ROR GAMMA (RORY) MODULATORS

Abstract

Compounds according to Formula I:

##STR00001##

or a pharmaceutically acceptable salt wherein: A.sub.1 is NR.sub.1 or CR.sub.1, with R.sub.1 herein; the cyclopropyl moiety with one or more methyl and one or more F; A.sub.2-A.sub.5 are N or CR.sub.2-CR.sub.5, with no more than two of the four positions A in A.sub.2-A.sub.5 can be simultaneously N; R.sub.2-R.sub.5 are described; R.sub.6 and R.sub.7 are independently H, F, methyl, ethyl, hydroxyl or methoxy or R.sub.6 and R.sub.7 together is carbonyl, all alkyl groups, if substituted with one or more F; R.sub.8 is H or C(1-6)alkyl; A.sub.9-A.sub.12 are N or CR.sub.9-CR.sub.12, with no more than two of the four positions A in A.sub.9-A.sub.12 can be simultaneously N; R.sub.9-R.sub.12 herein; R.sub.13 and R.sub.14 herein; or R.sub.13 and R.sub.14 fused forming a ring having 5 to 7 atoms by joining R.sub.13 being C(1-6)alkyl or C(2-6)alkenyl. The ROR compounds can treat ROR mediated diseases.

Claims

1. A compound according to Formula I ##STR00175## or a pharmaceutically acceptable salt thereof wherein A.sub.1 is NR.sub.1 or CR.sub.1, with R.sub.1 being H or methyl, with methyl, if present, optionally being substituted with one or more F; the cyclopropyl moiety can be optionally substituted with one or more methyl and one or more F; A.sub.2-A.sub.5 are N or CR.sub.2-CR.sub.5, respectively, with the proviso that no more than two of the four positions A in A.sub.2-A.sub.5 can be simultaneously N; R.sub.2-R.sub.5 are independently H, halogen, amino, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-6)alkyl; R.sub.6 and R.sub.7 are independently H, F, methyl, ethyl, hydroxyl or methoxy or R.sub.6 and R.sub.7 together is carbonyl, all alkyl groups, if present, optionally being substituted with one or more F; R.sub.8 is H or C(1-6)alkyl; A.sub.9-A.sub.12 are N or CR.sub.9-CR.sub.12, respectively, with the proviso that no more than two of the four positions A in A.sub.9-A.sub.12 can be simultaneously N; R.sub.9-R.sub.12 are independently H, halogen, amino, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-6)alkyl; R.sub.13 is H, C(1-6)alkyl, C(2-6)alkenyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-4)alkyl, C(2-5)heterocycloalkyl, C(2-5)heterocycloalkyl-C(1-4)alkyl, C(6-10)aryl, C(6-10)arylC(1-4)alkyl, C(1-9)heteroaryl or C(1-9)heteroarylC(1-4)alkyl, all groups optionally substituted with one or more halogen, amino, hydroxyl, cyano, C(1-3)alkoxy, C(1-3)alkoxycarbonyl, (di)C(1-3)alkylamino or C(1-3)alkyl; and R.sub.14 is H, C(1-6)alkyl, C(2-6)alkenyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-4)alkyl, C(2-5)heterocycloalkyl, C(2-5)heterocycloalkyl-C(1-4)alkyl, C(6-10)aryl, C(6-10)arylC(1-4)alkyl, C(1-9)heteroaryl or C(1-9)heteroarylC(1-4)alkyl, all groups optionally substituted with one or more halogen, amino, hydroxyl, cyano, C(1-3)alkoxy, C(1-3)alkoxycarbonyl, (di)C(1-3)alkylamino or C(1-3)alkyl; or R.sub.13 and R.sub.14 are fused and form a ring having 5 to 7 atoms by joining R.sub.13 being C(1-6)alkyl or C(2-6)alkenyl with an independent substituent within the definition of R.sub.14, all groups optionally substituted with one or more halogen, amino, hydroxy, cyano, C(1-3)alkoxy, C(1-3)alkoxycarbonyl, (di)C(1-3)alkylamino or C(1-3)alkyl.

2. The compound according to claim 1 where A.sub.1 is CR.sub.1 and R.sub.1 is hydrogen.

3. The compound according to claim 1 where A.sub.1 is NR.sub.1 and R.sub.1 is hydrogen.

4. The compound according to claim 1 wherein all of the positions A in A.sub.2-A.sub.5 are carbon and all of the position R in R.sub.2-R.sub.5 are H.

5. The compound according to claim 1 where R.sub.6 and R.sub.7 are independently H, methyl or hydroxyl.

6. The compound according to claim 1 where R.sub.8 is H.

7. The compound according to claim 1 wherein all positions A of A.sub.9-A.sub.12 are carbon or wherein position A in either A.sub.9 or A.sub.10 is nitrogen and the remaining positions A in A.sub.9-A.sub.12 are carbon.

8. The compound according to claim 1 wherein R.sub.9-R.sub.12 are independently H, halogen, methyl or methoxy.

9. The compound according to claim 1 wherein R.sub.13 and R.sub.14 are independently H, C(1-6)alkyl, C(2-6)alkenyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-4)alkyl, C(2-5)heterocycloalkyl, C(2-5)heterocycloalkyl-C(1-4)alkyl, C(6-10) aryl, C(6-10) arylC (1-4)alkyl, C(1-9)hetero aryl or C(1-9)heteroarylC(1-4)alkyl, all groups optionally substituted with one or more halogen, hydroxyl, cyano, C(1-3)alkoxy, C(1-3)alkoxycarbonyl or C(1-3)alkyl.

10. The compound according to claim 1 wherein R.sub.13 and R.sub.14 are fused and form a ring consisting of 5 to 7 atoms by joining C(1-6)alkyl or C(2-6)alkenyl at R.sub.13 with a substituent at R.sub.14 selected from C(1-6)alkyl, C(2-6)alkenyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-4)alkyl, C(2-5)heterocycloalkyl, C(2-5)heterocycloalkyl-C(1-4)alkyl, C(6)aryl, C(6)arylC(1-4)alkyl, C(1-5)heteroaryl or C(1-5)heteroarylC(1-4)alkyl, with all groups optionally substituted with one or more halogen, hydroxy, cyano, C(1-3)alkoxy, C(1-3)alkoxycarbonyl, or C(1-3)alkyl.

