Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • 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]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
  • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
  • C07D491/14—Ortho-condensed systems
  • C07D491/153—Ortho-condensed systems the condensed system containing two rings with oxygen as ring hetero atom and one ring with nitrogen as ring hetero atom

Definitions

• the present application relates to tricyclic compounds which may be useful 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 pro-inflammatory 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 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, 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 beneficial 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 beneficial in the treatment of asthma and COPD.
• PGE 2 is involved in malignant growth. PGE 2 facilitates tumor 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 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 has 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.
• the present invention relates to a compound of formula (I)
• A is selected from C 6 _i 4 aryl, 5-14 membered heteroaryl, and 3-15 membered heterocyclyl;
• Z is selected from N and CR 1 ;
• Y 1 is selected from O, N and NR 4 ;
• Y 2 is selected from CR 3 , CR 5 R 6 , N and NR 4 ;
• Y 3 is selected from CR 3 , CR 5 R 6 , N and NR 4 ;
• Y 4 is selected from O, CR 3 , CR 5 R 6 , N and NR 4 ;
• X 1 is selected from N and NR Z ;
• X 2 is selected from N and NR Z ;
• dotted line [— ] inside the ring represents an optional bond
• L is a bond or is selected from -(CR x R y ) n - and -C(O)-;
• each occurrence of R 1 is independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, Ci_ 8 alkyl, C 2 _i 0 alkenyl, C 2 _i 0 alkynyl, Ci_ 8 alkoxyCi_ 8 alkyl, haloCi.galkyl, hydroxyCi.galkyl, C 3 _i 2 cycloalkyl, C 3 _ 8 CycloalkylCi_galkyl, C 3 _ gcycloalkenyl, C 3 - 8 cycloalkenylCi_ 8 alkyl, C 6-14 aryl, C 6 -i 4 arylCi_galkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi-salkyl, 5-14 membered heteroaryl, 5-14 membered heteroarylCi_ 8 alkyl, -C(0)R a , -C(0)NR a R b , -C
• R 2 is selected from hydrogen, halogen, nitro, cyano, hydroxyl, Ci_ 8 alkyl, C 2 _ loalkenyl, C 2 _i 0 alkynyl, Ci_ 8 alkoxy, Ci_ 8 alkoxyCi_ 8 alkyl, haloCi_ 8 alkyl, haloCi_ 8alkoxy, hydroxyCi_ 8 alkyl, C 3 _i 2 cycloalkyl, C 3 _ 8 cycloalkylCi_ 8 alkyl, C 3 _ 8 cycloalkenyl, C 3 _ 8 cycloalkenylCi_ 8 alkyl, C 6-14 aryl, C 6 -i 4 aryloxy, C 6 _i 4 arylCi_ 8 alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi_ 8 alkyl, 5-14 membered heteroaryl, 5-14 membered heteroarylCi_ 8 al
• each occurrence of R 3 is independently selected from hydrogen, Ci_ 8 alkyl, C 3- i 2 cycloalkyl, C 3 - 8 cycloalkylCi_ 8 alkyl, C 6-14 aryl, C 6 -i 4 arylCi_ 8 alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi_ 8 alkyl, 5-14 membered heteroaryl, 5-14 membered heteroarylCi_ 8 alkyl; -C(0)R a , -C(0)NR a R b and -NR a R b ;
• each occurrence of R 4 is independently selected from hydrogen, Ci_ 8 alkyl, C 3- i 2 cycloalkyl, C 3 - 8 cycloalkylCi_ 8 alkyl, C 6-14 aryl, C 6 -i 4 arylCi_ 8 alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi_ 8 alkyl, 5-14 membered heteroaryl, 5-14 membered heteroarylCi_ 8 alkyl; -C(0)R a , -C(0)NR a R b and -NR a R b ;
• each occurrence of R 5 is independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, Ci_ 8 alkyl, C 2 _ioalkenyl, C 2 _ioalkynyl, Ci_ 8 alkoxy, Ci_ 8 alkoxyCi_ 8alkyl, haloCi_ 8 alkyl, haloCi_ 8 alkoxy, hydroxyCi_ 8 alkyl, C 3 _i 2 cycloalkyl, C 3- 8 cycloalkylCi_ 8 alkyl, C 3 _ 8 cycloalkenyl, C 3 _ 8 cycloalkenylCi_ 8 alkyl, C 6-14 aryl, C 6- i 4 aryloxy, C 6 _i 4 arylCi_ 8 alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylC i_ 8 alkyl, 5-14 membered heteroaryl, 5-14 membered heteroarylCi
• each occurrence of R 6 is independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, Ci_ 8 alkyl, C 2 _ioalkenyl, C 2 _ioalkynyl, Ci_ 8 alkoxy, Ci_ 8 alkoxyCi_ 8alkyl, haloCi_ 8 alkyl, haloCi_ 8 alkoxy, hydroxyCi_ 8 alkyl, C 3 _i 2 cycloalkyl, C 3- 8 cycloalkylCi_ 8 alkyl, C 3 _ 8 cycloalkenyl, C 3 _ 8 cycloalkenylCi_ 8 alkyl, C 6-14 aryl, C 6- i 4 aryloxy, C 6 _i 4 arylCi_ 8 alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylC i_ 8 alkyl, 5-14 membered heteroaryl, 5-14 membered heteroarylCi
• R 7 is selected from hydrogen, Ci_ 8 alkyl, C 3 _i 2 cycloalkyl, C 3 _ 8 cycloalkylCi_ 8alkyl, C 6 _i 4 aryl, C 6 -i 4 arylCi_ 8 alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylC i_ 8 alkyl, 5-14 membered heteroaryl, 5-14 membered heteroarylCi_galkyl; -C(0)R a , -C(0)NR a R b and -NR a R b ;
• each occurrence of R 8 is independently selected from halogen, nitro, cyano, hydroxyl, Ci_galkyl, C 2 _ioalkenyl, C 2 _ioalkynyl, Ci_galkoxy, Ci_galkoxyCi_galkyl, haloCi.galkyl, haloCi_galkoxy, hydroxyCi_galkyl, C 3 _i 2 cycloalkyl, C 3 _gcycloalkylCi_ galkyl, C 3 _gcycloalkenyl, C 3 _gcycloalkenylCi_galkyl, C 6-14 aryl, C 6 -i 4 aryloxy, C 6- i 4 arylCi_galkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi_galkyl, 5-14 membered heteroaryl, 5-14 membered heteroarylCi_galkyl, -C(0)R a ,
• each occurrence of R a and R b are independently selected from hydrogen, Ci_ 8 alkyl, Ci_ 8 alkoxyCi_galkyl, haloCi_ 8 alkyl, hydroxyCi.galkyl, C 3 _i 2 cycloalkyl, C 3 _gcycloalkylCi_galkyl, C 6-14 aryl, C 6 -i 4 arylCi_ 8 alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi_galkyl, 5-14 membered heteroaryl and 5-14 membered heteroarylCi_galkyl; or R a and R b together with the atom to which they are attached, form a cyclic ring which is substituted or unsubstituted and wherein the cyclic ring optionally contains one or more hetero atoms selected from O, N or S;
• each occurrence of R x and R y are independently selected from hydrogen, Ci_galkyl, Ci_galkoxyCi_galkyl, haloCi_galkyl, hydroxyCi.galkyl, C 3 _i 2 cycloalkyl, C 3 _gcycloalkylCi_galkyl, C 6-14 aryl, C 6 -i 4 arylCi_galkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi_galkyl, 5-14 membered heteroaryl and 5-14 membered heteroarylCi_galkyl; or R x and R y together with the atom to which they are attached, form a cyclic ring which is substituted or unsubstituted and wherein the cyclic ring optionally contains one or more hetero atoms selected from O, N or S;
• each occurrence R z is selected from hydrogen, Ci_ 8 alkyl, C 3 _i 2 cycloalkyl, C 3 _ gcycloalkylCi-galkyl, C 6-14 aryl, C 6 _i 4 arylCi_galkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi-salkyl, 5-14 membered heteroaryl, 5-14 membered heteroarylCi_ 8 alkyl; -C(0)R a , -C(0)NR a R b and -NR a R b ;
• 'm' is an integer ranging from 0 to 5, both inclusive;
• 'n' is an integer ranging from 1 to 2, both inclusive;
• 'q' is an integer ranging from 0 to 2, both inclusive.
• the compounds of formula (I) may involve one or more embodiments.
• Embodiments of formula (I) include compounds of formula (II), formula (III) and formula (IV), 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, claim 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 (I) as defined above wherein L is a bond (according to an embodiment defined below), R 7 is hydrogen (according to another embodiment defined below) and 'm' is 1 or 2 (according to yet another embodiment defined below).
• Y 1 is O
• Y 2 and Y 3 are CR 5 R 6 and Y 4 is O.
• R 4 is hydrogen or Ci_ 4 alkyl (e.g. methyl).
• Y 1 is N
• Y 2 and Y 3 are CH
• Y 4 is N or CH.
• Y 1 is NCH 3
• Y 2 is absent
• Y 3 is CH or CCH 3
• Y 4 is N.
• R z is hydrogen or Ci_ 4 alkyl (e.g. methyl or ethyl).
• R 2 is Ci_ 8 alkyl, -C(0)NR a R b or -C(0)OR a .
