ROR gamma (RORy) modulators

Abstract

The present invention relates to compounds according to Formula I: or a pharmaceutically acceptable salt thereof. The compounds can be used as inhibitors of RORy and are useful for the treatment of RORy mediated diseases such as autoimmune and inflammatory diseases. ##STR00001##

Claims

1. A compound according to Formula I ##STR00053## or a pharmaceutically acceptable salt thereof wherein: A.sub.1-A.sub.8 are CR.sub.1-CR.sub.8; R.sub.1-R.sub.8 are independently H, halogen, amino, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-6)alkyl; R.sub.9 is C(1-6)alkyl; R.sub.10 and R.sub.11 are independently H, F, methyl, ethyl, hydroxy or methoxy or R.sub.10 and R.sub.11 together is carbonyl, all alkyl groups, if present, optionally being substituted with one or more F; R.sub.12 is H or C(1-6)alkyl; R.sub.13 is C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(2-5)heterocycloalkyl, C(2-5)heterocycloalkylC(1-3)alkyl, C(6- 10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)hetero-aryl or C(1-9)heteroarylC(1-3)alkyl, 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; R.sub.14 is H, C(1-6)alkyl, C(2-6)alkenyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(2-5)heterocycloalkyl, C(2-5)heterocycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl or C(1-9)heteroarylC(1-3)alkyl, 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; 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; the term C(1-9)heteroaryl denotes an aromatic group having 1-9 carbon atoms and 1-4 heteroatoms, which is attached via a nitrogen atom or a carbon atom, and all carbon atoms of the aromatic group may optionally be substituted with one or more halogen or methyl; the term C(2-5)heterocycloalkyl denotes a saturated cyclic hydrocarbon group having 2-5 carbon atoms and 1-3 heteroatoms, which is attached via a nitrogen atom or a carbon atom, and all carbon atoms of the saturated cyclic hydrocarbon group may optionally be substituted with one or more halogen or methyl; and the term heteroatom denotes a nitrogen, sulfur or oxygen atom.

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

3. The compound according to claim 1, wherein R.sub.9 is C(1-3)alkyl.

4. The compound according to claim 1, wherein R.sub.10 and R.sub.11 are both H.

5. The compound according to claim 1, wherein R.sub.12 is H.

6. The compound according to claim 1, wherein R.sub.13 is C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(2-5)heterocycloalkyl, C(4)heterocycloalkyl-C(1-3)alkyl, C(6)aryl, C(6)arylC(1-3)alkyl, C(1-5)heteroaryl or C(1-5)heteroaryl-C(1-3)alkyl, 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.

7. The compound according to claim 1, wherein R.sub.14 is H, C(1-6)alkyl, C(2-6)alkenyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(4)heterocycloalkyl, C(2-5)heterocycloalkylC(1-3)alkyl, C(6)aryl, C(6)arylC(1-3)alkyl, C(1-5)heteroaryl or C(1-5)heteroarylC(1-3)alkyl, 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; and the term C(1-5)heteroaryl denotes an aromatic group having 1-5 carbon atoms and 1-4 heteroatoms, which is attached via a nitrogen atom or a carbon atom, and all carbon atoms in the aromatic group may optionally be substituted with one or more halogen or methyl.

8. The compound according to claim 1, wherein 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 R.sub.14 substituent selected from C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(2-5)heterocycloalkyl, C(2-5)heterocycloalkyl-C(1-3)alkyl, C(6)aryl, C(6)arylC(1-3)alkyl, C(1-5)heteroaryl or C(1-5)heteroaryl-C(1-3)alkyl, 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; and the term C(1-5)heteroaryl denotes an aromatic group having 1-5 carbon atoms and 1-4 heteroatoms, which is attached via a nitrogen atom or a carbon atom, and all carbon atoms of the aromatic group may optionally be substituted with one or more halogen or methyl.