11. The compound as defined in claim 1 which is selected from the group of: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-propylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-phenylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N,N-dimethylbenzamide; N-benzyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2-phenylpropan-2-yl)benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-propylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-(2-methylpropyl)benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(cyclopropylmethyl)-N-propylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-(2-phenylethyl)benzamide; N-tert-butyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzamide; N,N-dibenzyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzamide; N-benzyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(1-phenylethyl)benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N,N-bis(2-methylpropyl)benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-phenylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-(pyridin-2-yl)benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-[(1S)-1-phenylethyl]benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-phenyl-N-propylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-propyl-N-(pyridin-3-yl)benzamide; N-benzyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-propylbenzamide; 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-phenyl-N-propylbenzamide; N-benzyl-4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-propylbenzamide; N,N-dibenzyl-4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}benzamide; ethyl 1-{4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzoyl}piperidine-3-carboxylate; N-tert-butyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methylbenzamide; N,N-dicyclobutyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(2-methylpiperidine-1-carbonyl)phenyl]acetamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-(4-methylphenyl)benzamide; methyl 3-{N-ethyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzamido} benzoate; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-(3-methylphenyl)benzamide; ethyl 2-(N-benzyl-1-{4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]phenyl}formamido)acetate; ethyl 6-{4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzoyl}-4H,5H,6H,7H-thieno[2,3-c]pyridine-2-carboxylate; N-cyclohexyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methylbenzamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(2-phenylpyrrolidine-1-carbonyl)phenyl]acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(piperidine-1-carbonyl)phenyl]acetamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2-methylpropyl)-N-phenylbenzamide; ethyl 2-(1-{4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzoyl}pyrrolidin-2-yl)-1,3-thiazole-4-carboxylate; 2-(4-cyclopropylmethanesulfonylphenyl)-N-{4-[2-(morpholin-4-ylmethyl)piperidine-1-carbonyl]phenyl}acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(1,2,3,4-tetrahydroquinoline-1-carbonyl)phenyl]acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(2,3-dihydro-1H-indole-1-carbonyl)phenyl]acetamide; N-benzyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethylbenzamide; 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-ethyl-N-phenylbenzamide; 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-methyl-N-phenylbenzamide; 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-ethyl-N-(4-methylphenyl)benzamide; 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-ethyl-N-(3-methylphenyl)benzamide; methyl 3-(N-ethyl-4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}benzamido)benzoate; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(3-phenylpiperidine-1-carbonyl)phenyl]acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(2-phenylpiperidine-1-carbonyl)phenyl]acetamide; 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-ethyl-N-(pyridin-3-yl)benzamide; 6-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-phenylpyridine-3-carboxamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-(pyridin-3-yl)benzamide; 3-chloro-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-phenylbenzamide; 6-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-ethyl-N-phenylpyridine-3-carboxamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl]acetamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-[(5-methyl-1,2-oxazol-3-yl)methyl]benzamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)phenyl]acetamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-2-methoxy-N-phenylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(furan-2-ylmethyl)-N-methylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-[2-methyl-1-(morpholin-4-yl)propan-2-yl]benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N,N-bis(prop-2-en-1-yl)benzamide; 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N,N-bis(2-methylpropyl)benzamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl)phenyl]acetamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(4-methyl-5-methyl-1,3-thiazol-2-yl)-N-ethylbenzamide; 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-propyl-N-(pyridin-3-yl)benzamide; 2-[4-(cyclopropylsulfamoyl)phenyl]-N-[4-(2-phenylpiperidine-1-carbonyl)phenyl]acetamide; 2-chloro-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-(pyridin-2-yl)benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-[2-(pyridin-3-yl)propan-2-yl]benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-[(2R)-1,1,1-trifluoro-3-methylbutan-2-yl]benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-[(1S)-1-(2-methoxyphenyl)ethyl]benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-[(1S)-1-(2-fluorophenyl)ethyl]benzamide; N-[cyano(thiophen-2-yl)methyl]-4-[2-(4-cyclopropylmethanesulfonylphenyl) acetamido]benzamide; N-[cyano(phenyl)methyl]-4-[2-(4-cyclopropylmethanesulfonylphenyl) acetamido]benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-[2-(trifluoromethoxy)phenyl]benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2,6-dimethylphenyl)benzamide; N-[(1R)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl]-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzamide; N-cyclopropyl-4-[[2-[4-(cyclopropylmethylsulfonyl)phenyl]acetyl]amino]-N-(2-hydroxyethyl)benzamide; N-cyclopropyl-4-[[2-[4-(cyclopropylmethylsulfonyl)phenyl]acetyl]amino]-N-[(1-hydroxycyclobutyl)methyl]benzamide; N-cyclopropyl-4-[[2-[4-(cyclopropylmethylsulfonyl)phenyl]acetyl]amino]-N-(2-methoxyethyl)benzamide; N-cyclopropyl-4-[[2-[4-(cyclopropylmethylsulfonyl)phenyl]acetyl]amino]-N-tetrahydropyran-4-yl-benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-propyl-N-(thiophen-3-yl)benzamide; N-butyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(1,3-thiazol-2-yl)benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-propyl-N-(1,3-thiazol-2-yl)benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-(1,3-thiazol-2-yl)benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-(1,3-thiazol-2-yl)benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(1,3-dimethyl-1H-pyrazol-5-yl)-N-propylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(5-methyl-1,2-oxazol-3-yl)-N-propylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(1,3-dimethyl-1H-pyrazol-5-yl)-N-ethylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-(5-methyl-1,2-oxazol-3-yl)benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-(5-methyl-1,2-oxazol-3-yl)benzamide; 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-methyl-N-(5-methyl-1,2-oxazol-3-yl)benzamide; 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-(1,3-dimethyl-1H-pyrazol-5-yl)-N-propylbenzamide; 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-(5-methyl-1,2-oxazol-3-yl)-N-prop ylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-(3-methyl-1,2-oxazol-5-yl)benzamide; 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-ethyl-N-(3-methyl-1,2-oxazol-5-yl)benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide; 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-ethyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide; 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-ethyl-3-methoxy-N-phenylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-2-fluoro-N-phenylbenzamide; 2-chloro-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-phenylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-3-methoxy-N-phenylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-3-fluoro-N-phenylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-(1,2-oxazol-3-yl)benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-phenyl-N-(2,2,2-trifluoroethyl)benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-3-methyl-N-phenylbenzamide; 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-ethyl-3-methyl-N-phenylbenzamide; 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-(4-methyl-5-methyl-1,3-thiazol-2-yl)-N-ethyl-benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(dimethyl-1,2-oxazol-4-yl)-N-ethyl-benzamide; 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-phenyl-N-(2,2,2-trifluoroethyl)benzamide; 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-(dimethyl-1,2-oxazol-4-yl)-N-ethylbenzamide; 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-ethyl-2-fluoro-N-phenylbenzamide; 2-chloro-4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-ethyl-N-phenylbenzamide; N-benzyl-N-tert-butyl-4-[2-(4-cyclopropylmethanesulfonylphenyl) acetamido]benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(1-methylpiperidin-4-yl)-N-phenylbenzamide; N-(4-bromophenyl)-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-phenylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-2-fluoro-N-methyl-N-(2-methylphenyl)benzamide; 2-chloro-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-(2-methylphenyl)benzamide; N-(2-chlorophenyl)-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-2-fluorobenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2,3-dimethylphenyl)-N-ethyl-2-fluorobenzamide; 2-chloro-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2,3-dimethylphenyl)-N-ethylbenzamide; N-[4-(3-tert-butyl-3,4-dihydro-2H-1,4-benzoxazine-4-carbonyl)phenyl]-2-(4-cyclopropylmethanesulfonylphenyl)acetamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2-methoxyphenyl)-N,2-dimethylbenzamide; 2-chloro-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-phenyl-N-(2,2,2-trifluoroethyl)benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-2-fluoro-N-(2-methoxyphenyl)-N-methylbenzamide; 2-chloro-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2-methoxyphenyl)-N-methylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-2-fluoro-N-(2-fluorophenyl)-N-methylbenzamide; 2-chloro-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2-fluorophenyl)-N-methylbenzamide; 2-chloro-N-(2-chlorophenyl)-4-[2-(4-cyclopropylmethanesulfonylphenyl) acetamido]-N-ethylbenzamide; 2-chloro-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-(2-methylphenyl)benzamide; N-tert-butyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-phenylbenzamide; N-tert-butyl-4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-phenylbenzamide; 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-(4-methylphenyl)-N-[2-(oxolan-2-yl)propan-2-yl]benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(4-methylphenyl)-N-[2-(oxolan-2-yl)propan-2-yl]benzamide; N-tert-butyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-3-fluoro-N-phenylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-[2-(oxolan-2-yl)propan-2-yl]-N-phenylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(oxolan-3-yl)-N-(pyridin-2-yl)benzamide; N-cyclopropyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(pyridin-2-yl)benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(1-hydroxy-2-methylpropan-2-yl)-N-phenylbenzamide; N-cyclobutyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(pyridin-2-yl)benzamide; N-cyclopropyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-phenylbenzamide; N-cyclobutyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-phenylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(1-methylcyclopropyl)-N-phenylbenzamide; N-cyclopropyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(pyridin-3-yl)benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(3,3-difluorocyclobutyl)-N-phenylbenzamide; methyl 2-(1-{4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]phenyl}-N-phenylformamido)-2-methylpropanoate; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-phenyl-N-(1,1,1-trifluoropropan-2-yl)benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2,6-dichlorophenyl)benzamide; 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-phenyl-N-(1,1,1-trifluoropropan-2-yl)benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(oxetan-3-yl)-N-phenylbenzamide; N-(4-(7-oxa-4-azaspiro[2.5]octane-4-carbonyl)phenyl)-2-(4-((cyclopropylmethyl) sulfonyl)phenyl)acetamide; N-(tert-butyl)-4-(2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetamido)-N-(2-hydroxyethyl)benzamide; 4-(2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetamido)-N-(2-hydroxyethyl)-N-isobutylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(1-hydroxy-2-methylpropan-2-yl)-N-(4-methylphenyl)benzamide; 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-(1-hydroxy-2-methylpropan-2-yl)-N-(4-methylphenyl)benzamide; 4-[2-(6-cyclopropylmethanesulfonylpyridin-3-yl)acetamido]-N-phenyl-N-(2,2,2-trifluoroethyl)benzamide; 4-[2-(6-cyclopropylmethanesulfonylpyridin-3-yl)acetamido]-N-ethyl-2-fluoro-N-phenylbenzamide; 2-chloro-4-[2-(6-cyclopropylmethanesulfonylpyridin-3-yl)acetamido]-N-ethyl-N-phenylbenzamide; N-tert-butyl-4-[2-(6-cyclopropylmethanesulfonylpyridin-3-yl)acetamido]-N-phenylbenzamide; N-tert-butyl-4-[2-(6-cyclopropylmethanesulfonylpyridin-3-yl)acetamido]-3-fluoro-N-phenylbenzamide; 4-[2-(6-cyclopropylmethanesulfonylpyridin-3-yl)acetamido]-N-[2-(oxolan-2-yl)propan-2-yl]-N-phenylbenzamide; 4-[2-(6-cyclopropylmethanesulfonylpyridin-3-yl)acetamido]-N-(1-hydroxy-2-methylpropan-2-yl)-N-(4-methylphenyl)benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-2-methyl-N-phenylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N,2-dimethyl-N-(2-methylphenyl)benzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2,3-dimethylphenyl)-N-ethyl-2-methylbenzamide; 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2-fluorophenyl)-N,2-dimethylbenzamide and N-(2-chlorophenyl)-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-2-methylbenzamide.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof for use in therapy.