• each occurrence of R a and R b are independently selected from hydrogen, Ci_ 8 alkyl (e.g. methyl or ethyl), C 3 _i 2 cycloalkyl (e.g. cyclohexyl, 4,4- dimethylcyclohexyl, trans-4-(trifluoromethyl)cyclohexyl or (lr,4r)-4- (trifluoromethyl)cyclohexyl), C 3 _8CycloalkylCi_galkyl (e.g.
• C 6 _ i 4 aryl e.g. 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 4-fluoro-3- (trifluoromethyl)phenyl, 3 -fluoro-5 -(trifluoromethyl)phenyl, 2-fluoro-5- itrifluoromeihyijphenyl or 4-(cyclopropylethynyl)-3-fluorophenyl
• C 6 _i 4 arylCi_ 8 alkyl e.g.
• each occurrence of R a and R b are independently selected from hydrogen, methyl, ethyl, cyclohexyl, 4,4-dimethylcyclohexyl, trans-4- (trifluoromethyl)cyclohexyl, (lr,4r)-4-(trifluoromethyl)cyclohexyl, ((lr,4r)-4- (trifluoromethyl)cyclohexyl)methyl, trans-4-(trifluoromethyl)cyclohexylmethyl, 3 - (trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 4-fluoro-3-
• R 2 is -C(0)NR a R b .
• one of the R a and R b is hydrogen and other is C 3 -i 2 cycloalkyl (e.g. cyclohexyl, 4,4-dimethylcyclohexyl, trans- 4-(trifluoromethyl)cyclohexyl or (lr,4r)-4-(trifluoromethyl)cyclohexyl), C 3 _ 8 CycloalkylCi_ 8 alkyl (e.g.
• R 2 is -C(0)NR a R b .
• R a is hydrogen and R b is cyclohexyl, cyclohexylmethyl, phenyl, benzyl or pyridinyl, optionally substituted with one or more substituents independently selected from halogen (e.g. F, CI, Br or I), Ci_ 8 alkyl (e.g. methyl), haloCi.galkyl (e.g. trifluoromethyl) and C 2 -ioalkynyl (e.g. cy clopropy lethyny 1) .
• halogen e.g. F, CI, Br or I
• Ci_ 8 alkyl e.g. methyl
• haloCi.galkyl e.g. trifluoromethyl
• C 2 -ioalkynyl e.g. cy clopropy lethyny 1 .
• R 2 is -C(0)NR a R b .
• R a is hydrogen and R b is cyclohexyl, cyclohexylmethyl, phenyl, benzyl or pyridinyl, optionally substituted with one or more substituents independently selected from fluorine, methyl, trifluoromethyl and cy clopropy lethyny 1.
• R 2 is -C(0)NR a R b .
• R a is hydrogen and R b is cyclohexyl, 4,4-dimethylcyclohexyl, trans-4-(trifluoromethyl)cyclohexyl, (lr,4r)-4- (trifluoromethyl)cyclohexyl), ((lr,4r)-4-(trifluoromethyl)cyclohexyl)methyl, trans-4- (trifluoromethyl)cyclohexylmethyl, 3-(trifluoromethyl)phenyl, 4-
• R 8 is independently selected from halogen (e.g. F, CI, Br or I), Ci_ 4 alkyl (e.g. methyl, ethyl or tert-butyl) and haloCi_galkyl (e.g. trifluoromethyl).
• halogen e.g. F, CI, Br or I
• Ci_ 4 alkyl e.g. methyl, ethyl or tert-butyl
• haloCi_galkyl e.g. trifluoromethyl
• R 8 is independently selected from CI, F and CH 3 .
• R 8 is independently selected from CI, F and CH 3 and 'm' is 2.
• the invention specifically provides compounds of formula (II), (III) and (IV) wherein 'm' is 1 or 2 and consequently there is also provided a compound of formula (I) wherein 'm' is 1 or 2.
• the invention also provides a compound of formula (II) which is an embodiment of a compound of formula (I).
• Z is selected from N and CR 1 ;
• Y 1 is selected from O, N and NR 4 ;
• Y 2 is selected from CR 3 and CR 5 R 6 ;
• Y 3 is selected from CR 3 and CR 5 R 6 ;
• Y 4 is selected from O, CR 3 and N;
• X 1 is selected from N and NR Z ;
• X 2 is selected from N and NR Z ;
• dotted line [— ] inside the ring represents an optional bond
• R 1 is selected from hydrogen, halogen, cyano, hydroxyl and Ci_ 8 alkyl;
• R 2 is selected from Ci_ 8 alkyl, -C(0)NR a R b and -C(0)OR a ;
• each occurrence of R 3 is independently selected from hydrogen, Ci_ 8 alkyl, and C3_i 2 cycloalkyl;
• each occurrence of R 4 is independently selected from hydrogen, Ci_ 8 alkyl, and C 3 _i 2 cycloalkyl;
• each occurrence of R 5 is hydrogen
• each occurrence of R 6 is independently selected from hydrogen and Ci_ 4 alkyl; each occurrence of R 8 is independently selected from halogen, cyano, hydroxyl, Ci_ 8 alkyl, haloCi_ 8 alkyl, Ci_ 8 alkoxy and haloCi_ 8 alkoxy; each occurrence of R a and R b which may be the same or different, are independently selected from hydrogen, Ci.galkyl, haloCi.galkyl, C 3 _i 2 cycloalkyl, C 3 _ 8 cycloalkylCi_ 8 alkyl, C 6 _i 4 aryl, C 6 -i 4 arylCi_ 8 alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi_galkyl, 5-14 membered heteroaryl and 5-14 membered heteroarylCi_ 8 alkyl; or R a and R b together with the atom to which they are attached, form a cyclic
• each occurrence of R z is independently selected from hydrogen, Ci_ 8 alkyl and C 3 _ 6 cycloalkyl;
• 'm' is an integer ranging from 0 to 5, both inclusive
• 'q' is O or 1.
• 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, claim 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 Z is N or CH (according to an embodiment defined below), X 1 is N and X 2 is NH, NCH 3 or NCH 2 CH 3 (according to another embodiment defined below) and 'm' is 1 or 2 (according to yet another embodiment defined below).
• R 3 is hydrogen or Ci_ 4 alkyl (e.g. methyl).
• R 4 is hydrogen or Ci_ 4 alkyl (e.g. methyl).
• Y 1 is NCH 3
• Y 2 is absent
• Y 3 is CH or CCH 3
• Y 4 is N.
• R z is hydrogen or Ci_ 4 alkyl (e.g. methyl or ethyl).
• each occurrence of R a and R b are independently selected from hydrogen, Ci.galkyl (e.g. methyl or ethyl), C 3 -i 2 cycloalkyl (e.g. cyclohexyl, 4,4- dimethylcyclohexyl, trans-4-(trifluoromethyl)cyclohexyl or (lr,4r)-4- (trifluoromethyl)cyclohexyl), C 3 _8CycloalkylCi_galkyl (e.g.
• C 6 _ i 4 aryl e.g. 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 4-fluoro-3- (trifluoromethyl)phenyl, 3 -fluoro-5 -(trifluoromethyl)phenyl, 2 ⁇ fl uoro-5 ⁇
• each occurrence of R a and R b are independently selected from hydrogen, methyl, ethyl, cyclohexyl, 4,4-dimethylcyclohexyl, trans-4- (trifluoromethyl)cyclohexyl, (lr,4r)-4-(trifluoromethyl)cyclohexyl, ((lr,4r)-4- (trifluoromethyl)cyclohexyl)methyl, trans-4-(trifluoromethyl)cyclohexylmethyl, 3 - (trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 4-fluoro-3-
• R 2 is -C(0)NR a R b .
• one of the R a and R b is hydrogen and other is C 3 _i 2 cycloalkyl (e.g. cyclohexyl, 4,4-dimethylcyclohexyl, trans-4-(trifluoromethyl)cyclohexyl or (lr,4r)-4-(trifluoromethyl)cyclohexyl), C 3 _ gcycloalkylCi.galkyl (e.g.
• C 6 -i 4 aryl e.g. 3-(trifluoromethyl)phenyl, 4- (trifluoromethyl)phenyl, 4-fluoro-3 -(trifluoromethyl)phenyl, 3 -fluoro-5 - (trifluoromethyl )phenyl, 2- ⁇ 1uoro-5-(trif]uoromethyS)pheny[ or 4-(cyclopropylethynyl)- 3 -fluorophenyl), C6_i 4 arylCi_galkyl (e.g.
• R 2 is -C(0)NR a R b .
• R a is hydrogen and R b is cyclohexyl, cyclohexylmethyl, phenyl, benzyl or pyridinyl, optionally substituted with one or more substituents independently selected from halogen (e.g. F, CI, Br or I), Ci_ 8 alkyl (e.g. methyl), haloCi_galkyl (e.g. trifluoromethyl) and C 2 _ioalkynyl (e.g. cy clopropy lethyny 1) .
• halogen e.g. F, CI, Br or I
• Ci_ 8 alkyl e.g. methyl
• haloCi_galkyl e.g. trifluoromethyl
• C 2 _ioalkynyl e.g. cy clopropy lethyny 1 .
• R 2 is -C(0)NR a R b .
• R a is hydrogen and R b is cyclohexyl, cyclohexylmethyl, phenyl, benzyl or pyridinyl, optionally substituted with one or more substituents independently selected from fluorine, methyl, trifluoromethyl and cy clopropy lethyny 1.
