WO2013072825A1 - Dérivés de phtalazinone en tant qu'inhibiteurs de mpges-1 - Google Patents

Dérivés de phtalazinone en tant qu'inhibiteurs de mpges-1 Download PDF

Info

Publication number
WO2013072825A1
WO2013072825A1 PCT/IB2012/056285 IB2012056285W WO2013072825A1 WO 2013072825 A1 WO2013072825 A1 WO 2013072825A1 IB 2012056285 W IB2012056285 W IB 2012056285W WO 2013072825 A1 WO2013072825 A1 WO 2013072825A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
chloro
dihydrophthalazin
oxo
Prior art date
Application number
PCT/IB2012/056285
Other languages
English (en)
Inventor
Laxmikant Atmaram Gharat
Abhisek Banerjee
Neelima Khairatkar-Joshi
Vidya Ganapati Kattige
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.
Publication of WO2013072825A1 publication Critical patent/WO2013072825A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • 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
    • C07D403/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present patent application is directed to bicyclic compounds which may be useful as microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors.
  • mPGES-1 microsomal prostaglandin E synthase-1
  • Inflammatory diseases that affect the population include asthma, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, rhinitis, conjunctivitis and dermatitis. Inflammation is also a common cause of pain.
  • COX cyclooxygenase
  • PGE 2 is particularly known to be a strong proinflammatory mediator, and is also known to induce fever and pain. Consequently, numerous drugs have been developed with a view to inhibiting the formation of PGE 2 , including "NSAIDs” (non-steroidal anti-inflammatory drugs) and “coxibs” (selective COX-2 inhibitors). These drugs act predominantly by inhibition of COX-1 and/or COX-2, thereby reducing the formation of PGE 2 .
  • NSAIDs non-steroidal anti-inflammatory drugs
  • coxibs selective COX-2 inhibitors
  • drugs which act by inhibition of COXs are therefore known / suspected to cause adverse biological effects.
  • the non-selective inhibition of COXs by NSAIDs may give rise to gastrointestinal side-effects and affect platelet and renal function.
  • Even the selective inhibition of COX-2 by coxibs, whilst reducing such gastrointestinal side-effects, is believed to give rise to cardiovascular problems.
  • PGE 2 A combination of pharmacological, genetic and neutralizing antibody approaches demonstrates the importance of PGE 2 in inflammation.
  • the conversion of PGH 2 to PGE 2 by prostaglandin E synthases (PGES) may therefore represent a pivotal step in the propagation of inflammatory stimuli.
  • Microsomal prostaglandin E synthase- 1 (mPGES-1) is an inducible PGES after exposure to pro-inflammatory stimuli.
  • mPGES-1 is induced in the periphery and CNS by inflammation and represents therefore a target for acute and chronic inflammatory disorders.
  • PGE 2 is a major prostanoid, produced from arachidonic acid liberated by phospholipases (PLAs), which drives the inflammatory processes.
  • Arachidonic acid is transformed by the action of prostaglandin H synthase (PGH synthase, cycloxygenase) into PGH 2 which is a substrate for mPGES-1, which is the terminal enzyme transforming PGH 2 to the pro-inflammatory PGE 2 .
  • PGH synthase prostaglandin H synthase
  • PGH 2 may be transformed to PGE 2 by prostaglandin E synthases (PGES).
  • PGES prostaglandin E synthases
  • mPGES-1 and mPGES-2 microsomal prostaglandin E synthases
  • cPGES cytosolic prostaglandin E synthase
  • agents that are capable of inhibiting the action of mPGES-1, and thus reducing the formation of the specific arachidonic acid metabolite PGE 2 are likely to be of benefit in the treatment of inflammation.
  • agents that are capable of inhibiting the action of the proteins involved in the synthesis of the leukotrienes are also likely to be of benefit in the treatment of asthma and COPD.
  • PGE 2 is involved in malignant growth. PGE 2 facilitates tumour progression by stimulation of cellular proliferation and angiogenesis and by modulation of immunosupression. In support of a role for PGE 2 in cancers, genetic deletion of mPGES-1 in mice suppresses the intestinal tumourogenesis (Nakanishi et. al., Cancer Research 2008, 68(9), 3251-9). In human beings, mPGES-1 is also upregulated in cancers such as colorectal cancer ⁇ Schroder Journal of Lipid Research 2006, 47, 1071-80).
  • Myositis is chronic muscle disorder characterized by muscle weakness and fatigue. Proinflammatory cytokines and prostanoids have been implicated in the development of myositis. In skeletal muscle tissue from patients suffering from myositis an increase in cyclooxygenases and mPGES-1 has been demonstrated, implicating mPGES-1 as a target for treating this condition. (Korotkova Annals of the Rheumatic Diseases 2008, 67, 1596- 1602).
  • Atherosclerosis inflammation of the vasculature leads to atheroma formation that eventually may progress into infarction.
  • carotid atherosclerosis an increase in mPGES-1 in plaque regions have been reported (Gomez -Hernandez Atherosclerosis 2006,187, 139-49).
  • mice lacking the mPGES-1 receptor were found to show a retarded atherogenesis and a concomitant reduction in macrophage-derived foam cells together with an increase in vascular smooth muscle cells (Wang, Proceedings of National Academy of Sciences 2006, 103(39), 14507-12).
  • the present application is directed to compounds that may be inhibitors of the mPGES-1 enzyme and would therefore be useful for the treatment of pain and inflammation in a variety of diseases or conditions.
  • A is selected from C 6 -i 4 aryl, 5-14 membered heteroaryl and 3-15 membered heterocyclyl;
  • G 1 , G 2 and G 3 which may be same or different, are independently selected from nitrogen and CR 3 ;
  • L is a bond or selected from -(CR x R y ) n NR x -, -(CR x R y ) n C(0)NR x -, -(CR x R y ) n C(0)0-, - (CR x R y ) n NR x C(0)-, -(CR x R y ) n NR x C(0)NR y -, -(CR x R y ) n NR x C(0)0-, -(CR x R y ) n NR x S0 2 -, - (CR x R y ) n OC(0)-, -(CR x R y ) n OC(0)0-, -(CR x R y ) n OC(0)NR x -, -(CR x R y ) n S(0)-, - (CR x R y ) n S0 2 -, -(CR
  • W is selected from hydrogen, substituted or unsubstituted Ci_ 8 alkyl, substituted or unsubstituted C 2 _ioalkenyl, substituted or unsubstituted C 2 _ioalkynyl, substituted or unsubstituted Ci.galkoxyCi.galkyl, substituted or unsubstituted haloCi_galkyl, substituted or unsubstituted hydroxyCi_galkyl, substituted or unsubstituted C 3 _i 2 cycloalkyl, substituted or unsubstituted C 3 _ 8 cycloalkenyl, substituted or unsubstituted C 6 _i 4 aryl, substituted or unsubstituted 3 to 15 membered heterocyclyl, and substituted or unsubstituted 5 to 14 membered heteroaryl;
  • R 1 is selected from hydrogen, substituted or unsubstituted Ci_galkyl, substituted or unsubstituted C 2 _ioalkenyl, substituted or unsubstituted C 2 _ioalkynyl, substituted or unsubstituted Ci_ 8 alkoxyCi_ 8 alkyl, substituted or unsubstituted haloCi_ 8 alkyl, substituted or unsubstituted hydroxyCi_ 8 alkyl, substituted or unsubstituted C 3 -i 2 cycloalkyl, substituted or unsubstituted C 3 _ 8 cycloalkylCi_ 8 alkyl, substituted or unsubstituted C 3 _ 8 cycloalkenyl, substituted or unsubstituted C 3 _ 8 cycloalkenylCi_ 8 alkyl, substituted or unsubstituted C 6 -i 4 aryl, substituted or unsubstituted
  • R 2 and R 3 are independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, substituted or unsubstituted Ci_ 8alkyl, substituted or unsubstituted C 2 _ioalkenyl, substituted or unsubstituted C 2 _ioalkynyl, substituted or unsubstituted Ci_ 8 alkoxy, substituted or unsubstituted Ci_ 8 alkoxyCi_ 8 alkyl, substituted or unsubstituted haloCi_ 8 alkyl, substituted or unsubstituted haloCi_ 8 alkoxy, substituted or unsubstituted hydroxyCi_ 8 alkyl, substituted or unsubstituted C 3 _i 2 cycloalkyl, substituted or unsubstituted C 3 _ 8 cycloalkylCi_ 8 alkyl, substituted or unsubstituted C 3 _i 2 cycloalkyl, substitute
  • R 4 is selected from halogen, nitro, cyano, hydroxyl, substituted or unsubstituted Ci_ 8 alkyl, substituted or unsubstituted C 2 _i 0 alkenyl, substituted or unsubstituted C 2 _i 0 alkynyl, substituted or unsubstituted Ci_ 8 alkoxy, substituted or unsubstituted Ci_ galkoxyCi.galkyl, substituted or unsubstituted haloCi_ 8 alkyl, substituted or unsubstituted haloCi.galkoxy, substituted or unsubstituted hydroxyCi_galkyl, substituted or unsubstituted C 3 _ i 2 cycloalkyl, substituted or unsubstituted C 3 _gcycloalkylCi_galkyl, substituted or unsubstituted C 3 _ 8 cycloalkenyl, substituted or unsubd or unsubsti
  • R a and R b which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted Ci_ 8 alkyl, substituted or unsubstituted Ci_ 8 alkoxyCi_ 8 alkyl, substituted or unsubstituted haloCi_ 8 alkyl, substituted or unsubstituted hydroxyCi_ 8 alkyl, substituted or unsubstituted C 3 _i 2 cycloalkyl, substituted or unsubstituted C 3 _ 8 cycloalkylCi_ 8 alkyl, substituted or unsubstituted C 6 -i 4 aryl, substituted or unsubstituted C 6 _ i 4 arylCi_ 8 alkyl, substituted or unsubstituted 3-15 membered heterocyclyl, substituted or unsubstituted 3-15 membered heterocyclylCi_ 8 alkyl, substituted or unsubstituted
