WO2013153535A1 - TRICYCLIC COMPOUNDS AS mPGES-1 INHIBITORS - Google Patents

TRICYCLIC COMPOUNDS AS mPGES-1 INHIBITORS Download PDF

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Publication number
WO2013153535A1
WO2013153535A1 PCT/IB2013/052921 IB2013052921W WO2013153535A1 WO 2013153535 A1 WO2013153535 A1 WO 2013153535A1 IB 2013052921 W IB2013052921 W IB 2013052921W WO 2013153535 A1 WO2013153535 A1 WO 2013153535A1
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Prior art keywords
methyl
trifluoromethyl
chloro
amino
dihydro
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PCT/IB2013/052921
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French (fr)
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Laxmikant Atmaram Gharat
Nagarajan Muthukaman
Sanjay Deshmukh
Neelima Khairatkar-Joshi
Vidya Ganapati Kattige
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Glenmark Pharmaceuticals S.A.
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Publication of WO2013153535A1 publication Critical patent/WO2013153535A1/en

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    • 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.

Abstract

The present disclosure is directed to compounds of formula (I), and pharmaceutically acceptable salts thereof, as m PGES-1 inhibitors. These compounds are inhibitors of the microsomal prostaglandin E synthase-1 (m PGES-1) enzyme and are therefore useful in the treatment of pain and/or inflammation from a variety of diseases or conditions, such as asthma, osteoarthritis, rheumatoid arthritis, acute or chronic pain and neurodegenerative diseases.

Description

TRICYCLIC COMPOUNDS AS mPGES-1 INHIBITORS
Related Applications
This application claims the benefit of Indian Provisional Application Nos. 1214/MUM/2012 filed on April 13, 2012; and 2887/MUM/2012 filed on October 01, 2012; and U.S. Provisional Application Nos. 61/640,419 filed on April 30, 2012; and 61/716,897 filed on October 22, 2012; each of which is hereby incorporated by reference in its entirety.
Technical Field
The present application relates to tricyclic compounds which may be useful microsomal prostaglandin E synthase- 1 (mPGES-1) inhibitors.
Background of the Invention
There are many diseases or disorders that are inflammatory in their nature. One of the major problems associated with existing treatments of inflammatory conditions is inadequate efficacy and/or the prevalence of side effects. 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.
The enzyme cyclooxygenase (COX) converts arachidonic acid to an unstable intermediate, prostaglandin H2 (PGH2), which is further converted to other prostaglandins, including PGE2, PGF2a, PGD2, prostacyclin and thromboxane A2. These arachidonic acid metabolites are known to have pronounced physiological and pathophysiological activity, including pro-inflammatory effects. The COX enzyme exists in two forms, one that is constitutively expressed in many cells and tissues (COX-1), and another that in most cells and tissues is induced by pro-inflammatory stimuli, such as cytokines, during an inflammatory response (COX-2).
Among all prostaglandin metabolites, PGE2 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 PGE2, 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 PGE2. However, the inhibition of COXs has the disadvantage in that it results in the reduction of the formation of all metabolites of PGH2, thereby decreasing the beneficial properties of some of the metabolites. In view of this, drugs which act by inhibition of COXs are therefore suspected to cause adverse biological effects. For example, 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.
A combination of pharmacological, genetic and neutralizing antibody approaches demonstrates the importance of PGE2 in inflammation. The conversion of PGH2 to PGE2 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. PGE2 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 PGH2 which is a substrate for mPGES-1, the terminal enzyme transforming PGH2 to the pro-inflammatory PGE2.
PGH2 may be transformed to PGE2 by prostaglandin E synthases (PGES). There are two microsomal prostaglandin E synthases (mPGES-1 and mPGES-2), and one cytosolic prostaglandin E synthase (cPGES). Thus, agents that are capable of inhibiting the action of mPGES-1, and thus reducing the formation of the specific arachidonic acid metabolite PGE2, are beneficial in the treatment of inflammation. Further, 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.
Blocking the formation of PGE2 in animal models of inflammatory pain results in reduced inflammation, pain and fever response (Kojima et. al, The Journal of Immunology 2008, 180, 8361-6; Xu et. al., The Journal of Pharmacology and Experimental Therapeutics 2008, 326, 754-63). In abdominal aortic aneurism, inflammation leads to connective tissue degradation and smooth muscle apoptosis ultimately leading to aortic dilation and rupture. In animals lacking mPGES-1 a slower disease progression and disease severity has been demonstrated (Wang et. al, Circulation, 2008, 117, 1302-1309).
Several lines of evidence indicate that PGE2 is involved in malignant growth. PGE2 facilitates tumor progression by stimulation of cellular proliferation and angiogenesis and by modulation of immunosupression. In support of a role for PGE2 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).
In atherosclerosis inflammation of the vasculature leads to atheroma formation that eventually may progress into infarction. In patients with carotid atherosclerosis an increase in mPGES-1 in plaque regions has been reported (Gomez-Hernandez Atherosclerosis 2006,187, 139-49). In an animal model of atherosclerosis, 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).
International Publication Nos. WO 2006/063466, WO 2007/059610, WO 2010/034796, WO 2010/100249, WO 2012/055995, WO 2012/110860 and WO 2013/038308 Al disclose numerous heterocyclic compounds which are stated to be inhibitors of microsomal prostaglandin E synthase- 1 (mPGES-1) enzyme.
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. Summary of the Invention
aspect, the present invention relates to a compound of formula (I)
Figure imgf000005_0001
wherein,
A is selected from C6_i4aryl, 5-14 membered heteroaryl, and 3-15 membered heterocyclyl;
Z is selected from N and CR1;
Y1 is selected from O, N and NR4;
Y2 is selected from CR3, CR5R6, N and NR4;
Y3 is selected from CR3, CR5R6, N and NR4;
Y4 is selected from O, CR3, CR5R6, N and NR4;
X1 is selected from N and NRZ;
X2 is selected from N and NRZ;
dotted line [— ] inside the ring represents an optional bond;
with a proviso that when Y1 is O then Y2 and Y3 are CR5R6 and Y4 is O;
with another proviso that, when Y1 is N or NR4 then at least one of the Y2, Y3 and Y4 is CR3 or CR5R6;
with another proviso that, when Y1 is N or Y2, Y3 and Y4 are independently selected from N or CR3 then dotted line [— ] inside the ring represents a bond;
with another proviso that, when X1 is N then X2 is NRZ or when X2 is N then X1 is NRZ and dotted line [— ] inside the ring attached to N only represents a bond;
L is a bond or is selected from -(CRxRy)n- and -C(O)-;
each occurrence of R1 is independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, Ci_8alkyl, C2_i0alkenyl, C2_i0alkynyl, Ci_8alkoxyCi_8alkyl, haloCi.galkyl, hydroxyCi.galkyl, C3_i2cycloalkyl, C3_8CycloalkylCi_galkyl, C3_ gcycloalkenyl, C3-8cycloalkenylCi_8alkyl, C6-14aryl, C6-i4arylCi_galkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi-salkyl, 5-14 membered heteroaryl, 5-14 membered heteroarylCi_8alkyl, -C(0)Ra, -C(0)NRaRb, -C(0)ORa, -NRaRb, - NRaC(0)Rb, -NRaC(0)NRaRb, -NRaC(0)ORb, -N(Ra)S02Rb, -OC(0)Ra, -OC(0)ORa, -OC(0)NRaRb, -S(0)Ra, -S02Ra, -S(0)NRaRb, -S02NRaRb and -SRa;
R2 is selected from hydrogen, halogen, nitro, cyano, hydroxyl, Ci_8alkyl, C2_ loalkenyl, C2_i0alkynyl, Ci_8alkoxy, Ci_8alkoxyCi_8alkyl, haloCi_8alkyl, haloCi_ 8alkoxy, hydroxyCi_8alkyl, C3_i2cycloalkyl, C3_8cycloalkylCi_8alkyl, C3_8cycloalkenyl, C3_8cycloalkenylCi_8alkyl, C6-14aryl, C6-i4aryloxy, C6_i4arylCi_8alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi_8alkyl, 5-14 membered heteroaryl, 5-14 membered heteroarylCi_8alkyl, -C(0)Ra, -C(0)NRaRb, -C(0)ORa, -NRaRb, - NRaC(0)Rb, -NRaC(0)NRaRb, -NRaC(0)ORb, -N(Ra)S02Rb, -OC(0)Ra, -OC(0)ORa, -OC(0)NRaRb, -S(0)Ra, -S02Ra, -S(0)NRaRb, -S02NRaRb and -SRa;
each occurrence of R3 is independently selected from hydrogen, Ci_8alkyl, C3- i2cycloalkyl, C3-8cycloalkylCi_8alkyl, C6-14aryl, C6-i4arylCi_8alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi_8alkyl, 5-14 membered heteroaryl, 5-14 membered heteroarylCi_8alkyl; -C(0)Ra, -C(0)NRaRb and -NRaRb;
each occurrence of R4 is independently selected from hydrogen, Ci_8alkyl, C3- i2cycloalkyl, C3-8cycloalkylCi_8alkyl, C6-14aryl, C6-i4arylCi_8alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi_8alkyl, 5-14 membered heteroaryl, 5-14 membered heteroarylCi_8alkyl; -C(0)Ra, -C(0)NRaRb and -NRaRb;
each occurrence of R5 is independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, Ci_8alkyl, C2_ioalkenyl, C2_ioalkynyl, Ci_8alkoxy, Ci_8alkoxyCi_ 8alkyl, haloCi_8alkyl, haloCi_8alkoxy, hydroxyCi_8alkyl, C3_i2cycloalkyl, C3- 8cycloalkylCi_8alkyl, C3_8cycloalkenyl, C3_8cycloalkenylCi_8alkyl, C6-14aryl, C6- i4aryloxy, C6_i4arylCi_8alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylC i_8alkyl, 5-14 membered heteroaryl, 5-14 membered heteroarylCi_8alkyl, -C(0)Ra, -C(0)NRaRb, -C(0)ORa, -NRaRb, -NRaC(0)Rb, -NRaC(0)NRaRb, - NRaC(0)ORb, -N(Ra)S02Rb, -OC(0)Ra, -OC(0)ORa, -OC(0)NRaRb, -S(0)Ra, - S02Ra, -S(0)NRaRb, -S02NRaRb and -SRa;
each occurrence of R6 is independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, Ci_8alkyl, C2_ioalkenyl, C2_ioalkynyl, Ci_8alkoxy, Ci_8alkoxyCi_ 8alkyl, haloCi_8alkyl, haloCi_8alkoxy, hydroxyCi_8alkyl, C3_i2cycloalkyl, C3- 8cycloalkylCi_8alkyl, C3_8cycloalkenyl, C3_8cycloalkenylCi_8alkyl, C6-14aryl, C6- i4aryloxy, C6_i4arylCi_8alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylC i_8alkyl, 5-14 membered heteroaryl, 5-14 membered heteroarylCi_8alkyl, -C(0)Ra, -C(0)NRaRb, -C(0)ORa, -NRaRb, -NRaC(0)Rb, -NRaC(0)NRaRb, - NRaC(0)ORb, -N(Ra)S02Rb, -OC(0)Ra, -OC(0)ORa, -OC(0)NRaRb, -S(0)Ra, - S02Ra, -S(0)NRaRb, -S02NRaRb and -SRa;
R7 is selected from hydrogen, Ci_8alkyl, C3_i2cycloalkyl, C3_8cycloalkylCi_ 8alkyl, C6_i4aryl, C6-i4arylCi_8alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylC i_8alkyl, 5-14 membered heteroaryl, 5-14 membered heteroarylCi_galkyl; -C(0)Ra, -C(0)NRaRb and -NRaRb;
each occurrence of R8 is independently selected from halogen, nitro, cyano, hydroxyl, Ci_galkyl, C2_ioalkenyl, C2_ioalkynyl, Ci_galkoxy, Ci_galkoxyCi_galkyl, haloCi.galkyl, haloCi_galkoxy, hydroxyCi_galkyl, C3_i2cycloalkyl, C3_gcycloalkylCi_ galkyl, C3_gcycloalkenyl, C3_gcycloalkenylCi_galkyl, C6-14aryl, C6-i4aryloxy, C6- i4arylCi_galkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi_galkyl, 5-14 membered heteroaryl, 5-14 membered heteroarylCi_galkyl, -C(0)Ra, - C(0)NRaRb, -C(0)ORa, -NRaRb, -NRaC(0)Rb, -NRaC(0)NRaRb, -NRaC(0)ORb, - N(Ra)S02Rb, -OC(0)Ra, -OC(0)ORa, -OC(0)NRaRb, -S(0)Ra, -S02Ra, -S(0)NRaRb, - S02NRaRb and -SRa;
each occurrence of Ra and Rb, which may be the same or different, are independently selected from hydrogen, Ci_8alkyl, Ci_8alkoxyCi_galkyl, haloCi_8alkyl, hydroxyCi.galkyl, C3_i2cycloalkyl, C3_gcycloalkylCi_galkyl, C6-14aryl, C6-i4arylCi_8alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi_galkyl, 5-14 membered heteroaryl and 5-14 membered heteroarylCi_galkyl; or Ra and Rb 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 Rx and Ry, which may be the same or different, are independently selected from hydrogen, Ci_galkyl, Ci_galkoxyCi_galkyl, haloCi_galkyl, hydroxyCi.galkyl, C3_i2cycloalkyl, C3_gcycloalkylCi_galkyl, C6-14aryl, C6-i4arylCi_galkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi_galkyl, 5-14 membered heteroaryl and 5-14 membered heteroarylCi_galkyl; or Rx and Ry 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 Rz is selected from hydrogen, Ci_8alkyl, C3_i2cycloalkyl, C3_ gcycloalkylCi-galkyl, C6-14aryl, C6_i4arylCi_galkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi-salkyl, 5-14 membered heteroaryl, 5-14 membered heteroarylCi_8alkyl; -C(0)Ra, -C(0)NRaRb and -NRaRb;
'm' is an integer ranging from 0 to 5, both inclusive;
'n' is an integer ranging from 1 to 2, both inclusive; and
'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. For example, the invention provides compounds of formula (I) as defined above wherein L is a bond (according to an embodiment defined below), R7 is hydrogen (according to another embodiment defined below) and 'm' is 1 or 2 (according to yet another embodiment defined below).
According to one embodiment, specifically provided are compounds of formula (I), in which Z is N.
According to another embodiment, specifically provided are compounds of formula (I), in which Z is CR1.
According to yet another embodiment, specifically provided are compounds of formula (I), in which Y1 is O, Y2 and Y3 are CR5R6 and Y4 is O.
According to yet another embodiment, specifically provided are compounds of formula (I), in which Y1 is N, and Y2, Y3 and Y4 are CR3.
According to yet another embodiment, specifically provided are compounds of formula (I), in which Y1 is N, Y2 and Y3 are CR3 and Y4 is N.
According to yet another embodiment, specifically provided are compounds of formula (I), in which Y1 is NR4, Y2 is absent as q is 0, Y3 is CR3 and Y4 is N.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R3 is hydrogen or Ci_4alkyl (e.g. methyl). According to yet another embodiment, specifically provided are compounds of formula (I), in which R3 is hydrogen or methyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R4 is hydrogen or Ci_4alkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which R4 is hydrogen or methyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R5 is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R6 is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R5 andR6 are hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (I), in which Y1 is O, Y2 and Y3 are CH2 and Y4 is O.
According to yet another embodiment, specifically provided are compounds of formula (I), in which Y1 is N, Y2, Y3 and Y4 are CH.
According to yet another embodiment, specifically provided are compounds of formula (I), in which Y1 is N, Y2 and Y3 are CH and Y4 is N.
According to yet another embodiment, specifically provided are compounds of formula (I), in which Y1 is N, Y2 and Y3 are CH and Y4 is N or CH.
According to yet another embodiment, specifically provided are compounds of formula (I), in which Y1 is NCH3, Y2 is absent, Y3 is CH or CCH3 and Y4 is N.
According to yet another embodiment, specifically provided are compounds of formula (I), in which Z is N or CH.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R7 is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (I), in which X1 is N and X2 is NRZ.
According to yet another embodiment, specifically provided are compounds of formula (I), in which X1 is NRZ and X2 is N.
According to yet another embodiment, specifically provided are compounds of formula (I), in which Rz is hydrogen or Ci_4alkyl (e.g. methyl or ethyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which Rz is hydrogen, methyl or ethyl. According to yet another embodiment, specifically provided are compounds of formula (I), in which X1 is NH or NCH3 and X2 is N.
According to yet another embodiment, specifically provided are compounds of formula (I), in which X1 is N and X2 is NH, NCH3 or NCH2CH3.
According to yet another embodiment, specifically provided are compounds of formula (I), in which L is a bond.
According to yet another embodiment, specifically provided are compounds of formula (I), in which A is C6_i4aryl (e.g. phenyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which A is phenyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R2 is Ci_8alkyl, -C(0)NRaRb or -C(0)ORa.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R2 is methyl or -C(0)NRaRb.
According to yet another embodiment, specifically provided are compounds of formula (I), in which each occurrence of Ra and Rb are independently selected from hydrogen, Ci_8alkyl (e.g. methyl or ethyl), C3_i2cycloalkyl (e.g. cyclohexyl, 4,4- dimethylcyclohexyl, trans-4-(trifluoromethyl)cyclohexyl or (lr,4r)-4- (trifluoromethyl)cyclohexyl), C3_8CycloalkylCi_galkyl (e.g. ((lr,4r)-4- (trifluoromethyl)cyclohexyl)methyl or trans-4-(trifluoromethyl)cyclohexylmethyl), C6_ i4aryl (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), C6_i4arylCi_8alkyl (e.g. 3-(trifluoromethyl)benzyl or 3 -fluoro-5 -(trifluoromethyl)benzyl) and 5-14 membered heteroaryl (e.g. 6-(cyclopropylethynyl)pyridin-3-yl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which each occurrence of Ra and Rb 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-
(trif uoromethyl)phenyl, 3 -fluoro-5 -(trifluoromethyl)phenyl, 2-tl uoro-5 -
{trifluoroniethyl)phenyl, 4-(cyclopropylethynyl)-3-fluorophenyl, 3- (trifluoromethyl)benzyl, 3-fluoro-5-(trifiuoromethyl)benzyl and 6-
(cyclopropylethynyl)pyridin-3-yl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R2 is -C(0)NRaRb. In this embodiment, one of the Ra and Rb is hydrogen and other is C3-i2cycloalkyl (e.g. cyclohexyl, 4,4-dimethylcyclohexyl, trans- 4-(trifluoromethyl)cyclohexyl or (lr,4r)-4-(trifluoromethyl)cyclohexyl), C3_ 8CycloalkylCi_8alkyl (e.g. ((lr,4r)-4-(trifluoromethyl)cyclohexyl)methyl or trans-4- (trifluoromethyl)cyclohexylmethyl), C6-i4aryl (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-i4arylCi_galkyl (e.g. 3-(trifluoromethyl)benzyl or 3-fluoro-5- (trifluoromethyl)benzyl) and 5-14 membered heteroaryl (e.g. 6- (cyclopropylethynyl)pyridin-3 -yl) .
According to yet another embodiment, specifically provided are compounds of formula (I), in which R2 is -C(0)NRaRb. In this embodiment, Ra is hydrogen and Rb 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_ 8alkyl (e.g. methyl), haloCi.galkyl (e.g. trifluoromethyl) and C2-ioalkynyl (e.g. cy clopropy lethyny 1) .
According to yet another embodiment, specifically provided are compounds of formula (I), in which R2 is -C(0)NRaRb. In this embodiment, Ra is hydrogen and Rb 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.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R2 is -C(0)NRaRb. In this embodiment, Ra is hydrogen and Rb 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-
(trifluoromethyl)phenyl, 4-fluoro-3 -(trifluoromethyl)phenyl, 3 -fluoro-5 -
(trifluoromethyl )phenyl, 2~fluoro-5~(trifluoiOmeihyl)phenyl, 4-(cyclopropy lethyny l)-3- fluorophenyl, 3-(trifluoromethyl)benzyl, 3 -fluoro-5 -(trifluoromethyl)benzyl or 6- (cyclopropylethynyl)pyridin-3-yl. According to yet another embodiment, specifically provided are compounds of formula (I), in which R2 is -C(0)NRaRb In this embodiment, one of the Ra and Rb is hydrogen and other is substituted phenyl. In this embodiment, substituent(s) on phenyl may be one or more and are independently selected from fluorine, methyl, trifluoromethyl and cyclopropylethynyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R8 is independently selected from halogen (e.g. F, CI, Br or I), Ci_4alkyl (e.g. methyl, ethyl or tert-butyl) and haloCi_galkyl (e.g. trifluoromethyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which R8 is independently selected from CI, F and CH3.
According to yet another embodiment, specifically provided are compounds of formula (I), in which 'm' is 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R8 is independently selected from CI, F and CH3 and 'm' is 2.
According to yet another embodiment, specifically provided are compounds of formula (I), in which 'q' is 0 or 1.
According to one embodiment, specifically provided are compounds of formula (I) with an IC50 value of less than 500 nM, preferably, less than 100 nM, more preferably, less than 50 nM with respect to mPGES-1 activity.
