ROR gamma (RORγ) modulators

Abstract

Novel compounds according to Formula I ##STR00001##
Meta or para or a pharmaceutically acceptable salt thereof wherein:
A.sub.11-A.sub.14 are N or CR.sub.11, CR.sub.12, CR.sub.13, CR.sub.14, respectively, with the proviso that no more than two of the four positions A in A.sub.11-A.sub.14 can be simultaneously N; A.sub.6, A.sub.7, A.sub.8, A.sub.9, A.sub.10 are N or CR.sub.6, CR.sub.7, CR.sub.8, CR.sub.9, CR.sub.10, respectively, with the proviso that at least one but no more than two of the five positions A in A.sub.6, A.sub.7, A.sub.8, A.sub.9, A.sub.10 is N; R.sub.1 is C(2-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, (di)C(3-6)cycloalkylamino or (di)(C(3-6)cycloalkylC(1-3)alkyl)amino; R.sub.5 is H, hydroxyethyl, methoxyethyl, C(1-6)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkylC(1-3)alkyl; the sulfonyl group with R.sub.1 is represented by one of R.sub.7, R.sub.8 or R.sub.9; R.sub.15 is H, C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl; and R.sub.16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl.

Claims

1. A compound according to Formula I ##STR00087## Meta or para or a pharmaceutically acceptable salt thereof wherein: A.sub.11-A.sub.14 are N or CR.sub.11, CR.sub.12, CR.sub.13, CR.sub.14, respectively, with the proviso that no more than two of the four positions A in A.sub.11-A.sub.14 can be simultaneously N; A.sub.6, A.sub.7, A.sub.8, A.sub.9, A.sub.10 are N or CR.sub.6, CR.sub.7, CR.sub.8, CR.sub.9, CR.sub.10, respectively, with the proviso that at least one but no more than two of the five positions A in A.sub.6, A.sub.7, A.sub.8, A.sub.9, A.sub.10 is N; R.sub.1 is C(2-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, (di)C(3-6)cycloalkylamino or (di)(C(3-6)cycloalkylC(1-3)alkyl)amino, with all carbon atoms of alkyl groups optionally substituted with one or more F and all carbon atoms of cycloalkyl groups optionally substituted with one or more F or methyl; R.sub.2 and R.sub.3 are independently H, F, methyl, ethyl, hydroxy, 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.4 is H or C(1-6)alkyl; R.sub.5 is H, hydroxyethyl, methoxyethyl, C(1-6)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkylC(1-3)alkyl, all groups optionally substituted with one or more F, C(1-2)alkoxy or cyano; the sulfonyl group with R.sub.1 is represented by one of R.sub.7, R.sub.8 or R.sub.9; the remaining R.sub.6-R.sub.14 are independently H, halogen, amino, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-6)alkyl, all of the alkyl groups optionally being substituted with one or more F; and R.sub.15 is H, C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl, all groups optionally substituted with one or more F, C(1-2)alkoxy or cyano; and R.sub.16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl, all groups optionally substituted with one or more F, C(1-2)alkyl, C(1-2)alkoxy or cyano.

2. The compound according to claim 1 wherein: A.sub.11-A.sub.14 are N or CR.sub.11, CR.sub.12, CR.sub.13, CR.sub.14, respectively, with the proviso that no more than two of the four positions A in A.sub.11-A.sub.14 can be simultaneously N; A.sub.6, A.sub.7, A.sub.9, A.sub.10 are N or CR.sub.6, CR.sub.7, CR.sub.9, CR.sub.10, respectively, with the proviso that at least one but no more than two of the four positions A in A.sub.6, A.sub.7, A.sub.9, A.sub.10 is N; A.sub.8 is CR.sub.8; R.sub.1 is C(3-6)cycloalkylC(1-3)alkyl or (di)C(3-6)cycloalkylamino with all carbon atoms of alkyl groups optionally substituted with one or more F and all carbon atoms of cycloalkyl groups optionally substituted with one or more F or methyl; R.sub.2 and R.sub.3 are independently H; R.sub.4 is H; R.sub.5 is H, hydroxyethyl, methoxyethyl, C(1-6)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkylC(1-3)alkyl, all groups optionally substituted with one or more F, C(1-2)alkoxy or cyano; the sulfonyl group with R.sub.1 is represented by R.sub.8; the remaining R.sub.6-R.sub.14 are independently H, halogen, C(1-3)alkoxy or C(1-6)alkyl, all of the alkyl groups optionally being substituted with one or more F or hydroxy; and R.sub.15 is C(1-6)alkyl or C(3-6)cycloalkyl, all groups optionally substituted with one or more F, C(1-2)alkoxy or cyano; and R.sub.16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl, all groups optionally substituted with one or more F, C(1-2)alkyl, C(1-2)alkoxy or cyano.

3. The compound according to claim 1 wherein: A.sub.11-A.sub.14 are respectively CR.sub.11, CR.sub.12, CR.sub.13, CR.sub.14; A.sub.6, A.sub.7, A.sub.9, A.sub.10 are N or CR.sub.6, CR.sub.7, CR.sub.9, CR.sub.10, respectively, with the proviso that at least one but no more than two of the four positions A in A.sub.6, A.sub.7, A.sub.9, A.sub.10 is N; A.sub.8 is CR.sub.8; R.sub.1 is C(3-6)cycloalkylC(1-3)alkyl, all carbon atoms of cycloalkyl groups optionally substituted with one or more F or methyl; R.sub.2 and R.sub.3 are independently H; R.sub.4 is H; R.sub.5 is H, hydroxyethyl, methoxyethyl, C(1-6)alkyl or C(2-5)heterocycloalkylC(1-3)alkyl; the sulfonyl group with R.sub.1 is represented by R.sub.8; the remaining R.sub.6-R.sub.14 are independently H, halogen, C(1-3)alkoxy or C(1-6)alkyl, all carbon atoms of alkyl groups optionally substituted with one hydroxy; R.sub.15 is C(1-6)alkyl or C(3-6)cycloalkyl, all carbon atoms of the alkyl groups optionally substituted with one or more F; and R16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl or C(6-10)aryl, all carbon atoms of the alkyl groups optionally substituted with one or more F.

4. The compound according to claim 1 wherein: A.sub.11 or A.sub.14 is N, the remaining position A being CR.sub.11 or CR.sub.14; A.sub.12 and A.sub.13 are respectively CR.sub.12 and CR.sub.13; A.sub.6, A.sub.7, A.sub.9, A.sub.10 are N or CR.sub.6, CR.sub.7, CR.sub.9, CR.sub.10, respectively, with the proviso that at least one but no more than two of the four positions A in A.sub.6, A.sub.7, A.sub.9, A.sub.10 is N; A.sub.8 is CR.sub.8; R.sub.1 is C(3-6)cycloalkylC(1-3)alkyl; R.sub.2 and R.sub.3 are independently H; R.sub.4 is H; R.sub.5 is H; the sulfonyl group with R.sub.1 is represented by R.sub.8; the remaining R.sub.6-R.sub.14 are independently H; R.sub.15 is C(1-6)alkyl, all carbon atoms of alkyl groups optionally substituted with one or more F; and R.sub.16 is C(1-6)alkyl, all carbon atoms of alkyl groups optionally substituted with one or more F.