13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof for the treatment of ROR-mediated diseases or conditions.

14. A pharmaceutical composition, which comprises a compound of Formula I according to claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

15. A pharmaceutical composition according to claim 14, which further comprises at least one additional therapeutically active agent.

Description

EXAMPLES

[0185] All building blocks used are commercially available, known or prepared according to methods known to those skilled in the art.

Examples 1-166

1: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-propylbenzamide

[0186] ##STR00009##

[0187] i) To a suspension of 4-aminobenzoic acid (20 g) in methanol (150 mL) was added at room temperature concentrated HCl (25 mL). The reaction mixture was stirred overnight at room temperature. The reaction was quenched by addition of a saturated aqueous NaHCO.sub.3 solution. The organic solvent was removed under reduced pressure and the aqueous layer was extracted several times with ethyl acetate. The combined organic layers were washed with water then brine, dried over MgSO.sub.4 and concentrated under reduced pressure giving methyl 4-aminobenzoate (22.1 g) as an off-white solid. The product was used in the next step without further purification.

[0188] ii) To a solution of the product obtained in the previous step (710 mg), 2-(4-cyclopropylmethanesulfonylphenyl)acetic acid (1.0 g) and DMAP (100 mg) in CH.sub.2Cl.sub.2 (2 mL) was added dropwise at 0 C. a solution of EDCl (900 mg) in CH.sub.2Cl.sub.2. The reaction mixture was stirred overnight at room temperature. The organic layer was washed with a saturated aqueous NaHCO.sub.3 solution, water then brine, dried over MgSO.sub.4 and concentrated under reduced pressure. The residue was purified on SiO.sub.2, using 1% to 10% ethyl acetate in heptane as the eluent, giving methyl 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzoate (1.3 g) as a white solid.

[0189] iii) A suspension of the product obtained in the previous step (1.3 g) and a 2N aqueous NaOH solution (6 mL) in ethanol (20 mL) was stirred overnight at room temperature. Ethanol was removed under reduced pressure and water was added. The solution was washed with CH.sub.2Cl.sub.2 and the aqueous phase was acidified by adding a 2N aqueous HCl solution until pH=1. The product was extracted into ethyl acetate and the ethyl acetate layer was washed with water then brine, dried over MgSO.sub.4 and concentrated under reduced pressure giving 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzoic acid (840 mg). The product was used without further purification.

[0190] iv) A solution of the product obtained in the previous step (40 mg), n-propylamine (12 uL), EDCl (25 mg) and DMAP (14 mg) in CH.sub.2Cl.sub.2 (2 mL) was stirred overnight at room temperature. The organic layer was washed with water, a saturated aqueous NaHCO.sub.3 solution, brine, dried over MgSO.sub.4 and concentrated under reduced pressure. The residue was purified on reverse phase HPLC, giving the title compound 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-propylbenzamide (23 mg) as a white solid. MS (ES.sup.+) m/z 415.2 (M+H).sup.+.

[0191] Following a procedure analogous to that described for Example 1, using appropriate starting materials, the following compounds have been prepared.

2: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethylbenzamide

[0192] ##STR00010##

[0193] MS (ES.sup.+) m/z 401.1 (M+H).sup.+.

3: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-phenylbenzamide

[0194] ##STR00011##

[0195] MS (ES.sup.+) m/z 463.2 (M+H).sup.+.

4: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N,N-dimethylbenzamide

[0196] ##STR00012##

[0197] MS (ES.sup.+) m/z 401.1 (M+H).sup.+.

5: N-benzyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methylbenzamide

[0198] ##STR00013##

[0199] MS (ES.sup.+) m/z 477.2 (M+H).sup.+.

6: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2-phenylpropan-2-yl)benzamide

[0200] ##STR00014##

[0201] MS (ES.sup.+) m/z 491.2 (M+H).sup.+.

7: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-propylbenzamide

[0202] ##STR00015##

[0203] MS (ES.sup.+) m/z 428.2 (M+H).sup.+.

8: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-(2-methylpropyl)benzamide

[0204] ##STR00016##

[0205] MS (ES.sup.+) m/z 443.2 (M+H).sup.+.

9: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(cyclopropylmethyl)-N-propylbenzamide

[0206] ##STR00017##

[0207] MS (ES.sup.+) m/z 469.2 (M+H).sup.+.

10: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-(2-phenylethyl)benzamide

[0208] ##STR00018##

[0209] MS (ES.sup.+) m/z 491.2 (M+H).sup.+.

11: N-tert-butyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzamide

[0210] ##STR00019##

[0211] MS (ES.sup.+) m/z 429.2 (M+H).sup.+.

12: N,N-dibenzyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzamide

[0212] ##STR00020##

[0213] MS (ES.sup.+) m/z 553.2 (M+H).sup.+.

13: N-benzyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzamide

[0214] ##STR00021##

[0215] MS (ES.sup.+) m/z 463.2 (M+H).sup.+.

14: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(1-phenylethyl)benzamide

[0216] ##STR00022##

[0217] MS (ES.sup.+) m/z 477.2 (M+H).sup.+.

15: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N,N-bis(2-methylpropyl)benzamide

[0218] ##STR00023##

[0219] MS (ES.sup.+) m/z 485.2 (M+H).sup.+.

16: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-phenylbenzamide

[0220] ##STR00024##

[0221] MS (ES.sup.+) m/z 477.2 (M+H).sup.+.

17: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-(pyridin-2-yl)benzamide

[0222] ##STR00025##

[0223] MS (ES.sup.+) m/z 464.2 (M+H).sup.+.

18: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-[(1S)-1-phenylethyl]benzamide

[0224] ##STR00026##

[0225] MS (ES.sup.+) m/z 491.2 (M+H).sup.+.

19: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-phenyl-N-propylbenzamide

[0226] ##STR00027##

[0227] MS (ES.sup.+) m/z 491.2 (M+H).sup.+.

20: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-propyl-N-(pyridin-3-yl)benzamide

[0228] ##STR00028##

[0229] MS (ES.sup.+) m/z 492.2 (M+H).sup.+.

21: N-benzyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-propylbenzamide

[0230] ##STR00029##

[0231] MS (ES.sup.+) m/z 505.2 (M+H).sup.+.

22: 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-phenyl-N-propylbenzamide

[0232] ##STR00030##

[0233] MS (ES.sup.+) m/z 492.2 (M+H).sup.+.

23: N-benzyl-4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-propylbenzamide

[0234] ##STR00031##

[0235] MS (ES.sup.+) m/z 506.2 (M+H).sup.+.

24: N,N-dibenzyl-4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}benzamide

[0236] ##STR00032##

[0237] MS (ES.sup.+) m/z 554.2 (M+H).sup.+.

25: ethyl 1-{4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzoyl}piperidine-3-carboxylate

[0238] ##STR00033##

[0239] MS (ES.sup.+) m/z 513.2 (M+H).sup.+.

26: N-tert-butyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methylbenzamide

[0240] ##STR00034##

[0241] MS (ES.sup.+) m/z 443.2 (M+H).sup.+.

[0242] 27: N,N-dicyclobutyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzamide.

##STR00035##

[0243] MS (ES.sup.+) m/z 481.2 (M+H).sup.+.

28: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(2-methylpiperidine-1-carbonyl)phenyl]acetamide

[0244] ##STR00036##

[0245] MS (ES.sup.+) m/z 455.2 (M+H).sup.+.

29: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-(4-methylphenyl)benzamide

[0246] ##STR00037##

[0247] MS (ES.sup.+) m/z 491.2 (M+H).sup.+.

30: methyl 3-{N-ethyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzamido} benzoate

[0248] ##STR00038##

[0249] MS (ES.sup.+) m/z 535.2 (M+H).sup.+.

31: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-(3-methylphenyl)benzamide

[0250] ##STR00039##

[0251] MS (ES.sup.+) m/z 491.2 (M+H).sup.+.

32: ethyl 2-(N-benzyl-1-{4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]phenyl} formamido)acetate

[0252] ##STR00040##

[0253] MS (ES.sup.+) m/z 549.2 (M+H).sup.+.

33: ethyl 6-{4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzoyl}-4H,5H,6H,7H-thieno[2,3-c]pyridine-2-carboxylate

[0254] ##STR00041##

[0255] MS (ES.sup.+) m/z 567.2 (M+H).sup.+.

34: N-cyclohexyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methylbenzamide

[0256] ##STR00042##

[0257] MS (ES.sup.+) m/z 469.2 (M+H).sup.+.

35: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(2-phenylpyrrolidine-1-carbonyl)phenyl] acetamide

[0258] ##STR00043##

[0259] MS (ES.sup.+) m/z 503.2 (M+H).sup.+.

36: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(piperidine-1-carbonyl)phenyl]acetamide

[0260] ##STR00044##

[0261] MS (ES.sup.+) m/z 441.2 (M+H).sup.+.

37: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2-methylpropyl)-N-phenylbenzamide

[0262] ##STR00045##

[0263] MS (ES.sup.+) m/z 505.2 (M+H).sup.+.