Further embodiments relating to groups L, Z, ring A, Y1, Y2, Y3, Y4, X1, X2, R2, R7, R8, m and q (and groups defined therein) are described hereinafter in relation to the compounds of formula (II), formula (III) and formula (IV). It is to be understood that these embodiments are not limited to use in conjunction with formula (II), (III) and (IV), but apply independently and individually to the compounds of formula (I). For example, in an embodiment described hereinafter, the invention specifically provides compounds of formula (II), (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).
Accordingly the invention provides a compound of formula (II):
Figure imgf000013_0001
or a pharmaceutically acceptable salt thereof,
wherein,
Z is selected from N and CR1;
Y1 is selected from O, N and NR4;
Y2 is selected from CR3 and CR5R6;
Y3 is selected from CR3 and CR5R6;
Y4 is selected from O, CR3 and N;
X1 is selected from N and NRZ;
X2 is selected from N and NRZ;
dotted line [— ] inside the ring represents an optional bond;
with a proviso that when Y1 is O then Y2 and Y3 are CR5R6 and Y4 is O;
with another proviso that, when Y1 is N then Y2 and Y3 are CR3 and Y4 is N or CR3 and dotted lines [— ] inside the ring represents a bond;
with another proviso that, when Y1 is NR4 then Y2 is absent as q is 0, Y3 is CR3 and Y4 is N and the dotted line [— ] between Y3 and Y4 inside the ring represents a bond;
with another proviso that, when X1 is N then X2 is NRZ or when X1 is NRZ then X2 is N and dotted line [— ] inside the ring attached to N only represents a bond;
R1 is selected from hydrogen, halogen, cyano, hydroxyl and Ci_8alkyl;
R2 is selected from Ci_8alkyl, -C(0)NRaRb and -C(0)ORa;
each occurrence of R3 is independently selected from hydrogen, Ci_8alkyl, and C3_i2cycloalkyl;
each occurrence of R4 is independently selected from hydrogen, Ci_8alkyl, and C3_i2cycloalkyl;
each occurrence of R5 is hydrogen;
each occurrence of R6 is independently selected from hydrogen and Ci_4alkyl; each occurrence of R8 is independently selected from halogen, cyano, hydroxyl, Ci_8alkyl, haloCi_8alkyl, Ci_8alkoxy and haloCi_8alkoxy; each occurrence of Ra and Rb which may be the same or different, are independently selected from hydrogen, Ci.galkyl, haloCi.galkyl, C3_i2cycloalkyl, C3_ 8cycloalkylCi_8alkyl, C6_i4aryl, C6-i4arylCi_8alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi_galkyl, 5-14 membered heteroaryl and 5-14 membered heteroarylCi_8alkyl; or Ra and Rb 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 Rz is independently selected from hydrogen, Ci_8alkyl and C3_6cycloalkyl;
'm' is an integer ranging from 0 to 5, both inclusive; and
'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. For example, the invention provides compounds of formula (II) as defined above wherein Z is N or CH (according to an embodiment defined below), X1 is N and X2 is NH, NCH3 or NCH2CH3 (according to another embodiment defined below) and 'm' is 1 or 2 (according to yet another embodiment defined below).
According to one embodiment, specifically provided are compounds of formula (II), in which Z is N.
According to another embodiment, specifically provided are compounds of formula (II), in which Z is CR1.
According to yet another embodiment, specifically provided are compounds of formula (II), in which Y1 is O, Y2 and Y3 are CR5R6 and Y4 is O.
According to yet another embodiment, specifically provided are compounds of formula (II), in which Y1 is N, and Y2, Y3 and Y4 are CR3.
According to yet another embodiment, specifically provided are compounds of formula (II), in which Y1 is N, Y2 and Y3 are CR3 and Y4 is N.
According to yet another embodiment, specifically provided are compounds of formula (II), in which Y1 is NR4, Y2 is absent as q is 0, Y3 is CR3 and Y4 is N. According to yet another embodiment, specifically provided are compounds of formula (II), in which R1 is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (II), in which R3 is hydrogen or Ci_4alkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (II), in which R3 is hydrogen or methyl.
According to yet another embodiment, specifically provided are compounds of formula (II), in which R4 is hydrogen or Ci_4alkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (II), in which R4 is hydrogen or methyl.
According to yet another embodiment, specifically provided are compounds of formula (II), in which R6 is hydrogen or methyl.
According to yet another embodiment, specifically provided are compounds of formula (II), in which R5 and R6 are hydrogen.
According to another embodiment, specifically provided are compounds of formula (II), in which Z is N or CH.
According to yet another embodiment, specifically provided are compounds of formula (II), in which Y1 is O, Y2 and Y3 are CH2 and Y4 is O.
According to yet another embodiment, specifically provided are compounds of formula (II), in which Y1 is N, Y2, Y3 and Y4 are CH.
According to yet another embodiment, specifically provided are compounds of formula (II), in which Y1 is N, Y2 and Y3 are CH and Y4 is N.
According to yet another embodiment, specifically provided are compounds of formula (II), in which Y1 is N, Y2 and Y3 are CH and Y4 is N or CH.
According to yet another embodiment, specifically provided are compounds of formula (II), in which Y1 is NCH3, Y2 is absent, Y3 is CH or CCH3 and Y4 is N.
According to yet another embodiment, specifically provided are compounds of formula (II), in which X1 is N and X2 is NRZ.
According to yet another embodiment, specifically provided are compounds of formula (II), in which X1 is NRZ and X2 is N.
According to yet another embodiment, specifically provided are compounds of formula (II), in which Rz is hydrogen or Ci_4alkyl (e.g. methyl or ethyl).
According to yet another embodiment, specifically provided are compounds of formula (II), in which Rz is hydrogen, methyl or ethyl. According to yet another embodiment, specifically provided are compounds of formula (II), in which X1 is NH or NCH3 and X2 is N.
According to yet another embodiment, specifically provided are compounds of formula (II), in which X1 is N and X2 is NH, NCH3 or NCH2CH3.
According to yet another embodiment, specifically provided are compounds of formula (II), in which R2 is methyl or -C(0)NRaRb.
According to yet another embodiment, specifically provided are compounds of formula (II), in which each occurrence of Ra and Rb are independently selected from hydrogen, Ci.galkyl (e.g. methyl or ethyl), C3-i2cycloalkyl (e.g. cyclohexyl, 4,4- dimethylcyclohexyl, trans-4-(trifluoromethyl)cyclohexyl or (lr,4r)-4- (trifluoromethyl)cyclohexyl), C3_8CycloalkylCi_galkyl (e.g. ((lr,4r)-4- (trifluoromethyl)cyclohexyl)methyl or trans-4-(trifluoromethyl)cyclohexylmethyl), C6_ i4aryl (e.g. 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 4-fluoro-3- (trifluoromethyl)phenyl, 3 -fluoro-5 -(trifluoromethyl)phenyl, 2~fl uoro-5~
(tri fluorom et hy 1) ph enyl or 4-(cyclopropylethynyl)-3-fluorophenyl), C6-i4arylCi_8alkyl (e.g. 3-(trifluoromethyl)benzyl or 3 -fluoro-5 -(trifluoromethyl)benzyl) and 5-14 membered heteroaryl (e.g. 6-(cyclopropylethynyl)pyridin-3-yl).
According to yet another embodiment, specifically provided are compounds of formula (II), in which each occurrence of Ra and Rb 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-
(trifluoromethyl)phenyl, 3 -fluoro-5 -(trifluoromethyl)phenyl, 2-fliioro-5 ~
( irifl uoromeihy ί )pheny 1 , 4-(cyclopropylethynyl)-3-fluorophenyl, 3-
(trifluoromethyl)benzyl, 3 -fluoro-5 -(trifluoromethyl)benzyl and 6-
(cyclopropylethynyl)pyridin-3-yl.
According to yet another embodiment, specifically provided are compounds of formula (II), in which R2 is -C(0)NRaRb. In this embodiment, one of the Ra and Rb is hydrogen and other is C3_i2cycloalkyl (e.g. cyclohexyl, 4,4-dimethylcyclohexyl, trans-4-(trifluoromethyl)cyclohexyl or (lr,4r)-4-(trifluoromethyl)cyclohexyl), C3_ gcycloalkylCi.galkyl (e.g. ((lr,4r)-4-(trifluoromethyl)cyclohexyl)methyl or trans-4- (trifluoromethyl)cyclohexylmethyl), C6-i4aryl (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_i4arylCi_galkyl (e.g. 3-(trifluoromethyl)benzyl or 3-fluoro-5- (trifluoromethyl)benzyl) and 5-14 membered heteroaryl (e.g. 6- (cyclopropylethynyl)pyridin-3 -yl) .
According to yet another embodiment, specifically provided are compounds of formula (II), in which R2 is -C(0)NRaRb. In this embodiment, Ra is hydrogen and Rb 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_ 8alkyl (e.g. methyl), haloCi_galkyl (e.g. trifluoromethyl) and C2_ioalkynyl (e.g. cy clopropy lethyny 1) .
According to yet another embodiment, specifically provided are compounds of formula (II), in which R2 is -C(0)NRaRb. In this embodiment, Ra is hydrogen and Rb 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.
According to yet another embodiment, specifically provided are compounds of formula (II), in which R2 is -C(0)NRaRb. In this embodiment, Ra is hydrogen and Rb 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-
(trifluoromethyl)phenyl, 4-fluoro-3 -(trifluoromethyl)phenyl, 3 -fluoro-5 -
(trifluoromethyl )phenyl, 2~fluoro-5~(trifluoiOmeihyl)phenyl, 4-(cyclopropy lethyny l)-3- fluorophenyl, 3-(trifluoromethyl)benzyl, 3 -fluoro-5 -(trifluoromethyl)benzyl or 6- (cyclopropylethynyl)pyridin-3-yl.
According to yet another embodiment, specifically provided are compounds of formula (II), in which R2 is -C(0)NRaRb. In this embodiment, one of the Ra and Rb is hydrogen and other is substituted C6_i4aryl (e.g. phenyl). In this embodiment, 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 C2_ loalkynyl (e.g. cyclopropylethynyl).
According to yet another embodiment, specifically provided are compounds of formula (II), in which R2 is -C(0)NRaRb. In this embodiment, Ra is hydrogen and Rb is phenyl, optionally substituted with one or more substituents independently selected from fluorine, methyl, trifluoromethyl and cyclopropylethynyl. According to yet another embodiment, specifically provided are compounds of formula (II), in which R8 is independently selected from halogen (e.g. F, CI, Br or I), Ci_4alkyl (e.g. methyl, ethyl or tert-butyl) and haloCi_galkyl (e.g. trifluoromethyl).
According to yet another embodiment, specifically provided are compounds of formula (II), in which R8 is independently selected from CI, F and CH3.
According to yet another embodiment, specifically provided are compounds of formula (II), in which 'm' is 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (II), in which R8 is independently selected from CI, F and CH3 and 'm' is 2.
According to yet another embodiment, specifically provided are compounds of formula (II), in which 'q' is 1.
According to one embodiment, specifically provided are compounds of formula (II) with an IC50 value of less than 500 nM, preferably, less than 100 nM, more preferably, less than 50 nM with respect to mPGES-1 activity.
Further embodiments relating to groups Z, Y 1, Y 2, Y3, Y4, X 1, X 2, R2, R8, m and q (and groups defined therein) are described hereinafter in relation to the compounds of formula (III) and formula (IV). It is to be understood that these embodiments are not limited to use in conjunction with formula (III) and (IV), but apply independently and individually to the compounds of formula (II). For example, in an embodiment described hereinafter, the invention specifically provides compounds of formula (III) and formula (IV) wherein 'm' is 1 or 2 and consequently there is also provided a compound of formula (II) wherein 'm' is 1 or 2.
The invention also provides a compound of formula (III) which is an embodiment of a compound of formula (I).
Accordingly the invention provides a compound of formula (III):
Figure imgf000018_0001
(III)
or a pharmaceutically acceptable salt thereof, wherein,
R5 is hydrogen;
R6 is independently selected from hydrogen and methyl;
each occurrence of R8 is independently selected from halogen, cyano, hydroxyl, Ci-galkyl, haloCi_galkyl, Ci_galkoxy and haloCi_galkoxy;
Ra and Rb which may be the same or different, are independently selected from hydrogen, Ci_galkyl, haloCi_galkyl, C3-i2cycloalkyl, C3-gcycloalkylCi_galkyl, C6-14aryl, C6_i4arylCi_galkyl, 5-14 membered heteroaryl and 5-14 membered heteroarylCi_galkyl;
Rz is independently selected from hydrogen, Ci_4alkyl and C3-6cycloalkyl; and
'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. For example, the invention provides compounds of formula (III) as defined above wherein R5 and R6 are hydrogen (according to an embodiment defined below) and Rz is hydrogen or methyl (according to an embodiment defined below).
According to one embodiment, specifically provided are compounds of formula (III), in which R6 is hydrogen.
According to another embodiment, specifically provided are compounds of formula (III), in which R5 and R6 are hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (III), in which Rz is hydrogen or Ci_4alkyl (e.g. methyl or ethyl).
According to yet another embodiment, specifically provided are compounds of formula (III), in which Rz is hydrogen, methyl or ethyl.
According to yet another embodiment, specifically provided are compounds of formula (III), in which one of the Ra and Rb is hydrogen and other is Ci_galkyl (e.g. methyl or ethyl), C3-i2cycloalkyl (e.g. cyclohexyl, 4,4-dimethylcyclohexyl, trans-4- (trifluoromethyl)cyclohexyl or (lr,4r)-4-(trifluoromethyl)cyclohexyl), C3_ gcycloalkylCi-galkyl (e.g. ((lr,4r)-4-(trifluoromethyl)cyclohexyl)methyl or trans-4- (trifluoromethyl)cyclohexylmethyl), C6-i4aryl (e.g. 3-(trifluoromethyl)phenyl, 4- (trifluoromethyl)phenyl, 4-fluoro-3 -(trifluoromethyl)phenyl, 3 -fluoro-5 -
(trifluoromethyl)phenyl, 2"fliioro~5~(trifli!orometliyl)phenyl or 4-(cyclopropylethynyl)- 3 -fluorophenyl), C6-i4arylCi_8alkyl (e.g. 3-(trifluoromethyl)benzyl or 3-fluoro-5- (trifluoromethyl)benzyl) and 5-14 membered heteroaryl (e.g. 6- (cyclopropylethynyl)pyridin-3 -yl) .
According to yet another embodiment, specifically provided are compounds of formula (III), in which one of the Ra and Rb is 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-
(trifluoromethyl)phenyl, 4-fluoro-3 -(trifluoromethyl)phenyl, 3 -fluoro-5 -
(trifluoromethyl)phenyl, 2-fluoro-5 -(trifluoromethyl)phenyl, 4-(cyclopropylethynyl)-3 - fluorophenyl, 3-(trifluoromethyl)benzyl, 3 -fluoro-5 -(trifluoromethyl)benzyl or 6- (cyclopropylethynyl)pyridin-3-yl.
According to yet another embodiment, specifically provided are compounds of formula (III), in which Ra is hydrogen and Rb is C3_i2cycloalkyl (e.g. cyclohexyl, 4,4-dimethylcyclohexyl, trans-4-(trifluoromethyl)cyclohexyl or (lr,4r)-4- (trifluoromethyl)cyclohexyl), C3-8cycloalkylCi_galkyl (e.g. ((lr,4r)-4- (trifluoromethyl)cyclohexyl)methyl or trans-4-(trifluoromethyl)cyclohexylmethyl), C6_ i4aryl (e.g. 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 4-fluoro-3- (trifluoromethyl)phenyl, 3 -fluoro-5 -(trifluoromethyl)phenyl, 2-fktoro~5-
(trifluorometliyl)phenyl or 4-(cyclopropylethynyl)-3-fluorophenyl), C6-i4arylCi_8alkyl (e.g. 3-(trifluoromethyl)benzyl or 3 -fluoro-5 -(trifluoromethyl)benzyl) and 5-14 membered heteroaryl (e.g. 6-(cyclopropylethynyl)pyridin-3-yl).
According to yet another embodiment, specifically provided are compounds of formula (III), in which Ra is hydrogen and Rb 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_8alkyl (e.g. methyl), haloCi_8alkyl (e.g. trifluoromethyl) and C2_ioalkynyl (e.g. cyclopropylethynyl).
According to yet another embodiment, specifically provided are compounds of formula (III), in which Ra is hydrogen and Rb is cyclohexyl, cyclohexylmethyl, phenyl, benzyl or pyridinyl, optionally substituted with one or more substituents independently selected from fluorine, methyl, trifluoromethyl and cyclopropylethynyl. According to yet another embodiment, specifically provided are compounds of formula (III), in which Ra is hydrogen and Rb 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-
(trifluoromethyl)phenyl, 3 -fluoro-5 -(trifluoromethyl)phenyl, 2-fiuoro-5-
( irifl uoromeihy ί )pheny 1 , 4-(cyclopropylethynyl)-3-fluorophenyl, 3-
(trifluoromethyl)benzyl, 3 -fluoro-5 -(trifluoromethyl)benzyl or 6-
(cyclopropylethynyl)pyridin-3-yl.
According to yet another embodiment, specifically provided are compounds of formula (III), in which one of the Ra and Rb is hydrogen and other is substituted C6_ i4aryl (e.g. phenyl). In this embodiment, substituent(s) on aryl may be one or more and are independently selected from halogen (e.g. F, CI, Br or I), Ci_8alkyl (e.g. methyl), haloCi.galkyl (e.g. trifluoromethyl) and C2_ioalkynyl (e.g. cyclopropylethynyl).
According to yet another embodiment, specifically provided are compounds of formula (III), in which one of the Ra and Rb is hydrogen and other is substituted phenyl. In this embodiment, substituent(s) on phenyl may be one or more and are independently selected from fluorine, methyl, trifluoromethyl and cyclopropylethynyl.
According to yet another embodiment, specifically provided are compounds of formula (III), in which Ra is hydrogen and Rb is phenyl optionally substituted with one or more substituents independently selected from fluorine, methyl, trifluoromethyl and cyclopropylethynyl .
According to yet another embodiment, specifically provided are compounds of formula (III), in which R8 is independently selected from halogen (e.g. F, CI, Br or I), Ci_4alkyl (e.g. methyl, ethyl or tert-butyl) and haloCi-salkyl (e.g. trifluoromethyl).
According to yet another embodiment, specifically provided are compounds of formula (III), in which R8 is independently selected from CI, F and CH3.
According to yet another embodiment, specifically provided are compounds of formula (III), in which 'm' is 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (III), in which R8 is independently selected from CI, F and CH3 and 'm' is 2.
According to yet another embodiment, specifically provided are compounds of formula (III), in which:
R5 and R6 are hydrogen; each occurrence of R8 is independently selected from halogen (e.g. F, CI or Br), and Ci_4alkyl (e.g. methyl);
Ra is hydrogen and Rb is cyclohexyl, cyclohexylmethyl, phenyl, benzyl or pyridinyl, optionally substituted with one or more substituents independently selected from fluorine, methyl, trifluoromethyl and cyclopropylethynyl;
Rz is hydrogen or Ci_4alkyl (e.g. methyl or ethyl); and 'm' is 2.
According to one embodiment, specifically provided are compounds of formula (III) with an IC50 value of less than 500 nM, preferably, less than 100 11M, more preferably, less than 50 nM with respect to mPGES-1 activity.
The invention also provides a compound of formula (IV) which is an embodiment of a compound of formula (I).
Accordingly the invention provides a compound of formula (IV):
Figure imgf000022_0001
(IV)
or a pharmaceutically acceptable salt thereof,
wherein,
at each occurrence, R8 is independently selected from CI, F and methyl;
Ra is hydrogen;
Rb 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 -(trifluoromethyl)phenyl, 3 -fluoro-5 -
(trifluoromethyl)phenyl, 2-fluoro-5 -(trifluoromethyl)phenyl, 4-(cyclopropylethynyl)- 3 -fluorophenyl, 3-(trifluoromethyl)benzyl, 3 -fluoro-5 -(trifluoromethyl)benzyl or 6- (cyclopropylethynyl)pyridin-3-yl;
Rz is hydrogen, methyl or ethyl;
and 'm' is 1 or 2. According to one embodiment, specifically provided are compounds of formula (IV) with an IC50 value of less than 500 nM, preferably, less than 100 nM, more preferably, less than 50 nM with respect to mPGES-1 activity.
Compounds of the present invention include the compounds in Examples 1-
42.
It should be understood that the formula (I), (II), (III) and (IV) structurally encompasses all geometrical isomers, stereoisomers, enantiomers and diastereomers, N-oxides, and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the genera described herein.
The present application also provides a pharmaceutical composition that includes at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. The compounds described herein may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a 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.
Detailed Description of the Invention
Definitions
The terms "halogen" or "halo" means fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo).
The term "alkyl" refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. 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). The term "Ci_6 alkyl" refers to an alkyl chain having 1 to 6 carbon atoms. The term "Ci_4alkyl" refers to an alkyl chain having 1 to 4 carbon atoms. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
The term "alkenyl" refers to a hydrocarbon chain containing from 2 to 10 carbon atoms (i.e. C2-ioalkenyl) and including at least one carbon-carbon double bond. Non- limiting examples of 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.
The term "alkynyl" refers to a hydrocarbyl radical having at least one carbon- carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred i.e. C2_ioalkynyl). Non-limiting examples of 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.