  • R x and R y which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted Ci_ 8 alkyl, substituted or unsubstituted Ci_ 8 alkoxyCi_ 8 alkyl, substituted or unsubstituted haloCi_ 8 alkyl, substituted or unsubstituted hydroxyCi_ 8 alkyl, substituted or unsubstituted C 3 _i 2 cycloalkyl, substituted or unsubstituted C 3 _ 8 cycloalkylCi_ 8 alkyl, substituted or unsubstituted C 6 -i 4 aryl, substituted or unsubstituted C 6 _ i 4 arylCi_ 8 alkyl, substituted or unsubstituted 3-15 membered heterocyclyl, substituted or unsubstituted 3-15 membered heterocyclylCi_ 8 alkyl, substituted or unsubstituted or unsubstit
  • 'm' is an integer ranging from 0 to 4, both inclusive;
  • 'n' is an integer ranging from 0 to 6, both inclusive.
  • the compounds of formula (I) may involve one or more embodiments.
  • Embodiments of formula (I) include compounds of formula (II) and (III), 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 R 2 is hydrogen (according to an embodiment defined below) and R 3 is hydrogen (according to another embodiment defined below).
  • R 1 is hydrogen, substituted or unsubstituted Ci.galkyl (e.g. methyl, isopropyl, hexyl), substituted or unsubstituted haloCi_ 8 alkyl (e.g. 2,2,2-trifluoroethyl), substituted or unsubstituted C 3 _i 2 cycloalkyl (e.g. cyclobutyl, cyclohexyl, 4,4- dimethylcyclohexyl, ( 15 , ,45 , )-4-(trifluoromethyl)cyclohexyl, ( 1 r,4r)-4-
  • (trifluoromethyl)cyclohexyl substituted or unsubstituted C 3 - 8 cycloalkylCi_galkyl (e.g. cyclopropylmethyl, cyclohexylmethyl) or substituted or unsubstituted C 6 _i 4 aryl (e.g. 4- (trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4- fluorophenyl, 2,4-difluorophenyl, 4-isopropylphenyl, 4-bromophenyl).
  • C 3 - 8 cycloalkylCi_galkyl e.g. cyclopropylmethyl, cyclohexylmethyl
  • C 6 _i 4 aryl e.g. 4- (trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 2-fluorophenyl, 3
  • R 1 is substituted or unsubstituted Ci.galkyl, preferably unsubstituted Ci_ 6 alkyl (e.g. methyl, isopropyl, hexyl).
  • R 1 is substituted or unsubstituted haloCi_ 8 alkyl, preferably unsubstituted haloCi_ 4 alkyl (e.g. 2,2,2-trifluoroethyl).
  • R 1 is substituted or unsubstituted C 3 _i 2 cycloalkyl, preferably substituted or unsubstituted C 3 _ 6 cycloalkyl (e.g. cyclohexyl, cyclobutyl).
  • substituent(s) on C 3 _i 2 cycloalkyl or C 3 _ 6 cycloalkyl may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci_ 4 alkyl (e.g. methyl) and haloCi.galkyl (e.g. trifluoromethy 1) .
  • R 1 is cyclobutyl or cyclohexyl optionally substituted with one or more substituents independently selected from halogen (e.g. F, CI or Br), Ci_ 4 alkyl (e.g. methyl) and haloCi_ 8 alkyl (e.g. trifluoromethy 1).
  • halogen e.g. F, CI or Br
  • Ci_ 4 alkyl e.g. methyl
  • haloCi_ 8 alkyl e.g. trifluoromethy 1).
  • R 1 is substituted or unsubstituted C 3 _8CycloalkylCi_galkyl, preferably C 3 _
  • cycloalkylCi_ 4 alkyl e.g. cyclopropylmethyl, cyclohexylmethyl.
  • R 1 is substituted or unsubstituted C6 -14 aryl, preferably substituted or unsubstituted phenyl, more preferably substituted phenyl.
  • substituent(s) on phenyl may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci_ 4 alkyl (e.g. methyl, isopropyl) and haloCi-salkyl (e.g. trifluoromethy 1).
  • halogen e.g. F, CI or Br
  • Ci_ 4 alkyl e.g. methyl, isopropyl
  • haloCi-salkyl e.g. trifluoromethy 1).
  • R 1 is phenyl optionally substituted with one or more substituents selected from halogen (e.g. F, CI or Br), Ci_ 4 alkyl (e.g. methyl, isopropyl) and haloCi.galkyl (e.g. trifluoromethy 1) .
  • halogen e.g. F, CI or Br
  • Ci_ 4 alkyl e.g. methyl, isopropyl
  • haloCi.galkyl e.g. trifluoromethy 1 .
  • R 1 is hydrogen, methyl, isopropyl, hexyl, 2,2,2-trifluoroethyl, cyclobutyl, cyclohexyl, 4,4-dimethylcyclohexyl, (l5',45')-4-(trifluoromethyl)cyclohexyl, (lr,4r)-4-(trifluoromethyl)cyclohexyl, cyclopropylmethyl, cyclohexylmethyl, 4-
  • R 4 is halogen (e.g. F, CI or Br), Ci_ 4 alkyl (e.g. methyl) or Ci.galkoxy (e.g. methoxy).
  • R 4 is CI, F, CH 3 or OCH 3 .
  • L is a bond and W is substituted or unsubstituted hydroxyC i.galkyl (e.g. 3-hydroxy-3-methylbutyl, 2-hydroxypropan-2-yl) or substituted or unsubstituted 5 to 14 membered heteroaryl (e.g. 5 -methyl- lH-pyrazol-3-yl, lH-l,2,3-triazol-4-yl).
  • W is substituted or unsubstituted hydroxyC i.galkyl (e.g. 3-hydroxy-3-methylbutyl, 2-hydroxypropan-2-yl) or substituted or unsubstituted 5 to 14 membered heteroaryl (e.g. 5 -methyl- lH-pyrazol-3-yl, lH-l,2,3-triazol-4-yl).
  • R x and R y are independently selected from hydrogen, Ci_ 4 alkyl (e.g. methyl) and n is 1 or 2.
  • compounds of formula (I) in which W is hydrogen, substituted or unsubstituted Ci_ 8 alkyl (e.g. methyl, tert- butyl, isopropyl), substituted or unsubstituted C 3 _i 2 cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted 3-15 membered heterocyclyl (e.g. 3-oxabicyclo[3.1.0]hexane)
  • W is hydrogen, methyl, tert-butyl, isopropyl, cyclopropyl or 3- oxabicyclo[3.1.0]hexanyl.
  • 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 mPGES-1 activity.
  • the invention also provides a compound of formula (II), which is an embodiment of a compound of formula (I).
  • Q 1 , Q 2 , Q 3 and Q 4 are selected from N, CH and CR 4 , with a proviso that Q 2 , Q 3 and Q 4 are not N simultaneously;
  • L is a bond or selected from -(CR x R y ) n NR x -, -(CR x R y ) n C(0)NR x -, and -
  • W is selected from hydrogen, substituted or unsubstituted Ci.galkyl, substituted or unsubstituted Ci_galkoxyCi_galkyl, substituted or unsubstituted haloCi_galkyl, substituted or unsubstituted hydroxyCi_ 8 alkyl, substituted or unsubstituted C 3 _i 2 cycloalkyl, substituted or unsubstituted C6 -14 aryl, substituted or unsubstituted 3 to 15 membered heterocyclyl, and substituted or unsubstituted 5 to 14 membered heteroaryl; with a proviso that when L is a bond then W is hydroxyCi_ 8 alkyl or 5 to 14 membered heteroaryl;
  • R 1 is selected from substituted or unsubstituted Ci_ 8 alkyl, substituted or unsubstituted Ci-galkoxyCi.galkyl, substituted or unsubstituted haloCi_ 8 alkyl, substituted or unsubstituted hydroxyCi.galkyl, substituted or unsubstituted C 3 _i 2 cycloalkyl, substituted or unsubstituted C 3 _ gcycloalkylCi_ 8 alkyl, substituted or unsubstituted C 6 _i 4 aryl, substituted or unsubstituted C 6 _ i 4 arylCi_ 8 alkyl, substituted or unsubstituted 3-15 membered heterocyclyl, substituted or unsubstituted 3-15 membered heterocyclylCi_ 8 alkyl, substituted or unsubstituted 5-14 membered heteroaryl and substituted or unsubstituted 5-14 membered hetero
  • R x and R y which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted Ci_ 8 alkyl, substituted or unsubstituted C 3 _ i 2 cycloalkyl, substituted or unsubstituted C 6 -i 4 aryl and substituted or unsubstituted C 6 _i 4 arylCi_ 8 alkyl; and
  • 'n' is an integer ranging from 1 to 6, both inclusive.
  • the compounds of formula (II) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, or 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 (II) as defined above wherein Q 2 is N or CH (according to an embodiment defined below), Q 3 is CH (according to another embodiment defined below) and Q 4 is CH or CR 4 (according to an embodiment defined below).
  • R 1 is substituted or unsubstituted Ci_ 8 alkyl (e.g. methyl, isopropyl, hexyl), substituted or unsubstituted haloCi_ 8 alkyl (e.g. 2,2,2-trifluoroethyl), substituted or unsubstituted C 3 _ i 2 cycloalkyl (e.g.
  • cyclobutyl cyclohexyl, 4,4-dimethylcyclohexyl, (ls,4s)-4- (trifluoromethyl)cyclohexyl, (lr,4r)-4-(trifluoromethyl)cyclohexyl), substituted or unsubstituted C 3 _ 8 cycloalkylCi_ 8 alkyl (e.g. cyclopropylmethyl, cyclohexylmethyl) or substituted or unsubstituted C 6 _i 4 aryl (e.g.
  • R 1 is substituted or unsubstituted Ci.galkyl, preferably unsubstituted Ci_ 6 alkyl
  • R 1 is substituted or unsubstituted haloCi.galkyl, preferably unsubstituted haloCi_ 4 alkyl (e.g. 2,2,2-trifluoroethyl).
  • R 1 is substituted or unsubstituted C 3 _i 2 cycloalkyl, preferably substituted or unsubstituted C 3 _ 6 cycloalkyl (e.g. cyclohexyl, cyclobutyl).
  • substituent(s) on C 3 _i 2 cycloalkyl or C 3 _ 6 cycloalkyl may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci_ 4 alkyl (e.g. methyl) and haloCi.galkyl (e.g. trifluoromethy 1) .
  • R 1 is cyclobutyl or cyclohexyl optionally substituted with one or more substituents independently selected from halogen (e.g. F, CI or Br), Ci_ 4 alkyl (e.g. methyl) and haloCi_ 8 alkyl (e.g. trifluoromethy 1).
  • halogen e.g. F, CI or Br
  • Ci_ 4 alkyl e.g. methyl
  • haloCi_ 8 alkyl e.g. trifluoromethy 1).
  • R 1 is substituted or unsubstituted C 3 _ 8 cycloalkylCi_ 8 alkyl, preferably C 3 _
  • CycloalkylCi_ 4 alkyl e.g. cyclopropylmethyl, cyclohexylmethyl.
  • R 1 is substituted or unsubstituted C6 -14 aryl, preferably substituted or unsubstituted phenyl, more preferably substituted phenyl.
  • substituent(s) on phenyl may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci_ 4 alkyl
  • haloCi.galkyl e.g. trifluoromethy 1).
  • R 1 is phenyl optionally substituted with one or more substituents selected from halogen (e.g. F, CI or Br), Ci_ 4 alkyl (e.g. methyl, isopropyl) and haloCi.galkyl
  • halogen e.g. F, CI or Br
  • Ci_ 4 alkyl e.g. methyl, isopropyl
  • R 1 is methyl, isopropyl, hexyl, 2,2,2-trifluoroethyl, cyclobutyl, cyclohexyl, 4,4-dimethylcyclo hexyl, ( ⁇ -(trifluoromethy ⁇ cyclohexyl, (lr,4r)-4- (trifluoromethyl)cyclohexyl, cyclopropylmethyl, cyclohexylmethyl, 4- (trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4- fluorophenyl, 2,4-difluorophenyl or 4-isopropylphenyl.
  • R 4 is halogen (e.g. F, CI or Br), Ci_ 4 alkyl (e.g. methyl) or Ci.galkoxy (e.g. methoxy).
  • R 4 is CI, F, CH 3 or OCH 3 .
  • hydroxyCi.galkyl e.g. 3-hydroxy-3-methylbutyl, 2-hydroxypropan-2-yl
  • substituted or unsubstituted 5 to 14 membered heteroaryl e.g. 5 -methyl- lH-pyrazol-3-yl, lH-l ,2,3-triazol-4-yl.
  • R x and R y are independently selected from hydrogen, Ci_ 4 alkyl (e.g. methyl) and n is 1 or 2.
  • W is hydrogen, substituted or unsubstituted Ci.galkyl (e.g. methyl, tert- butyl, isopropyl), substituted or unsubstituted C 3 -i 2 cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted 3-15 membered heterocyclyl (e.g. 3-oxabicyclo[3.1.0]hexane)
  • Ci.galkyl e.g. methyl, tert- butyl, isopropyl
  • C 3 -i 2 cycloalkyl e.g. cyclopropyl
  • substituted or unsubstituted 3-15 membered heterocyclyl e.g. 3-oxabicyclo[3.1.0]hexane
  • the invention also provides a compound of formula (III), which is an embodiment of a compound of formula (I).
  • W is selected from hydrogen, substituted or unsubstituted Ci_ 8 alkyl, substituted or unsubstituted C 3 _i 2 cycloalkyl and substituted or unsubstituted 3 to 15 membered heterocyclyl;
  • R 1 is selected from substituted or unsubstituted Ci_ 8 alkyl, substituted or unsubstituted Ci-galkoxyCi.galkyl, substituted or unsubstituted haloCi_ 8 alkyl, substituted or unsubstituted hydroxyCi.galkyl, substituted or unsubstituted C 3 _i 2 cycloalkyl, substituted or unsubstituted C 3 _ gcycloalkylCi_ 8 alkyl, substituted or unsubstituted C 6 _i 4 aryl, substituted or unsubstituted C 6 _ i 4 arylCi_ 8 alkyl, substituted or unsubstituted 3-15 membered heterocyclyl and substituted or unsubstituted 5-14 membered heteroaryl;
  • R 4 is selected from halogen, cyano, hydroxyl, substituted or unsubstituted Ci_ 8 alkyl, substituted or unsubstituted Ci_ 8 alkoxy, substituted or unsubstituted Ci_ 8 alkoxyCi_ 8 alkyl, substituted or unsubstituted haloCi_ 8 alkyl and substituted or unsubstituted hydroxyCi_ 8 alkyl;
  • R x is selected from hydrogen or substituted or unsubstituted Ci_ 8 alkyl
  • 'm' is an integer ranging from 0 to 4, both inclusive;
  • 'n' is an integer ranging from 1 to 4, both inclusive;
  • the compounds of formula (III) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.
  • the invention provides compounds of formula (III) as defined above wherein n is 1 (according to an embodiment defined below) and R x is hydrogen or methyl (according to another embodiment defined below).
  • R 1 is substituted or unsubstituted Ci_ 8 alkyl (e.g. methyl, isopropyl, hexyl), substituted or unsubstituted haloCi_ 8 alkyl (e.g. 2,2,2-trifluoroethyl), substituted or unsubstituted C 3 -i 2 cycloalkyl (e.g.
  • cyclobutyl cyclohexyl, 4,4-dimethylcyclohexyl, (ls,4s)-4- (trifluoromethyl)cyclohexyl, (lr,4r)-4-(trifluoromethyl)cyclohexyl), substituted or unsubstituted C 3 _ 8 cycloalkylCi_ 8 alkyl (e.g. cyclopropylmethyl, cyclohexylmethyl) or substituted or unsubstituted C 6 -i 4 aryl (e.g.
  • R 1 is substituted or unsubstituted Ci_galkyl, preferably unsubstituted Ci_ 6 alkyl (e.g. methyl, isopropyl, hexyl).
  • R 1 is substituted or unsubstituted haloCi.galkyl, preferably unsubstituted haloCi_ 4 alkyl (e.g. 2,2,2-trifluoroethyl).
  • R 1 is substituted or unsubstituted C 3 -i 2 cycloalkyl, preferably substituted or unsubstituted C 3 - 6 cycloalkyl (e.g. cyclohexyl, cyclobutyl).
  • substituent(s) on C 3 _i 2 cycloalkyl or C 3 - 6 cycloalkyl may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci_ 4 alkyl (e.g. methyl) and haloCi_ 8 alkyl (e.g. trifluoromethy 1) .
  • R 1 is cyclobutyl or cyclohexyl optionally substituted with one or more substituents independently selected from halogen (e.g. F, CI or Br), Ci_ 4 alkyl (e.g. methyl) and haloCi_galkyl (e.g. trifluoromethy 1).
  • halogen e.g. F, CI or Br
  • Ci_ 4 alkyl e.g. methyl
  • haloCi_galkyl e.g. trifluoromethy 1).
  • R 1 is substituted cyclohexyl and substituent(s) are independently selected from methyl and trifluoromethy 1.
  • R 1 is substituted or unsubstituted C 3 _ 8 cycloalkylCi_ 8 alkyl, preferably
  • C 3 _ 6 cycloalkylCi_ 4 alkyl e.g. cyclopropylmethyl, cyclohexylmethyl.
  • R 1 is substituted or unsubstituted C 6 -i 4 aryl, preferably substituted or unsubstituted phenyl, more preferably substituted phenyl.
  • substituent(s) on phenyl may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci_ 4 alkyl
  • haloCi.galkyl e.g. trifluoromethy 1).
  • R 1 is phenyl optionally substituted with one or more substituents selected from halogen (e.g. F, CI or Br), Ci_ 4 alkyl (e.g. methyl, isopropyl) and haloCi.galkyl
  • halogen e.g. F, CI or Br
  • Ci_ 4 alkyl e.g. methyl, isopropyl
  • R 1 is substituted phenyl and substituent(s) are independently selected from fluoro, methyl, isopropyl and trifluoromethyl.
  • R 1 is methyl, isopropyl, hexyl, 2,2,2-trifluoroethyl, cyclobutyl, cyclohexyl, 4,4-dimethylcyclo hexyl, ( ⁇ -(trifluoromethy ⁇ cyclohexyl, (lr,4r)-4- (trifluoromethyl)cyclohexyl, cyclopropylmethyl, cyclohexylmethyl, 4-
  • R 4 is halogen (e.g. F, CI or Br), Ci_ 4 alkyl (e.g. methyl) or Ci_ 8 alkoxy (e.g. methoxy).
  • R 4 is CI, F, CH 3 or OCH 3 .
  • R x is hydrogen or Ci_ 4 alkyl (e.g. methyl).
  • W is substituted or unsubstituted Ci.galkyl (e.g. iert-butyl, isopropyl), substituted or unsubstituted C 3 _i 2 cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted 3- 15 membered heterocyclyl (e.g. 3-oxabicyclo[3.1.0]hexane).
  • the present application also provides a pharmaceutical composition that includes at least one compound described herein and at least one pharmaceutically acceptable excipients (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 mPGES-1 , which is believed to be related to a variety of disease states.
  • the present patent application further provides a method of inhibiting mPGES-1 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
  • 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.galkyl), and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1 ,1-dimethylethyl (t- butyl).
  • Ci_ 6 alkyl refers to an alkyl chain having 1 to 6 carbon atoms.
  • 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. C 2 _ioalkenyl) and including at least one carbon-carbon double bond.
  • alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), z ' sopropenyl, 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. C2_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 .
  • all alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkoxyalkyl refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above (i.e. Ci.galkoxyCi.galkyl or Ci_ 8 alkyloxyCi_galkyl).
  • 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-salkyl).
  • 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_galkoxy).
  • 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.
  • hydroxy alkyl 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 moiety 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, for example C 3 _i 2 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl.
  • C 3 _6cycloalkyl 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, for example 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, cyclobutylethyl, and cyclopentylethyl. 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, for example C 3 _gcycloalkenyl, such as cyclopropenyl, cyclobutenyl, and cyclop entenyl. 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, for example 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). Examples of aryloxy moiety 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 substituted or unsubstituted non-aromatic 3 to 15 membered ring radical which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • heterocyclic ring or heterocyclyl may optionally contain one or more olefmic 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, oxadiazolyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl,
  • 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. 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 to substituted or unsubstituted
  • 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, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazol
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group (i.e. heterarylCi-salkyl).
  • 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. Unless set forth or recited to the contrary, 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, methylsulf
  • 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 term "acute pain” is usually self-limiting. The sensation of pain can be triggered by any number of physical or chemical stimuli and the sensory neurons which mediate the response to this harmful stimulus are termed as “nociceptors”.
  • Nociceptors are primary sensory afferent (C and ⁇ fibers) neurons that are activated by a wide variety of noxious stimuli including chemical, mechanical, thermal, and proton (pH ⁇ 6) modalities.
  • Nociceptors are the nerves which sense and respond to parts of the body which suffer from damage. They signal tissue irritation, impending injury, or actual injury. When activated, they transmit pain signals (via the peripheral nerves as well as the spinal cord) to the brain.
  • chronic pain usually refers to pain which persists for 3 months or longer and can lead to significant changes in a patient's personality; lifestyle, functional ability and overall quality of life.
  • Chronic pain can be classified as either nociceptive or neuropathic.
  • Nociceptive pain includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis.