• R 2 is -C(0)NR a R b .
• R a is hydrogen and R b is cyclohexyl, 4,4-dimethylcyclohexyl, trans-4-(trifluoromethyl)cyclohexyl, (lr,4r)-4- (trifluoromethyl)cyclohexyl, (( 1 r,4r)-4-(trifluoromethyl)cyclohexyl)methyl, trans-4- (trifluoromethyl)cyclohexylmethyl, 3-(trifluoromethyl)phenyl, 4-
• R 2 is -C(0)NR a R b .
• one of the R a and R b is hydrogen and other is substituted C 6 _i 4 aryl (e.g. phenyl).
• substituent(s) on aryl may be one or more and are independently selected from halogen (e.g. F, CI, Br or I), Ci_galkyl (e.g. methyl), haloCi_galkyl (e.g. trifluoromethyl) and C 2 _ l oalkynyl (e.g. cyclopropylethynyl).
• R 2 is -C(0)NR a R b .
• R a is hydrogen and R b is phenyl, optionally substituted with one or more substituents independently selected from fluorine, methyl, trifluoromethyl and cyclopropylethynyl.
• R 8 is independently selected from halogen (e.g. F, CI, Br or I), Ci_ 4 alkyl (e.g. methyl, ethyl or tert-butyl) and haloCi_galkyl (e.g. trifluoromethyl).
• R 8 is independently selected from CI, F and CH 3 .
• R 8 is independently selected from CI, F and CH 3 and 'm' is 2.
• the invention also provides a compound of formula (III) which is an embodiment of a compound of formula (I).
• R 5 is hydrogen
• R 6 is independently selected from hydrogen and methyl
• each occurrence of R 8 is independently selected from halogen, cyano, hydroxyl, Ci-galkyl, haloCi_galkyl, Ci_galkoxy and haloCi_galkoxy;
• R a and R b which may be the same or different, are independently selected from hydrogen, Ci_galkyl, haloCi_galkyl, C 3 -i 2 cycloalkyl, C 3 -gcycloalkylCi_galkyl, C 6-14 aryl, C 6 _i 4 arylCi_galkyl, 5-14 membered heteroaryl and 5-14 membered heteroarylCi_galkyl;
• R z is independently selected from hydrogen, Ci_ 4 alkyl and C 3 - 6 cycloalkyl
• 'm' is an integer ranging from 0 to 5, 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, claim 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 (III) as defined above wherein R 5 and R 6 are hydrogen (according to an embodiment defined below) and R z is hydrogen or methyl (according to an embodiment defined below).
• R z is hydrogen or Ci_ 4 alkyl (e.g. methyl or ethyl).
• R a and R b are hydrogen and other is Ci_galkyl (e.g. methyl or ethyl), C 3 -i 2 cycloalkyl (e.g. cyclohexyl, 4,4-dimethylcyclohexyl, trans-4- (trifluoromethyl)cyclohexyl or (lr,4r)-4-(trifluoromethyl)cyclohexyl), C 3 _ gcycloalkylCi-galkyl (e.g.
• R a and R b are hydrogen and other is methyl, ethyl, cyclohexyl, 4,4-dimethylcyclohexyl, trans-4-(trifluoromethyl)cyclohexyl, (lr,4r)-4- (trifluoromethyl)cyclohexyl, (( 1 r,4r)-4-(trifluoromethyl)cyclohexyl)methyl, trans-4- (trifluoromethyl)cyclohexylmethyl, 3-(trifluoromethyl)phenyl, 4-
• R a is hydrogen and R b is C 3 _i 2 cycloalkyl (e.g. cyclohexyl, 4,4-dimethylcyclohexyl, trans-4-(trifluoromethyl)cyclohexyl or (lr,4r)-4- (trifluoromethyl)cyclohexyl), C 3 - 8 cycloalkylCi_galkyl (e.g. ((lr,4r)-4- (trifluoromethyl)cyclohexyl)methyl or trans-4-(trifluoromethyl)cyclohexylmethyl), C 6 _ i 4 aryl (e.g.
• R a is hydrogen and R b is cyclohexyl, cyclohexylmethyl, phenyl, benzyl or pyridinyl, optionally substituted with one or more substituents independently selected from halogen (e.g. F, CI, Br or I), Ci_ 8 alkyl (e.g. methyl), haloCi_ 8 alkyl (e.g. trifluoromethyl) and C 2 _ioalkynyl (e.g. cyclopropylethynyl).
• halogen e.g. F, CI, Br or I
• Ci_ 8 alkyl e.g. methyl
• haloCi_ 8 alkyl e.g. trifluoromethyl
• C 2 _ioalkynyl e.g. cyclopropylethynyl
• R a is hydrogen and R b is cyclohexyl, cyclohexylmethyl, phenyl, benzyl or pyridinyl, optionally substituted with one or more substituents independently selected from fluorine, methyl, trifluoromethyl and cyclopropylethynyl.
• R a is hydrogen and R b is cyclohexyl, 4,4-dimethylcyclohexyl, trans-4-(trifluoromethyl)cyclohexyl, ( 1 r,4r)-4-(trifluoromethyl)cyclohexyl, (( 1 r,4r)-4- (trifluoromethyl)cyclohexyl)methyl, trans-4-(trifluoromethyl)cyclohexylmethyl, 3 - (trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 4-fluoro-3-
• substituent(s) on aryl may be one or more and are independently selected from halogen (e.g. F, CI, Br or I), Ci_ 8 alkyl (e.g. methyl), haloCi.galkyl (e.g. trifluoromethyl) and C 2 _ioalkynyl (e.g. cyclopropylethynyl).
• halogen e.g. F, CI, Br or I
• Ci_ 8 alkyl e.g. methyl
• haloCi.galkyl e.g. trifluoromethyl
• C 2 _ioalkynyl e.g. cyclopropylethynyl
• substituent(s) on phenyl may be one or more and are independently selected from fluorine, methyl, trifluoromethyl and cyclopropylethynyl.
• R a is hydrogen and R b is phenyl optionally substituted with one or more substituents independently selected from fluorine, methyl, trifluoromethyl and cyclopropylethynyl .
• R 8 is independently selected from halogen (e.g. F, CI, Br or I), Ci_ 4 alkyl (e.g. methyl, ethyl or tert-butyl) and haloCi-salkyl (e.g. trifluoromethyl).
• halogen e.g. F, CI, Br or I
• Ci_ 4 alkyl e.g. methyl, ethyl or tert-butyl
• haloCi-salkyl e.g. trifluoromethyl
• R 8 is independently selected from CI, F and CH 3 .
• R 8 is independently selected from CI, F and CH 3 and 'm' is 2.
• R 5 and R 6 are hydrogen; each occurrence of R 8 is independently selected from halogen (e.g. F, CI or Br), and Ci_ 4 alkyl (e.g. methyl);
• R a is hydrogen and R b is cyclohexyl, cyclohexylmethyl, phenyl, benzyl or pyridinyl, optionally substituted with one or more substituents independently selected from fluorine, methyl, trifluoromethyl and cyclopropylethynyl;
• R z is hydrogen or Ci_ 4 alkyl (e.g. methyl or ethyl); and 'm' is 2.
• the invention also provides a compound of formula (IV) which is an embodiment of a compound of formula (I).
• R 8 is independently selected from CI, F and methyl
• R a is hydrogen
• R b is cyclohexyl, 4,4-dimethylcyclohexyl, trans-4-(trifluoromethyl)cyclohexyl, ( 1 r,4r)-4-(trifluoromethyl)cyclohexyl, (( 1 r,4r)-4-(trifluoromethyl)cyclohexyl)methyl, trans-4-(trifluoromethyl)cyclohexylmethyl, 3 -(trifluoromethyl)phenyl, 4-
• R z is hydrogen, methyl or ethyl
• the present application also provides a pharmaceutical composition that includes at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
• the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.
• the compounds described herein may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a 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 related to a variety of disease states.
• the present invention 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 an amount effective to cause inhibition of such receptor.
• halogen or halo means fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo).
• alkyl refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. Ci_8alkyl), 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_8alkyl 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_8alkyl), and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n- buty
• 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 ' so-propenyl, 2 -methyl- 1-propenyl, 1-butenyl, and 2-butenyl. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
• alkynyl refers to a hydrocarbyl radical having at least one carbon- carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred i.e. C 2 _ioalkynyl).
• alkynyl groups include ethynyl, propynyl, and butynyl. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
• alkoxy denotes an alkyl group attached via an oxygen linkage to the rest of the molecule (i.e. Ci_ 8 alkoxy).
• Representative examples of such groups are -OCH 3 and -OC 2 H 5 .
• all alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
• alkoxyalkyl or “alkyloxyalkyl” refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above (i.e. Ci_ 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_ 8 alkyl).
• haloalkyl moiety include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. Unless set forth or recited to the contrary, all haloalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
• haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms (i.e. haloCi-salkoxy).
• 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 alky 1 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.galkyl).
• hydroxyalkyl moieties include, but are not limited to -CH 2 OH, -C 2 H 4 OH and -CH(OH)C 2 H 4 OH.
• cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, (i.e.C3_i 2 cycloalkyl).
• monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
• multicyclic cycloalkyl groups include, but are not limited to, perhydronapthyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl.