The term "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 -OCH3 and -OC2H5. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
The term "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_8alkyloxyCi_galkyl). Example of such alkoxyalkyl moiety includes, but are not limited to, -CH2OCH3 and -CH2OC2H5. Unless set forth or recited to the contrary, all alkoxyalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
The term "haloalkyl" refers to at least one halo group (selected from F, CI, Br or I), linked to an alkyl group as defined above (i.e. haloCi_8alkyl). Examples of such 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.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms (i.e. haloCi-salkoxy). Examples of "haloalkoxy" include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-bromoethoxy. Unless set forth or recited to the contrary, all haloalkoxy groups described herein may be straight chain or branched, substituted or unsubstituted.
The term "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). Examples of hydroxyalkyl moieties include, but are not limited to -CH2OH, -C2H4OH and -CH(OH)C2H4OH.
The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, (i.e.C3_i2cycloalkyl). Examples of monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapthyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl. The term "C3_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.
The term "cycloalkylalkyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group (i.e. C3_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.
The term "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. C3_ 8Cycloalkenyl). 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.
The term "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. C3_8cycloalkenylCi_8alkyl). 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.
The term "aryl" refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C6_i4aryl), 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.
The term "aryloxy" refers to an aryl group as defined above attached via an oxygen linkage to the rest of the molecule (i.e. C6-i4aryloxy). Examples of 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.
The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, i.e. C6-i4arylCi_8alkyl, such as -CH2C6H5 and - C2H4C6H5. Unless set forth or recited to the contrary, all arylalkyl groups described or claimed herein may be substituted or unsubstituted.
The term "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. In addition, the nitrogen atom may be optionally quaternized; also, unless otherwise constrained by the definition the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s). Examples of such heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, oxadiazolyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl or tetrahydrofuranyl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamorpholinyl sulfone. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be substituted or unsubstituted.
The term "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.
The term "heteroaryl" unless otherwise specified 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. Examples of such 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, thiadiazolyl, indolizinyl, acridinyl, phenazinyl and phthalazinyl. Unless set forth or recited to the contrary, all heteroaryl groups described or claimed herein may be substituted or unsubstituted.
The term "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.
Unless otherwise specified, the term "substituted" as used herein refers to substitution with any one or any combination of the following substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyl alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, -COORx, - C(0)Rx', -C(S)RX', -C(0)NRxRy', -C(0)ONRxRy', -NRxCONRy,Rz', -N(Rx')SORy', - N(Rx')S02Ry', -(=N-N(Rx)Ry), -NRxC(0)ORy', -NRxRy, -NRxC(0)R , -NRxC(S)Ry', -NRxC(S)NRy,Rz', -SONRxRy, -S02NRxRy', -ORx', -OC(0)NRyRz', -OC(0)OR , - OC(0)Rx', -OC(0)NRxR , -SRX', -SORx', -S02Rx', and -ON02, wherein each occurrence of Rx , Ry and Rz are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, and substituted or unsubstituted heterocyclic ring. The substituents in the aforementioned "substituted" groups cannot be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl", the substituent on "substituted aryl" can be unsubstituted alkenyl but cannot be "substituted alkenyl".
The term "pharmaceutically acceptable salt" includes salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Examples of such salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Examples of salts derived from inorganic bases include, but are not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, and zinc.
The term "treating" or "treatment" of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non- domestic animals (such as wildlife).
A "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
The sensation of pain can be triggered by any number of physical or chemical stimuli and the sensory neurons which mediate the response to this harmful stimulus are termed as "nociceptors". Nociceptors are primary sensory afferent (C and Αδ 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.
The term "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.
Pharmaceutical Compositions
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. Typically, the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use. The pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, and solvents.
Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylene.
The pharmaceutical 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.
The pharmaceutical 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.
The pharmaceutical compositions of the present patent application may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20th 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.
In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound as described herein, a second therapeutic agent, and optionally a pharmaceutically-acceptable excipient. In one embodiment, 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.
Methods of Treatment
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. Compounds of the invention are thus useful in the treatment of those conditions in which inhibition of a PGES, and particularly mPGES-1, is required.
Compounds of the invention are thus expected to be useful in the treatment of inflammation. The term "inflammation" will be understood by those skilled in the art to include any condition characterized by a localized or a systemic protective response, which may be elicited by physical trauma, infection, chronic diseases, 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.
The term "inflammation" is also understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterized by inflammation as a symptom, including inter alia acute, chronic, ulcerative, specific, allergic, infection by pathogens, immune reactions due to hypersensitivity, entering foreign bodies, physical injury, and necrotic inflammation, and other 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. breast cancer, colon cancer, and prostate cancer), 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, iritis, 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 component.
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.
By virtue of the mPGES-1 inhibitory activity of compounds of the present invention, 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. 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, neurodegeneration, stroke, post stroke pain, inflammatory disorders, oesophagitis, gastroeosophagal reflux disorder (GERD), irritable bowel syndrome, inflammatory bowel disease, pelvic hypersensitivity, urinary incontinence, cystitis, stomach duodenal ulcer, muscle pain, pain due to colicky and referred pain. Compounds of the present invention may also be useful for the treatment or prevention of endometriosis, hemophilic arthropathy and Parkinson's disease.
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.
In addition, the compounds of the present invention may inhibit cellular neoplastic transformations and metastic tumor growth and hence can be used in the treatment of cancer, and pain associated with cancer. Furthermore, the present invention provides preferred embodiments of the methods and uses as described herein, in which cancer includes Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adolescents Cancer, Adrenocortical Carcinoma, Anal Cancer, Appendix Cancer, Astrocytomas, Atypical Teratoid, Basal Cell Carcinoma, Bile Duct Cancer, Extrahepatic, Bladder Cancer, Bone Cancer, Brain Stem Glioma, Brain Tumor, Breast Cancer, Bronchial Tumors, Burkitt Lymphoma, Carcinoid Tumor, Carcinoma of Unknown Primary, Cardiac (Heart) Tumors, Central Nervous System tumors, Cervical Cancer, Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Chronic Myeloproliferative Disorders, Colon Cancer, Colorectal Cancer, Craniopharyngioma, Cutaneous T-Cell Lymphoma, Duct Bile Extrahepatic cancer, Ductal Carcinoma In Situ, Embryonal Tumors, Central Nervous System cancer, Endometrial Cancer, Ependymoma, Esophageal Cancer, Esthesioneuroblastoma, Ewing Sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer, Fibrous Histiocytoma of Bone, Malignant, and Osteosarcoma, Gall bladder Cancer, Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumors, Germ Cell Tumor, Gestational Trophoblastic Tumor, Glioma, Hairy Cell Leukemia, Head and Neck Cancer, Heart Cancer, Hepatocellular (Liver) Cancer, Histiocytosis, Langerhans Cell, Hodgkin Lymphoma, Hypopharyngeal Cancer, Intraocular Melanoma, Islet Cell Tumors, Pancreatic Neuroendocrine Tumors, Kaposi Sarcoma, Kidney cancer, Langerhans Cell Histiocytosis, Laryngeal Cancer, Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Hairy Cell Leukemia, Lip and Oral Cavity Cancer, Liver Cancer, Lobular Carcinoma In Situ, Lung Cancer, AIDS- Related Lymphoma, Cutaneous T-Cell Lymphoma, Hodgkin Lymphoma, Non- Hodgkin Lymphoma, Primary Central Nervous System (CNS) Lymphoma, Macroglobulinemia, Waldenstrom, Male Breast Cancer, Malignant Fibrous Histiocytoma of Bone and Osteosarcoma, Melanoma, Merkel Cell Carcinoma, Mesothelioma, Malignant, Metastatic Squamous Neck Cancer with Occult Primary, Midline Tract Carcinoma Involving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplasia Syndromes, Myelodysplastic/Myeloproliferative Neoplasms, Myelogenous Leukemia, Chronic, Myeloid Leukemia Acute, Multiple Myeloma, Chronic Myeloproliferative Disorders, Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non- Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Lip and, Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Ovarian Cancer, Pancreatic Cancer, Papillomatosis, Paraganglioma, Paranasal Sinus and Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Pituitary Tumor, Plasma Cell Neoplasm/Multiple Myeloma, Pleuropulmonary Blastoma, Pregnancy and Breast Cancer, Primary Central Nervous System (CNS) Lymphoma, Prostate Cancer, Rectal Cancer, Renal Cell (Kidney) Cancer, Renal Pelvis and Ureter, Transitional Cell Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Ewing Sarcoma, Kaposi Sarcoma, Osteosarcoma, Rhadomyosarcoma, Soft Tissue Sarcoma, Uterine Sarcoma, Sezary Syndrome, Skin Cancer, Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma, Squamous Neck Cancer with Occult Primary, Metastatic, Stomach (Gastric) Cancer, T-Cell Lymphoma, Cutaneous, Testicular Cancer, Throat Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Trophoblastic Tumor, Gestational, Unknown Primary, Carcinoma of, Ureter and Renal Pelvis, Transitional Cell Cancer, Urethral Cancer, Uterine Cancer, Endometrial, Uterine Sarcoma, Vaginal Cancer, Vulvar Cancer, Waldenstrom, Macroglobulinemia, Wilms Tumor and Women's Cancers.
Compounds of the present invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions. For the above- mentioned therapeutic uses 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.
General Methods of Preparation
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. These compounds can be purified by using any of the methods for purification of organic compounds known in the art, for example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios. All possible geometrical isomers and stereoisomers are envisioned within the scope of this invention.
The starting materials for the below reaction schemes are commercially available or can be prepared according to methods known to one skilled in the art or by methods disclosed herein. In general, intermediates and compounds of the present application may be prepared using the reaction scheme as follows, wherein all symbols are as defined above.
Synthesis of the compounds of formula (I) (wherein Y1, Y2, Y3, Y4, X1, X2, Z,
R2, R7, R8, m, q, A and L are defined with respect to the compound of Formula (I)) can be performed as described in Synthetic scheme 1.
Synthetic Scheme-1
Figure imgf000037_0001
A compound of formula (1) (wherein, X1 and X2 are independently selected from NH2 and NHRZ, with a proviso that when X1' is NH2 then X2' is NHRZ and when X1' is NHRZ then X2 is NH2) 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), R7 is not hydrogen) with R7-LG' (3) (wherein R7 is not hydrogen and LG' is good leaving group such as CI, Br or I) under appropriate conditions.
Synthetic Scheme-2
Figure imgf000037_0002
Synthesis of the compounds of formula (la) (wherein Y1, Y2, Y3, Y4, X1, X2, R1, Ra, Rb, R7, R8, m, q, A and L are as defined with respect to a compound of Formula (I)) can be performed as described in Synthetic scheme 2, which involves the treatment of amine compound of formula (5) with appropriate acyl compound of formula (4), wherein LG represent OH or CI or Br or O-alkyl or O-aryl or 0(C=0)-alkyl. When LG represents O-alkyl (e.g. OMe, OEt) 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. Similarly, when LG represent O-aryl or 0(C=0)-alkyl 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. Furthermore, when LG represents OH 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). Alternatively, when 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 as DIPEA.
A compound of formula (Ila) can be prepared following the synthetic steps depicted in Synthetic scheme 3 (wherein Y4, X1, X2, R1, Ra, Rb, R3, R7, R8, m, A and L are as defined for compound of formula (I)).
Synthetic Scheme-3
Figure imgf000038_0001
A compound of formula (6) (wherein, X1 and X2 are independently selected from NH2 and NHRZ, with a proviso that when X1' is NH2 then X2' is NHRZ and when X1' is NHRZ then X2 is NH2) 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), R7 is not hydrogen) with R7- LG' (3) (wherein R7 is not hydrogen and LG' is good leaving group such as CI, Br or I) under appropriate conditions. 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 NHRaRb 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. Alternatively, 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) (NHRaRb) 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.
A compound of formula (lib) can be prepared following the synthetic steps depicted in Synthetic scheme 4 (wherein X1, X2, R1, Ra, Rb, R3, R7, R8, 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).
Figure imgf000040_0001
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 R3 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 NHRaRb (compound of formula (5)) 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. Alternatively, 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. 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) (NHRaRb) 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.
A compound of formula (lie) can be prepared following the synthetic steps depicted in Synthetic scheme 5 (wherein X1, X2' R1, Ra, Rb, R4, R3, R7, R8, 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).
Figure imgf000041_0001
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 R3 is H], triethylortho acetate [when R3 is C¾]) 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 NHRaRb (compound of formula (5)) 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) in the presence of solvents such as toluene, acetonitrile at temperature range of 0-100°C. Alternatively, 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. 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) (NHRaRb) 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.
A compound of formula (lid) can be prepared following the synthetic steps depicted in Synthetic scheme 6 (wherein, R1, Ra, Rb, R3, R8 and m are as defined with respect to a compound of formula (I)). S nthetic Scheme-6
Figure imgf000042_0001
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. Alternatively, 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
(24) can be converted to a compound of formula (25) by reacting with an isothiocyanate derivative of formula (2') under appropriate conditions followed by cyclization using a reagent such as diisopropylcarbodiimide. 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
(compound of formula (5)) using 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. Alternatively, the compound of formula (26) can be converted to a compound of formula (lid) under amidation conditions using an appropriate amine of formula (5) (NHRaRb) 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.
A compound of formula (He) can be prepared following the synthetic steps depicted in Synthetic scheme 7 (wherein R1, Rz, Ra, Rb, R3, R8 and m are as defined with respect to compound of formula (II)). S nthetic Scheme-7
Figure imgf000044_0001
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. Alternatively, 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 R3 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 (NH2RZ e.g. methyl amine when Rz is CH3) 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. 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). A compound of formula (36) can be converted to the compound of formula (He) by reacting with an amine
(compound of formula (5)) using 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. Alternatively, the compound of formula (35) can be converted to a compound of formula (He) under amidation conditions using an appropriate amine (NHRaRb) 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.
A compound of formula (Hf) (wherein R1, R3, R8, Ra, Rb and m are as defined for compound of formula (II)) is prepared according to the sequence depicted in Synthetic Scheme 8. Synthetic Scheme-8
Figure imgf000046_0001
(39) (40)
Figure imgf000046_0002
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 R3 is H], triethylortho acetate [when R3 is C¾]) 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 NHRaRb (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. Alternatively, 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) (NHRaRb) 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.
Synthesis of the compounds of formula (IIIA) (wherein Ra, Rb, R5, R6, R8, and m are as defined with respect to a compound of Formula (III)) can be performed as described in Synthetic scheme 9.
S nthetic Scheme-9
Figure imgf000048_0001
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. H2SO4 and cone. HNO3; fuming nitric acid in the presence of an acid such as sulphuric acid or mild nitration condition such as K O3 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. Alternatively, 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. H2SO4 and cone. HNO3; fuming nitric acid in the presence of an acid such as sulphuric acid or mild nitration condition such as K O3 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. Alternatively, 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. 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). Alternatively, 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. 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 (IIIA).
Synthesis of the compounds of formula (IIIB) (wherein Ra, Rb, R8, Rz and m are as defined with respect to a compound of Formula (III)) can be performed as described in Synthetic scheme 10.
Figure imgf000050_0001
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. H2SO4 and cone. HNO3; fuming nitric acid in the presence of an acid such as sulphuric acid or mild nitration condition such as K O3 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 RZ-NH2 (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. 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, FeCl3 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. 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 (Ilia). Alternatively, 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. 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 (IIIB).
Synthesis of the compounds of formula (IIIC) (wherein Ra, Rb, R5, R6, R8, and m are as defined with respect to a compound of Formula (III), and Rz' is Ci_4alkyl or C3_6cycloalkyl) can be performed as described in Synthetic scheme 11.
S nthetic Scheme-11
Figure imgf000052_0001
n erme a e-
A compound of formula (53) can be converted to a compound of formula (65) by reacting with compound of formula Rz -LG' (wherein Rz is Ci_4alkyl or C3_6cycloalkyl 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, Et3N 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. Alternatively, 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, FeCl3 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-9C, 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 (IIIC). Alternatively, 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).
Synthetic Scheme-12
Figure imgf000053_0001
Synthesis of the compounds of formula (III) (wherein Ra, Rb, R5, R6, R8, Rz and m are as defined with respect to a compound of Formula (III)) can be performed as described in Synthetic scheme 12, which involves the treatment of amine compound of formula (5) with corresponding ester or appropriate acyl compound of formula (Intermediate- 11 A), wherein LG represent OH or CI or Br or 0-Ci_4alkyl or O-aryl or 0(C=0)-Ci_4alkyl. When LG represents 0-Ci_4alkyl (e.g. OMe, OEt) the reaction can be performed with 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. Similarly, when LG represent O-aryl or 0(C=0)-alkyl the reaction can be performed with a suitable reagent such as trimethyl aluminium or a strong base such as sodium hydride (NaH) in a suitable solvent such as toluene or DMF. Furthermore, when LG represents OH 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). Alternatively, when 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 as DIPEA.
Synthesis of the compounds of formula (II) (wherein Υ 1, Υ 2, Υ 3, Υ 4, Χ 1, Χ 2,
Z, R 2 , R 8 , m and q are defined with respect to the compound of Formula (II)) can be performed as described in Synthetic scheme 13.
Synthetic Scheme- 13
Figure imgf000054_0001
(I I)
A compound of formula (66) (wherein, X 1 ' and X 2' are independently selected from NH2 and NHRZ, with a proviso that when X1' is NH2 then X2' is NHRZ and when X1 is NHRZ then X2 is NH2) 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.
Experimental
Unless otherwise stated, 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, unless otherwise mentioned, implies purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. The following abbreviations are used in the text: DMSC)-^: hexadeuterodimethyl sulfoxide; DMF: N,N-dimethylformamide; THF: Tetrahydrofuran; HOBT: 1- Hydroxybenzotriazole; DIC: N,N-di-isopropyl carbodimide CDI: Ι, - 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-
Dimethylaminopropyl)-N'-ethylcarbodiimide; BOP: Benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; Ni: nickel; J: coupling constant in units of Hz; RT: room temperature (22-26°C); h: hour(s); aq.: aqueous; EtOAc: ethyl acetate; equiv.: equivalents; cat. amt.: catalytic amount.
Intermediates
Intermediate- 1
l-Chloro-3-fluoro-2-isothiocyanatobenzene
Figure imgf000055_0001
To a solution of 2-chloro-6-fluoro aniline (3.0 g, 19.35 mmol) in DCM (10 mL), N- ethyl di-isopropyl amine (8.0 g, 64.00 mmol) was added. The reaction mass was stirred at RT for 30 minutes. The reaction mass was cooled at 0°C and drop-wise thiophosgene (5.01 g, 43.47 mmol) was added to the reaction mixture. The reaction mass was stirred RT for 3-4 h. After completion of reaction, the reaction mass was diluted with DCM and purified by using column chromatography to afford 1.0 g of desired title product. 1H NMR (DMSO-d6): δ 7.26 (m, 2H), 7.06 (t, J= 9.6Hz, 1H).
Intermediate-2
Methyl 2-((2-chloro-6-fluorophenyl)amino)-lH-imidazo[4,5-fJquinoline-5- carboxylate
Figure imgf000055_0002
Scheme for synthesis of Intermediate-2
Figure imgf000056_0001
Step-1 : Preparation of 8-methyl-5-nitroquinoline
To a cold solution of 8-methylquinoline (2.0 g, 0.0119 mol) in cone. H2SO4 (10.0 mL) was added potassium nitrate (1.32 g, 0.013 mol) at 0°C. The reaction mass was stirred at 0°C for 2-4 h. After completion of reaction, the reaction mass was diluted with EtOAc and basified with NaHC03. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 2.0 g of the desired product. 1H NMR (DMSO- e): δ 2.788 (s, 3H), 7.77 (d, J = 7.8Hz, 2H), 8.34 (d, J = 7.8Hz, 1H), 8.86 (d, J= 8.1Hz, 1H), 9.05 (s, 1H).
Step-2: Preparation of 8-methylquinolin-5-amine
To a solution of 8-methyl-5-nitroquinoline (10.0 g, 0.05 mol) in methanol (100 mL) slowly iron powder (cat. amt.) and cone. HC1 (20 mL) were added. The reaction mass stirred at RT for 1-2 h. After completion of reaction, the reaction mass was quenched with water and filtered, filtrate was basified with NaHC03 and extracted with DCM. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 8.0 g of desired product. 1H NMR (DMSO-d6): δ 2.52 (s, 3H), 5.69 (s, 2H), 6.63 (d, J= 7.8Hz, 1H), 7.28 (d, J= 7.8Hz, 1H), 7.35-7.39 (m, 1H), 8.49 (d, J = 8.4Hz, 1H), 8.81 (d, J = 3.0Hz, 1H); MS [M+H]+: 159.12.
Step-3: Preparation of N-(8-methylquinolin-5-yl)acetamide
To a solution of 8-methylquinolin-5-amine (5.0 g, 0.0316 mol) in THF (25 mL) was added TEA (10 ml), acetic anhydride (4.8 g, 0.047 mol) at 0°C. The reaction mass was stirred at 0°C for 3-4 h. After completion of reaction, the reaction mass was diluted with water and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 4.8 g of desired title product. 1H NMR (DMSO- 6): δ 2.16 (s, 3H), 2.68 (s, 3H), 7.59 (m, 3H), 8.43 (d, J = 8.4Hz, 1H), 8.93 (s, 1H), 9.97 (s, 1H); MS [M+H]+ : 201.10.