9. The compound selected from claim 1, which is selected from the group of: 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-methyl-N-(5-methyl-1,2-oxazol-3-yl)benzamide; N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethylbenzamide; 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-(3-methyl-1,2-oxazol-5-yl)benzamide; 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide; 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(5-methyl-1,2-oxazol-3-yl)-N-propylbenzamide; N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-propylbenzamide; 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-2-fluoro-N-phenylbenzamide; 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-3-fluoro-N-phenylbenzamide; 2 chloro-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-phenylbenzamide; 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-(1,2-oxazol-3-yl)benzamide; 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenyl-N-(2,2,2-trifluoroethyl)benzamide; 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-3-methyl-N-phenylbenzamide; N-(4-methyl-5-methyl-1,3-thiazol-2-yl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethylbenzamide; N-(dimethyl-1,2-oxazol-4-yl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethylbenzamide; 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-2-methyl-N-phenylbenzamide; N-tert-butyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenylbenzamide; 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(4-methylphenyl)-N-[2-(oxolan-2-yl)propan-2-yl]benzamide; 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-[2-(oxolan-2-yl)propan-2-yl]-N-phenylbenzamide; N-cyclopropyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenylbenzamide; N-cyclobutyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenylbenzamide; N-(3,3-difluorocyclobutyl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenylbenzamide; 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenyl-N-(1,1,1-trifluoropropan-2-yl)benzamide 4-{2[4-(ethanesulfonyl)phenyl]acetamido}-N-methyl-N-(pyridin-2-yl)benzamide; 6-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-phenylpyridine-3-carboxamide; N-benzyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-propylbenzamide; N-benzyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-methylbenzamide; N-(cyclopropylmethyl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-propylbenzamide; 2-[4-(ethanesulfonyl)phenyl]-N-[4-(1,2,3,4-tetrahydroquinoline-1-carbonyl)phenyl]acetamide; 2-[4 (ethanesulfonyl)phenyl]-N-[4-(2-phenylpyrrolidine-1-carbonyl)phenyl]acetamide; 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-methyl-N-phenylbenzamide; 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-propyl-N-(pyridin-3-yl)benzamide; 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-(pyridin-3-yl)benzamide; 2-[4-(ethanesulfonyl)phenyl]-N-[4-(2-phenylpiperidine-1-carbonyl)phenyl]acetamide; 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-phenylbenzamide; N,N-dicyclobutyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}benzamide; 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-[(5-methyl-1,2-oxazol-3-yl)methyl]benzamide; 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(furan-2-ylmethyl)-N-methylbenzamide; N,N-dibenzyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}benzamide; 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(oxolan-3-yl)-N-(pyridin-2-yl)benzamide; N-cyclopropyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(pyridin-2-yl)benzamide; N-cyclobutyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(pyridin-2-yl)benzamide; 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(1-hydroxy-2-methylpropan-2-yl)-N-(4-methylphenyl)benzamide; 4-{2-[6-(ethanesulfonyl)pyridin-3-yl]acetamido}-N-ethyl-2-fluoro-N-phenylbenzamide; N-tert-butyl-4-{2-[6-(ethanesulfonyl)pyridin-3-yl]acetamido}-N-phenylbenzamide; and 2-chloro-4-{2-[6-(ethanesulfonyl)pyridin-3-yl]acetamido}-N-ethyl-N-phenylbenzamide.

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

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.

General Methods of Preparation

(2) The compounds described herein, including compounds of general Formula I 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. 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. 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 for 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.

(3) 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.

(4) Abbreviations used herein are as follow: r.t.: room temperature; HATU: 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; DMF: Dimethyl formamide; DiPEA: Diisopropylethylamine; DMAP: 4-(dimethylamino)pyridine; DCC: N,N-Dicyclohexylcarbodiimide; mCPBA: 3-chloroperoxybenzoic acid; TFA: Trifluoroacetic acid; THF: Tetrahydrofuran; DMSO: Dimethylsulfoxide; PyBOP: (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; EtOH: Ethanol; EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide; AIBN: Azobisisobutyronitrile; NBS: N-bromosuccinimide; TBAF: tetra-n-butylammonium fluoride; TMSCN: trimethylsilyl cyanide.

(5) Chemical names are preferred IUPAC names, generated using MarvinSketch version 6.3.0.

(6) 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.