• C 3 _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 (i.e. C 3 _8CycloalkylCi_ galkyl).
• 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, (i.e. C 3 _ 8 Cycloalkenyl).
• Examples of “cycloalkenyl” include but are not limited to cyclopropenyl, cyclobutenyl, and cyclopentenyl. Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted.
• cycloalkenylalkyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, directly attached to an alkyl group, (i.e. C 3 _ 8 cycloalkenylCi_ 8 alkyl).
• the cycloalkenylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all cycloalkenylalkyl groups described or claimed herein may be substituted or unsubstituted.
• aryl refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C 6 _i 4 aryl), including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl. Unless set forth or recited to the contrary, all aryl groups described or claimed herein may be substituted or unsubstituted.
• aryloxy refers to an aryl group as defined above attached via an oxygen linkage to the rest of the molecule (i.e. C 6 -i 4 aryloxy).
• aryloxy moieties include, but are not limited to phenoxy and naphthoxy. Unless set forth or recited to the contrary, all aryloxy groups described herein may be substituted or unsubstituted.
• arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, i.e. C 6 -i 4 arylCi_ 8 alkyl, such as -CH 2 C 6 H 5 and - C 2 H 4 C 6 H 5 . Unless set forth or recited to the contrary, all arylalkyl groups described or claimed herein may be substituted or unsubstituted.
• heterocyclic ring or “heterocyclyl” unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical (i.e. 3 to 15 membered heterocyclyl) which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur.
• the heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
• heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s).
• heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 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. 3 to 15 membered heterocyclylCi.galkyl).
• 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 5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S (i.e. 5 to 14 membered heteroaryl).
• the heteroaryl may be a mono-, bi- or tricyclic ring system.
• the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
• heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, 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. 5 to 14 membered heterarylCi_galkyl).
• 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.
• 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).
• 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 invention extends to all these stereoisomeric forms and to mixtures thereof.
• the different stereoisomeric forms of the compounds described herein may be separated from one another by the methods known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated. It is also to be understood that compounds described herein may exist in solvated forms (such as hydrates) as well as unsolvated forms, and that the invention encompasses all such forms.
• the compounds of the invention are typically administered in the form of a pharmaceutical composition.
• Such compositions can be prepared using procedures 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, and solvents.
• 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.
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising a compound as described herein, a second therapeutic agent, and optionally a pharmaceutically-acceptable excipient.
• the pharmaceutical composition includes a compound as described herein and a second therapeutic agent, wherein each of the compound described herein and the second therapeutic agent is formulated in admixture with a pharmaceutically-acceptable excipient.
• Compounds of the present invention are particularly useful because they may inhibit the activity of prostaglandin E synthases ⁇ and particularly microsomal prostaglandin E synthase-1 (mPGES-1) ⁇ , i.e., they prevent, inhibit, or suppress 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.
• mPGES-1 microsomal prostaglandin E synthase-1
• 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 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.
• 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, myo
• 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 such as multiple sclerosis and spinal-cord injury, fibromyalgia, nerve injury, ischaemia, neuro
• Compounds of the present invention 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.
• 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
• Compounds of the present invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.
• the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
• the daily dosage of the compound of the invention may be in the range from 0.05 mg/kg to 100 mg/kg.
• the compounds described herein, including compounds of formula (I), (II), (III) and (IV) may be prepared using techniques known in the art through the reaction sequences depicted in schemes provided below, as well as by other methods. Furthermore, in the following schemes, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents etc. may be used and are included within the scope of the present invention. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention. The compounds obtained by using the general reaction sequences may be of insufficient purity.
• R 2 , R 7 , R 8 , m, q, A and L are defined with respect to the compound of Formula (I)) can be performed as described in Synthetic scheme 1.
• a compound of formula (1) (wherein, X 1 and X 2 are independently selected from NH 2 and NHR Z , with a proviso that when X 1' is NH 2 then X 2' is NHR Z and when X 1' is NHR Z then X 2 is NH 2 ) can be converted to a compound of formula (I) by first reacting with isothiocyanate derivative of formula (2) under appropriate conditions followed by cyclization using a reagent such as diisopropylcarbodiimide, which may optionally further reacted (when in the compound of formula (I), R 7 is not hydrogen) with R 7 -LG' (3) (wherein R 7 is not hydrogen and LG' is good leaving group such as CI, Br or I) under appropriate conditions.
• a reagent such as diisopropylcarbodiimide
• the reaction can be performed with a suitable reagent such as trimethyl aluminum (e.g. 2.0 M solution of trimethyl aluminum in toluene) or a strong base such as sodium hydride (NaH) in a suitable solvent such as toluene or DMF.
• a suitable reagent such as trimethyl aluminum (e.g. 2.0 M solution of trimethyl aluminum in toluene) 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 reagent such as trimethyl aluminum 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 in the art for example, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) or Benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) 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 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.
• a compound of formula (Ila) can be prepared following the synthetic steps depicted in Synthetic scheme 3 (wherein Y 4 , X 1 , X 2 , R 1 , R a , R b , R 3 , R 7 , R 8 , m, A and L are as defined for compound of formula (I)).
• a compound of formula (6) (wherein, X 1 and X 2 are independently selected from NH 2 and NHR Z , with a proviso that when X 1' is NH 2 then X 2' is NHR Z and when X 1' is NHR Z then X 2 is NH 2 ) can be converted to a compound of formula (7) by first reacting with an isothiocyanate derivative of formula (2) under appropriate conditions followed by cyclization using a reagent such as diisopropylcarbodiimide, optionally further reacted (when in the compound of formula (6), R 7 is not hydrogen) with R 7 - LG' (3) (wherein R 7 is not hydrogen and LG' is good leaving group such as CI, Br or I) under appropriate conditions.
• a reagent such as diisopropylcarbodiimide
• the compound of formula (7) can be converted to a compound of formula (8) by oxidation reaction using appropriate oxidising agent such as periodic acid and chromium trioxide in suitable solvent such as acetonitrile.
• a compound of formula (8) can be reacted under the esterification condition with alcohol having formula R'-OH (wherein R' is Ci_ 4 alkyl such as methyl or ethyl) using an acid such as sulphuric acid or hydrochloric acid or the like at suitable temperature, for example the temperature range may be of 60-100°C, to obtain the compound of formula (9).
• a compound of formula (9) can be converted to a compound of formula (Ila) by reacting with an amine of the formula NHR a R b using organometallic coupling reagents such as trimethyl aluminum (e.g. 2.0 M solution of trimethyl aluminum in toluene) or a strong base such as sodium hydride (NaH) or the like in presence of solvents such as toluene, acetonitrile at temperature range of 0-100°C.
• organometallic coupling reagents such as trimethyl aluminum (e.g. 2.0 M solution of trimethyl aluminum in toluene) or a strong base such as sodium hydride (NaH) or the like in presence of solvents such as toluene, acetonitrile at temperature range of 0-100°C.
• a compound of formula (8) can be converted to a compound of formula (Ila) under amidation conditions using an appropriate amine of the formula (5) (NHR a R b ) in the presence of suitable coupling reagent such as TBTU, HATU, EDCI, BOP or the like in the presence of a base such as triethylamine, diisopropylethylamine, N-methyl morpholine or the like in a suitable solvent such as DMF, THF or the like at an appropriate temperature range such as 20-100°C.
• suitable coupling reagent such as TBTU, HATU, EDCI, BOP or the like
• a base such as triethylamine, diisopropylethylamine, N-methyl morpholine or the like
• suitable solvent such as DMF, THF or the like at an appropriate temperature range such as 20-100°C.
• a compound of formula (lib) can be prepared following the synthetic steps depicted in Synthetic scheme 4 (wherein X 1 , X 2 , R 1 , R a , R b , R 3 , R 7 , R 8 , m, A and L are as defined with respect to a compound of formula (I) and R' is Ci_ 4 alkyl such as methyl or ethyl).
• a compound of formula (10) can be converted to a compound of formula (12) by reacting with glyoxal derivative of formula (11) (e.g. glyoxal wherein R 3 is H) under appropriate conditions like using base such as sodium hydrogen carbonate or the like at suitable temperature, for example at reflux temperature.
• a compound of formula (12) can be converted to the compound of formula (lib) by reacting with an amine NHR a R b (compound of formula (5)) using organometallic coupling reagents such as trimethyl aluminum (e.g.
• a compound of formula (12) can be converted to a compound of formula (13) under hydrolysis condition in the presence of an inorganic base such as sodium hydroxide, potassium carbonate, lithium hydroxide or the like in an alcoholic solvent in the presence of water at a temperature range of 20-100°C.
• an inorganic base such as sodium hydroxide, potassium carbonate, lithium hydroxide or the like in an alcoholic solvent in the presence of water at a temperature range of 20-100°C.
• a compound of formula (13) can be converted to a compound of formula (lib) under amidation conditions using an appropriate amine of the formula (5) (NHR a R b ) in the presence of coupling reagent such as TBTU, HOBT, DMAP, HATU, EDCI, BOP or the like in presence of a organic base such as triethylamine, diisopropylethylamine, N-methyl morpholine or the like in a suitable solvent such as DMF, THF, DMSO or the like at appropriate temperature range such as 20-100°C.
