"BENZAMIDE COMPOUNDS AS ROR GAMMA MODULATORS "

RELATED APPLICATIONS

This application claims the benefit of Indian Provisional Application No. 201621017144 filed on May 18, 2016; which is hereby incorporated by reference in its entirety.

TECHNICAL FIELD

The present patent application is directed to aryl amide compounds which may be useful as retinoid-related orphan receptor gamma t (RORyt) modulators.

BACKGROUND OF THE INVENTION

Retinoid-related orphan receptors (RORs) are transcription factors which belong to the steroid hormone nuclear receptor super family. The ROR family consists of three members, ROR alpha (RORa), ROR beta (RORβ) and ROR gamma (RORy), also known as NR1F1, NR1F2 and NR1F3 respectively (and each encoded by a separate gene RORA, RORB and RORC, respectively). RORs contain four principal domains shared by the majority of nuclear receptors: an N- terminal A B domain, a DNA-binding domain, a hinge domain, and a ligand binding domain. Each ROR gene generates several isoforms which differ only in their N- terminal A/B domain. Two isoforms of RORy, RORyl and RORyt (also known as RORy2) have been identified.

RORyt is a truncated form of RORy, lacking the first N-terminal 21 amino acids and is exclusively expressed in cells of the lymphoid lineage and embryonic lymphoid tissue inducers (Sun et al., Science, 2000, 288, 2369-2372; Eberl et al., Nat Immunol., 2004, 5: 64-73) in contrast to RORy which is expressed in multiple tissues (heart, brain, kidney, lung, liver and muscle).

RORyt has been identified as a key regulator of Thl7 cell differentiation. Thl7 cells are a subset of T helper cells which produce IL- 17 and other proinflammatory cytokines and have been shown to have key functions in several mouse autoimmune disease models including experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). In addition, Thl7 cells have also been associated in the pathology of a variety of human inflammatory and autoimmune disorders including multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease and asthma (Jetten et al., Nucl. Recept. Signal, 2009, 7:e003; Manel et al., Nat. Immunol., 2008, 9, 641-649). The pathogenesis of chronic autoimmune diseases including multiple sclerosis and rheumatoid arthritis arises from the break in tolerance towards self-antigens and the development of auto-aggressive effector T cells infiltrating the target tissues. Studies have shown that Thl7 cells are one of the important drivers of the inflammatory process in tissue-specific autoimmunity (Steinman et al., J. Exp. Med., 2008, 205: 1517- 1522; Leung et al., Cell. Mol. Immunol., 20107: 182-189). Thl7 cells are activated during the disease process and are responsible for recruiting other inflammatory cells types, especially neutrophils, to mediate pathology in the target tissues (Korn et al., Annu. Rev. Immunol., 2009, 27:485-517) and RORyt has been shown to play a critical role in the pathogenic responses of Thl7 cells (Ivanov et al., Cell, 2006 126: 1121-1133). RORyt deficient mice have shown no Thl7 cells and also resulted in amelioration of EAE. The genetic disruption of RORy in a mouse colitis model also prevented colitis development (Buonocore et al., Nature, 2010, 464: 1371- 1375). The role of RORyt in the pathogenesis of autoimmune or inflammatory diseases has been well documented in the literature. ( Jetten et al., Adv. Dev. Biol., 2006, 16:313-355; Meier et al. Immunity, 2007, 26:643-654; Aloisi et al., Nat. Rev. Immunol, 2006, 6:205-217; Jager et al., J. Immunol, 2009, 183:7169-7177; Serafmi et al., Brain Pathol, 2004, 14: 164-174; Magliozzi et al., Brain, 2007, 130: 1089-1104; Barnes et al., Nat. Rev. Immunol, 2008, 8: 183- 192).

In addition, RORyt is also shown to play a crucial role in other non-Thl7 cells, such as mast cells (Hueber et al., J Immunol, 2010, 184: 3336-3340). RORyt expression and secretion of Thl7-type of cytokines has also been reported in NK T-cells (Eberl et al., Nat. Immunol, 2004, 5: 64-73) and gamma-delta T-cells (Sutton et al, Nat. Immunol, 2009, 31: 331-341; Louten et al., J Allergy Clin. Immunol, 2009, 123: 1004-1011), suggesting an important function for RORyt in these cells.

PCT Publication Nos. WO 2012/139775, WO 2012/027965, WO 2012/028100, WO 2012/100732, WO 2012/100734, WO2012/064744, WO 2013/171729 and WO 2015/008234 discloses heterocyclic compounds which are modulators of retinoid-related orphan receptor gamma (RORy) receptor activity.

In view of the above, a need exists for new therapeutic agents that modulate the activity of RORyt and thus will provide new methods for treating diseases or condition associated with the modulation of RORyt.

The present application is directed to compounds that are modulators of the RORyt receptor.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to compound of formula (I)

or tautomers thereof, stereoisomers thereof or pharmaceutically acceptable salt thereof, wherein,

Ring A is selected from C _6-14 aryl, 5 to 14 membered heteroaryl and C _3-6 cycloalkyl;

R ¹ is selected from C _1-8 alkyl and haloC _1-8 alkyl;

each occurrence of R ² is independently selected from halogen, hydroxyl, cyano, C _{1- 8} alkyl, C _1-8 alkoxy, haloC _1-8 alkyl, haloC _1-8 alkoxy, hydroxyC _1-8 alkyl and C _3-6 cycloalkyl;

R ³ is independently selected from hydrogen, C _1-8 alkyl, haloC _1-8 alkyl and C ₃ - ₆ cycloalkylC _1-8 alkyl;

R ⁴ is independently selected from C _1-8 alkyl, C _1-8 alkoxy, haloC _1-8 alkyl, hydroxyC _1- ealkyl, C _3-6 cycloalkyl, C _3-6 cycloalkylC _1-8 alkyl, 3- to 15- membered heterocyclyl and C _6-14 aryl; wherein C ₃ -6cycloalkyl and C _6-14 aryl are optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano or C _1-8 alkyl; or R ⁴ along with the carbon atom to which it is attached form a bicyclic ring along with ring A; wherein bicyclic ring may be carbocyclic ring or 5- to 15- heterocyclyl ring;

each occurrence of R ⁵ is independently selected from halogen, cyano, hydroxyl and C _1-

₈ alkyl;

'n' is 0, 1, 2 or 3; and

'p' is 0, 1 or 2.

The compounds of formula (I) may involve one or more embodiments. Embodiments of formula (I) include compounds of formula (II) as described hereinafter. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (I) as defined above wherein R ¹ is -C2H5 (according to an embodiment defined below); R ² is ~F, -CI, methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl or cyclopropyl (according to another embodiment defined below); 'η' is 0, 1 or 2 (according to yet another embodiment defined below); and 'p' is 0 or 1 (according to yet another embodiment defined below).

According to one embodiment, specifically provided are compounds of formula (I), in which ring A is C _6-14 aryl (e.g. phenyl) or C _3-6 cycloalkyl (e.g. cyclohexyl).

According to another embodiment, specifically provided are compounds of formula (I), in which ring A is phenyl or cyclohexyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ¹ is C _1-8 alkyl (e.g. methyl or ethyl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ¹ is ethyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ² is halogen (e.g. F, CI, Br or I), C _1-8 alkyl (e.g. methyl, ethyl, isopropyl, isobutyl or tert-butyl), haloC _1-8 alkyl (e.g. trifluoromethyl, difluoromethyl or 2,2,2-trifluoroethyl) or C3- 6cycloalkyl (e.g. cyclopropyl, cyclobutyl or cyclopentyl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ² is -F, -CI, methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl or cyclopropyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ² is -F, -CI, methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl or cyclopropyl and 'n' is 1 or 2.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ³ is hydrogen, C _1- 4alkyl (e.g. methyl or ethyl), haloC _1-8 alkyl (e.g. 2,2,2- trifluoroethyl) or C _3-6 cycloalkylC _1-8 alkyl (e.g. cyclopropylmethyl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ³ is hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl or cyclopropylmethyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ⁴ is C _1- 4alkyl (e.g. methyl, ethyl, n-propyl or 1-methylethyl), haloC _1-8 alkyl (e.g.

2,2,2-trifluoroethyl), hydroxyC _1-8 alkyl (e.g. 1-hydroxyethyl), C _3-6 cycloalkyl (e.g.

3- to 15- membered heterocyclyl (e.g. or C _6-14 aryl (e.g. In this embodiment, C3-

6cycloalkyl and C _6-14 aryl are optionally substituted with one or more substituents selected from halogen (e.g. CI, F or Br) and C _1-8 alkyl (e.g. methyl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ⁴ is methyl, ethyl, n-propyl, 1-methylethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl,

According to yet another embodiment, specifically provided are compounds of formula

(I), in which R ⁴ along with the carbon atom to which it is attached forms along with ring A.

According to yet another embodiment, specifically provided are compounds of formula

(I), in which R ⁵ is halogen (e.g. F or CI),

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ⁵ is F.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ⁵ is F and 'p' is 1.

According to yet another embodiment, specifically provided are compounds of formula (I), in which 'n' is 0, 1 or 2.

According to yet another embodiment, specifically provided are compounds of formula (I), in which 'p' is 0 or 1.

According to yet another embodiment, specifically provided are compounds of formula

(I), in which is cyclohexyl, 4,4-difluorocyclohexyl, phenyl, 2-chlorophenyl, 3- chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 4- isopropylphenyl, 4-isobutylphenyl, 4-(tert-butyl)phenyl, 3,5-dimethylphenyl, 2-chloro-4- methylphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 4-fluorophenyl, 4- (trifluoromethyl)phenyl or 4-cyclopropylphenyl. According to yet another embodiment, specifically provided are compounds of formula

(I), in which is (1R)-l-phenylethyl, (lS)-l-phenylethyl, (1R)-l- phenylpropyl, (15)-l-phenylpropyl, (1R)-l-(o-tolyl)ethyl, , (15)-l-(o-tolyl)ethyl, (1R)-l-(o- tolyl)propyl, (1R)-l-(p-tolyl)ethyl, (1R)-l-(p-tolyl)propyl, (1R)-l-(4-ethylphenyl)ethyl, (1R)- 1 -(4-isopropylphenyl)ethyl, ( 1R)- 1 -(4-isobutylphenyl)ethyl, ( 1R)- 1 -(4-(tert- butyl)phenyl)ethyl, (1R)-l-(3,5-dimethylphenyl)ethyl, l-(3-chlorophenyl)ethyl, (1R)-l-(3- chlorophenyl)ethyl, ( 1R)- 1 -(4-chlorophenyl)ethyl, ( 1R)-(4-chlorophenyl)(4,4- difluorocyclohexyl)methyl, ( 1R)- 1 -(4-chlorophenyl)-3 ,3 ,3-trifluoropropyl, ( 1R)- 1 -(2- chlorophenyl)ethyl, (1R)-l-(4-chlorophenyl)propyl, (1R)-l-(4-chlorophenyl)butyl, (1R)-l-(4- chlorophenyl)-2-cyclopropylethyl, ( 1R)- 1 -(2,4-dichlorophenyl)propyl, ( 1R)- 1 -(2,4- difluorophenyl)ethyl, (1R)-l-(4-fluorophenyl)propyl, (1R)-l-(4-(trifluoro- methyl)phenyl)propyl, ( 1R)-(2-chloro-4-methylphenyl)(phenyl)methyl, ( 1R)-(4- chlorophenyl)-2-methylpropyl, ( 1R)-(4-chlorophenyl)(phenyl)methyl, ( 1R)-(4- chlorophenyl)(p-tolyl)methyl, (1R)-(4-chlorophenyl)(cyclohexyl)methyl, (1R)-(4- chlorophenyl)(cyclopropyl)methyl, ( 1R)-(4-chlorophenyl)(cyclobutyl)methyl, ( 1R)-(4- chlorophenyl)(cyclopentyl)methyl, ( 1R)- 1 -(4-chlorophenyl)-2-cyclopropylethyl, ( 1R)-(4- chlorophenyl)(tetrahydro-2H-pyran-4-yl)methyl, ( 1R)- 1 -(4-cyclopropylphenyl)ethyl, ( 1S,2S)- 2-hydroxy-l-(p-tolyl)-propyl, (15,2R)-2-hydroxy-l-(p-tolyl)-propyl, (lS,2S)-l-(4- chlorophenyl)-2-hydroxypropyl, (1R)-l-cyclohexylethyl or (1R)-l-(4,4- difluorocyclohexyl)propyl, 2,3-dihydro-lH-inden-l-yl or 5-cldoro-2,3-dihydro-lH-inden-l- yi-

According to yet another embodiment, specifically provided are compounds of formula (I), in which

ring A is phenyl or cyclohexyl;

R ¹ is ethyl;

R ² is -F, -CI, methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl or cyclopropyl;

R ³ is hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl or cyclopropylmethyl; methyl, ethyl, n-propyl, 1-methylethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl,

or R ⁴ along with the

carbon atom to which it is attached forms with ring A;

R ⁵ is F;

'n' is 0, 1 or 2; and

'p' is 0 or 1.