General Procedures

(7) ##STR00003##

(8) As depicted in scheme 1, the derivatives of the invention having Formula I can be prepared by methods known in the art of organic chemistry. Compounds of the invention can for example be obtained by an amide coupling reaction between a (hetero)aryl acetic acid derivative 1, wherein A.sub.5, A.sub.6, A.sub.7, A.sub.8, R.sub.9, R.sub.10 and R.sub.11 have the meaning as previously described, and a (hetero)aryl amino derivative 2, wherein A.sub.1, A.sub.2, A.sub.3, A.sub.4, R.sub.12, R.sub.13 and R.sub.14 have the meaning as previously described, which can easily be prepared by someone skilled in the art of organic chemistry, using a coupling reagent such as EDCI, HATU, DCC, or PyBOP or the like, in the presence of a suitable base such as DiPEA or catalyst such as DMAP.

(9) In an alternative way, a (hetero)aryl acetic acid derivative 1 can be converted into an acid chloride, using for example SOCl.sub.2 or oxalyl chloride, which then can be coupled, in the presence of a suitable base such as Et.sub.3N or the like, with (hetero)aryl amino derivative 2, obtaining derivatives of Formula I.

(10) Alternatively, a (hetero)aryl acetic acid derivative 1 can be condensed with a suitable acid protected (hetero)aryl amino derivative 3, wherein A.sub.1, A.sub.2, A.sub.3, A.sub.4, and R.sub.12 have the meaning as previously described, using methods as described above. After removal of the protecting group, the obtained carboxylic acid derivative 4 can be condensed with a suitable amine 5, wherein R.sub.13 and R.sub.14 have the meaning as previously described, using methods as described before, giving derivatives of Formula I.

(11) ##STR00004##

(12) Conditions: i) H.sub.2SO.sub.4, EtOH, 60 C.; ii) Alkylhalide, K.sub.2CO.sub.3, CH.sub.3CN, r.t.; iii) mCPBA, CH.sub.2Cl.sub.2, r.t.; iv) 2N NaOH, EtOH, r.t.

(13) Scheme 2 illustrates a general method for preparing 2-[4-(alkylsulfonyl)phenyl]acetic acid derivatives of building block 1 wherein and R.sub.9, R.sub.10, R.sub.11, A.sub.5, A.sub.6, A.sub.7 and A.sub.8 have the meaning as previously described.

(14) Esterification of 4-mercaptophenylacetic acid derivatives 6 under acidic conditions, using for example H.sub.2SO.sub.4 in ethanol, provides ethyl 2-(4-mercaptophenyl)acetate derivatives 7. Alkylation of the sulfur group using an alkylhalide in the presence of a base, such as K.sub.2CO.sub.3, gives the corresponding ethyl 2-[4-(alkylsulfanyl)phenyl]acetate derivatives 8. Oxidation, using e.g. mCPBA, gives ethyl 2-(4-alkylsulfonylphenyl)acetate derivatives 9 which after saponification of the ester moiety under basic conditions, e.g. NaOH in ethanol, gives the corresponding 2-[4-(alkylsulfonyl)phenyl]acetic acid derivatives 1.

(15) ##STR00005##

(16) Conditions (A.sub.6=N): i) Thiourea, HCl (aq), reflux; ii) alkyl halide, K.sub.2CO.sub.3, CH.sub.3CN, r.t.; iii) mCPBA, CH.sub.2Cl.sub.2, 0 C.->RT; iv) NBS, AIBN, CH.sub.3CN, 60 C.; v) TMSCN, TBAF, CH.sub.3CN, reflux; vi) NaOH, EtOH, reflux.

(17) Scheme 3 shows a general method for the preparation of 2-(6-alkylsulfonylpyridin-3-yl)acetic acid derivatives of building block 1 wherein A.sub.6 is N and R.sub.9, R.sub.10, R.sub.11, A.sub.5, A.sub.7 and A.sub.8 have the meaning as previously described.