  • Neuropathic pain is caused by damage to the sensory nerves of the peripheral or central nervous system and is maintained by aberrant somatosensory processing. The pain is typically well localized, constant, and often with an aching or throbbing quality.
  • Visceral pain is the subtype of nociceptive pain that involves the internal organs. It tends to be episodic and poorly localized.
  • Nociceptive pain is usually time limited, meaning when the tissue damage heals, the pain typically resolves (arthritis is a notable exception in that it is not time limited).
  • the compound described in the present patent application may form salts.
  • Non- limiting examples of pharmaceutically acceptable salts forming part of this patent application include salts derived from inorganic bases salts of organic bases salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids.
  • Certain compounds of present patent application are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers). With respect to the overall compounds described by the general formula (I) the present patent application extends to these stereoisomeric forms and to mixtures thereof.
  • 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, viscosifying 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, flavoring 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.
  • Compounds of the present invention are particularly useful because they may selectively inhibit the activity of prostaglandin E synthases ⁇ and particularly microsomal prostaglandin E synthase-1 (mPGES-1) ⁇ , i.e., they prevent the action of mPGES-1 or a complex of which the mPGES-1 enzyme forms a part, and/or may elicit mPGES-1 modulating effect.
  • Compounds of the invention may thus be useful in the treatment of those conditions in which inhibition of a PGES, and particularly mPGES-1, is required.
  • 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, such as those mentioned hereinbefore, 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.
  • 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 invention, inflammatory pain, pain generally and/or fever.
  • the compounds of the present invention may also be useful in the treatment of asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritable bowel syndrome, inflammatory pain, chronic pain, acute pain, fever, migraine, headache, low back pain, fibromyalgia, myofascial disorders, viral infections (e.g. influenza, common cold, herpes zoster, hepatitis C and AIDS), bacterial infections, fungal infections, dysmenorrhea, burns, surgical or dental procedures, malignancies (e.g. influenza, common cold, herpes zoster, hepatitis C and AIDS), bacterial infections, fungal infections, dysmenorrhea, burns, surgical or dental procedures, malignancies (e.g.
  • hyperprostaglandin E syndrome classic Bartter syndrome, atherosclerosis, gout, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, juvenile onset rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, Hodgkin's disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, ulceris, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes mellitus, neurodegenerative disorders such as Alzheimer's disease and multiple sclerosis, autoimmune diseases, allergic disorders, rhinitis, ulcers, mild to moderately active ulcerative colitis, familial adenomatous polyposis, coronary heart disease, sarcoidosis and any other disease with an inflammatory
  • Compounds of the invention may also have effects that are not linked to inflammatory mechanisms, such as in the reduction of bone loss in a subject.
  • Conditions that may be mentioned in this regard include osteoporosis, osteoarthritis, Paget's disease and/or periodontal diseases.
  • the compounds of Formula (I), (II) or (III) are useful for the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, migraine (acute and prophylactic treatment), toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, juvenile rheumatoid arthritis, degenerative joint diseases (osteoarthritis), acute gout and ankylosing spondylitis, acute, subacute and chronic musculoskeletal pain syndromes such as bursitis, burns, injuries, and pain following surgical (post-operative pain) and dental procedures as well as the preemptive treatment of surgical pain.
  • the pain may be mild pain, moderate pain, severe pain, musculoskeletal pain, complex regional pain syndrome, neuropathic pain, back pain such as acute visceral pain, neuropathies, acute trauma, chemotherapy - induced mononeuropathy pain states, polyneuropathy pain states (such as diabetic peripheral neuropathy & chemotherapy induced neuropathy), autonomic neuropathy pain states, pheriphaeral nervous system (PNS) lesion or central nervous system (CNS) lesion or disease related pain states, polyradiculopathies of cervical, lumbar or sciatica type, cauda equina syndrome, piriformis syndrome, paraplegia, quadriplegia, pain states related to various Polyneuritis conditions underlying various infections, chemical injuries, radiation exposure, underlying disease or deficiency conditions (such as beriberi, vitamin deficiencies, hypothyroidism, porphyria, cancer, HIV, autoimmune disease like multiple sclerosis and spinal-cord injury, fibromyalgia, nerve injury, ischaemia, neurode
  • Such a compound may inhibit cellular neoplastic transformations and metastic tumour growth and hence can be used in the treatment of cancer.
  • Compounds of Formula (I), (II) or (III) may also be useful for the treatment or prevention of endometriosis, hemophilic arthropathy and Parkinson's disease.
  • Compounds of Formula (I), (II) or (III) will also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of dysmenorrhea, premature labor and asthma.
  • the cancer includes Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adolescents Cancer, Adrenocortical Carcinoma, Anal Cancer, Appendix Cancer, Astrocytomas, Atypical Teratoid, Basal Cell Carcinoma, Bile Duct Cancer, Extrahepatic, Bladder Cancer, Bone Cancer, Brain Stem Glioma, Brain Tumor, Breast Cancer, Bronchial Tumors, Burkitt Lymphoma, Carcinoid Tumor, Carcinoma of Unknown Primary, Cardiac (Heart) Tumors, Central Nervous System tumors, Cervical Cancer, Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Chronic Myeloproliferative Disorders, Colon Cancer, Colorectal Cancer, Craniopharyngio
  • Compounds of the 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 reaction can be performed with a suitable coupling reagent known to those skilled in the art for example, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) in a suitable solvent such as dimethylformamide (DMF) or tetrahydrofuran (THF) in the temperature range of 0-120°C, optionally in the presence of a suitable base such as N,N-diisoporpylethylamine (DIPEA).
  • a suitable coupling reagent known to those skilled in the art for example, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) in a suitable solvent such as dimethylformamide (DMF) or tetrahydrofuran (THF) in the temperature range of 0-120°C, optionally in the presence of a suitable base such as N,N-diisoporpylethylamine (DIPEA).
  • the reaction can be performed using a suitable reagent such as isobutyl chloroformate, oxalyl chloride or thionyl chloride in a suitable solvent such as DMF, DCM or THF, in the presence of a suitable base such as DIPEA.
  • a suitable reagent such as isobutyl chloroformate, oxalyl chloride or thionyl chloride in a suitable solvent such as DMF, DCM or THF, in the presence of a suitable base such as DIPEA.
  • a suitable solvent such as DMF, DCM or THF
  • a suitable base such as DIPEA
  • the reaction can be performed with a suitable reagent such as trimethylaluminium or a strong base such as sodium hydride (NaH) in a suitable solvent such as toluene or DMF.
  • a suitable reagent such as trimethylaluminium or a strong base such as sodium hydride (NaH) in a suitable solvent such as toluene or DMF.
  • the reaction can be performed with a suitable coupling reagent known to those skilled in the art for example, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) in a suitable solvent such as dimethylformamide (DMF) or tetrahydrofuran (THF) in the temperature range of 0-120°C, optionally in the presence of a suitable base such as N,N-diisoporpylethylamine (DIPEA).
  • a suitable coupling reagent known to those skilled in the art for example, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) in a suitable solvent such as dimethylformamide (DMF) or tetrahydrofuran (THF) in the temperature range of 0-120°C, optionally in the presence of a suitable base such as N,N-diisoporpylethylamine (DIPEA).
  • the reaction can be performed using a suitable reagent such as isobutyl chloroformate, oxalyl chloride or thionyl chloride in a suitable solvent such as DMF, DCM or THF, in the presence of a suitable base such as DIPEA.
  • a suitable reagent such as isobutyl chloroformate, oxalyl chloride or thionyl chloride in a suitable solvent such as DMF, DCM or THF, in the presence of a suitable base such as DIPEA.
  • a suitable solvent such as DMF or THF in the temperature range of 0-120°C, optionally in the presence of a suitable base such as DIPEA.
  • the reaction can be performed with a suitable reagent such as trimethylaluminium or a strong base such as sodium hydride (NaH) in a suitable solvent such as toluene or DMF.
  • a suitable reagent such as trimethylaluminium or a strong base such as sodium hydride (NaH) in a suitable solvent such as toluene or DMF.
  • the reaction can be performed with a suitable coupling reagent known to those skilled in the art for example, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) in a suitable solvent such as dimethylformamide (DMF) or tetrahydrofuran (THF) in the temperature range of 0-120°C, optionally in the presence of a suitable base such as N,N-diisoporpylethylamine (DIPEA).
  • a suitable coupling reagent known to those skilled in the art for example, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) in a suitable solvent such as dimethylformamide (DMF) or tetrahydrofuran (THF) in the temperature range of 0-120°C, optionally in the presence of a suitable base such as N,N-diisoporpylethylamine (DIPEA).
  • the reaction can be performed using a suitable reagent such as isobutyl chloroformate, oxalyl chloride or thionyl chloride in a suitable solvent such as DMF, DCM or THF, in the presence of a suitable base such as DIPEA.
  • a suitable reagent such as isobutyl chloroformate, oxalyl chloride or thionyl chloride in a suitable solvent such as DMF, DCM or THF, in the presence of a suitable base such as DIPEA.
  • a suitable solvent such as DMF or THF in the temperature range of 0-120°C, optionally in the presence of a suitable base such as DIPEA.
  • the reaction can be performed with a suitable reagent such as trimethylaluminium or a strong base such as sodium hydride (NaH) in a suitable solvent such as toluene or DMF.
  • a suitable reagent such as trimethylaluminium or a strong base such as sodium hydride (NaH) in a suitable solvent such as toluene or DMF.
  • the synthesis of the compound of formula (3) can be performed as described in synthetic scheme 5.
  • the reaction of the phthalide compound (10) with the appropriate nitrating agent such as potassium nitrate or cone, nitric acid in cone, sulphuric acid or acetic acid in the temperature range -10 to 100°C can provide the compound of formula (11).
  • the bromination of the compound of formula (11) with appropriate brominating agent such as N-bromosuccinimide and azobisisobutyronitrile in a suitable solvent such as carbon tetrachloride in the temperature range 0-150°C can provide the compound of formula (12).
  • reaction of the compound of formula (12) under acidic conditions provides an intermediate which upon reaction with an appropriate hydrazine of formula (13) can provide the compound of formula (14).
  • reaction of the compound of formula (12) under acidic conditions with hydrazine hydrate can provide the phthalazine derivative, which can then be appropriately substituted under the conditions known to those skilled in the art or disclosed herein to provide the compound of formula (14).
  • the nitro group of the compound of formula (14) can be reduced to provide the compound of formula (3) under the conditions known to those skilled in the art such as using iron powder in presence of ammonium chloride or hydrochloric acid in a suitable solvent such as methanol or ethanol in the temperature range 0-100°C.
  • 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 (Na 2 S0 4 ), filtration and evaporation of the solvent under reduced pressure.
  • Purification includes purification by silica gel chromatographic techniques, in suitable solvents of a suitable polarity as the mobile phase.
  • DMSO- ⁇ i6 Hexadeuterodimethyl sulfoxide; CDC1 3 : deuterated chloroform; DMSO: dimethyl sulfoxide; DMF: N,N- Dimethylformamide; DMA: dimethylacetamide; DCM: dichloromethane; DIPEA: N,N- diisopropylethylamine; EDCI: l-ethyl-3-(3-dimethylaminopropyl)carbodiimide); HOBt: hydroxybenzotriazole; /: Coupling constant in units of Hz; RT or rt: room temperature (22- 26°C); aq.: aqueous; equiv. or eq.: equivalents; cone. : concentrated; i.e. : that is; h : hours; /: coupling constant in units of Hz.
  • Step 1 Preparation of 7-nitro-2- -(trifluoromethyl)phenyl)phthalazin-l(2H)-one
  • Step 1 Preparation of 2-chloro-5- ⁇ [(trifluoroacetyl)amino]methyl ⁇ benzoic acid: To a solution of 2-chloro benzoic acid (500 mg, 3.49 mmol) in cone. H 2 S0 4 (3 mL) was added 2,2,2-trifluoro-N-(hydroxymethyl)acetamide (547 mg, 3.49 mmol). The mixture was stirred at rt for 16 h. The reaction mixture was poured into ice-water and stirred for 2 h. The precipitate was collected by filtration. The filter cake was re-crystallized from toulene:butan- 2-one (7: 1) to afford 800 mg of the title product.
  • Step 2 Preparation of methyl 2-chloro-5-((2,2,2-trifluoro-N- methylacetamido)methyl)benzoate
  • Step 4 Preparation of methyl 5-(((iert-butoxycarbonyl)(methyl)amino)methyl)-2- chlorobenzoate
  • Step 5 Preparation of methyl 2-chloro-5-((N-methylpivalamido)methyl)benzoate
  • Step 1 Preparation of 5- ⁇ [(iert-butoxycarbonyl)amino]methyl ⁇ -2-chlorobenzoic acid
  • Step 2 Preparation of methyl 5-(((iert-butoxycarbonyl)amino)methyl)-2-chlorobenzoate
  • Step 1 Preparation of 2-cyclohexyl- -nitrophthalazin-l(2H)-one
  • Step 1 Preparation of 2-chloro-5 -(5 -methyl- 1 H-pyrazol-3 -yl)benzohydrazide
  • Step 2 Preparation of ethyl 2-chloro-5 -(5 -methyl- 1 H-pyrazol-3 -yl)benzoate
  • Step 3 Preparation of 7-amino-2-(cyclopropylmethyl)phthalazin-l(2H)-one
  • Step 1 Preparation of methyl 5-(3-(iert-butoxy)-3-oxoprop-l-en-l-yl)-2-chlorobenzoate
  • Step 2 Preparation of methyl 5-(3-(iert-butoxy)-3-oxopropyl)-2-chlorobenzoate
  • Step 3 Preparation of 3-(4-chloro-3-(methoxycarbonyl)phenyl)propanoic acid
  • Step 4 Preparation of methyl 5-(3-amino-3-oxopropyl)-2-chlorobenzoate
  • Step 2 Preparation of 7-amino-2-methylphthalazin-l(2H)-one
  • the title compound was prepared following the procedure described in Step 2 of Intermediate-2 using 2-methyl-7-nitrophthalazin-l(2H)-one (150 mg, 0.73 mmol), iron powder (326 mg, 5.85 mmol) and ammonium chloride (387 mg, 7.31 mmol) in EtOH (3 mL) and water (1 mL) to afford 120 mg of the title product.
  • 1H NMR 300 MHz, DMSO-d 6 ): ⁇ 8.05 (s, 1H), 7.55 (m, 1H), 7.25 (s, 1H), 7.07 (m, 1H), 6.23 (br s, 2H), 3.63 (s, 3H).
  • Step 1 Preparation of 7-nitro-2-(2,2,2-trifluoroethyl)phthalazin-l(2H)-one
  • Step 2 Preparation of 7-amino-2-(2,2,2-trifluoroethyl)phthalazin-l(2H)-one
  • the title compound was prepared following the procedure described in Step 2 of lntermediate-2 using 7-nitro-2-(2,2,2-trifluoroethyl)phthalazin-l(2H)-one (300 mg, 0.804 mmol), iron powder (360 mg, 6.432 mmol) and ammonium chloride (426 mg, 8.04 mmol) in EtOH (4 mL) and water (1 mL) to afford 255 mg of the title product.
  • Step 1 Preparation of 7-nitro-2-(3-(trifluoromethyl)phenyl)phthalazin-l(2H)-one
  • Step 1 Preparation of 2-(2,4-diflu rophenyl)-7-nitrophthalazin-l(2H)-one
  • Step 1 Preparation of 2-fluoro-5-((2,2,2-trifluoroacetamido)methyl)benzoic acid
  • Step 3 Preparation of methyl 5-(( iert-butoxycarbonyl)amino)methyl)-2-fluorobenzoate
  • Step 1 Preparation of 2-(4-isopropylphenyl)-7-nitrophthalazin-l(2H)-one
  • Step 1 Preparation of 2-methyl-5-((2,2,2-trifluoroacetamido)methyl)benzoic acid
  • Step 3 Preparation of methyl 5-(( iert-butoxycarbonyl)amino)methyl)-2-methylbenzoate
  • Step 1 Preparation of methyl 2,5-dichloroisonicotinate 3
  • Step 5 Preparation of methyl 2-(((iert-butoxycarbonyl)amino)methyl)-5-chloroisonicotinate
  • Step 1 Preparation of ethyl 3-(aminomethyl)-6-chloro-2-fluorobenzoate
  • Step 2 Preparation of ethyl 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoate
  • Step 1 Preparation of ethyl 3-chloro-6-iodopicolinate
  • Step 3 Preparation of ethyl 6-(((iert-butoxycarbonyl)amino)methyl)-3-chloropicolinate
  • Step 4 Preparation of ethyl 3-chloro-6-(pivalamidomethyl)picolinate
  • Step 1 Preparation of ( R ⁇ -ethyl 2-o -3-oxabicyclo[3.1.0]hexane-l-carboxylate
  • Step 2 Preparation of ( S ⁇ -ethyl l ,2-bis(hydroxymethyl)cyclopropanecarboxylate
  • Step 5 Preparation of methyl 5-(((15 , ,55 , )-3-oxabicyclo[3.1.0]hexane-l-carboxamido)methyl)- 2-chlorobenzoate
  • Step 1 Preparation of 2,6-dimeth l-3-((2,2,2-trifluoroacetamido)methyl)benzoic acid
  • Step 1 Preparation of 7-nitro-2- -(trifluoromethyl)cyclohexyl)phthalazin-l(2H)-one
  • Step 2 Preparation of 7-amino-2-((l5 , ,45 , )-4-(trifluoromethyl)cyclohexyl)phthalazin-l(2H)- one and 7-amino-2-(( 1 r,4r)-4-(trifluoromethyl)cyclohexyl)phthalazin- 1 (2H)-one
  • Step 1 Preparation of 5-(aminomethyl)-2-chloro-N-(4-oxo-3-(4-(trifiuoromethyl)phi dihydrophthalazin-6-yl)benzamide
  • Step 2 Preparation of 2-chloro-N-(4-oxo-3-(4-(trifluoromethyl)phenyl)-3,4- dihydrophthalazin-6-yl)-5-(pivalamidomethyl)benzamide
  • the title compound was prepared following the procedure described in Example-2 using 7- aminophthalazin-l(2H)-one (Intermediate- 15, 90 mg, 0.56 mmol), methyl 2-chloro-5- (pivalamidomethyl)benzoate (Intermediate-5, 167 mg, 0.56 mmol) and Me 3 Al (0.5 mL, 2M solution in toluene) in toluene (2 mL) to afford 25 mg of the title product.
  • the title compound was prepared following the procedure described in Example-2 using 7- amino-2-cyclobutylphthalazin-l(2H)-one (Intermediate- 16, 80 mg, 0.37 mmol), methyl 2- chloro-5-(pivalamidomethyl)benzoate (Intermediate-5, 1 1 1 mg, 0.37 mmol) and Me 3 Al (0.5 mL, 2M solution in toluene) in toluene (1.5 mL) to afford 19 mg of the title product.
