WO2015052675A1 - Utilisation de composés substitués dihydro-benzimidazole comme modulateurs du ror gamma - Google Patents

Utilisation de composés substitués dihydro-benzimidazole comme modulateurs du ror gamma Download PDF

Info

Publication number
WO2015052675A1
WO2015052675A1 PCT/IB2014/065175 IB2014065175W WO2015052675A1 WO 2015052675 A1 WO2015052675 A1 WO 2015052675A1 IB 2014065175 W IB2014065175 W IB 2014065175W WO 2015052675 A1 WO2015052675 A1 WO 2015052675A1
Authority
WO
WIPO (PCT)
Prior art keywords
oxo
dihydro
mmol
chloro
imidazol
Prior art date
Application number
PCT/IB2014/065175
Other languages
English (en)
Inventor
Sanjib Das
Abraham Thomas
Neelima Khairatkar-Joshi
Daisy Manish Shah
Malini Bajpai
Original Assignee
Glenmark Pharmaceuticals S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glenmark Pharmaceuticals S.A. filed Critical Glenmark Pharmaceuticals S.A.
Priority to SG11201604755QA priority Critical patent/SG11201604755QA/en
Priority to CA2933618A priority patent/CA2933618A1/fr
Publication of WO2015052675A1 publication Critical patent/WO2015052675A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present patent application is directed to substituted dihydro-benzimidazole compounds which may be useful as retinoid-related orphan receptor gamma t (RORyt) modulators.
  • RORs Retinoid-related orphan receptors
  • the ROR family consists of three members, ROR alpha (RORa), ROR beta (RORp) 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).
  • 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).
  • EAE experimental autoimmune encephalomyelitis
  • CIA collagen-induced arthritis
  • 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).
  • 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, 2010 7: 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.
  • RORyt is also shown to play a crucial role in other non-T 7 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 K 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.
  • the present application is directed to compounds that may be modulators of the RORyt receptor.
  • RORyt plays in the pathogenesis of diseases, it is desirable to prepare compounds that modulate RORyt activity, which can be used in the treatment of diseases mediated by RORyt.
  • the present inventi n relates to compound of formula (I)
  • L is selected from -C(O)-, -CH 2 -, -S(0) 2 - and -S(0)-;
  • M is C 6- i 4 aryl, 5 to 14-membered heteroaryl or 3 to 15 membered heterocyclyl, each being optionally substituted with one or more R 6 ;
  • Y 1 and Y 2 are each independently selected from CH and N;
  • Y 3 is selected from CH and N;
  • R 1 is selected from cyano, -C(0)OR 9 , -C(0) R 7 R 8 , -S(0) 2 R 7 R 8 , -S(0) 2 R 10 , - P(0)(OR u ) 2 , 5 to 14 membered heteroaryl and 3 to 15 membered heterocyclyl;
  • each occurrence of R 2 is independently selected from cyano, halogen, hydroxyl, Ci. 8 alkyl, Ci -8 alkoxy, haloCi -8 alkyl, hydroxyCi -8 alkyl, Ci -8 alkoxyCi -8 alkyl, C3-i 2 cycloalkyl, - R y R z and -CH 2 R y R z ;
  • each occurrence of R 5 is independently selected from cyano, halogen, hydroxyl, Ci. 8 alkyl, Ci -8 alkoxy, haloCi -8 alkyl, C3-i 2 cycloalkyl and -C(0)OH;
  • each occurrence of R 6 is independently selected from cyano, halogen, hydroxyl, Ci. 8 alkyl, Ci -8 alkoxy, haloCi -8 alkyl and C 3- i 2 cycloalkyl;
  • R and R are each independently selected from hydrogen, Ci -8 alkyl and C 3- 6 cycloalkyl;
  • R 9 is selected from hydrogen, Ci -8 alkyl, haloCi -8 alkyl, C 3-6 Cycloalkyl, C 6 -i 4 rylCi. 8 alkyl and -(CH 2 ) q COOR x ;
  • R 10 is selected from Ci -8 alkyl and haloCi -8 alkyl
  • R 11 is selected from hydrogen and Ci -8 alkyl
  • R x is selected from hydrogen and
  • R y and R z are each independently selected from hydrogen, and C 3- 6 cycloalkyl
  • 'm' is an integer ranging from 0 to 2, both inclusive;
  • 'n' is an integer ranging from 0 to 3, both inclusive;
  • 'q' is an integer ranging from 1 to 4, both inclusive.
  • the compounds of formula (I) may involve one or more embodiments.
  • Embodiments of formula (I) includes compounds of formula (la) 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.
  • the invention provides compounds of formula (I) as defined above wherein L is -C(O)- (according to an embodiment defined below), Y 1 and Y 2 are CH (according to another embodiment defined below), 'm' is 0 or 1 (according to yet another embodiment defined below) and 'n' is 0 or 1 (according to yet another embodiment defined below).
  • M is C 6 -i 4 aryl (e.g. phenyl or naphthyl) or 5- to 14- membered heteroaryl (e.g. pyridinyl).
  • each occurrence of R 6 is independently halogen (e.g. F, CI or Br), Ci. 8 alkyl (e.g. methyl or ethyl), Ci -8 alkoxy (e.g. methoxy), haloCi -8 alkyl (e.g. CHF 2 or CF 3 ) or C 3- i 2 cycloalkyl (e.g. cyclopropyl).
  • halogen e.g. F, CI or Br
  • Ci. 8 alkyl e.g. methyl or ethyl
  • Ci -8 alkoxy e.g. methoxy
  • haloCi -8 alkyl e.g. CHF 2 or CF 3
  • C 3- i 2 cycloalkyl e.g. cyclopropyl
  • M is phenyl optionally substituted with one or two R 6 substituent(s) independently selected from halogen (e.g. F, CI or Br), Ci -4 alkyl (e.g. methyl or ethyl), Ci. 8 alkoxy (e.g. methoxy), haloCi -8 alkyl (e.g. CHF 2 or CF 3 ) and C 3-6 Cycloalkyl (e.g. cyclopropyl).
  • R 6 substituent(s) independently selected from halogen (e.g. F, CI or Br), Ci -4 alkyl (e.g. methyl or ethyl), Ci. 8 alkoxy (e.g. methoxy), haloCi -8 alkyl (e.g. CHF 2 or CF 3 ) and C 3-6 Cycloalkyl (e.g. cyclopropyl).
  • M is phenyl or pyridine, each being optionally substituted with one or two R 6 substituent(s) independently selected from F, CI, Br, OCH 3 , CFIF 2 , CF 3 and cyclopropyl.
  • M is phenyl or pyridin-4-yl, each being optionally substituted at 2 or 6 position with one or more of R 6 substituent(s) independently selected from F, CI, Br, OCH 3 , CFIF 2 , CF 3 and cyclopropyl.
  • M is 2,6-dichlorophenyl, 2-bromo-6-chlorophenyl, 2-chloro-6- methoxyphenyl, 2-fluoro-6-methoxyphenyl, 2-chloro-6-(difluoromethyl)phenyl, 2-chloro-6- (trifluoromethyl)phenyl, 2-(trifluoromethyl)phenyl, 2-chloro-6-cyclopropylphenyl, 1-naphthyl or 3,5-dichloropyridin-4-yl.
  • L-M is 2,6-dichlorobenzoyl, 2-bromo-6-chlorobenzoyl, 2-chloro-6- methoxybenzoyl, 2-fluoro-6-methoxybenzoyl, 2-chloro-6-(difluoromethyl)benzoyl, 2-chloro- 6-(trifluoromethyl)benzoyl, 2-chloro-6-cyclopropylbenzoyl, 1-naphthoyl, (3,5- dichloropyridin-4-yl)carbonyl, 2,6-dichlorobenzyl or [2-(trifluoromethyl)phenyl]sulfonyl.
  • R 1 is -C(0)OR 9 .
  • R 9 is hydrogen or Ci -4 alkyl (e.g. methyl, ethyl, propyl or tert-buty ⁇ ).
  • R 1 is -C(0) R 7 R 8 or -S(0) 2 R 7 R 8 .
  • R 7 is hydrogen or C3- 6 cycloalkyl (e.g. cyclopropyl) and R 8 is hydrogen.
  • R 1 is -P(0)(OR u ) 2 .
  • R 11 is hydrogen or Ci -4 alkyl (e.g. methyl or ethyl).
  • R 1 is 5- to 14-membered heteroaryl (e.g. tetrazolyl or oxadiazolyl).
  • R 1 is cyano, -C(0)OH, -C(0)OCH 3 , -C(0)OC 2 H 5 , -C(0)OC(CH 3 ) 3 , - C(0) H 2 , -C(0) H-cyclopropyl, -S(0) 2 H-cyclopropyl, -P(0)(OC 2 H 5 ) 2 , 2H-tetrazol-5-yl or 5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl.
  • R 2 is optional substituent present on Y 1 or Y 2 when Y 1 or Y 2 is CH.
  • R 2 is cyano, halogen (e.g. CI or F), hydroxyCi -8 alkyl (e.g. hydroxymethyl or 2-hydroxy- 1, 1 -dimethyl-ethyl), Ci -8 alkoxyCi -8 alkyl (e.g. 2-methoxy-l, l- dimethyl-ethyl), Ci -8 alkoxy (e.g. 3-methyl-oxetan-3-ylmethoxy), - R y R z and -CH 2 R y R z
  • R y and R z are each independently selected from Ci -4 alkyl (e.g. methyl or ethyl) or C 3-6 cycloalkyl (e.g. cyclopropyl or cyclobutyl).
  • R 2 is CN, halogen (e.g. CI or F), hydroxyCi -8 alkyl (e.g. hydroxymethyl or 2-hydroxy- 1, 1 -dimethyl-ethyl), Ci -8 alkoxyCi -8 alkyl (e.g. 2-methoxy- 1, 1 -dimethyl-ethyl), Ci -8 alkoxy (e.g. 3 -methyl -oxetan-3-ylmethoxy), -CH 2 N(CH 3 ) 2 , -N(CH 3 ) 2 or and 'm' is 0 or 1.
  • R 2 is CN, F, -CH 2 OH, H 3 ⁇ 4 3 ⁇ 4 e°» ,
  • H 3 C C , C H 3 , CH 3 or C-CH 2 N(CH 3 ) 2 .
  • Y 1 is N, C-H or C-F
  • Y 2 is N, C-H, C-F, C-CN, C-CH 2 OH, H3 C C C OH , or C-CH 2 N(CH 3 ) 2
  • m is 0 or 1.
  • R 3 is hydrogen and R 4 is (e.g. methyl or ethyl).
  • R 5 is halogen (e.g. CI or F).
  • Y 1 and Y 2 are each independently selected from CH and N;
  • Y 3 is selected from CH and N;
  • R 1 is cyano, -C(0)OH, -C(0)OCH 3 , -C(0)OC 2 H 5 , -C(0)OC(CH 3 ) 3 , -C(0) H 2 , -
  • R 2 is CN, halogen, hydroxyCi -8 alkyl, Ci -8 alkoxyCi -8 alkyl, Ci -8 alkoxy, -CH 2 N(CH 3 ) 2 ,
  • L is -C(O)-
  • M is phenyl, naphthyl or pyridinyl; each being optionally substituted with one or two
  • R 5 is F or CI
  • R 6 is F, CI, Br, OCH 3 , CHF 2 , CF 3 or cyclopropyl
  • 'm' is 0 or 1 ; and 'n' is 0 or 1.
  • Y 1 and Y 2 are each independently selected from CH and N;
  • Y 3 is selected from CH and N;
  • R 1 is cyano, -C(0)OH, -C(0)OCH 3 , -C(0)OC 2 H 5 , -C(0)OC(CH 3 ) 3 , -C(0) H 2 , - C(0) H-cyclopropyl, -S(0) 2 H-cyclopropyl, -P(0)(OC 2 H 5 ) 2 , 2H-tetrazol-5-yl or 5-oxo-4,5- dihydro-l,2,4-oxadiazol-3-yl;
  • R 2 is CN, F, -CH 2 OH,
  • R 5 is F or CI; 'm' is 0 or 1 ; 'n' is 0 or 1 ; and
  • L-M is 2,6-dichlorobenzoyl, 2-bromo-6-chlorobenzoyl, 2-chloro-6-methoxybenzoyl, 2-fluoro-6-methoxybenzoyl, 2-chloro-6-(difluoromethyl)benzoyl, 2-chloro-6- (trifluoromethyl)benzoyl, 2-chloro-6-cyclopropylbenzoyl, 1 -naphthoyl, (3,5-dichloropyridin- 4-yl)carbonyl, 2,6-dichlorobenzyl or [2-(trifluoromethyl)phenyl]sulfonyl.
  • Y 1 and Y 2 are each independently selected from CH and N;
  • R 2 is CN, F, -CH 2 OH, , , H 3 C , C H 3 ,
  • 'm' is 0 or 1 ;
  • L-M is 2,6-dichlorobenzoyl, 2-bromo-6-chlorobenzoyl, 2-chloro-6-methoxybenzoyl, 2-fluoro-6-methoxybenzoyl, 2-chloro-6-(difluoromethyl)benzoyl, 2-chloro-6- (trifluoromethyl)benzoyl, 2-chloro-6-cyclopropylbenzoyl, 1 -naphthoyl, (3,5-dichloropyridin- 4-yl)carbonyl, 2,6-dichlorobenzyl or [2-(trifluoromethyl)phenyl]sulfonyl.
  • compounds of formula (I) with an IC 50 value of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM with respect to RORyt activity.
  • IC 50 value of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM with respect to RORyt activity.
  • groups R 1 , R 2 , R 3 , R 4 , R 5 , L, M, Y 1 , Y 2 , Y 3 , m and n (and groups defined therein) are described hereinafter in relation to the compounds of formula (la) or formula (lb). It is to be understood that these embodiments are not limited to use in conjunction with formula (la) or formula (lb), but apply independently and individually to the compounds of formula (I).
  • the invention specifically provides compounds of formula (la) or formula (lb), in which 'n' is 0 or 1 and consequently there is also provided a compound of formula (I) in which 'n' is 0 or 1.
  • the invention also provides a compound of formula (la), which is an embodiment of a compound of formula (I).
  • Y 1 and Y 2 are each independently selected from CH and N;
  • Y 3 is selected from CH and N;
  • Y 4 is selected from CH and N;
  • R 1 is selected from cyano, -C(0)OR 9 , -C(0) H 2 , -C(0) H-cyclopropyl, -S(0) 2 H- cyclopropyl, -P(0)(OC 2 H 5 ) 2 , 2H-tetrazol-5-yl and 5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl; each occurrence of R 2 is independently selected from cyano, halogen, each occurrence of R 5 is independently selected from cyano, halogen, hydroxyl, Ci.
  • each occurrence of R 6 is independently selected from halogen, Ci -8 alkyl, Ci -8 alkoxy, haloCi -8 alkyl and C 3-6 Cycloalkyl;
  • R 9 is selected from hydrogen and Ci -8 alkyl
  • 'm' is an integer ranging from 0 to 2, both inclusive; 'n' is an integer ranging from 0 to 3, both inclusive; and
  • 'p' is an integer ranging from 1 to 4, both inclusive.
  • the compound of formula (la) 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 of 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 (la) as defined above wherein Y 1 and Y 2 are CH (according to an embodiment defined below), 'm' is 0 or 1 (according to another embodiment defined below) and 'n' is 0 or 1 (according to yet another embodiment defined below).
  • R 1 is -C(0)OR 9 .
  • R 9 is hydrogen or Ci -8 alkyl (e.g. methyl, ethyl, propyl or tert-butyl).
  • R 1 is -C(0) H 2 , -C(0) H-cyclopropyl, -S(0) 2 H-cyclopropyl, - P(0)(OC 2 H 5 ) 2 , 2H-tetrazol-5-yl and 5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl.
  • R 1 is cyano, -C(0)OH, -C(0)OCH 3 , -C(0)OC 2 H 5 , -C(0)OC(CH 3 ) 3 , - C(0) H 2 , -C(0) H-cyclopropyl, -S(0) 2 H-cyclopropyl, -P(0)(OC 2 H 5 ) 2 , 2H-tetrazol-5-yl or 5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl.
  • R 2 is CN, F, -CH 2 OH, H 3 ⁇ 4 3 ⁇ 4 e°» ,3 ⁇ 4 ⁇ c ⁇ » ,*- ⁇ H 3 C ⁇
  • H 3 C C , C H 3 , CH 3 or C-CH 2 N(CH 3 ) 2 .
  • Y 1 is N, C-H or C-F
  • Y 2 is N, C-H, C-F, C-CN, C-CH 2 OH
  • HSC OH HSC > oc H 3 c -° ⁇ x> C-N ⁇
  • R 5 is halogen (e.g. CI or F).
  • each occurrence of R 6 is independently halogen (e.g. F, CI or Br), Ci. 8 alkyl (e.g. methyl or ethyl), Ci -8 alkoxy (e.g. methoxy), haloCi -8 alkyl (e.g. CHF 2 or CF 3 ) or C 3-6 cycloalkyl (e.g. cyclopropyl).
  • halogen e.g. F, CI or Br
  • Ci. 8 alkyl e.g. methyl or ethyl
  • Ci -8 alkoxy e.g. methoxy
  • haloCi -8 alkyl e.g. CHF 2 or CF 3
  • C 3-6 cycloalkyl e.g. cyclopropyl
  • each occurrence of R 6 is independently halogen (e.g. F, CI or Br), Ci. 8 alkyl (e.g. methyl or ethyl), Ci -8 alkoxy (e.g. methoxy), haloCi -8 alkyl (e.g. CHF 2 or CF 3 ) or C 3-6 Cycloalkyl (e.g. cyclopropyl); and 'p' is 1 or 2.
  • halogen e.g. F, CI or Br
  • Ci. 8 alkyl e.g. methyl or ethyl
  • Ci -8 alkoxy e.g. methoxy
  • haloCi -8 alkyl e.g. CHF 2 or CF 3
  • C 3-6 Cycloalkyl e.g. cyclopropyl
  • 'p' is 1 or 2.
  • R 6 is independently selected from F, CI, Br, OCH 3 , CHF 2 , CF 3 and cyclopropyl.
  • R 6 is independently selected from F, CI, Br, OCH 3 , CHF 2 , CF 3 and cyclopropyl; and 'p' is 1 or 2.
  • ⁇ ring is optionally substituted at 2 or 6 position with one or two R 6 substituent(s) independently selected from F, CI, Br, OCH 3 , CFIF 2 , CF 3 and cyclopropyl.
  • R is independently halogen (e.g. F, CI or Br), Ci -8 alkyl (e.g. methyl or ethyl), Ci -8 alkoxy (e.g. methoxy), haloCi. 8 alkyl (e.g. CFIF 2 or CF 3 ) or C 3-6 Cycloalkyl (e.g. cyclopropyl).
  • R is independently halogen (e.g. F, CI or Br), Ci -8 alkyl (e.g. methyl or ethyl), Ci -8 alkoxy (e.g. methoxy), haloCi. 8 alkyl (e.g. CFIF 2 or CF 3 ) or C 3-6 Cycloalkyl (e.g. cyclopropyl).
  • formula (la) in which is independently selected from F, CI, Br, OCH 3 , CHF 2 , CF 3 and cyclopropyl.
  • compounds of formula (la) in which P is 2,6-dichlorophenyl, 2-bromo-6-chlorophenyl, 2-chloro- 6-methoxyphenyl, 2-fluoro-6-methoxyphenyl, 2-chloro-6-(difluoromethyl)phenyl, 2-chloro- 6-(trifluoromethyl)phenyl, 2-chloro-6-cyclopropylphenyl or 3,5-dichloropyridin-4-yl.
  • R 9 is hydrogen or (e.g. methyl, ethyl, propyl or tert-butyl).
  • R 9 is hydrogen, methyl, ethyl, propyl or tert-butyl.
  • Y 1 and Y 2 are each independently selected from CH and N;
  • Y 3 is selected from CH and N;
  • Y 4 is selected from CH and N;
  • R 1 is cyano, -C(0)OH, -C(0)OCH 3 , -C(0)OC 2 H 5 , -C(0)OC(CH 3 ) 3 , -C(0) H 2 , - C(0) H-cyclopropyl, -S(0) 2 H-cyclopropyl, -P(0)(OC 2 H 5 ) 2 , 2H-tetrazol-5-yl or 5-oxo-4,5- dihydro-l,2,4-oxadiazol-3-yl;
  • R 2 is CN, F, -CH 2 OH,
  • R 5 is F or CI
  • R 6 is F, CI, Br, OCH 3 , CHF 2 , CF 3 or cyclopropyl
  • Y 1 and Y 2 are each independently selected from CH and N;
  • Y 3 is selected from CH and N:
  • R 1 is cyano, -C(0)OH, -C(0)OCH 3 , -C(0)OC 2 H 5 , -C(0)OC(CH 3 ) 3 , -C(0) H 2 , - C(0) H-cyclopropyl, -S(0) 2 H-cyclopropyl, -P(0)(OC 2 H 5 ) 2 , 2H-tetrazol-5-yl or 5-oxo-4,5- dihydro-l,2,4-oxadiazol-3-yl;
  • R 2 is CN, F, -CH 2 OH,
  • P is 2,6-dichlorophenyl, 2-bromo-6-chlorophenyl, 2-chloro-6- methoxyphenyl, 2-fluoro-6-methoxyphenyl, 2-chloro-6-(difluoromethyl)phenyl, 2-chloro-6- (trifluoromethyl)phenyl, 2-chloro-6-cyclopropylphenyl or 3,5-dichloropyridin-4-yl;
  • R 5 is F or CI
  • 'm' is 0 or 1
  • 'n' is 0 or 1.
  • Y 1 and Y 2 are each independently selected from CH and N;
  • R 2 is CN, F, -CH 2 OH,
  • ' ' is 0 or 1; is 2,6-dichlorophenyl, 2-bromo-6-chlorophenyl, 2-chloro-6- methoxyphenyl, 2-fluoro-6-methoxyphenyl, 2-chloro-6-(difluoromethyl)phenyl, 2-chloro-6- (trifluoromethyl)phenyl, 2-chloro-6-cyclopropylphenyl or 3,5-dichloropyridin-4-yl; and
  • compounds of formula (la) with an IC 50 value of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM with respect to RORyt activity.
  • IC 50 value of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM with respect to RORyt activity.
  • groups R 1 , R 2 , R 5 , R 6 , R 9 , Y 1 , Y 2 , Y 3 , Y 4 , m, n and p (and groups defined therein) are described hereinafter in relation to the compounds of formula (lb). It is to be understood that these embodiments are not limited to use in conjunction with formula (lb), but apply independently and individually to the compounds of Formula (I) or Formula (la).
  • the invention specifically provides compounds of formula (lb), in which 'n' is 0 or 1 and consequently there is also provided a compound of Formula (I) or Formula (la) in which 'n' is 0 or 1.
  • the invention also provides a compound of formula (lb), which is an embodiment of a compound of formula (I).
  • each occurrence of R is independently selected from cyano, F, -CH 2 OH,
  • each occurrence of R 5 is independently selected from cyano, halogen, hydroxyl, Ci. 8 alkyl and haloCi -8 alkyl;
  • each occurrence of R 6 is independently selected from halogen, Ci -8 alkyl, Ci -8 alkoxy, haloCi -8 alkyl and C 3-6 cycloalkyl;
  • R 9 is selected from hydrogen and Ci -8 alkyl
  • 'm' is an integer ranging from 0 to 2, both inclusive;
  • 'n' is an integer ranging from 0 to 3, both inclusive;
  • 'p' is an integer ranging from 1 to 4, both inclusive.
  • the compounds of formula (lb) 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 of any other embodiment defined herein. Thus, the invention contemplates all possible combinations and permutations of the various independently described embodiments.
  • the invention provides compounds of formula (lb) as defined above wherein R 5 is F or CI (according to an embodiment defined below), 'm' is 0 or 1 (according to another embodiment defined below) and 'n' is 0 or 1 (according to yet another embodiment defined below).