5. The compound as defined in claim 1 which is selected from the group of: 2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide; 2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]phenyl]acetamide; 2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[3-methyl-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide; 2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[3-fluoro-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide; N-[3-chloro-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]acetamide; 2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[3-methoxy-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide; 2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[2-methyl-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide; 2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[2-fluoro-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide; 2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[2-methoxy-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide; 2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-2-pyridyl]acetamide; 2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[1-hydroxy-1-(trifluoromethyl)butyl]phenyl]acetamide; 2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[1-hydroxy-3-methyl-1-(trifluoromethyl)butyl]phenyl]acetamide; 2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[1-hydroxy-4-methyl-1-(trifluoromethyl)pentyl]phenyl]acetamide; N-[4-(1-cyclopentyl-2,2,2-trifluoro-1-hydroxy-ethyl)phenyl]-2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]acetamide; N-[4-[1-(cyclopentylmethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]-2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]acetamide; N-[4-[1-(cyclohexylmethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]-2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]acetamide; 2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[5-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-2-pyridyl]acetamide; 2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[dicyclopropyl(hydroxy)methyl]phenyl]acetamide; 2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-(2,2,2-trifluoro-1-hydroxy-1-phenyl-ethyl)phenyl]acetamide; 2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[1-hydroxy-1-(trifluoromethyl)propyl]phenyl]acetamide (racemate); ()-2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide (levogyre enantiomer); (+)-2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide (dextrogyre enantiomer); 2-[6-[(2-methylcyclopropyl)methylsulfonyl]-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide; 2-[6-[(2,2-difluorocyclopropyl)methylsulfonyl]-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide (racemate); (+)-2-[6-[(2,2-difluorocyclopropyl)methylsulfonyl]-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide (dextrogyre enantiomer); ()-2-[6-[(2,2-difluorocyclopropyl)methylsulfonyl]-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide (levogyre enantiomer); 2-[6-(cyclopropylmethylsulfonyl)-4-methyl-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide; 2-[6-(cyclopropylmethylsulfonyl)-2-methyl-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide; 2-[6-(cyclopropylmethylsulfonyl)-5-methyl-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide; 2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-(oxetan-3-ylmethoxy)-1-(trifluoromethyl)ethyl]phenyl]acetamide; 2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-(2-methoxyethoxy)-1-(trifluoromethyl)ethyl]phenyl]acetamide; 2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-(2-hydroxyethoxy)-1-(trifluoromethyl)ethyl]phenyl]acetamide; 2-[5-(cyclopropylmethylsulfonyl)-2-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide; 2-[5-(cyclopropylmethylsulfonyl)-2-pyridyl]-N-[4-[2,2,2-trifluoro-1-isopropoxy-1-(trifluoromethyl)ethyl]phenyl]acetamide; 2-[5-(cyclopropylmethylsulfonyl)-2-pyridyl]-N-[3-methyl-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]; 2-[5-(cyclopropylmethylsulfonyl)-2-pyridyl]-N-[3-fluoro-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide; 2-[5-(cyclopropylmethylsulfonyl)-2-pyridyl]-N-[4-[dicyclopropyl(hydroxy)methyl]phenyl]acetamide; 2-[5-(cyclopropylmethylsulfonyl)-2-pyridyl]-N-[4-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]phenyl]acetamide; 2-[5-(cyclopropylmethylsulfonyl)pyrimidin-2-yl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide; 2-[5-(cyclopropylmethylsulfonyl)pyrazin-2-yl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide; 2-[6-(cyclopropylmethylsulfonyl)pyridazin-3-yl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide; 2-[2-(cyclopropylmethylsulfonyl)pyrimidin-5-yl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide.

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

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

8. A medicament according to claim 1 or a pharmaceutically acceptable salt thereof.

9. 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.

10. The pharmaceutical composition according to claim 9, which further comprises at least one additional therapeutically active agent.

Description

EXEMPLIFICATION

(1) As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the invention, the following general methods, and other methods known to one skilled in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.

(2) General Methods of Preparation.

(3) The compounds described herein, including compounds of general Formula I, building blocks II, III, IV and V can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. Many of the reactions can also be carried out under microwave conditions or using conventional heating or utilizing other technologies such as solid phase reagents/scavengers or flow chemistry. For example, hydrogenation reactions can be performed using a continuous flow chemistry apparatus such as the H-Cube Pro from ThalesNano Nanotechnology company in Budapest, Hungary. In these reactions, it is also possible to make use of variants which are themselves known to those skilled in the art, but are not mentioned in greater detail.

(4) For example, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents, solvents etc. may be used and are included within the scope of the present invention. Furthermore, other methods for preparing compounds of the invention will be readily apparent to a person of ordinary skill in the art in light of the following reaction schemes and examples. In cases where synthetic intermediates and final products contain potentially reactive functional groups, for example amino, hydroxyl, thiol and carboxylic acid groups that may interfere with the desired reaction, it may be advantageous to employ protected forms of the intermediate. Methods for the selection, introduction and subsequent removal of protecting groups are well known to those skilled in the art. The compounds obtained by using the general reaction sequences may be of insufficient purity. The compounds can be purified by using any of the methods of purification of organic compounds, for example, crystallization or silica gel or alumina column chromatography, using different solvents in suitable ratios. All possible stereoisomers are envisioned within the scope of the invention. In the discussion below variables have the meaning indicated above unless otherwise indicated.

(5) The abbreviations used in these experimental details are listed below and additional ones should be considered known to a person skilled in the art of synthetic chemistry.

(6) Abbreviations used herein are as follow: HATU: 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; DMF: Dimethylformamide; DiPEA: Diisopropylethylamine; DMAP: 4-(dimethylamino)pyridine; CH.sub.2Cl.sub.2, DCM: dichloromethane; DCC: N,N-Dicyclohexylcarbodiimide; mCPBA: 3-chloroperoxybenzoic acid; TFA: Trifluoroacetic acid; TFAA: Trifluoroacetic anhydride; THF: Tetrahydrofuran; DMSO: Dimethylsulfoxide; PTSA: p-Toluenesulfonic acid; PyBOP: (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; EtOH: Ethanol; DIAD: Diisopropyl azodicarboxylate; TLC: Thin Layer Chromatography; Pd(dba).sub.2: Bis(dibenzylideneacetone)palladium(0); PPh.sub.3: Triphenyl phosphine; NMP: N-Methyl-2-pyrrolidinone; EDCl: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; n-BuLi: n-Butyl lithium; TBAF: Tetra-N-butylammonium fluoride; TMS: Trimethylsilyl; NBS: N-bromosuccinimide; AIBN: 2,2-azobis(2-methylpropionitrile); DCE: dichloroethane; TMSCN: trimethylsilyl cyanide; EtOAc: ethyl acetate; ACN, CH.sub.3CN: acetonitrile; RT: room temperature; MeOH: methanol; Et.sub.3N, TEA: triethylamine; NaIO.sub.4: sodium periodate; K.sub.2CO.sub.3: potassium carbonate; MgSO.sub.4: magnesium sulfate; NaBH.sub.3CN: sodium cyanoborohydride; NaCl: sodium chloride; NaHCO.sub.3: sodium bicarbonate; Na.sub.2CO.sub.3: sodium carbonate; Na.sub.2SO.sub.4: sodium sulfate; Na.sub.2SO.sub.3: sodium sulfite; NH.sub.4Cl: ammonium chloride; NH.sub.4OAc: ammonium acetate; TMSCF.sub.3: Trifluoromethyltrimethylsilane; CsF: cesium fluoride; H.sub.2O: water; HCl: hydrochloric acid; CuOSO.sub.2CF.sub.3: copper(I) trifluoromethanesulfonate; Cu.sub.2O: copper(I) oxide; NaOMe: sodium methoxide; NaOH: sodium hydroxide; NH.sub.4OH: ammonium hydroxide; SOCl.sub.2: thionyl chloride; Et.sub.2O: diethyl ether; DBU: 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine; KH.sub.2PO.sub.4: potassium dihydrogen phosphate; TES: triethylsilyl; AlMe.sub.3: trimethylalumane; Pd(PtBu.sub.3).sub.2: bis(tri-tert-butylphosphine)palladium (0); ZnF.sub.2: difluorozinc; TES: triethylsilyl.