(18) Reaction of 2-bromo-5-methylpyridine derivatives 10 with thiourea under acidic conditions gives 5-methylpyridine-2-thiol derivatives 11 which can be alkylated in the presence of a suitable base such as potassium carbonate to give the corresponding 2-(alkylsulfanyl)-5-methylpyridine derivatives 12. Oxidation using mCPBA for example to the corresponding sulfone derivatives 13, which upon radical bromination with NBS in presence of a radical initiator such as AIBN provides 5-(bromomalkyl)-2-(ethylsulfanyl)pyridine derivatives 14. These bromide derivatives can be converted to the corresponding nitrile derivatives 15 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 15 can provide the corresponding carboxylic acid derivatives of building block 1 wherein A.sub.6 is N.

(19) Some of the building blocks 1 are commercially available, known or prepared according to methods known to those skilled in the art.

(20) ##STR00006##

(21) Conditions: i) Ethanol, HCl.sub.(conc.), r.t.; ii) a suitable derivative 1, EDCI, DMAP, CH.sub.2Cl.sub.2, 60 C.; iii) 2N NaOH, EtOH, reflux; iv) A suitable amine 5, EDCI, DMAP, CH.sub.2Cl.sub.2, 60 C.

(22) Scheme 4 demonstrates a general method for the preparation of Formula I amide derivatives wherein R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14, A.sub.1, A.sub.2, A.sub.3, A.sub.4, A.sub.5, A.sub.6, A.sub.7 and A.sub.8 have the meaning as previously described.

(23) Reaction of carboxylic acid derivatives 16 with ethanol, under acidic conditions, give the corresponding ethyl ester derivatives 17, which can be condensed with 2-[4-(alkylsulfonyl)phenyl]acetic acid derivatives 1, in the presence of for example EDCI and DMAP, gives derivatives 18. After saponification of the ester moiety under basic conditions, by using for example NaOH in ethanol, the obtained derivatives 4 can be condensed with amine derivatives 5, in the presence of for example EDCI and DMAP, giving derivatives of Formula I.

(24) ##STR00007##

(25) Conditions: i) SOCl.sub.2, CH.sub.2Cl.sub.2, r.t.; ii) A suitable amine 5, triethyl amine, CH.sub.2Cl.sub.2, r.t.; iii) A suitable amine 5, EDCI, DMAP, CH.sub.2Cl.sub.2, 60 C.; iv) Zinc powder, NH.sub.4Cl, THF, water 65 C.; v) a suitable derivative 1, EDCI, DMAP, CH.sub.2Cl.sub.2, 60 C.

(26) Scheme 5 demonstrates an alternative route for the preparation of Formula I amide derivatives wherein R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14, A.sub.1, A.sub.2, A.sub.3, A.sub.4, A.sub.5, A.sub.6, A.sub.7 and A.sub.8 have the meaning as previously described.

(27) 4-Nitrobenzoic acid derivatives 19 can be condensed with suitable amines, in the presence of for example EDCI and DMAP, giving 4-nitrobenzamide derivatives 21. Alternatively, 4-nitrobenzoic acid derivatives can easily be converted into the corresponding 4-nitrobenzoyl chloride derivatives 20 by using for example SOCl.sub.2 or oxalyl chloride, which then can be coupled with suitable amines in the presence of a base such as Et.sub.3N or the like.

(28) The nitro group of derivatives 21 can be reduced, by using for example NH.sub.4Cl in the presence of zinc or iron, giving the 4-aminobenzamide derivatives 22, which can be condensed with derivatives 1, in the presence of for example EDCI and DMAP, giving derivatives of Formula I wherein R.sub.12 is hydrogen.

EXAMPLES

(29) All building blocks used are commercially available, known or prepared according to methods known to those skilled in the art.

Examples 1-45

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

(30) ##STR00008##

(31) i) To a solution of N,5-dimethyl-1,2-oxazol-3-amine (0.5 g) and triethyl amine (1.9 mL) in CH.sub.2Cl.sub.2 (5 mL) was added 4-nitrobenzoyl chloride (0.91 g) in CH.sub.2Cl.sub.2 (5 mL). The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was washed with water, an aqueous 1M HCl solution, water, a saturated aqueous NaHCO.sub.3 solution, water, brine and dried over MgSO.sub.4. The combined organic layers were concentrated under reduced pressure and the residue was purified on SiO.sub.2, using 0% to 6% CH3OH/ethyl acetate (1:1) in CH.sub.2Cl.sub.2 as the eluent, giving N-methyl-N-(5-methyl-1,2-oxazol-3-yl)-4-nitrobenzamide (824 mg).