  • the title compound was prepared following the procedure described in Example-2 using 7- amino-2-(4-fiuorophenyl)phthalazin-l(2H)-one (Intermediate- 18, 80 mg, 0.380 mmol), methyl 2-chloro-5-(pivalamidomethyl)benzoate (Intermediate-5, 162 mg, 0.457 mmol) and Me 3 Al (0.5 mL, 2M solution in toluene) in toluene (1.5 mL) to afford 25 mg of the title product.
  • the title compound was prepared following the procedure described in Example-2 using 7- amino-2-(3-(trifluoromethyl)phenyl)phthalazin-l(2H)-one (Intermediate-20, 50 mg, 0.163 mmol), methyl 2-chloro-5-(pivalamidomethyl)benzoate (Intermediate-5, 51 mg, 0.180 mmol) and Me 3 Al (0.5 mL, 2M solution in toluene) in toluene (0.5 mL) to afford 27 mg of the title product.
  • the title compound was prepared following the procedure described in Example-2 using 7- amino-2-(2,4-difluorophenyl)phthalazin-l(2H)-one (Intermediate-21 , 100 mg, 0.366 mmol), methyl 2-chloro-5-(pivalamidomethyl)benzoate (Intermediate-5, 124 mg, 0.439 mmol) and Me 3 Al (0.5 mL, 2M solution in toluene) in toluene (1.5 mL) to afford 26 mg of the title product.
  • the title compound was prepared following the procedure described in Example-2 using 7- amino-2-(3-fluorophenyl)phthalazin-l(2H)-one (Intermediate-23, 80 mg, 0.380 mmol), methyl 2-chloro-5-(pivalamidomethyl)benzoate (Intermediate-5, 162 mg, 0.457 mmol) and Me 3 Al (0.5 mL, 2M solution in toluene) in toluene (1.5 mL) to afford 23 mg of the title product.
  • the title compound was prepared following the procedure described in Example-2 using 7- amino-2-(4-isopropylphenyl)phthalazin-l(2H)-one (Intermediate-25, 80 mg, 0.286 mmol), methyl 2-chloro-5-(pivalamidomethyl)benzoate (Intermediate-5, 97 mg, 0.344 mmol) and Me 3 Al (0.5 mL, 2M solution in toluene) in toluene (1 mL) to afford 23 mg of the title product.
  • the title compound was prepared following the procedure described in Example-2 using 7- amino-2-(3-(trifluoromethyl)phenyl)phthalazin-l(2H)-one (Intermediate-20, 70 mg, 0.229 mmol), methyl 5-chloro-2-(pivalamidomethyl)isonicotinate (Intermediate-29, 65 mg, 0.229 mmol) and Me 3 Al (0.5 mL, 2M solution in toluene) in toluene (1 mL) to afford 26 mg of the title product.
  • the title compound was prepared following the procedure described in Example-2 using 7- amino-2-(4-(trifluoromethyl)phenyl)phthalazin-l(2H)-one (Intermediate-3, 136 mg, 0.537 mmol), methyl 2-chloro-5 -(3 -hydroxy-3 -methylbut- l-yn-l-yl)benzoate (Intermediate-27, 163 mg, 0.537 mmol) and Me 3 Al (0.5 mL, 2M solution in toluene) in toluene (2 mL) at rt to afford 100 mg of the title product.
  • Step 2 -Preparation of 2-chloro-5 -(3 -hydroxy-3 -methylbutyl)-N-(4-oxo-3 -(4- (trifluoromethyl) phenyl)-3 ,4-dihydrophthalazin-6-yl)benzamide
  • the title compound was prepared following the procedure described in Example-2 using 7- amino-2-(3-fluorophenyl)phthalazin-l(2H)-one (Intermediate -23, 100 mg, 0.392 mmol), ethyl 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoate (lntermediate-30, 124 mg, 0.392 mmol) and Me 3 Al (0.5 mL, 2M solution in toluene) in toluene (1.5 mL) to afford 25 mg of the title product.
  • the title compound was prepared following the procedure described in Example-2 using 7- amino-2-(3-fluorophenyl)phthalazin-l(2H)-one (Intermediate-23, 1 10 mg, 0.49 mmol), ethyl 3-chloro-6-(pivalamidomethyl)picolinate (Intermediate-31 , 134 mg, 0.49 mmol) and Me 3 Al (0.5 mL, 2M solution in toluene) in toluene (2 mL) to afford 10 mg of the title product.
  • the title compound was prepared following the procedure described in Example-2 using 7- amino-2-(3-(trifluoromethyl)phenyl)phthalazin-l(2H)-one (Intermediate-20, 50 mg, 0.164 mmol), ethyl 3-chloro-6-(pivalamidomethyl)picolinate (Intermediate-31 , 46 mg, 0.164 mmol) and Me 3 Al (0.5 mL, 2M solution in toluene) in toluene (1 mL) to afford 25 mg of the title product.
  • the concentrate was dissolved in CH 2 C1 2 (1 mL) and was added to a solution of 7-amino-2-(4,4- dimethylcyclohexyl)phthalazin-l(2H)-one (Intermediate-33, 80 mg, 0.276 mmol) in CH 2 C1 2 (2 mL) and DIPEA (95 mg, 0.736 mmol) at 0 °C.
  • the reaction mass was stirred at rt for 2 h before it was quenched with water and was extracted with chloroform. The organic layer was separated, dried, filtered, and concentrated. The residue was purified by column chromatography to afford 41 mg of the title product.
  • Step 1 Preparation of iert-butyl 4-chloro-3-((3-(4,4-dimethylcyclohexyl)-4- dihydrophthalazin-6-yl)carbamoyl)benzylcarbamate
  • the title compound was prepared following the procedure described in Example-34 using 7- amino-2-(4,4-dimethylcyclohexyl)phthalazin-l(2H)-one (Intermediate-33, 160 mg, 0.148 mmol) and 5- ⁇ [(ieri-butoxycarbonyl)amino]methyl ⁇ -2-chlorobenzoic acid (Intermediate-5, step-1, 252 mg, 0.885 mmol), oxalyl chloride (223 mg, 1.77 mmol), and DIPEA (57 mg, 0.444 mmol) in CH 2 C1 2 (3 mL) to afford 80 mg of the title product.
  • Step 2 Preparation of 2-chloro-5-(cyclopropanecarboxamidomethyl)-N-(3-(4,4- dimethylcyclohexyl)-4-oxo-3,4-dihydrophthalazin-6-yl)benzamide
  • the title compound was prepared following the procedure described in Example-34 using 7- amino-2-(4,4-dimethylcyclohexyl)phthalazin-l(2H)-one (Intermediate-33, 118 mg, 0.435 mmol) and 2,6-dimethyl-3-(pivalamidomethyl)benzoic acid (Intermediate-35, 229 mg, 0.87 mmol), oxalyl chloride (219 mg, 1.74 mmol), and DIPEA (169 mg, 1.31 mmol) in CH 2 C1 2 (5 mL) to afford 10 mg of the title product.
  • the title compound was prepared following the procedure described in Example-34 using 7- amino-2-(( 1 r,4r)-4-(trifluoromethyl)cyclohexyl)phthalazin- 1 (2H)-one (Intermediate-37, 60 mg, 0.192 mmol) and 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-38, 77 mg, 0.289 mmol), oxalyl chloride (73 mg, 0.578 mmol), and DIPEA (74 mg, 0.576 mmol) in CH 2 C1 2 (2 mL) to afford 23 mg of the title product.
  • the title compound was prepared following the procedure described in Example-34 using 7- amino-2-((l5',45')-4-(trifluoromethyl)cyclohexyl)phthalazin-l(2H)-one (Intermediate-36, 80 mg, 0.257 mmol) and 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-38, 103 mg, 0.385 mmol), oxalyl chloride (97 mg, 0.77 mmol), and DIPEA (100 mg, 0.77 mmol) in CH2CI2 (3 mL) to afford 17 mg of the title product.
  • the title compound was prepared following the procedure described in Example-34 using 7- amino-2-(4,4-dimethylcyclohexyl)phthalazin-l(2H)-one (Intermediate-33, 90 mg, 0.332 mmol) and 6-chloro-2-methoxy-3-(pivalamidomethyl)benzoic acid (Intermediate-39, 149 mg, 0.498 mmol), oxalyl chloride (125 mg, 0.996 mmol), and DIPEA (128 mg, 0.996 mmol) in CH 2 C1 2 (2 mL) to afford 32 mg of the title product.
  • mPGES-1 microsomal prostaglandin E synthase-1
  • PGH 2 prostaglandin H 2
  • product PGE 2 prostaglandin E 2
  • GSH reduced glutathione
  • mPGES-1 inhibitors were screened by assessing their ability to inhibit formation of PGE 2 from PGH 2 in presence of mPGES-1 using anti-PGE 2 antibody based detection method.
  • Recombinant human mPGES-1 was generated in-house by expressing in CHO cells (Ouellet M et al. (2002), Protein Expression and Purification 26: 489 - 495).
  • Assay was set up using crude microsomal fractions at protein concentration of 40-60 ⁇ g/mL.
  • Test compounds were prepared in 100 % dimethyl sulfoxide (DMSO) to obtain 20 mM stock solution and then diluted using assay buffer comprising 0.1 M Potassium phosphate buffer with 2 mM EDTA. Final concentration of DMSO in reaction was 0.5 % (v/v).
  • Negative controls comprised of all assay reagents except the enzyme.
  • Positive controls comprised of enzyme reaction in the absence of any inhibitor.
  • Test compounds were incubated for 10 minutes in assay buffer containing 2.5 mM GSH and mPGES-1 enzyme followed by addition of PGH 2 at a concentration of 15 ⁇ for 1 minute.
  • 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 200nM, preferably less than lOOnM, more preferably less than 50nM or most preferably less than 20nM.
  • the 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.
  • A549 cell line was monitored as inhibition of IL- ⁇ induced PGE 2 release.
  • A549 cells were maintained in DMEM medium with 10% FBS and 1%) Penicillin-Streptomycin Solution in 5% C0 2 at 37°C. Cells were seeded 24 h prior to the assay in 96 well plates in DMEM containing 1% Penicillin- Streptomycin and 2% FBS so as to get ⁇ 40,000 cells per well on the day of experiment. Assay was carried out in a total volume of 200 ⁇ . Test compounds were dissolved in dimethyl sulfoxide (DMSO) to prepare 2 mM stock solution and then diluted using plain DMEM. Final concentration of DMSO in the reaction was 0.55% (v/v).
  • DMSO dimethyl sulfoxide
  • Concentration response curves were plotted as % of maximal response obtained in the absence of test antagonist.
  • IC 50 value was calculated from concentration response curve by nonlinear regression analysis using GraphPad PRISM software.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés bicycliques de formule (I) ou un sel pharmaceutiquement acceptable de ceux-ci, en tant qu'inhibiteurs de mPGES-1. Ces composés sont des inhibiteurs de l'enzyme microsomale prostaglandine E synthase-1 (mPGES-1) et sont par conséquent utiles dans le traitement de la douleur et/ou de l'inflammation provenant d'une variété de maladies ou d'états, telle que l'asthme, l'arthrose, la polyarthrite rhumatoïde, la douleur aiguë ou chronique et des maladies neurodégénératives.
PCT/IB2012/056285 2011-11-16 2012-11-09 Dérivés de phtalazinone en tant qu'inhibiteurs de mpges-1 WO2013072825A1 (fr)