38: ethyl 2-(1-{4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzoyl}pyrrolidin-2-yl)-1,3-thiazole-4-carboxylate

[0264] ##STR00046##

[0265] MS (ES.sup.+) m/z 582.2 (M+H).sup.+.

39: 2-(4-cyclopropylmethanesulfonylphenyl)-N-{4-[2-(morpholin-4-ylmethyl)piperidine-1-carbonyl]phenyl}acetamide

[0266] ##STR00047##

[0267] MS (ES.sup.+) m/z 540.2 (M+H).sup.+.

40: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(1,2,3,4-tetrahydroquinoline-1-carbonyl) phenyl]acetamide

[0268] ##STR00048##

[0269] MS (ES.sup.+) m/z 489.2 (M+H).sup.+.

41: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(2,3-dihydro-1H-indole-1-carbonyl)phenyl]acetamide

[0270] ##STR00049##

[0271] MS (ES.sup.+) m/z 475.2 (M+H).sup.+.

42: N-benzyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethylbenzamide

[0272] ##STR00050##

[0273] MS (ES.sup.+) m/z 491.2 (M+H).sup.+.

43: 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-ethyl-N-phenylbenzamide

[0274] ##STR00051##

[0275] MS (ES.sup.+) m/z 478.2 (M+H).sup.+.

44: 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-methyl-N-phenylbenzamide

[0276] ##STR00052##

[0277] MS (ES.sup.+) m/z 464.2 (M+H).sup.+.

45: 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-ethyl-N-(4-methylphenyl) benzamide

[0278] ##STR00053##

[0279] MS (ES.sup.+) m/z 492.2 (M+H).sup.+.

46: 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-ethyl-N-(3-methylphenyl) benzamide

[0280] ##STR00054##

[0281] MS (ES.sup.+) m/z 492.2 (M+H).sup.+.

47: methyl 3-(N-ethyl-4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}benzamido) benzoate

[0282] ##STR00055##

[0283] MS (ES.sup.+) m/z 536.2 (M+H).sup.+.

48: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(3-phenylpiperidine-1-carbonyl)phenyl] acetamide

[0284] ##STR00056##

[0285] MS (ES.sup.+) m/z 517.2 (M+H).sup.+.

49: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(2-phenylpiperidine-1-carbonyl)phenyl] acetamide

[0286] ##STR00057##

[0287] MS (ES.sup.+) m/z 517.2 (M+H).sup.+.

50: 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-ethyl-N-(pyridin-3-yl)benzamide

[0288] ##STR00058##

[0289] MS (ES.sup.+) m/z 479.2 (M+H).sup.+.

51: 6-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-phenylpyridine-3-carboxamide

[0290] ##STR00059##

[0291] MS (ES.sup.+) m/z 478.2 (M+H).sup.+.

52: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-(pyridin-3-yl) benzamide

[0292] ##STR00060##

[0293] MS (ES.sup.+) m/z 478.2 (M+H).sup.+.

53: 3-chloro-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-phenylbenzamide

[0294] ##STR00061##

[0295] MS (ES.sup.+) m/z 512.2 (M+H).sup.+.

54: 6-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-ethyl-N-phenylpyridine-3-carboxamide

[0296] ##STR00062##

[0297] MS (ES.sup.+) m/z 479.2 (M+H).sup.+.

55: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl]acetamide

[0298] ##STR00063##

[0299] MS (ES.sup.+) m/z 489.2 (M+H).sup.+.

56: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-[(5-methyl-1,2-oxazol-3-yl)methyl]benzamide

[0300] ##STR00064##

[0301] MS (ES.sup.+) m/z 496.2 (M+H).sup.+.

57: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)phenyl]acetamide

[0302] ##STR00065##

[0303] MS (ES.sup.+) m/z 532.3 (M+H).sup.+.

58: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-2-methoxy-N-phenylbenzamide

[0304] ##STR00066##

[0305] MS (ES.sup.+) m/z 507.2 (M+H).sup.+.

59: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(furan-2-ylmethyl)-N-methylbenzamide

[0306] ##STR00067##

[0307] MS (ES.sup.+) m/z 467.2 (M+H).sup.+.

60: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-[2-methyl-1-(morpholin-4-yl)propan-2-yl]benzamide

[0308] ##STR00068##

[0309] MS (ES.sup.+) m/z 514.3 (M+H).sup.+.

61: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N,N-bis(prop-2-en-1-yl)benzamide

[0310] ##STR00069##

[0311] MS (ES.sup.+) m/z 453.2 (M+H).sup.+.

62: 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N,N-bis(2-methylpropyl)benzamide

[0312] ##STR00070##

[0313] MS (ES.sup.+) m/z 486.2 (M+H).sup.+.

63: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl)phenyl]acetamide

[0314] ##STR00071##

[0315] MS (ES.sup.+) m/z 503.2 (M+H).sup.+.

64: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(4-methyl-5-methyl-1,3-thiazol-2-yl)-N-ethylbenzamide

[0316] ##STR00072##

[0317] MS (ES.sup.+) m/z 512.2 (M+H).sup.+.

65: 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-propyl-N-(pyridin-3-yl)benzamide

[0318] ##STR00073##

[0319] MS (ES.sup.+) m/z 493.2 (M+H).sup.+.

66: 2-[4-(cyclopropylsulfamoyl)phenyl]-N-[4-(2-phenylpipendine-1-carbonyl)phenyl]acetamide

[0320] ##STR00074##

[0321] MS (ES.sup.+) m/z 518.2 (M+H).sup.+.

67: 2-chloro-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-(pyridin-2-yl)benzamide

[0322] ##STR00075##

[0323] MS (ES.sup.+) m/z 498.2 (M+H).sup.+.

68: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-[2-(pyridin-3-yl)propan-2-yl]benzamide

[0324] ##STR00076##

[0325] MS (ES.sup.+) m/z 492.2 (M+H).sup.+.

69: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-[(2R)-1,1,1-trifluoro-3-methylbutan-2-yl]benzamide

[0326] ##STR00077##

[0327] MS (ES.sup.+) m/z 497.2 (M+H).sup.+.

70: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-[(1S)-1-(2-methoxyphenyl)ethyl]benzamide

[0328] ##STR00078##

[0329] MS (ES.sup.+) m/z 507.2 (M+H).sup.+.

71: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-[(1S)-1-(2-fluorophenyl)ethyl]benzamide

[0330] ##STR00079##

[0331] MS (ES.sup.+) m/z 495.2 (M+H).sup.+.

72: N-[cyano(thiophen-2-yl)methyl]-4-[2-(4-cyclopropylmethanesulfonylphenyl) acetamido]benzamide

[0332] ##STR00080##

[0333] MS (ES.sup.+) m/z 495.2 (M+H).sup.+.

73: N-[cyano(phenyl)methyl]-4-[2-(4-cyclopropylmethanesulfonylphenyl) acetamido]benzamide

[0334] ##STR00081##

[0335] MS (ES.sup.+) m/z 488.2 (M+H).sup.+.

74: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-[2-(trifluoromethoxy)phenyl]benzamide

[0336] ##STR00082##

[0337] MS (ES.sup.+) m/z 533.2 (M+H).sup.+.

75: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2,6-dimethylphenyl) benzamide

[0338] ##STR00083##

[0339] MS (ES.sup.+) m/z 477.2 (M+H).sup.+.

76: N-[(1R)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl]-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzamide

[0340] ##STR00084##

[0341] MS (ES.sup.+) m/z 565.2 (M+H).sup.+.

77: N-cyclopropyl-4-[[2-[4-(cyclopropylmethylsulfonyl)phenyl]acetyl]amino]-N-(2-hydroxyethyl)benzamide

[0342] ##STR00085##

[0343] MS (ES.sup.+) m/z 457.1 (M+H).sup.+.

78: N-cyclopropyl-4-[[2-[4-(cyclopropylmethylsulfonyl)phenyl]acetyl]amino]-N-[(1-hydroxycyclobutyl)methyl]benzamide

[0344] ##STR00086##

[0345] MS (ES.sup.+) m/z 497.2 (M+H).sup.+.

79: N-cyclopropyl-4-[[2-[4-(cyclopropylmethylsulfonyl)phenyl]acetyl]amino]-N-(2-methoxyethyl)benzamide

[0346] ##STR00087##

[0347] MS (ES.sup.+) m/z 471.2 (M+H).sup.+.

80: N-cyclopropyl-4-[[2-[4-(cyclopropylmethylsulfonyl)phenyl]acetyl]amino]-N-tetrahydropyran-4-yl-benzamide

[0348] ##STR00088##

[0349] MS (ES.sup.+) m/z 497.2 (M+H).sup.+.

81: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-propyl-N-(thiophen-3-yl)benzamide

[0350] ##STR00089##

[0351] i) To a solution of N-propylthiophen-3-amine (147 mg) and triethyl amine (283 uL) in CH.sub.2Cl.sub.2 (2 mL) was added a solution of 4-nitrobenzoyl chloride (218 mg) in CH.sub.2Cl.sub.2 (2 mL) and the reaction mixture was stirred overnight at room temperature. Water was added and the organic phase was washed with a 1N aqueous HCl solution, water, a saturated aqueous NaHCO.sub.3 solution, water and brine. The organic phase was dried over MgSO.sub.4 and concentrated under reduced pressure. The residue was purified on SiO.sub.2, using 10% to 30% ethyl acetate in toluene, as the eluent, giving 4-nitro-N-propyl-N-(thiophen-3-yl)benzamide (80 mg).