According to yet another embodiment, specifically provided are compounds of formula (I), in which

R ¹ is ethyl;

R ³ is hydrogen methyl, ethyl, 2,2,2-trifluoroethyl or cyclopropylmethyl;

R ⁴ is methyl, ethyl, n-propyl, 1-methylethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl,

R ⁵ is F; is cyclohexyl, 4,4-difluorocyclohexyl, phenyl, 2-chlorophenyl, 3- chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 4- isopropylphenyl, 4-isobutylphenyl, 4-(tert-butyl)phenyl, 3,5-dimethylphenyl, 2-chloro-4- methylphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 4-fluorophenyl, 4- (trifluoromethyl)phenyl or 4-cyclopropylphenyl; and

'p' is O or l.

According to yet another embodiment, specifically provided are compounds of formula (I), in which

R ¹ is ethyl;

R ³ is hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl or cyclopropylmethyl;

R ⁵ is F; is (1R)-l-phenylethyl, (1S)-l-phenylethyl, (1R)-l-phenylpropyl, (1S)-l-phenylpropyl, (1R)-l-(o-tolyl)ethyl, , (1S)-l-(o-tolyl)ethyl, (1R)-l-(o-tolyl)propyl, (1R)-l-(p-tolyl)ethyl, (1R)-l-(p-tolyl)propyl, (1R)-l-(4-ethylphenyl)ethyl, (1R)-l-(4- isopropylphenyl)ethyl, ( 1R)- 1 -(4-isobutylphenyl)ethyl, ( 1R)- 1 -(4-(tert-butyl)phenyl)ethyl, (1R)-l-(3,5-dimethylphenyl)ethyl, l-(3-chlorophenyl)ethyl, (1R)-l-(3-chlorophenyl)ethyl, ( 1R)- 1 -(4-chlorophenyl)ethyl, ( 1R)-(4-chlorophenyl)(4,4-difluorocyclohexyl)methyl, ( 1R)- 1 - (4-chlorophenyl)-3,3,3-trifluoropropyl, (1R)-l-(2-chlorophenyl)ethyl, (1R)-l-(4- chlorophenyl)propyl, ( 1R)- 1 -(4-chlorophenyl)butyl, ( 1R)- 1 -(4-chlorophenyl)-2- cyclopropylethyl, (1R)-l-(2,4-dichlorophenyl)propyl, (1R)-l-(2,4-difluorophenyl)ethyl, (1R)- 1 -(4-fluorophenyl)propyl, ( 1R)- 1 -(4-(trifluoro-methyl)phenyl)propyl, ( 1R)-(2-chloro-4- methylphenyl)(phenyl)methyl, ( 1R)-(4-chlorophenyl)-2-methylpropyl, ( 1R)-(4- chlorophenyl)(phenyl)methyl, ( 1R)-(4-chlorophenyl)(p-tolyl)methyl, ( 1R)-(4- chlorophenyl)(cyclohexyl)methyl, ( 1R)-(4-chlorophenyl)(cyclopropyl)methyl, ( 1R)-(4- chlorophenyl)(cyclobutyl)methyl, ( 1R)-(4-chlorophenyl)(cyclopentyl)methyl, ( 1R)- 1 -(4- chlorophenyl)-2-cyclopropylethyl, (1R)-(4-chlorophenyl)(tetrahydro-2H-pyran-4-yl)methyl, (1R)-l-(4-cyclopropylphenyl)ethyl, (1S,2S')-2-hydroxy-l-(p-tolyl)-propyl, (1S,2R)-2- hydroxy- 1 -(p-tolyl)-propyl, ( 1 S ,2S)- 1 -(4-chlorophenyl)-2-hydroxypropyl, ( 1R)- 1 - cyclohexylethyl, (1R)-l-(4,4-difluorocyclohexyl)propyl, 2,3-dihydro-lH-inden-l-yl or 5- chloro-2,3-dihydro-lH-inden-l-yl; and

'p' is 0 or 1.

According to an embodiment, the compounds of formula (I) may be (R)- or (S)- enantiomer or the racemate. Preferably, the compound of formula (I) is the (R)-enantiomer.

According to yet another embodiment, the definition of "compounds of formula (I)" inherently includes all stereoisomers of the compound of formula (I) either as pure stereoisomer or as a mixture of two or more stereomers. The word stereoisomers includes enantiomers, diasteroisomers, racemates, cis isomers, trans isomers and mixture thereof.

According to yet another embodiment, the compounds of formula (I) is a compound that may exist in the form of one or more stereoisomers, wherein one or more of those steroisomers is therapeutically active.

According to yet another embodiment, the compounds of formula (I) comprises a therapeutically active stereoisomer that is substantially free of other stereoisomers. According to yet another embodiment, compounds of formula (I) comprises a therapeutically active stereoisomer that has less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, or less than about 1% by weight of other steroisomers.

According to an embodiment, specifically provided are compounds of formula (I) with an ICso value of less than 1000 nM, preferably less than 100 nM, more preferably less than 50 nM, with respect to RORyt activity.

Further embodiments relating to groups R ¹ , R ² , R ³ , R ⁴ , R ⁵ , p, n and ring A (and groups defined therein) are described hereinafter in relation to the compounds of formula (II). It is to be understood that these embodiments are not limited to use in conjunction with formula (II) but apply independently and individually to the compounds of formula (I). For example, in an embodiment described hereinafter, the invention specifically provides compounds of formula (II) in which 'n' is 0, 1 or 2 and consequently there is also provided a compound of formula (I) in which 'n' is 0, 1 or 2.

The invention also provides a compound of formula (II), which is an embodiment of a compound of formula (I).

Accordingly the invention provides a compound of formula (II)

or tautomers thereof, stereoisomers thereof or pharmaceutically acceptable salt thereof, wherein,

Ring A is selected from C _6-14 aryl, 5 to 14 membered heteroaryl and C _3-6 cycloalkyl; R ¹ is selected from C _1-8 alkyl and haloC _1-8 alkyl;

each occurrence of R ² is independently selected from halogen, hydroxyl, cyano, Cl- 8alkyl, C _1-8 alkoxy, haloC _1-8 alkyl, haloC _1-8 alkoxy, hydroxylC _1-8 alkyl and C _3-6 cycloalkyl;

each occurrence of R ⁵ is independently selected from halogen, cyano, hydroxyl and C _{1- 8} alkyl;

R ⁶ is independently selected from C _1-8 alkyl;

R ⁷ is independently selected from haloC _1-8 alkyl, hydroxyC _1-8 alkyl, C _3-6 cycloalkyl, C3- 6cycloalkylC _1-8 alkyl, 3- to 15- membered heterocyclyl and C _6-14 aryl; wherein C _3-6 cycloalkyl and C _6-14 aryl are optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano or C _1-8 alkyl; or R ⁷ along with the carbon atom to which it is attached form a bicyclic ring along with ring A; wherein bicyclic ring may be carbocyclic ring or 5- to 15- heterocyclyl ring;

'n' is 0, 1, 2 or 3; and

'p' is 0, 1 or 2.

The compounds of formula (II) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (II) as defined above wherein R ¹ is - ethyl (according to an embodiment defined below); R ² is -CI or methyl (according to another embodiment defined below); and 'n' is 1 or 2 (according to yet another embodiment defined below).

According to one embodiment, specifically provided are compounds of formula (II), in which ring A is C _6-14 aryl (e.g. phenyl).

According to another embodiment, specifically provided are compounds of formula (II), in which ring A is phenyl.

According to yet another embodiment, specifically provided are compounds of formula (II), in which R ¹ is C _1-8 alkyl (e.g. methyl or ethyl).

According to yet another embodiment, specifically provided are compounds of formula (II), in which R ¹ is ethyl.

According to yet another embodiment, specifically provided are compounds of formula

(II), in which R ² is halogen (e.g. F, CI, Br or I) or C _1-8 alkyl (e.g. methyl, ethyl, isopropyl, isobutyl or f erf-butyl).

According to yet another embodiment, specifically provided are compounds of formula (II), in which R ² is -CI or methyl.

According to yet another embodiment, specifically provided are compounds of formula

(II), in which R ⁵ is halogen (e.g. F or CI),

According to yet another embodiment, specifically provided are compounds of formula (II), in which R ⁵ is F. According to yet another embodiment, specifically provided are compounds of formula (II), in which R ⁶ is C _1-4 alkyl (e.g. methyl or ethyl).

According to yet another embodiment, specifically provided are compounds of formula (II), in which R ⁶ is -CH ₃ or -CH2CH3.

According to yet another embodiment, specifically provided are compounds of formula (II), in which R ⁷ is haloC _1-8 alkyl (e.g. 2,2,2-trifluoroethyl), hydroxyC _1-8 alkyl (e.g. 1-

hydroxyethyl), C _3-6 cycloalkyl

salkyl (e.g. 3- to 15- membered heterocyclyl (e.g. or C _6-14 aryl (e.g. or

In this embodiment, C _3-6 cycloalkyl and C _6-14 aryl are optionally substituted with one or more substituents selected from halogen (e.g. CI, F or Br) and C _1-8 alkyl (e.g. methyl).

According to yet another embodiment, specifically provided are compounds of formula

(II), in which R ⁷ is 2-hydroxyethyl, 2,2,2-trifluoroethyl,

According to yet another embodiment, specifically provided are compounds of formula

(II), in which R ⁷ along with the carbon atom to which it is attached forms along with ring A.

According to yet another embodiment, specifically provided are compounds of formula (II), in which 'n' is 1 or 2. According to yet another embodiment, specifically provided are compounds of formula (II), in which 'p' is 0 or 1.

According to yet another embodiment, specifically provided are compounds of formula (II), in which is 4-chlorophenyl, 4-methylphenyl or 2-chloro-4-methylphenyl.

According to yet another embodiment, specifically provided are compounds of formula

(II), in which is (1R)-(4-chlorophenyl)(4,4-difluorocyclohexyl)methyl,

( 1R)- 1 -(4-chlorophenyl)-3 ,3 ,3-trifluoropropyl, ( 1R)- 1 -(4-chlorophenyl)-2-cyclopropylethyl, ( 1R)-(2-chloro-4-methylphenyl)(phenyl)methyl, ( 1R)-(4-chlorophenyl)(phenyl)methyl, ( 1R)- (4-chlorophenyl)(p-tolyl)methyl, ( 1R)-(4-chlorophenyl)(cyclohexyl)methyl, ( 1R)-(4- chlorophenyl)(cyclopropyl)methyl, ( 1R)-(4-chlorophenyl)(cyclobutyl)methyl, ( 1R)-(4- chlorophenyl)(cyclopentyl)methyl, ( 1R)- 1 -(4-chlorophenyl)-2-cyclopropylethyl, ( 1R)-(4- chlorophenyl)(tetrahydro-2H-pyran-4-yl)methyl, (1S,2S)-2-hydroxy-l-(p-tolyl)-propyl, (15,2R)-2-hydroxy-l-(p-tolyl)-propyl, (1S,2S)-l-(4-chlorophenyl)-2-hydroxypropyl, (1S,2R)- l-(4-chlorophenyl)-2-hydroxypropyl, 2,3-dihydro-lH-inden-l-yl or 5-chloro-2,3-dihydro-lH- inden-l-yl.

