=337.2 [M+H].sup.+.

Example F4

(3-((2-(tert-Butyl)-4-chloro-5-methylphenoxy)methyl)-1H-pyrazol-5-yl)(pyrrolidin-1-yl)methanone

(717) ##STR00634##

Step 1: [5-[(2-tert-Butyl-4-chloro-5-methyl-phenoxy)methyl]-2-tetrahydropyran-2-yl-pyrazol-3-yl]-pyrrolidin-1-yl-methanone

(718) ##STR00635##

(719) To a solution of pyrrolidine (12.9 mg, 15 μL) in DCM (0.3 mL) was added a 2M solution of trimethylaluminum in hexane (90 μL) dropwise at rt and the mixture was stirred for 15 minutes. Then, a solution of methyl 5-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-2-tetrahydropyran-2-yl-pyrazole-3-carboxylate (50 mg, example F3, step 1) in DCM (0.6 mL) was added slowly. The reaction mixture was heated to reflux overnight. The mixture was carefully diluted with 1 M HCl, extracted with DCM, and the combined organic layers were dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified by chromatography (20 g silica gel; heptane/EtOAc 100/0 to 1/1) to obtain the title compound (36 mg, 66%) as a colorless oil. MS (ESI): m/z=376.3 [M-THP+H].sup.+.

Step 2: (3-((2-(tert-Butyl)-4-chloro-5-methylphenoxy)methyl)-1H-pyrazol-5-yl)(pyrrolidin-1-yl)methanone

(720) ##STR00636##

(721) The title compound was prepared in analogy to example F3, step 2, from [5-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-2-tetrahydropyran-2-yl-pyrazol-3-yl]-pyrrolidin-1-ylmethanone (36 mg) and was obtained as a white solid (21 mg, 71%). MS (EST): m/z=376.3 [M+H].sup.+.

Example F

3-((2-(tert-Butyl)-4-chloro-5-methylphenoxy)methyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide

(722) ##STR00637##

(723) The title compound was prepared in analogy to example F4, steps 1 and 2, from methyl 5-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-2-tetrahydropyran-2-yl-pyrazole-3-carboxylate (example F3, step 1) and dimethylamine hydrochloride and was obtained as a white solid. MS (ESI): m/z=350.3 [M+H].sup.+.

Example F6

4-[(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl]-2H-triazole

(724) ##STR00638##

Step 1: 1-tert-Butyl-5-chloro-4-methyl-2-prop-2-ynoxybenzene

(725) ##STR00639##

(726) In a 25 mL round-bottomed flask, 2-(tert-butyl)-4-chloro-5-methylphenol (CAS: 30894-16-7, 200 mg), 3-bromoprop-1-yne (80% in toluene) (225 mg, 163 μL) and potassium carbonate (209 mg) were combined with CH.sub.3CN (4 mL) to give a white suspension. The reaction mixture was stirred for 15 h and was then concentrated in vacuo. The reaction mixture was poured into ethyl acetate (25 mL) and the organic layer was washed with H.sub.2O (1×10 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated in vacuo to provide the title compound (180 mg, 74%). MS (m/z): 236.1 [M].sup.+.

Step 2: 4-(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl-2H-triazole

(727) ##STR00640##

(728) In a 25 mL round-bottomed flask, 1-(tert-butyl)-5-chloro-4-methyl-2-(prop-2-yn-1-yloxy)benzene (180 mg) was combined with DMF (4 mL) and water (4 mL) to give a white suspension. Copper(II)sulfate pentahydrate (38 mg) and L-ascorbic acid sodium salt (304 mg) were added. The system was evacuated twice and flushed with nitrogen. Trimethylsilyl azide (746 mg) was added and the reaction mixture was heated to 90° C. for 2 h with stirring. The mixture was diluted with H.sub.2O (50 mL) and ethyl acetate (100 mL) and the layers were separated. The aqueous phase was extracted with more ethyl acetate (2×50 mL). The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give a crude oil. The crude material was purified by flash chromatography (20 g silica gel cartridge, 0% to 10% MeOH in CH.sub.2Cl.sub.2) to afford the title compound as a colorless foam (80 mg, 37%). MS (m/z): 280.2 [M+H].sup.+.

Example F7

3-[(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl]-5-phenyl-1H-pyrazole

(729) ##STR00641##

Step 1: 3-(Chloromethyl)-5-phenyl-1H-pyrazole

(730) ##STR00642##

(731) This known intermediate (CAS: 755700-32-4) was made from (5-phenyl-1H-pyrazol-3-yl)methanol which is commercially available (CAS: 179057-19-3), as follows: In a 25 mL round-bottomed flask, (5-phenyl-1H-pyrazol-3-yl)methanol (50 mg) was combined with CH.sub.2Cl.sub.2 (3 mL) and the mixture was cooled to 0° C. under an argon atmosphere. Then, thionyl chloride (68.3 mg, 41.6 μL) was added dropwise over a period of 2 minutes and after 30 minutes the ice bath was removed. The reaction mixture was allowed to stir at RT for another 2 hours. The mixture was poured into ice and NaHCO.sub.3 solution. The aqueous layer was then extracted twice with ethyl acetate and the organic layers where washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give a crude light yellow solid (55 mg, 95%) that was used without further purification. MS (m/z): 193.0 [M+H].sup.+.

Step 2: 3-(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl-5-phenyl-1H-pyrazole

(732) ##STR00643##

(733) 2-(tert-Butyl)-4-chloro-5-methylphenol (CAS: 30894-16-7, 62.4 mg), potassium carbonate (233 mg) and 3-(chloromethyl)-5-phenyl-1H-pyrazole (55 mg) were combined with acetonitrile (4 mL) at RT under an argon atmosphere. The reaction mixture was then heated to 50° C. for 16 hours, whereas TLC confirmed formation of some product. The reaction mixture was poured into ice/water and the aqueous layer was basified with 2M NaOH solution and was extracted twice with ethyl acetate. The organic layers were washed once with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude material was purified by flash chromatography (25 g silica gel cartridge, 0% to 40% ethyl acetate in heptane) to provide—besides some other unidentified materials—the title compound as a colorless solid (16 mg, 16%). MS (m/z): 355.2 [M+H].sup.+.

(734) The following examples of type F were synthesized from the suitable phenol building blocks/intermediates in analogy to Example F7, step 2:

(735) TABLE-US-00034 Inter- Building block/ mediate Systematic Name intermediate MS, m/z F8 5-tert-Butyl-2-methyl-4-[(5-phenyl-1H- pyrazol-3-yl)methoxylbenzonitrile 5-tert-Butyl-4-hydroxy-2- methylbenzonitrile Intermediate A16 346.2 [M + H].sup.+

Example A

(736) A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:

(737) TABLE-US-00035 Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg

Example B

(738) A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:

(739) TABLE-US-00036 Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg