ROR gamma (RORγ) modulators

Abstract

Compounds according to Formula I: ##STR00001##
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.2 and R.sub.3 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; R.sub.9 is selected from the group consisting of Formula II, III, IV and V ##STR00002## The compounds can be used as inhibitors of ROR and are useful for the treatment of ROR mediated diseases.

Claims

1. A compound according to Formula I ##STR00061## 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.3, A.sub.4 and A.sub.5 are independently N or CR.sub.2, CR.sub.3, CR.sub.4 and CR.sub.5, respectively, with the proviso that no more than two of the four positions A in A.sub.2, A.sub.3, A.sub.4 and A.sub.5 can be simultaneously N; R.sub.2, R.sub.3, R.sub.4, and 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, wherein methyl or ethyl groups, if present, may be optionally substituted with one or more F; R.sub.8 is H or C(1-6)alkyl; R9 is selected from the group consisting of Formula II, III, IV and V ##STR00062## wherein: A.sub.10, A.sub.11, A.sub.12, and A.sub.13 are independently N or CR.sub.10, CR.sub.11, CR.sub.12, and CR.sub.13, respectively, with the proviso that no more than two of the four positions A in A.sub.10, A.sub.11, A.sub.12, and A.sub.13 can be simultaneously N; R.sub.10, R.sub.11, R.sub.12, and R.sub.13 are independently H, halogen, amino, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-6)alkyl; X.sub.14 is either C(6-10)aryl or C(1-9)heteroaryl, with all carbon atoms optionally substituted with halogen, amino, cyano, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-3)alkyl; ##STR00063## wherein: A.sub.20, A.sub.21, A.sub.22, A.sub.23, A.sub.24, A.sub.25, A.sub.26 and A.sub.27 are N or CR.sub.20, CR.sub.21, CR.sub.22, CR.sub.23, CR.sub.24, CR.sub.25, CR.sub.26 and CR.sub.27, respectively, with the proviso that no more than two of the three positions A in A.sub.20, A.sub.21 and A.sub.22 can be simultaneously N and that no more than three of the five positions A in A.sub.23, A.sub.24, A.sub.25, A.sub.26 and A.sub.27 can be simultaneously N; R.sub.20, R.sub.21 and R.sub.22 are independently H, halogen, amino, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-6)alkyl; R.sub.23, R.sub.24, R.sub.25, R.sub.26 and R.sub.27 are independently H, halogen, amino, cyano, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-3)alkyl; X.sub.28 is either C(6-10)aryl or C(1-9)heteroaryl, with all carbon atoms optionally substituted with halogen, amino, cyano, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-3)alkyl; ##STR00064## wherein: A.sub.30 is N or C; A.sub.31 is O, carbonyl, NR.sub.31 or CR.sub.32; R.sub.31 is H or C(1-6)alkyl; R.sub.32 is H, OH, or C(1-3)alkyl, with all alkyl groups optionally substituted with one or more F or OH; A.sub.33, A.sub.34, A.sub.35, A.sub.36, A.sub.37, A.sub.38, A.sub.39, A.sub.40, A.sub.41 and A.sub.42 are N or CR.sub.33, CR.sub.34, CR.sub.35, CR.sub.36, CR.sub.37, CR.sub.38, CR.sub.39, CR.sub.40, CR.sub.41 and CR.sub.42 respectively, with the proviso that no more than three of the five positions A in A.sub.33, A.sub.34, A.sub.35, A.sub.36 and A.sub.37 can be simultaneously N and that no more than three of the five positions A in A.sub.38, A.sub.39, A.sub.40, A.sub.41 and A.sub.42 can be simultaneously N; R.sub.33, R.sub.34, R.sub.35, R.sub.36, R.sub.37, R.sub.38, R.sub.39, R.sub.40, R.sub.41 and R.sub.42 are independently H, halogen, amino, cyano, C(1-3)alkoxy, (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.

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

4. The compound according to claim 1 where R.sub.1 is hydrogen.

5. The compound according to claim 1 wherein R.sub.6, and R.sub.7 are both H.

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

7. The compound according to claim 1 wherein all positions A in A.sub.2, A.sub.3, A.sub.4 and A.sub.5 are CR.sub.2, CR.sub.3, CR.sub.4 and CR.sub.5, and all positions R in R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are H.

8. The compound according to claim 1 where R9 is according to Formula II wherein: A.sub.10, A.sub.11, A.sub.12 and A.sub.13 are N or CR.sub.10, CR.sub.11, CR.sub.12 and CR.sub.13 respectively, with the proviso that no more than two of the four positions A in A.sub.10, A.sub.11, A.sub.12 and A.sub.13 can be simultaneously N; R.sub.10, R.sub.11, R.sub.12 and R.sub.13 are independently H, amino, halogen, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-6)alkyl; X.sub.14 is either C(6)aryl or C(1-5)heteroaryl, with all carbon atoms optionally substituted with halogen, cyano, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-3)alkyl.

9. The compound according to claim 1 where R9 is according to Formula III wherein: A.sub.20, A.sub.21, A.sub.22, A.sub.23, A.sub.24, A.sub.25, A.sub.26 and A.sub.27 are N or CR.sub.20, CR.sub.21, CR.sub.22, CR.sub.23, CR.sub.24, CR.sub.25, CR.sub.26 and CR.sub.27 respectively, with the proviso that no more than two of the three positions A in A.sub.20, A.sub.21 and A.sub.22 can be simultaneously N and that no more than three of the five positions A in A.sub.23, A.sub.24, A.sub.25, A.sub.26 and A.sub.27 can be simultaneously N; R.sub.20, R.sub.21 and R.sub.22 are independently H, halogen, amino, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-6)alkyl; R.sub.23, R.sub.24, R.sub.25, R.sub.26 and R.sub.27 are independently H, halogen, cyano, amino, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-3)alkyl; X.sub.28 is either C(6)aryl or C(1-5)heteroaryl, with all carbon atoms optionally substituted with halogen, cyano, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-3)alkyl.

10. The compound according to claim 1 where R9 is according to Formula IV or V wherein: A.sub.30 is N or C; A.sub.31 is O, carbonyl, NR.sub.31 or CR.sub.32; R.sub.31 is H or C(1-6)alkyl; R.sub.32 is H, OH or C(1-6)alkyl, with all alkyl groups optionally substituted with one or more F or OH; A.sub.33, A.sub.34, A.sub.35, A.sub.36, A.sub.37, A.sub.38, A.sub.39, A.sub.40, A.sub.41 and A.sub.42 are N or CR.sub.33, CR.sub.34, CR.sub.35, CR.sub.36, CR.sub.37, CR.sub.38, CR.sub.39, CR.sub.40, CR.sub.41 and CR.sub.42 respectively, with the proviso that no more than three of the five positions A.sub.33, A.sub.34, A.sub.35, A.sub.36 and A.sub.37 can be simultaneously N and that no more than three of the five positions A.sub.38, A.sub.39, A.sub.40, A.sub.41 and A.sub.42 can be simultaneously N; R.sub.33, R.sub.34, R.sub.35, R.sub.36, R.sub.37, R.sub.38, R.sub.39, R.sub.40, R.sub.41 and R.sub.42 are independently H, halogen, cyano, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-3)alkyl.

11. The compound as defined in claim 1 which is selected from the group of: 2-(4-cyclopropylmethanesulfonylphenyl)-N-(3-phenoxy-4-phenylphenyl)acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(3-fluorophenyl)-3-(3-methoxyphenoxy)phenyl]acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[3-(3-methoxyphenoxy)-4-(4-methyl-1H-imidazol-1-yl)phenyl]acetamide; N-[3-(3-chlorophenoxy)-4-(3-fluorophenyl)phenyl]-2-(4-cyclopropylmethanesulfonylphenyl)acetamide; N-[3-(3-chlorophenoxy)-4-(3,4-difluorophenyl)phenyl]-2-(4-cyclopropylmethanesulfonylphenyl)acetamide; N-[3-(3-cyanophenoxy)-4-(3,4-difluorophenyl)phenyl]-2-(4-cyclopropylmethanesulfonylphenyl)acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[3-(3-methoxyphenoxy)-4-(5-methyl-1H-pyrazol-1-yl)phenyl]acetamide; N-[3-(3-chlorophenoxy)-4-(3,5-difluorophenyl)phenyl]-2-(4-cyclopropylmethanesulfonylphenyl)acetamide; N-[4-(4-cyanophenyl)-3-(3-fluorophenoxy)phenyl]-2-(4-cyclopropylmethanesulfonylphenyl)acetamide; N-[3-(3-chlorophenoxy)-4-(3-cyanophenyl)phenyl]-2-(4-cyclopropylmethanesulfonylphenyl)acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(3-fluorophenyl)-3]3-(trifluoromethyl)phenoxy]phenyl]acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[3-(3-fluorophenoxy)-4-(4-fluorophenyl)phenyl]acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[3-(3,5-difluorophenoxy)-4-(3-fluorophenyl)phenyl]acetamide; 2-[4-(cyclopropylsulfamoyl)phenyl]-N-[3-(3-methoxyphenoxy)-4-(4-methyl-1H-imidazol-1-yl)phenyl]acetamide; 2-[4-(cyclopropylsulfamoyl)phenyl]-N-[3-(3-methoxyphenoxy)-4-(5-methyl-1H-pyrazol-1-yl)phenyl]acetamide; 2-[4-(cyclopropylsulfamoyl)phenyl]-N-[4-(3-fluorophenyl)-3-(3-methoxyphenoxy)phenyl]lacetamide; N-[3-(3-chlorophenoxy)-4-(3-fluorophenyl)phenyl]-2-[4-(cyclopropylsulfamoyl)phenyl]acetamide; N-[3-(3-chlorophenoxy)-4-(3,4-difluorophenyl)phenyl]-2-[4-(cyclopropylsulfamoyl)phenyl]acetamide; 2-[4-(cyclopropylsulfamoyl)phenyl]-N-[4-(3-fluorophenyl)-3-[3-(trifluoromethyl)phenoxy]phenyl]acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-(5-phenoxy-4-phenyl-1,3-thiazol-2-yl)acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-phenyl-5-(pyridin-3-yloxy)-1,3-thiazol-2-yl]acetamide; N-(5-benzoyl-4-phenyl-1,3-thiazol-2-yl)-2-(4-cyclopropylmethanesulfonylphenyl)acetamide; N-[5-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1,3-thiazol-2-yl]-2-(4-cyclopropylmethanesulfonylphenyl)acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-(4-phenylthiophen-2-yl)acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(pyridin-3-yl)thiophen-2-yl]acetamide; N-(5-benzoyl-4-phenyl-1,3-thiazol-2-yl)-2-[4-(cyclopropylsulfamoyl)phenyl]acetamide; N-(5-benzoyl-4-phenylthiophen-2-yl)-2-(4-cyclopropylmethanesulfonylphenyl)acetamide; N-{3-chloro-4-[2-(trifluoromethoxy)phenyl]phenyl}-2-(4-cyclopropylmethanesulfonylphenyl)acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-{3-methyl-4-[2-(trifluoromethoxy)phenyl]phenyl}acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-{3,5-dichloro-4-[2-(trifluoromethoxy)phenyl]phenyl}acetamide; 2-(4-cyclopropylmethane sulfonylphenyl)-N-{4-methyl-5-[2-(trifluoromethoxy)phenyl]pyridin-2-yl}acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-{6-methyl-5-[2-(trifluoromethoxy)phenyl]pyridin-2-yl}acetamide; N-{3-chloro-4-[2-(trifluoromethoxy)phenyl]phenyl}-2-[4-(cyclopropylsulfamoyl)phenyl]acetamide; 2-[4-(cyclopropylsulfamoyl)phenyl]-N-{6-methyl-5-[2-(trifluoromethoxy)phenyl]pyridin-2-yl}acetamide; 2-[4-(cyclopropylsulfamoyl)phenyl]-N-{4-methyl-5-[2-(trifluoromethoxy)phenyl]pyridin-2-yl}acetamide; 2-[4-(cyclopropylsulfamoyl)phenyl]-N-{3-methyl-4-[2-(trifluoromethoxy)phenyl]phenyl}acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-{4,6-dimethyl-5-[2-(trifluoromethoxy)phenyl]pyridin-2-yl}acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(4-methyl-1H-imidazol-1-yl)phenyl]acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(5-methyl-1H-imidazol-1-yl)phenyl]acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(3-methyl-1H-pyrazol-1-yl)phenyl]acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(5-methyl-1H-pyrazol-1-yl)phenyl]acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(4-methyl-1H-pyrazol-1-yl)phenyl]acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(1,3-oxazol-5-yl)phenyl]acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(1H-pyrazol-1-yl)phenyl]acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(1H-imidazol-1-yl)phenyl]acetamide; 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(1H-1,2,4-triazol-1-yl)phenyl]acetamide and 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(1,2,4-oxadiazol-3-yl)phenyl]acetamide.

12. 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.

13. A method for the treatment of rheumatoid arthritis, psoriasis, inflammatory bowel disease, Crohn's disease or multiple sclerosis comprising administering to a patent in need thereof the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

14. A method for the treatment of osteoarthritis or asthma comprising administering to a patent in need thereof the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

15. A method for the treatment of mucosal leishmaniasis comprising administering to a patent in need thereof the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

16. A method for the treatment of Kawaski disease or Hashimoto's thyroiditis comprising administering to a patent in need thereof the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

Description

EXAMPLES

Examples 1-47

1: 2-(4-cyclopropylmethanesulfonylphenyl)-N-(3-phenoxy-4-phenylphenyl)acetamide

(1) ##STR00014##

(2) i) To a solution of 2-(4-cyclopropylmethanesulfonylphenyl)acetic acid (29 mg), 3-phenoxy-4-phenylaniline (30 mg) and DMAP (3 mg) in CH.sub.2Cl.sub.2 (0.5 mL) was added dropwise at 0 C. a solution of EDCI (32 mg) in CH.sub.2Cl.sub.2. The reaction mixture was stirred at 60 C. for 1 hour in a microwave. After cooling to 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% methanol in CH.sub.2Cl.sub.2 as the eluent, giving the title compound 2-(4-cyclopropylmethanesulfonylphenyl)-N-(3-phenoxy-4-phenylphenyl)acetamide (70 mg) as a white solid. MS(ES.sup.+) m/z 498.2 (M+H).sup.+.

(3) Following a procedure described for Example 1, the following compounds have been prepared.

2: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(3-fluorophenyl)-3-(3-methoxyphenoxy)phenyl]acetamide

(4) ##STR00015##

3: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[3-(3-methoxyphenoxy)-4-(4-methyl-1H-imidazol-1-yl)phenyl]acetamide

(5) ##STR00016##

4: N-[3-(3-chlorophenoxy)-4-(3-fluorophenyl)phenyl]-2-(4-cyclopropylmethanesulfonylphenyl)acetamide

(6) ##STR00017##

5: N-[3-(3-chlorophenoxy)-4-(3,4-difluorophenyl)phenyl]-2-(4-cyclopropylmethanesulfonylphenyl)acetamide

(7) ##STR00018##

6: N-[3-(3-cyanophenoxy)-4-(3,4-difluorophenyl)phenyl]-2-(4-cyclopropylmethanesulfonylphenyl)acetamide

(8) ##STR00019##

7: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[3-(3-methoxyphenoxy)-4-(5-methyl-1H-pyrazol-1-yl)phenyl]acetamide

(9) ##STR00020##

8: N-[3-(3-chlorophenoxy)-4-(3,5-difluorophenyl)phenyl]-2-(4-cyclopropylmethanesulfonylphenyl)acetamide

(10) ##STR00021##

9: N-[4-(4-cyanophenyl)-3-(3-fluorophenoxy)phenyl]-2-(4-cyclopropylmethanesulfonylphenyl)acetamide

(11) ##STR00022##

10: N-[3-(3-chlorophenoxy)-4-(3-cyanophenyl)phenyl]-2-(4-cyclopropylmethanesulfonylphenyl)acetamide

(12) ##STR00023##

11: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(3-fluorophenyl)-3-[3-(trifluoromethyl)phenoxy]phenyl]acetamide

(13) ##STR00024##

12: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[3-(3-fluorophenoxy)-4-(4-fluorophenyl)phenyl]acetamide

(14) ##STR00025##

13: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[3-(3,5-difluorophenoxy)-4-(3-fluorophenyl)phenyl]acetamide

(15) ##STR00026##

14: 2-[4-(cyclopropylsulfamoyl)phenyl]-N-[3-(3-methoxyphenoxy)-4-(4-methyl-1H-imidazol-1-yl)phenyl]acetamide

(16) ##STR00027##

15: 2-[4-(cyclopropylsulfamoyl)phenyl]-N-[3-(3-methoxyphenoxy)-4-(5-methyl-1H-pyrazol-1-yl)phenyl]acetamide

(17) ##STR00028##

16: 2-[4-(cyclopropylsulfamoyl)phenyl]-N-[4-(3-fluorophenyl)-3-(3-methoxyphenoxy)phenyl]acetamide

(18) ##STR00029##

17: N-[3-(3-chlorophenoxy)-4-(3-fluorophenyl)phenyl]-2-[4-(cyclopropylsulfamoyl)phenyl]acetamide

(19) ##STR00030##

18: N-[3-(3-chlorophenoxy)-4-(3,4-difluorophenyl)phenyl]-2-[4-(cyclopropylsulfamoyl)phenyl]acetamide

(20) ##STR00031##

19: 2-[4-(cyclopropylsulfamoyl)phenyl]-N-[4-(3-fluorophenyl)-3-[3-(trifluoromethyl)phenoxy]phenyl]acetamide

(21) ##STR00032##

20: 2-(4-cyclopropylmethanesulfonylphenyl)-N-(5-phenoxy-4-phenyl-1,3-thiazol-2-yl)acetamide

(22) ##STR00033##

21: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-phenyl-5-(pyridin-3-yloxy)-1,3-thiazol-2-yl]acetamide

(23) ##STR00034##

22: N-(5-benzoyl-4-phenyl-1,3-thiazol-2-yl)-2-(4-cyclopropylmethanesulfonylphenyl)acetamide

(24) ##STR00035##

23: N-[5-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1,3-thiazol-2-yl]-2-(4-cyclopropylmethanesulfonylphenyl)acetamide

(25) ##STR00036##

24: 2-(4-cyclopropylmethanesulfonylphenyl)-N-(4-phenylthiophen-2-yl)acetamide

(26) ##STR00037##

25: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(pyridin-3-yl)thiophen-2-yl]acetamide

(27) ##STR00038##

26: N-(5-benzoyl-4-phenyl-1,3-thiazol-2-yl)-2-[4-(cyclopropylsulfamoyl)phenyl]acetamide

(28) ##STR00039##

27: N-(5-benzoyl-4-phenylthiophen-2-yl)-2-(4-cyclopropylmethanesulfonylphenyl)acetamide

(29) ##STR00040##

28: N-{3-chloro-4-[2-(trifluoromethoxy)phenyl]phenyl}-2-(4-cyclopropylmethanesulfonylphenyl)acetamide