[0352] ii) To a solution of the product obtained in the previous step (81 mg) in ethanol (20 mL) was added at room temperature SnCl.sub.2 (264 mg) and the reaction was stirred for 1 hour at 70 C. The reaction mixture was quenched by pouring onto ice and a 2N aqueous NaOH solution was added dropwise until pH=4. The product was extracted into ethyl acetate and the organic phase was washed with water, brine, dried over MgSO.sub.4 and concentrated under reduced pressure giving 4-amino-N-propyl-N-(thiophen-3-yl)benzamide (66 mg). The product was used in the next step without further purification.

[0353] iii) Following a procedure analogous to that described in Example 1, step iv), the product obtained in the previous step (66 mg) was converted to the title compound 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-propyl-N-(thiophen-3-yl)benzamide (72 mg). MS (ES.sup.+) m/z 496.6 (M+H).sup.+.

[0354] Following a procedure analogous to that described for Example 81, using appropriate starting materials, the following compounds have been prepared.

82: N-butyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(1,3-thiazol-2-yl)benzamide

[0355] ##STR00090##

[0356] MS (ES.sup.+) m/z 512.2 (M+H).sup.+.

83: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-propyl-N-(1,3-thiazol-2-yl)benzamide

[0357] ##STR00091##

[0358] MS (ES.sup.+) m/z 498.2 (M+H).sup.+.

84: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-(1,3-thiazol-2-yl)benzamide

[0359] ##STR00092##

[0360] MS (ES.sup.+) m/z 484.2 (M+H).sup.+.

85: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-(1,3-thiazol-2-yl)benzamide

[0361] ##STR00093##

[0362] MS (ES.sup.+) m/z 470.2 (M+H).sup.+.

86: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(1,3-dimethyl-1H-pyrazol-5-yl)-N-propylbenzamide

[0363] ##STR00094##

[0364] MS (ES.sup.+) m/z 509.2 (M+H).sup.+.

87: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(5-methyl-1,2-oxazol-3-yl)-N-propylbenzamide

[0365] ##STR00095##

[0366] MS (ES.sup.+) m/z 496.2 (M+H).sup.+.

88: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(1,3-dimethyl-1H-pyrazol-5-yl)-N-ethylbenzamide

[0367] ##STR00096##

[0368] MS (ES.sup.+) m/z 495.2 (M+H).sup.+.

89: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-(5-methyl-1,2-oxazol-3-yl)benzamide

[0369] ##STR00097##

[0370] MS (ES.sup.+) m/z 482.2 (M+H).sup.+.

90: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-(5-methyl-1,2-oxazol-3-yl)benzamide

[0371] ##STR00098##

[0372] MS (ES.sup.+) m/z 468.2 (M+H).sup.+.

91: 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-methyl-N-(5-methyl-1,2-oxazol-3-yl)benzamide

[0373] ##STR00099##

[0374] MS (ES.sup.+) m/z 469.2 (M+H).sup.+.

92: 4-{2-[4-(cyclopropylsuIfamoyl)phenyl]acetamido}-N-(1,3-dimethyl-1H-pyrazol-5-yl)-N-propylbenzamide

[0375] ##STR00100##

[0376] MS (ES.sup.+) m/z 510.2 (M+H).sup.+.

93: 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-(5-methyl-1,2-oxazol-3-yl)-N-propylbenzamide

[0377] ##STR00101##

[0378] MS (ES.sup.+) m/z 497.2 (M+H).sup.+.

94: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-(3-methyl-1,2-oxazol-5-yl)benzamide

[0379] ##STR00102##

[0380] MS (ES.sup.+) m/z 482.2 (M+H).sup.+.

95: 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-ethyl-N-(3-methyl-1,2-oxazol-5-yl)benzamide

[0381] ##STR00103##

[0382] MS (ES.sup.+) m/z 483.2 (M+H).sup.+.

96: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide

[0383] ##STR00104##

[0384] MS (ES.sup.+) m/z 499.2 (M+H).sup.+.

97: 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-ethyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide

[0385] ##STR00105##

[0386] MS (ES.sup.+) m/z 500.2 (M+H).sup.+.

98: 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-ethyl-3-methoxy-N-phenylbenzamide

[0387] ##STR00106##

[0388] MS (ES.sup.+) m/z 508.2 (M+H).sup.+.

99: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-2-fluoro-N-phenylbenzamide

[0389] ##STR00107##

[0390] MS (ES.sup.+) m/z 495.2 (M+H).sup.+.

100: 2-chloro-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-phenylbenzamide

[0391] ##STR00108##

[0392] MS (ES.sup.+) m/z 512.1 (M+H).sup.+.

101: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-3-methoxy-N-phenylbenzamide

[0393] ##STR00109##

[0394] MS (ES.sup.+) m/z 507.2 (M+H).sup.+.

102: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-3-fluoro-N-phenylbenzamide

[0395] ##STR00110##

[0396] MS (ES.sup.+) m/z 495.2 (M+H).sup.+.

103: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-(1,2-oxazol-3-yl)benzamide

[0397] ##STR00111##

[0398] MS (ES.sup.+) m/z 468.2 (M+H).sup.+.

104: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-phenyl-N-(2,2,2-trifluoroethyl)benzamide

[0399] ##STR00112##

[0400] MS (ES.sup.+) m/z 531.2 (M+H).sup.+.

105: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-3-methyl-N-phenylbenzamide

[0401] ##STR00113##

[0402] MS (ES.sup.+) m/z 491.2 (M+H).sup.+.

106: 4-{2-[4-(cyclopropylsuIfamoyl)phenyl]acetamido}-N-ethyl-3-methyl-N-phenylbenzamide

[0403] ##STR00114##

[0404] MS (ES.sup.+) m/z 492.2 (M+H).sup.+.

107: 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-(4-methyl-5-methyl-1,3-thiazol-2-yl)-N-ethyl-benzamide

[0405] ##STR00115##

[0406] MS (ES.sup.+) m/z 513.2 (M+H).sup.+.

108: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(dimethyl-1,2-oxazol-4-yl)-N-ethyl-benzamide

[0407] ##STR00116##

[0408] MS (ES.sup.+) m/z 496.2 (M+H).sup.+. 109: 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-phenyl-N-(2,2,2-trifluoroethyl) benzamide.

##STR00117##

[0409] MS (ES.sup.+) m/z 532.2 (M+H).sup.+.

110: 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-(dimethyl-1,2-oxazol-4-yl)-N-ethylbenzamide

[0410] ##STR00118##

[0411] MS (ES.sup.+) m/z 497.2 (M+H).sup.+.

111: 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-ethyl-2-fluoro-N-phenylbenzamide

[0412] ##STR00119##

[0413] MS (ES.sup.+) m/z 496.2 (M+H).sup.+.

112: 2-chloro-4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-ethyl-N-phenylbenzamide

[0414] ##STR00120##

[0415] MS (ES.sup.+) m/z 513.2 (M+H).sup.+.

113: N-benzyl-N-tert-butyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido] benzamide

[0416] ##STR00121##

[0417] MS (ES.sup.+) m/z 519.2 (M+H).sup.+.

114: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(1-methylpiperidin-4-yl)-N-phenylbenzamide

[0418] ##STR00122##

[0419] MS (ES.sup.+) m/z 546.3 (M+H).sup.+.

115: N-(4-bromophenyl)-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-phenylbenzamide

[0420] ##STR00123##

[0421] MS (ES.sup.+) m/z 602.1 (M+H).sup.+.

116: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-2-fluoro-N-methyl-N-(2-methylphenyl)benzamide

[0422] ##STR00124##

[0423] MS (ES.sup.+) m/z 495.2 (M+H).sup.+.

117: 2-chloro-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-(2-methylphenyl)benzamide

[0424] ##STR00125##

[0425] MS (ES.sup.+) m/z 511.2 (M+H).sup.+.

118: N-(2-chlorophenyl)-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-2-fluorobenzamide

[0426] ##STR00126##

[0427] MS (ES.sup.+) m/z 529.2 (M+H).sup.+.

119: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2,3-dimethylphenyl)-N-ethyl-2-fluorobenzamide

[0428] ##STR00127##

[0429] MS (ES.sup.+) m/z 523.3 (M+H).sup.+.

120: 2-chloro-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2,3-dimethylphenyl)-N-ethylbenzamide

[0430] ##STR00128##

[0431] MS (ES.sup.+) m/z 539.3 (M+H).sup.+.

121: N-[4-(3-tert-butyl-3,4-dihydro-2H-1,4-benzoxazine-4-carbonyl)phenyl]-2-(4-cyclopropylmethanesulfonylphenyl)acetamide

[0432] ##STR00129##

[0433] MS (ES.sup.+) m/z 547.3 (M+H).sup.+.

122: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2-methoxyphenyl)-N,2-dimethylbenzamide

[0434] ##STR00130##

[0435] MS (ES.sup.+) m/z 507.3 (M+H).sup.+.

123: 2-chloro-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-phenyl-N-(2,2,2-trifluoroethyl)benzamide

[0436] ##STR00131##

[0437] MS (ES.sup.+) m/z 565.2 (M+H).sup.+.

124: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-2-fluoro-N-(2-methoxyphenyl)-N-methylbenzamide

[0438] ##STR00132##

[0439] MS (ES.sup.+) m/z 511.3 (M+H).sup.+.

125: 2-chloro-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2-methoxyphenyl)-N-methylbenzamide

[0440] ##STR00133##

[0441] MS (ES.sup.+) m/z 527.2 (M+H).sup.+.

126: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-2-fluoro-N-(2-fluorophenyl)-N-methylbenzamide

[0442] ##STR00134##

[0443] MS (ES.sup.+) m/z 499.2 (M+H).sup.+.

127: 2-chloro-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2-fluorophenyl)-N-methylbenzamide

[0444] ##STR00135##

[0445] MS (ES.sup.+) m/z 515.2 (M+H).sup.+.

128: 2-chloro-N-(2-chlorophenyl)-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethylbenzamide

[0446] ##STR00136##

[0447] MS (ES.sup.+) m/z 545.2 (M+H).sup.+.

129: 2-chloro-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-(2-methylphenyl)benzamide

[0448] ##STR00137##

[0449] MS (ES.sup.+) m/z 525.3 (M+H).sup.+.

130: N-tert-butyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-phenylbenzamide

[0450] ##STR00138##

[0451] MS (ES.sup.+) m/z 505.3 (M+H).sup.+.

131: N-tert-butyl-4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-phenylbenzamide

[0452] ##STR00139##

[0453] MS (ES.sup.+) m/z 506.3 (M+H).sup.+.

132: 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-(4-methylphenyl)-N-[2-(oxolan-2-yl)propan-2-yl]benzamide

[0454] ##STR00140##

[0455] MS (ES.sup.+) m/z 576.2 (M+H).sup.+.

133: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(4-methylphenyl)-N-[2-(oxolan-2-yl)propan-2-yl]benzamide

[0456] ##STR00141##

[0457] MS (ES.sup.+) m/z 575.2 (M+H).sup.+.

134: N-tert-butyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-3-fluoro-N-phenylbenzamide

[0458] ##STR00142##

[0459] MS (ES.sup.+) m/z 523.2 (M+H).sup.+.

135: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-[2-(oxolan-2-yl)propan-2-yl]-N-phenylbenzamide

[0460] ##STR00143##

[0461] MS (ES.sup.+) m/z 561.2 (M+H).sup.+.

136: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(oxolan-3-yl)-N-(pyridin-2-yl)benzamide

[0462] ##STR00144##

[0463] MS (ES.sup.+) m/z 520.1 (M+H).sup.+.

137: N-cyclopropyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(pyridin-2-yl)benzamide

[0464] ##STR00145##

[0465] MS (ES.sup.+) m/z 490.1 (M+H).sup.+.

138: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(1-hydroxy-2-methylpropan-2-yl)-N-phenylbenzamide

[0466] ##STR00146##

[0467] MS (ES.sup.+) m/z 521.2 (M+H).sup.+.

139: N-cyclobutyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(pyridin-2-yl)benzamide

[0468] ##STR00147##

[0469] MS (ES.sup.+) m/z 504.2 (M+H).sup.+.

140: N-cyclopropyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-phenylbenzamide

[0470] ##STR00148##

[0471] MS (ES.sup.+) m/z 489.1 (M+H).sup.+.

141: N-cyclobutyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-phenylbenzamide

[0472] ##STR00149##

[0473] MS (ES.sup.+) m/z 503.2 (M+H).sup.+.

142: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(1-methylcyclopropyl)-N-phenylbenzamide

[0474] ##STR00150##

[0475] MS (ES.sup.+) m/z 503.2 (M+H).sup.+.

143: N-cyclopropyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(pyridin-3-yl)benzamide

[0476] ##STR00151##

[0477] MS (ES.sup.+) m/z 490.1 (M+H).sup.+.

144: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(3,3-difluorocyclobutyl)-N-phenylbenzamide

[0478] ##STR00152##

[0479] MS (ES.sup.+) m/z 539.1 (M+H).sup.+.

145: methyl 2-(1-{4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]phenyl}-N-phenylformamido)-2-methylpropanoate

[0480] ##STR00153##

[0481] MS (ES.sup.+) m/z 549.1 (M+H).sup.+.

146: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-phenyl-N-(1,1,1-trifluoropropan-2-yl)benzamide

[0482] ##STR00154##

[0483] MS (ES.sup.+) m/z 545.1 (M+H).sup.+.

147: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2,6-dichlorophenyl)benzamide

[0484] ##STR00155##

[0485] MS (ES.sup.+) m/z 517.1 (M+H).sup.+.

148: 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-phenyl-N-(1,1,1-trifluoropropan-2-yl)benzamide

[0486] ##STR00156##

[0487] MS (ES.sup.+) m/z 546.2 (M+H).sup.+.

149: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(oxetan-3-yl)-N-phenylbenzamide

[0488] ##STR00157##

[0489] MS (ES.sup.+) m/z 505.2 (M+H).sup.+.

150: N-(4-(7-oxa-4-azaspiro[2.5]octane-4-carbonyl)phenyl)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetamide

[0490] ##STR00158##

[0491] MS (ES.sup.+) m/z 469.2 (M+H).sup.+.

151: N-(tert-butyl)-4-(2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetamido)-N-(2-hydroxyethyl)benzamide

[0492] ##STR00159##

[0493] i) To a solution of 2-(tert-butylamino)ethan-1-ol (50 mg) and triethyl amine (66 L) in CH.sub.2Cl.sub.2 (2 mL) was added tert-butylchlorodiphenylsilane (122 L) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and purified on SiO.sub.2, using 0% to 2% methanol in dichloromethane, as the eluent, giving N-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-methylpropan-2-amine (135 mg).

[0494] ii) To a solution of the product obtained in the previous step (105 mg) and triethyl amine (79 L) in CH.sub.2Cl.sub.2 (2 mL) was added a solution of 4-nitrobenzoyl chloride (50 mg) in CH.sub.2Cl.sub.2 (1 mL) and the reaction mixture was stirred overnight at room temperature. Water was added and the organic phase was separated. The aqueous phase was extracted with dichloromethane. The combined organic phases were filtered on a water repellent filter cartridge and concentrated under reduced pressure. The residue was purified on SiO.sub.2, using 0% to 1% methanol in dichloromethane, as the eluent, giving N-(tert-butyl)-N-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-nitrobenzamide (101 mg) as a white solid.

[0495] iii) To a solution of the product obtained in the previous step (100 mg) in ethanol (5 mL) were added water (0.5 mL), acetic acid (0.5 mL) and iron (33 mg) at room temperature and the reaction was stirred for 4 hours at 60 C. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure, taken into dichloromethane, washed with water, brine, filtered on a water repellent filter cartridge and concentrated under reduced pressure giving 4-amino-N-(tert-butyl)-N-(2-((tert-butyldiphenylsilyl)oxy)ethyl)benzamide (100 mg).

[0496] iv) A solution of the product obtained in the previous step (103 mg), 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetic acid (50 mg), EDCl (42 mg) and DMAP (4.8 mg) in CH.sub.2Cl.sub.2 (3 mL) was stirred overnight at room temperature. The organic layer was washed with water, brine, filtered on a water repellent filter cartridge and concentrated under reduced pressure. The residue was purified on SiO.sub.2, using 0% to 4% methanol in dichloromethane, as the eluent, giving the title compound N-(tert-butyl)-N-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-(2-(4-(cyclopropylmethyl)sulfonyl)phenyl)acetamido)benzamide (86 mg) as a white solid.

[0497] v) To a solution of the product obtained in the previous step (86 mg) in THF (3 mL) was added a 1M solution of tetrabutylammonium fluoride in THF (360 L) and the reaction was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with dichloromethane. The organic phase was filtered on a water repellent filter cartridge, concentrated under reduced pressure and triturated with pentane/CH.sub.2Cl.sub.2 (10/1) giving the title compound N-(tert-butyl)-4-(2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetamido)-N-(2-hydroxyethyl)benzamide (22 mg) as a white solid. MS (ES.sup.+) m/z 473.2 (M+H).sup.+.

[0498] Following a procedure analogous to that described for Example 151, using appropriate starting materials, the following compound has been prepared.

152: 4-(2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetamido)-N-(2-hydroxyethyl)-N-isobutylbenzamide

[0499] ##STR00160##

[0500] MS (ES.sup.+) m/z 473.2 (M+H).sup.+.

153: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(1-hydroxy-2-methylpropan-2-yl)-N-(4-methylphenyl)benzamide

[0501] ##STR00161##

[0502] MS (ES.sup.+) m/z 535.2 (M+H).sup.+.