(7) Chemical names are preferred IUPAC names, generated using Accelrys Draw 4.1.

(8) If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates.

(9) General Procedures

(10) ##STR00041##
Conditions: i) EDCl, DMAP, DCM.

(11) Scheme 1 demonstrates two alternative routes for the preparation of derivatives of Formula I wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.15, R.sub.16, A.sub.6, A.sub.7, A.sub.8, A.sub.9, A.sub.10 A.sub.11, A.sub.12, A.sub.13 and A.sub.14 are as defined for compounds of Formula I.

(12) Compounds of the invention can for example be obtained by an amide coupling reaction between a phenylacetic acid derivative of building block II (X.sub.1=OH) and an aniline derivative of building block III, using a coupling reagent such as EDCl, HATU, DCC or PyBOP or the like, in the presence of a suitable base such as DiPEA or DMAP. The reaction is usually performed at room temperature but it could be heated in certain cases to 60 C. under microwave irradiation.

(13) Alternatively, the phenylacetic acid derivative of building block II (X.sub.1=OH) can be converted into an acyl chloride derivative of building block II (X.sub.1=Cl), using for example SOCl.sub.2 or oxalyl chloride. The obtained acyl chloride derivative of building block II (X.sub.1=Cl) can be coupled with an aniline derivative of building block III in the presence of a suitable base such as Et.sub.3N or the like.

(14) Alternatively, when R.sub.5=CH.sub.2CH.sub.2OH, the building block III in which the hydroxyl group in R.sub.5 is protected as an acetal, such as a tetrahydropyran-2-yl group, can be condensed with building block II as described above followed by deprotection of the protecting group under acidic conditions to provide the derivatives of Formula I.

(15) ##STR00042##

(16) Conditions: i) CuOSO.sub.2CF.sub.3, 1,2-diaminocyclohexane, DMSO, 125 C.; ii) R.sub.1SH, NaOMe, MeOH, 85 C., sealed tube; iii) mCPBA, DCM, 0 C..fwdarw.RT.

(17) Scheme 2 demonstrates two alternative routes for the preparation of derivatives of Formula I wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.15, R.sub.16, A.sub.6, A.sub.7, A.sub.8, A.sub.9, A.sub.10 A.sub.11, A.sub.12, A.sub.13 and A.sub.14 are as defined for compounds of Formula I.

(18) Compounds of the invention can be obtained for example by a coupling of an heteroaryl halide derivative (X.sub.2=I, Br or Cl) of building block IV and a sulfinic acid salt derivative of building block V such as a sodium sulfinate, using a copper(I) catalyst such as copper(I) trifluoromethanesulfonate benzene complex, copper(I) iodide or the like, in the presence of a suitable ligand such as trans-1,2-diaminocyclohexane, phenanthroline, dimethylimidazolidinone, or the like. The reaction is performed by heating the mixture in a polar solvent such as DMSO, DMF or the like at temperature between 80 and 140 C. using microwave or conventional heating conditions.

(19) Alternatively, certain heteroaryl chloride derivatives (X.sub.2=Cl) of building block IV can be treated with a thiol R.sub.1SH, wherein R.sub.1 has the meaning as previously described, in presence of a base such as sodium methoxide or the like, to give the corresponding thioether derivative 1, which upon oxidation using mCPBA or the like can provide derivatives of the invention having Formula I.

(20) Alternatively, when R.sub.5=H, the hydroxyl group of the building block IV can be protected as silyl ether, such as TES or the like. Subsequent deprotection, for example by treatment with a fluoride source such as TBAF, provides the derivatives of Formula I wherein R.sub.5=H.

(21) ##STR00043##

(22) Conditions (R.sub.2, R.sub.3=H): i) alkyl halide, K.sub.2CO.sub.3, CH.sub.3CN; ii) mCPBA, DCM, 0 C..fwdarw.RT; iii) NBS, AIBN, DCE, 70 C.; iv) TMSCN, TBAF, CH.sub.3CN, reflux; v) NaOH, reflux.

(23) Scheme 3 shows a general method for the preparation of building block II, wherein R.sub.2=R.sub.3=H and R.sub.1, A.sub.6, A.sub.7, A.sub.8, A.sub.9, A.sub.10 are as defined for compounds of Formula I.

(24) Thiol derivatives 2 can be alkylated in the presence of a suitable base such as potassium carbonate and oxidized using mCPBA for example to give the corresponding sulfone derivatives 3, which upon radical bromination with NBS in presence of a radical initiator such as AIBN provide bromide derivatives 4. These bromide derivatives can be converted to the corresponding nitrile derivatives 5 by treating them with a cyanide source such as TMSCN or potassium cyanide or the like. If TMSCN is used, it is required to add a fluoride source such as TBAF or the like to generate the cyanide nucleophile in situ. Hydrolysis of the nitrile derivatives 5 can provide the corresponding carboxylic acid derivatives of building block II wherein R.sub.2 and R.sub.3 are H.

(25) Some of the building blocks II are commercially available, known or prepared according to methods known to those skilled in the art.

(26) ##STR00044##

(27) Conditions: i) (R.sub.15, R.sub.16=CF.sub.3, R.sub.5=H), hexafluoroacetone hydrate; ii) n-BuLi, ketone; iii) DIAD, PPh.sub.3, DMAP, R.sub.5OH; iv) deprotection.

(28) Scheme 4 shows two general methods for the preparation of (4-aminophenyl) methanol derivatives of building block III, wherein R.sub.4, R.sub.5, R.sub.15, R.sub.16, A.sub.11, A.sub.12, A.sub.13 and A.sub.14 are as defined for compounds of Formula I.

(29) If R.sub.15 and R.sub.16 are both CF.sub.3, then heating the aniline derivatives 6 in 1,1,1,3,3,3-hexafluoroacetone hydrate as the solvent in a sealed tube in a microwave, provides in one step 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol derivatives (R.sub.5=H) of building block III.

(30) Alternatively, the 1,1,1,3,3,3-hexafluoropropan-2-ol moiety can be introduced by treating suitable (N-protected)bromoaniline derivatives 7 with n-butyl lithium to form the corresponding lithiated intermediate, which then can be converted by treatment with 1,1,1,3,3,3-hexafluoroacetone gas followed by deprotection of the amine moiety to the desired 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol derivatives (R.sub.5=H) of building block III. This method can also be used for the introduction of other tertiary alcohols, by using e.g. dry dicyclopropylmethanone, dry 2,2,2-trifluoro-1-phenyl-ethanone or the like, as the corresponding ketone.

(31) The alcohol derivatives of building block III (R.sub.5=H) can, for example, be converted under Mitsunobu conditions, using e.g. DIAD, PPh.sub.3, DMAP and a suitable alcohol, to the corresponding ether derivatives of building block III (R.sub.5=e.g. alkyl, cycloalkyl).

(32) ##STR00045##

(33) Conditions: i) TMSCF.sub.3, CsF, Toluene/DCM; ii) NH.sub.4OH, Cu.sub.2O, NMP, 80 C., microwave; iii) DIAD, PPh.sub.3, DMAP, R.sub.5OH.

(34) Scheme 5 shows an alternative general method for the preparation of 1-(4-aminophenyl)-2,2,2-trifluoroethanol derivatives of building block III, wherein R.sub.5, R.sub.16, A.sub.11, A.sub.12, A.sub.13 and A.sub.14 have the meaning as previously described and R.sub.15 is CF.sub.3.

(35) Aryl or heteroaryl halide derivatives 8 (X=I, Br or Cl) can be converted via a cesium fluoride or TBAF catalyzed trifluoromethylation to the corresponding TMS protected 1-(4-aminophenyl)-2,2,2-trifluoroethanol derivatives 9, which can be transformed into the corresponding 1-(4-aminophenyl)-2,2,2-trifluoroethanol derivatives III (R.sub.5=H) by a copper catalyzed amination, using Cu.sub.2O for example in the presence of ammonia. These alcohol derivatives of building block III can, for instance, be converted under Mitsunobu conditions, using e.g. DIAD, PPh.sub.3, DMAP and a suitable alcohol, to the corresponding ether derivatives of building block III (R.sub.5=e.g. alkyl, cycloalkyl).

(36) Alternatively, when in the building block III R.sub.5 contains a hydroxyl group, this group can be protected as an acetal for example, such as a tetrahydropyran-2-yl group.

(37) Some of the building blocks III are commercially available, known or prepared according to methods known to those skilled in the art.

(38) ##STR00046##

(39) Conditions: i) EDCl, DMAP, DCM.

(40) Scheme 6 shows two general methods for the preparation of derivatives of building block IV, wherein X.sub.2 is Cl, Br or I and R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.15, R.sub.16, A.sub.6, A.sub.7, A.sub.8, A.sub.9, A.sub.10, A.sub.11, A.sub.12, A.sub.13 and A.sub.14 are as defined for compounds of Formula I.

(41) The building blocks IV can be prepared by an amide coupling reaction between a carboxylic acid derivative 10 (X.sub.1=OH) and an aniline derivative of building block III, using a coupling reagent such as EDCl, HATU, DCC, or PyBOP or the like, in the presence of a suitable base such as DiPEA or DMAP.

(42) Alternatively, the carboxylic acid derivative 10 (X.sub.1=OH) can be converted into an acyl chloride derivative of 10 (X.sub.1=Cl), using for example SOCl.sub.2 or oxalyl chloride. The obtained acyl chloride derivative of 10 (X.sub.1=Cl) can be coupled with an aniline derivative of building block III are as defined for compounds of Formula I, in the presence of a suitable base such as Et.sub.3N or the like.

(43) Alternatively, an ester derivative 10 (X.sub.1=OMe) can be condensed with an aniline derivative of building block III in the presence of a suitable Lewis acid such as AlMe.sub.3 or the like, to provide the building blocks IV.

(44) Alternatively, when R5=H, the building block III can be protected as silyl ether, such as TES or the like. As a consequence, the resulting building blocks IV can also be protected.

(45) ##STR00047##

(46) Conditions: i) Na.sub.2SO.sub.3, NaHCO.sub.3, H.sub.2O, 50 C.

(47) Scheme 7 shows a general reaction scheme for the preparation of building blocks V wherein R.sub.1 has the meaning as previously described.

(48) Sulfonyl chloride derivatives 11 can be converted to sodium sulfinate derivatives of building block V by treatment with sodium sulfite in water in the presence of a suitable base such as sodium bicarbonate.

(49) Some of the building blocks V are commercially available, known or prepared according to methods known to those skilled in the art.

(50) ##STR00048##

(51) Conditions (R.sub.2, R.sub.3=H): i) alkyl halide, K.sub.2CO.sub.3, CH.sub.3CN, DMF; ii) (CH.sub.3).sub.3CSi(CH.sub.3).sub.2OC(OCH.sub.3)=CH.sub.2, Pd(PtBu.sub.3).sub.2, ZnF.sub.2, DMF, 100 C., microwave; iii) mCPBA, DCM, 0 C..fwdarw.RT; iv) NaOH, THF, MeOH.

(52) Thiol derivatives 12 can be alkylated in the presence of a suitable base such as potassium carbonate to give the corresponding thioether derivatives 13 substituted with a halogen X.sub.3=I, Br, Cl. These halide derivatives can be converted to the corresponding the corresponding carboxylic acid derivatives of building block II wherein R.sub.2 and R.sub.3 are H by a Heck coupling with tert-butyl-(1-methoxyvinyloxy)-dimethyl-silane catalyzed, for example by Pd(PtBu.sub.3).sub.2 and ZnF.sub.2, followed by oxydation of the thioether into the sulfone and hydrolysis of the ester.

(53) Some of the building blocks II are commercially available, known or prepared according to methods known to those skilled in the art.

(54) Building Block II-1

(55) ##STR00049##

(56) i) To a suspension of 5-methylpyridine-2-thiol (3 g) and K.sub.2CO.sub.3 (6.59 g) in ACN (30 mL) was added (bromomethyl)cyclopropane (2.48 mL). After stirring overnight at RT, the reaction mixture was filtered and concentrated under reduced pressure. The residue was taken up in DCM, washed with water, filtered on a water repellent filter cartridge and concentrated under reduced pressure to obtain 4.35 g of the 2-(cyclopropylmethylsulfanyl)-5-methyl-pyridine. MS(ES.sup.+) m/z 180.0 [M+H].sup.+.

(57) ii) To a cooled (0 C.) solution of the product obtained in the previous step (3.3 g) in DCM (50 mL) was added portionwise mCPBA (9.94 g). After stirring overnight at RT, DCM was added followed by a saturated aqueous solution of K.sub.2CO.sub.3. The mixture was stirred for 1 hour, the organic layer was separated, washed twice with water and concentrated under reduced pressure to obtain 3.85 g of the 2-(cyclopropylmethylsulfonyl)-5-methyl-pyridine. MS(ES.sup.+) m/z 212.0 [M+H].sup.+.

(58) iii) To a solution of the product obtained in the previous step (610 mg) in DCE (10 mL), was added AIBN (50 mg) followed by NBS (514 mg). The reaction mixture was heated to 70 C. for 7 hours and concentrated under reduced pressure. Water was added to the residue and it was extracted with DCM. The extract was filtered on a water repellent filter cartridge, concentrated under reduced pressure and purified by column chromatography on silica gel using 10% EtOAc in heptane as the eluent to obtain 210 mg of the 5-(bromomethyl)-2-(cyclopropylmethylsulfonyl)pyridine. MS(ES.sup.+) m/z 289.9 [M+H].sup.+.

(59) iv) To a solution of the product obtained in the previous step (200 mg) in ACN (10 mL) was added TMSCN (102 mg) and a 1N solution of TBAF in THF (1 mL). The reaction mixture was heated to reflux for 5 minutes, poured into a diluted aqueous solution of ammonia, extracted with EtOAc and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using 20% EtOAc in heptane as the eluent to obtain 90 mg of the 2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]acetonitrile. MS(ES.sup.+) m/z 237.0 [M+H].sup.+.

(60) v) To the product obtained in the previous step (90 mg) was added an aqueous 15% w/w NaOH solution (2.5 mL). The reaction mixture was refluxed for 30 minutes. After allowing to cool down to RT, water and an aqueous 2N HCl solution (3 mL) were added and it was extracted three times with ether then twice with EtOAc. The extracts were concentrated under reduced pressure, taken into DCM, filtered on a water repellent filter cartridge and concentrated under reduced pressure to obtain 70 mg of the expected product. MS(ES.sup.+) m/z 256.0 [M+H].sup.+.

(61) Building Block II-2

(62) ##STR00050##

(63) i) To a suspension of 5-bromopyridine-2-thiol (600 mg) and K.sub.2CO.sub.3 (881 mg) in ACN (10 mL) were added 1-(bromomethyl)-2-methyl-cyclopropane (545 mg) dropwise and DMF (2 mL). After stirring 2 hours at RT, Et.sub.2O (100 mL) was added to the reaction mixture and the organic layer was washed with water (100 mL), with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to obtain 790 mg of 5-bromo-2-[(2-methylcyclopropyl)methylsulfanyl]pyridine. The crude product was used in the next step without further purification. MS(ES.sup.+) m/z 258.1, 260.1 [M+H].sup.+.

(64) ii) To a solution of the product obtained in the previous step (790 mg) in anhydrous DMF (5 mL) placed in a microwave tube were added tert-butyl-(1-methoxyvinyloxy)-dimethyl-silane (1.19 g) and difluorozinc (160 mg). The reaction mixture was degazed, and bis(tri-tert-butylphosphine)palladium (0) (156 mg) was added. The tube was sealed and heated to 100 C. under microwave irradiation for 45 minutes. The reaction mixture was poured onto EtOAc (50 mL), and the organic layer was washed with water (250 mL), brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using 0% to 30% EtOAc in cyclohexane as the eluent to obtain 520 mg of methyl 2-[6-[(2-methylcyclopropyl)methylsulfanyl]-3-pyridyl]acetate. MS(ES.sup.+) m/z 252.2 [M+H].sup.+.

(65) iii) To a cooled (0 C.) solution of the product obtained in the previous step (520 mg) in DCM (10 mL) was added portionwise mCPBA (1.02 g). After stirring overnight at RT, a saturated aqueous solution of NaHCO.sub.3 (50 mL) was added and the mixture was stirred for 15 minutes, followed by addition of DCM (80 mL) and a saturated aqueous solution of NaHCO.sub.3 (50 mL). The organic layer was separated, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using 0 to 60% EtOAc in cyclohexane as the eluent to obtain 430 mg of methyl 2-[6-[(2-methylcyclopropyl)methylsulfonyl]-3-pyridyl]acetate. MS(ES.sup.+) m/z 284.0 [M+H].sup.+.

(66) iv) A 1N aqueous solution of NaOH (1.5 mL) was added to a solution of the product obtained in the previous step (430 mg) in THF (8 mL) and MeOH (2 mL) and the mixture was stirred overnight at RT. Water (20 mL) and DCM (50 mL) were added, and the organic layer was discarded. The aqueous layer was acidified using HCl 1N, and extracted with DCM (350 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to obtain 350 mg of the expected product. MS(ES.sup.+) m/z 270.1 [M+H].sup.+.

(67) Following a procedure analogous to that described for compound 11-2, the following compounds were prepared.

(68) ##STR00051##

(69) i) To a solution of 1-(4-bromophenyl)butan-1-one (1.0 g) in a mixture of toluene and DCM (2 mL, 9:10) was added TMSCF.sub.3 (0.65 mL). To this suspension CsF (67 mg) was added. After a few minutes an exothermic reaction started and the reaction mixture was stirred for another 30 minutes until completion. The reaction mixture was quenched by the addition of water. The organic layer was washed with water, brine, dried over MgSO.sub.4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 0% to 40% EtOAc in heptane as the eluent to obtain 1.5 g of [1-(4-bromophenyl)-1-(trifluoromethyl)butoxy]-trimethyl-silane.

(70) ii) To a solution of the product obtained in the previous step (1.5 g) in NMP (4 mL) were added Cu.sub.2O (30 mg) and an aqueous NH.sub.4OH solution (4 mL). The reaction mixture was stirred for 15 hours at 80 C. in a microwave. The blue reaction mixture was poured into water and the product was extracted with EtOAc. The organic extract was washed with water, brine, dried over MgSO.sub.4 and concentrated under reduced pressure to obtain the expected compound. The crude product was used without further purification. MS(ES.sup.+) m/z 234.1 [M+H].sup.+.

(71) Following a procedure analogous to that described for Example III-1, the following compounds were prepared.

(72) ##STR00052##
Building Blocks III-9-III-11

(73) ##STR00053##

(74) To a solution of 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (500 mg) and oxetan-3-ylmethanol (177 mg) in THF (5 mL) cooled at 10 C. were successively added PPh.sub.3 (1.01 g) and dropwise DIAD (0.760 mL). The reaction mixture was stirred at RT overnight and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using 20% to 40% EtOAc in heptane as the eluent to obtain 389 mg of 4-[2,2,2-trifluoro-1-(oxetan-3-ylmethoxy)-1-(trifluoromethyl)ethyl]aniline. MS(ES.sup.+) m/z 330.1 [M+H].sup.+.

(75) Following a procedure analogous to that described for compound III-9, the following compounds were prepared.

(76) ##STR00054##
Building Block III-12

(77) ##STR00055##

(78) i) To a solution of tert-butyl N-(4-bromophenyl)carbamate (20.1 g) in dry THF (400 mL) at 78 C. under nitrogen atmosphere was added dropwise n-BuLi (59.1 mL, 2.5 M in hexanes). After stirring at 78 C. for 2 hours, dicyclopropylmethanone (9.28 mL) was added dropwise and the reaction mixture was allowed to slowly warm up to RT overnight. The reaction mixture was quenched by addition of a saturated aqueous NH.sub.4Cl solution (200 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2200 mL). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using DCM as the eluent to obtain 16.5 g of tert-butyl N-[4-[dicyclopropyl(hydroxy)methyl]phenyl]carbamate.

(79) ii) To a solution of the product obtained in the previous step (16.5 g) in dry THF (200 mL) under a nitrogen atmosphere was added at RT a 1 M solution of TBAF in THF (82 mL). The reaction mixture was stirred at 80 C. overnight. The next day, a 1 M solution of TBAF in THF (103 mL) was added and the reaction mixture was stirred at 80 C. overnight. The next day, the reaction mixture was concentrated to half of the volume, a 1 M solution of TBAF in THF (120 mL) was added and the reaction mixture was stirred at 80 C. overnight. After being cooled to RT, the reaction mixture was quenched with a mixture of water (900 mL) and a saturated aqueous Na.sub.2CO.sub.3 solution (100 mL) and was extracted with EtOAc (3300 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using 5% to 40% EtOAc in n-heptane as the eluent to obtain 7.8 g of the expected compound.

(80) MS(ES.sup.+) m/z 186.1 [(M-18)+H].sup.+.

(81) .sup.1H NMR (500 MHz, CDCl.sub.3): 7.40-7.34 (m, 2H), 6.67-6.62 (m, 2H), 3.62 (s, 2H), 1.39 (s, 1H), 1.26-1.11 (m, 2H), 0.57-0.45 (m, 4H), 0.39-0.32 (m, 4H).

(82) Building Block III-13

(83) ##STR00056##

(84) i) To a solution of tert-butyl N-(4-bromophenyl)carbamate (1.0 g) in dry THF (20 mL) at 78 C. under nitrogen atmosphere was added dropwise n-BuLi (3.7 mL, 2.5 M in hexanes). After stirring for 2 hours at 78 C., 2,2,2-trifluoro-1-phenyl-ethanone (0.7 g) was added dropwise and the reaction mixture was allowed to slowly warm up to RT overnight. The reaction mixture was quenched by addition of a saturated aqueous NH.sub.4Cl solution (200 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2200 mL). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to obtain 384 mg of tert-butyl N-[4-(2,2,2-trifluoro-1-hydroxy-1-phenyl-ethyl)phenyl]carbamate.

(85) ii) To a solution of the product obtained in the previous step (379 mg) in DCM (10 mL) under a nitrogen atmosphere was added hydrochloric acid (1.29 mL, 4N in dioxane). The reaction mixture was stirred overnight at RT. The next day, hydrochloric acid (1.29 mL, 4N in dioxane) was added and the reaction mixture was stirred at RT for 2 days. The reaction mixture was then concentrated under reduced pressure, and the solid was suspended in DCM and again concentrated under reduced pressure to obtain 293 mg of the expected compound.

(86) MS(ES.sup.+) m/z 268.0 [M+H].sup.+.

(87) Building Blocks IV-1-IV-9

(88) ##STR00057##

(89) i) To a solution of 2-(5-bromopyridin-2-yl)acetic acid (500 mg) in DCM (4 mL) were added 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (625 mg), EDCl (476 mg) and DMAP (57 mg). The reaction mixture was stirred at RT for 1 hour, poured into water, filtered on a water repellent filter cartridge and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using 10% EtOAc in heptane as the eluent, followed by trituration with ether/pentane to obtain 820 mg of the expected compound. MS(ES.sup.+) m/z 456.9 [M+H].sup.+.