  • R 5 is halogen (e.g. CI or F).
  • each occurrence of R 6 is independently halogen (e.g. F, CI or Br), Ci. 8 alkyl (e.g. methyl or ethyl), Ci -8 alkoxy (e.g. methoxy), haloCi -8 alkyl (e.g. CFIF 2 or CF 3 ) or C 3-6 cycloalkyl (e.g. cyclopropyl).
  • halogen e.g. F, CI or Br
  • Ci. 8 alkyl e.g. methyl or ethyl
  • Ci -8 alkoxy e.g. methoxy
  • haloCi -8 alkyl e.g. CFIF 2 or CF 3
  • C 3-6 cycloalkyl e.g. cyclopropyl
  • each occurrence of R 6 is independently halogen (e.g. F, CI or Br), Ci. 8 alkyl (e.g. methyl or ethyl), Ci -8 alkoxy (e.g. methoxy), haloCi -8 alkyl (e.g. CHF 2 or CF 3 ) or C 3-6 Cycloalkyl (e.g. cyclopropyl); and 'p' is 1 or 2.
  • halogen e.g. F, CI or Br
  • Ci. 8 alkyl e.g. methyl or ethyl
  • Ci -8 alkoxy e.g. methoxy
  • haloCi -8 alkyl e.g. CHF 2 or CF 3
  • C 3-6 Cycloalkyl e.g. cyclopropyl
  • 'p' is 1 or 2.
  • R 6 is independently selected from F, CI, Br, OCH 3 , CHF 2 , CF 3 and cyclopropyl.
  • R 6 is independently selected from F, CI, Br, OCH 3 , CF£F 2 , CF 3 and cyclopropyl; and 'p' is 1 or 2.
  • ⁇ -— ? ' ring is optionally substituted at 2 or 6 position with one or two R 6 substituent(s) independently selected from F, CI, Br, OCH 3 , CHF 2 , CF 3 and cyclopropyl.
  • R is independently selected from F, CI, Br, OCH 3 , CHF 2 , CF 3 and cyclopropyl.
  • ⁇ R is 2,6-dichlorophenyl, 2-bromo-6-chlorophenyl, 2-chloro-
  • 6-methoxyphenyl 2-fluoro-6-methoxyphenyl, 2-chloro-6-(difluoromethyl)phenyl, 2-chloro- 6-(trifluoromethyl)phenyl or 2-chloro-6-cyclopropylphenyl.
  • R 9 is hydrogen or Ci -8 alkyl (e.g. methyl, ethyl, propyl or tert-butyl).
  • R 9 is hydrogen, methyl, ethyl, propyl or tert-butyl.
  • R 2 is CN, F, -CH 2 OH, H 3 ⁇ 4 ° » , , H 3 C >0 ,
  • R 5 is F or CI
  • R 6 is F, CI, Br, OCH 3 , CHF 2 , CF 3 or cyclopropyl
  • R 9 is hydrogen, methyl, ethyl, propyl or tert-butyl
  • 'm' is O or l
  • 'n' is 0 or 1
  • 'p' is 1 or 2.
  • 'p is 2,6-dichlorophenyl, 2-bromo-6-chlorophenyl, 2-chloro-6- methoxyphenyl, 2-fluoro-6-methoxyphenyl, 2-chloro-6-(difluoromethyl)phenyl, 2-chloro-6- (trifluoromethyl)phenyl, or 2-chloro-6-cyclopropylphenyl;
  • R 5 is F or CI
  • R 9 is hydrogen, methyl, ethyl, propyl or tert-butyl
  • 'm' is 0 or 1 ;
  • Compounds of the present invention include the compounds in Examples 1-44.
  • esters of the compounds of present invention refer to a modified version or a precursor of a parent compound, designed to enhance the delivery properties and be converted to the parent compound in the body.
  • Ester of the compounds of present invention are entities structurally related to parent acidic drug compound (-COOH), which, after administration, release the parent drug in vivo as the result of some metabolic process, such as enzymatic or chemical hydrolysis of a susceptible functionality.
  • -COOH parent acidic drug compound
  • R 1 is -COOR 9 Ester (wherein R 9 is Ci -8 alkyl) of the compounds of present invention are entities structurally related to parent acidic drug compound (R 9 is -COOH), which, after administration, release the parent drug in vivo as the result of some metabolic process, such as enzymatic or chemical hydrolysis of a susceptible functionality.
  • 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).
  • the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.
  • the compounds described in the present patent application 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 capsule, sachet, paper or other container.
  • the compounds and pharmaceutical compositions of the present invention are useful for inhibiting the activity of RORyt, which is believed to be related to a variety of disease states.
  • the present patent application 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.
  • halogen or halo means fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo).
  • 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. Ci-salkyl), and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1 -methyl ethyl (isopropyl), n-butyl, n-pentyl, and 1, 1 -dimethyl ethyl (t- butyl).
  • Ci-salkyl carbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. Ci-salkyl), and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1 -methyl ethyl (isopropyl),
  • Ci -4 alkyl 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, substituted or unsubstituted.
  • alkenyl refers to a hydrocarbon chain containing from 2 to 10 carbon atoms (i.e. C2-ioalkenyl) and including at least one carbon-carbon double bond.
  • alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), zso-propenyl, 2- methyl-l-propenyl, 1-butenyl, and 2-butenyl. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkynyl refers to a hydrocarbyl radical having at least one carbon-carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred i.e. C 2- ioalkynyl).
  • alkynyl groups include ethynyl, propynyl, and butynyl. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkoxy denotes an alkyl group attached via an oxygen linkage to the rest of the molecule (i.e. Ci -8 alkoxy). Representative examples of such groups are -OCH 3 and - OC 2 H 5 . Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkoxyalkyl or “alkyloxyalkyl” refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above (i.e. Ci -8 alkoxyCi -8 alkyl or Ci -8 alkyloxyCi -8 alkyl).
  • alkoxyalkyl moiety includes, but are not limited to, - CH 2 OCH 3 and -CH 2 OC 2 H 5 . Unless set forth or recited to the contrary, all alkoxyalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • 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. haloCi -8 alkyl).
  • haloalkyl moiety include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. Unless set forth or recited to the contrary, all haloalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms (i.e. haloCi -8 alkoxy).
  • haloalkoxy include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1 -bromoethoxy.
  • all haloalkoxy groups described herein may be straight chain or branched, substituted or unsubstituted.
  • hydroxyalkyl refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyCi -8 alkyl).
  • hydroxyalkyl moieties include, but are not limited to - CH 2 OH, -C 2 H 4 OH and -CH(OH)C 2 H 4 OH.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, (i.e.C 3- i 2 cycloalkyl).
  • monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • 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.
  • C 3-6 Cycloalkyl refers to the cyclic ring having 3 to 6 carbon atoms. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkylalkyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group (i.e. C 3-8 cycloalkylCi -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, cyclobutyl ethyl, and cyclopentyl ethyl. Unless set forth or recited to the contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkenyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, (i.e. C 3 - 8 cycloalkenyl).
  • Examples of “cycloalkenyl” include but are not limited to cyclopropenyl, cyclobutenyl, and cyclopentenyl. Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkenylalkyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, directly attached to an alkyl group, (i.e. C 3-8 cycloalkenylCi -8 alkyl).
  • the cycloalkenylalkyl 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. Unless set forth or recited to the contrary, all cycloalkenylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • aryl refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C 6 - i 4 aryl), including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl. Unless set forth or recited to the contrary, all aryl groups described or claimed herein may be substituted or unsubstituted.
  • aryloxy refers to an aryl group as defined above attached via an oxygen linkage to the rest of the molecule (i.e. C 6- i 4 aryloxy).
  • aryloxy moieties include, but are not limited to phenoxy and naphthoxy. Unless set forth or recited to the contrary, all aryloxy groups described herein may be substituted or unsubstituted.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, i.e. C 6- i 4 arylCi -8 alkyl, such as -CH 2 C 6 H 5 and -C 2 H 4 C 6 H 5 . Unless set forth or recited to the contrary, all arylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • heterocyclic ring or “heterocyclyl” unless otherwise specified refers to non-aromatic 3 to 15 membered ring radical (i.e. 3 to 15 membered heterocyclyl) 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.
  • heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s).
  • heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2- oxoazepinyl, octahydroin
  • 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.
  • heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group (i.e. 3 to 15 membered heterocyclylCi-salkyl).
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • heteroaryl refers 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.
  • heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, iso
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group (i.e. 5 to 14 membered heterarylCi -8 alkyl).