(32) ii) To a solution of the product obtained in the previous step (0.82 g) in ethanol (20 mL) was added SnCl.sub.2 (2.99 g). The reaction mixture was stirred for 1 hour at 70 C. After cooling to room temperature, the reaction mixture was quenched by pouring it onto ice and the pH was set to 14 by addition of an aqueous 2M NaOH solution. The aqueous layer was washed with ethyl acetate and the combined organic layers were washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure giving 4-amino-N-methyl-N-(5-methyl-1,2-oxazol-3-yl)benzamide (687 mg). The product was used in the next step without further purification.

(33) iii) To a solution of the product obtained in the previous step (45 mg), 2-[4-(ethanesulfonyl)phenyl]acetic acid (54 mg) and DMAP (5 mg) in CH.sub.2Cl.sub.2 (2 mL) was added dropwise at 0 C. a solution of EDCI (45 mg) in CH.sub.2Cl.sub.2. The reaction mixture was stirred at room temperature overnight. 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 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-methyl-N-(5-methyl-1,2-oxazol-3-yl)benzamide (42 mg) as a white solid. MS(ES.sup.+) m/z 442.1 (M+H).sup.+.

(34) Following a procedure analogous to that described for example 1, the following compounds have been prepared.

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

(35) ##STR00009##

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

(36) ##STR00010##

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

(37) ##STR00011##

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

(38) ##STR00012##

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

(39) ##STR00013##

7: 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-2-fluoro-N-phenylbenzamide

(40) ##STR00014##

8: 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-3-fluoro-N-phenylbenzamide

(41) ##STR00015##

9: 2-chloro-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-phenylbenzamide

(42) ##STR00016##

10: 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-(1,2-oxazol-3-yl)benzamide

(43) ##STR00017##

11: 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenyl-N-(2,2,2-trifluoroethyl)benzamide

(44) ##STR00018##

12: 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-3-methyl-N-phenylbenzamide

(45) ##STR00019##

13: N-(4-methyl-5-methyl-1,3-thiazol-2-yl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethylbenzamide

(46) ##STR00020##

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

(47) ##STR00021##

15: 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-2-methyl-N-phenylbenzamide

(48) ##STR00022##

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

(49) ##STR00023##

17: 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(4-methylphenyl)-N-[2-(oxolan-2-yl)propan-2-yl]benzamide

(50) ##STR00024##

18: 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-[2-(oxolan-2-yl)propan-2-yl]-N-phenylbenzamide

(51) ##STR00025##

19: N-cyclopropyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenylbenzamide

(52) ##STR00026##

20: N-cyclobutyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenylbenzamide

(53) ##STR00027##

21: N-(3,3-difluorocyclobutyl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenylbenzamide

(54) ##STR00028##

22: 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenyl-N-(1,1,1-trifluoropropan-2-yl)benzamide

(55) ##STR00029##

23: 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-methyl-N-(pyridin-2-yl)benzamide

(56) ##STR00030##

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

(58) ii) Following a procedure analogous to that described in example 1, step iii, using the product obtained in the previous step (390 mg) and 2-[4-(ethanesulfonyl)phenyl]acetic acid (500 mg) as the starting materials, methyl 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}benzoate (560 mg) has been synthesized.

(59) iii) To a solution of the product obtained in the previous step (560 mg) in ethanol was added a aqueous 2N NaOH solution (5 mL) and the resulting mixture was stirred overnight at room temperature. After adding water (100 mL) the mixture was washed with CH.sub.2Cl.sub.2 and acidified to pH=6 by addition of an aqueous 6M HCl solution. The precipitate was filtered off, washed with water and dried at 40 C. under reduced pressure. The obtained 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}benzoic acid (390 mg) was used in the next step without further purification.