154: 4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-(1-hydroxy-2-methylpropan-2-yl)-N-(4-methylphenyl)benzamide

[0503] ##STR00162##

[0504] MS (ES.sup.+) m/z 536.2 (M+H).sup.+.

155: 4-[2-(6-cyclopropylmethanesulfonylpyridin-3-yl)acetamido]-N-phenyl-N-(2,2,2-trifluoroethyl)benzamide

[0505] ##STR00163##

[0506] i) To a suspension of 2-bromo-5-methylpyridine (25 g) in water (200 ml) was added at room temperature an aqueous 8N HCl solution, after which thiourea (24.2) was added until the reaction mixture became a clear solution. The reaction mixture was stirred at reflux temperature for 48 hours during which more thiourea (18 g) was added portion wise, until complete conversion. The reaction mixture was cooled to 0 C. and quenched by the addition of an aqueous 4N NaOH solution (130 ml). The formed precipitate was dissolved in CH.sub.2Cl.sub.2 (220 mL) and the organic layer was washed with water. The aqueous layer was acidified to pH=3 and extracted with CH.sub.2Cl.sub.2 3 times. The combined organic layers were dried over MgSO.sub.4 and concentrated under vacuo. The residue was recrystallized from ethanol to give 5-methylpyridine-2-thiol (11.2 g) as a white solid.

[0507] ii) To a suspension of the product obtained in the previous step (2.3 g) and K.sub.2CO.sub.3 (600 mg) in acetonitrile (45 mL) was added at room temperature (bromomethyl)cyclopropane (10.4 mL). After stirring for 48 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 2-[(cyclopropylmethyl)sulfanyl]-5-methylpyridine (17 g). The product was used in the next step without further purification.

[0508] iii) m-CPBA (38.1 g) was added to an ice cold solution of the product obtained in the previous step (17 g) in CH.sub.2Cl.sub.2 (250 mL). After stirring the reaction mixture over the weekend at room temperature, the reaction mixture was filtered and the filtrate was washed with a saturated aqueous NaHCO.sub.3 solution, water and brine. The organic layer was dried on MgSO.sub.4 and concentrated under reduced pressure to give 2-cyclopropylmethanesulfonyl-5-methylpyridine (17 g) as a white solid. The product was used in the next step without further purification.

[0509] iv) To a solution of the product obtained in the previous step (17 g) in acetonitrile (150 mL) were added NBS (15.8 g) and AIBN (660 mg). The reaction mixture was stirred for 17 hours at reflux temperature under a nitrogen atmosphere. After cooling, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified on SiO.sub.2, using 0% to 30% ethyl acetate in heptane as the eluent, to give 5-(bromomethyl)-2-cyclopropylmethanesulfonylpyridine (10.6 g).

[0510] v) The product obtained in the previous step (9 g) was added to a nitrogen purged solution of trimethylsilyl cyanide (3.1 g) and TBAF (31 mL) in acetonitrile (75 mL). The reaction mixture was stirred at 90 C. in a microwave reactor for 30 minutes. After cooling to room temperature the reaction mixture was diluted with a 3 to 1 mixture of CH.sub.2Cl.sub.2 and 2-propanol. The resulting mixture was washed with water, brine, dried on MgSO.sub.4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified on SiO.sub.2, using 0% to 80% ethyl acetate in heptane as the eluent to give 2-(6-cyclopropylmethanesulfonylpyridin-3-yl)acetonitrile (2.1 g) as a white solid.

[0511] vi) To a solution of the product obtained in the previous step (2.1 g) in ethanol (28 mL) was added a 2N aqueous NaOH solution (28 mL). The reaction mixture was stirred for 17 hours in a microwave reactor at 80 C. After cooling to room temperature, the reaction mixture was washed with CH.sub.2Cl.sub.2. The aqueous layer was acidified to pH=3 and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried on MgSO.sub.4, filtered and concentrated under reduced pressure to give 2-(6-cyclopropylmethanesulfonylpyridin-3-yl)acetic acid (1.9 g) as the crude product. The product was used in the next step without further purification.

[0512] vii) Following a procedure analogous to that described for example 1, using the product obtained in the previous step and appropriate starting materials, the title compound 4-[2-(6-cyclopropylmethanesulfonylpyridin-3-yl)acetamido]-N-phenyl-N-(2,2,2-trifluoroethyl)benzamide (63 mg) has been prepared. MS (ES.sup.+) m/z 532.2 (M+H).sup.+.

[0513] Following a procedure analogous to that described for example 155, the following compounds have been prepared.

156: 4-[2-(6-cyclopropylmethanesulfonylpyridin-3-yl)acetamido]-N-ethyl-2-fluoro-N-phenylbenzamide

[0514] ##STR00164##

[0515] MS (ES.sup.+) m/z 496.2 (M+H).sup.+.

157: 2-chloro-4-[2-(6-cyclopropylmethanesulfonylpyridin-3-yl)acetamido]-N-ethyl-N-phenylbenzamide

[0516] ##STR00165##

[0517] MS (ES.sup.+) m/z 512.2 (M+H).sup.+.

158: N-tert-butyl-4-[2-(6-cyclopropylmethanesulfonylpyridin-3-yl)acetamido]-N-phenylbenzamide

[0518] ##STR00166##

[0519] MS (ES.sup.+) m/z 506.2 (M+H).sup.+.

159: N-tert-butyl-4-[2-(6-cyclopropylmethanesulfonylpyridin-3-yl)acetamido]-3-fluoro-N-phenylbenzamide

[0520] ##STR00167##

[0521] MS (ES.sup.+) m/z 524.2 (M+H).sup.+.

160: 4-[2-(6-cyclopropylmethanesulfonylpyridin-3-yl)acetamido]-N-[2-(oxolan-2-yl)propan-2-yl]-N-phenylbenzamide

[0522] ##STR00168##

[0523] MS (ES.sup.+) m/z 562.2 (M+H).sup.+.

161: 4-[2-(6-cyclopropylmethanesulfonylpyridin-3-yl)acetamido]-N-(1-hydroxy-2-methylpropan-2-yl)-N-(4-methylphenyl)benzamide

[0524] ##STR00169##

[0525] i) The title compound 4-[2-(6-cyclopropylmethanesulfonylpyridin-3-yl)acetamido]-N-(1-hydroxy-2-methylpropan-2-yl)-N-(4-methylphenyl)benzamide has been prepared following a procedure analogous to that described for example 151, using 2-(6-cyclopropylmethanesulfonylpyridin-3-yl)acetic acid (example 155. step vi) as the starting material. MS (ES.sup.+) m/z 536.2 (M+H).sup.+.

162: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-2-methyl-N-phenylbenzamide

[0526] ##STR00170##

[0527] i) Following a procedure analogous to that described in Example 1, step iv), using 4-bromo-2-methylbenzoic acid (1.0 g) and N-ethylaniline (0.64 mL) as the starting materials, 4-bromo-N-ethyl-2-methyl-N-phenylbenzamide was synthesized (1.2 g).

[0528] ii) To a solution of the product obtained in the previous step (0.5 g) in NMP were added Cu.sub.2O (11 mg) and an aqueous 35% NH.sub.4OH solution (2 mL) and the mixture was stirred, for 8 hours, in a sealed tube at 80 C. in a microwave. The blue reaction mixture was poured into water and the product was extracted into ethyl acetate. The organic phase was washed with brine, dried on MgSO.sub.4 and concentrated under reduced pressure giving 4-amino-N-ethyl-2-methyl-N-phenylbenzamide (0.4 g). The crude product was used without further purification in the next step.

[0529] iii) Following a procedure analogous to that described in Example 1, step iv), the product obtained in the previous step (54 mg) was converted to the title compound 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-2-methyl-N-phenylbenzamide (60 mg). MS (ES.sup.+) m/z 491.2 (M+H).sup.+.

[0530] Following a procedure analogous to that described for Example 162, using appropriate starting materials, the following compounds have been prepared.

163: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N,2-dimethyl-N-(2-methylphenyl)benzamide

[0531] ##STR00171##

[0532] MS (ES.sup.+) m/z 491.2 (M+H).sup.+.

164: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2,3-dimethylphenyl)-N-ethyl-2-methylbenzamide

[0533] ##STR00172##

[0534] MS (ES.sup.+) m/z 519.3 (M+H).sup.+.

165: 4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2-fluorophenyl)-N,2-dimethylbenzamide

[0535] ##STR00173##

[0536] MS (ES.sup.+) m/z 495.3 (M+H).sup.+.

166: N-(2-chlorophenyl)-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-2-methylbenzamide

[0537] ##STR00174##

[0538] MS (ES.sup.+) m/z 525.3 (M+H).sup.+.

Example 167

[0539] ROR GAL4 Reporter Gene Assay

[0540] Example inhibitors 1-166 were tested for their ability to inhibit ROR activity in a ROR GAL4 reporter gene assay. The assay procedure and results are described below.