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
IN3235MU2011 2011-11-16
IN3235/MUM/2011 2011-11-16
US201161576813P 2011-12-16 2011-12-16
US61/576,813 2011-12-16
IN1577MU2012 2012-05-25
IN1577/MUM/2012 2012-05-25
US201261665279P 2012-06-27 2012-06-27
US61/665,279 2012-06-27
IN2559MU2012 2012-09-03
IN2559/MUM/2012 2012-09-03
US201261707842P 2012-09-28 2012-09-28
US61/707,842 2012-09-28

Publications (1)

Publication Number Publication Date
WO2013072825A1 true WO2013072825A1 (fr) 2013-05-23

Family

ID=48429051

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2012/056285 WO2013072825A1 (fr) 2011-11-16 2012-11-09 Dérivés de phtalazinone en tant qu'inhibiteurs de mpges-1

Country Status (1)

Country Link
WO (1) WO2013072825A1 (fr)

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014167444A1 (fr) 2013-04-08 2014-10-16 Glenmark Pharmaceuticals S.A. Composés bicycliques substitués utilisés en tant qu'inhibiteurs de mpges-1
WO2015059618A1 (fr) 2013-10-22 2015-04-30 Glenmark Pharmaceuticals S.A. Composés de pyrimidine substitués utilisés en tant qu'inhibiteurs de mpges-1
WO2015158204A1 (fr) * 2014-04-14 2015-10-22 上海恒瑞医药有限公司 Dérivés d'amides et leurs sels pharmaceutiquement acceptables, leur procédé de préparation et leur utilisation médicale
WO2019101826A1 (fr) 2017-11-22 2019-05-31 Khondrion Ip B.V. Composés en tant qu'inhibiteurs de mpges-1
WO2020263830A1 (fr) 2019-06-25 2020-12-30 Gilead Sciences, Inc. Protéines de fusion flt3l-fc et procédés d'utilisation
WO2021076908A1 (fr) 2019-10-18 2021-04-22 Forty Seven, Inc. Polythérapies pour le traitement de syndromes myélodysplasiques et de la leucémie myéloïde aiguë
WO2021087064A1 (fr) 2019-10-31 2021-05-06 Forty Seven, Inc. Traitement d'un cancer du sang basé sur une thérapie anti-cd47 et anti-cd20
WO2021096860A1 (fr) 2019-11-12 2021-05-20 Gilead Sciences, Inc. Inhibiteurs de mcl1
WO2021130638A1 (fr) 2019-12-24 2021-07-01 Carna Biosciences, Inc. Composés modulant la diacylglycérol kinase
WO2021163064A2 (fr) 2020-02-14 2021-08-19 Jounce Therapeutics, Inc. Anticorps et protéines de fusion se liant à ccr8, et leurs utilisations
WO2021222522A1 (fr) 2020-05-01 2021-11-04 Gilead Sciences, Inc. Composés de 2,4-dioxopyrimidine inhibant cd73
CN114302874A (zh) * 2019-08-26 2022-04-08 国际药品株式会社 吲哚甲酰胺衍生物和包含吲哚甲酰胺衍生物的药物组合物
WO2022221304A1 (fr) 2021-04-14 2022-10-20 Gilead Sciences, Inc. CO-INHIBITION DE LA LIAISON CD47/SIRPα ET DE LA SOUS-UNITÉ RÉGULATRICE DE L'ENZYME E1 ACTIVANT NEDD8 POUR LE TRAITEMENT DU CANCER
WO2022245671A1 (fr) 2021-05-18 2022-11-24 Gilead Sciences, Inc. Méthodes d'utilisation de protéines de fusion flt3l-fc
WO2022271684A1 (fr) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés modulant les diacylglycérol kinases
WO2022271659A1 (fr) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés modulant les diacylglycérol kinases
WO2022271677A1 (fr) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés de modulation de la diacylglycérol kinase
WO2022271650A1 (fr) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés de modulation de la diacylglycérol kinase
WO2023077030A1 (fr) 2021-10-29 2023-05-04 Gilead Sciences, Inc. Composés cd73
WO2023076983A1 (fr) 2021-10-28 2023-05-04 Gilead Sciences, Inc. Dérivés de pyridine-3(2h)-one
WO2023122615A1 (fr) 2021-12-22 2023-06-29 Gilead Sciences, Inc. Agents de dégradation des doigts de zinc de la famille ikaros et leurs utilisations
WO2023122581A2 (fr) 2021-12-22 2023-06-29 Gilead Sciences, Inc. Agents de dégradation de doigt de zinc de la famille ikaros et utilisations associées
WO2023147418A1 (fr) 2022-01-28 2023-08-03 Gilead Sciences, Inc. Inhibiteurs de parp7
EP4245756A1 (fr) 2022-03-17 2023-09-20 Gilead Sciences, Inc. Agents de dégradation de la famille des doigts de zinc de l'ikaros et leurs utilisations
WO2023183817A1 (fr) 2022-03-24 2023-09-28 Gilead Sciences, Inc. Polythérapie pour le traitement de cancers exprimant trop -2
WO2023196784A1 (fr) 2022-04-05 2023-10-12 Gilead Sciences, Inc. Combinaisons de thérapies par anticorps pour traiter le cancer colorectal
WO2023205719A1 (fr) 2022-04-21 2023-10-26 Gilead Sciences, Inc. Composés modulateurs de kras g12d
WO2024006929A1 (fr) 2022-07-01 2024-01-04 Gilead Sciences, Inc. Composés cd73
WO2024064668A1 (fr) 2022-09-21 2024-03-28 Gilead Sciences, Inc. POLYTHÉRAPIE ANTICANCÉREUSE PAR RAYONNEMENT IONISANT FOCAL ET PERTURBATION CD47/SIRPα

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006063466A1 (fr) 2004-12-17 2006-06-22 Merck Frosst Canada Ltd. 1h-phénanthro[9,10-d]imidazoles substitués en 2 par un phényle ou un hétérocycle en tant qu'inhibiteurs de mpges-1
WO2007059610A1 (fr) 2005-11-23 2007-05-31 Merck Frosst Canada Ltd. 2-(phenyl ou heterocyclique)-1h-phenantrho[9,10-d]imidazoles utilisees comme inhibiteurs de la mpges-1
WO2010034796A1 (fr) 2008-09-25 2010-04-01 Boehringer Ingelheim International Gmbh <sp>1</sp>h-benzimidazole-5-carboxamides comme agents anti-inflammatoires
WO2010100249A1 (fr) 2009-03-05 2010-09-10 Boehringer Ingelheim International Gmbh 3h-imidazo[4,5-c]pyridine-6-carboxamides en tant qu'anti-inflammatoires
WO2011048004A1 (fr) * 2009-10-23 2011-04-28 Boehringer Ingelheim International Gmbh Inhibiteurs de la prostaglandine e2 synthase-1 microsomale

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006063466A1 (fr) 2004-12-17 2006-06-22 Merck Frosst Canada Ltd. 1h-phénanthro[9,10-d]imidazoles substitués en 2 par un phényle ou un hétérocycle en tant qu'inhibiteurs de mpges-1
WO2007059610A1 (fr) 2005-11-23 2007-05-31 Merck Frosst Canada Ltd. 2-(phenyl ou heterocyclique)-1h-phenantrho[9,10-d]imidazoles utilisees comme inhibiteurs de la mpges-1
WO2010034796A1 (fr) 2008-09-25 2010-04-01 Boehringer Ingelheim International Gmbh <sp>1</sp>h-benzimidazole-5-carboxamides comme agents anti-inflammatoires
WO2010100249A1 (fr) 2009-03-05 2010-09-10 Boehringer Ingelheim International Gmbh 3h-imidazo[4,5-c]pyridine-6-carboxamides en tant qu'anti-inflammatoires
WO2011048004A1 (fr) * 2009-10-23 2011-04-28 Boehringer Ingelheim International Gmbh Inhibiteurs de la prostaglandine e2 synthase-1 microsomale