Step-4: Preparation of N-(8-methyl-6-nitroquinolin-5-yl)acetamide
To a solution of N-(8-methylquinolin-5-yl)acetamide (4.8 g, 0.024 mol) in cone. H2SO4 (15 mL), drop wise fuming nitric acid (2.0 mL) was added at 0°C. The reaction mass was stirred at 0°C for 2-3 h. After completion of reaction, the reaction mass was quenched using aq. NH3 at 0°C and extracted with DCM. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 4.0 g of desired product. 1H NMR (DMSO-d6): δ 2.16 (s, 3H), 2.76 (s, 3H), 7.76-7.78 (m, 1H), 8.09 (s, 1H), 8.62 (d, J = 8.4Hz, 1H), 9.11 (s, 1H), 10.53 (s, 1H); MS [M]+ : 246.08.
Step 5-: Preparation of 8-methyl-6-nitroquinolin-5-amine
To a solution of N-(8-methyl-6-nitroquinolin-5-yl)acetamide (2.0 g 0.008 mol) in methanol (10 mL) was added cone. H2SO4 (1.0 mL). The reaction mass was refluxed for 5-6 h. After completion of reaction, methanol was removed under vacuum. Water was added to the obtained reaction mass, basified with NaHC03 and extracted with DCM. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 1.5 g of desired product. 1H NMR (DMSO-d6): δ 2.50 (s, 3H), 7.62-7.64 (m, 1H), 8.07 (s, 1H), 8.65 (s, 2H), 9.00 (d, J= 8.1Hz, 2H).
Step-6: Preparation of 8-methylquinoline-5,6-diamine
To a solution of 8-methyl-6-nitroquinolin-5-amine (1.5 g, 0.007 mol) in methanol (10 mL) was added Raney Ni (cat. amt), hydrazine hydrate (1.0 mL) slowly at RT. The reaction mass was stirred at RT for 2-3 h. After completion of reaction, the reaction mass was filtered through celite bed and filtrate was concentrated under vacuum. The obtained dry mass was diluted with water and extracted with DCM. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 1.0 g of desired product. 1H NMR (DMSO-d6): δ 2.50 (s, 3H), 4.75 (s, 2H), 4.80 (s, 2H), 7.03 (s, 1H), 7.23 (dd, J = 3.9Hz, 3.9Hz, 1H), 8.28 (d, J = 8.4Hz, 1H), 8.50 (d, J = 3.6Hz, 1H); MS [M+H]+: 174.26.
Step-7: Preparation of N-(2-chloro-6-fluorophenyl)-5-methyl-lH-imidazo[4,5- f]quinolin-2-amine
To a solution 8-methylquinoline-5,6-diamine (0.700 g, 4.02 mmol) in acetonitrile (5.0 mL) was added l-chloro-3-fluoro-2-isothiocyanatobenzene (Intermediate- 1, 1.0 g, 5.37 mmol). The reaction mass was stirred at RT for 24 h followed by the addition of N,N-di-isopropyl carbodimide (0.6 mL). Then the reaction mass was stirred for another 4-6 h at RT. After completion of reaction, acetonitrile was removed under vacuum. The obtained crude product was further purified by column chromatography on silica gel eluting with 1 % MeOH in DCM to afford 0.200 g of desired product. 1H NMR (DMSO- e): δ 2.72 (s, 3H), 7.29-7.48 (m, 4H), 7.56 (s, 1H), 8.54 (d, J= 7.8Hz, 1H), 8.76 (s, 1H), 9.00 (br s, 1H), 11.60 (br s, 1H); MS [M+H]+: 327.23.
Step-8: Preparation of 2-((2-chloro-6-fluorophenyl)amino)-lH-imidazo[4,5- fJquinoline-5-carboxylic acid
To a solution of periodic acid (0.418 g, 1.83 mmol) in acetonitrile (5.0 ml) was added chromium trioxide (0.079 g, 0.795 mmol). The reaction mass was stirred at RT for 30 minutes followed by addition of N-(2-chloro-6-fluorophenyl)-5-methyl-lH- imidazo[4,5-f]quinolin-2-amine (0.200 g, 0.612 mmol). The reaction mass was stirred at RT for 2-3 h. After completion of reaction, acetonitrile was removed under vacuum and obtained mass was diluted with water and extracted with mixture of 5 % MeOH in DCM. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.050 g of desired product. MS [M+l]+: 357.17.
Step-9: Preparation of methyl 2-((2-chloro-6-fluorophenyl)amino)-lH-imidazo[4,5- f]quinoline-5-carboxylate
To a solution of 2-((2-chloro-6-fluorophenyl)amino)-lH-imidazo[4,5-f]quinoline-5- carboxylic acid (0.050g, 0.014 mmol) in methanol (10 mL) was added cone. H2SO4 (1 mL). The reaction mass was refluxed for 12 h. After completion of reaction, methanol was removed under vacuum. Water was added to the obtained reaction mass, basified with NaHCC"3 and extracted with DCM. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.030 g of the desired product. MS [M+H]+ : 371.04.
Intermediate-3
Methyl 2-((2-chloro-6-fluorophenyl)amino)-3-methyl-3H-imidazo[4,5-f]quinoxaline- 5-carboxylate
Figure imgf000058_0001
Scheme for synthesis of Intermediate-3
Figure imgf000059_0001
INTERMEDIATE-3
Step-1 : Preparation of 5-bromo-3-methylbenzene-l,2-diamine
The title compound was prepared by following the procedure as described for step-2 of Intermediate-2 by using 4-bromo-2-methyl-6-nitroaniline (5.0 g, 0.021 mol), iron powder (cat. amt.) and cone. HC1 (8 mL), methanol (30 mL) to afford 8.0 g of desired product. 1H NMR (DMSO- 6): δ 2.04 (s, 3H), 4.31 (br s, 2H), 4.72 (br s, 2H), 6.42 (s, 1H), 6.53 (d, J= 2.1Hz, 1H).
Step-2: Preparation of 7-bromo-5-methylquinoxaline
To a solution of 5-bromo-3-methylbenzene-l,2-diamine (8.0 g. 0.039 mol) in ethanol (50 mL), NaHCC"3 (6.68 g, 0.079 mol) and glyoxal (16 mL) were added. The reaction mass was refiuxed for 2-3 h. After completion of reaction, ethanol was removed under vacuum and water was added to the reaction mass and filtered to obtain 6.0 g of desired solid product. 1H NMR (DMSO-d6): δ 2.72 (s, 3H), 7.91 (s, 1H), 8.16 (s, 1H), 8.98 (d, J= 3.3Hz, 2H).
Step-3: Preparation of 6-bromo-8-methyl-5-nitroquinoxaline
The title compound was prepared by following the procedure as described for step-4 of Intermediate-2 by using 7-bromo-5-methylquinoxaline (2 g, 0.008 mol), cone. H2SO4 (10 mL) and fuming nitric acid (4 mL) to afford 2.1 g of desired product. 1H NMR (DMSO-de): δ 2.78 (s, 3H), 8.19 (s, 1H), 9.09 (s, 1H), 9.17 (s, 1H).
Step-4: Preparation of N,8-dimethyl-5-nitroquinoxalin-6-amine
To a solution of 6-bromo-8-methyl-5-nitroquinoxaline (0.200 g, 0.746 mmol) in acetonitrile (3 mL) was added aq. methyl amine (40 %) (0.4 mL). The reaction mass was stirred at 80°C for 2-3 h. After completion of reaction, acetonitrile was removed under vacuum and water was added to the reaction mass. The reaction mixture was filtered to obtain 0.150 g of desired solid product. 1H NMR (DMSO-d6): δ 2.67 (s, 3H), 3.00 (d, J = 4.5Hz, 3H), 7.47 (s, 1H), 7.55 (brs, 1H), 8.65 (s, 1H), 8.79 (s, 1H); MS [M+H]+ : 219.13.
Step-5: Preparation of A^^-dimethylquinoxaline-S^-diamine
The title compound was prepared by following the procedure as described for step-6 of Intermediate-2 by using N,8-dimethyl-5-nitroquinoxalin-6-amine (0.500g, 0.0029 mmol), Raney Ni (cat. amt), hydrazine hydrate (0.229 g, 0.0048 mol) and methanol (2.0 ml) to afford 0.400 g of desired product. 1H NMR (DMSO-d6): δ 2.59 (s, 3H), 2.90 (s, 3H), 4.98 (s, 2H), 5.29 (brs 1H), 7.16 (s, 1H), 8.51 (s, 1H), 8.59 (s, 1H).
Step-6: Preparation of N-(2-chloro-6-fluorophenyl)-3,5-dimethyl-3H-imidazo[4,5- f]quinoxalin-2-amine
The title compound was prepared by following the procedure as described for step-7 of Intermediate-2 by using A^^-dimethylquinoxaline-S^-diamine (0.450 g, 0.0013 mol), N,N-di-isopropyl carbodimide (1.0 mL), l-chloro-3-fluoro-2- isothiocyanatobenzene (Intermediate- 1, 0.342 g, 0.0019 mol) and acetonitrile (5.0 mL). The obtained crude was further purified by column chromatography on basic alumina eluting with 5 % EtOAc in DCM to afford 0.200 g of desired product 1H NMR (DMSO-de): δ 2.78 (s, 3Η), 3.87 (s, 3Η), 7.37 (m, 2Η), 7.44 (m, 1Η), 7.88 (s, 1Η), 8.78 (d, J= 7.2Hz, 3H); MS [M+H]+ : 342.25.
Step-7: Preparation of 2-((2-chloro-6-fluorophenyl)amino)-3-methyl-3H-imidazo[4,5- f]quinoxaline-5-carboxylic acid
To a solution of periodic acid (0.933 g, 0.040 mmol) in acetonitrile (5.0 ml) was added chromium trioxide (0.087 g, 0.879 mmol). The reaction mass was stirred at RT for 30 minutes followed by addition of N-(2-chloro-6-fluorophenyl)-3,5-dimethyl-3H- imidazo[4,5-f]quinoxalin-2-amine (0.200 g, 0.586 mmol). The reaction mass was stirred at RT for 2-3 h. After completion of reaction, acetonitrile was removed under vacuum and obtained mass was diluted with water and pH was adjusted to 5-6 with NaHCC"3 and it was extracted with mixture of 5% MeOH in DCM. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.020 g of desired product. MS [M+H]+ : 372.31.
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.H2S04 (1 mL) to afford 0.020 g of desired product. 1H NMR (DMSO- de): δ 3.92 (s, 3H), 3.93 (s, 3H), 7.39-7.48 (m, 3H), 8.34 (s, 1H), 8.81 (s, 1H), 8.86 (s, 1H), 9.16 (s, 1H); MS [M-H]" : 384.18.
Intermediate-4
Methyl 7-((2-chloro-6-fluorophenyl)amino)-3,8-dimethyl-3,8-dihydrobenzo[l ,2- d:3,4-d']diimidazole-4-carboxylate
Figure imgf000061_0001
Scheme for synthesis of Intermediate-4
Figure imgf000061_0002
INTERMEDIATE-4
Step 1 :- Preparation of 2,4-difluoro-5-nitrobenzoic acid
The title compound was prepared by following the procedure as described for step-4 of Intermediate-2 by using 2,4-difluoro benzoic acid (3.0 g, 18.98 mmol), cone. H2S04 (10 mL) and fuming HNO3 (3 mL) to afford 3.0 g of the desired product. 1H NMR (DMSO- e): δ 7.83-7.90 (m, 1H), 8.57-8.62 (m, 1H).
Step 2:- Preparation of methyl 2,4-difluoro-5-nitrobenzoate
The title compound was prepared by following the procedure as described for step-9 of Intermediate-2 by using 2,4-difluoro-5-nitrobenzoic acid (3.3 g, 16.25 mmol), methanol (20 mL) and cone. H2S04 (3 mL) to afford 3.5 g of the desired product. 1H NMR (CDC13): δ 1.42 (t, J = 7.5 Hz, 3H), 4.44 (q, J = 7.2 Hz, 2H), 7.10-7.16 (m, 1H), 8.76-8.81 (m, 1H). Step-3: Preparation of methyl 2,4-bis(methylamino)-5-nitrobenzoate
To a solution of methyl 2,4-difluoro-5-nitrobenzoate (5.0 g, 0.0246 mol) in THF,
TEA (10 mL) and methyl amine HC1 (4.15 g, 0.067 mol) were added. The reaction mass was stirred at RT for 12 h. After completion of reaction, THF was removed and the obtained mass was diluted with water and extracted with EtOAc. The organic layer was separated and dried over anhydrous sodium sulphate and concentrated to afford 4.5 g of the desired product. 1H NMR (DMSO- 6): δ 2.93 (s, 6H), 3.79 (s, 3H),
5.61 (s, 1H), 8.19 (br s, 1H), 8.43 (br s, 1H), 8.67 (s, 1H).
Step-4: Preparation of methyl 5-amino-2,4-bis(methylamino)benzoate
The title compound was prepared by following the procedure as described for step-2 of Intermediate-2 by using methyl 2,4-bis(methylamino)-5-nitrobenzoate (4.5 g, 0.018 mol), iron powder (cat. amt), cone. HC1 (4 mL) and methanol (25 mL) to afford 3.8 g of desired product. 1H NMR (DMSO- 6): δ 2.78 (s, 3H), 2.80 (s, 3H), 3.65 (s, 3H),
3.87 (s, 3H), 5.54-5.55 (m, 1H), 5.59 (s, 1H), 7.02 (s, 1H), 7.26 (d, J= 4.8Hz, 1H).
Step-5: Preparation of methyl 2-((2-chloro-6-fluorophenyl)amino)-l-methyl-6-
(methylamino)-lH-benzo[d]imidazole-5-carboxylate
The title compound was prepared by following the procedure as described for step-7 of Intermediate-2 by using methyl 5-amino-2,4-bis(methylamino)benzoate (3.8 g, 0.014 mol), NN-di-isopropyl carbodimide (3.0 mL), l-chloro-3-fluoro-2- isothiocyanatobenzene (Intermediate- 1, 3.8 g, 0.020 mol) and acetonitrile (20.0 mL) to afford 3.0 g of desired product. 1H NMR (DMSO-d6): δ 2.89 (d, J = 4.8Hz, 3H), 3.43 (s, 3H), 3.73 (s, 3H), 6.39 (s, 1H), 6.97-7.01 (m, 1H), 7.15-7.29 (m, 3H), 7.63 (d, J= 4.8Hz, 1H), 10.19 (s, 1H).
Step-6: Preparation of methyl 2-((2-chloro-6-fluorophenyl)amino)-l-methyl-6- (methylamino)-7-nitro-lH-benzo[d]imidazole-5-carboxylate
The title compound was prepared by following the procedure as described for step-1 of Intermediate-2 by using methyl 2-((2-chloro-6-fluorophenyl)amino)-l-methyl-6- (methylamino)-lH-benzo[d]imidazole-5-carboxylate (0.470 g, 1.28 mmol), cone. H2SO4 (0.5 mL), potassium nitrate (0.144 g, 1.04 mmol) and acetic acid (3.0 mL). The reaction mass was stirred at RT to afford 0.400 g of desired product. lH NMR (DMSO-de): δ 2.74 (s, 3H), 3.48 (s, 3H), 3.81 (s, 3H), 7.42 (m, J = 7.8Hz, 4H), 7.74 (s, 1H); MS [M]+ : 408.02.
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 To a solution of methyl 2-((2-chloro-6-fluorophenyl)amino)-l-methyl-6- (methylamino)-7-nitro-lH-benzo[d]imidazole-5-carboxylate (0.200 g, 0.49 mmol) in acetic acid (5.0 mL) was added iron powder (0.500 g, 8.92 mmol) and triethyl ortho formate (0.435 g, 2.93 mmol). The reaction mass was refluxed for 6-7 h. After completion of reaction, acetic acid was removed under vacuum. The obtained dry mass was diluted with water and extracted with 20% MeOH in DCM. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.100 g of desired product. 1H NMR (DMSO- 6): δ 2.49 (s, 3H), 3.86 (s, 3H), 3.95 (s, 3H), 7.29-7.35 (m, 3H), 8.26 (s, 1H), 8.35 (s, 1H); MS [M+H]+: 388.13.
Intermediate-5
Methyl 7-((2-chloro-6-fluorophenyl)amino)-2,3,8-trimethyl-3,8-dihydrobenzo[l,2- d:3,4-d']diimidazole-4-carbox late
Figure imgf000063_0001
The title compound was prepared by following the procedure described for step-7 of Intermediate-4 by using methyl 2-((2-chloro-6-fluorophenyl)amino)-l-methyl-6- (methylamino)-7-nitro-lH-benzo[d]imidazole-5-carboxylate (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) and triethyl ortho acetate (0.470 g, 2.89 mmol) to afford 0.100 g of desired product. 1H NMR (DMSO- 6): δ 1.83 (s, 3Η), 2.60 (s, 3Η), 3.78 (s, 3Η), 3.86 (s, 3Η), 7.27-7.34 (m, 4H); MS [M+H]+: 402.17.
Intermediate-6
Methyl 2-((2-chloro-6-fluorophenyl)amino)-7,8-dihydro- 1H- [l,4]dioxino[2',3':3,4]benzo[ -d]imidazole-5-carboxylate
Figure imgf000063_0002
Scheme for synthesis of Intermediate-6
Figure imgf000064_0001
Step 1 :- Preparation of 2, 3-dihydrobenzo[b][l,4]dioxine-5-carbaldehyde
A solution of 2,3-dihydroxybenzaldehyde (5.0 g, 36.20 mmol) in DMF (70 mL) was heated to 60-70°C and potassium carbonate (19.87 g, 144 mmol) was added. The reaction mass was further stirred for 1 h at same temperature. Then 1,2- dibromoethane (27.07 g, 144 mmol) was added and the reaction was continued stirring at 80-90°C for 16 h. After completion of reaction, reaction mixture was concentrated under reduced pressure and then diluted with water. Solid obtained was filtered off and dried to afford 6.0 g of desired product. 1H NMR (DMSO- 6): δ 4.32 (dd, 2H), 4.39 (dd, 2H), 6.94 (t, J= 7.8 Hz, 1H), 7.16 (d, J= 7.8 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 10.28 (s, 1H).
Step 2:- Preparation of 2,3-dihydrobenzo[b][l,4]dioxine-5-carboxylic acid
A solution of 2,3-dihydrobenzo[b][l,4]dioxine-5-carbaldehyde (0.500 g, 3.04 mmol) in acetone (10 mL) was stirred at 0-5°C and aqueous solution of sulphamic acid (0.455 g, 4.5 mmol) was added. The reaction mass was stirred for 20 min. Then aqueous solution of sodium chlorite (0.421 g, 4.5 mmol) was added and the reaction was further continued at RT for 18 h. After completion of reaction, reaction mixture was concentrated under reduced pressure and reaction mass was quenched with water. Solid obtained was filtered off and vacuum dried to afford 0.332 g of desired product. 1H NMR (DMSO-de): δ 4.27 (s, 4H), 6.84 (t, J = 7.2 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 7.20 (d, J= 7.5 Hz, 1H), 12.5 (bs, 1H); MS [M+H]+: 181.12.
Step 3:- Preparation of methyl 2,3-dihydrobenzo[b][l,4]dioxine-5-carboxylate Solution of 2,3-dihydrobenzo[b][l,4]dioxine-5-carboxylic acid (0.300 g, 1.6 mmol) in DMF (3 mL) and potassium carbonate (0.442 g, 3.2 mmol) was heated at 60-70°C for 1 h. Then methyl iodide (0.454 g, 3.2 mmol) was added slowly and reaction was continued stirring at 80-90°C for 16 h. After completion of reaction, reaction mixture was concentrated under reduced pressure and quenched with water. Solid obtained was filtered off and vacuum dried to afford 0.188 g of desired product. 1H NMR (DMSO- e): δ 3.77 (s, 3H), 4.27 (m, 4H), 6.87 (t, J = 7.8 Hz, 1H), 7.052 (d, J = 7.5 Hz, 1H), 7.22 (d, J= 7.5 Hz, 1H); MS [M+H]+: 195.17.
Step 4:- Preparation of methyl 6,7-dibromo-2,3-dihydrobenzo[b][l,4]dioxine-5- carboxylate
To a solution of methyl 2,3-dihydrobenzo[b][l,4]dioxine-5-carboxylate (4.00 g, 20.61 mmol) in acetic acid (32 mL) was added bromine in acetic acid (10.02 g, 60 mmol, in
16 mL) 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.
NaHC03 followed by sodium metabisulphate and then concentrated. The crude product was purified by silica gel chromatography on eluting with 1 to 2 % methanol in DCM to afford 1.0 g of desired product.
1H NMR (DMSO-de): δ 3.84 (s, 3H), 4.30 (s, 4H), 7.43 (s, 1H).
Step 5:- Preparation of methyl 6,7-dibromo-8-nitro-2,3-dihydrobenzo[b][l,4]dioxine-
5-carboxylate
To a cold fuming nitric acid (1 mL) at -50°C to -55°C was added methyl 6,7-dibromo-
2,3-dihydrobenzo[b][l,4]dioxine-5-carboxylate (0.100 g) and stirred for 30 minutes.
After completion of reaction, reaction mass was quenched with solid ice. The product obtained as a solid was filtered off and vacuum dried to afford 0.050 g of desired product. 1H NMR (DMSO-d6): δ 3.89 (s, 3H), 4.45 (s, 4H).
Step 6:- Preparation of methyl 8-amino-2,3-dihydrobenzo[b][l,4]dioxine-5- carboxylate
To a solution of 6,7-dibromo-8-nitro-2,3-dihydrobenzo[b][l,4]dioxine-5-carboxylate (0.050 g) in methanol (2 mL) was added Pd/C (catalytic) and TEA (0.5 mL). The reaction mass was hydrogenated at 60 psi for 5 h. The reaction mass was filtered through celite and filtrate was concentrated to afford 0.045 g of desired product. 1H NMR (DMSO-de): δ 3.66 (s, 3H), 4.24 (s, 4H), 5.53 (bs, 2H), 6.21 (d, J = 8.1 Hz, 1H), 7.16 (d, J= 8.7 Hz, 1H); MS [M+H]+: 210.16.
Step 7:- Preparation of methyl 8-amino-7-nitro-2,3-dihydrobenzo[b][l,4]dioxine-5- carboxylate
To a cold solution of methyl 8-amino-2,3-dihydrobenzo[b][l,4]dioxine-5-carboxylate (0.384 g, 1.83 mmol) in trifluoroacetic acid (10 mL) was added KN03 (0.204 g, 2.02 mmol) at 0-5°C. The reaction mixture was stirred at RT for 3 h. After completion of reaction, the reaction mass was quenched in ice and extracted in ethyl acetate. The organic layer was dried and concentrated to afford 0.322 g of desired product. 1H NMR (DMSO- e): δ 3.76 (s, 3H), 4.38 (bs, 4H), 7.41 (m, 2H), 8.21 (s, 1H). MS [M+H]+: 255.15.
Step 8:- Preparation of methyl 7,8-diamino-2,3-dihydrobenzo[b][l,4]dioxine-5- carboxylate
To a solution of methyl 8-amino-7-nitro-2,3-dihydrobenzo[b][l,4]dioxine-5- carboxylate (0.300 g) in methanol (20 mL) was added Iron powder (catalytic), cone. HC1 (2 mL). The reaction mass was stirred at RT for 2 h. The reaction mass was quenched with water and extracted in MeOH:DCM (1 :9). The organic layer was dried and concentrated to afford 0.220 g of desired product. MS [M+H]+: 225.30.
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
To a solution of methyl 7,8-diamino-2,3-dihydrobenzo[b][l,4]dioxine-5-carboxylate (0.220 g) in acetonitrile (5 mL) was added l-chloro-3-fluoro-2-isothiocyanatobenzene (Intermediate- 1, 0.220 g). The reaction mass was stirred at RT for 5-6 h. Then FeCl3 (0.150 g) was added to the reaction mixture and heated to 70-80°C for 18 h. After completion of reaction, reaction mixture was concentrated under reduced pressure, diluted with water and basified with NaHC03 and extracted with ethyl acetate. The organic layer was dried and concentrated and purified by silica gel chromatography on eluting with 1 to 5% methanol in DCM to afford 0.060 g of desired product. 1H NMR (DMSO- e): δ 3.71 (s, 3H), 4.22 (bs, 4H), 7.16 (m, 1H), 7.31- 7.38 (m, 3H), 9.04 (m, 1H), 11.14 (m, 1H); MS [M+H]+: 378.
Intermediate-7
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
Figure imgf000066_0001
Scheme for synthesis of Intermediate-7
Figure imgf000067_0001
Intermediate - 7
Step 1 :- Preparation of methyl 8-(methylamino)-7-nitro-2,3- dihydrobenzo [b] [ 1 ,4] dioxine-5 -carboxylate
To a cold solution of methyl 8-amino-7-nitro-2,3-dihydrobenzo[b][l,4]dioxine-5- carboxylate (step-7 of Intermediate-6, 0.500 g, 1.96 mmol) in DMF (2 mL) was added sodium hydride (0.056 g, 2.35 mmol) at 0-10°C and continued stirring for 15-20 minutes. Then methyl iodide (0.556 g, 3.92 mmol) was added to the reaction mixture and further stirred at RT for 18 h. After completion of reaction, 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. The 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. 1H NMR (DMSO- e): δ 3.06 (m, 3H), 3.73 (s, 3H), 4.28 (m, 2H), 4.35 (m, 2H), 7.89 (bs, 1H), 8.12 (s, 1H); MS [M+H]+: 269.23.
Step 2:- Preparation of methyl 7-amino-8-(methylamino)-2,3- dihydrobenzo [b] [ 1 ,4] dioxine-5 -carboxylate
The title compound was prepared by following the procedure as described in step-8 of intermediate-6 by using methyl 8-(methylamino)-7-nitro-2,3- dihydrobenzo[b][ 1,4] dioxine-5 -carboxylate (0.500 g, 1.86 mmol), Iron powder (catalytic), methanol (10 mL) and hydrochloric acid (1 mL) to afford 0.450 g of desired product. MS [M+H]+: 239.23.
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
The title compound was prepared by following the procedure as described in step-9 of intermediate-6 by using methyl 7-amino-8-(methylamino)-2,3- dihydrobenzo[b][ 1,4] dioxine-5 -carboxylate (0.450 g, 1.89 mmol), l-chloro-3-fluoro- 2-isothiocyanatobenzene (intermediate- 1, 0.353 g, 1.89 mmol), FeCl3 (0.458 g, 2.83 mmol) and acetonitrile (30 mL) to afford 0.100 g of desired product. MS [M+H]+: 392.18. Intermediate- 8
1- Chloro-2-isothiocyanato-3 -methylbenzene
Figure imgf000068_0001
The title compound was prepared by following the procedure as described in Intermediate- 1 by using 2-chloro-6-methyl aniline (3.0 g) in DCM (10 mL), N-ethyl di-isopropyl amine (8.0 g), thiophosgene (5.01 g) to obtain 1.5 g of desired product.
Intermediate-9
2- ((2-Chloro-6-methylphenyl)amino)-l-methyl-7,8-dihydro-lH- [ 1 ,4] dioxino [2',3 ' : 3 ,4]benzo [ 1 ,2-d]imidazole-5 -carboxylic acid
Figure imgf000068_0002
Scheme for synthesis of Intermediate-9
Figure imgf000068_0003
Intermediate -9
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
The title compound was prepared by following the procedure as described for step-9 of Intermediate-6 by using methyl 7-amino-8-(methylamino)-2,3- dihydrobenzo[b][l,4]dioxine-5-carboxylate (0.700 g), l-chloro-2-isothiocyanato-3- methylbenzene (Intermediate-8, 1.0 g), FeCl3 (0.400 g) and acetonitrile (30 mL). The obtained crude product was further purified by column chromatography on neutral alumina eluting with 0.2% E.A in DCM to afford 0.200 g of desired product. MS [M+H]+: 388.27. 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
To a solution 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 (0.360 g) in methanol (2.0 mL) was added aq. solution of NaOH (3.0 mL) and water (3.0 L). The reaction mass was refluxed for 4 h. After completion of reaction, the reaction mass was washed with DEE and aqueous layer was acidified with acetic acid and obtained solid was filtered to get 0.100 g of desired product. MS [M+H]+: 374.24.
Intermediate- 10
2-((2-Chloro-6-fluorophenyl)amino)- 1 -methyl-7,8-dihydro- 1H- [ 1 ,4] dioxino [2',3 ' : 3 ,4]benzo [ 1 ,2-d]imidazole-5 -carboxylic acid
Figure imgf000069_0001
The title compound was prepared by following the procedure as described for step-2 of intermediate-9 by using 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
(Intermediate-7, 1.0 g), methanol (5.0 mL), aq. solution of NaOH (10.0 mL) and water (3.0 L) to afford 0.500 g of desired product. 1H NMR (DMSO- 6): δ 7.53-7.35 (m, 4H), 4.42-4.35 (br d, 4H), 3.98 (s, 3H); MS [M]+2: 379.38.
Intermediate- 11
Methyl 2-((2-chloro-6-fluorophenyl)amino)-l-methyl-7,8-dihydro-lH- [l,4]dioxino[2,3-d]imidazo[ -b]pyridine-5-carboxylate
Figure imgf000069_0002
Step-1 : -Preparation of 3-(benzylo -2-methyl-4H-pyran-4-one
Figure imgf000069_0003
To a solution of 3-hydroxy-2-methyl-4H-pyran-4-one (2.0g, 0.0158 mol) in DMF (10 mL) was added 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. After completion of reaction, 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. 1H NMR (DMSO- 6): δ 2.10 (s, 3Η), 5.0 (s, 2Η), ), 6.37 (d, J = 9.30 Hz, 1H), 7.60-7.30 (m, 5H), 8.07 (d, J= 6.0Hz, 1H), MS [M+H]+ : 258.08.
Step-2: -Preparation of 3-(benzylo -2-methylpyridin-4(lH)-one
Figure imgf000070_0001
To a solution of 3-(benzyloxy)-2-methyl-4H-pyran-4-one (2.3 g) in acetonitirle (5 ml) was added aq.N¾ in seal tube. The reaction mixture was heated at 80-90°C for 18 h. After completion of reaction, the reaction mixture was cooled at RT and diluted with ethyl acetate. The organic layer was separated and further aqueous layer was extracted with 10% MeOH in DCM. The organic layer was concentrated to afford 2.3 g of desired product. 1H NMR (DMSO-d6): δ2.0 (s, 3H), 5.0 (s, 2H), 6.20 (s, 1H), 7.20- 7.40 (m, 6H), 11.20 (br s, 1H); MS [M+H]+ : 216.13.
Step-3:- Preparation of 3-(benzyloxy)-5-bromo-2-methylpyridin-4(lH)-one
Figure imgf000070_0002
To a cold solution of 3-(benzyloxy)-2-methylpyridin-4(lH)-one (0.200 g, 0.929 mol) in acetonitrile (5 ml) was added n-bromosuccinamide (0.181 g, 1.02 mol) at 0°C. The reaction mixture was stirred at RT for 4-5 h. After completion of reaction, the obtained solid was filtered to afford 0.180 g of desired product. 1H NMR (DMSO-d6): δ 2.0 (s, 3Η), 5.0 (s, 2Η), 7.30-7.40 (m, 5Η), 8.0 (s, 1Η), 11.90 (s, 1H); MS [M+H]+ : 296.02.
Step-4: -Preparation of 5-bromo-2-methylpyridine-3,4-diol
Figure imgf000071_0001
Solution of the 3-(benzyloxy)-5-bromo-2-methylpyridin-4(lH)-one (7.20 g) in 30 % HBr in Acetic acid (40 mL) was refluxed for 4 h. After completion of reaction, excess of solvent was removed under vacuum and sticky mass thus obtained was triturated with n-Pentane to afford 0.200 g of desired product. 1H NMR (DMSO-d6): δ 2.30 (s, 3H), 8.20 (s, 1H), 12.0-14.0 (br s, 2H); MS [M+H]+ : 206.12.
Step-5: Preparation of 8-bromo-5-methyl-2,3-dihydro-[l,4]dioxino[2,3-c]pyridine
Figure imgf000071_0002
The title compound was prepared by following the procedure as described for step-1 of Intermediate-6 by using 5-bromo-2-methylpyridine-3,4-diol (0.100 g. 0.490 mol), 1 ,2-diboroethane (0.184 g, 0.980 mol) and potassium carbonate (0.202 g, 1.47 mol) to afford 0.035 g of desired product. 1H NMR (DMSO- 6): 62.26 (s, 3H), 4.34 (d, J = 5.70 Hz, 2H), 4.44 (d, J= 5.7Hz, 2H), 8.0 (s, 1H); MS [M+H]+ : 230.16.
Step-6: Preparation of 8-bromo-5-methyl-7-nitro-2,3-dihydro-[l,4]dioxino[2,3- c]pyridine
Figure imgf000071_0003
To the cold solution of 8-bromo-5-methyl-2,3-dihydro-[l,4]dioxino[2,3-c]pyridine (0.035 g) in cone. H2SO4 was added fuming HNO3 at 0-5°C. The reaction mixture was stirred at RT for 5-6 h. After completion of reaction, the reaction mass was quenched in ice and basified with Na2C03 and extracted with ethyl acetate. The organic layer was concentrated to afford desired 0.035 g product. 1H NMR (DMSO-d6): 52.360 (s, 3H), 4.45 (d, J= 1.80 Hz, 2H), 4.54 (d, J= 2.7Hz, 2H); MS [M+H]+ : 275.11.
Step-7: Preparation of 8-bromo-7-nitro-2,3-dihydro-[l,4]dioxino[2,3-c]pyridine-5- carboxylic acid
Figure imgf000071_0004
To the cold solution of 8-bromo-5-methyl-7-nitro-2,3-dihydro-[l,4]dioxino[2,3- c]pyridine (0.035 g, 0.125 mol) in cone. H2SO4, 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. The organic layers were dried over anhydrous sodium sulphate and concentrated to afford 0.018 g of desired product. 1H NMR (DMSO-d6): 53.90-3.70 (br hump, 1H), 4.48-4.50 (br d, 2H), 4.51-4.62 (br d, 2H); MS [M+H]+ : 304.98.
Step-8: Preparation of methyl 8-bromo-7-nitro-2,3-dihydro-[l,4]dioxino[2,3- c]pyridine-5 -carboxylate
Figure imgf000072_0001
To a solution of 8-bromo-7-nitro-2,3-dihydro-[l,4]dioxino[2,3-c]pyridine-5- carboxylic acid (0.200 g) in methanol was added cone. H2SO4. The reaction mass was heated at 70-80°C for 6 h. After completion of reaction, removed excess of solvent under vacuum and obtained reaction mass was basified with NaHC03 and extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulphate and concentrated to afford 0.150 g of desired product.
Step-9: Preparation of methyl 8-(methylamino)-7-nitro-2,3-dihydro-[l,4]dioxino[2,3- c]pyridine-5 -carboxylate
Figure imgf000072_0002
To a solution of methyl 8-bromo-7-nitro-2,3-dihydro-[l,4]dioxino[2,3-c]pyridine-5- carboxylate in acetonitrile was added TEA (0.5mL) and aq. n-methyl amine (5 mL). The reaction mass was heated at 70°C for 22 h. After completion of reaction, removed excess of solvent under vacuum. 1H NMR (DMSO-d6): δ 2.95 (d, J = 4.20 Hz, 3H), 3.77 (s, 3H), 4.40-4.43 (m, 4H), 7.29-7.30 (br s, 1H); MS [M+H]+ : 270.01.
Step-10: Preparation of methyl 7-amino-8-(methylamino)-2,3-dihydro- [ 1 ,4]dioxino[2,3-c]pyridine-5-carboxylate
Figure imgf000072_0003
To a solution of methyl 8-(methylamino)-7-nitro-2,3-dihydro-[l,4]dioxino[2,3- c]pyridine-5-carboxylate (0.150 g) in methanol was added iron powder (cat.amt) and cone. HC1. The reaction mixture was refluxed for 2 h. After completion of reaction, the reaction mass was filtered and removed excess of solvent under vacuum. The remaining reaction mass was quenched with water and basified with NaHC03 and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.110 g of desired product. 1H NMR (DMSO- e): δ 2.81 (s. 3H), 3.68 (s, 3H), 3.83-3.94 (m, 2H), 4.19-4.28 (m, 2H), 5.25 (br hump, 2H).
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
To a solution methyl 7-amino-8-(methylamino)-2,3-dihydro-[l,4]dioxino[2,3- c] pyridine-5-carboxylate (0.110 g,0.460 mmol) in acetonitrile (5.0 mL) was added 1- chloro-3-fluoro-2-isothiocyanatobenzene (Intermediate- 1, 0.119 g, 0.687 mmol). The reaction mass was stirred at RT for 12 h. The reaction mixture was further added anhydrous FeCl3 (0.215 g, 1.3 mmol) and refluxed the reaction mass for 3-4 h. After completion of reaction, removed excess of solvent under vacuum. The obtained reaction mass was quenched with water and basified with NaHC03 and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate and concentrated to afford crude which was further purified by column chromatography on silica gel eluting with 1.5% MeOH in DCM to afford 0.080 g of desired product. 1H NMR (DMSO- 6): δ 3.75 (s, 3H), 3.85 (s, 3H) 4.33 (dd, J = 2.70 Hz, 2H), 4.5 (dd, J = 2.40Hz, 1.50 Hz, 2H), 7.32-7.40 (m, 3H), 9.97 (s, 1H); MS [M+H]+ : 393.13.
Intermediate- 12
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
Figure imgf000073_0001
To a solution 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 (Intermediate- 11, 0.250 g, 0.636 mmol) in methanol (2.0 mL) was added (50 %) aqueous solution of sodium hydroxide (0.152 g, 3.8 mmol). The reaction mass was stirred at 60°C for 3-4 h. After completion of reaction, the reaction mass was quenched in water, acidified with dil. acetic acid and obtained solid was filtered to afford 0.010 g desired product. 1H NMR (DMSO- e): δ 7.90 (s, 1H), 7.35-7.34 (m, 1H), 7.26-7.20 (m, 2H), 4.43 (d, J = 2.36 Hz, 2H), 4.29 (d, J= 2.20 Hz, 2H) ; MS [M+H]+ : 379.11.
Intermediate- 13
Methyl 2-((2-chloro-6-methylphenyl)amino)- 1 -methyl-7,8-dihydro- 1H- [l,4]dioxino[2,3-d]imidazo[ -b]pyridine-5-carboxylate
Figure imgf000074_0001
The title compound was prepared by following the procedure as described for step-9 of Intermediate-6 by using methyl 7-amino-8-(methylamino)-2,3-dihydro-
[l,4]dioxino[2,3-c]pyridine-5-carboxylate (step-10 of Intermediate- 11 0.110 g,0.460 mmol), acetonitrile (5.0 mL), 1 -chloro-2-isothiocyanato-3 -methylbenzene
(Intermediate-8, 0.125 g, 0.682 mmol) and anhydrous FeCl3 (0.215 g, 1.3 mmol) to afford 0.080 of desired product. 1Η NMR (DMSO-d6): δ 8.75 (s, 1Η), 7.39 (d, J = 10.0 Hz, 1H), 7.30-7.11 (m, 2H), 4.47 (dd, J = 7.50 Hz, 2H), 4.40 (br s, 2H), 3.93 (s, 3H), 3.75 (s, 3H), 2.08 (s, 3H)
Intermediate- 14
Methyl 2-((2-chloro-6-methylphenyl)amino)-7,8-dihydro- 1H- [l,4]dioxino[2',3':3,4]benzo[ -d]imidazole-5-carboxylate
Figure imgf000074_0002
The title compound was prepared by following the procedure as described for step-9 of Intermediate-6 by using methyl 7,8-diamino-2,3-dihydrobenzo[b][l,4]dioxine-5- carboxylate (step-8 of Intermediate-6, 0.220 g), acetonitrile (5 mL), l-chloro-2- isothiocyanato-3-methylbenzene (Intermediate-8, 0.220 g), anhydrous FeCl3 (0.325 g) to afford 0.060 g of desired product.
Intermediate- 15
5-Methyl-2,3-dihydro-[l,4]dioxino[2,3-c]pyridine-7,8-diamine
Figure imgf000075_0001
Step-1 :-Preparation of 5-methyl-7-nitro-2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-8
Figure imgf000075_0002
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.N¾ (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.
Intermediate- 16
Methyl 2-((2-chloro-6-fluorophenyl)amino)- 1 -ethyl-7,8-dihydro
[l,4]dioxino[2',3':3,4]benzo -d]imidazole-5-carboxylate
Figure imgf000075_0003
Scheme for synthesis of Intermediate- 16
Figure imgf000075_0004
Intermediate - 7
Step 1 :- Preparation of methyl 8-(ethylamino)-7-nitro-2,3-dihydrobenzo[b][l,4] dioxine-5 -carboxylate To a cold solution of methyl 8-amino-7-nitro-2,3-dihydrobenzo[b][l,4]dioxine-5- carboxylate (step-7 of Intermediate-6, 0.500 g, 1.96 mmol) in DMF (2 mL) was added sodium hydride (0.094 g, 3.2 mmol) at 0-10°C and stirred further for 15- 20 minutes. Then ethyl bromide (0.257 g, 2.36 mmol) was added to the reaction mixture and further stirred at RT for 18 h. After completion of reaction, reaction mixture was concentrated under reduced pressure and quenched with water. Product was extracted with ethyl acetate and the organic layer was dried and concentrated to afford 0.300 g of desired product. 1H NMR (DMSO- 6): δ 1.15 (t, J = 6.9 Hz, 3H), 3.59 (t, J = 5.1 Hz, 2H), 3.73 (s, 3H), 4.29 (m, 2H), 4.38 (m, 2H), 8.02 (m, 1H), 8.18 (s, 1H); MS [M+H]+: 283.25.
Step 2:- Preparation of methyl 7-amino-8-(ethylamino)-2,3-dihydrobenzo[b][l,4] dioxine-5 -carboxylate
The title compound was prepared by following the procedure as described for step-2 of Intermediate-2 by using methyl 8-(ethylamino)-7-nitro-2,3-dihydrobenzo[b][l,4] dioxine-5 -carboxylate (0.500 g, 1.86 mmol), Iron powder (catalytic), methanol (10 mL) and dil. HC1 (1 mL) to afford 0.450 g of desired product.