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • all heteroarylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids 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, methyl sul
  • 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.
  • 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).
  • domestic animals e.g., household pets including cats and dogs
  • 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 the invention are typically administered in the form of a pharmaceutical composition.
  • Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention.
  • the pharmaceutical composition of the present patent application comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients.
  • 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, viscosif ing agents, solvents and the like.
  • 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 composition 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.
  • compositions may be in conventional forms, for example, capsules, tablets, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present invention may be formulated so as to provide desired release profile.
  • Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition can be carried out using any of the accepted routes of administration of pharmaceutical compositions.
  • 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.
  • Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular, or topical.
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges.
  • Liquid formulations include, but are not limited to, syrups, emulsions, and sterile injectable liquids, such as suspensions or solutions.
  • Topical dosage forms of the compounds include ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration.
  • compositions of the present patent application may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 th Ed., 2003 (Lippincott Williams & Wilkins). Suitable doses of the compounds for use in treating the diseases and disorders described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Mode of administration, dosage forms, and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present patent application. Methods of Treatment
  • Compounds of the present invention are particularly useful because they may inhibit the activity of Retinoid-related orphan receptor gamma ⁇ and particularly Retinoid-related orphan receptor gamma t (RORyt) ⁇ , i.e., they prevent, inhibit, or suppress the action of RORyt, and/or may elicit RORyt modulating effect.
  • RORyt Retinoid-related orphan receptor gamma ⁇ and particularly Retinoid-related orphan receptor gamma t
  • 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.
  • autoimmune diseases will be understood by those skilled in the art 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 blood vessels, connective tissues, endocrine glands such as the thyroid or pancreas, joints, muscles, red blood cells, and skin.
  • 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 - spru
  • 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.
  • 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 forms 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 rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, and other arthritic conditions.
  • the compounds of the present invention may be used for treatment of respiratory disorders such as chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and cough.
  • COPD chronic obstructive pulmonary disease
  • asthma asthma
  • bronchospasm bronchospasm
  • cough cough
  • respiratory disorders include 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
  • the compounds of the present invention may be used for treatment of pain conditions.
  • the pain can be acute or chronic pain.
  • the compounds of the present invention may be used for treatment of inflammatory pain, arthritic pain, neuropathic pain, post-operative 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, post-traumatic injury, or pain associated with irritable bowel syndrome.
  • the compounds of the present invention may be used for treatment of gastrointestinal disorder such as 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.
  • gastrointestinal disorder such as 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.
  • the compounds of the present invention may be useful in the treatment of cancer, and pain associated with cancer.
  • cancers include 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.
  • COPD chronic obstructive pulmonary disease
  • the methods of treatment of the present patent application comprise administering a safe and effective amount of a compound according to Formula I or a pharmaceutically- acceptable salt thereof to a patient (particularly a human) in need thereof.
  • the present patent application relates to the use of the compounds in the preparation of a medicament for the treatment of diseases mediated by RORyt.
  • Compounds of the present invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the daily dosage of the compound of the invention may be in the range from 0.05 mg/kg to 100 mg/kg.
  • the Buchwald coupling reaction of 2-halo nitrobenzene derivative (3) with aniline derivative (4) using palladium catalyst such as palladium acetate in the presence of a base such as cesium carbonate also affords Intermediate (5).
  • the reduction of the nitro intermediate (5) to amine of general formula (6) followed by cyclization using 1, 1-carbodiimidazole (CDI) yields benzimidazolone Intermediate of formula (7).
  • the coupling reaction of compound of formula (7) with the compound of formula (8) yields the compound of formula (la).
  • the compound of formula (7) may be reacted with compound of formula (8) in the presence of a suitable base.
  • the suitable base may be sodium hydride.
  • the reaction may be carried out in a suitable solvent or mixture of solvents.
  • the suitable solvent may be DMF.
  • the compound of formula (la) may be optionally further converted to pharmaceutically acceptable salt.
  • Intermediate (7) can also be prepared from compound of general formula (11) and substituted phenyl halide of formula (12) as shown in scheme 4.
  • the reaction may be carried out in the presence of base such as ethylene diamine and potassium hydrogen sulphate.
  • the reaction may be carried out in the presence of catalyst such as copper iodide.
  • the compound of formula (23) is reacted with compound of formula (8A) in the presence of a suitable base.
  • the suitable base may be sodium hydride.
  • the reaction may be carried out in a suitable solvent or mixture thereof.
  • the suitable solvent may be DMF.
  • compound of general formula (Ia-2) (wherein R 1 , R 5 , R 6 , 'n' and 'p' are as defined with respect to a compound of formula (la)) can be prepared as depicted in scheme 8.
  • the aldehyde group of the Intermediate (21) is reduced to corresponding alcohol (24) using sodium borohydride followed by the reaction with 3,4-dihydro-2H-pyran (DHP) to give the THP protected Intermediate (25).
  • DHP 3,4-dihydro-2H-pyran
  • the nitro group reduction of the Intermediate (25) followed by cyclization yields the Intermediate (26).
  • the coupling of the Intermediate (26) with the acid chloride of formula (8A) followed by deprotection affords the final compound of formula (Ia-2).
  • the suitable base may be sodium hydride.
  • reaction may be carried out in a suitable solvent.
  • suitable solvent may be DMF.
  • the compound of formula (7) is reacted with a compound of formula (8) in the presence of sodium hydride in DMF.
  • R 2 , R 5 , R 6 , R 9 , ' m', 'n' and 'p' are as defined with respect to a compound of formula (lb)) is shown in scheme 11.
  • the compound of formula (29) is reacted with compound of formula (8A) in the presence of a suitable base.
  • the suitable base may be sodium hydride.
  • reaction may be carried out in a suitable solvent.
  • suitable solvent may be DMF.
  • the compound of formula (29) is reacted with a compound of formula (8A) in the presence of sodium hydride in DMF.
  • 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 sulphate, filtration and evaporation of the solvent.
  • Purification 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.
  • Step 1 tert-Butyl 4-[(2-nitrophenyl)amino]benzoate:
  • Step 1 intermediate 500 mg, 1.592 mmol
  • methanol (10 mL) methanol
  • catalytic amount of 10% palladium on carbon was added to the stirred solution of Step 1 intermediate (500 mg, 1.592 mmol) in methanol (10 mL)
  • the reaction mixture was filtered through celite pad and the filtrate was concentrated to yield 370 mg of the desired product as off white solid.
  • Step 3 tert-Butyl 4-(2-oxo-2,3-dihydro-lH-benzimidazol-l-yl)benzoate:
  • Step 2 intermediate 360 mg, 1.266 mmol
  • THF 10 mL
  • CDI 313 mg, 1.90 mmol
  • the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), brine (20 mL) and dried over anhydrous Na 2 S0 4 .
  • the solvent was distilled off under reduced pressure. The residue obtained was purified by column chromatography to afford 310 mg of the title product as off-white solid.
  • Step 1 tert-Butyl 2-chloro-4-[(2-nitrophenyl)amino]benzoate:
  • Step 2 tert-Butyl 2-chloro-4-(2-oxo-2,3-dihydro-lH-benzimidazol-l-yl)benzoate:
  • Step 1 intermediate 280 mg, 0.8027 mmol
  • ethyl acetate 15 mL
  • ethanol 3 mL
  • CDI 186 mg, 1.1292 mmol
  • THF 10 mL
  • the title compound was prepared by the reaction of l-iodo-2-nitro benzene (800 mg, 3.212 mmol) with tert-butyl 4-amino-2-fluorobenzoate (678 mg, 3.212 mmol) in the presence of palladium acetate (72 mg, 0.3212 mmol), XPhos (223 mg, 0.321 mmol) and cesium carbonate (1.56 g, 4.819 mmol) in 1,4-dioxane (10 mL) as per the process described in step 1 of the Intermediate 2 to yield 710 mg of the product as yellow solid.
  • Step 2 tert-Butyl 2-fluoro-4-(2-oxo-2,3-dihydro-lH-benzimidazol-l-yl)benzoate
  • step 1 intermediate 650 mg, 1.155 mmol
  • methanol 15 mL
  • step 2 and 3 of Intermediate 1 respectively to yield 220 mg of the product as yellow solid.
  • step 1 intermediate 400 mg, 1.203 mmol
  • methanol (10 mL) was hydrogenated in the presence of 10% palladium on carbon in a Parr apparatus for 3 hours at RT.
  • the reaction mixture was filtered through celite and the filtration bed was thoroughly rinsed with methanol (2 x 20 mL).
  • the mother liquor and washings were combined and concentrated under reduced pressure to obtain 350 mg of the title product as light yellow oil.
  • Step 3 tert-Butyl 3-fluoro-4-(2-oxo-2,3-dihydro-lH-benzimidazol-l-yl)benzoate
  • Step 2 intermediate 350 mg, 1.157 mmol
  • THF 10 mL
  • Step 1 tert-Butyl 6-[(2-nitrophenyl)amino]pyridine-3-carboxylate:
  • the title compound was prepared by the reaction of 2-nitroaniline (200 mg, 1.448 mmol) and tert-butyl 6-chloropyridine-3-carboxylate (309 mg, 1.448 mmol) in the presence of palladium acetate (33 mg, 0.1448 mmol), XPhos (100 mg, 0.1737 mmol) and cesium carbonate (706 mg, 2.172 mmol) in 1,4-dioxane (10 mL) as per the process described in step 1 of Intermediate 2 to yield 150 mg of the product as orange solid.
  • Step 2 tert-Butyl 6-(2-oxo-2,3-dihydro-lH-benzimidazol-l-yl)pyridine-3-carboxylate:
  • step 1 intermediate 600 mg, 1.9028 mmol
  • methanol 10 mL
  • CDI 442 mg, 2.681 mmol
  • THF 10 mL
  • Step 1 tert-Butyl 3-fluoro-4-[(3-nitropyridin-4-yl)amino]benzoate:
  • the title compound was prepared by the reaction of 4-chloro-3-nitropyridine (450 mg, 2.840 mmol) and tert-butyl 4-amino-3-fluorobenzoate (600 mg, 2.8407 mmol) in the presence of palladium acetate (64 mg, 0.284 mmol), XPhos (198 mg, 0.341 mmol) and cesium carbonate (1.38 g, 4.26 mmol) in 1,4-dioxane (15 mL) as per the process described in step 1 of Intermediate 2 to yield 610 mg of the product as yellow solid.
  • Step 2 tert-Butyl 3-fluoro-4-(2-oxo-2,3-dihydro-lH-imidazo[4,5-c]pyridin-l-yl)benzoate:
  • the title compound was prepared by palladium catalyzed hydrogenation of step 1 intermediate (600 mg, 1.801 mmol) in methanol (10 mL) followed by the cyclization of the corresponding diamine derivative (500 mg, 1.648 mmol) in the presence of CDI (408 mg, 2.472 mmol) in THF (10 mL) as per the process described in step 2 and 3 of Intermediate 1 respectively to yield 400 mg of the product as light brown solid.
  • Step 1 tert-Butyl 3-fluoro-4-[(3-nitropyridin-2-yl)amino]benzoate:
  • the title compound was prepared by the reaction of 2-chloro-3-nitropyridine (250 mg, 1.5768 mmol) and tert-butyl-4-amino-3-fluorobenzoate (332 mg, 1.5760 mmol) in the presence of palladium acetate (35 mg, 0.157 mmol), XPhos (109 mg, 0.189 mmol) and cesium carbonate (772 mg, 2.37 mmol) in 1,4-dioxane (10 mL) as per the process described in step 1 of Intermediate 2 to yield 410 mg of the product as yellow solid.
  • Step 2 tert-Butyl 3-fluoro-4-(2-oxo-l,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)benzoate
  • step 1 intermediate 400 mg, 1.200 mmol
  • methanol 10 mL
  • step 2 tert-Butyl 3-fluoro-4-(2-oxo-l,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)benzoate
  • Step 1 tert-Butyl 4-[(5-fluoro-2-nitrophenyl)amino]benzoate:
  • the title compound was prepared by the reaction of tert-butyl 4-amino benzoate (384 mg, 2.727 mmol) with 2-bromo-4-fluoro-l -nitrobenzene (500 mg, 2.272 mmol) in the presence of palladium acetate (51 mg, 0.227 mmol), XPhos (157 mg, 0.272 mmol) and cesium carbonate (1.12 g, 3.409 mmol) in 1,4-dioxane (10 mL) as per the process described in step 1 of Intermediate 2 to yield 520 mg of the product as yellow oil.
  • Step 2 tert-Butyl 4-(6-fluoro-2-oxo-2,3-dihydro-lH-benzimidazol-l-yl)benzoate:
  • step 1 intermediate 500 mg, 1.504 mmol
  • methanol 10 mL
  • CDI 286 mg, 1.736 mmol
  • THF 10 mL
  • Step 1 tert-Butyl 3-fluoro-4-[(2-fluoro-6-nitrophenyl)amino]benzoate:
  • Step 2 tert-Butyl 3-fluoro-4-(7-fluoro-2-oxo-2,3-dihydro-lH-benzimidazol-l-yl)benzoate: To the stirred solution of Step 1 intermediate (300 mg, 0.8571 mmol) in methanol (10 mL) was added catalytic amount of 10% palladium on carbon and the mixture was stirred for 5 h under hydrogen atmosphere. The reaction mixture was filtered through celite pad and the filtrate was concentrated. The obtained solid was dissolved in THF (10 mL) and CDI (201 mg, 1.212 mmol) was added and the reaction mixture was refluxed for 18 h.
  • reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), brine (20 mL) and dried over anhydrous Na 2 S0 4 . The solvent was distilled off under reduced pressure. The residue obtained was purified by column chromatography to afford 200 mg of the product as off white solid.
  • Step 1 tert-Butyl 4-[(4-cyano-2-nitrophenyl)amino]-3-fluorobenzoate:
  • the title compound was prepared by the reaction of 4-bromo-3-nitrobenzonitrile (374 mg, 1.65 mmol) with tert-butyl 4-amino-3-fluorobenzoate (350 mg, 1.65 mmol) in the presence of palladium acetate (18 mg, 0.082 mmol), XPhos (57 mg, 0.099 mmol) and cesium carbonate (804 mg, 2.47 mmol) in 1,4-dioxane (20 mL) as per the process described in step 1 of Intermediate 2 to yield 513 mg of the product as brown solid.
  • step 1 intermediate To a stirred suspension of step 1 intermediate (504 mg, 1.411 mmol) and ammonium chloride (754 mg, 14.11 mmol) in water (8 mL) and ethanol (16 mL) was added iron powder (236 mg, 4.23 mmol) at 60 °C and it was stirred at the same temperature for 2 hours.
  • the reaction mixture was cooled to RT and diluted with ethyl acetate (50 mL).
  • the organic mixture was washed with saturated aqueous solution of sodium bicarbonate (20 mL), brine (20 mL), the organic layer was separated and dried over anhydrous sodium sulfate.
  • the solvent was recovered under reduced pressure to yield 448 mg of the title product as yellow oil.
  • Step 3 tert-Butyl 4-(5-cyano-2-oxo-2,3-dihydro-lH-benzimidazol-l-yl)-3-fluorobenzoate
  • the title compound was prepared by the cyclization of step 2 intermediate (441 mg, 1.348 mmol) in the presence of CDI (327 mg, 2.022 mmol) in THF (10 mL) as per the process described in step 3 of Intermediate 1 to yield 324 mg of the product as pale yellow solid.
  • Step 1 tert-Butyl 4- ⁇ [4-(dimethylamino)-2-nitrophenyl]amino ⁇ -3-fluorobenzoate
  • step 1 intermediate 700 mg, 1.865 mmol
  • methanol 15 mL
  • CDI 159 mg, 0.984 mmol
  • THF 10 mL
  • step 1 intermediate A mixture of step 1 intermediate (573 mg, 2.728 mmol), potassium carbonate (564 mg, 4.092 mmol) and methyl iodide (0.25 mL, 4.092 mmol) in DMF (5 mL) was heated to 50 °C for 15 hours in a sealed tube.
  • the reaction mixture was cooled to RT and diluted with ethyl acetate (25 mL).
  • the organic mixture was washed with water (2 x 20 mL) followed by brine (20 mL) and dried over anhydrous sodium sulfate.
  • the solution was filtered, concentrated and the residue thus obtained was purified by silica gel column chromatography to yield 547 mg of the title product as yellow solid.
  • Step 3 tert-Butyl 4-[(4- ⁇ cyclobutyl-methyl-amino ⁇ -2-nitrophenyl)amino]benzoate
  • step 2 intermediate 354 mg, 1.955 mmol
  • tert-butyl 4-aminobenzoate 465 mg, 1.955 mmol
  • sodium hydride 60% w/w, 117 mg, 2.932 mmol
  • DMF 7 mL
  • Step 4 tert-Butyl 4-[5-(cyclobutyl-methyl-amino)-2-oxo-2,3-dihydro-benzoimidazol-l-yl]- benzoate
  • step 3 intermediate The title compound was synthesized by the catalytic hydrogenation reaction of step 3 intermediate (422 mg, 1.062 mmol) followed by the cyclization of the corresponding diamine derivative (303 mg, 0.825 mmol) by using CDI (200 mg, 1.237 mmol) in THF (10 mL) as per the process described in respective step 2 and 3 of Intermediate 1 to yield 142 mg of the product as white solid.
  • Step 1 tert-Butyl 4-[(4-formyl-2-nitrophenyl)amino]benzoate
  • Step 2 tert-Butyl 4-( ⁇ 4-[(dimethylamino)methyl]-2-nitrophenyl ⁇ amino)benzoate:
  • Step 1 intermediate 500 mg, 1.460 mmol
  • EDC EDC
  • dimethylamine hydrochloride 238 mg, 2.920 mmol
  • STAB 618 mg, 2.920 mmol
  • the reaction mixture was diluted with ethyl acetate (50 mL) and washed with aqueous solution of sodium bicarbonate (2 x 25 mL) and brine (20 mL).
  • the solution was dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography to afford 660 mg of the title product as off-white solid.
  • Step 3 tert-Butyl 4-( ⁇ 2-amino-4-[(dimethylamino)methyl]phenyl ⁇ amino) benzoate:
  • Step 2 intermediate To the stirred solution of Step 2 intermediate (658 mg, 1.77 mmol) in methanol (10 mL) was added catalytic amount of 10% palladium on carbon and the reaction mixture was stirred for 5 h under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated to yield 570 mg of the product.
  • Step 4 tert-Butyl 4- ⁇ 5-[(dimethylamino)methyl]-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl ⁇ benzoate:
  • Step 3 intermediate 555 mg, 1.626 mmol
  • THF 10 mL
  • CDI 395 mg, 2.43 mmol
  • the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (2 x 50 mL), brine (50 mL) and dried over anhydrous Na 2 S0 4 .
  • the solvent was distilled out under reduced pressure and the residue thus obtained was purified by column chromatography to afford 250 mg of the title product as white solid.
  • Step 1 tert-Butyl 4-[(4-formyl-2-nitrophenyl)amino]benzoate:
  • step 1 intermediate (1 g, 2.92 mmol) in methanol (10 mL) was added sodium borohydride (143 mg, 3.79 mmol) at 0 °C and the reaction mixture was stirred at the same temperature for 30 minutes.
  • the reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated solution of ammonium chloride (50 mL) and brine (25 mL).
  • the solvent was distilled under reduced pressure and the residue thus obtained was purified by silica gel column chromatography to yield 750 mg of the product as off white solid.
  • Step 2 intermediate 200 mg, 0.580 mmol
  • DCM DCM
  • DHP 0.6 mL, 0.696 mmol
  • PTSA catalytic amount of PTSA
  • the reaction mixture was stirred at RT for 2h.
  • the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL).
  • the combined organic layers were washed with water (2 x 50 mL), brine (25 mL) and dried over anhydrous Na 2 S0 4 .
  • the solvent was distilled out under reduced pressure and the residue thus obtained was purified by column chromatography to afford 200 mg of the title product as off-white solid.
  • Step 4 tert-Butyl 4-[(2-amino-4- ⁇ [(tetrahydro-2H-pyran-2-yl)oxy]methyl ⁇ phenyl)amino]benzoate:
  • Step 3 intermediate 200 mg, 0.467 mmol
  • methanol 5 mL
  • catalytic amount of 10% palladium on carbon was added to the stirred solution of Step 3 intermediate (200 mg, 0.467 mmol) in methanol (5 mL)
  • the reaction mixture was filtered through celite and the filtrate was concentrated to yield 155 mg of the title product.
  • Step 5 fert-Butyl 4-(2-oxo-5- ⁇ [(tetrahydro-2H-pyran-2-yl)oxy]methyl ⁇ -2,3-dihydro-lH- benzo[d]imidazol- 1 -yl)benzoate:
  • Step 4 intermediate 150 mg, 0.376
  • THF 1, 1-carbodiimidazole
  • CD I 1-carbodiimidazole
  • the reaction mixture was stirred at the same temperature for 1 hour.
  • the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL).
  • the combined organic layers were washed with water (2 x 25 mL), brine (25 mL) and dried over anhydrous Na 2 S0 4 .
  • the solvent was recovered under reduced pressure and the residue obtained was purified by column chromatography to afford 100 mg of the title product as off -white solid.
  • Step 1 tert-Butyl 3-fluoro-4-[(4-formyl-2-nitrophenyl)amino]benzoate
  • the title compound was prepared by the reaction of 4-bromo-3-nitrobenzaldehyde (1 g, 4.340 mmol) with tert-butyl 4-amino-3-fluorobenzoate (1 g, 4.78 mmol) in the presence of palladium acetate (48 mg, 0.217 mmol), XPhos (150 mg, 0.260 mmol) and cesium carbonate (2.12 g, 6.51 mmol) in 1,4-dioxane (20 mL) as per the process described in step 1 of Intermediate 14 to yield 1.4 g of the product as yellow solid.
  • step 1 intermediate 800 mg, 2.22 mmol
  • sodium borohydride 109 mg, 2.88 mmol
  • methanol 10 mL
  • Step 3 tert-Butyl 3-fluoro-4-[2-nitro-4-(tetrahydro-pyran-2-yloxymethyl)-phenylamino]- benzoate
  • Step 4 tert-Butyl 4-[2-amino-4-(tetrahydro-pyran-2-yloxymethyl)-phenylamino]-3-fluoro- benzoate
  • Step 5 tert-Butyl 3-fluoro-4-(2-oxo-5- ⁇ [(tetrahydro-2H-pyran-2-yl)oxy]methyl ⁇ -2,3-dihydro- lH-benzo[d]imidazol- 1 -yl)benzoate
  • step 4 intermediate was prepared by cyclization reaction of step 4 intermediate (475 mg, 1.141 mmol) in the presence of CDI (277 mg, 1.712 mmol) in THF (10 mL) as per the process described in step 5 of Intermediate 14 to yield 420 mg of the product as white solid.
  • Step 1 l-Fluoro-4-(l-methoxy-2-methylpropan-2-yl)benzene
  • Step 2 l-Fluoro-4-(l-methoxy-2-methylpropan-2-yl)-2-nitrobenzene
  • step 1 intermediate 300 mg, 1.650 mmol
  • cone, sulphuric acid 2.7 mL, 50.84 mmol
  • fuming nitric acid 0.3 mL, 6.75 mmol
  • the reaction mixture was poured in to crushed ice and extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with water (25 mL), brine (25 mL) and dried over anhydrous sodium sulfate.
  • Step 3 tert-Butyl 3-fluoro-4-[4-(2-methoxy-l,l-dimethyl-ethyl)-2-nitro-phenylamino]- benzoate
  • the title compound was synthesized by the reaction of step 2 intermediate (500 mg, 2.200 mmol) and tert-butyl 4-amino-3-fluorobenzoate (511 mg, 2.42 mmol) in the presence of sodium hydride (60% w/w, 132 mg, 3.30 mmol) in DMF (40 mL) as per the process described in step 1 of Intermediate 1 to yield 752 mg of the product as bright orange liquid.
  • Step 4 tert-Butyl 4-[2-amino-4-(2-methoxy-l, l-dimethyl-ethyl)-phenylamino]-3- fluorobenzoate
  • step 3 intermediate 746 mg, 1.780 mmol
  • methanol (10 mL) methanol (10 mL) as per the process described in step 2 of Intermediate 1 to yield 566 mg of the product as white solid.
  • Step 5 tert-Butyl 3-fluoro-4-[5-(2-methoxy-l, l-dimethyl-ethyl)-2-oxo-2,3-dihydro- benzoimidazol- 1 -yl]-benzoate
  • step 4 intermediate was synthesized by the reaction of step 4 intermediate (560 mg, 1.442 mmol) and CDI (351 mg, 2.16 mmol) in THF (20 mL) as per the process described in step 3 of Intermediate 1 to yield 522 mg of the product as off white solid.
  • Step 1 3-[(4-Iodo-3-nitrophenoxy)methyl]-3-methyloxetane
  • Step 2 tert-Butyl 3-fluoro-4-[4-(3-methyl-oxetan-3-ylmethoxy)-2-nitro-phenylamino] benzoate
  • step 1 intermediate (612 mg, 1.752 mmol) and tert-butyl 4-amino-3-fluorobenzoate (370 mg, 1.7529 mmol) in the presence of palladium acetate (39 mg, 0.1752 mmol), XPhos (121 mg, 0.210 mmol) and cesium carbonate (856 mg, 2.629 mmol) in 1,4-dioxane (10 mL) as per the process described in step 1 of Intermediate 2 to yield 692 mg of the title product as yellow solid.
  • Step 3 tert-Butyl 4-[2-amino-4-(3-methyl-oxetan-3-ylmethoxy)-phenylamino]-3- fluorobenzoate
  • step 2 intermediate was synthesized by the catalytic hydrogenation of step 2 intermediate (673 mg, 1.556 mmol) in methanol (10 mL) as per the process described in step 2 of Intermediate 1 to yield 463 mg of the product as off white solid.
  • Step 4 tert-Butyl 3-fluoro-4-[5-(3-methyl-oxetan-3-ylmethoxy)-2-oxo-2,3-dihydro- benzoimidazol-l-yl]-benzoate
  • step 3 intermediate 443 mg, 1.100 mmol
  • CDI 272 mg, 1.65 mmol
  • THF 10 mL
  • step 1 intermediate 500 mg, 1.746 mmol
  • methanol 10 mL
  • step 2 and 3 of Intermediate 1 respectively to yield 300 mg of the product as off white solid.
  • Step 1 4-[(2-Nitrophenyl)amino]benzonitrile
  • the title compound was prepared by the reaction of 4-aminobenzonitrile (1 g, 8.47 mmol) with l-fluoro-2-nitrobenzene (892 mg, 8.47 mmol) in the presence of sodium hydride (60% w/w, 406 mg, 10.16 mmol) in DMF (10 mL) as described in step 1 of Intermediate 1 to yield 810 mg of the product as off white solid.
  • Step 2 4-(2-Oxo-2,3 -dihydro- lH-benzimidazol-l-yl)benzonitrile
  • step 1 intermediate 800 mg, 3.344 mmol
  • methanol 10 mL
  • CDI 697 mg, 4.30 mmol
  • THF 10 mL
  • Step 1 N-Cyclopropyl-4-[(2-nitrophenyl)amino]benzenesulfonamide
  • the title compound was prepared by the reaction of l-iodo-2-nitrobenzene (495 mg, 1.987 mmol) with 4-amino-N-cyclopropylbenzenesulfonamide (600 mg, 2.204 mmol) in the presence of palladium acetate (45 mg, 0.198 mmol), XPhos (137 mg, 0.238 mmol) and cesium carbonate (1.95 g, 5.963 mmol) in 1,4-dioxane (15 mL) as per the process described in step 1 of Intermediate 2 to yield 230 mg of the product as yellow solid.
  • Step 2 N-Cyclopropyl-4-(2-oxo-2,3-dihydro-lH-benzimidazol-l-yl)benzenesulfonamide
  • step 1 intermediate 230 mg, 0.688 mmol
  • methanol 8 mL
  • step 2 N-Cyclopropyl-4-(2-oxo-2,3-dihydro-lH-benzimidazol-l-yl)benzenesulfonamide
  • Step 1 Ethyl propyl ⁇ 4-[(2-nitrop enyl)amino]phenyl ⁇ phosphonate
  • the title compound was prepared from l-iodo-2-nitro benzene (482 mg, 1.94 mmol) and diethyl (4-aminophenyl)phosphonate (370 mg, 1.614 mmol) in the presence of palladium acetate (36 mg, 0.161 mmol), XPhos (112 mg, 0.194 mmol) and cesium carbonate (789 mg, 2.42 mmol) in 1,4-dioxane (10 mL) as per the process described in step 1 of Intermediate 2 to yield 416 mg of the product as brown solid.
  • step 1 intermediate The title compound was prepared by the nitro reduction of step 1 intermediate (416 mg, 1.187 mmol) in the presence of iron powder (198 mg, 3.560 mmol) and ammonium chloride (663 mg, 11.875 mmol) in water (3.0 mL) and methanol (15 mL) as per the process described in step 2 of Intermediate 10 followed by cyclization of the diamine derivative (360 mg, 1.124 mmol) by using CDI (273 mg, 1.68 mmol) in THF (10 mL) to yield 300 mg of the product as off white solid.