According to yet another embodiment, specifically provided are compounds of formula (II), in which

ring A is phenyl;

R ¹ is ethyl;

R ² is -CI or methyl

R ⁵ is F;

R ⁶ is -CH3 or -CH ₂ CH3;

R ⁷ is 2-hydroxyethyl, 2,2,2-trifluoroethyl,

'n' is 1 or 2; and

'p' is 0 or 1. According to yet another embodiment, specifically provided are compounds of formula (II), in which

R ¹ is ethyl;

R ⁵ is F;

R ⁶ is -CH3 or -CH ₂ CH3;

R ⁷ is 2-hydroxyethyl, 2,2,2-trifluoroethyl,

is 4-chlorophenyl, 4-methylphenyl or 2-chloro-4-methylphenyl; and 'p' is O or l.

According to yet another embodiment, specifically provided are compounds of formula (II), in which

R ¹ is ethyl;

R ³ is hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl or cyclopropylmethyl;

R ⁵ is F; is (1R)-(4-chlorophenyl)(4,4-difluorocyclohexyl)methyl, (1R)-l- (4-chlorophenyl)-3 ,3 ,3-trifluoropropyl, ( 1R)- 1 -(4-chlorophenyl)-2-cyclopropylethyl, ( 1R)-(2- chloro-4-methylphenyl)(phenyl)methyl, ( 1R)-(4-chlorophenyl)(phenyl)methyl, ( 1R)-(4- chlorophenyl)(p-tolyl)methyl, (1R)-(4-chlorophenyl)(cyclohexyl)methyl, (1R)-(4- chlorophenyl)(cyclopropyl)methyl, ( 1R)-(4-chlorophenyl)(cyclobutyl)methyl, ( 1R)-(4- chlorophenyl)(cyclopentyl)methyl, ( 1R)- 1 -(4-chlorophenyl)-2-cyclopropylethyl, ( 1R)-(4- chlorophenyl)(tetrahydro-2H-pyran-4-yl)methyl, (1S,2S)-2-hydroxy-l-(p-tolyl)-propyl, (1S,2R)-2-hydroxy-l-(p-tolyl)-propyl, (1S,2S)-l-(4-chlorophenyl)-2-hydroxypropyl or (1S,2R)-l-(4-chlorophenyl)-2-hydroxypropyl, 2,3-dihydro-lH-inden-l-yl or 5-chloro-2,3- dihydro-lH-inden-l-yl; and

'p' is 0 or 1. According to yet another embodiment, the compounds of formula (II) may be (R)- enantiomer.

According to yet another embodiment, the compounds of formula (II) comprises a therapeutically active R-enantiomer that is substantially free of other S-enantiomer.

According to yet another embodiment, compounds of formula (II) comprises a therapeutically active R-enantiomer that has less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, or less than about 1% by weight of other S-enantiomer.

According to yet another embodiment, the definition of "compounds of formula (II)" inherently includes all stereoisomers of the compound of formula (II) either as pure stereoisomer or as a mixture of two or more stereomers. The word stereoisomers includes enantiomers, diasteroisomers, racemates, cis isomers, trans isomers and mixture thereof.

According to an embodiment, specifically provided are compounds of formula (II) that exhibit an IC50 value with respect to RORyt activity of less than about 1000 nM, preferably less than about 100 nM, more preferably less than about 50 nM.

Compounds of the present invention include the compounds in Examples 1-54.

It should be understood that formulas (I) and (II) structurally encompass all geometrical isomers, stereoisomers, enantiomers and diastereomers, N-oxides, solvates and pharmaceutically acceptable salts thereof.

The present application also provides a pharmaceutical composition that includes at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. The compounds described herein may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a tablet, capsule, sachet, paper or other container.

The compounds and pharmaceutical compositions of the present invention are useful for inhibiting the activity of RORyt. Thus, the present invention further provides a method of inhibiting RORyt in a subject in need thereof by administering to the subject one or more compounds described herein in the amount effective to cause inhibition of such receptor.

In a further aspect, the present invention relates to a method of treating a disease, disorder or condition modulated by RORyt, such as autoimmune disease, inflammatory disease, respiratory disorders, pain and cancer comprising administering to a subject in need thereof a compound according to any of the embodiments described herein. In another further aspect, the present invention relates to a method of treating a disease, disorder or condition modulated by RORyt, such as chronic obstructive pulmonary disease (COPD), asthma, cough, pain, inflammatory pain, chronic pain, acute pain, arthritis, osteoarthritis, multiple sclerosis, rheumatoid arthritis, colitis, ulcerative colitis and inflammatory bowel disease, comprising administering to a subject in need thereof a compound according to any of the embodiments described herein.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The terms "halogen" or "halo" means fluorine (fluoro), chlorine (chloro), bromine

(bromo), or iodine (iodo).

The term "alkyl" refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. C _1-8 alkyl), and which is attached to the rest of the molecule by a single bond, such as, but not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl). The term "C _1- 6alkyl" refers to an alkyl chain having 1 to 6 carbon atoms. The term "C _1- 4alkyl" refers to an alkyl chain having 1 to 4 carbon atoms. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched.

The term "alkoxy" denotes an alkyl group attached via an oxygen linkage to the rest of the molecule (i.e. C _1-8 alkoxy). Representative examples of such groups are -OCH3 and -OC2H5. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched.

The term "haloalkyl" refers to at least one halo group (selected from F, CI, Br or I), linked to an alkyl group as defined above (i.e. haloC _1-8 alkyl). Examples of such haloalkyl moiety include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. The term "haloC _1- 4alkyl" refers to at least one halo group linked an alkyl chain having 1 to 4 carbon atoms. Unless set forth or recited to the contrary, all haloalkyl groups described herein may be straight chain or branched.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms (i.e. haloC _1-8 alkoxy). Examples of "haloalkoxy" include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-bromoethoxy. Unless set forth or recited to the contrary, all haloalkoxy groups described herein may be straight chain or branched.

The term "hydroxyC _1-8 alkyl" refers to a C _1-8 alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyC _1- 4alkyl). Examples of hydroxyC _1- 4alkyl moieties include, but are not limited to - CH2OH and -C2H4OH.

The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, (i.e.C3-i2cycloalkyl). Examples of monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapthyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl. The term "C _3-6 cycloalkyl" refers to the cyclic ring having 3 to 6 carbon atoms. Examples of "C3- 6cycloalkyl" include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

The term "cycloalkylalkyl" refers to a cyclic ring-containing radical having 3 to about 6 carbon atoms directly attached to an alkyl group (i.e. C _3-6 cycloalkylC _1-8 alkyl). The cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.

The term "carbocyclic ring" refers to a ring composed exclusively of 3 to IS carbon atoms, including C _6-14 aryl or C3-i2cycloalkyl ring defined herein. The carbocyclic ring may be saturated or unsaturated.

The term "aryl" refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C _6-14 aryl), including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.

The term "heteroaryl" unless otherwise specified refers to 5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S (i.e. 5 to 14 membered heteroaryl). The heteroaryl may be a mono-, bi- or tricyclic ring system. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Examples of such heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridyl, pyrirnidinyl, pyrazinyl, pyridazinyl, pyrazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl and phthalazinyl.

The term "heterocyclyl" or "heterocyclic ring" unless otherwise specified refers to substituted or unsubstituted non-aromatic 3- to IS- membered heterocyclyl ring radical which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur. The heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; also, unless otherwise constrained by the definition the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s). Examples of such heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazohdinyl, morpholinyl, oxazolinyl, oxazolidinyl, oxadiazolyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamorpholinyl sulfone. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be substituted or unsubstituted.

The term "pharmaceutically acceptable salt" includes salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Examples of such salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Examples of salts derived from inorganic bases include, but are not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, and zinc.

The term "treating" or "treatment" of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).

A "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.

The compounds of formula (I) or (II) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of formula (I) or (II) as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by the reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolysing) the individual diastereomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of chiral HPLC column. The chiral centres of the present invention can have the S or R configuration as defined by the IUPAC 1974. The terms "salt" or "solvate", and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, ro tamers, tautomers, positional isomers or racemates of the inventive compounds.

Pharmaceutical Compositions

The compounds of the invention are typically administered in the form of a pharmaceutical composition. The pharmaceutical compositions described herein comprise one or more compounds described herein and one or more pharmaceutically acceptable excipients. Typically, the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use. The pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, solvents and the like.

Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylene.

The pharmaceutical compositions described herein may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavouring agents, colorants or any combination of the foregoing.

Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition, can be carried out using any of route of administration, such as orally or parenterally. The route of administration may be any route which effectively transports the active compound of the patent application to the appropriate or desired site of action.

Methods of Treatment

The compounds of the present invention are particularly useful because they inhibit the activity of retinoid-related orphan receptor gamma, particularly retinoid -related orphan receptor gamma t (RORyt), i.e., they prevent, inhibit, or suppress the action of RORyt, and/or may elicit a RORyt modulating effect. Compounds of the invention are therefore useful in the treatment of those conditions in which inhibition of ROR gamma activity, and particularly RORyt, is required. The compounds of the present patent application are modulators of RORyt and can be useful in the treatment of diseases/disorder mediated by RORyt. Accordingly, the compounds and the pharmaceutical compositions of this invention may be useful in the treatment of inflammatory, metabolic and autoimmune diseases mediated by RORyt.

The term "autoimmune diseases" will be understood by those skilled in the art to refer to a condition that occurs when the immune system mistakenly attacks and destroys healthy body tissue. An autoimmune disorder may result in the destruction of one or more types of body tissue, abnormal growth of an organ, and changes in organ function. An autoimmune disorder may affect one or more organ or tissue types which include, but are not limited to, blood vessels, connective tissues, endocrine glands such as the thyroid or pancreas, joints, muscles, red blood cells, and skin. Examples of autoimmune (or autoimmune-related) disorders include multiple sclerosis, arthritis, rheumatoid arthritis, psoriasis, Crohn's disease, gastrointestinal disorder, inflammatory bowel disease, irritable bowel syndrome, colitis, ulcerative colitis, Sjorgen's syndrome, atopic dermatitis, optic neuritis, respiratory disorder, chronic obstructive pulmonary disease (COPD), asthma, type I diabetes, neuromyelitis optica, Myasthenia Gavis, uveitis, Guillain- Barre syndrome, psoriatic arthritis, Gaves' disease, allergy, osteoarthritis, Kawasaki disease, mucosal leishmaniasis, Hashimoto's thyroiditis, Pernicious anemia, Addison's disease, Systemic lupus erythematosus, Dermatomyositis, Sjogren syndrome, Lupus erythematosus, Myasthenia gravis, Reactive arthritis, Celiac disease - sprue (gluten-sensitive enteropathy), Graves's disease, thymopoiesis and Lupus.

Compounds of the present patent application may also be useful in the treatment of inflammation. The term "inflammation" will be understood by those skilled in the art to include any condition characterized by a localized or a systemic protective response, which may be elicited by physical trauma, infection, chronic diseases, and/or chemical and/or physiological reactions to external stimuli (e.g. as part of an allergic response). Any such response, which may serve to destroy, dilute or sequester both the injurious agent and the injured tissue, may be manifest by, for example, heat, swelling, pain, redness, dilation of blood vessels and/or increased blood flow, invasion of the affected area by white.

The term "inflammation" is also understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterized by inflammation as a symptom, including inter alia acute, chronic, ulcerative, specific, allergic, infection by pathogens, immune reactions due to hypersensitivity, entering foreign bodies, physical injury, and necrotic inflammation, and other farms of inflammation known to those skilled in the art. The term thus also includes, for the purposes of this present patent application, inflammatory pain, pain generally and/or fever.

The compounds of the present invention may be used for treatment of arthritis, including, but are not limited to, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, collagen-induced arthritis (CIA) and other arthritic conditions.

The compounds of the present invention may be used for treatment of respiratory disorders including, but are not limited to, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and cough.

Other respiratory disorders include, but are not limited to, bronchitis, bronchiolitis, bronchiectasis, acute nasoparyngitis, acute and chronic sinusitis, maxillary sinusitis, pharyngitis, tonsillitis, laryngitis, tracheitis, epiglottitis, croup, chronic disease of tonsils and adenoids, hypertrophy of tonsils and adenoids, peritonsillar abscess, rhinitis, abscess or ulcer and nose, pneumonia, viral and bacterial pneumonia, bronchopneumonia, influenza, extrinsic allergic alveolitis, coal workers' pneumoconiosis, asbestosis, pneumoconiosis, pneumonopathy, respiratory conditions due to chemical fumes, vapors and other external agents, emphysema, pleurisy, pneumothorax, abscess of lung and mediastinum, pulmonary congestion and hypostasis, postinflammatory pulmonary fibrosis, other alveolar and parietoalveolar pneumonopathy, idiopathic fibrosing alveolitis, Hamman-Rich syndrome, atelectasis, ARDS, acute respiratory failure, mediastinitis.