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
The title compound was prepared by following the procedure as described in step-9 of Intermediate-6 by using methyl 7-amino-8-(ethylamino)-2,3-dihydrobenzo[b][l,4] dioxine-5 -carboxylate (0.450 g, 1.89 mmol), l-chloro-3-fluoro-2- isothiocyanatobenzene (Intermediate- 1, 0.353 g, 1.89 mmol), FeCl3 (0.458 g, 2.83 mmol) and acetonitrile (30 mL) to afford 0.100 g of desired product. lH NMR (DMSO-de): δ 1.39 (t, 3Η), 3.60-3.64 (m, 2Η), 3.76 (s, 3Η), 4.38-4.43 (m, 4Η), 7.51 (m, 4H); MS [M+H]+: 406.53.
Intermediate- 17
2-[(2-Chloro-6-methylphenyl)amino]-7,8-dihydro- lH-[ 1 ,4]dioxino[2,3- e]benzimidazole-5-carboxylic acid
Figure imgf000076_0001
The title compound was prepared by following the procedure as described for step-2 of Intermediate-9 by using methyl 2-((2-chloro-6-methylphenyl)amino)-7,8-dihydro- iH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxylate (Intermediate- 14, 0.800 g), methanol (5.0 mL), aq. solution of NaOH (10.0 mL) and water (3.0 L) to afford 0.550 g of desired product. 1H NMR (DMSO- 6): δ 2.22 (s, 3H), 4.23 (s, 3H), 716-7.40 (m, 4H), 10.72 (br s, 1H); MS [M+H]+: 360.48.
Intermediate- 18
2-((2-Chloro-6-fluorophenyl)amino)-7,8-dihydro-lH-[l,4]dioxino[2*,3*:3,4]benzo[l,2- d]imidazole-5-carboxylic acid
Figure imgf000077_0001
The title compound was prepared by following the procedure as described for step-2 of Intermediate-9 by using 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 (Intermediate-6, 1.0 g), methanol (5.0 mL), aq. solution of NaOH (10.0 mL) and water (3.0 L) to afford 0.500 g of desired product. 1H NMR (DMSO- 6): δ 7.53-7.35 (m, 4H), 4.42-4.35 (br d, 4H); MS [M]+2: 364.04.
Intermediate- 19
4-(2-Cyclopropylethynyl)-3-fluorobenzenamine
Figure imgf000077_0002
Step 1 :- Preparation of l-(2-cyclopropylethynyl)-2-fluoro-4-nitrobenzene
Figure imgf000077_0003
Under N2-atmosphere to a solution of 2-fluoro-l-iodo-4-nitrobenzene (0.500 g, 0.187 mmol) in THF (5.0 mL) was added Cul (0.0017g, 0.074 mmol), TEA (1.0 mL), Bis triphenyl phosphine Palladium (II) acetate (0.052 g, 0.074 mmol) and prop-l-yn-1- ylcyclopropane (0.185 g, 0.250 mmol). The reaction mass was stirred at RT for 16 h. After completion of reaction, the reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.450 g of desired product. 1H NMR (DMSO-d6): δ 0.82 (m, 2H), 0.97-0.99 (m, 2H), 1.68 (m, 1H), 7.91 (t, J = 7.8Hz, 1H), 8.03 (d, J = 8.7Hz, 1H), 8.17 (d, J= 9.3Hz, 1H). Step 2:- Preparation of 4-(cyclopropylethynyl)-2-fluoroaniline
The title compound was prepared by following the procedure as described for step-2 of Intermediate-2 by using 4-(cyclopropylethynyl)-2-fluoro-l -nitrobenzene (0.450 g), Iron powder (0.500 g), cone. HC1 (3-4 mL), methanol (10 mL) to afford 0.350 g of desired product. 1H NMR (DMSO- 6): δ 0.63-0.65 (m, 2H), 0.79-0.86 (m, 2H), 1.46- 1.50 (m, 1H), 5.71 (s, 2H), 6.29 (d, J = 10.8Hz, 2H), 7.02 (t, J = 7.8Hz, 1H); MS [M+H]+: 176.16.
Intermediate-20
6-(Cyclopropylethynyl)pyridin- -amine
Figure imgf000078_0001
Preparation of 2-(cyclopropylethynyl)-5-nitropyridine
Figure imgf000078_0002
The title compound was prepared by following the procedure as described for step-1 of intermediate- 19 by using 2-bromo-5-nitropyridine (1.000 g, 4.96 mmol), THF (5.0 mL), Cul (0.037g, 0.196 mmol), TEA (1.0 mL), Bis triphenyl phosphine Palladium (II) acetate (0.138 g, 0.196 mmol) and prop-l-yn-l-ylcyclopropane 0.487 g, 7.37 mmol) to afford 0.800 g of desired product. 1H NMR (DMSO-d6): δ 0.85-0.98 (m, 2H), 10.99-1.22 (m, 2H), 1.63-1.72 (m, 1H), 7.68 (d, J= 8.4Hz, 1H), 8.51 (dd, J = 3.0Hz, 2.7Hz, 1H), 9.27 (s, 1H)
Step 2:- Preparation of 6-(cyclopropylethynyl)pyridin-3 -amine
The title compound was prepared by following the procedure as described for step-2 of Intermediate-2 by using 2-(cyclopropylethynyl)-5-nitropyridine (0.750 g), Iron powder (0.750 g), cone. HC1 (3-4 mL), methanol (10 mL) to afford 0.500 g of desired product. 1H NMR (DMSO-d6): δ 0.67 (m, 2H), 0.84 (m, 2H), 1.47 (br s, 1H), 5.58 (br s, 2H), 6.81 (d, 1H), 7.05 (d, J= 8.4 Hz, 1H), 7.81 (s, 1H).
Example- 1
2-((2-Chloro-6-fluorophenyl)amino)-N-(3-(trifluoromethyl)phenyl)-lH-imidazo[4,5- f]quinoline-5-carboxamide
Figure imgf000079_0001
Under inert atmosphere to a solution of methyl 2-((2-chloro-6-fluorophenyl)amino)- lH-imidazo[4,5-f]quinoline-5-carboxylate (Intermediate -2, 0.030 g, 0.080 mmol) in dry toluene was added 3-trifluoromethyl aniline (0.019 g, 0.121 mmol) and trimethyl aluminum ( 2.0 M solution in toluene) (0.011 g, 0.15 mmol). The reaction mixture was refluxed for 3 h. After completion of reaction, toluene was removed under vacuum and obtained dry mass was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained crude product was purified by column chromatography on neutral alumina eluting with 1.5 % MeOH in DCM to afford 0.150 g of the desired product. 1H NMR (DMSO- 6): δ 7.47-7.43 (m, 4H), 7.66-7.61 (m, 2H), 8.02 (d, J = 8.7Hz, 1H), 8.50 (s, 1H), 8.72 (s, 1H), 8.78 (m, 1H), 9.08 (s, 1H), 9.60 (br s, 1H), 12.02 (br s, 1H), 14.22 (br s, 1H); MS [M-H]": 498.37.
Example-2
2-((2-Chloro-6-fluorophenyl)amino)-3-methyl-N-(3-(trifluoromethyl)phenyl)-3H- imidazo [4 , 5 -f] quinoxaline-5 -carboxamide
Figure imgf000079_0002
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. 1H NMR (DMSO-d6): δ 3.99 (s, 3Η), 7.49 (m, 4Η), 7.65 (m, 1Η), 8.06 (d, J = 8.1Hz, 1H), 8.45 (s, 1H), 8.80 (s, 1H), 8.97 (s, 1H), 9.05 (s, 1H), 9.28 (s, 1H), 12.88 (s, 1H); MS [M+H]+: 515.09.
Example-3 7-((2-Chloro-6-fluorophenyl)amino)-3,8-dimethyl-N-(3-(trifluoromethyl)ph dihydrobenzo[l,2-d:3,4- ']diimidazole-4-carboxamide
Figure imgf000080_0001
The title compound was prepared by following the procedure as described for Example-1 by using methyl 7-((2-chloro-6-fluorophenyl)amino)-3,8-dimethyl-3,8- dihydrobenzo[l,2-d:3,4-d']diimidazole-4-carboxylate (Intermediate-4, 0.100 g, 0.258 mmol), 3-trifluoromethyl aniline (0.062 g, 0.285 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. 1H NMR (CDC13): δ 3.97 (s, 3H), 4.20 (s, 3H), 7.06 (m, 2H), 7.22 (m, 1H), 7.39 (d, J = 7.8Hz, 1H), 7.44-7.50 (m, 1H), 7.72-7.78 (m, 2H), 7.87 (s, 1H), 8.01 (s, 1H), 8.37 (s, 1H). MS [M+H]+: 517.20.
Example-4
7-((2-Chloro-6-fluorophenyl)amino)-2,3,8-trimethyl-N-(3-(trifluoromethyl)phenyl)- 3,8-dihydrobenzo[l,2-d: -d']diimidazole-4-carboxamide
Figure imgf000080_0002
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. 1H NMR (CDC13): δ 2.70 (s, 3H), 3.85 (s, 3H), 4.18 (s, 3H), 7.20 (m, 2H), 7.33 (m, 1H), 7.42 (m, 1H), 7.50 (m, 2H), 7.92 (m, 1H), 8.15 (s, 1H); MS [M+H]+: 531.19.
Example-5
2-((2-Chloro-6-fluorophenyl)amino)-N-(3-(trifluoromethyl)phenyl)-7,8-dihydro-lH- [l,4]dioxino [2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide
Figure imgf000081_0001
Under inert atmosphere, to a solution 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
(Intermediate-6, 0.060 g, 0.159 mmol) in dry toluene (2 mL) was added 3- trifluoromethyl aniline (0.038 g, 0.236 mmol) and trimethyl aluminum ( 2.0 M solution in toluene, 0.6 mL). The reaction mixture was stirred at RT for 18 h. After completion of reaction, the reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.025 g of the desired product. 1H NMR (DMSO-d6):5 4.33- 4.41 (m, 4Η), 7.33-7.43 (m, 5Η), 7.57 (t, J = 9.0 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 8.26 (s, 1H), 9.05 (bs, 1H), 10.23 (s, 1H), 11.23 (bs, 1H); MS [M+H]+: 507.28.
Example-6
2-((2-Chloro-6-fluorophenyl)amino)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-7,8- dihydro-lH-[l,4]dioxino 2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide
Figure imgf000081_0002
The title compound was prepared following the procedure described in Example-5 using methyl 2-((2-chloro-6-fluorophenyl)amino)-7,8-dihydro
[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxylate (Intermediate-6, 0.072 g, 0.191 mmol), 4-fluoro-3-(trifluoromethyl) aniline (0.051 g, 0.287 mmol), trimethyl aluminum ( 2.0 M solution in toluene) in toluene to afford 0.024 g of the title product. 1H NMR (DMSO-d6):6 4.32- 4.39 (m, 4Η), 7.32- 7.53 (m, 5Η), 7.99 (m, 1Η), 8.26 (m, 1Η), 9.05 (bs, 1Η), 10.22 (s, 1Η), 11.22 (bs, 1H); MS [M+H]+: 525.27.
Example-7
2-((2-Chloro-6-fluorophenyl)amino)-N-(4-(trifluoromethyl)phenyl)-7,8-dihydro-lH- [ 1 ,4] dioxino [2',3 ' : 3 ,4]benzo [ 1 ,2-d]imidazole-5 -carboxamide
Figure imgf000082_0001
The title compound was prepared following the procedure described in Example-5 using methyl 2-((2-chloro-6-fluorophenyl)amino)-7,8-dihydro
[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxylate (Intermediate-6, 0.071 g, 0.18 mmol), 4-(trifluoromethyl) aniline (0.045 g, 0.27 mmol), trimethyl aluminum (2.0 M solution in toluene) in toluene to afford 0.014 g of the title product. 1H NMR (DMSO- e): δ 4.31- 4.40 (m, 4H), 7.33 (m, 4H), 7.69 (d, J= 7.8 Hz, 2H), 7.95 (d, J = 8.4 Hz, 2H), 9.04 (bs, 1H), 10.25 (bs, 1H), 11.22 (bs, 1H); MS [M+H]+: 507.11.
Example-8
2-((2-Chloro-6-fluorophenyl)amino)-l-methyl-N-(3-(trifluoromethyl)phenyl)-7,8- dihydro-lH-[l,4]dioxin ',3':3,4]benzo[l,2-d]imidazole-5-carboxamide
Figure imgf000082_0002
The title compound was prepared following the procedure described in Example-5 using methyl 2-((2-chloro-6-fluorophenyl)amino)- 1 -methyl-7,8-dihydro- 1H- [l,4]dioxino [2',3':3,4]benzo[l,2-d]imidazole-5-carboxylate (Intermediate-7, 0.057 g, 0.195 mmol), 3-(trifluoromethyl) aniline (0.035 g, 0.217 mmol), trimethyl aluminum (2.0 M solution in toluene) in toluene to afford 0.018 g of the title product. lH NMR (CDC -d): δ 3.88 (s, 3Η), 4.48 (m, 2Η), 4.57 (m, 2Η), 7.06 (m, 3Η), 7.26 (m, 1Η), 7.34 (d, J = 7.2 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.86 (m, 2H), 7.91 (d, J = 7.8 Hz, 1H), 9.68 (bs, 1H); MS M+H]+: 521.21.
Example-9
2-((2-Chloro-6-fluorophenyl)amino)-N-(4-fluoro-3 -(trifluoromethyl)phenyl)- 1 - methyl-7,8-dihydro-lH- l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide
Figure imgf000082_0003
The title compound was prepared following the procedure described in Example-5 using methyl 2-((2-chloro-6-fluorophenyl)amino)- 1 -methyl-7,8-dihydro- 1H- [l,4]dioxino [2',3':3,4]benzo[l,2-d]imidazole-5-carboxylate (Intermediate-7, 0.070 g, 0.179 mmol), 4-fiuoro-3-(trifluoromethyl) aniline (0.048 g, 0.268 mmol), trimethyl aluminum (2.0 M solution in toluene) in toluene to afford 0.018 g of the title product. 1H NMR (CDC -d): δ 3.88 (bs, 3Η), 4.46 (bs, 2Η), 4.56 (bs, 2Η), 7.04 (m, 2Η), 7.15- 7.26 (m, 3Η), 7.81 (m, 3Η), 9.61 (bs, 1H); MS [M+H]+: 539.27.
Example- 10
2-((2-Chloro-6-fluorophenyl)amino)-l-methyl-N-(4-(trifluoromethyl)phenyl)-7,8- dihydro-lH-[l,4]dioxin 2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide
Figure imgf000083_0001
The title compound was prepared following the procedure described in Example-5 using methyl 2-((2-chloro-6-fluorophenyl)amino)- 1 -methyl-7,8-dihydro- 1H- [l,4]dioxino [2',3':3,4]benzo[l,2-d]imidazole-5-carboxylate (Intermediate-7, 0.058 g, 0.145 mmol), 4-(trifluoromethyl) aniline (0.036 g, 0.223 mmol), trimethyl aluminum (2.0 M solution in toluene) in toluene to afford 0.023 g of the title product. 1H NMR (CDC -d): δ 3.88 (s, 3Η), 4.48 (bs, 2Η), 4.56 (m, 2Η), 7.05 (m, 3Η), 7.26 (m, 2Η), 7.58 (d, J=8.4 Hz, 2H), 7.77 (d, J=8.1 Hz, 2H), 9.71 (bs, 1H); MS [M+H]+: 521.19.
Example- 11
2-((2-Chloro-6-fluorophenyl)amino)-N-(3 -fluoro-5 -(trifluoromethyl)phenyl)- 1 - methyl-7,8-dihydro-lH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide
Figure imgf000083_0002
The title compound was prepared following the procedure described in Example-5 using methyl 2-((2-chloro-6-fluorophenyl)amino)- 1 -methyl-7,8-dihydro- 1H- [l,4]dioxino [2',3':3,4]benzo[l,2-d]imidazole-5-carboxylate (Intermediate-7, 0.080 g, 0.20 mmol), 3-amino-5-fluoro benzotrifluoride (0.055 g, 0.30 mmol), trimethyl aluminum (2.0 M solution in toluene) in toluene to afford 0.020 g of the title product. 1H NMR (CDC -d): δ 3.90 (s, 3H), 4.49 (bs, 2H), 4.58 (m, 2H), 7.01 (m, 6H), 7.48 (s, 1H), 7.96 (d, 1H), 9.78 (bs, 1H); MS [M+H]+: 539.23.
Example- 12
2-((2-Chloro-6-fluorophenyl)amino)-N-(3-fluoro-5-(trifluorornethyl)phenyl)-7,8- dihydro-lH-[l,4]dioxin ',3':3,4]benzo[l,2-d]imidazole-5-carboxamide
Figure imgf000084_0001
The title compound was prepared following the procedure described in Example-5 using methyl 2-((2-chloro-6-fluorophenyl)amino)-7,8-dihydro
[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxylate (Intermediate-6, 0.060 g, 0.159 mmol), 3-amino-5-fluoro benzotrifluoride (0.043 g, 0.238 mmol), trimethyl aluminum ( 2.0 M solution in toluene) in toluene to afford 0.012 g of the title product. 1H NMR (CDCh-d): δ 4.45 (bs, 2Η), 4.55 (m, 2Η), 7.05 (d, J = 7.8 Hz, 1H), 7.17 (m, 2H), 7.26 (m, 3H), 7.52 (s, 1H), 7.77 (bs, 1H), 7.90 (d, J = 11.1 Hz, 1H), 9.94 (s, 1H); MS [M+H]+: 525.24.
Example- 13
2-((2-Chloro-6-methylphenyl)amino)-N-(4,4-dimethylcyclohexyl)-l-methyl-7,8- dihydro-lH-[l,4]dioxino[2',3': -d]imidazole-5-carboxamide
Figure imgf000084_0002
To a solution 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 (Intermediate-9, 0.113 g, 0.302 mmol) in mixture of THF:DCM (2.0 mL:0.5 mL) was added BOP (0.200 g, 0.450 mmol), DIPEA (0.5 mL). The reaction mass was stirred at RT for 30 minutes under N2 atmosphere. Then solution of 4,4-dimethyl cyclohexyl amine hydrochloride (0.075 g, 0.450 mmol) in THF (3.0 mL) was added. The reaction mass was stirred at RT for 48 h. After completion of reaction, the reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was concentrated to afford 0.020 g of desired product. 1H NMR (CDC -d): δ 0.94 (s, 6H), 1.18-1.85 (m, 8H), 2.41 (s, 3H), 3.76 (s, 3H), 3.89 (m, 1H), 4.44-4.47 (br d, 4H), 7.15-7.69 (m, 4H); MS [M+H] : 484.21.
Example- 14
2-((2-Chloro-6-fluorophenyl)amino)-N-(4,4-dimethylcyclohexyl)-l-methyl-7,8- dihydro-lH-[l,4]dioxino[2',3' -d]imidazole-5-carboxamide
Figure imgf000085_0001
The title compound was prepared following the procedure described in Example using 2-((2-chloro-6-fluorophenyl)amino)- 1 -methyl-7,8-dihydro- 1H-
[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxylic acid (Intermediate- 10, 0.100 g, 0.265 mmol), THF:DCM (5.0 mL: 1.0 mL), BOP (0.165 g, 0.395 mmol), DIPEA (0.5 mL), 4,4-dimethyl cyclohexyl amine hydrochloride (0.075 g, 0.450 mmol). The obtained crude product was further purified by column chromatography on basic alumina eluting with 1.5 % MeOH:DCM to afford 0.010 g of desired product. 1H NMR (CDC -d): δ 0.90 (s, 6H), 0.98-2.06 (m, 8H), 3.86 (s, 3H), 3.97 (m, 1H), 4.35-4.48 (br d, 4H), 6.97-7.08 (m, 2H), 7.69 (br d, 1H), 8.09 (br s, 1H) ; MS [M+H]+: 487.21.
Example- 15
2-((2-Chloro-6-fluorophenyl)amino)- 1 -methyl-N-(trans-4- (trifluoromethyl)cyclohexyl)-7,8-dihydro- lH-[ 1 ,4]dioxino[2',3':3,4]benzo[ 1 ,2- d]imidazole-5 -carboxamide
Figure imgf000085_0002
The title compound was prepared following the procedure described in Example usmg 2-((2-chloro-6-fluorophenyl)amino)- 1 -methyl-7,8-dihydro- 1H-
[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxylic acid (Intermediate- 10, 0.100 g, 0.265 mmol), THF:DCM (5.0 mL: 1.0 mL), BOP (0.175 g, 0.397 mmol), DIPEA (0.5 mL), (lr,4r)-4-(trifluoromethyl)cyclohexanamine hydrochloride (0.080 g, 0.397 mmol) to afford 0.029 g of desired product. 1H NMR (CDC -d): δ 1.31-2.03 (m, 8H), 3.95 (s, 3H), 4.05-4.36 (m, 1H), 4.42-4.46 (br d, 4H), 6.99-7.08 (m, 1H), 7.09-7.23 (m, 1H), 7.80-7.81 (d, 1H), 7.83 (s, 1H, 8.09 (s, 1H), 8.80 (s, 1H) ; MS [M+H]+: 527.31.