• coupling reagent such as TBTU, HOBT, DMAP, HATU, EDCI, BOP or the like
• organic base such as triethylamine, diisopropylethylamine, N-methyl morpholine or the like
• a suitable solvent such as DMF, THF, DMSO or the like at appropriate temperature range such as 20-100°C.
• a compound of formula (lie) can be prepared following the synthetic steps depicted in Synthetic scheme 5 (wherein X 1 , X 2 ' R 1 , R a , R b , R 4 , R 3 , R 7 , R 8 , m, A and L are as defined with respect to a compound of formula (I) and R' is Ci_ 4 alkyl such as methyl or ethyl).
• a compound of formula (14) can be converted to a compound of formula (16) by using metal such as tin, iron or the like and compound of formula (15) (e.g. triethylortho formate [when R 3 is H], triethylortho acetate [when R 3 is C3 ⁇ 4]) in acetic acid at reflux temperature.
• a compound of formula (16) can be converted to a compound of formula (lie) by reacting with an amine NHR a R b (compound of formula (5)) using organometallic coupling reagents such as trimethyl aluminum (e.g.
• a compound of formula (16) can be converted to a compound of formula (17) under hydrolysis condition in the presence of an inorganic base such as sodium hydroxide, potassium carbonate, lithium hydroxide or the like in an alcoholic solvent in the presence of water at a temperature range of 20-100°C.
• an inorganic base such as sodium hydroxide, potassium carbonate, lithium hydroxide or the like in an alcoholic solvent in the presence of water at a temperature range of 20-100°C.
• a compound of formula (17) can be converted to a compound of formula (lie) under amidation conditions using an appropriate amine of the formula (5) (NHR a R b ) in the presence of coupling reagent such as TBTU, HOBT, DMAP, HATU, EDCI, BOP or the like in presence of a organic base such as triethylamine, diisopropylethylamine, N- methyl morpholine or the like in a suitable solvent such as DMF, THF, DMSO or the like at appropriate temperature range such as 20-100°C.
• coupling reagent such as TBTU, HOBT, DMAP, HATU, EDCI, BOP or the like
• organic base such as triethylamine, diisopropylethylamine, N- methyl morpholine or the like in a suitable solvent such as DMF, THF, DMSO or the like at appropriate temperature range such as 20-100°C.
• a compound of formula (lid) can be prepared following the synthetic steps depicted in Synthetic scheme 6 (wherein, R 1 , R a , R b , R 3 , R 8 and m are as defined with respect to a compound of formula (I)).
• Synthetic scheme 6 wherein, R 1 , R a , R b , R 3 , R 8 and m are as defined with respect to a compound of formula (I)).
• a compound of formula (18) can be converted to a compound of formula (19) by nitration reaction known in the art of organic synthesis, for example, using potassium nitrate in the presence of acid such as sulphuric acid.
• a compound of formula (19) can be converted to a compound of formula (20) under reductive conditions using a metal such as iron or the like in the presence of an acid such as hydrochloric acid in an alcoholic solvent at a temperature range of 20-100°C.
• the compound of formula (19) can also be converted to a compound of formula (20) under hydrogenation conditions.
• a compound of formula (20) is converted to a compound of formula (21) by following acetylation procedure known in the art of organic synthesis, for example, using acetic anhydride in the presence of base such as triethylamine or pyridine.
• a compound of formula (21) is converted to a compound of formula (22) by following nitration procedure known in the art of organic synthesis, for example, using fuming nitric acid in the presence of acid such as sulphuric acid.
• a compound of formula (22) is converted to the deacetylated compound of formula (23) by following deacetylation procedure known in the art of organic synthesis, for example, using cone, sulphuric acid at reflux temperature.
• a compound of formula (23) can be converted to a compound of formula (24) under reductive conditions using Raney Ni and hydrazine hydrate.
• a compound of formula (25) can be converted to a compound of formula (26) by oxidation reaction using appropriate oxidising agent such as periodic acid and chromium trioxide in suitable solvent such as acetonitrile.
• a compound of formula (26) can be reacted under the esterification condition with alcohol having formula R'-OH (wherein R' is alkyl such as methyl or ethyl) using an acid such as sulphuric acid or hydrochloric acid or the like at suitable temperature, for example the temperature range may be of 60-100°C, to obtain the compound of formula (27).
• a compound of formula (27) can be converted to the compound of formula (lid) by reacting with an amine
• organometallic coupling reagents such as trimethyl aluminum (e.g. 2.0 M solution of trimethyl aluminum in toluene) or the like in presence of solvents such as toluene, acetonitrile at temperature range of 0-100°C.
• the compound of formula (26) can be converted to a compound of formula (lid) under amidation conditions using an appropriate amine of formula (5) (NHR a R b ) in the presence of suitable coupling reagent such as TBTU, HATU, EDCI, BOP or the like in the presence of a base such as triethylamine, diisopropylethylamine, N-methyl morpholine or the like in a suitable solvent such as DMF, THF or the like at an appropriate temperature range such as 20-100°C.
• suitable coupling reagent such as TBTU, HATU, EDCI, BOP or the like
• a base such as triethylamine, diisopropylethylamine, N-methyl morpholine or the like
• suitable solvent such as DMF, THF or the like at an appropriate temperature range such as 20-100°C.
• a compound of formula (He) can be prepared following the synthetic steps depicted in Synthetic scheme 7 (wherein R 1 , R z , R a , R b , R 3 , R 8 and m are as defined with respect to compound of formula (II)).
• Synthetic scheme 7 wherein R 1 , R z , R a , R b , R 3 , R 8 and m are as defined with respect to compound of formula (II)).
• a compound of formula (28) can be converted to a compound of formula (29) under reductive conditions using a metal such as iron or the like in the presence of an acid such as hydrochloric acid in an alcoholic solvent at a temperature range of 20- 100°C.
• the compound of formula (28) can also be converted to a compound of formula (29) under hydrogenation conditions.
• a compound of formula (29) can be converted to a compound of formula (30) by reacting with glyoxal derivative of formula (11) (e.g. glyoxal when R 3 is H) under appropriate conditions like using base such as sodium hydrogen carbonate or the like at suitable temperature, for example at reflux temperature.
• the compound of formula (30) is converted to the compound of formula (31) by following nitration procedure known in the art of organic synthesis, for example, using fuming nitric acid in the presence of acid such as sulphuric acid.
• a compound of formula (31) can be converted to a compound of formula (32) by reacting with substituted amine (NH 2 R Z e.g. methyl amine when R z is CH 3 ) preferably in the presence of a organic base such as triethylamine, diisopropylethylamine or the like in a suitable solvent such as THF or acetonitrile at a suitable temperature which may be in the range of 0-100°C preferably by using acetonitrile as solvent and at 80 °C.
• substituted amine NH 2 R Z e.g. methyl amine when R z is CH 3
• a organic base such as triethylamine, diisopropylethylamine or the like
• suitable solvent such as THF or
• a compound of formula (32) can be converted to a compound of formula (33) under reductive conditions using Raney Ni and hydrazine hydrate.
• a compound of formula (33) can be converted to a compound of formula (34) reacting with an isothiocyanate derivative of formula (2') under appropriate conditions using a reagent such as diisopropylcarbodiimide.
• a compound of formula (34) can be converted to a compound of formula (35) by oxidation reaction using appropriate oxidising agent such as periodic acid and chromium trioxide in suitable solvent such as acetonitrile.
• a compound of formula (35) can be reacted under the esterification condition with alcohol having formula R'-OH (wherein R' is alkyl such as methyl or ethyl) using an acid such as sulphuric acid or hydrochloric acid or the like at suitable temperature, for example the temperature range may be of 60-100°C, to obtain the compound of formula (36).
• R'-OH alkyl such as methyl or ethyl
• an acid such as sulphuric acid or hydrochloric acid or the like
• suitable temperature for example the temperature range may be of 60-100°C
• organometallic coupling reagents such as trimethyl aluminum (e.g. 2.0 M solution of trimethyl aluminum in toluene) or the like in presence of solvents such as toluene, acetonitrile at temperature range of 0-100°C.
• the compound of formula (35) can be converted to a compound of formula (He) under amidation conditions using an appropriate amine (NHR a R b ) in the presence of suitable coupling reagent such as TBTU, HATU, EDCI, BOP or the like in the presence of a base such as triethylamine, diisopropylethylamine, N-methyl morpholine or the like in a suitable solvent such as DMF, THF or the like at an appropriate temperature range such as 20-100°C.
• suitable coupling reagent such as TBTU, HATU, EDCI, BOP or the like
• a base such as triethylamine, diisopropylethylamine, N-methyl morpholine or the like
• suitable solvent such as DMF, THF or the like at an appropriate temperature range such as 20-100°C.
• a compound of formula (37) is converted to the compound of formula (38) by following nitration procedure known in the art of organic synthesis, for example, using fuming nitric acid in the presence of acid such as sulphuric acid.
• a compound of formula (38) can be reacted under the esterification condition with alcohol having formula R'-OH (wherein R' is alkyl such as methyl or ethyl) using an acid such as sulphuric acid or hydrochloric acid or the like at suitable temperature, for example the temperature range may be of 60-100°C, to obtain the compound of formula (39).
• a compound of formula (39) can be converted to a compound of formula (40) by reacting with an methyl amine or any other substituted amine in the presence of a organic base such as triethylamine, diisopropylethylamine or the like in a suitable solvent such as THF, DMF or DMSO at a suitable temperature which may be in the range of 0-100°C, preferable by using TEA in THF and at room temperature.