The compounds of the present invention may also be used for treatment of pain conditions. The pain can be acute or chronic pain. Thus, the compounds of the present invention may be used for treatment of e.g., inflammatory pain, arthritic pain, neuropathic pain, postoperative pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, cancer pain, pain due to burns; migraine or cluster headaches, nerve injury, neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, viral, parasitic or bacterial infection, posttraumatic injury, or pain associated with irritable bowel syndrome.

The compounds of the present invention may further be used for treatment of gastrointestinal disorder such as, but not limited to, irritable bowel syndrome, inflammatory bowel disease, colitis, ulcerative colitis, biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, and pain associated with gastrointestinal distension.

In addition, the compounds of the present invention may be useful in the treatment of cancer, and pain associated with cancer. Such cancers include, e.g., multiple myeloma and bone disease associated with multiple myeloma, melanoma, medulloblastoma, acute myelogenous leukemia (AML), head and neck squamous cell carcinoma, hepatocellular carcinoma, gastric cancer, bladder carcinoma and colon cancer.

The compounds of the present invention may be useful in a treatment of disease, disorder, syndrome or condition selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, cough, pain, inflammatory pain, chronic pain, acute pain, arthritis, osteoarthritis, multiple sclerosis, rheumatoid arthritis, colitis, ulcerative colitis and inflammatory bowel disease.

Any of the methods of treatment described herein comprise administering an effective amount of a compound according to Formula I, (la) or (lb), or a pharmaceutically-acceptable salt thereof, to a subject (particularly a human) in need thereof.

The present inventions further relates to the use of the compounds described herein in the preparation of a medicament for the treatment of diseases mediated by RORyt.

The compounds of the invention are effective both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions. For the above-mentioned therapeutic uses the dosage administered may vary with the compound employed, the mode of administration, the treatment desired and the disorder.

The daily dosage of the compound of the invention administered may be in the range from about 0.05 mg/kg to about 100 mg/kg. General Methods of Preparation

The compounds, described herein, including those of general formula (I) and (II) and specific examples are prepared through the synthetic methods as depicted in Schemes 1 to 5. Furthermore, in the following schemes, where specific acids, bases, reagents, coupling reagents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling reagents, solvents etc. may be used and are included within the scope of the present invention. The modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention. The compounds obtained using the general reaction sequences may be of insufficient purity. These compounds can be purified using any of the methods for purification of organic compounds known to persons skilled in the art, for example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios. All possible geometrical isomers and stereoisomers are envisioned within the scope of this invention.

The starting materials used herein are commercially available or were prepared by methods known in the art to those of ordinary skill or by methods disclosed herein. In general, the intermediates and compounds of the present invention can be prepared through the reaction schemes as follows.

A general approach for the preparation of compound of formula (I) (wherein Ring A, R ¹ , R ² , R ³ , R ⁴ , R ^s , n and p are as defined with respect to compound of formula (I)) is depicted in the Synthetic Scheme 1.

Synthetic Scheme 1

The coupling reaction of amine compound of formula (1) with [4-

(alkylsulfonyl)phenyl] acetic acid of formula (2) in the presence of a suitable coupling agent such as EDCI and optional presence of HOBt, DCC, T3P or HATU, gives compound of formula (I). The reaction may be optionally carried out in the presence of suitable base selected from Et3N, DIPEA, pyridine or DMAP. The suitable solvent for the reaction may be selected from CH2CI2, CHCI3, DMF or mixture thereof.

A general approach for the preparation of a compound of formula (la) (wherein Ring A, R ² , R ³ , R ⁴ , R ^s , n and p are as defined with respect to a compound of formula (I)) is depicted in the Synthetic Scheme 2.

Synthetic Scheme 2

The reaction of a suitably substituted aryl ketone compound of formula (3) with ammonium acetate in a polar protic solvent such as methanol yields a inline which on in situ reduction using sodium cyanoborohydride affords the amine compound of formula (4). The reaction of amine compound of formula (4) with nitro compound of formula (S) (when X = CI or Br) in presence of a suitable base, such as Et ₃ N, DIPEA, pyridine and DMAP or combination thereof, under suitable reaction conditions gives the amide compound of formula (6). Alternatively, the amine compound of formula (4) may be reacted with a compound of formula (S) (when X = OH) using an appropriate coupling agent such as EDCI, DCC or HATU under suitable reaction conditions, to give amide compound of formula (6). The reaction may be carried out in a suitable solvent selected from CH ₂ CI ₂ , CHCI ₃ , DMF and THF or combination thereof. The N-alkylation of compound of formula (6) with an alkylating agent of formula (7) (wherein X is halogen) using a base such as sodium hydride in a solvent, like THF, DMF, etc. affords the nitro benzamide derivative of formula (8). The reduction of nitro group of compound of formula (8) using iron powder in the presence of aqueous acetic acid or ammonium chloride furnishes the corresponding amine compound of formula (la). The reduction reaction may be carried out in suitable solvent selected from ethanol, water or combination thereof.

A general approach for the synthesis of compound of formula (R or S)-(1b) (wherein Ring A, R ² , R ³ , R ⁴ , R ⁵ , n and p are as defined with respect to a compound of formula (I)) is depicted in Synthetic Scheme 3.

Synthetic Scheme 3

A suitably substituted alkyl aryl ketone of formula (9) on condensation reaction with appropriate isomer of (R or S)-2-methylpropane-2-sulfinamide (10) in the presence of a suitable dehydrating agent (eg. titanium (VI) isopropoxide or titanium (VI) ethoxide) gives the imine compound of formula (R or S)-(l 1). The reduction of the imine compound of formula (R or S)-

(11) with sodium borohydride or sodium cyanoborohydride in a suitable solvent such as THF gives predominantly the diastereoisomer (R,R) or (S,S)-(12). Alternatively, a suitably substituted imine compound of formula (R or S)-(H') can be prepared by condensation of appropriately substituted aryl aldehyde (9') with (R or S)-2-methylpropane-2-sulfinamide (10) in the presence of a suitable base such as cesium carbonate in a solvent such as dichloromethane, which on futher reaction with Grignard reagent of formula R ⁴ MgX gives substantially pure (R,R) or (S,S)-(12) diastereomer after chromatographic purification (WO 2012177893, 2012). The acid catalyzed removal of chiral auxiliary of compound of formula (R,R) or (S,S)-(12) gives the chiral amine of formula (R or S)-(13) as its acid addition salt. The coupling of amine compound of formula (R or S)-(13) with acyl halide of formula (S) (wherein X = CI or Br) in the presence of suitable base such as Et ₃ N, DIPEA, pyridine and DMAP provides the amide of formula (R or S)-(14). The N-alkylation of compound of formula (R or 5)-(14) using a suitable alkyl halide of formula (7) in the presence of sodium hydride as base gives the compound of formula (R or 5)-(15). The nitro group reduction in compound of formula (R or S)-(15) using iron powder in aqueous ammonium chloride gives the amine compound of formula (R or S)-(lb).

A general approach for the preparation of compound of formula (R or S)-(Ia) (wherein

R ¹ , R ² , R ³ , R ⁵ , n and p are as defined with respect to a compound of formula (I) and R ⁸ is C _{1- 8} alkyl) is depicted in the Synthetic Scheme 4.

Synthetic Scheme 4

The optically pure compound of formula (R or S)-(16) (wherein R ^' is C _1-4 alkyl) reacts with benzyl trichloroacetate (17) to give the benzyl ether compound of formula (18). The reduction of the ester group in compound of formula (18) in the presence of suitable reducing agent like lithium aluminium hydride gives the hydroxyl compound of formula (19). The oxidation of compound of formula (19) using suitable oxidizing agent, such as Dess-Martin periodinane, in suitable solvent such as dichloromethane, affords the aldehyde compound of formula (20). Titanium (IV) isopropoxide or titanium (IV) ethoxide mediated condensation of compound of formula (20) with (R or S)-2-methylpropane-2-sulfinamide (10) gives the imine compound of formula (21). The imine compound of formula (21) on reaction with Grignard reagent of formula (22) gives compound of formula (23) (/. Org. Chem. 2003, 68, 9948-9957). Acid catalyzed removal of chiral auxiliary gives amino compound of formula (24) with two chiral centers, as a salt of the corresponding acid (e.g. HQ). The coupling of amine compound of formula (24) with acyl halide of formula (5) (wherein X = CI or Br), in the presence of suitable base such as triethylamine, gives the nitrobenzamide compound of formula (25). The N-alkylation of compound of formula (25) with suitable alkyl halide of formula (7) in the presence of sodium hydride as base and suitable solvent such as dichloromethane gives compound of formula (26). The reduction of nitro group in compound of formula (26) using iron powder in the presence of aqueous hydrogen chloride or ammonium chloride gives the amine compound of formula (lc). Condensation of amine compound of formula (lc) with carboxylic acid compound of formula (2) under standard amide coupling conditions described in Scheme 1 provides compounds of formula (27). The deprotection of compound of formula (27) using suitable reducing agent such as hydrogen gas in the presence of palladium catalyst in suitable solvent such as methanol or ethanol or using anhydrous ferric chloride in dichloromethane gives the compound of general formula (la).

The scheme is applicable for synthesis of the alternate isomer (R-isomer) by using appropriate starting materials under the same reaction conditions.

A general approach for the preparation of a compound of formula (R or S)-(ld)

(wherein R ² , R ⁴ , R ^s , and n and p are as defined with respect to a compound of formula (I) and R ⁹ is C _1- 4alkyl or haloC _1- 4alkyl) is depicted in the Synthetic Scheme 5.

Synthetic Scheme 5

The acetylation of the amine compound of formula (R or S)-(13) using acetyl halide of formula

(28) (wherein X = halogen) in the presence of suitable base and solvent yields the N-acetyl derivative of formula (R or S)-(29). The suitable base for the reaction may be triethylamine, DIPEA, pyridine, etc. and solvent may be THF, dichloromethane or chloroform. The reduction of carbonyl group in compound of formula (R or S)-(29) using borane-DMS complex affords the amine compound of formula (R or S)-(30), which on coupling with acyl halide of formula

(5) (wherein X = CI or Br), in presence of suitable base such as triethylamine or N,N- diisopropylethylamine yields the nitrobenzamide compound of formula (R or S)-(31). The nitro group reduction of compound of formula (R or S)-(31) under the same reaction conditions as discussed previously furnishes the amine compound of formula (R or S)-(ld).

Experimental Section

Unless otherwise stated, work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulfate, filtration and evaporation of the solvent. The purification, unless otherwise mentioned, includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses.

The abbreviations, symbols and terms used in the examples and assays have the following meanings throughout: DCM: dichloromethane; DMSO-d ₆ : Hexadeuterodimethyl sulfoxide; DMSO dimethyl sulfoxide; ¹ H NMR: Proton Nuclear Magnetic Resonance; DMF: N,N-dimethyl formamide; EDCI.HC1: l-emyl-3-(3-dimethylammopropyl)carbodii.mide hydrochloride; HOBT: 1-hydroxybenzotriazole; NaOH: Sodium Hydroxide; KOH: Potassium Hydroxide; LiOH: Lithium Hydroxide; DIPEA: N,N-diisopropylemylamine; THF: Tetrahydofuran; HCl: hydrochloric acid; Na ₂ SO ₄ : Sodium sulfate; J: Coupling constant in units of Hertz (Hz); h: hour(s); RT or rt: Room Temperature (22-26°C); o: ortho; m:meta; p: para; APCI-MS: Atmospheric Pressure Chemical Ionization Mass Spectrometry; MHz: Megahertz Preparation of Intermediates

Intermediate 1

4-Ammo-N-(3-Chlorobenzyl-N-methylbenzamide

Step 1: l-(3-Chlorophenyl)-N-methylmemanamine

An ethanolic solution of methylamine (33% w/v, 17 mL) was added to 4-chlorobenzyl chloride (2.0 g, 12.42 mmol) and the resulting mixture was refluxed overnight. Ethanol was removed by distillation. The residue was diluted with water (100 mL) and washed with ethyl acetate (ISO mL x 2). The aqueous layer was basified with solid potassium carbonate till pH 8 and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with water (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 1.7 g of Ihe titled compound. ¹ H NMR (300 MHz, DMSO-rfe) δ 2.22 (s, 3H), 3.32 (br s, 1H), 3.62 (s, 2H), 7.25-7.38 (m, 4H); ESI-MS (m/z) 156 (M+H) ⁺ .