[0541] ROR GAL4 Reporter Gene Assay Description

[0542] A GAL4 one-hybrid reporter system employing luciferase readout was established to determine inhibition of ROR in 293FT cells. The ROR ligand-binding domain (LBD) was fused to the yeast GAL4 DNA binding domain (DBD) and placed under the control of the human cytomegalovirus (CMV) immediate early promoter, using expression vector pFN26A (Promega) and standard recombinant DNA cloning methods. To serve as a control in the assay, a similar vector was generated in which the GAL4-DBD was fused to Herpes simplex virus protein 16 (VP16), a constitutive transcriptional activator.

[0543] To monitor the inhibitory effect of compounds on ROR, a transcriptional reporter construct was used. The pGL4.35 vector (Promega) contains nine copies of the GAL4 Upstream Activator Sequence (UAS). This sequence drives the transcription of the luciferase reporter gene luc2P in response to binding of a fusion protein containing the GAL4 DNA binding domain, as for example expressed by the GAL4-ROR-LBD and GAL4-VP16 expression vectors described above. To allow a GAL4 fusion protein to drive the expression of the luciferase reporter, the pGL4.35 expression vector and the appropriate GAL4 fusion protein expression vector were bulk transfected in the 293FT cells using standard transfection techniques.

[0544] The day after transfection, cells were plated into 96 well plates, test compound was added and the plates were incubated overnight. Subsequently, the firefly luciferase activity was quantified using luciferase detection reagent and luminescence readout.

[0545] Detailed Assay Description

[0546] 293FT cells (Invitrogen) were transfected with a GAL4 fusion protein expression vector (as described above) and the transcriptional reporter construct (pGL4.35, Promega). 60 L of TransIT-293 transfection reagent (Mirus Bio) was added drop wise to 1500 l Opti-MEM I Reduced Serum Medium (Invitrogen) and incubated at room temperature (RT) for 5 to 20 minutes. 1500 L of this reagent mixture was added to 5 g of GAL4 fusion protein expression vector and 5 g of the transcriptional reporter construct, and incubated at RT for 20 minutes.

[0547] To harvest 293FT cells from a T75 flask, first the culture medium was taken off the cells. Subsequently, the cells were washed with Phosphate Buffered Saline (PBS) (Lonza), after which the PBS was removed. To dissociate the cells, 1 ml of TrypLE Express (Invitrogen) was added to the flask, followed by incubation at RT until the cells visually started to detach. Cells were collected in 5 mL of assay medium (DMEM culture medium (Lonza), 10% dialyzed FBS (Invitrogen) and Pen/Strep (Lonza)) to achieve a single cell suspension. 1010.sup.6 cells were spun down and re-suspended in 10 mL of assay medium. Subsequently, the cell suspension was added to the transfection mix tube, and then transferred as a whole to a T75 flask (Greiner), followed by overnight (16-24 hours) incubation at 37 C. and 5% CO.sub.2.

[0548] For compound screening, the cells were harvested (as described above) and counted. 1310.sup.6 cells were spun down, the supernatant was aspirated and the cells were re-suspended in 17.3 mL of assay medium obtaining a cell suspension of 0.7510.sup.6 cells/mL. 80 L of cell suspension (60,000 cells) was plated per well into a white, flat bottom, tissue culture treated, 96 well screening plates (Greiner).

[0549] Test compounds were diluted, starting from a 10 mM dimethylsulfoxide (DMSO) stock solution, to serial dilutions in DMSO at 500 the final test concentration. Subsequently, these solutions were diluted to 5 the final test concentration in two 10-fold-dilution steps in assay medium. The final DMSO concentration of the 5 test compound solution was 1%. 20 L of the 5 test compound solution was added to each test well of the 96 well plate previously plated with 80 l cell suspension, resulting in the final test concentration with 0.2% DMSO.

[0550] The plates were incubated overnight (16-24 hours) at 37 C. and 5% CO.sub.2.

[0551] For the luciferase readout, the luciferase reagent (Britelite Plus, Perkin Elmer) was brought to RT. To each test well of the screening plates, 100 L of 2.5-fold diluted Britelite Plus reagent was added, followed by incubation at RT for 10 minutes. The luciferase luminescence signal was measured using a Wallac Victor Microplate Reader (Perkin Elmer).

[0552] The half maximum inhibitory concentration (1050) values for the test compounds were calculated from the luciferase signal using GraphPad Prism software (GraphPad Software).

[0553] All exemplified compounds of Formula I (Examples 1-166) were found to have mean pIC.sub.50 values above 5.

[0554] Examples 1-3, 5-76, 79, 81-97, 99-149 and 153-166 were found to have mean pIC.sub.50 values above or equal to 6.

[0555] Examples 3, 5, 6, 9, 10, 12, 14-22, 24, 27, 29-32, 35, 37, 40, 42-49, 51-53, 55-59, 61, 63, 64, 66, 71, 74, 75, 81-84, 86-90, 92-96, 99, 100, 102-105, 107-109, 113, 115-146, 148, 149 and 153-166 were found to have mean pIC.sub.50 values above or equal to 7.

[0556] Examples 3, 16, 19-21, 29, 31, 32, 37, 40, 43, 45, 46, 49, 63, 64, 81, 83, 86-90, 92-94, 99, 102-104, 109, 113, 117-119, 122-131, 134, 139, 140-142, 144-146, 149, 155, 158, 159, 163, 164 and 166 were found to have mean pIC.sub.50 values above or equal to 8.

Example 168

[0557] Peripheral Blood Mononuclear Cell (PBMC) IL-17 Assay

[0558] Example inhibitors 3, 6, 9, 16, 17, 19, 20, 31, 35, 40, 45, 64, 71, 81, 86-89, 94, 103, 104, 115, 121, 130, 131, 133, 135, 137, 140, 144-146, 153, 155 and 158-160 were tested for their ability to inhibit the IL-17A production in anti-CD3/anti-CD28 stimulated peripheral blood mononuclear cells (PBMCs) isolated from human blood. The assay procedure and results are described below.

[0559] PBMC IL-17 Assay Description

[0560] This assay is designed to measure the levels of IL-17A secreted from anti-CD3/anti-CD28 stimulated PBMCs with the aim of measuring ROR mediated inhibition of IL-17A production.

[0561] The assay medium consists of 90% RPMI 1640 (Lonza), 10% heat inactivated fetal bovin serum (FBS, Lonza) and 100 U/mL penicillin/streptomycin solution.

[0562] Assay Description

[0563] Anti-CD3 antibody (BD Pharmingen) was diluted to 10 g/ml in PBS (Lonza). 30 L of 10 g/ml anti-CD3 solution was added to the inner 60 wells, excluding any negative control wells, of a 96-well cell culture treated U-bottom plate (Greiner). Plates were incubated overnight (16-24 hours) at 37 C. and 5% CO.sub.2.

[0564] Peripheral blood mononuclear cells were separated from buffy coats (Sanquin) using Ficoll-Paque PREMIUM separation medium (GE Healthcare Life Sciences) according to manufacturer's protocol and re-suspended in assay medium at 37 C.

[0565] Test compounds were diluted, starting from a 10 mM dimethylsulfoxide (DMSO) stock solution, to serial dilutions in DMSO at 200 the final test concentration. Subsequently, these solutions were diluted in two dilution steps in assay medium to 10 the final test concentration. The DMSO concentration of the 10 test compound solution was 5%.

[0566] Anti-CD28 antibody (BD Pharmingen) was diluted to 20 g/mL in PBS. The PBMCs were diluted to a concentration of 2.510.sup.6 cells/mL in assay medium at 37 C.

[0567] For compound screening, the anti-CD3 coated plates were washed three times with PBS, the wells were subsequently aspirated using vacuum. To each screening well 80 L of the PBMC suspension, 10 L of the anti-CD28 solution and 10 L of the 10 test compound solution was added, resulting in the final test concentration with 0.5% DMSO. All outer wells were filled with assay medium to prevent evaporation. Plates were incubated for 5 days at 37 C. and 5% CO.sub.2.

[0568] After incubation the plates were spun down at 1500 rpm for 4 minutes and the supernatant was collected. Subsequently, the IL-17A levels in the supernatants was determined using an IL-17 ELISA kit (human IL-17 DuoSet, R&D systems) according to manufacturer's protocol.

[0569] The half maximum inhibitory concentration (1050) values for the test compounds were calculated from the IL-17A signal using GraphPad Prism software (GraphPad Software).

[0570] The tested examples 3, 6, 9, 16, 17, 19, 20, 31, 35, 40, 45, 64, 71, 81, 86-89, 94, 103, 104, 115, 121, 130, 131, 133, 135, 137, 140, 144-146, 153, 155 and 158-160 were found to have mean pIC.sub.50 values above or equal to 6.

[0571] Examples 3, 16, 17, 19, 20, 31, 35, 40, 64, 81, 86-89, 94, 104, 115, 121, 130, 131, 133, 135, 137, 140, 144-146, 153, 155 and 158-160 were found to have mean pIC.sub.50 values above or equal to 7.

[0572] Examples 3, 16, 19, 20, 31, 64, 81, 86-89, 94, 104, 115, 130, 133, 140, 144-146, 155 and 158 were found to have mean pIC.sub.50 values above or equal to 8.