(60) iv) Following a procedure analogous to that described in example 1, step iii, using the product obtained in the previous step (40 mg) and 2-(methylamino)pyridine (15 mg) as the starting materials, methyl 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}benzoate (19 mg) was synthesized. MS(ES.sup.+) m/z 438.2 [M+H].sup.+.

(61) Following a procedure analogous to that described for example 23, the following compounds have been prepared.

24: 6-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-phenylpyridine-3-carboxamide

(62) ##STR00031##

25: N-benzyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-propylbenzamide

(63) ##STR00032##

26: N-benzyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-methylbenzamide

(64) ##STR00033##

27: N-(cyclopropylmethyl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-propylbenzamide

(65) ##STR00034##

28: 2-[4-(ethanesulfonyl)phenyl]-N-[4-(1,2,3,4-tetrahydroquinoline-1-carbonyl)phenyl]acetamide

(66) ##STR00035##

29: 2-[4-(ethanesulfonyl)phenyl]-N-[4-(2-phenylpyrrolidine-1-carbonyl)phenyl]acetamide

(67) ##STR00036##

30: 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-methyl-N-phenylbenzamide

(68) ##STR00037##

31: 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-propyl-N-(pyridin-3-yl)benzamide

(69) ##STR00038##

32: 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-(pyridin-3-yl)benzamide

(70) ##STR00039##

33: 2-[4-(ethanesulfonyl)phenyl]-N-[4-(2-phenylpiperidine-1-carbonyl)phenyl]acetamide

(71) ##STR00040##

34: 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-phenylbenzamide.

(72) ##STR00041##

35: N, N-dicyclobutyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}benzamide

(73) ##STR00042##

36: 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-[(5-methyl-1,2-oxazol-3-yl)methyl]benzamide

(74) ##STR00043##

37: 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(furan-2-ylmethyl)-N-methylbenzamide

(75) ##STR00044##

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

(76) ##STR00045##

39: 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(oxolan-3-yl)-N-(pyridin-2-yl)benzamide

(77) ##STR00046##

40: N-cyclopropyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(pyridin-2-yl)benzamide

(78) ##STR00047##

41: N-cyclobutyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(pyridin-2-yl)benzamide

(79) ##STR00048##

42: 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(1-hydroxy-2-methylpropan-2-yl)-N-(4-methylphenyl)benzamide

(80) ##STR00049##

(81) i) Following a procedure analogous to that described for example 1, using appropriate starting materials, N-{1-[(tert-butyldiphenylsilyl)oxy]-2-methylpropan-2-yl}-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(4-methylphenyl)benzamide has been prepared.

(82) ii) A suspension of the product obtained in the previous step (82 mg) and NH.sub.4F (41 mg) in methanol (20 mL) was stirred overnight at 60 C. The reaction mixture was concentrated under vacuo and the residue was dissolved in ethyl acetate. This solution was washed with water, brine, dried over magnesium sulfate and concentrated under reduced vacuo. The residue was purified on reverse phase HPLC, giving the title compound 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(1-hydroxy-2-methylpropan-2-yl)-N-(4-methylphenyl)benzamide (10 mg). MS(ES.sup.+) m/z 509.2 (M+H).sup.+.

43: 4-{2-[6-(ethanesulfonyl)pyridin-3-yl]acetamido}-N-ethyl-2-fluoro-N-phenylbenzamide

(83) ##STR00050##

(84) i) To a suspension of 2-bromo-5-methylpyridine (10 g) in water (70 ml) was added at room temperature an aqueous 25% HCl solution, after which thiourea (9.6) 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 (7.3 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 (51 ml). The formed precipitate was dissolved in CH.sub.2Cl.sub.2 (200 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 (4.5 g) as a white solid.