Step 2: N-(3-Chlorobenzyl)-N-methyl-4-nitrobenzamide

To a stirred solution of Step 1 intermediate (100 mg, 0.64 mmol) in THF (6.0 mL) at 0 °C were added triethylamine (195 mg, 1.93 mmol) and 4-nitrobenzoyl chloride (132 mg, 0.70 mmol). The mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL) and saturated ammonium chloride solution (20 mL). The organic layer was washed with water (30 mL) and dried over anhydrous sodium sulfate. The residue thus obtained was purified by silica gel column chromatography to yield 152 mg of titled compound. *H NMR (300 MHz, DMSO-rfe): δ 2.82 (s, 3H), 2.94 (s, 2H), 7.38-7.44 (m, 5H), 7.68-7.77 (m, 3H).

Step 3: 4-Ammo-N-(3-chlorobenzyl)-iV-methylbenzamide

To a stirred solution of Step 2 intermediate (300 mg, 0.98 mmol) in a mixture of ethanol and water (4: 1, 5 mL) was added ammonium chloride (527 mg, 9.84 mmol) at RT and the resulting mixture was refluxed for 2 h. Iron powder (165 mg, 2.95 mmol) was added to it in portions and the mixture was further refluxed for 2h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with water (40 mL), dried over anhydrous sodium sulfate and concentrated to obtain 255 mg of the titled product. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.88 (s, 3H), 4.59 (s, 2H), 5.51 (s, 2H), 6.53 (d, J = 7.8 Hz, 2H), 7.16-7.19 (m, 3H), 7.30-7.40 (m, 3H); APCI-MS (m/z) 275 (M+H) ⁺ . Intermediate 2

4-Ammo-N-[2-(3-chlorophenyl)propan-2-yl]-N-methylbenzamide

Step 1: 2-(3-Chlorophenyl)-2-methylpropanenitrile

To a stirred solution of 3-chlorobenzyl cyanide (2.01 g, 13.26 mmol) in THF (4.0 mL) were added sodium hydride (60% w/w, 2.6 g, 66.25 mmol) and methyl iodide (9.3 mL, 65.96 mmol) at 0 °C. The mixture was stirred at 0 -10 °C for 3 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with water (20 mL), dried over anhydrous sodium sulfate and concentrated to afford 2.13 g of the titled compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.59 (s, 6H), 7.26-7.38 (m, 3H), 7.45 (s, 1H); APCI-MS (m/z) 180 (M+H) ⁺ .

Step 2: 2-(3-Chlorophenyl)-2-methylpropanoic acid

To a solution of Step 1 intermediate (1.02 g, 5.68 mmol) in 1,4-dioxane (10 mL) was added 60% aqueous sulfuric acid (10 mL) at RT and the mixture was stirred overnight at 120 °C. The mixture was cooled to RT and quenched with ice cold water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with water (10 mL), dried over anhydrous sodium sulfate and concentrated. The residue obtained was purified by silica gel column chromatography to afford 651 mg of the titled compound. *H NMR (300 MHz, CDCb) δ 1.59 (s, 7H), 7.24-7.28 (m, 3H), 7.38 (s, 1H); APCI-MS (m/z) 202 (M+H) ⁺ .

Step 3: feri-Butyl [2-(3-chlorophenyl)propan-2-yl]carbamate

To a stirred solution of Step 2 intermediate (403 mg, 2.02 mmol) in dichloromethane (5 mL) were added diphenylphosphoryl azide (837 mg, 3.04 mmol) and triethylamine (910 mg, 4.05 mmol) at RT. The mixture was stirred for 3 h at RT. The reaction was quenched with ice cold water (50 mL), acidified with HC1 till pH 2 and extracted with dichloromethane (100 mL). The organic layer was washed with water (50 mL), dried over anhydrous sodium sulfate and concentrated to give the acyl azide. The acyl azide obtained was dissolved in tert-butanol (10 mL) and refluxed overnight under stirring. The mixture was cooled to RT and concentrated under reduced pressure to yield 562 mg of the titled product. The crude product obtained was used as such for next step.

Step 4: 2-(3-Chlorophenyl)propan-2-amine trifluoroacetic acid To a stirred solution of Step 3 intermediate (562 mg, 2.08 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (3.0 mL) at 0 °C. The resulting mixture was stirred at RT for 3 h. The solvent was evaporated under reduced pressure to obtain 310 mg of the titled compound. The crude product obtained was used as such for next step.

Step 5: N-[2-(3-Chloro phenyl)propan-2-yl]-4-nitrobenzamide

To a stirred solution of Step 4 intermediate (310 mg, 1.07 mmol) in dichloromethane (10 mL) at 0 °C were added emylamine (819 mg, 8.10 mmol), DMAP (20 mg, 0.16 mmol) and 4- nitrobenzoyl chloride (301 mg, 1.62 mmol). The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL) and saturated ammonium chloride solution (20 mL). The organic layer was washed with water (30 mL), dried over anhydrous sodium sulfate and concentrated. The residue thus obtained was triturated with diethyl ether (10 mL), filtered and dried well to yield 261 mg of titled compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.66 (s, 6H), 7.24-7.38 (m, 4H), 8.06 (d, J = 8.4 Hz, 2H), 8.29 (d, J = 8.7 Hz, 2H), 8.88 (s, 1H); ESI- MS (w¾ 319 (M+H) ⁺ .

Step 6: N-r2-(3-Chlorophenyl)propan-2-yll-N-methyl-4-nitrobenzamide

To a stirred solution of Step S intermediate (249 mg, 0.78 mmol) in dry DMF (3.0 mL) was added sodium hydride (60% w/w, 40 mg, 1.01 mmol) at 0 °C followed by methyl iodide (165 mL, 1.17 mmol) and stirring continued for 15 min. The resultant suspension was stirred at RT for 2h. The mixture was quenched with cold water (5 mL), the precipitate obtained was filtered and dried under vacuum to afford 213 mg of the titled compound. ¹ H NMR (300 MHz, CDCb) δ 1.77 (s, 6H), 2.98 (s, 3H), 7.19-7.25 (m, 1H), 7.28 (d, J = 6.3 Hz, 2H), 7.37 (s, 1H), 7.58 (d, J= 8.4 Hz, 2H), 8.25 (d, 7= 8.1 Hz, 2H); ESI-MS (m/z) 333 (M+H) ⁺ .

Step 7: 4-Ammo-N-[2-(3-chlorophenyl)propan-2-yl]-N-methylbenzamide

To a stirred suspension of Step 6 intermediate (204 mg, 0.61 mmol) and ammonium chloride (324 mg, 6.13 mmol) in a mixture of ethanol and water (3:1, 10 mL) at 70 °C was added iron powder (102 mg, 1.83 mmol) in portions and the mixture was heated at 100 °C for lh. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with water (40 mL), dried over anhydrous sodium sulfate and concentrated. The residue thus obtained was triturated with diethyl ether (10 mL), filtered and dried well to yield 113 mg of titled compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.60 (s, 6H), 3.03 (s, 3H), 5.51 (s, 2H), 6.52 (d, J = 8.1 Hz, 2H), 7.17-7.30 (m, 3H), 7.31-7.37 (m, 3H); ESI-MS (m/z) 303 (M+H) ⁺ . Intermediate 3

4- Amino-N- [ 1 -(3 -chlorophenyl)ethyl] -N-methylbenzamide

Step 1: l-(3-Chloro phenyl)ethanamine

To a stirred solution of 3-chloroacetophenone (2.01 g, 10.0 mmol) in methanol (20 mL) was added ammonium acetate (10.0 g, 130 mmol) followed by sodium cyanoborohydride (1.63 g, 30.0 mmol) at RT and the mixture was stirred overnight. The solvent was evaporated under reduced pressure and the residue was diluted with water (30 mL). The mixture was acidified with HC1 till pH 2-3 and washed with diethyl ether (50 mL). The aqueous layer was basified with sodium hydroxide pellets till pH 10 and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with water (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1.21 g of titled compound. *H NMR (300 MHz, DMSO-d ₆ ) δ 1.21 (d, J = 6.3 Hz, 3H), 1.98 (br s, 2H), 3.96 (q, J = 6.3 Hz, 1H), 7.22-7.30 (m, 3H), 7.44 (s, 1H); ESI-MS (m/z) 156 (M) ⁺ .

Step 2: N-[l-(3-Chlorophenyl)ethyl]-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate (201 mg, 1.29 mmol) with 4-nitrobenzoyl chloride (287 mg, 1.54 mmol) in the presence of triethylamine (390 mg, 3.87 mmol) and DMAP (16 mg, 0.29 mmol) in dichloromethane (10 mL) at 0 °C as per the procedure described in step 5 of Intermediate 2 to yield 208 mg of the product. *H NMR (300 MHz, DMSO-rfe) δ 1.48 (d, J = 6.9 Hz, 3H), 5.16 (t, J = 6.9 Hz, 1H), 7.28-7.37 (m, 3H), 7.46 (s, 1H), 8.11 (d, J= 8.7 Hz, 2H), 8.32 (d, J = 8.1 Hz, 2H), 9.19 (d, J = 7.5 Hz, 1H); APCI-MS (m/z) 305 (M+H) ⁺ .

Step 3: N- [ 1 -(3 -Chlorophenyl)ethyl] -N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 2 intermediate (203 mg, 0.67 mmol) with methyl iodide (63 mL, 1.00 mmol) using sodium hydride (60% w/w, 34 mg, 0.86 mmol) in dry DMF (5.0 mL) at 0 °C as per the procedure described in step 6 of Intermediate 2 to yield 208 mg of the desired product. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.56 (br s, 3H), 2.58, 2.72 (s, 3H, rotamer), 4.78, 5.83 (br s, 1H, rotamer), 7.26-7.40 (m, 4H), 7.74 (d, J = 8.4 Hz, 2H), 8.29 (d, J = 8.7 Hz, 2H); APCI-MS (m/z) 319 (M+H) ⁺ .

Step 4: 4-Ammo-N-[l-(3-chlorophenyl)ethyl]-N-methylbenzamide

The titled compound was prepared by the nitro reduction of Step 3 intermediate (202 mg, 0.63 mmol) using iron powder (106 mg, 1.90 mmol) and ammonium chloride (339 mg, 6.33 mmol) in a mixture of ethanol and water (3:1, 10 mL) at 70 °C as per the procedure described in step 7 of Intermediate 2 to yield 132 mg of the product. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.53 (d, J= 6.9 Hz, 3H), 2.64 (s, 3H), 5.51 (br s, 3H), 6.57 (d, J= 8.1 Hz, 2H), 7.17 (d, J= 8.1 Hz, 2H), 7.22-7.44 (m, 4H); ESI-MS (m/z) 289 (M+H) ⁺ .

Intermediate 4

4- Amino-iV- [(1R)-l-(3 -chlorophenyl)ethyl] -iV-methylbenzamide

Step 1: N-((R)- l-(3-Chloro phenyl)emyl)-2-methylpropane-2-sulfinamide

To a stirred solution of l-(3-chlorophenyl)ethanone (458 mg, 2.98 mmol) and titanium (VI) isopropoxide (1.84 g, 6.58 mmol) in THF (10 mL) was added (R)-(+)-2-methyl-2- propanesulfinamide (397 mg, 3.28 mmol) under inert atmosphere at room temperature. The reaction mixture was stirred at 70 °C for 18 h. Sodium borohydride (362 mg, 9.53 mmol) was added to the mixture and was further stirred for 3 h at RT. The reaction was quenched with methanol (10 mL) at 0 °C. The precipitate obtained was filtered and washed with ethyl acetate (50 mL x 2). The combined organic layers were washed with water (40 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to yield 328 mg of the titled product. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.79 (t, J = 7.5 Hz, 3H), 1.22 (s, 9H), 1.98-2.10 (m, 2H), 3.37 (s, 1H), 4.25 (s, 1H), 7.22-7.34 (m, 4H); ESI-MS (m/z) 273 (M) ⁺ .