Example- 16
2-((2-Chloro-6-methylphenyl)amino)- 1 -methyl-N-(trans-4- (trifluoromethyl)cyclohexyl)-7,8-dihydro- lH-[ 1 ,4]dioxino[2',3':3,4]benzo[ 1 ,2- d]imidazole-5 -carboxami
Figure imgf000086_0001
The title compound was prepared following the procedure described in Example using 2-((2-chloro-6-methylphenyl)amino)- 1 -methyl-7,8-dihydro- 1H-
[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxylic acid (Intermediate-9, 0.090 g, 0.241 mmol), THF:DCM (5.0 mL: 1.0 mL), BOP (0.159 g, 0.360 mmol), DIPEA (0.5 mL), (lr,4r)-4-(trifluoromethyl)cyclohexanamine hydrochloride (0.074 g, 0.356 mmol) to afford 0.010 g of desired product. 1H NMR (CDC -d): δ 1.25-2.41 (m, 8H), 2.45 (s, 3H), 3.66 (s, 3H), 3.91-3.95 (m, 1H), 4.35-4.35 (br d, 4H), 7.20-7.32 (m, 4H), 11.36 (br s, 1H); MS [M+H]+: 523.32.
Example- 17
2-((2-Chloro-6-fluorophenyl)amino)-N-(3 -fluoro-5 -(trifluoromethyl)phenyl)- 1 - methyl-7,8-dihydro-lH-[l,4]dioxino[2,3-d]imidazo[4,5-b]pyridine-5-carboxamide
Figure imgf000086_0002
To a solution 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 (Intermediate-11, 0.040 g, 0.10 mmol) in dry toluene was added 3-fluoro-5-(trifluoromethyl)aniline (0.027 g, 0.15 mmol) followed by addition of trimethyl aluminum (2M solution in toluene) (0.5 mL). The reaction mixture was stirred at RT for 3h under inert atmosphere. After completion of reaction, quenched the reaction mass with water and extracted with DCM and concentrated. The obtained product was purified with column chromatography on silica gel eluting with 1.0% MeOH in DCM to afford 0.033 g of desired product. 1H NMR (DMSO- 6): δ 3.88 (s, 3H), 4.37 (s, 2H), 4.49 (dd, J = 2.10 Hz, 1.80, 2H), 7.45-7.29 (m, 4H), 8.02 (d, J = 3.0 Hz, 1H), 8.15 (s, 1H), 9.08 (s, 1H), 10.71 (s, 1H); MS [M+H]+ : 540.10.
Example- 18
2-((2-Chloro-6-fluorophenyl)amino)-N-(4-fluoro-3 -(trifluoromethyl)phenyl)- 1 - methyl-7,8-dihydro-lH-[l,4]dioxino[2,3-d]imidazo[4,5-b]pyridine-5-carboxamide
Figure imgf000087_0001
The title compound was prepared by following the procedure as described for Example-5 by using 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 (Intermediate- 11, 0.040 g, 0.10 mmol), dry toluene, 4-fluoro-3-(trifluoromethyl)aniline (0.027 g, 0.15 mmol) and trimethyl aluminum (2M solution in toluene) (0.5 mL) to afford 0.033 g of desired product. 1H NMR (DMSO-d6): δ 3.88 (s, 3Η), 4.36 (d, J = 1.20 Hz, 2H), 4.48 (d, J = 1.50 Hz, 2H), 7.37-7.47 (m, 4H), 8.04-8.08 (br s, 1H), 8.33-8.35 (br s, 1H), 9.05 (s, 1H), 10.55 (s, 1H); MS [M+H]+ : 540.32.
Example- 19
2-((2-Chloro-6-fluorophenyl)amino)-N-(4,4-dimethylcyclohexyl)-l-methyl-7,8- dihydro-lH-[l,4]dioxino -d]imidazo[4,5-b]pyridine-5-carboxamide
Figure imgf000087_0002
To a solution of 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) in DMF (0.5 mL) was added BOP (0.291 g, 0.660 mmol), DIPEA (0.085g, 0.660 mmol). The reaction mass was stirred at RT for 30 minutes. Then added 4,4-dimethylcyclohexanamine HCl (0.064 g, 0.396 mmol). The reaction mass was stirred at RT for 14-16 h. After completion of reaction, the reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.040 g of product. 1H NMR (DMSO- e): δ 8.95 (s, 1H), 7.89 (d, J= 5.7 Hz, 1H), 7.43-7.11 (m, 3H), 4.45-4.43 (m, 2H), 4.30 (br s, 2H), 3.84 (s, 3H), 3.63-3.57 (m, 1H), 1.75-1.09 (m, 8H), 0.88-0.85 (m, 6H); MS [M+H]+ : 540.32.
Example-20
2-((2-Chloro-6-fluorophenyl)amino)-l-methyl-N-((lr,4r)-4- (trifluoromethyl)cyclohexyl)-7,8-dihydro- lH-[ 1 ,4]dioxino[2,3-d]imidazo[4,5- b]pyridine-5-carboxamide
Figure imgf000088_0001
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. 1H NMR (DMSO-d6): δ 8.94 (s, 1Η), 7.95 (d, J= 15.0 Hz, 1H), 7.43-7.34 (m, 3H), 4.44 (d, J= 1.8 Hz, 2H), 4.29 (d, J= 1.5 Hz, 2H), 3.84 (s, 3H), 3.64 (s, 1H), 1.87 (d, J = 6.6 Hz, 4H), 1.38-1.28 (m, 4H); MS [M+H]+ : 528.25.
Example-21
2-((2-Chloro-6-methylphenyl)amino)-N-(4-fluoro-3 -(trifluoromethyl)phenyl)- 1 - methyl-7,8-dihydro-lH- -d]imidazo[4,5-b]pyridine-5-carboxamide
Figure imgf000088_0002
The title compound was prepared by following the procedure as described for Example-5 by using methyl 2-((2-chloro-6-methylphenyl)amino)-l-methyl-7,8- dihydro-lH-[l,4]dioxino[2,3-d]imidazo[4,5-b]pyridine-5-carboxylate (Intermediate- 13, 0.040 g, 0.10 mmol), dry toluene, 4-fluoro-3-(trifluoromethyl)aniline (0.027 g, 0.15 mmol) and trimethyl aluminum (2M solution in toluene) (0.5 mL) to afford 0.020 g of desired product. 1H NMR (DMSO- 6): δ 10.55 (s, 1Η), 8.58 (s, 1Η), 8.14-8.06 (m, 1Η), 7.48-7.40 (m, 1Η), 7.30-6.96 (m, 4Η), 4.50 (br s, 2Η), 4.36 (br s, 2Η), 3.89 (s, 3Η), 2.25 (s, 3H); MS [M+H]+: 536.04.
Example-22
2-((2-Chloro-6-methylphenyl)amino)-N-(3 -fluoro-5 -(trifluoromethyl)phenyl)- 1 - methyl-7,8-dihydro-lH- -d]imidazo[4,5-b]pyridine-5-carboxamide
Figure imgf000089_0001
The title compound was prepared by following the procedure as described for Example-5 by using methyl 2-((2-chloro-6-methylphenyl)amino)-l-methyl-7,8- dihydro-lH-[l,4]dioxino[2,3-d]imidazo[4,5-b]pyridine-5-carboxylate (Intermediate- 13, 0.040 g, 0.10 mmol), dry toluene (2.0 mL), 3-fluoro-5-(trifluoromethyl)aniline (0.027 g, 0.15 mmol) and trimethyl aluminum (2M solution in toluene) (0.5 mL) to afford 0.020 g of desired product. 1H NMR (DMSO- 6): δ 10.71 (s, 1Η), 8.87 (s, 1Η), 8.17 (s, 1Η), 8.02 (d, J = 11.5 Hz, 1H), 7.42-7.40 (m, 1H), 7.32-7.24 (m, 3H), 4.50 (m, 2H), 4.37 (m, 2H), 3.89 (s, 3H), 2.25 (s, 3H); MS [M+H]+ : 536.04.
Example-23
2-((2-Chloro-6-methylphenyl)amino)-l-methyl-N-(3-(trifluoromethyl)phenyl)-7,8- dihydro-lH-[l,4]dioxin -d]imidazo[4,5-b]pyridine-5-carboxamide
Figure imgf000089_0002
The title compound was prepared by following the procedure as described for Example-5 by using methyl 2-((2-chloro-6-methylphenyl)amino)-l-methyl-7,8- dihydro-iH-[ 1 ,4]dioxino[2,3-d]imidazo[4,5-b]pyridine-5-carboxylate (Intermediate- 13, 0.040 g, 0.10 mmol), dry toluene, 3-(trifluoromethyl)aniline (0.024 g, 0.15 mmol) and trimethyl aluminum (2M solution in toluene) (0.5 mL) to afford 0.018 g of desired product. 1H NMR (DMSO- 6): δ 10.50 (s, 1H), 8.89 (br s, 1H), 8.32 (s, 1H), 7.97 (d, J= 10.0 Hz, 1H), 7.53-7.30 (m, 4H), 4.50 (s, 2H), 4.37 (m, 2H), 3.89 (s, 3H), 2.25 (s, 3H); MS [M+H]+: 518.06.
Example-24
2-((2-Chloro-6-fluorophenyl)amino)- 1 -methyl-N-(3 -(trifluoromethyl)phi
dihydro-lH-[l,4]dioxin -d]imidazo[4,5-b]pyridine-5-carboxamide
Figure imgf000090_0001
The title compound was prepared by following the procedure as described for Example-5 by using 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 (Intermediate- 11, 0.040 g, 0.10 mmol), dry toluene, 3-(trifluoromethyl)aniline (0.024 g, 0.15 mmol) and trimethyl aluminum (2M solution in toluene) (0.5 mL) to afford 0.025 g of desired product. 1H NMR (DMSO-d6): δ 10.52 (s, 1Η), 9.07 (s, 1Η), 8.33 (s, 1Η), 7.99 (d, J = 1.20 Hz, 1H), 7.55-7.37 (m, 5H), 4.50 (s, 2H), 4.50 (s, 2H), 4.38 (s, 3H); MS [M+H]+ : 522.00.
Example-25
2-((2-Chloro-6-fluorophenyl)amino)-l-methyl-N-(4-(trifluoromethyl)phenyl)-7,8- dihydro-lH-[l,4]dioxin -d]imidazo[4,5-b]pyridine-5-carboxamide
Figure imgf000090_0002
The title compound was prepared by following the procedure as described for Example-5 by using 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 (Intermediate- 11, 0.040 g, 0.10 mmol), dry toluene, 4-(trifluoromethyl)aniline (0.024 g, 0.15 mmol) and trimethyl aluminum (2M solution in toluene) (0.5 mL) to afford 0.033 g of desired product. 1H NMR (DMSO-d6): δ 10.52 (s, 1Η), 9.07 (s, 1Η), 9.04 (d, J = 15.96 Hz, 2H), 7.99-7.70 (m, 3H), 7.69-7.46 (m, 2H), 4.50 (s, 2H), 4.38 (s, 2H), 3.89 (s, 3H); MS [M+H]+ : 522.03. Example-26
2~((2-€liloro-0 TuorQplienyl)a:m
xnethy]-7,8~dibydro-l H-[i
Figure imgf000091_0001
The title compound was prepared by following the procedure as described for Example-5 by using 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 (Intermediate- 1 1 , 0.040 g, 0.10 mmol), dry toluene, 2-fluoro-5-(trifluoromethyl)aniline (0.024 g, 0.15 mmol) and trimethyl aluminum (2M solution in toluene) (0.5 mL) to afford 0.033 g of desired product. 1H NMR (DMSO- 6): δ 10.32 (s, 1Η), 9.15 (s, 1Η), 8.63 (d, J = 5.84Hz, 1H), 7.58-7.36 (m, 5H), 4.52 (br s, 2H), 4.40 (br s, 2H), 3.90 (s, 3H); MS [M+H]+ : 540.07.
Example-27
2-((2-chloro-6-methylphenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-7,8- dihydro-lH-[l ,4]dioxino 2',3':3,4]benzo[l ,2-d]imidazole-5-carboxamide
Figure imgf000091_0002
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. 1H NMR (CDCl3-< ): δ 2.23 (s, 2Η), 4.31 (br d, 2Η), 4.41 (br d, 2Η), 7.23-7.37 (m, 4Η), 7.97-8.04 (m, 3Η), 8.88 (s, 1Η), 10.36 (s, 1Η), 1 1.04 (br s, 1H); MS [M+H]+: 521.23.
Example-28 N-(2-Chloro-6-fluorophenyl)-5-methyl-7,8-dihydro-lH-[l,4]dioxino[2,3- d]imidazo[4,5-b]pyridin-2-amine
Figure imgf000092_0001
The title compound was prepared by following the procedure as described for step-9 of Intermediate-6 by using 5-methyl-2,3-dihydro-[l,4]dioxino[2,3-c]pyridine-7,8- diamine (Intermediate- 15, 0.100 g), acetonitrile (5.0 mL), l-chloro-3-fluoro-2- isothiocyanatobenzene (Intermediate- 1, 0.100 g) and anhydrous FeCl3 (0.215 g) to afford 0.080 of desired product. 1H NMR (DMSO- 6): δ 3.34 (s, 3Η), 4.26 (m, 4Η), 7.30 (m, 2Η), 7.37 (m, 1Η), 8.71 (s, 1Η), 11.53 (s, 1H); MS [M+H]+: 335.53.
Example-29
2-((2-Chloro-6-fluorophenyl)amino)- 1 -ethyl-N-(3 -fluoro-5 -(trifluoromethyl)phenyl)- 7,8-dihydro-lH-[l,4]dioxino 2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide
Figure imgf000092_0002
The title compound was prepared by following the procedure as described for Example-5 by using 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 (Intermediate- 16,
0.050 g, 0.10 mmol), dry toluene, 3-amino-5-fluoro benzotrifluoride (0.037 g, 0.15 mmol) and trimethyl aluminum (2M solution in toluene) (0.5 mL) to afford 0.023 g of desired product. 1H NMR (DMSO- 6): δ 1.47 (t, 3Η), 4.35 (m, 2Η), 4.58 (m, 4Η), 7.06 (m, 3Η), 7.26 (s, 2Η), 7.48 (s, 1Η), 7.93 (m, 1Η), 9.79 (s, 1H); MS [M+H]+ : 553.43.
Example-30
2-((2-Chloro-6-fluorophenyl)amino)-l-methyl-N-(3-(trifluoromethyl)benzyl)-7,8- dihydro-lH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide
Figure imgf000093_0001
The title compound was prepared by following the procedure as described for Example-5 by using 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
(Intermediate-7, 0.050 g, 0.10 mmol), dry toluene, 3- (trifluoromethyl)phenyl)methanamine (0.020 g, 0.15 mmol) and trimethyl aluminum (2M solution in toluene) (0.5 mL) to afford 0.023 g of desired product. 1H NMR (DMSO- e): δ 3.87 (s, 3Η), 4.41 (d, J = 3.9 Hz, 4H), 4.72 (d, J = 6.0 Hz, 2H), 7.04 (m, 3H), 7.22 (s, 1H), 7.47-7.60 (m, 4H), 8.01 (m, 1H); MS [M+H]+ : 535.47.
Example-31
2-((2-Chloro-6-fluorophenyl)amino)-N-(2-fluoro-5 -(trifluoromethyl)phenyl)- 1 - methyl-7,8-dihydro-lH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide
Figure imgf000093_0002
The title compound was prepared by following the procedure as described for Example-5 by using methyl 2-((2-chloro-6-fluorophenyl)amino)-l-methyl-7,8- dihydro- 1H- [ 1 ,4] dioxino ',3':3,4]benzo[l,2-d]imidazole-5-carboxylate
(Intermediate-7, 0.050 g, 0.10 mmol), dry toluene, 2-fluoro-5-(trifluoromethyl) benzenamine (0.020 g, 0.15 mmol) and trimethyl aluminum (2M solution in toluene) (0.5 mL) to afford 0.018 g of desired product. 1H NMR (DMSO-d6): δ 3.64 (s, 3Η), 4.47 (br d, 2Η), 4.55 (br d, 2Η), 7.15 (s, 1Η), 7.24-7.36 (m, 2Η), 7.43 (m, 1Η), 7.55 (m, 2Η), 8.72 (s, 1Η), 10.32 (s, 1Η), 10.62 (s, 1H); MS [M+H]+ : 535.47.
Example-32
2-((2-Chloro-6-methylphenyl)amino)-N-((lr,4r)-4-(trifluoromethyl)cyclohexyl)-7,8- dihydro-lH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide
Figure imgf000094_0001
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. 1H NMR (DMSO- 6): δ 1.34 (m, 4Η), 1.88 (m, 2Η), 2.27 (s, 2Η), 3.73 (m, 1Η), 4.33 (m, 4Η), 7.27 (m, 3Η), 7.37 (s, 1Η), 7.78 (d, 1Η), 8.77 (s, 1Η), 10.92 (s, 1H); MS [M+H]+ : 509.58.
Example-33
2-((2-Chloro-6-fluorophenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)benzyl)-7,8- dihydro-lH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide
Figure imgf000094_0002
The title compound was prepared by following the procedure as described for Example-5 by using 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 (Intermediate-6, 0.100 g, 0.275 mmol), dry toluene, trimethyl aluminum (2M solution in toluene) (0.5 mL) and 3-fluoro-5-(trifluoromethyl)phenyl)methanamine hydrochloride (0.068 g, 0.396 mmol) to afford 0.018 g of desired product. 1H NMR (DMSO- 6): δ 4.34 (m, 4Η), 4.57 (d, J = 6.0 Hz, 2H), 7.32-7.49 (m, 5H), 7.56 (s, 2H), 8.72 (s, 1H), 9.00 (s, 1H), 11.17 (s, 1H); MS [M+H]+ : 539.43.
Example-34
2-((2-Chloro-6-fluorophenyl)amino)-N-(3 -fluoro-5 -(trifluoromethyl)benzyl)- 1 - methyl-7,8-dihydro-lH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide
Figure imgf000095_0001
The title compound was prepared by following the procedure as described for Example-5 by using 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
(Intermediate-7, 0.050 g, 0.10 mmol), dry toluene, 3-fluoro-5-(trifluoromethyl) phenyl)methanamine hydrochloride (0.020 g, 0.15 mmol) and trimethyl aluminum (2M solution in toluene) (0.5 mL) to afford 0.018 g of desired product. 1H NMR (DMSO- e): δ 3.62 (m, 3Η), 4.40 (s, 4Η), 4.56 (d, J= 5.7 Hz, 2H), 7.00-7.40 (m, 5H), 7.55 (m, 2H), 8.72 (br s, 1H); MS [M+H]+ : 553.44.
Example-35
2-((2-Chloro-6-fluorophenyl)amino)-N-(4,4-dimethylcyclohexyl)-7,8-dihydro-lH- [ 1 ,4] dioxino [2',3 ' : 3 ,4]benz -d]imidazole-5 -carboxamide
Figure imgf000095_0002
The title compound was prepared following the procedure described in Example by using 2-((2-chloro-6-fluorophenyl)amino)-7,8-dihydro
[1 ,4]dioxino[2',3':3,4]benzo[l ,2-d]imidazole-5-carboxylic acid (Intermediate- 18, 0.100 g, 0.268 mmol), THF:DCM (5.0 mL: 1.0 mL), BOP (0.165 g, 0.395 mmol), DIPEA (0.5 mL), 4,4-dimethyl cyclohexyl amine hydrochloride (0.075 g, 0.450 mmol). The obtained crude product was further purified by column chromatography on basic alumina eluting with 1.5 % MeOfLDCM to afford 0.010 g of desired product. 1H NMR (DMSO-d6): δ 0.92 (d, J = 7.8 Hz, 4H), 1.22 (d, J = 6.9 Hz, 4H), 1.67 (m, 1H), 2.50 (s, 6H), 4.28-4.35 (m, 4H), 7.31 (m, 4H), 7.84 (m, 1H); MS [M+H]+ : 473.53.
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
Figure imgf000096_0001
The title compound was prepared following the procedure described in Example- 13 using 2-((2-chloro-6-fluorophenyl)amino)- 1 -methyl-7,8-dihydro- 1H-
[l ,4]dioxino[2',3':3,4]benzo[l ,2-d]imidazole-5-carboxylic acid (Intermediate- 10, 0.100 g, 0.265 mmol), THF:DCM (5.0 mL: 1.0 mL), BOP (0.292 g, 0.602 mmol), DIPEA (0.5 mL), (lr,4r)-4-(trifluoromethyl)cyclohexyl)methanamine (0.057 g, 0.318 mmol) to afford 0.025 g of desired product. 1H NMR (DMSO- 6): δ 1.00-1.45 (m, 8H), 1.82 (m, 1H), 2.20 (m, 1H), 3.10 (m, 2H),3.45 (s, 3H), 3.77 (m, 1H), 4.38 (s, 4H), 7.04 (s, 1H), 7.36 (m, 3H), 8.04 (s, 1H); MS [M+H]+: 541.28.