(30) ##STR00041##

29: 2-(4-cyclopropylmethanesulfonylphenyl)-N-{3-methyl-4-[2-(trifluoromethoxy)phenyl]phenyl}acetamide

(31) ##STR00042##

30: 2-(4-cyclopropylmethanesulfonylphenyl)-N-{3,5-dichloro-4-[2-(trifluoromethoxy)phenyl]phenyl}acetamide

(32) ##STR00043##

31: 2-(4-cyclopropylmethanesulfonylphenyl)-N-{4-methyl-5-[2-(trifluoromethoxy)phenyl]pyridin-2-yl}acetamide

(33) ##STR00044##

32: 2-(4-cyclopropylmethanesulfonylphenyl)-N-{6-methyl-5-[2-(trifluoromethoxy)phenyl]pyridin-2-yl}acetamide

(34) ##STR00045##

33: N-{3-chloro-4-[2-(trifluoromethoxy)phenyl]phenyl}-2-[4-(cyclopropylsulfamoyl)phenyl]acetamide

(35) ##STR00046##

34: 2-[4-(cyclopropylsulfamoyl)phenyl]-N-{6-methyl-5-[2-(trifluoromethoxy)phenyl]pyridin-2-yl}acetamide

(36) ##STR00047##

35: 2-[4-(cyclopropylsulfamoyl)phenyl]-N-{4-methyl-5-[2-(trifluoromethoxy)phenyl]pyridin-2-yl}acetamide

(37) ##STR00048##

36: 2-[4-(cyclopropylsulfamoyl)phenyl]-N-{3-methyl-4-[2-(trifluoromethoxy)phenyl]phenyl}acetamide

(38) ##STR00049##

37: 2-(4-cyclopropylmethanesulfonylphenyl)-N-{4,6-dimethyl-5-[2-(trifluoromethoxy)phenyl]pyridin-2-yl}acetamide

(39) ##STR00050##

38: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(4-methyl-1H-imidazol-1-yl)phenyl]acetamide

(40) ##STR00051##

39: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(5-methyl-1H-imidazol-1-yl)phenyl]acetamide

(41) ##STR00052##

40: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(3-methyl-1H-pyrazol-1-yl)phenyl]acetamide

(42) ##STR00053##

41: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(5-methyl-1H-pyrazol-1-yl)phenyl]acetamide

(43) ##STR00054##

42: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(4-methyl-1H-pyrazol-1-yl)phenyl]acetamide

(44) ##STR00055##

43: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(1,3-oxazol-5-yl)phenyl]acetamide

(45) ##STR00056##

44: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(1H-pyrazol-1-yl)phenyl]acetamide

(46) ##STR00057##

45: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(1H-imidazol-1-yl)phenyl]acetamide

(47) ##STR00058##

46: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(1H-1,2,4-triazol-1-yl)phenyl]acetamide

(48) ##STR00059##

47: 2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(1,2,4-oxadiazol-3-yl)phenyl]acetamide

(49) ##STR00060##

Example 48

(50) ROR GAL4 Reporter Gene Assay

(51) Example inhibitors 1-47 were tested for their ability to inhibit ROR activity in a ROR GAL4 reporter gene assay. The assay procedure and results are described below.

(52) ROR GAL4 Reporter Gene Assay Description

(53) 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.

(54) 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.

(55) 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.

(56) Detailed Assay Description

(57) 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.

(58) 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.

(59) 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).

(60) Test compounds were diluted, starting from a 10 mM dimethylsulf oxide (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.

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

(62) 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).

(63) The half maximum inhibitory concentration (IC.sub.50) values for the test compounds were calculated from the luciferase signal using GraphPad Prism software (GraphPad Software).

(64) All exemplified compounds of Formula I (Examples 1-47) were found to have mean pIC.sub.50 values above 5.

(65) Examples 1-14, 16-37, 40-44, and 46-47 were found to have mean pIC50 values above or equal to 6.

(66) Examples 2-13, 22, 23, 26-34, 36, and 37 were found to have mean pIC50 values above or equal to 7.