Step 2: (R)- 1 -(3 -Chloro phenyl)emanarnine hydrochloride

To an ice cold solution of Step 1 intermediate (311 mg, 1.14 mmol) in diethyl ether (10 mL) was added 4 M HC1 in dioxane (2.85 mL, 11.43 mmol) at RT. The resulting mixture was stirred at 0 °C for lh. The solvent was evaporated under reduced pressure and the residue thus obtained was dried under vacuum to obtain 231 mg of the titled compound. *H NMR (300 MHz, DMSO- d ₆ ) δ 0.73 (t, J = 7.5 Hz, 3H), 1.76-1.83 (m, 1H), 1.94-2.01 (m, 1H), 4.14 (s, 1H), 7.52 (q, J = 7.8 Hz, 4H), 8.64 (s, 2H); ESI-MS (m z) 170 (M+H) ⁺ .

Step 3: (R)-N-(1-(3-chlorophenyl)emyl)-4-nitrobenzarnide

The titled compound was prepared by the reaction of Step 2 intermediate (503 mg, 3.23 mmol) with 4-nitrobenzoyl chloride (719 mg, 3.87 mmol) in the presence of triethylamine (1.36 g, 9.77 mmol) and DMAP (39 mg, 0.32 mmol) in dichloromethane (10 mL) at 0 °C as per the procedure described in step 5 of Intermediate 2 to yield 712 mg of the product. *H NMR (300 MHz, CDCl ₃ ) δ 1.60 (d, J = 7.5 Hz, 3H), 5.26 (q, J = 7.5 Hz, 1H), 6.62 (br s, 1H), 7.27-7.35 (m, 4H), 7.93 (d, J = 7.5 Hz, 2H), 8.26 (d, J = 8.7 Hz, 2H); ESI-MS (m/z) 234 (M+H) ⁺ .

Step 4: N-[(1R)-l-(3-Chloro phenyl)ethyl]-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 3 intermediate (256 mg, 0.84 mmol) with methyl iodide (178 mg, 1.26 mmol) using sodium hydride (60% w/w, 44 mg, 1.09 mmol) in dry DMF (4 mL) at 0 °C as per the procedure described in step 6 of Intermediate 2 to yield 203 mg of the desired product. ¹ H NMR (300 MHz, CDCb) δ 2.61 (s, 3H), 2.87 (s, 3H), 4.86, 6.12 (br s, 1H, rotamer), 7.27-7.37 (m, 4H), 7.61 (d, J= 7.5 Hz, 2H), 8.29 (d, 7 = 7.5 Hz, 2H); APCI-MS (m/z) 317 (M-H) ^" .

Step 5: 4-Ammo-N-[(1R)-l-(3-Chlorophenyl)emyl]-N-methylbenzamide

The titled compound was prepared by the nitro reduction of Step 4 intermediate (198 mg, 0.62 mmol) using iron powder (104 mg, 1.86 mmol) and ammonium chloride (332 mg, 6.21 mmol) in a mixture of ethanol and water (3:1, 10 mL) at 70 °C as per the procedure described in step 7 of Intermediate 2 to yield 127 mg of the product. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.52 (d, J= 8.7 Hz, 3H), 2.63 (s, 3H), 5.49 (br s, 3H), 6.54 (d, J= 8.7 Hz, 2H), 7.14 (d, 7= 8.1Hz, 2H), 7.24-7.41 (m, 4H); ESI-MS (m/z) 289 (M+H) ⁺ .

The structure, chemical name and analytical data of the intermediates prepared by following the procedure described in Intermediate 4 are given in Table 1.

Table 1: Structure, Chemical name and Analytical data of Intermediate 5-9, 12, 16-25, 27-30, 35-38, 40^3, 47 and 51-54

Intermediate 13

4-Ammo-N-((1S,2S)-2-(benzyloxy)-l-(p-tolyl)propyl)-N-methylb enzamide

Step 1: (S)-Methyl 2-(benzyloxy)propanoate

To a cooled (0 °C) solution of (5)-methyl lactate (2.0 g, 19.21 mmol) in a mixture of cyclohexane (20 mL) and dichloromethane (10 mL) were added benzyl 2,2,2- trichloroacetimidate (4.3 mL, 23.05 mmol) followed by trifluoromethane sulfonic acid (140 μί,, 1.53 mmol) and the resultant mixture was stirred at 0 °C for 15 min. The mixture was warmed up to RT and stirred for 6 h. The reaction mixture was quenched with saturated aqueous solution of sodium bicarbonate and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by silica gel column chromatography to obtain 1.78 g of titled product. ¹ H NMR (300 MHz, CDCb) δ 1.44 (d, J= 6.9 Hz, 3H), 3.75 (s, 3H), 4.07 (q, J = 6.9 Hz, 1H), 4.45 (d, J = 11.7 Hz, 1H), 4.69 (d, J = 11.7 Hz, 1H), 7.27-7.37 (m, 5H).

Step 2: (5)-2-(Benzyloxy)propan-l-ol

To a cooled (0 °C) suspension of lithium aluminium hydride (334 mg, 8.80 mmol) in THF (10 mL) was added dropwise a solution of Step 1 intermediate (1.71 g, 8.80 mmol) and the resultant mixture was stirred at RT for 2 h. The reaction mixture was quenched with saturated aqueous solution of ammonium chloride, diluted with ethyl acetate and filtered through celite bed. The filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by silica gel column chromatography to obtain 1.65 g of titled product. ¹ H NMR (300 MHz, CDCb) δ 1.18 (d, J = 6.6 Hz, 3H), 3.46-3.54 (m, 1H), 3.58-3.69 (m, 2H), 4.49 (d, J= 11.4 Hz, 1H), 4.66 (d, J= 11.1 Hz, 1H), 7.27-7.37 (m, 5H).

Step 3: (5)-2-(Benzyloxy)propanal

To a stirred solution of Step 2 intermediate (1.4 g, 8.42 mmol) in dichloromethane (100 mL) was added Dess-Martin periodinane (3.57 g, 8.42 mmol) followed by addition of wet dichloromethane. The mixture was stirred at RT for 2 h. The reaction mixture was diluted with dichloromethane (100 mL) and washed with saturated aqueous sodium bicarbonate solution, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by silica gel column chromatography to obtain 682 mg of titled product. ¹ H NMR (300 MHz, CDCb) δ 1.33 (d, J = 7.2 Hz, 3H), 1.90 (q, J = 6.6 Hz, 1H), 4.57-4.69 (m, 2H), 7.28-7.38 (m, 5H), 9.67 (s, 1H).

Step 4: (5)-N-((S)-2-(Benzyloxy)propyMene)-2-methylpropane-2-sulfina mide

The titled compound was prepared by the reaction of Step 3 intermediate (680 mg, 4.14 mmol) with (S)-(-)-2-methyl-2-propanesulfmamide (553 mg, 4.56 mmol) using titanium (VI) isopropoxide (1.84 g, 6.58 mmol) in THF (30 mL) as per the procedure described in the Step 1 of Intermediate 4 to yield 798 mg of the product. ¹ H NMR (300 MHz, CDCb) δ 1.23 (s, 9H), 1.41 (d, J = 6.0 Hz, 3H), 4.31-4.37 (m, 1H), 4.48 (d, J = 11.7 Hz, 1H), 4.65 (d, J = 11.4 Hz, 1H), 7.32-7.36 (m, 5H), 8.07 (d, J= 4.5 Ηζ,ΙΗ); ESI-MS (m/z) 265 (M-H) ^" .

Step 5: (5)-N-((1S,2S)-2-(Benzyloxy)- l-(p-tolyl)propyl)-2-methylpropane-2-sulfmarnide

To a stirred solution of Step 4 intermediate (510 mg, 1.91 mmol) in anhydrous toluene (20 mL) at -78 °C was added /j-tolylmagnesium bromide (lAf, 3.8 mL, 3.81 mmol) and the reaction was stirred for 3h at -78 °C. The reaction was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to yield 402 mg of the titled compound. ¹ H NMR (300 MHz, CDCb) δ 1.03 (d, J= 6.3 Hz, 3H), 1.12 (s, 9H), 2.34 (s, 3H), 3.59-3.68 (m, 1H), 4.25 (d, J = 8.4 Hz, 1H), 4.42 (d, J = 11.7 Hz, 2H), 4.70 (d, J = 11.7 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.28-7.38 (m, 5H); ESI-MS (m z) 360 (M+H) ⁺ .

Step 6: (1S,2S)-2-(Benzyloxy)-l-(p-tolyl)propan-l-amine hydrochloride

To an ice cooled solution of Step 5 intermediate (400 mg, 1.11 mmol) in methanol (15 mL) was added 4Af HC1 in 1,4-dioxane (1.4 mL, 5.56 mmol) at RT and the resulting mixture was stirred for 2 h. The solvents were evaporated under reduced pressure and the residue obtained was triturated twice with n-pentane (5 mL). The solid was filtered and dried under vacuum to yield 257 mg of the desired product. ¹ H NMR (300 MHz, CDCb) δ 0.88 (d, J = 6.3 Hz, 3H), 2.06 (s, 2H), 2.21 (s, 3H), 3.85-3.89 (m, 1H), 3.38-4.02 (m, 1H), 4.50 (d, J = 11.4 Hz, 1H), 4.66 (d, J= 11.4 Hz, 1H), 7.05 (d, J= 8.4 Hz, 2H), 7.27-7.39 (m, 5H), 8.67-8.72 (m, 2H); ESI- MS (m/z) 256 (M+H) ⁺ (free base).

Step 7: N-((1S,2S)-2-(benzyloxy)-l-(p-tolyl)rffopyl)-4-nitrobenzamid e

The titled compound was prepared by the reaction of Step 6 intermediate (245 mg, 0.84 mmol) with 4-nitrobenzoyl chloride (187 mg, 1.00 mmol) in the presence of triethylamine (425 mg, 4.19 mmol) in dichloromethane (20 mL) at RT as per the procedure described in step 5 of Intermediate 2 to yield 308 mg of the product. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.02 (d, J = 5.7 Hz, 3H), 2.28 (s, 3H), 3.92-3.96 (m, 2H), 4.45-4.51 (m, 1H), 5.07 (t, J = 7.8 Hz, 1H), 7.15 (d, J = 7.8 Hz, 3H), 7.24 (s, 4H), 7.35 (d, J = 7.8 Hz, 2H), 8.04 (d, J = 8.7 Hz, 2H), 8.32 (d, J = 8.7 Hz, 2H), 9.11 (d, J = 8.4 Hz, 1H); APCI-MS (m/z) 405 (M+H) ⁺ .

Step 8: N-((1S,2S)-2-(Benzyloxy)-l-(p-tolyl^

The titled compound was prepared by the reaction of Step 7 intermediate (300 mg, 0.74 mmol) with methyl iodide (126 mg, 0.89 mmol) using sodium hydride (60% w/w, 44 mg, 1.11 mmol) in DMF (5.0 mL) at 0 °C as per the procedure described in step 6 of Intermediate 2 to yield 208 mg of the product. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.92, 1.20 (d, J = 6.0 Hz, 3H, rotamer), 2.29 (s, 3H), 2.61, 2.79 (s, 3H, rotamer), 4.38-4.55 (m, 2H), 4.73 (d, J = 11.7 Hz, 1H), 5.65- 5.71 (m, 1H), 7.10 (d, J = 7.8 Hz, 1H), 7.13-7.20 (m, 2H), 7.25-7.47 (m, 6H), 7.58 (d, J = 8.4 Hz, 2H), 8.21 (d, J = 8.4 Hz, 1H), 8.28 (d, J= 8.7 Hz, 1H); APCI-MS (m/z) 419 (M+H) ⁺ . Step 9: 4-Ammo-N-((1S,2S)-2-(benzyloxy)-l-(p-tolyl)propyl)-N-methylb enzamide

The titled compound was prepared by the nitro reduction of Step 8 intermediate (100 mg, 0.23 mmol) using iron powder (67 mg, 1.19 mmol) and ammonium chloride (128 mg, 2.39 mmol) in a mixture of ethanol and water (5:1, 18 mL) at 90 °C as per the procedure described in step 7 of Intermediate 2 to yield 83 mg of the product. The crude product obtained was used as such for next step. ESI-MS (m z) 389 (M+H) ⁺ . The structure, chemical name and analytical data of the intermediates prepared by following the procedure described in Intermediate 13 are given in Table 2.