(90) Following a procedure analogous to that described for compound IV-1, using the appropriate building blocks III or any commercially available ones, the following compounds were prepared.

(91) ##STR00058## ##STR00059## ##STR00060##

(92) i) To a solution of 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (2 g) in DMF (50 mL) were added chloro(triethyl)silane (1.74 g), and DBU (1.84 g) dropwise. After stirring at RT for 2 hours, the reaction mixture was quenched by addition of water and Et.sub.2O. The layers were separated and the aqueous layer was extracted twice with Et.sub.2O. The combined organic extracts were concentrated under reduced pressure, and the residue was taken up in DCM, washed with water, filtered on a water repellent filter cartridge and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using 5% EtOAc in heptane as the eluent to obtain 1.9 g of 4-[2,2,2-trifluoro-1-triethylsilyloxy-1-(trifluoromethyl)ethyl]aniline. MS(ES.sup.+) m/z 374.1 [M+H].sup.+.

(93) ii) Trimethylalumane (2.49 mL, 2M in toluene) was added to a solution of the product obtained in the previous step (1.86 g) in toluene (50 mL) and the reaction mixture was stirred at RT for 30 minutes before adding ethyl 2-(6-chloropyridazin-3-yl)acetate (500 mg). The reaction mixture was refluxed for 2 hours, then cooled to RT and stirred overnight. It was quenched by pouring onto a mixture of water and EtOAc, and adding a saturated aqueous solution of KH.sub.2PO.sub.4. The organic layer was recovered, washed with water, concentrated under reduced pressure, and the residue was taken up in DCM, washed with water, filtered on a water repellent filter cartridge and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using 10% EtOAc in heptane as the eluent to obtain 375 mg of the expected product. MS(ES.sup.+) m/z 528.1 [M+H].sup.+.

(94) Building Block V-1

(95) ##STR00061##

(96) i) A solution of Na.sub.2SO.sub.3 (414 mg) in water (1.3 mL) was stirred for 10 minutes at RT. To the resulting mixture was added NaHCO.sub.3 (547 mg). After stirring for 1 hour at 50 C., cyclopropylmethanesulfonyl chloride (430 mg) was added dropwise. The reaction mixture was stirred at 50 C. for 4 hours. Water was evaporated by flushing argon. The residue was dried under high vacuum. The residue was taken up into MeOH (1.3 mL), filtered and concentrated under reduced pressure to obtain 380 mg of the expected compound. MS(ES.sup.+) m/z 120.9 [M+H].sup.+.

Examples 1-27

(97) ##STR00062##

(98) i) To a solution of acid II-1 (55 mg) in DCM (4 mL) were added 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (59 mg), EDCl (44 mg) and DMAP (5 mg). The reaction mixture was stirred at RT for 1 hour. DCM and water were added and the mixture was filtered on a water repellent filter cartridge and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using 10% to 50% EtOAc in heptane as the eluent, followed by trituration with ether/pentane to obtain 45 mg of the expected compound. MS(ES.sup.+) m/z 497.0 [M+H].sup.+.

(99) 1H NMR (400 MHz, DMSO-d6) ppm 10.50 (s, 1H) 8.73 (d, J=1.25 Hz, 1H) 8.59 (br s, 1H) 8.04-8.11 (m, 2H) 7.68-7.73 (m, 2H) 7.61 (d, J=8.78 Hz, 2H) 3.92 (s, 2H) 3.35-3.43 (m, 2H) 0.82-0.92 (m, 1H) 0.40-0.46 (m, 2H) 0.12-0.17 (m, 2H).

(100) Following a procedure analogous to that described for Example 1, using the appropriate building blocks II and III or any commercially available or known ones, the following compounds were prepared.

(101) ##STR00063##

(102) 1H NMR (400 MHz, DMSO-d6) ppm 10.58 (s, 1H) 8.73 (d, J=1.25 Hz, 1H) 8.02-8.13 (m, 2H) 7.79 (d, J=8.04 Hz, 2H) 7.51 (d, J=8.78 Hz, 2H) 3.93 (s, 2H) 3.34-3.45 (m, 5H) 0.82-0.96 (m, 1H) 0.39-0.47 (m, 2H) 0.10-0.19 (m, 2H).

(103) ##STR00064## ##STR00065## ##STR00066## ##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071## ##STR00072##

(104) 1H NMR (400 MHz, DMSO-d6) ppm 10.34 (s, 1H) 8.72 (dd, J=2.2, 0.8 Hz, 1H) 8.10 (dd, J=8.1, 2.2 Hz, 1H) 8.05 (dd, J=8.1, 0.8 Hz, 1H) 7.60 (d, J=9.0 Hz, 2H) 7.46 (br d, J=9.0 Hz, 2H) 6.28 (br s, 1H) 3.89 (s, 2H) 3.39 (d, J=7.3 Hz, 2H) 2.13 (m, 1H) 1.97 (m, 1H) 0.88 (m, 1H) 0.67 (t, J=7.4 Hz, 3H) 0.42 (m, 2H) 0.14 (m, 2H).

(105) The 2 enantiomers of example 20 were separated by chiral chromatography using a column Chiralpak AD 20 m, 76.5350 mm and a mobile phase, EtOH:MeOH:TEA 60:40:0.1, 300 mL/min, with UV detection at 254 nm.

(106) Starting from 225 mg of racemate, after concentration, 104 mg of ()-2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[1-hydroxy-1-(trifluoromethyl)propyl]phenyl]acetamide (first isomer to be eluted) and 116 mg of (+)-2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[1-hydroxy-1-(trifluoromethyl)propyl]phenyl]acetamide were obtained.

()-20: ()-2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[1-hydroxy-1-(trifluoromethyl)propyl]phenyl]acetamide

(107) Optical rotation: [].sub.D.sup.20=7.31 (c=0.2152, DMSO).

(+)-20: (+)-2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[1-hydroxy-1-(trifluoromethyl)propyl]phenyl]acetamide

(108) Optical rotation: [].sub.D.sup.20=+13.56 (c=0.2644, DMSO).

(109) ##STR00073##

(110) 1H NMR (400 MHz, DMSO-d6) ppm 10.50 (s, 1H) 8.73 (dd, J=2.3, 0.8 Hz, 1H) 8.59 (br s, 1H) 8.10 (dd, J=8.2, 2.3 Hz, 1H) 8.05 (dd, J=8.2, 0.8 Hz, 1H) 7.71 (d, J=9.2 Hz, 2H) 7.61 (br d, J=9.2 Hz, 2H) 3.42 (dd, J=14.7, 6.6 Hz, 1H) 3.38-3.28 (m, 1H) 0.92-0.80 (m, 1H) 0.79 (d, J=6.0 Hz, 2H) 0.65-0.40 (m, 4H) 0.30 (m, 1H) 0.20 (m, 1H).

(111) ##STR00074##

(112) 1H NMR (400 MHz, DMSO-d6) ppm 10.52 (s, 1H) 8.76 (dd, J=2.2, 0.8 Hz, 1H) 8.61 (br s, 1H) 8.11 (dd, J=8.1, 2.2 Hz, 1H) 8.08 (dd, J=8.1, 0.8 Hz, 1H) 7.71 (d, J=9.1 Hz, 2H) 7.61 (br d, J=9.1 Hz, 2H) 3.92 (s, 2H) 3.65 (dd, J=7.6, 2.4 Hz, 2H) 1.92 (m, 1H) 1.70 (m, 1H) 1.31 (m, 1H).

(113) The 2 enantiomers of example 22 were separated by chiral chromatography using a column Chiralpak AD 10 m, 30250 mm and a mobile phase, CO.sub.2:EtOH:TEA 75:25:0.1, 120 mL/min, with UV detection at 254 nm, and column temperature of 35 C.