  • Step 1 Ethyl 4-[(2-nitrophenyl)amino]benzoate:
  • Step 1 intermediate 300 mg, 1.048 mmol
  • methanol 10 mL
  • catalytic amount of 10% palladium on carbon was added to the stirred solution of Step 1 intermediate (300 mg, 1.048 mmol) in methanol (10 mL)
  • the reaction mixture was filtered through celite and the filtrate was concentrated to yield 200 mg of the product.
  • Step 3 Ethyl 4-[(2- ⁇ [(2,6-dichlorophenyl)carbonyl]amino ⁇ phenyl)amino] benzoate:
  • Step 2 intermediate 350 mg, 1.365 mmol
  • DCM DCM
  • DIPEA 1,3-dichlorobenzoyl chloride
  • the reaction mixture was stirred overnight at RT.
  • the reaction mixture was diluted with water (10 mL) and the precipitate thus obtained was filtered.
  • the obtained product was purified by silica gel column chromatography to yield 450 mg of the title product as off white solid.
  • Step 1 tert-Butyl 4-[3-(2,6-dichlorobenzoyl)-2-oxo-2,3-dihydro-lH-benzo [d]imidazol-l- yljbenzoate:
  • Step 2 4-[3-(2,6-Dichlorobenzoyl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl]benzoic acid:
  • Step 1 product 100 mg, 0.206 mmol
  • dichloromethane 3 mL
  • trifluoroacetic acid 3 mL
  • Step 1 tert-Butyl-4- ⁇ 3-[2-chloro-6-(trifluoromethyl)benzoyl]-2-oxo-2,3-dihydro-lH-benzo[d] imidazol- 1 -yl ⁇ -3 -fluorobenzoate
  • Step 2 4- ⁇ 3-[2-Chloro-6-(trifluoromethyl)benzoyl]-2-oxo-2,3-dihydro-lH-benzo[d] imidazol- l-yl ⁇ -3-fluorobenzoic acid
  • step 1 intermediate (1 10 mg, 0.205 mmol) in DCM (3 mL) was treated with TFA (1 mL) and the resulting mixture was stirred at RT for 4 hours.
  • the solvent and excess of reagent were removed under reduced pressure and the residue obtained was diluted with water (10 mL).
  • the aqueous mixture was extracted with ethyl acetate (2 x 10 mL).
  • the combined organic layers were washed with brine (10 mL) and dried over anhydrous sodium sulfate.
  • the solution was filtered and concentrated under reduced pressure.
  • the residue thus obtained was purified by silica gel column chromatography to obtain 25 mg of the title product as white solid.
  • Example 10 To a well stirred and cooled (0 °C) solution of Example 10 (60 mg, 0.125 mmol) in methanol (2 mL) was added IN aqueous solution of sodium hydroxide (0.13 mL, 0.125 mmol) and the reaction mixture was stirred at the same temperature for lh. The solvent was recovered under reduced pressure and the residue obtained was triturated with diethyl ether to yield 38 mg of the product as white solid.
  • Step 2 4-[3-(2-Chloro-6-cyclopropylbenzoyl)-7-fluoro-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl]-3-fluorobenzoic acid: To a well stirred and cooled (0 °C) solution of Step 1 intermediate (168 mg, 0.3200 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (2 mL) and the reaction mixture was stirred at RT for 3h. The solvents were recovered under reduced pressure and the residue obtained was washed with water, triturated with diethyl ether and dried to yield 54 mg of the title product as white solid.
  • Step 1 tert-Butyl 4-[3-(2-chloro-6-trifluoromethyl-benzoyl)-5-(2-methoxy-l, l-dimethyl- ethyl)-2-oxo-2,3-dihydro-benzoimidazol-l-yl]-3-fluorobenzoate
  • Step 2 4- ⁇ 3-(2-Chloro-6-trifluoromethyl-benzoyl)-5-(2-hydroxy-l, l-dimethyl-ethyl)-2-oxo- 2,3-dihydro-benzoimidazol-l-yl ⁇ -3-fluoro-benzoic acid
  • step 1 intermediate 72 mg, 0.1 16 mmol
  • DCM dimethylethyl sulfoxide
  • step 1 intermediate 72 mg, 0.1 16 mmol
  • DCM a solution of boron tribromide (1M in DCM, 1.2 mL) in DCM (5 mL).
  • the reaction mixture was allowed to warm up to RT and it was stirred for 1 hour at RT.
  • the reaction mixture was poured into crushed ice and extracted with ethyl acetate (2 x 10 mL).
  • the combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the residue thus obtained was purified by silica gel column chromatography to yield 23 mg of the title product as yellow solid.
  • Example 1 To a well stirred solution of Example 1 (80 mg, 0.187 mmol) in DMSO (3 mL) were added BOP (124 mg, 0.281 mmol) and ammonium chloride (100 mg, 1.877 mmol) followed by DIPEA (0.01 mL, 0.563 mmol) and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with water (10 mL) and the precipitate thus obtained was filtered. The obtained product was purified by silica gel column chromatography to yield 20 mg of the title product as white solid.
  • Example 1 To a well stirred and cooled (0 °C) solution of Example 1 (100 mg, 0.234 mmol) in DMF (5 mL) were added EDCI (69 mg, 0.351 mmol) and DMAP (9 mg, 0.070 mmol) and the reaction mixture was stirred for 10 minutes. Cyclopropylamine (100 mL, 0.234 mmol) was added to the reaction mixture and it was stirred at RT overnight. The reaction mixture was diluted with water (10 mL) and the precipitate obtained was filtered and purified by silica gel column chromatography to yield 21 mg of the title product as white solid.
  • Example 39 To a well stirred solution of Example 39 (168 mg, 0.411 mmol) in DMF (5 mL) were added sodium azide (34 mg, 0.534 mmol) and ammonium chloride (28 mg, 0.534 mmol) and the reaction mixture was heated at 80 °C overnight. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with water (3 x 25 mL), brine (25 mL) and dried over anhydrous Na 2 S0 4 . The solvent was distilled off under reduced pressure. The residue obtained was purified by column chromatography to afford 60 mg of the title product as white solid. 1H NMR (300 MHz,
  • Step 1 4- ⁇ 3-[(2,6-Dichlorophenyl)carbonyl]-2-oxo-2,3-dihydro-lH-benzimidazol-l-yl ⁇ -N- hydroxy benzenecarboximidamide:
  • Example 39 To a well stirred solution of Example 39 (100 mg, 0.244 mmol) in dry DMSO (3 mL) was added hydroxylamine hydrochloride (63 mg, 0.906 mmol) followed by DIPEA (0.15 mL, 0.906 mmol) and the reaction mixture was heated at 80 °C overnight. The reaction mixture was diluted with water and the precipitate thus obtained was filtered and dried to obtain 65 mg of the title product as white solid. APCI-MS (m/z) 441 (M) + .
  • Step 2 3- ⁇ 4-[3-(2,6-Dichlorobenzoyl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl]phenyl ⁇ - l,2,4-oxadiazol-5(4H)-one: To the well stirred solution of Step 1 intermediate (65 mg, 0.147 mmol) in dry DMF (2 mL) was added CDI (36 mg, 0.220 mmol) and the reaction mixture was heated at 80 °C overnight. The reaction mixture was diluted with water (25 mL) and product was extracted in ethyl acetate (2 x 100 mL).
  • Example 1 to yield 10 mg of the product as white solid.
  • Step 1 Ethyl 4-(3-(2,6-dichlorobenzoyl)-2-methyl-2,3-dihydro-lH-benzo[d] imidazol-1- yl)benzoate:
  • Step 2 4-[3-(2,6-Dichlorobenzoyl)-2-methyl-2,3-dihydro-lH-benzo[d]imidazol-l-yl] benzoic acid:
  • Step 1 intermediate 100 mg, 0.219 mmol
  • methanol (2 mL) and water (1 mL) lithium hydroxide (27 mg, 0.658 mmol)
  • the reaction mixture was stirred at RT for 2 h.
  • the reaction mixture was diluted with water (20 mL) and acidified by using IN HC1.
  • the product was extracted with ethyl acetate (2 x 20 ml) and the layers were separated.
  • the combined organic layers were washed with water (2 x 20 mL), brine (20 mL) and dried over anhydrous Na 2 S0 4 .
  • the solvent was removed under reduced pressure.
  • the residue thus obtained was purified by column chromatography to afford 60 mg of the title product as off-white solid.
  • 1H NMR 300 MHz,
  • 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 were dissolved in dimethylsulfoxide (DMSO) to prepare 10.0 mM stock solution and diluted suitably to get the desired concentration. Final concentration of DMSO in the reaction was 4% (v/v).
  • Assay mixture was prepared by mixing ⁇ 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 lhr.
  • the pre-incubation step was terminated by addition of the detection mixture containing 300nM Fluorescein-D22 co-activator peptide and ⁇ lantha screen Tb-anti GST antibody into the reaction mixture. After shaking for 5 minutes the reaction was further incubated for 2 hr at room temperature and read the next day at 4°C on an Infinite F500 reader as per the kit instructions (Invitrogen). The inhibition of test compound is calculated based on the TR-FRET ratio of 520/495. The activity was calculated as a percent of control reaction. IC 50 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 ⁇ and 10.0 ⁇ are given in the table along with IC 50 (nM) details for selected examples. The compounds prepared were tested using the above assay procedure and were found to have IC 50 less than 500nM, preferably less than lOOnM or more preferably less than 50nM.
  • IC 50 (nM) values of the compounds are set forth in Table 1 wherein "A” refers to an IC 50 value of less than 50 nM, “B” refers to IC 50 value in range of 50.01 to 100.0 nM and “C” refers to IC 50 values more than 100 nM.
  • Example 30 0 1.8 -
  • Example 31 36.01 38.47 -
  • Example 35 0.00 8.52 -
  • Example 36 11.02 10.42 -
  • Example 37 0.57 12.64 -
  • Example 39 0.08 6.02 -
  • Example 43 0.0 17.70 -