Table 2: Structure, Chemical name and Analytical data of Intermediate 14, 33-34

Intermediate 15

(R)-4-Amino-N-((2-Chloro-4-methylphenyl)(phenyl)methyl)-N-me thylbenzamide

Step 1: (R)-N-(2-chloro -4-methylbenzylidene)-2-methylpropane-2-sulfinamide

To a stirred solution of 2-chloro-3-methyl-benzaldehyde (327 mg, 2.12 mmol) in dichloromethane (10 mL) was added (R)-(+)-2-methyl-2-propanesulfinidine (308 mg, 2.54 mmol) and cesium carbonate (993 mg, 3.05 mmol) at RT. The resulting mixture was stirred overnight at 45 °C. The reaction mixture was filtered through celite bed and the bed was washed with dichloromethane (5 mL x 2). The combined filtrates were concentrated and the residue thus obtained was purified by silica gel column chromatography to yield 442 mg of the titled compound. ¹ H NMR (300 MHz, CDCI ₃ ) δ 1.27 (s, 9H), 1.41 (s, 1H), 2.39 (s, 3H), 7.15 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 7.8 Hz, 1H), 8.99 (s, 1H); ESI-MS (m/z) 258 (M+H) ⁺ .

Step 2: (R)-N-((R)-(2-Chloro -4-methylphenyl)(phenyl)methyl)-2-methylpropane-2- sulfinamide To a stirred solution of Step 1 intermediate (406 mg, 1.57 mmol) in dry THF (10 mL) at -20 °C was added phenylmagnesium bromide (1.57 mL, 4.72 mmol) and the reaction was stirred at 0 °C for lh. The reaction was quenched with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with water (50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to yield 431 mg of the titled compound. *H NMR (300 MHz, CDCb) δ 1.25 (s, 9H), 1.40 (s, 1H), 2.31 (s, 3H), 3.70 (br s, 1H), 6.08 (s, 1H), 7.09 (d, J = 7.8 Hz, 1H), 7.18-7.45 (m, 5H), 7.47 (d, J = 7.8 Hz, 1H); ESI-MS (m/z) 336 (M+H) ⁺ .

Step 3: (R)- 1 -(2-Chloro-4-methylphenyl)- 1 -phenylmethanamine hydrochloride

To an ice cooled solution of Step 2 intermediate (391 mg, 1.16 mmol) in diethyl ether (5 mL) was added 4Af HC1 in dioxane (3 mL, 11.67 mmol) at RT and the resulting mixture was stirred for lh. The solvents were evaporated under reduced pressure and the residue obtained was triturated with diethyl ether (5 mL). The solid was filtered and dried under vacuum to yield 331 mg of the desired product. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.67 (s, 1H), 2.31 (s, 3H), 7.28- 7.47 (m, 7H), 7.80 (d, J = 7.8 Hz, 1H), 9.28 (s, 2H); ESI-MS (m/z) 232 (M+H) ⁺ .

Step 4: (R)-N-((2-Chloro -4-methylphenyl)(phenyl)methyl)-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 3 intermediate (320 mg, 1.19 mmol) with 4-nitrobenzoyl chloride (264 mg, 1.43 mmol) in the presence of triethylamine (326 mg, 3.57 mmol) in dichloromethane (10 mL) as per the procedure described in step 5 of Intermediate 2 to yield 254 mg of the product. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.30 (s, 3H), 6.65 (d, J = 7.8 Hz, 1H), 7.17-7.39 (m, 8H), 8.13 (d, J= 8.7 Hz, 2H), 8.32 (d, J= 8.7 Hz, 2H), 9.64 (d, J = 8.4 Hz, 1H)); ESI-MS (m/z) 381 (M+H) ⁺ .

Step 5: (R)-N-((2-Chloro -4-methylphenyl)(phenyl)methyl)-N-methyl-4-nitrobenzamide The titled compound was prepared by the reaction of Step 4 intermediate (240 mg, 0.63 mmol) with methyl iodide (139 mg, 0.94 mmol) using sodium hydride (60% w/w, 32 mg, 0.81 mmol) in dry DMF (3.0 mL) at 0 °C as per the procedure described in step 6 of Intermediate 2 to yield 231 mg of the product. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.32 (s, 3H), 2.59,2.89 (br s, 3H, rotamer), 6.96 (d, J = 8.4 Hz, 2H), 7.15-7.21 (m, 3H), 7.25-7.55 (m, 5H), 7.70-7.76 (m, 1H), 8.16-8.31 (m, 2H); ESI-MS (m/z) 395 (M+H) ⁺ .

Step 6: (R)-4-Ammo-N-((2-chloro-4-methylphenyl)(phenyl)methyl)-N-met hylbenzamide The titled compound was prepared by the nitro reduction of Step 5 intermediate (210 mg, 0.53 mmol) using iron powder (89 mg, 1.59 mmol) and ammonium chloride (284 mg, 5.31 mmol) in a mixture of ethanol and water (3: 1, 10 mL) at 100 °C as per the procedure described in step 7 of Intermediate 2 to yield 145 mg of the titled compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.31 (s, 3H), 2.66 (s, 3H), 5.50 (s, 1H), 6.48 (d, J = 7.8 Hz, 2H), 6.64 (s, 1H), 6.95 (d, J = 8.4 Hz, 1H), 7.08-7.17 (m, 5H), 7.35-7.41 (m, 5H); ESI-MS (m/z) 366 (M+2H) ⁺ .

The structure, chemical name and analytical data of the intermediates prepared by following the procedure described in Intermediate 15 are given in Table 3.

Table 3: Structure, Chemical name and Analytical data of Intermediate 10-11, 31-32 and 39

Intermediate 26

4- Amino-iV- [( 1R)- 1 -(4-chlorophenyl)ethyl] -2-fluoro-iV-methylbenzamide

Step 1: N-[(1R)-l-(4-chlorophenyl)emyl]-2-fluoro-4-nitrobenzamide

To a stirred solution of (R)-(+)- l-(4-chlorophenyl)ethyl amine (507 mg, 3.26 mmol) in DMF (10 mL) were added 2-fluoro-4-nitrobenzoic acid (503 mg, 2.71 mmol), EDCI.HC1 (779 mg, 4.07 mmol), HOBt (551 mg, 4.07 mmol) and N,N -diisopropylemylamine (1.0 g, 8.15 mmol) at RT and the mixture was stirred for 2h at room temperature. The reaction mixture was poured into ice cold water (50 mL). The precipitated a solid was collected by filtration and dried well under vacuum to obtain 519 mg of titled product. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.42 (d, J = 6.3 Hz, 3H), 5.10-5.13 (m, 1H), 7.40 (s, 4H), 7.79-7.82 (m, 1H), 8.12 (d, J = 8.1 Hz, 1H), 8.22 (d, J = 9.6 Hz, 1H), 9.20 (d, J = 6.3 Hz, 1H).

Step 2: N- [( 1R)- 1 -(4-Chlorophenyl)ethyl] -2-fluoro-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate (506 mg, 1.56 mmol) with methyl iodide (339 mg, 2.35 mmol) using sodium hydride (60% w/w, 81 mg, 2.03 mmol) in dry DMF (5.0 mL) at 0 °C as per the procedure described in step 6 of Intermediate 2 to yield 451 mg of the product. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.55 (t, J = 7.2 Hz, 3H), 2.73 (s, 3H), 4.71, 5.89 (br s, 1H, rotamer), 7.26 (d, J = 7.2 Hz, 1H), 7.45 (q, J= 8.1 Hz, 3H), 7.75-7.80 (m, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.26 (t, J = 8.1 Hz, 1H); ESI-MS (m/z) 337 (M+H) ⁺ .

Step 3: 4- Amino-iV- [( 1R)- 1 -(4-chlorophenyl)ethyl] -2-fluoro-iV-methylbenzamide

The titled compound was prepared by the nitro reduction of Step 2 intermediate (431 mg, 1.27 mmol) using iron powder (214 mg, 3.83 mmol) and ammonium chloride (684 mg, 12.79 mmol) in a mixture of ethanol and water (3:1, 10 mL) at 70 °C as described in step 7 of Intermediate 2 to obtain 318 mg of the product. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.50 (d, J= 7.2 Hz, 3H), 2.56 (s, 3H), 5.73 (s, 2H), 6.29-6.42 (m, 2H), 7.04 (t, J= 8.1 Hz, 1H), 7.29 (br s, 2H), 7.42 (d, J = 8.4 Hz, 2H); ESI-MS (m/z) 307 (M+H) ⁺ .

The structure, chemical name and analytical data of the compounds prepared by following the procedure described in Intermediate 26 are given in the table 4.

Table 4: Structure, Chemical name and Analytical data of Intermediate 48-50

Intermediate 44

4- Amino-N- [(R)-(4-chlorophenyl)(phenyl)methyl] -N-ethylbenzamide

Step 1: N-[(R)-(4-Chlorophenyl)(phenyl)memyl]acetamide

To a stirred solution of (R)-l-(4-chlorophenyl)-l-phenymiemanamine hydrochloride (503 mg, 1.97 mmol) in dichloromethane (10 mL) at 0 °C was added triethylamine (883 μL, 6.33 mmol) followed by acetyl chloride (212 μL, 2.46 mmol). The mixture was warmed to RT and stirred overnight. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (50 mL) and concentrated. The residue thus obtained was purified by silica gel column chromatography to afford 383 mg of the product. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.90 (s, 3H), 6.09 (d, J= 9.3 Hz, 1H), 7.20-7.40 (m, 9H), 8.78 (d, J = 8.1 Hz, 1H); ESI-MS (m/z) 260 (M+H) ⁺ .

Step 2: N-[(R)-(4-Chloro phenyl)(phenyl)methyl]emanamine

To a stirred solution of Step 1 intermediate (361 mg, 1.38 mmol) in THF (10 mL) at 0 °C was added borane-DMS complex (303 μί, 3.19 mmol). The resulting mixture was warmed to RT and refluxed for 2 h. The mixture was cooled to 0 °C and quenched with methanol (2 mL) and stirred for 1 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with brine (20 mL) and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to obtain 243 mg of the product. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.01 (t, J = 5.4 Hz, 3H), 2.38-2.45 (m, 3H), 4.77 (s, 1H), 7.13-7.42 (m, 8H); ESI-MS (m/z) 246 (M+H) ⁺ . Step 3: N- [(R)-(4-Chlorophenyl)(phenyl)methyl] --V-ethyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 2 intermediate (231 mg, 0.94 mmol) with 4-nitrobenzoylchloride (209 mg, 1.12 mmol) in the presence of DMAP (12 mg, 0.09 mmol) and triethylamine (392 μL, 2.82 mmol) in dichloromethane (5.0 mL) at room temperature as per the procedure described in step 5 of Intermediate 2 to yield 351 mg of desired product. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.55 (t, J = 7.5 Hz, 3H), 3.23-3.32 (m, 2H), 5.96, 6.57 (d, J = 5.1 Hz, 1H, rotamer), 7.16-7.47 (m, 9H), 7.50-7.60 (m, 2H), 8.27 (d, J = 7.8 Hz, 2H).

Step 4: 4- Amino-iV- [(R)-(4-chlorophenyl)(phenyl)methyl] -N-ethylbenzamide

The titled compound was prepared by the nitro reduction of Step 3 intermediate (332 mg, 0.84 mmol) using iron powder (141 mg, 2.52 mmol) and ammonium chloride (450 mg, 8.40 mmol) in a mixture of ethanol and water (1:1, 10 mL) at 100 °C as per the procedure described in step 7 of Intermediate 2 to obtain 231 mg of the product. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.58 (t, 7 = 6.9 Hz, 3H), 3.31-3.39 (m, 2H), 5.47 (s, 2H), 6.45 (s, 1H), 6.52 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 7.17-7.25 (m, 4H), 7.32-7.45 (m, 5H). ESI-MS (m/z) 365 (M+H) ⁺ .

The structure, chemical name and analytical data of the compounds prepared by following the procedure described in Intermediate 44 are given in the table 5.