(114) Starting from 340 mg of racemate, 116.5 mg of (+)-2-[6-[(2,2-difluorocyclopropyl)methylsulfonyl]-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide (first isomer to be eluted) and 119.5 mg of ()-2-[6-[(2,2-difluorocyclopropyl)methylsulfonyl]-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide were obtained.

(+)-22: (+)-2-[6-[(2,2-difluorocyclopropyl)methylsulfonyl]-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide

(115) Optical rotation: [].sub.D.sup.20=+19.34 (c=0.3872, DMSO).

()-22: ()-2-[6-[(2,2-difluorocyclopropyl)methylsulfonyl]-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide

(116) Optical rotation: [].sub.D.sup.20=10.14 (c=0.4406, DMSO).

(117) ##STR00075## ##STR00076##

(118) 1H NMR (400 MHz, DMSO-d6) ppm 10.60 (s, 1H) 8.73 (d, J=2.3 Hz, 1H) 8.10 (dd, J=8.1, 2.3 Hz, 1H) 8.06 (d, J=8.1 Hz, 1H) 7.80 (d, J=9.0 Hz, 2H) 7.51 (br d, J=9.0 Hz, 2H) 4.67 (dd, J=8.0, 6.2 Hz, 1H) 4.35 (t, J=6.2 Hz, 2H) 3.92 (s, 2H) 3.78 (d, J=6.9 Hz, 2H) 3.39 (d, J=7.3 Hz, 2H) 3.30 (m, 1H) 0.88 (m, 1H) 0.43 (m, 2H) 0.14 (m, 2H).

(119) ##STR00077##

(120) 1H NMR (400 MHz, DMSO-d6) ppm 10.59 (s, 1H) 8.72 (dd, J=2.3, 0.8 Hz, 1H) 8.10 (dd, J=8.1, 2.2 Hz, 1H) 8.06 (dd, J=8.1, 0.8 Hz, 1H) 7.78 (d, J=9.0 Hz, 2H) 7.58 (br d, J=9.0 Hz, 2H) 3.92 (s, 2H) 3.68-3.48 (m, 4H) 3.40 (d, J=7.2 Hz, 2H) 3.30 (s, 3H) 0.88 (m, 1H) 0.42 (m, 2H) 0.14 (m, 2H).

Example 28

(121) ##STR00078##

(122) i) Following a procedure analogous to that described for Example 1, using the appropriate building blocks II-1 (65 mg) and III-11 (99 mg), the crude product was triturated successively with EtOAc and diisopropyl ether to obtain 65 mg of 2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-(2-tetrahydropyran-2-yloxyethoxy)-1-(trifluoromethyl)ethyl]phenyl]acetamide. MS(ES.sup.+) m/z 647.4 [M+Na].sup.+. ii) To a solution of the product obtained in the previous step (55 mg) in methanol (3 mL) was added PTSA (18 mg). The reaction mixture was stirred at RT for 1.5 hours and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using 60% to 80% EtOAc in heptane as the eluent to obtain 40 mg of the expected compound. MS(ES.sup.+) m/z 541.1 [M+H].sup.+.

(123) 1H NMR (400 MHz, DMSO-d6) ppm 10.58 (s, 1H) 8.73 (dd, J=2.2, 0.8 Hz, 1H) 8.10 (dd, J=8.1, 2.2 Hz, 1H) 8.06 (dd, J=8.1, 0.8 Hz, 1H) 7.77 (d, J=9.1 Hz, 2H) 7.61 (br d, J=9.1 Hz, 2H) 4.92 (t, J=5.6 Hz, 1H) 3.92 (s, 2H) 3.65 (q, J=5.6 Hz, 2H) 3.54 (t, J=5.6 Hz, 2H) 3.39 (d, J=7.3 Hz, 2H) 0.88 (m, 1H) 0.42 (m, 2H) 0.14 (m, 2H).

Examples 29-35

(124) ##STR00079##

(125) i) To a solution of the building block IV-1 (250 mg) in DMSO (3 mL) were added sodium cyclopropylmethanesulfinate V-1 (113 mg), (+/)-trans-1,2-diaminocyclohexane (26 L) and copper(I) trifluoromethanesulfonate benzene complex (46 mg). The resulting mixture was heated to 12500 under microwave irradiation in a sealed tube for 45 minutes. The reaction mixture was poured into water/ether and extracted with ether. The extract was concentrated under reduced pressure, taken up in DCM/water, filtered on a water repellent filter cartridge and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using 5% to 100% EtOAc in heptane as the eluent, followed by trituration with ether/pentane to obtain 95 mg of the expected compound. MS(ES.sup.+) m/z 497.0 [M+H].sup.+.

(126) 1H NMR (400 MHz, DMSO-d6) ppm 10.51 (s, 1H) 8.95 (d, J=2.01 Hz, 1H) 8.58 (s, 1H) 8.26 (dd, J=8.16, 2.38 Hz, 1H) 7.68-7.76 (m, 3H) 7.61 (br d, J=8.78 Hz, 2H) 4.05 (s, 2H) 3.32-3.41 (m, 2H) 0.83-0.92 (m, 1H) 0.44-0.50 (m, 2H) 0.09-0.14 (m, 2H).

(127) Following a procedure analogous to that described for Example 29, using the appropriate building blocks IV and V-1, the following compounds were prepared.

(128) ##STR00080##

(129) 1H NMR (400 MHz, DMSO-d6) ppm 10.60 (s, 1H) 8.95 (s, 1H) 8.26 (dd, J=8.28, 2.51 Hz, 1H) 7.78 (d, J=8.11 Hz, 2H) 7.70 (d, J=8.78 Hz, 1H) 7.58 (d, J=8.53 Hz, 2H) 4.05 (s, 2H) 3.93 (dt, J=12.11, 5.87 Hz, 1H) 3.34-3.39 (m, 2H) 1.21 (d, J=6.02 Hz, 6H) 0.83-0.92 (m, 1H) 0.44-0.49 (m, 2H) 0.09-0.13 (m, 2H).

(130) ##STR00081## ##STR00082##

(131) 1H NMR (400 MHz, DMSO-d6) ppm 10.22 (s, 1H) 8.95 (d, J=1.76 Hz, 1H) 8.25 (dd, J=8.16, 2.38 Hz, 1H) 7.69 (d, J=8.28 Hz, 1H) 7.41-7.54 (m, 4H) 4.30 (s, 1H) 4.00 (s, 2H) 3.33-3.40 (m, 2H) 1.09-1.20 (m, 2H) 0.81-0.96 (m, 1H) 0.44-0.55 (m, 4H) 0.23-0.41 (m, 4H) 0.08-0.22 (m, 4H).

(132) ##STR00083##

(133) 1H NMR (400 MHz, DMSO-d6) ppm 10.53 (s, 1H) 9.20 (s, 2H) 8.59 (s, 1H) 7.72 (d, J=9.1 Hz, 2H) 7.61 (br d, J=9.1 Hz, 2H) 4.20 (s, 2H) 3.48 (d, J=7.2 Hz, 2H) 0.94 (m, 1H) 0.51 (m, 2H) 0.13 (m, 2H).

Example 36

(134) ##STR00084##

(135) i) To MeOH (5 mL) was added sodium (17 mg). The resulting mixture was stirred until complete dissolution and cyclopropylmethanethiol (64 mg) was added. After stirring for 10 minutes, the building block IV-7 (300 mg) was added. The resulting mixture was heated to 85 C. in a sealed tube for 1 hour, then poured into water/brine and extracted twice with ether. The extract was concentrated under reduced pressure, taken up in DCM/water, filtered on a water repellent filter cartridge and concentrated under reduced pressure to obtain 330 mg of 2-[5-(cyclopropylmethylsulfonyl)pyrazin-2-yl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide. MS(ES.sup.+) m/z 466.0 [M+H].sup.+.