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation de composés de formule (I) et de leurs sels pharmaceutiquement acceptables comme modulateur du récepteur orphelin apparenté au récepteur des rétinoïdes gamma t (RORyt). Ces composés préviennent, inhibent ou suppriment l'action du RORγt et sont donc utiles pour traiter les maladies, les troubles, les syndromes ou les pathologies associés au RORγt tels que la douleur, l'inflammation, la BPCO, l'asthme, la polyarthrite rhumatoïde, la colite, la sclérose en plaques, les maladies neurodégénératives ou le cancer.
PCT/IB2014/065175 2013-10-10 2014-10-09 Utilisation de composés substitués dihydro-benzimidazole comme modulateurs du ror gamma WO2015052675A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
SG11201604755QA SG11201604755QA (en) 2013-10-10 2014-10-09 Substituted dihydro-benzimidazole compounds as ror gamma modulators
CA2933618A CA2933618A1 (fr) 2013-10-10 2014-10-09 Utilisation de composes substitues dihydro-benzimidazole comme modulateurs du ror gamma

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3207MU2013 2013-10-10
IN3207/MUM/2013 2013-10-10

Publications (1)

Publication Number Publication Date
WO2015052675A1 true WO2015052675A1 (fr) 2015-04-16

Family

ID=52812568

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2014/065175 WO2015052675A1 (fr) 2013-10-10 2014-10-09 Utilisation de composés substitués dihydro-benzimidazole comme modulateurs du ror gamma

Country Status (3)

Country Link
CA (1) CA2933618A1 (fr)
SG (1) SG11201604755QA (fr)
WO (1) WO2015052675A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015139619A1 (fr) * 2014-03-18 2015-09-24 北京韩美药品有限公司 Composé servant de modulateur rorγ
CN107721930A (zh) * 2017-09-28 2018-02-23 湖南天济草堂制药股份有限公司 取代的1‑(2‑氟苯基)‑3‑（3‑丙基己基）脲类化合物、药物组合物及用途
WO2020054788A1 (fr) * 2018-09-13 2020-03-19 キッセイ薬品工業株式会社 Composé d'imidazopyridinone
CN112939961A (zh) * 2019-12-10 2021-06-11 上海挚盟医药科技有限公司 一类具有神经保护作用的化合物及其制备方法和用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1958947A1 (fr) * 2007-02-15 2008-08-20 Ranbaxy Laboratories Limited Inhibiteurs de la phosphodiestérase de type 4
WO2012027965A1 (fr) * 2010-09-01 2012-03-08 Glaxo Group Limited Nouveaux composés
WO2012100734A1 (fr) * 2011-01-24 2012-08-02 Glaxo Group Limited Composés utiles en tant que modulateurs du récepteur apparenté au récepteur des rétinoïdes gamma
WO2012131501A1 (fr) * 2011-03-28 2012-10-04 Glenmark Pharmaceuticals S.A. Composés benzimidazole substitués en tant qu'inhibiteurs de la kinase cot
WO2013171729A2 (fr) * 2013-01-08 2013-11-21 Glenmark Pharmaceuticals S.A. Composés d'aryl- et hétéroarylamide en tant que modulateur de rorγt

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1958947A1 (fr) * 2007-02-15 2008-08-20 Ranbaxy Laboratories Limited Inhibiteurs de la phosphodiestérase de type 4
WO2012027965A1 (fr) * 2010-09-01 2012-03-08 Glaxo Group Limited Nouveaux composés
WO2012100734A1 (fr) * 2011-01-24 2012-08-02 Glaxo Group Limited Composés utiles en tant que modulateurs du récepteur apparenté au récepteur des rétinoïdes gamma
WO2012131501A1 (fr) * 2011-03-28 2012-10-04 Glenmark Pharmaceuticals S.A. Composés benzimidazole substitués en tant qu'inhibiteurs de la kinase cot
WO2013171729A2 (fr) * 2013-01-08 2013-11-21 Glenmark Pharmaceuticals S.A. Composés d'aryl- et hétéroarylamide en tant que modulateur de rorγt

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015139619A1 (fr) * 2014-03-18 2015-09-24 北京韩美药品有限公司 Composé servant de modulateur rorγ
CN107721930A (zh) * 2017-09-28 2018-02-23 湖南天济草堂制药股份有限公司 取代的1‑(2‑氟苯基)‑3‑（3‑丙基己基）脲类化合物、药物组合物及用途
WO2020054788A1 (fr) * 2018-09-13 2020-03-19 キッセイ薬品工業株式会社 Composé d'imidazopyridinone
CN112939961A (zh) * 2019-12-10 2021-06-11 上海挚盟医药科技有限公司 一类具有神经保护作用的化合物及其制备方法和用途
CN114829359A (zh) * 2019-12-10 2022-07-29 上海挚盟医药科技有限公司 一类具有神经保护作用的化合物及其制备方法和用途
CN112939961B (zh) * 2019-12-10 2023-04-14 上海挚盟医药科技有限公司 一类具有神经保护作用的化合物及其制备方法和用途

Also Published As

Publication number Publication date
CA2933618A1 (fr) 2015-04-16
SG11201604755QA (en) 2016-07-28

Similar Documents

Publication Publication Date Title
US9718817B2 (en) Aryl and heteroaryl ether compounds as ROR gamma modulators
US9682977B2 (en) Bicyclic heteroaryl indole analogues useful as ROR gamma modulators
KR102229608B1 (ko) Ror 감마 조절제로서의 신규한 화합물
US20200339577A1 (en) 1-substituted 1,2,3,4-tetrahydro-1,7-naphthyridin-8-amine derivatives and their use as ep4 receptor antagonists
TWI582077B (zh) 作爲ＩＬ－１２、ＩＬ－２３及／或ＩＦＮα反應調節劑之經烷基－醯胺取代之吡啶化合物
WO2015008234A1 (fr) Composés hétécycliques bicycliques utilisés en tant que modulateurs des ror-gamma
EP2683693A1 (fr) Inhibiteurs de rorgammat
WO2014026327A1 (fr) Composés d'acide benzoïque à substitution 4-hétéroaryle en tant qu'inhibiteurs de rorgammat et leurs utilisations
CA2881699A1 (fr) Composes 3-aminocycloalkyl utilises en tant qu'inhibiteurs de rorgammat et utilisations de ceux-ci
WO2013072825A1 (fr) Dérivés de phtalazinone en tant qu'inhibiteurs de mpges-1
WO2018116285A1 (fr) Dérivés de morpholine substitués en tant que modulateurs de ror gamma
WO2015052675A1 (fr) Utilisation de composés substitués dihydro-benzimidazole comme modulateurs du ror gamma
KR20110052741A (ko) 신규한 벤즈이미다졸 유도체
WO2017051319A1 (fr) Composés éther d'aryle et éther d'hétéroaryle en tant que modulateurs de ror gamma
KR20180002796A (ko) 시클로프로판 카르복실산 유도체 및 이의 의약 용도
JP2009518356A (ja) Ｖｒ１受容体のアンタゴニストとして有用なクロモン誘導体
WO2012131501A1 (fr) Composés benzimidazole substitués en tant qu'inhibiteurs de la kinase cot
CN111278814A (zh) 作为毒蕈碱m1受体正向别构调节剂的多环酰胺
EP3448855A1 (fr) Composés de pyrimidinone fusionnés substitués
WO2018185675A1 (fr) Analogues d'oxoazétidine substitués en tant que modulateurs de ror gamma
CN116438162A (zh) Mas相关g蛋白受体x4的调节剂及相关产物和方法
WO2012090179A2 (fr) Dérivés d'isoquinoline en tant que modulateurs des récepteurs cannabinoïdes
EP3131880A1 (fr) Composés éther d'aryle et éther d'hétéroaryle en tant que modulateurs de ror gamma
KR20160095139A (ko) Ror 감마 조절인자로서 유용한 2환식 헤테로아릴 인돌 유사체

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14851682

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2933618

Country of ref document: CA

122 Ep: pct application non-entry in european phase

Ref document number: 14851682

Country of ref document: EP

Kind code of ref document: A1