Table 5: Structure, Chemical name and Analytical data of Intermediate 45

Intermediate 46

4- Amino-iV- [( 1R)- 1 -(4-chlorophenyl)ethyl] -iV-(cyclopropylmethyl)benzamide

Step 1: ( 1R)- 1 -(4-Chlorophenyl)-iV-(cyclopropylmethyl)

To a stirred solution of (R)-4-chloro-a-methylbenzyl amine (501 mg, 3.21 mmol) in ethanol (5 mL) was added cyclopropane carboxaldehyde (270 mg, 3.85 mmol) at RT. The mixture was stirred for 1 h at RT and then cooled to 0 °C. Sodium borohydride (195 mg, 5.14 mmol) was added to the reaction mixture and stirred for 1 h at RT. The mixture was quenched with IN HQ till pH 2-3 and the solvents were evaporated under reduced pressure. The mixture was washed with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic extracts were washed with water (30 mL), dried over anhydrous sodium sulfate and concentrated to yield 531 mg of the titled compound. *H NMR (300 MHz, DMSO-d ₆ ) δ -0.02-0.08(m, 2H), 0.30-0.36 (m, 2H), 0.77-0.85 (m, 1H), 1.18 (d, J = 6.3 Hz, 3H), 1.99-2.18 (m, 2H), 3.70 (d, J = 6.6 Hz, 1H), 7.32 (s, 4H), 8.62 (s, 1H); APCI-MS (m/z) 210 (M+H) ⁺ .

Step 2: N- [( 1R)- 1 -(4-Chlorophenyl)ethyl] -N-(cyclopropylmethyl)-4-mtrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate (491 mg, 2.39 mmol) with 4-nitrobenzoyl chloride (522.8 mg, 2.81 mmol) in the presence of triethylamine (712 mg, 7.04 mmol) and DMAP (28 mg, 0.23 mmol) in dichloromethane (10 mL) at 0 °C as per the procedure described in step 5 of Intermediate 2 to yield 278 mg of the product. *H NMR (300 MHz, DMSO-d ₆ ) δ -0.09 (br s, 2H), 0.25-0.28 (m, 2H), 0.58-0.91 (m, 1H), 1.59 (br s, 3H), 2.92-3.20 (m, 2H), 4.74, 5.56 (br s, 1H, rotamer), 7.22-7.32 (m, 4H), 7.73 (s, 2H), 8.28 (d, J = 8.1 Hz, 2H); ESI-MS (m/z) 359 (M+H) ⁺ .

Step 3: 4- Amino-N- [( 1R)- 1 -(4-chlorophenyl)ethyl] -N-(cyclopropylmethyl)benzamide The titled compound was prepared by the nitro reduction of Step 2 intermediate (268 mg, 0.74 mmol) using iron powder (125 mg, 2.24 mmol) and ammonium chloride (399 mg, 7.46 mmol) in a mixture of ethanol and water (3: 1, 10 mL) at 100 °C as per the procedure described in step 7 of Intermediate 2 to yield 161 mg of the product. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.00- 0.12 (m, 1H), 0.25-0.31 (m, 2H), 0.83-0.87 (m, 2H), 1.59 (d, J = 6.9 Hz, 3H), 2.65-2.71, 3.10- 3.21 (m, 2H, rotamer), 5.26 (br s, 1H), 5.46 (s, 2H), 6.55 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 7.2 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H); ESI-MS (m/z) 329 (M+H) ⁺ .

EXAMPLES

Method A

N-(3-Chloro benzyl)-4-(2-(4-(emylsulfonyl)phenyl)acetamido)-N-methyl-ben zamide

(Example 1)

To a stirred solution of Intermediate 1 (100 mg, 0.36 mmol) and [4- (ethylsulfonyl)phenyl]acetic acid (92 mg, 0.40 mmol) in DMF (3.0 mL) were added EDCI.HC1 (84 mg, 0.43 mmol), HOBt (59 mg, 0.43 mmol) and DIPEA (94 mg, 0.72 mmol) at RT. The reaction mixture was stirred overnight at RT. The mixture was poured into saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate and concentrated. The residue thus obtained was purified by silica gel column chromatography to obtain 55 mg of titled product. ¾ NMR (300 MHz, DMSO-d ₆ ) δ 1.08 (t, J= 7.2 Hz, 3H), 2.87 (s, 3H), 3.27 (q, J = 7.8 Hz, 2H), 3.82 (s, 2H), 4.63 (br s, 2H), 7.35-7.41 (m, 6H), 7.58-7.62 (m, 4H), 7.87 (d, J = 8.4 Hz, 2H), 10.44 (s, 1H); ESI-MS (m/z) 485 (M+H) ⁺ .

Method B

4-(2-(4-(Emylsulfonyl)phenyl)acetamido)-N-((15,25)-2-hydroxy -l-(p-tolyl)-propyl)-N- methylbenzamide (Example 13)

Step 1: N-((15,25)-2-(Benzyloxy)-l-(p-tolyl)propyl)-4-(2-(4-

(emylsulfonyl)phenyl)acetamido)-N-methylbenzamide

The titled compound was prepared by the reaction of Intermediate 13 (80 mg, 0.20 mmol) with [4-(ethylsulfonyl)phenyl] acetic acid (56 mg, 0.24 mmol) in the presence of EDCI.HC1 (59 mg, 0.30 mmol), HOBt (42 mg, 0.30 mmol) and N,N'-diisopropylethylamine (53 mg, 0.41 mmol) in DMF (7.0 mL) as per the procedure described in Example 1 to yield 128 mg of the desired product as a solid. H NMR (300 MHz, CDCl ₃ ) δ 0.85-1.05 (m, 3H), 1.19-1.30 (m, 6H), 2.33 (s, 3H), 2.68, 2.89 (br s, 1H, rotamer), 3.09 (q, J = 7.2 Hz, 2H), 3.80 (s, 2H), 4.74-4.48 (m, 2H), 6.95-6.99 (m, 1H), 7.10-7.20 (m, 4H), 7.27-7.65 (m, 9H), 7.56-7.60 (m, 2H), 7.84 (d, J = 8.2 Hz, 2H), 8.87 (br s, 1H); ESI-MS (m/z) 599 (M+H) ⁺ .

Step 2: 4-(2-(4-(Emylsulfonyl)phenyl)acetamido)-N-((15,25)-2-hydroxy -l-(p-tolyl)propyl)- N-methylbenzamide To a stirred solution of Step 1 intermediate (90 mg, 0. IS mmol) in methanol (10 mL) was added catalytic amount of palladium on carbon (10%, 50% wet) in methanol (10 mL) at RT and the resultant suspension was stirred under hydrogen atmosphere for 48 h. The reaction was diluted with methanol (S mL) and filtered through celite bed. The filtrate was concentrated and purified by silica gel column chromatography to yield 32 mg of the titled product. *H NMR (300 MHz, DMSO-d ₆ ) δ 0.85 (br s, 3H), 1.09 (t, J = 6.9 Hz, 3H), 2.27 (s, 3H), 2.79 (d, J = 7.2 Hz, 3H), 3.25-3.35 (m, 3H), 3.83 (s, 2H), 4.44 (br s, 1H), 4.91, 5.18 (br s, 1H, rotamer), 7.00- 7.02 (m, 1H), 7.12-7.14 (m, 2H), 7.29-7.43 (m, 3H), 7.60-7.63 (m, 4H), 7.84 (d, J = 8.1 Hz, 2H), 10.45 (s, 1H); ESI-MS (m/z) 509 (M+H) ⁺ .

Method C

N-(( 1S,2S)- 1 -(4-Chloro phenyl)-2-hydroxypropyl)-4-(2-(4-(emylsulfonyl)-phenyl)aceta mido)- N-methylbenzamide (Example 33)

Step. 1 : N-(( 1S,2S)-2-(Benzyloxy)- 1 -(4-chlorophenyl)propyl)-4-(2-(4-(ethyl- sulfonyl)phenyl)acetamido)-N-methylbenzamide

The titled compound was prepared by the reaction of Intermediate 33 (190 mg, 0.46 mmol) with [4-(ethylsulfonyl)phenyl] acetic acid (127 mg, 0.55 mmol) in the presence of EDCI.HC1 (134 mg, 0.69 mmol), HOBt (94 mg, 0.69 mmol) and N.N'-diisopropylemylamine (180 mg, 1.39 mmol) in DMF (5.0 mL) as per the procedure described in Example 1 to yield 247 mg of the desired product as a solid. The crude product was used as such for next step. ESI-MS (m/z) 619 (M+H) ⁺ .

Step 2: N-((15.25)-l-(4-Chlorophenyl)-2-hvdroxvpropvl)-4-(2-(4-(ethv lsulfonvl)- phenyl)acetarnido)-N-methylbenzarnide

To a stirred solution of Step 1 intermediate (100 mg, 0.16 mmol) in dichloromethane (15 mL) at RT was added anhydrous ferric chloride (104 mg, 0.64 mmol) portion wise. The resulting suspension was stirred at RT for 16 h. The reaction mixture was diluted with dichloromethane (100 mL) and washed with saturated aqueous sodium bicarbonate solution (SO mL) followed by water (SO mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue thus obtained was purified by silica gel column chromatography to yield 12 mg of titled compound as a solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.06-1.23 (m, 6H), 2.78 (s, 3H), 3.26 (q, J = 7.2 Hz, 2H), 3.82 (s, 2H), 5.00 (br s, 1H), 5.22 (br s, 1H), 5.41 (br s, 1H), 7.15-7.18 (m, 1H), 7.39-7.44 (m, 6H), 7.58-7.63 (m, 3H), 7.84 (d, J = 8.4 Hz, 2H), 10.44 (s, 1H); ESI-MS (m/z) 529 (M+H) ⁺ .

The structure, chemical name intermediate used and analytical data of Examples prepared by following either of the above methods are given below in Table 6.

Table 6: Structure, Chemical name and Analytical data of Example 2-12, 14-32 and 34-54

Pharmacological Activity

Biological Assay

The compounds described herein were screened for ROR gamma modulator activity using the TR-FRET assay by Lantha Screen as described in JBC 2011, 286, 26: 22707-10; and Drug Metabolism and Disposition 2009, 37, 10: 2069-78.

TR-FRET assay for ROR gamma:

The assay is based on the principle that binding of the agonist to the ROR gamma causes a conformational change around helix 12 in the ligand binding domain, resulting in higher affinity for the co-activator peptide. ROR gamma being constitutively active, the Fluorescein- D22 co-activator peptide used in the assay is recruited in the absence of a ligand. Binding of the co-activator peptide, causes an increase in the TR-FRET signal while binding of an antagonist decreases the recruitment of the co-activator peptide, causing a decrease in the TR- FRET signal compared to control with no compound. The assay was performed using a two- step procedure, pre-incubation step with the compound followed by the detection step on addition of the anti-GST tagged terbium (Tb) and fluorescein tagged fluorophores as the acceptor.

Test compounds or reference compounds such as T0901317 (Calbiochem) were dissolved in dimethylsulfoxide (DMSO) to prepare 10.0 mM stock solutions and diluted to the desired concentration. The final concentration of DMSO in the reaction was 4% (v/v). The assay mixture was prepared by mixing lOnM of the GST-tagged ROR gamma ligand binding domain (LBD) in the assay buffer containing 25 mM HEPES, 100 mM NaCl, 5mM DTT and 0.01% BSA with or without the desired concentration of the compound. The reaction was incubated at 22°C for 1 hour. The pre-incubation step was terminated by addition of the detection mixture containing 300nM Fluorescein-D22 co-activator peptide and lOnM lantha screen Tb-anti GST antibody into the reaction mixture. After shaking for S minutes the reaction was further incubated for 1 hour at room temperature and read at 4°C on an Infinite F500 reader as per the kit instructions (Invitrogen). The inhibition of test compound was calculated based on the TR-FRET ratio of 520/495. The activity was calculated as a per cent of control reaction. ICso values were calculated from dose response curve by nonlinear regression analysis using GraphPad Prism software.

The compounds prepared were tested using the above assay procedure and the results obtained are given in Table 1. Percentage inhibition at concentrations of 1.0 μΜ and 10.0 μΜ are given in the table along with ICso (nM) details for selected examples. The compounds were found to have ICso less than lOOOnM, preferably less than lOOnM, more preferably less than 50nM.

The ICso (nM) values are set forth in Table 7 wherein "A" refers to an IC50 value of less than 50 nM, "B" refers to IC50 value in range of 50.01 to 100.0 nM and "C" refers to IC50 values more than 100 nM.

Table 7: In-vitro screening results