(136) ii) To a cooled (0 C.) solution of the product obtained in the previous step (330 mg) in DCM (20 mL) was added portionwise mCPBA (245 mg). After stirring overnight at RT, additional mCPBA (172 mg) was added. The mixture was concentrated under reduced pressure and purified by column chromatography on silica gel, using 5% to 100% EtOAc in heptane as the eluent to obtain 160 mg of the expected compound. MS(ES.sup.+) m/z 498.0 [M+H].sup.+.

(137) 1H NMR (400 MHz, DMSO-d6) ppm 10.56 (s, 1H) 9.14 (s, 1H) 9.05 (s, 1H) 8.59 (s, 1H) 7.67-7.72 (m, 2H) 7.62 (d, J=8.78 Hz, 2H) 4.15 (s, 2H) 3.37-3.44 (m, 2H) 0.84-0.94 (m, 1H) 0.35-0.41 (m, 2H) 0.05-0.10 (m, 2H).

Example 37

(138) ##STR00085##

(139) i) To MeOH (5 mL) was added sodium (16 mg). The resulting mixture was stirred until complete dissolution and cyclopropylmethanethiol (62 mg) was added. After stirring for 10 minutes, the building block IV-9 (300 mg) was added. The resulting mixture was heated to 8500 in a sealed tube for 2 hours, then poured into water/brine and extracted twice with ether. The extract was concentrated under reduced pressure, taken up in DCM/water, filtered on a water repellent filter cartridge, concentrated under reduced pressure and purified by column chromatography on silica gel, using 30% to 40% EtOAc in heptane as the eluent to obtain 130 mg of 2-[6-(cyclopropylmethylsulfanyl)pyridazin-3-yl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide. MS(ES.sup.+) m/z 466.1 [M+H].sup.+.

(140) ii) To a cooled (0 C.) solution of the product obtained in the previous step (130 mg) in DCM (13 mL) was added portionwise mCPBA (138 mg). After stirring at 00 C. for 35 minutes, DCM/water was added brine. The aqueous layer was separated and extracted twice with DCM. The combined organic extracts were concentrated under reduced pressure and purified by column chromatography on silica gel to obtain 15 mg of the expected compound. MS(ES.sup.+) m/z 498.1 [M+H].sup.+. 1H NMR (400 MHz, DMSO-d6) ppm 10.62 (s, 1H) 8.60 (s, 1H) 8.32 (d, J=8.7 Hz, 1H) 8.10 (d, J=8.7 Hz, 1H) 7.72 (d, J=9.2 Hz, 2H) 7.62 (br d, J=9.2 Hz, 2H) 4.30 (s, 2H) 3.59 (d, J=7.3 Hz, 2H) 0.94 (m, 1H) 0.48 (m, 2H) 0.18 (m, 2H).

Example 38

(141) ##STR00086##

(142) i) K.sub.2CO.sub.3 (723 mg), bromomethylcyclopropane (297 mg) and 1,4,7,10,13,16-hexaoxacyclooctadecane (56 mg) were added to a solution of 5-bromo-1H-pyrimidine-2-thione (400 mg) in toluene (30 mL). The mixture was refluxed for 1 hour, then concentrated under reduced pressure. The residue was taken up in DCM, washed with water, filtered on a water repellent filter cartridge and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using 10% EtOAc in heptane as the eluent to obtain 470 mg of 5-bromo-2-(cyclopropylmethylsulfanyl)pyrimidine. MS(ES.sup.+) m/z 244.9 [M+H].sup.+.

(143) ii) To a solution of the product obtained in the previous step (470 mg) in anhydrous DMF (4 mL) placed in a microwave tube were added tert-butyl-(1-methoxyvinyloxy)-dimethyl-silane (722 mg) and ZnF.sub.2 (99 mg). The reaction mixture was degazed, and Pd(PtBu.sub.3).sub.2 (98 mg) was added. The tube was sealed and heated to 100 C. under microwave irradiation for 45 minutes. The reaction mixture was poured onto water, and the aqueous layer was extracted with isopropyl ether. The combined organic extracts were concentrated under reduced pressure, and the residue was taken up in DCM, washed with water, filtered on a water repellent filter cartridge and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using 5% to 20% EtOAc in heptane as the eluent to obtain 170 mg of methyl 2-[2-(cyclopropylmethylsulfanyl)pyrimidin-5-yl]acetate. MS(ES.sup.+) m/z 239.1 [M+H].sup.+.

(144) iii) NaOH 2N (533 L) was added to a solution of the product obtained in the previous step (127 mg) in THF (4 mL) and MeOH (1 mL) and the mixture was stirred for 30 minutes at RT. Water and DCM were added, the organic layer was extracted with water, then discarded. The aqueous layer was acidified using HCl 2N (0.6 mL), extracted with DCM, filtered on a water repellent filter cartridge and concentrated under reduced pressure to obtain 115 mg of 2-[2-(cyclopropylmethylsulfanyl)pyrimidin-5-yl]acetic acid. MS(ES.sup.+) m/z 225.1 [M+H].sup.+.

(145) iv) To a solution of the product obtained in the previous step (98 mg) in DCM (30 mL) were added 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (113 mg), EDCl (85 mg) and DMAP (11 mg). The reaction mixture was stirred at RT for 1 hour, poured onto a mixture of water and DCM, filtered on a water repellent filter cartridge and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using 10% to 20% EtOAc in heptane as the eluent to obtain 160 mg of 2-[2-(cyclopropylmethylsulfanyl)pyrimidin-5-yl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide. MS(ES.sup.+) m/z 466.1 [M+H].sup.+.

(146) v) To a cooled (0 C.) solution of the product obtained in the previous step (156 mg) in DCM (30 mL) and THF (1 mL) was added portionwise mCPBA (165 mg). After stirring for 30 minutes, the ice bath was removed and the mixture was allowed to stir an additional 1 h 30. mCPBA (40 mg) was added and stirring was continued during 1 h. A saturated aqueous solution of NaHCO.sub.3 (30 mL) was added and the mixture was stirred for 20 minutes. The organic layer was separated, filtered on a water repellent filter cartridge and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using 20% EtOAc in heptane as the eluent, followed by trituration in ether/pentane to obtain 135 mg of the expected compound. MS(ES.sup.+) m/z 498.1 [M+H].sup.+.

(147) 1H NMR (400 MHz, DMSO-d6) ppm 10.54 (s, 1H) 9.02 (s, 2H) 8.60 (br s, 1H) 7.71 (d, J=9.1 Hz, 2H) 7.62 (br d, J=9.1 Hz, 2H) 3.97 (s, 2H) 3.55 (d, J=7.3 Hz, 2H) 1.00 (m, 1H) 0.50 (m, 2H) 0.28 (m, 2H).

Example 39

(148) ROR GAL4 Reporter Gene Assay

(149) Example inhibitors 1-38 were tested for their ability to inhibit ROR activity in a ROR GAL4 reporter gene assay. The assay procedure and results are described below.

(150) ROR GAL4 Reporter Gene Assay Description

(151) 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.

(152) 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.

(153) 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.

(154) Detailed Assay Description

(155) 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 RT (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.

(156) 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.

(157) 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).

(158) 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.

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

(160) 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).

(161) 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).

(162) All exemplified compounds of Formula I (Examples 1-39) are expected to have mean pIC.sub.50 values around or above 5.

(163) Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, ()-20, (+)-20, ()-22, 23, 24, 26, 27, 28, 29, 30, 33, 34, 35, 37 and 38 were found to have mean pIC.sub.50 values above or equal to 6.

(164) Examples 1, 2, 3, 4, 5, 8, 12, 19, 27, 29, 30 and 34 were found to have mean pIC.sub.50 values above or equal to 7.