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 2003, LIPPINCOTT WILLIAMS & WILKINS
GOEDKEN RE ET AL., JOURNAL OF BIOMOLECULAR SCREENING, vol. 13, no. 7, 2008, pages 619 - 625
GOMEZ-HERNANDEZ, ATHEROSCLEROSIS, vol. 187, 2006, pages 139 - 49
KOJIMA, THE JOURNAL OF IMMUNOLOGY, vol. 180, 2008, pages 8361 - 6
KOROTKOVA ANNALS OF THE RHEUMATIC DISEASES, vol. 67, 2008, pages 1596 - 1602
MASSE F ET AL., JOURNAL OF BIOMOLECULAR SCREENING, vol. 10, no. 6, 2005, pages 599 - 605
NAKANISHI, CANCER RESEARCH, vol. 68, no. 9, 2008, pages 3251 - 9
OUELLET M ET AL., PROTEIN EXPRESSION AND PURIFICATION, vol. 26, 2002, pages 489 - 495
SCHRODER JOURNAL OF LIPID RESEARCH, vol. 47, 2006, pages 1071 - 80
WANG, CIRCULATION, vol. 117, 2008, pages 1302 - 1309
WANG, PROCEEDINGS OF NATIONAL ACADEMY OF SCIENCES, vol. 103, no. 39, 2006, pages 14507 - 12
XU, THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 326, 2008, pages 754 - 63

Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014167444A1 (fr) 2013-04-08 2014-10-16 Glenmark Pharmaceuticals S.A. Composés bicycliques substitués utilisés en tant qu'inhibiteurs de mpges-1
WO2015059618A1 (fr) 2013-10-22 2015-04-30 Glenmark Pharmaceuticals S.A. Composés de pyrimidine substitués utilisés en tant qu'inhibiteurs de mpges-1
WO2015158204A1 (fr) * 2014-04-14 2015-10-22 上海恒瑞医药有限公司 Dérivés d'amides et leurs sels pharmaceutiquement acceptables, leur procédé de préparation et leur utilisation médicale
CN105636951A (zh) * 2014-04-14 2016-06-01 上海恒瑞医药有限公司 酰胺类衍生物及其可药用盐、其制备方法及其在医药上的应用
JP2017513828A (ja) * 2014-04-14 2017-06-01 シャンハイ ヘンルイ ファーマスーティカル カンパニー リミテッドＳｈａｎｇｈａｉ Ｈｅｎｇｒｕｉ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． アミド誘導体およびそれらの薬学的に許容される塩、それらの製造方法およびそれらの医薬応用
CN105636951B (zh) * 2014-04-14 2018-05-15 上海恒瑞医药有限公司 酰胺类衍生物及其可药用盐、其制备方法及其在医药上的应用
US10081629B2 (en) 2014-04-14 2018-09-25 Jiangsu Hengrui Medicine Co., Ltd. Amide derivatives and pharmaceutically acceptable salts thereof, preparation method thereof and medicinal application thereof
RU2681537C2 (ru) * 2014-04-14 2019-03-07 Шанхай Хэнжуй Фармасьютикал Ко., Лтд. Амидные производные и их фармацевтически приемлемые соли, способ их получения и медицинское применение
AU2015246577B2 (en) * 2014-04-14 2019-10-03 Jiangsu Hengrui Medicine Co., Ltd. Amide derivatives and pharmaceutically acceptable salts thereof, preparation method therefor and medicinal application thereof
WO2019101826A1 (fr) 2017-11-22 2019-05-31 Khondrion Ip B.V. Composés en tant qu'inhibiteurs de mpges-1
US11672787B2 (en) 2017-11-22 2023-06-13 Khondrion Ip B.V. Compounds as mPGES-1 inhibitors
WO2020263830A1 (fr) 2019-06-25 2020-12-30 Gilead Sciences, Inc. Protéines de fusion flt3l-fc et procédés d'utilisation
EP4023638A4 (fr) * 2019-08-26 2023-10-04 Kukje Pharma Co., Ltd. Dérivé d'indole carboxamide et composition pharmaceutique le contenant
CN114302874A (zh) * 2019-08-26 2022-04-08 国际药品株式会社 吲哚甲酰胺衍生物和包含吲哚甲酰胺衍生物的药物组合物
JP7337260B2 (ja) 2019-08-26 2023-09-01 クッジェ ファーマ カンパニー，リミテッド インドールカルボキサミド誘導体及びそれを含む薬剤学的組成物
JP2022545744A (ja) * 2019-08-26 2022-10-28 クッジェ ファーマ カンパニー，リミテッド インドールカルボキサミド誘導体及びそれを含む薬剤学的組成物
EP4349413A2 (fr) 2019-10-18 2024-04-10 Forty Seven, Inc. Polythérapies pour le traitement de syndromes myélodysplasiques et de leucémie myéloïde aiguë
WO2021076908A1 (fr) 2019-10-18 2021-04-22 Forty Seven, Inc. Polythérapies pour le traitement de syndromes myélodysplasiques et de la leucémie myéloïde aiguë
WO2021087064A1 (fr) 2019-10-31 2021-05-06 Forty Seven, Inc. Traitement d'un cancer du sang basé sur une thérapie anti-cd47 et anti-cd20
WO2021096860A1 (fr) 2019-11-12 2021-05-20 Gilead Sciences, Inc. Inhibiteurs de mcl1
WO2021130638A1 (fr) 2019-12-24 2021-07-01 Carna Biosciences, Inc. Composés modulant la diacylglycérol kinase
US11692038B2 (en) 2020-02-14 2023-07-04 Gilead Sciences, Inc. Antibodies that bind chemokine (C-C motif) receptor 8 (CCR8)
WO2021163064A2 (fr) 2020-02-14 2021-08-19 Jounce Therapeutics, Inc. Anticorps et protéines de fusion se liant à ccr8, et leurs utilisations
WO2021222522A1 (fr) 2020-05-01 2021-11-04 Gilead Sciences, Inc. Composés de 2,4-dioxopyrimidine inhibant cd73
WO2022221304A1 (fr) 2021-04-14 2022-10-20 Gilead Sciences, Inc. CO-INHIBITION DE LA LIAISON CD47/SIRPα ET DE LA SOUS-UNITÉ RÉGULATRICE DE L'ENZYME E1 ACTIVANT NEDD8 POUR LE TRAITEMENT DU CANCER
WO2022245671A1 (fr) 2021-05-18 2022-11-24 Gilead Sciences, Inc. Méthodes d'utilisation de protéines de fusion flt3l-fc
WO2022271684A1 (fr) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés modulant les diacylglycérol kinases
WO2022271659A1 (fr) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés modulant les diacylglycérol kinases
WO2022271677A1 (fr) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés de modulation de la diacylglycérol kinase
WO2022271650A1 (fr) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés de modulation de la diacylglycérol kinase
WO2023076983A1 (fr) 2021-10-28 2023-05-04 Gilead Sciences, Inc. Dérivés de pyridine-3(2h)-one
WO2023077030A1 (fr) 2021-10-29 2023-05-04 Gilead Sciences, Inc. Composés cd73
WO2023122581A2 (fr) 2021-12-22 2023-06-29 Gilead Sciences, Inc. Agents de dégradation de doigt de zinc de la famille ikaros et utilisations associées
WO2023122615A1 (fr) 2021-12-22 2023-06-29 Gilead Sciences, Inc. Agents de dégradation des doigts de zinc de la famille ikaros et leurs utilisations
WO2023147418A1 (fr) 2022-01-28 2023-08-03 Gilead Sciences, Inc. Inhibiteurs de parp7
EP4245756A1 (fr) 2022-03-17 2023-09-20 Gilead Sciences, Inc. Agents de dégradation de la famille des doigts de zinc de l'ikaros et leurs utilisations
WO2023178181A1 (fr) 2022-03-17 2023-09-21 Gilead Sciences, Inc. Agents de dégradation des doigts de zinc de la famille ikaros et leurs utilisations
WO2023183817A1 (fr) 2022-03-24 2023-09-28 Gilead Sciences, Inc. Polythérapie pour le traitement de cancers exprimant trop -2
WO2023196784A1 (fr) 2022-04-05 2023-10-12 Gilead Sciences, Inc. Combinaisons de thérapies par anticorps pour traiter le cancer colorectal
WO2023205719A1 (fr) 2022-04-21 2023-10-26 Gilead Sciences, Inc. Composés modulateurs de kras g12d
WO2024006929A1 (fr) 2022-07-01 2024-01-04 Gilead Sciences, Inc. Composés cd73
WO2024064668A1 (fr) 2022-09-21 2024-03-28 Gilead Sciences, Inc. POLYTHÉRAPIE ANTICANCÉREUSE PAR RAYONNEMENT IONISANT FOCAL ET PERTURBATION CD47/SIRPα

Similar Documents

Publication Publication Date Title
WO2013072825A1 (fr) Dérivés de phtalazinone en tant qu&#39;inhibiteurs de mpges-1
US10821100B2 (en) Triazolone compounds as mPGES-1 inhibitors
WO2014167444A1 (fr) Composés bicycliques substitués utilisés en tant qu&#39;inhibiteurs de mpges-1
US9006257B2 (en) Bicyclic compounds as mPGES-1 inhibitors
WO2015059618A1 (fr) Composés de pyrimidine substitués utilisés en tant qu&#39;inhibiteurs de mpges-1
WO2013153535A1 (fr) Composés tricycliques à titre d&#39;inhibiteurs de la mpges-1
US8519149B2 (en) Tricyclic compounds as mPGES-1 inhibitors
WO2013038308A1 (fr) Composés à base d&#39;hétéroaryle bicyclique substitué capables d&#39;inhiber mpges-1
US20180258079A1 (en) 1,2-naphthoquinone based derivative and method of preparing the same
WO2012110860A1 (fr) Composés tricycliques en tant qu&#39;inhibiteurs de mpges-1
WO2015008234A1 (fr) Composés hétécycliques bicycliques utilisés en tant que modulateurs des ror-gamma
KR20190129034A (ko) 금속효소 억제제 화합물
CN114007652A (zh) 小分子靶向溴/乙酰蛋白及其用途
US20160039817A1 (en) Triazolopyridyl compounds as aldosterone synthase inhibitors
WO2015052675A1 (fr) Utilisation de composés substitués dihydro-benzimidazole comme modulateurs du ror gamma
US20220081420A1 (en) Metalloenzyme inhibitor compounds
WO2016128905A1 (fr) Composés de thiénopyrrole utilisés comme inhibiteurs de la s-nitrosoglutathione réductase
WO2016046782A1 (fr) Composés imidazole biaryle en tant qu&#39;inhibiteurs de la s-nitrosoglutathion réductase

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: 12799631

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12799631

Country of ref document: EP

Kind code of ref document: A1