• a compound of formula (40) can be converted to a compound of formula (41) under reductive conditions using a metal such as iron or the like in the presence of an acid such as hydrochloric acid in an alcoholic solvent at a temperature range of 20-100°C.
• the compound of formula (41) can be converted to a compound of formula (42) by reacting with isothiocyanate derivative of formula (2') and diisopropylcarbodiimide under appropriate conditions.
• a compound of formula (42) is converted to a compound of formula (43) by following nitration procedure known in the art of organic synthesis, for example, using potassium nitrate in the presence of acid such as sulphuric acid.
• a compound of formula (43) can be converted to a compound of formula (44) by using metal such as iron or the like and compound of formula (15) (e.g. triethylortho formate [when R 3 is H], triethylortho acetate [when R 3 is C3 ⁇ 4]) in acetic acid at reflux temperature.
• a compound of formula (44) can be converted to a compound of formula (Ilf) by reacting with an amine NHR a R b (compound of formula (5)) using organometallic coupling reagents such as trimethyl aluminum or the like in presence of solvents such as toluene, acetonitrile at temperature range of 0-100°C.
• the compound of formula (44) can be converted to a compound of formula (45) under hydrolysis condition in the presence of an inorganic base such as sodium hydroxide, potassium carbonate, lithium hydroxide or the like in an alcoholic solvent in the presence of water at a temperature range of 20-100°C.
• a compound of formula (45) can be converted to a compound of formula (Ilf) under amidation conditions using an appropriate amine of the formula (5) (NHR a R b ) in the presence of coupling reagent such as TBTU, HOBT, DMAP, HATU, EDCI, BOP or the like in presence of a organic base such as triethylamine, diisopropylethylamine, N-methyl morpholine or the like in a suitable solvent such as DMF, THF, DMSO or the like at appropriate temperature range such as 20-100°C.
• coupling reagent such as TBTU, HOBT, DMAP, HATU, EDCI, BOP or the like
• organic base such as triethylamine, diisopropylethylamine, N-methyl morpholine or the like
• a suitable solvent such as DMF, THF, DMSO or the like at appropriate temperature range such as 20-100°C.
• a compound of formula (46) is converted to the compound of formula (47) by an appropriate alkylhalide such as 1 ,2-dibromoethane in presence of a base such as potassium carbonate, triethylamine or the like in a suitable solvent such as DMF, dimethoxy ethane, THF or dioxane at a temperature range of RT-100°C.
• a compound of formula (47) can be converted to a compound of formula (48) by following oxidation procedure known in the art of organic synthesis, for example, using chromic acid, potassium dichromate, mixture of sulphamic acid and sodium chlorite in solvent such as acetone at a temperature range of 0°C-RT.
• a compound of formula (48) can be converted to a compound of formula (49) under esterification condition using an acid catalyst such as sulphuric acid or hydrochloric acid or the like in a suitable solvent such as alcohol (R'-OH, wherein R' is Ci_ 4 alkyl such as methyl or ethyl) at suitable temperature, for example the temperature range may be of 60-100°C.
• a compound of formula (49) can be converted to a compound of formula (50) under bromination condition using bromating agents such as Bromine, Aq. HBr, HBr in acetic acid, in solvent such as acetic acid at suitable temperature, for example the temperature range may be of RT-60°C.
• a compound of formula (50) can be converted to a compound of formula (51) by following nitration procedure known in the art of organic synthesis, for example, using nitrating mixture i.e. cone. H 2 SO 4 and cone. HNO 3 ; fuming nitric acid in the presence of an acid such as sulphuric acid or mild nitration condition such as K O 3 in solvent like acetic acid or TFA at suitable temperature, for example the temperature range may be of 0°C-RT.
• the compound of formula (51) can be converted to a compound of formula (52) under reductive conditions using a metal such as iron or the like in the presence of an acid such as hydrochloric acid in an alcoholic solvent at a temperature range of 20-100°C.
• the compound of formula (51) can also be converted to a compound of formula (52) under hydrogenation conditions.
• a compound of formula (52) can be converted to a compound of formula (53) by following nitration procedure known in the art of organic synthesis, for example, using nitrating mixture i.e. cone. H 2 SO 4 and cone. HNO 3 ; fuming nitric acid in the presence of an acid such as sulphuric acid or mild nitration condition such as K O 3 in solvent like acetic acid or TFA at suitable temperature, for example the temperature range may be of 0°C-RT.
• a compound of formula (53) can be converted to a compound of formula (54) under reductive conditions using a metal such as iron or the like in the presence of an acid such as hydrochloric acid in an alcoholic solvent at a temperature range of 20-100°C.
• a compound of formula (53) can also be converted to a compound of formula (54).
• a compound of formula (54) can be converted to Intermediate-9A by reacting with an isothiocyanate derivative of formula (2') under appropriate conditions followed by cyclization using a reagent such as diisopropylcarbodiimide, FeCl3 at suitable temperature, for example the temperature range may be of 35-100°C.
• acyl compound Treatment of amine compound of formula (5) with an appropriate acyl compound (Intermediate-9A, wherein R' is alkyl such as methyl or ethyl) in the presence of a suitable reagent such as trimethyl aluminium (e.g. 2.0 M solution of trimethyl aluminium in toluene) or a strong base such as sodium hydride (NaH) in a suitable solvent such as toluene or DMF can give compound of formula (IIIA).
• a suitable reagent such as trimethyl aluminium (e.g. 2.0 M solution of trimethyl aluminium in toluene) or a strong base such as sodium hydride (NaH) in a suitable solvent such as toluene or DMF
• ester group of Intermediate-9A can be hydrolysed under suitable hydrolysis condition known in the art to obtain acid compound which can be coupled with a amine compound of formula (5) using suitable coupling reagent known in the art e.g.
• a compound of formula (55) is converted to a compound of formula (56) by reacting with benzyl bromide in the presence of a base such as potassium carbonate, triethylamine or the like in a suitable solvent such as DCM, DMF, dimethoxyethane, or THF at a temperature range of RT-100°C.
• a compound of formula (56) can be converted to a compound of formula (57) using aqueous ammonia in a sealed tube at a temperature range of 70-80°C.
• a compound of formula (57) can be converted to the compound of formula (58) under bromination condition using bromating agents such as bromine, Aq.
• HBr or HBr in acetic acid in solvent such as acetic acid at suitable temperature, for example the temperature range may be of RT-60°C.
• a compound of formula (58) is converted to the compound of formula (59) by using deprotection methods such as HBr in acetic acid at a temperature range of 60-80°C.
• a compound of formula (59) is converted to the compound of formula (60) by an appropriate alkylhalide such as 1 ,2-dibromoethane in presence of a base such as potassium carbonate, triethylamine or the like in a suitable solvent such as DMF, dimethoxy ethane, THF or dioxane at a temperature range of RT-100°C.
• a compound of formula (61) can be prepared from the compound of formula (60) by following nitration procedure known in the art, for example, using nitrating mixture i.e. cone. H 2 SO 4 and cone. HNO 3 ; fuming nitric acid in the presence of an acid such as sulphuric acid or mild nitration condition such as K O 3 in solvent like acetic acid or TFA at suitable temperature, for example the temperature range may be of 0°C-RT.
• a compound of formula (62) can be prepared from the compound of formula (61) by following oxidation procedure known in the art for example, using chromic acid, potassium dichromate, mixture of sulphamic acid and sodium chlorite in solvent such as acetone at a temperature range of 0°C-RT.
• a compound of formula (63) can be prepared from the compound of formula (62) under esterification condition using an acid catalyst such as sulphuric acid or hydrochloric acid or the like in a suitable solvent such as alcohol (R'-OH, wherein R' is Ci_ 4 alkyl such as methyl or ethyl) at suitable temperature, for example the temperature range may be of 60-100°C.
• a compound of formula (64) can be prepared from the compound of formula (63) by reacting with an amine of formula R Z -NH 2 (e.g. methyl amine or ethyl amine) in the presence of a organic base such as triethylamine, diisopropylethylamine or the like in a suitable solvent such as THF, DMF or DMSO at a suitable temperature which may be in the range of 0-100°C, preferable by using TEA in THF and at room temperature.
• an amine of formula R Z -NH 2 e.g. methyl amine or ethyl amine
• a suitable solvent such as THF, DMF or DMSO
• a Intermediate- 9B can be obtained from compound of formula (64) by reacting it with an isothiocyanate derivative of formula (2') under appropriate conditions followed by cyclization using a reagent such as diisopropylcarbodiimide, FeCl 3 at suitable temperature, for example the temperature range may be of 35-100°C.
• a reagent such as diisopropylcarbodiimide, FeCl 3 at suitable temperature, for example the temperature range may be of 35-100°C.
• Treatment of amine compound of formula (5) with an appropriate acyl compound (Intermediate-9B, wherein R' is alkyl such as methyl or ethyl) in the presence of a suitable reagent such as trimethyl aluminium (e.g.
• ester group of Intermediate-9B can be hydrolysed under suitable hydrolysis condition known in the art to obtain acid compound which can be coupled with a amine compound of formula (5) using suitable coupling reagent known in the art e.g.