(85) 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 bromoethane (1.7 mL). After stirring for 17 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product (2.8 g) was purified via an acid-base extraction. The organic layer was dried on MgSO.sub.4 and concentrated under reduced pressure to give 2-(ethylsulfanyl)-5-methylpyridine (2.6 g)

(86) iii) m-CPBA (8.9 g) was added to an ice cold solution of the product obtained in the previous step (2.6 g) in CH.sub.2Cl.sub.2 (75 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. The crude product was purified on SiO.sub.2, using 0% to 50% ethyl acetate in heptane as the eluent to give 2-(ethanesulfonyl)-5-methylpyridine (2.0 g) as a white solid.

(87) iv) To a solution of the product obtained in the previous step (990 mg) in acetonitrile (25 mL) were added NBS (950 mg) and AIBN (44 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 50% ethyl acetate in heptane as the eluent, to give 5-(bromomethyl)-2-(ethanesulfonyl)pyridine (817 mg).

(88) v) The product obtained in the previous step (684 mg) was added to a nitrogen purged solution of trimethylsilyl cyanide (486 uL) and TBAF (3375 uL) in acetonitrile (25 mL). The reaction mixture was stirred at 85 C. in a microwave reactor for 4 hours. 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 70% ethyl acetate in heptane as the eluent to give 2-[6-(ethanesulfonyl)pyridin-3-yl]acetonitrile (315 mg) as a white solid.

(89) vi) To a solution of the product obtained in the previous step (315 mg) in ethanol (3 mL) was added a 2N aqueous NaOH solution. The reaction mixture was stirred for 2 hours in a microwave reactor at 100 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-(ethanesulfonyl)pyridin-3-yl]acetic acid as the crude product. The product was used in the next step without further purification.

(90) 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-(ethanesulfonyl)pyridin-3-yl]acetamido}-N-ethyl-2-fluoro-N-phenylbenzamide (61 mg) has been prepared. MS(ES.sup.+) m/z 470.2 (M+H).sup.+.

(91) Following a procedure analogous to that described for example 43, the following compounds have been prepared.

44: N-tert-butyl-4-{2-[6-(ethanesulfonyl)pyridin-3-yl]acetamido}-N-phenylbenzamide

(92) ##STR00051##

45: 2-chloro-4-{2-[6-(ethanesulfonyl)pyridin-3-yl]acetamido}-N-ethyl-N-phenylbenzamide

(93) ##STR00052##

Example 46

(94) ROR GAL4 Reporter Gene Assay

(95) Example inhibitors 1-45 were tested for their ability to inhibit ROR activity in a ROR GAL4 reporter gene assay. The assay procedure and results are described below.

(96) ROR GAL4 Reporter Gene Assay Description

(97) 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.

(98) 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.

(99) 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.

(100) Detailed Assay Description

(101) 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.

(102) 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.

(103) 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).

(104) Test compounds were diluted, starting from a 10 mM 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.

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

(106) 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).

(107) 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).

(108) All exemplified compounds of Formula I (Examples 1-45) were found to have mean pIC.sub.50 values above 5.

(109) Examples 1-22, 23-35, 37, 38 and examples 40-44 were found to have mean pIC.sub.50 values above or equal to 6.

(110) Examples 2, 3, 5, 6, 7-9, 11, 13, 16-22, 25, 28, 30, 31, 33, 34, 38, 42 and 44 were found to have mean pIC.sub.50 values above or equal to 7.

(111) Examples 11, 13, 16, 18 and 34 were found to have mean pIC.sub.50 values above or equal to 8.

Example 47

(112) Peripheral Blood Mononuclear Cell (PBMC) IL-17 Assay

(113) Example inhibitors 2, 5, 6, 11, 13, 16, 17, 18, 21 and 44 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.

(114) PBMC IL-17 Assay Description

(115) 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.

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

(117) Assay Description

(118) 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.

(119) 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.

(120) 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%.

(121) 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.

(122) 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 1 Ox 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.

(123) 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.

(124) The half maximum inhibitory concentration (IC.sub.50) values for the test compounds were calculated from the IL-17A signal using GraphPad Prism software (GraphPad Software).

(125) The tested examples 2, 5, 6, 11, 13, 16, 17, 18, 21 and 44 were found to have mean pIC.sub.50 values above or equal to 7.

(126) The tested examples 11 and 16 were found to have mean pIC50 values above or equal to 8.