• a compound of formula (53) can be converted to a compound of formula (65) by reacting with compound of formula R z -LG' (wherein R z is Ci_ 4 alkyl or C3_ 6 cycloalkyl and LG' is a good leaving group e.g. CI, Br or I) (e.g. methyl iodide or ethyl iodide) in the presence of base like NaH, Et 3 N or DIPEA in a solvent such as DMF or DCM.
• a compound of formula (65) can be converted to a compound of formula (66) under reductive conditions using a metal such as iron or the like in the presence of an acid such as hydrochloric acid in an alcoholic solvent at a temperature range of 20-100°C.
• a compound of formula (65) can also be converted to a compound of formula (66).
• a compound of formula (66) can be converted to Intermediate-9C by reacting with an isothiocyanate derivative of formula (2') under appropriate conditions followed by cyclization using a reagent such as diisopropylcarbodiimide, FeCl 3 at suitable temperature, for example the temperature range may be of 35-100°C.
• a reagent such as diisopropylcarbodiimide, FeCl 3
• suitable temperature for example the temperature range may be of 35-100°C.
• ester group of Intermediate-9C can be hydrolysed under suitable hydrolysis condition known in the art to obtain acid compound which can be coupled with a amine compound of formula (5) using suitable coupling reagent known in the art e.g. 1- ethyl-3 -(3 -dimethylaminopropyl)carbodiimide (EDCI), benzotriazol- 1 - yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), TBTU or
• HATU in the presence of a base such as triethylamine, diisopropylethylamine, N- methyl morpholine or the like in a suitable solvent such as DMF, THF, DCM or the like at an appropriate temperature range such as 20-100°C to obtain compound of formula (IIIC).
• a base such as triethylamine, diisopropylethylamine, N- methyl morpholine or the like
• a suitable solvent such as DMF, THF, DCM or the like
• LG represents 0-Ci_ 4 alkyl (e.g. OMe, OEt)
• the reaction can be performed with a suitable reagent such as trimethyl aluminium (e.g.
• the reaction can be performed with a suitable coupling reagent known 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).
• EDCI l-ethyl-3-(3-dimethylaminopropyl)carbodiimide
• a suitable solvent such as dimethylformamide (DMF) or tetrahydrofuran (THF)
• DIPEA N,N-diisoporpylethylamine
• LG represents CI the reaction can be performed in 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
• a compound of formula (66) (wherein, X 1 ' and X 2' are independently selected from NH 2 and NHR Z , with a proviso that when X 1' is NH 2 then X 2' is NHR Z and when X 1 is NHR Z then X 2 is NH 2 ) can be converted to a compound of formula (II) by first reacting with isothiocyanate derivative of formula (2') under appropriate conditions followed by cyclization using a reagent such as diisopropylcarbodiimide.
• work-up implies the following operations: distribution of the reaction mixture between the organic and aqueous phase, separation of layers, drying the organic layer over sodium sulfate, filtration and evaporation of the organic solvent.
• Purification implies purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase.
• DMSC hexadeuterodimethyl sulfoxide
• DMF N,N-dimethylformamide
• THF Tetrahydrofuran
• HOBT 1- Hydroxybenzotriazole
• DIC N,N-di-isopropyl carbodimide
• CDI ⁇ , - Carbonyldiimidazole
• TEA Triethyl amine
• DCM Dihloromethane
• DMAP 4- Dimethylaminopyridine
• EDC Ethylene dichloride
• TBTU O-(Benzotriazol-l-yl)- N,N,N',N'-tetramethyluronium tetrafluoroborate
• HATU 0-(7-Azabenzotriazol-l-yl)- N,N,N',N-tetramethyluronium hexafluorophosphate: EDCI: N-(3-
• Step-7 Preparation of N-(2-chloro-6-fluorophenyl)-5-methyl-lH-imidazo[4,5- f]quinolin-2-amine
• Step-8 Preparation of 2-((2-chloro-6-fluorophenyl)amino)-lH-imidazo[4,5- fJquinoline-5-carboxylic acid
• Step-9 Preparation of methyl 2-((2-chloro-6-fluorophenyl)amino)-lH-imidazo[4,5- f]quinoline-5-carboxylate
• Step-6 Preparation of N-(2-chloro-6-fluorophenyl)-3,5-dimethyl-3H-imidazo[4,5- f]quinoxalin-2-amine
• Step-7 Preparation of 2-((2-chloro-6-fluorophenyl)amino)-3-methyl-3H-imidazo[4,5- f]quinoxaline-5-carboxylic acid
• Step-8 Preparation of methyl 2-((2-chloro-6-fluorophenyl)amino)-3-methyl-3H- imidazo [4 , 5 -f] quinoxaline-5 -carboxy late
• the title compound was prepared by following the procedure as described for step-9 of Intermediate-2 by using 2-((2-chloro-6-fluorophenyl)amino)-3-methyl-3H- imidazo[4,5-f]quinoxaline-5-carboxylic acid (0.050 g, 0.134 mmol), methanol (10 mL) and conc.H 2 S0 4 (1 mL) to afford 0.020 g of desired product.
• Step 1 - Preparation of 2,4-difluoro-5-nitrobenzoic acid
• Step-4 Preparation of methyl 5-amino-2,4-bis(methylamino)benzoate
• Step-5 Preparation of methyl 2-((2-chloro-6-fluorophenyl)amino)-l-methyl-6-
• Step-6 Preparation of methyl 2-((2-chloro-6-fluorophenyl)amino)-l-methyl-6- (methylamino)-7-nitro-lH-benzo[d]imidazole-5-carboxylate
• Step-7 Preparation of methyl 7-((2-chloro-6-fluorophenyl)amino)-3,8-dimethyl-3,8- dihydrobenzo[l,2-d:3,4-d']diimidazole-4-carboxylate
• acetic acid 5.0 mL
• iron powder 0.500 g, 8.92 mmol
• triethyl ortho formate 0.35 g, 2.93 mmol
• step-6 product of Intermediate-4 0.200 g, 0.491 mmol
• acetic acid 5.0 mL
• iron powder 0.500 g, 8.92 mmol
• triethyl ortho acetate 0.470 g, 2.89 mmol
• Step 1 - Preparation of 2, 3-dihydrobenzo[b][l,4]dioxine-5-carbaldehyde
• Step 3 - Preparation of methyl 2,3-dihydrobenzo[b][l,4]dioxine-5-carboxylate
• DMF dimethyl methoxysulfoxide
• potassium carbonate 0.42 g, 3.2 mmol
• methyl iodide 0.54 g, 3.2 mmol
• reaction mixture was concentrated under reduced pressure and quenched with water.
• Step 4 Preparation of methyl 6,7-dibromo-2,3-dihydrobenzo[b][l,4]dioxine-5- carboxylate
• reaction mixture 16 mL was drop wise.
• the reaction mixture was further heated at 60-70 °C for 18 h. After completion of reaction, reaction mixture was quenched with ice water, ethyl acetate was added and organic layer was separated. The organic layer was washed with sat.
• Step 5 Preparation of methyl 6,7-dibromo-8-nitro-2,3-dihydrobenzo[b][l,4]dioxine-
• Step 6 Preparation of methyl 8-amino-2,3-dihydrobenzo[b][l,4]dioxine-5- carboxylate
• Step 7 Preparation of methyl 8-amino-7-nitro-2,3-dihydrobenzo[b][l,4]dioxine-5- carboxylate
• Step 8 Preparation of methyl 7,8-diamino-2,3-dihydrobenzo[b][l,4]dioxine-5- carboxylate
• Step 9 - Preparation of methyl 2-((2-chloro-6-fluorophenyl)amino)-7,8-dihydro-lH- [l,4]dioxino [2',3':3,4]benzo[l,2-d]imidazole-5-carboxylate
• Step 1 - Preparation of methyl 8-(methylamino)-7-nitro-2,3- dihydrobenzo [b] [ 1 ,4] dioxine-5 -carboxylate
• step-7 of Intermediate-6 0.500 g, 1.96 mmol
• sodium hydride 0.056 g, 2.35 mmol
• methyl iodide 0.556 g, 3.92 mmol
• reaction mixture was concentrated under reduced pressure and quenched with water.
• the reaction mixture was extracted with ethyl acetate and the organic layer was separated, dried and concentrated.
• reaction mass was purified by silica gel chromatography by eluting with 1 to 10% ethyl acetate in hexane to afford 0.595 g of desired product.
• Step 2 - Preparation of methyl 7-amino-8-(methylamino)-2,3- dihydrobenzo [b] [ 1 ,4] dioxine-5 -carboxylate
• Step 3 Preparation of methyl 2-((2-chloro-6-fluorophenyl)amino)-l-methyl-7,8- dihydro-lH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxylate
• Step-l -Preparation of methyl 2-((2-chloro-6-methylphenyl)amino)-l-methyl-7,8- dihydro-lH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxylate
• Step-2 -Preparation of 2-((2-chloro-6-methylphenyl)amino)-l-methyl-7,8-dihydro- lH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxylic acid
• Step-1 -Preparation of 3-(benzylo -2-methyl-4H-pyran-4-one
• DMF dimethyl methyl
• potassium carbonate 2.6 g, 0.0189 mol
• the reaction mass was stirred at RT for 30 minutes.
• the reaction mixture was added benzyl bromide (2.98 g, 0.017 mol) and continued stirring for 6 h at RT.
• the reaction mass was quenched with water and extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulphate and concentrated to afford 2.3 g of desired product.
• Step-2 -Preparation of 3-(benzylo -2-methylpyridin-4(lH)-one
• Step-4 -Preparation of 5-bromo-2-methylpyridine-3,4-diol
• Step-5 Preparation of 8-bromo-5-methyl-2,3-dihydro-[l,4]dioxino[2,3-c]pyridine
• Step-6 Preparation of 8-bromo-5-methyl-7-nitro-2,3-dihydro-[l,4]dioxino[2,3- c]pyridine
• Step-7 Preparation of 8-bromo-7-nitro-2,3-dihydro-[l,4]dioxino[2,3-c]pyridine-5- carboxylic acid
• 8-bromo-5-methyl-7-nitro-2,3-dihydro-[l,4]dioxino[2,3- c]pyridine 0.035 g, 0.125 mol
• H 2 SO 4 sodium dichromate (0.094 g, 0.318 mol) was added in portions at 0°C.
• the reaction mass was stirred at RT for 12 h. After completion of reaction, the reaction mass was quenched with ice and extracted with ethyl acetate.
• Step-8 Preparation of methyl 8-bromo-7-nitro-2,3-dihydro-[l,4]dioxino[2,3- c]pyridine-5 -carboxylate
• Step-9 Preparation of methyl 8-(methylamino)-7-nitro-2,3-dihydro-[l,4]dioxino[2,3- c]pyridine-5 -carboxylate
• Step-10 Preparation of methyl 7-amino-8-(methylamino)-2,3-dihydro- [ 1 ,4]dioxino[2,3-c]pyridine-5-carboxylate
• Step-11 Preparation of methyl 2-((2-chloro-6-fluorophenyl)amino)-l-methyl-7,8- dihydro-lH-[l,4]dioxino[2,3-d]imidazo[4,5-b]pyridine-5-carboxylate
• Step-1 -Preparation of 5-methyl-7-nitro-2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-8
• the title compound was prepared by following the procedure as described for step-2 of intermediate- 11 by using 8-bromo-5-methyl-7-nitro-2,3-dihydro-[l,4]dioxino[2,3- c]pyridine (0.100 g), aq.N3 ⁇ 4 (2.0 mL), acetonitrile (2.0 mL), copper iodide (Cul, cat. amt.) to afford 0.080 g of desired product.
• Step-2 -Preparation of 5-methyl-2,3-dihydro-[l,4]dioxino[2,3-c]pyridine-7,8-diamine
• the title compound was prepared by following the procedure as described for step-2 of Intermediate-2 by using 5-methyl-7-nitro-2,3-dihydro-[l,4]dioxino[2,3-c]pyridin- 8-amine (0.450 g), iron powder (cat.amt.), cone. HC1 (3.0 mL), methanol (5.0 mL) to afford 0.250 g of desired product.
• Step 1 - Preparation of methyl 8-(ethylamino)-7-nitro-2,3-dihydrobenzo[b][l,4] dioxine-5 -carboxylate
• step-7 of Intermediate-6, 0.500 g, 1.96 mmol
• DMF dimethyl sulfoxide
• Step 2 - Preparation of methyl 7-amino-8-(ethylamino)-2,3-dihydrobenzo[b][l,4] dioxine-5 -carboxylate
• Step 3 Preparation of methyl 2-((2-chloro-6-fluorophenyl)amino)-l-ethyl-7,8- dihydro-lH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxylate
• Step 1 - Preparation of l-(2-cyclopropylethynyl)-2-fluoro-4-nitrobenzene
• Step 2 Preparation of 6-(cyclopropylethynyl)pyridin-3 -amine
• the title compound was prepared by following the procedure as described for Example- 1 by using methyl 2-((2-chloro-6-fluorophenyl)amino)-3-methyl-3H- imidazo[4,5-f]quinoxaline-5-carboxylate (Intermediate-3, 0.020 g, 0.051 mmol), 3- trifluoromethyl aniline (0.012 g, 0.077 mmol), trimethyl aluminum (2.0 M solution in toluene) (0.007 g, 0.09 mmol) and dry toluene (3 mL) to afford 0.010 g of desired product.
• Example-3 7-((2-Chloro-6-fluorophenyl)amino)-3,8-dimethyl-N-(3-(trifluoromethyl)ph dihydrobenzo[l,2-d:3,4- ']diimidazole-4-carboxamide
• the title compound was prepared by following the procedure as described for Example-1 by using methyl 7-((2-chloro-6-fluorophenyl)amino)-2,3,8-trimethyl-3,8- dihydrobenzo[l,2-d:3,4-d']diimidazole-4-carboxylate (Intermediate-5, 0.100 g, 0.249 mmol), 3-trifluoromethyl aniline (0.060 g, 0.370 mmol), trimethyl aluminum ( 2.0 M solution in toluene) (0.035 g, 0.492 mmol) and dry toluene (3 mL) to afford 0.005 g of desired product.
• the title compound was prepared by following the procedure as described for Example- 19 by using 2-((2-chloro-6-fluorophenyl)amino)-l-methyl-7,8-dihydro-lH- [l,4]dioxino[2,3-d]imidazo[4,5-b]pyridine-5-carboxylic acid (Intermediate- 12, 0.100 g, 0.264 mmol), DMF (0.5 mL), BOP (0.291 g, 0.660 mmol), DIPEA (0.085g, 0.660 mmol) and (lr,4r)-4-(trifluoromethyl)cyclohexanamine hydrochloride (0.080 g, 0.396 mmol) to afford 0.040 g of desired product.
• the title compound was prepared by following the procedure as described for Example-5 by using methyl 2-((2-chloro-6-methylphenyl)amino)-7,8-dihydro-lH- [l ,4]dioxino[2',3':3,4]benzo[l ,2-d]imidazole-5-carboxylate (Intermediate- 14, 0.050g, 0.160 mmol), 3-amino-5-fluoro benzotrifluoride (0.043 g, 0.238 mmol), trimethyl aluminum (2.0 M solution in toluene) (0.5 mL), toluene (2.0 mL) to afford 0.012 g of the title product.
• the title compound was prepared by following the procedure as described for Example- 13 by using 2-[(2-chloro-6-methylphenyl)amino]-7,8-dihydro-iH- [l,4]dioxino[2,3-e]benzimidazole-5-carboxylic acid (Intermediate- 17, 0.100 g, 0.275 mmol), DMF (0.5 mL), BOP (0.225 g, 0.460 mmol), DIPEA (0.085g, 0.660 mmol) and (lr,4r)-4-(trifluoromethyl)cyclohexanamine hydrochloride (0.080 g, 0.396 mmol) to afford 0.040 g of desired product.
• Example-36 2-((2-Chloro-6-fluorophenyl)amino)- 1 -methyl-N-((( lr,4r)-4- (trifluoromethyl)cyclohexyl)methyl)-7,8-dihydro-lH-[l ,4]dioxino[2',3 ⁇ 3,4]b d]imidazole-5 -carboxamide
• the title compound was prepared by following the procedure as described for Example-5 by using methyl 2-((2-chloro-6-methylphenyl)amino)-7,8-dihydro-lH- [l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxylate (Intermediate- 14, 0.050g, 0.160 mmol), 6-(cyclopropylethynyl)pyridin-3-amine (Intermediate-20, 0.038 g, 0.238 mmol), trimethyl aluminum (2.0 M solution in toluene) (0.5 mL), toluene (2.0 mL) to afford 0.016 g 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 an anti-PGE 2 antibody based detection method.
• Recombinant human mPGES-1 was generated in-house by expression in CHO cells (Ouellet M et al. (2002), Protein Expression and Purification 26: 489 - 495).
• the 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. The final concentration of DMSO in reaction was 0.5 % (v/v).
• Negative controls were comprised of all assay reagents except the enzyme. Positive controls were comprised of the 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.
• Inhibition of mPGES-1 enzyme activity was measured using the percent of reaction occurring in the positive control. Concentration response curves were plotted using percent inhibition of maximum enzyme reaction. The IC 50 value was calculated from the concentration response curve by nonlinear regression analysis using GraphPad PRISM software.
• the compounds prepared were tested using the above assay procedure and the results obtained are given in Table 1. Percentage inhibition at concentrations of 1.0 ⁇ and 10.0 ⁇ are given in the table along with IC 50 (nM) details for selected examples.
• the compounds prepared were tested using the above assay procedure and were found to have IC 50 less than 200nM, preferably less than ⁇ , more preferably less than 50nM or most preferably less than 20nM.
• 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. The 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.
• DMSO dimethyl sulfoxide
• the final concentration of DMSO in the reaction was 0.55%) (v/v).
• Cells were treated with test compounds for 30 minutes followed by addition of IL- ⁇ ⁇ at a final concentration of 10 ng/mL for 16-20 h. Plates were then centrifuged at 1000 rpm for 10 min at 4°C. Supernatants were collected & analyzed by the addition of PGE 2 -D2 & anti-PGE 2 cryptate conjugate supplied by the CisBio HTRF kit in a 96 well half area blackwell EIA/RIA plate. The assay plate was incubated overnight at 4-5° C before being read in Artemis (K-101) (Japan) HTRF plate reader and levels of PGE 2 calculated by extrapolation from the standard curve.
• concentration response curves were plotted as % of maximal response obtained in the absence of test antagonist.
• the IC 50 value was calculated from the concentration response curve by nonlinear regression analysis using GraphPad PRISM software.

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