Example-37
2-((2-Chloro-6-fluorophenyl)amino)-N-(((lr,4r)-4-
(trifluoromethyl)cyclohexyl)methyl)-7,8-dihydro-lH-[l ,4]dioxino[2',3':3,4]benzo[l ,2- d]imidazole-5 -carboxamide
Figure imgf000096_0002
The title compound was prepared following the procedure described in Example- 13 using 2-((2-chloro-6-fluorophenyl)amino)-7,8-dihydro-iH- [1 ,4]dioxino[2',3':3,4]benzo[l ,2-d]imidazole-5-carboxylic acid (Intermediate- 18, 0.100 g, 0.268 mmol), THF:DCM (5.0 mL: 1.0 mL), BOP (0.175 g, 0.397 mmol), DIPEA (0.5 mL), ((lr,4r)-4-(trifluoromethyl)cyclohexyl)methanamine (0.085 g, 0.397 mmol) to afford 0.021 g of desired product. 1H NMR (DMSO- 6): δ 1.18-1.22 (m, 4H), 1.469 (m, 1H), 1.77-1.88 (m, 4H), 2.16 (m, 1H),3.13 (m, 2H), 4.27-4.32 (m, 4H), 7.29 (m, 3H), 7.37 (m, 1H), 8.01 (s, 1H), 11.10 (s, 1H); MS [M+H]+: 527.38.
Example-38
2-((2-Chloro-6-fluorophenyl)amino)-N-(4-(cyclopropylethynyl)-3-fluorophenyl)-7,8- dihydro-lH-[l,4]dioxi ',3':3,4]benzo[l,2-d]imidazole-5-carboxamide
Figure imgf000097_0001
The title compound was prepared by following the procedure as described for Example-5 by using 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 (Intermediate-6, 0.100 g, 0.275 mmol), dry toluene, 4-(2-cyclopropylethynyl)-3-fluorobenzenamine (Intermediate- 19, 0.072 g, 0.396 mmol) and trimethyl aluminum (2M solution in toluene) (0.5 mL) to afford 0.018 g of desired product. 1H NMR (DMSO- 6): δ 0.74 (m, 2Η), 0.88-0.90 (m, 2Η), 1.57 (m, 1Η), 4.31-4.39 (m, 4Η), 7.35-7.44 (m, 6Η), 7.78-7.82 (m, 1Η), 9.10 (s, 1Η), 10.19 (s, 1Η), 11.20 (s, 1H); MS [M+H]+ : 521.26.
Example-39
2-((2-Chloro-6-fluorophenyl)amino)-N-(4-(cyclopropylethynyl)-3 -fluorophenyl)- 1 - methyl-7,8-dihydro-l -[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide
Figure imgf000097_0002
The title compound was prepared by following the procedure as described for Example-5 by using 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
(Intermediate-7, 0.100 g, 0.256 mmol), dry toluene, 4-(2-cyclopropylethynyl)-3- fluorobenzenamine (Intermediate- 19, 0.062 g, 0.396 mmol) and trimethyl aluminum (2M solution in toluene) (0.5 mL) to afford 0.015 g of desired product. 1H NMR (DMSO- e): δ 0.84-0.91 (m, 4H), 1.49 (m, 1H), 4.80 (s, 3H), 4.53-4.82 (m, 4H), 7.18 (m, 2H), 7.33 (m, 4H), 7.68 (m, 1H), 9.80 (s, 1H); MS [M+H]+ : 535.27.
Example-40
2-((2-Chloro-6-fluorophenyl)amino)-N-(6-(cyclopropylethynyl)pyridin-3-yl)-7,8- dihydro-lH-[l,4]dioxi ',3':3,4]benzo[l,2-d]imidazole-5-carboxamide
Figure imgf000098_0001
The title compound was prepared by following the procedure as described for Example-5 by using 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 (Intermediate-6, 0.100 g, 0.275 mmol), dry toluene, 6-(cyclopropylethynyl)pyridin-3-amine (Intermediate-20, 0.065 g, 0.412 mmol) and trimethyl aluminum (2M solution in toluene) (0.5 mL) to afford 0.011 g of desired product. 1H NMR (DMSO- 6): δ 0.77 (m, 2Η), 0.91 (m, 2Η), 1.56 (m, 1Η), 4.32-4.41 (m, 4Η), 7.39-7.42 (m, 6Η), 8.15 (d, 1Η), 8.80 (s, 1Η), 10.17 (s, 1Η), 11.24 (br s, 1H); MS [M+H]+ : 504.17.
Example-41
2-((2-Chloro-6-fluorophenyl)amino)-N-(6-(cyclopropylethynyl)pyridin-3 -yl)- 1 - methyl-7,8-dihydro-l -[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide
Figure imgf000098_0002
The title compound was prepared by following the procedure as described for Example-5 by using 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 (Intermediate-7, 0.100 g, 0.256 mmol), dry toluene, 6-(cyclopropylethynyl)pyridin-3- amine (Intermediate -20, 0.060 g, 0.381 mmol) and trimethyl aluminum (2M solution in toluene) (0.5 mL) to afford 0.017 g of desired product. 1H NMR (DMSO-d6): δ 0.88 (m, 4H), 1.46 (m, 1H), 3.92 (br s, 3H), 4.49 (m, 2H), 4.59 (m, 2H), 7.08 (m, 2H), 7.28 (m, 1H), 7.37 (m, 1H), 7.79 (m, 1H), 8.38 (m, 1H), 8.49 (m, 1H), 9.73 (br s, 1H); MS [M+H]+ : 518.30.
Example-42
2-((2-chloro-6-methylphenyl)amino)-N-(6-(cyclopropylethynyl)pyridin-3-yl)-7,8- dihydro-lH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide
Figure imgf000099_0001
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. 1H NMR (DMSO- 6): δ 0.88-0.92 (m, 2Η), 1.06-1.11 (m, 2Η), 1.23 (m, 1Η), 1.56 (s, 3Η), 4.30 (m, 2Η), 4.40 (m, 2Η), 7.24-7.29 (m, 3Η), 7.40 (d, J = 8.1Hz, 2H), 8.15 (d, J = 7.5 Hz, 1H), 8.80 (s, 1H), 8.68 (s, 1H), 10.15 (s, 1H), 11.01 (s, 1H); MS [M+H]+: 500.29.
Pharmacological activity
In-vitro Protocol for screening of mPGES-1 inhibitors:
mPGES-1 (microsomal prostaglandin E synthase- 1) is a microsomal enzyme that converts endoperoxide substrate PGH2 (prostaglandin H2) to product PGE2 (prostaglandin E2) by isomerization in the presence of reduced glutathione (GSH). mPGES-1 inhibitors were screened by assessing their ability to inhibit formation of PGE2 from PGH2 in presence of mPGES-1 using an anti-PGE2 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 μg/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 PGH2 at a concentration of 15 μΜ for 1 minute. The reaction was stopped by addition of Stannous chloride (l lmg/ml) and PGE2 levels were measured (Masse F et al. (2005), Journal of Biomolecular Screening 10(6) 599 - 605., Goedken RE et al. (2008), Journal of Biomolecular Screening 13 (7): 619 - 625) by HTRF kit (CisBio)).
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 IC50 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 μΜ and 10.0 μΜ are given in the table along with IC50 (nM) details for selected examples. The compounds prepared were tested using the above assay procedure and were found to have IC50 less than 200nM, preferably less than ΙΟΟηΜ, more preferably less than 50nM or most preferably less than 20nM.
The IC50 (nM) values of the compounds are set forth in Table 1 wherein "A" refers to an IC50 value of less than 50 nM, "B" refers to IC50 value in range of 50.01 to 100.0 nM and "C" refers to IC50 values more than 100 nM.
Table 1 :
Figure imgf000100_0001
Sr. No. Example No. Percentage inhibition at ICso (nM)
1 μΜ 10 μΜ
4 Example-4 34.05 81.57 -
5 Example-5 100.00 100.00 A
6 Example-6 97.95 98.08 A
7 Example-7 99.95 99.52 A
8 Example-8 96.88 98.28 A
9 Example-9 100.00 100.00 A
10 Example- 10 99.87 100.00 A
11 Example- 11 100 99.34 A
12 Example- 12 97.57 99.81 A
13 Example- 13 96.17 99.45 A
14 Example- 14 97.76 98.46 A
15 Example- 15 99.06 99.76 A
16 Example- 16 96.09 97.42 B
17 Example- 17 80.06 96.80 C
18 Example- 18 67.75 95.22 -
19 Example- 19 75.14 73.53 -
20 Example-20 29.92 77.80 -
21 Example-21 30.31 80.06 -
22 Example-22 46.69 90.59 -
23 Example-23 8.47 73.78 -
24 Example-24 70.02 92.88 -
25 Example-25 76.58 95.37 -
26 Example-26 65.48 91.98 -
27 Example-27 99.60 100.00 A
28 Example-28 10.43 31.62 -
29 Example-29 88.90 96.78 A
30 Example-30 94.79 98.52 A
31 Example-31 96.47 98.64 B
32 Example-32 98.40 99.54 A
33 Example-33 97.74 100.00 B Sr. No. Example No. Percentage inhibition at ICso (nM)
1 μΜ 10 μΜ
34 Example-34 94.36 97.37 A
35 Example-35 95.81 99.24 A
36 Example-36 95.14 99.57 B
37 Example-37 100.00 100.00 C
38 Example-38 100.00 99.22 A
39 Example-39 99.87 99.80 A
40 Example-40 91.38 99.40 B
41 Example-41 97.07 99.96 B
42 Example-42 89.88 99.73 C
Screening for mPGES-1 inhibitors using the A549 cell based assay
The inhibition of mPGES-1 enzyme in A549 cell line was monitored as inhibition of IL-Ι β induced PGE2 release. A549 cells were maintained in DMEM medium with 10% FBS and 1% Penicillin-Streptomycin Solution in 5% C02 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 μί. Test compounds were dissolved in dimethyl sulfoxide (DMSO) to prepare 2 mM stock solution and then diluted using plain DMEM. 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-Ι β 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 PGE2-D2 & anti-PGE2 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 PGE2 calculated by extrapolation from the standard curve.
The concentration response curves were plotted as % of maximal response obtained in the absence of test antagonist. The IC50 value was calculated from the concentration response curve by nonlinear regression analysis using GraphPad PRISM software.

Claims

Claims:
1. A compound of formula (II):
Figure imgf000103_0001
(Π)
or a pharmaceutically acceptable salt thereof,
wherein,
Z is selected from N and CR1;
Y1 is selected from O, N and NR4;
Y2 is selected from CR3 and CR5R6;
Y3 is selected from CR3 and CR5R6;
Y4 is selected from O, CR3 and N;
X1 is selected from N and NRZ;
X2 is selected from N and NRZ;
dotted line [— ] inside the ring represents an optional bond;
with a proviso that when Y1 is O then Y2 and Y3 are CR5R6 and Y4 is O;
1 2 3 3 4 with another proviso that, when Y is N then Y and Y are CR and Y is N or
CR and dotted lines [— ] inside the ring represents a bond;
with another proviso that, when Y1 is NR4 then Y2 is absent as q is 0, Y3 is CR3 and Y4 is N and the dotted line [— ] between Y3 and Y4 inside the ring represents a bond;
with another proviso that, when X1 is N then X2 is NRZ or when X1 is NRZ then X is N and dotted line [— ] inside the ring attached to N only represents a bond;
R1 is selected from hydrogen, halogen, cyano, hydroxyl and Ci_8alkyl;
R2 is selected from Ci_8alkyl, -C(0)NRaRb and -C(0)ORa;
each occurrence of R is independently selected from hydrogen, Ci_8alkyl, and C3_i2cycloalkyl;
each occurrence of R4 is independently selected from hydrogen, Ci_8alkyl, and C3-i2cycloalkyl;
each occurrence of R5 is hydrogen;
each occurrence of R6 is independently selected from hydrogen and Ci_4alkyl; each occurrence of R is independently selected from halogen, cyano, hydroxyl, Ci_8alkyl, haloCi_8alkyl, Ci_8alkoxy and haloCi_8alkoxy;
each occurrence of Ra and Rb which may be the same or different, are independently selected from hydrogen, Ci_8alkyl, haloCi_8alkyl, C3_i2cycloalkyl, C3_ 8cycloalkylCi_8alkyl, C6-14aryl, C6_i4arylCi_8alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi_8alkyl, 5-14 membered heteroaryl and 5-14 membered heteroarylCi_8alkyl; or Ra and Rb 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 Rz is independently selected from hydrogen, Ci_8alkyl and C3_6cycloalkyl;
'm' is an integer ranging from 0 to 5, both inclusive; and
'q' is O or 1.
2. The compound according to claim 1 , wherein X is N and X 2 is NH, NCH3 or NCH2CH3.
3. The compound according to claim 1 or 2, wherein Ra and Rb 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- (trifluoromethyl)phenyl, 3 -fluoro-5 -(trifluoromethyl)phenyl, 2-fluoro-5 - (trifluoromethyl)phenyl, 4-(cyclopropylethynyl)-3-fluorophenyl, 3- (trifluoromethyl)benzyl, 3 -fluoro-5 -(trifluoromethyl)benzyl and 6- (cyclopropylethynyl)pyridin-3-yl.
4. The compound according to any one of claims 1 to 3, wherein R is
independently selected from CI, F and CH3 and 'm' is 2.
5. A compound of the formula (III):
Figure imgf000104_0001
(III)
harmaceutically acceptable salt thereof, wherein,
R5 is hydrogen;
R6 is independently selected from hydrogen and methyl;
each occurrence of R is independently selected from halogen, cyano, hydroxyl, Ci_8alkyl, haloCi-salkyl, Ci-salkoxy and haloCi-salkoxy;
Ra and Rb which may be the same or different, are independently selected from hydrogen, Ci-salkyl, haloCi-salkyl, C3-i2cycloalkyl, C3-8cycloalkylCi_8alkyl, C6-14aryl, C6_i4arylCi_8alkyl, 5-14 membered heteroaryl and 5-14 membered heteroarylCi.salkyl;
Rz is independently selected from hydrogen, Ci_4alkyl and C3_6cycloalkyl; and
'm' is an integer ranging from 0 to 5, both inclusive.
6. The compound according to claim 5, wherein R5 and R6 are hydrogen.
7. The compound according to claim 5 or 6, wherein Rz is hydrogen, methyl or ethyl.
8. The compound according to any one of claims 5 to 7, wherein Ra is hydrogen and Rb 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 -(trifluoromethyl)phenyl, 3 -fluoro-5 - (trifluoromethyl)phenyl, 2-fluoro-5 -(trifluoromethyl)phenyl, 4-(cyclopropylethynyl)- 3 -fluorophenyl, 3-(trifluoromethyl)benzyl, 3 -fluoro-5 -(trifluoromethyl)benzyl or 6- (cyclopropylethynyl)pyridin-3-yl.
9. The compound according to any one of claims 5 to 8, wherein R is independently selected from CI, F and CH3 and 'm' is 2.
10. A compound of the formula (IV):
Figure imgf000105_0001
(IV)
or a pharmaceutically acceptable salt thereof,
wherein,
at each occurrence, R is independently selected from CI, F and methyl;
Ra is hydrogen; Rb 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 -(trifluoromethyl)phenyl, 3 -fluoro-5 -
(trifluoromethyl)phenyl, 2-fluoro-5 -(trifluoromethyl)phenyl, 4-(cyclopropylethynyl)- 3 -fluorophenyl, 3-(trifluoromethyl)benzyl, 3-fiuoro-5-(trifluoromethyl)benzyl or 6- (cyclopropylethynyl)pyridin-3-yl;
Rz is hydrogen, methyl or ethyl;
and 'm' is 1 or 2.
11. A compound selected from
2-((2-Chloro-6-fiuorophenyl)amino)-N-(3-(trifiuoromethyl)phenyl)-7,8- dihydro-lH-[l,4]dioxino [2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide;
2-((2-Chloro-6-fiuorophenyl)amino)-N-(4-fluoro-3-(trifiuoromethyl)phenyl)- 7,8-dihydro-lH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide;
2-((2-Chloro-6-fiuorophenyl)amino)-N-(4-(trifiuoromethyl)phenyl)-7,8- dihydro-lH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide;
2-((2-Chloro-6-fiuorophenyl)amino)- 1 -methyl-N-(3 -(trifiuoromethyl)phenyl)- 7,8-dihydro-lH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide;
2-((2-Chloro-6-fiuorophenyl)amino)-N-(4-fluoro-3 -(trifiuoromethyl)phenyl)- 1 - methyl-7,8-dihydro-lH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide;
2-((2-Chloro-6-fiuorophenyl)amino)-l-methyl-N-(4-(trifiuoromethyl)phenyl)- 7,8-dihydro-lH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide;
2-((2-Chloro-6-fiuorophenyl)amino)-N-(3 -fluoro-5 -(trifiuoromethyl)phenyl)- 1 - methyl-7,8-dihydro-lH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide;
2-((2-Chloro-6-fluorophenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)phenyl)- 7,8-dihydro-lH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide;
2-((2-Chloro-6-methylphenyl)amino)-N-(4,4-dimethylcyclohexyl)-l-methyl- 7,8-dihydro-lH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide;
2-((2-Chloro-6-fluorophenyl)amino)-N-(4,4-dimethylcyclohexyl)-l-methyl- 7,8-dihydro-lH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide;
2-((2-Chloro-6-fluorophenyl)amino)- 1 -methyl-N-(trans-4- (trifluoromethyl)cyclohexyl)-7,8-dihydro- lH-[ 1 ,4]dioxino[2',3':3,4]benzo[ 1 ,2- d]imidazole-5 -carboxamide; 2-((2-Chloro-6-methylphenyl)amino)- 1 -methyl-N-(trans-4- (trifluoromethyl)cyclohexyl)-7,8-dihydro- lH-[ 1 ,4]dioxino[2',3':3,4]benzo[ 1 ,2- d]imidazole-5 -carboxamide;
2-((2-chloro-6-methylphenyl)amino)-N-(3-fl^
7,8-dihydro-lH-[l ,4]dioxino[2',3':3,4]benzo[l ,2-d]imidazole-5-carboxamide;
2-((2-Chloro-6-fluorophenyl)amino)- 1 -ethyl-N-(3-fluoro-5- (ixifluoromethyl)phenyl)-7,8-dihydro-lH-[l ,4]dioxino[2',3':3,4]benzo[l ,2- d]imidazole-5 -carboxamide;
2-((2-Chloro-6-fluorophenyl)amino)- 1 -methyl-N-(3 -(trifluoromethyl)benzyl)- 7,8-dihydro-lH-[l ,4]dioxino[2',3':3,4]benzo[l ,2-d]imidazole-5-carboxamide;
2-((2-Chloro-6-fluorophenyl)amino)-N-(2-fluoro-5-(trifluoromethyl)phenyl^ l-methyl-7,8-dihydro-lH-[l ,4]dioxino[2',3':3,4]benzo[l ,2-d]imidazole-5- carboxamide;
2-((2-Chloro-6-methylphenyl)amino)-N-((lr,4r)-4- (trifluoromethyl)cyclohexyl)-7,8-dihydro- lH-[ 1 ,4]dioxino[2',3':3,4]benzo[ 1 ,2- d]imidazole-5 -carboxamide;
2-((2-Chloro-6-fluorophenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)benzyl)- 7,8-dihydro-lH-[l ,4]dioxino[2',3':3,4]benzo[l ,2-d]imidazole-5-carboxamide;
2-((2-Chloro-6-fluorophenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)benzyl)- l-methyl-7,8-dihydro-lH-[l ,4]dioxino[2',3':3,4]benzo[l ,2-d]imidazole-5- carboxamide;
2-((2-Chloro-6-fluorophenyl)amino)-N-(4,4-dimethylcyclohexyl)-7,8-dihydro- lH-[l ,4]dioxino[2',3':3,4]benzo[l ,2-d]imidazole-5-carboxamide;
2-((2-Chloro-6-fluorophenyl)amino)- 1 -methyl-N-((( lr,4r)-4- (1xifluoromethyl)cyclohexyl)methyl)-7,8-dihydro-lH-[l ,4]dioxino[2',3':3,4]benzo[l ,2- d]imidazole-5 -carboxamide;
2-((2-Chloro-6-fluorophenyl)amino)-N-(((lr,4r)-4- (1xifluoromethyl)cyclohexyl)methyl)-7,8-dihydro-lH-[l ,4]dioxino[2',3':3,4]benzo[l ,2- d]imidazole-5 -carboxamide;
2-((2-Chloro-6-fluorophenyl)amino)-N-(4-(cyclopropylethynyl)-3- fluorophenyl)-7,8-dihydro-lH-[l ,4]dioxino[2',3':3,4]benzo[l ,2-d]imidazole-5- carboxamide; 2-((2-Chloro-6-fluorophenyl)amino)-N-(4-(cyclopropylethynyl)-3- fluorophenyl)-l -methyl-7,8-dihydro- lH-[ 1 ,4]dioxino[2',3':3,4]benzo[ 1 ,2-d]imidazole- 5-carboxamide;
2-((2-Chloro-6-fluorophenyl)amino)-N-(6-(cyclopropylethynyl)pyridin-3-yl)- 7,8-dihydro-lH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide;
2-((2-Chloro-6-fluorophenyl)amino)-N-(6-(cyclopropylethynyl)pyridin-3-yl)- l-methyl-7,8-dihydro-lH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5- carboxamide;
2-((2-chloro-6-methylphenyl)amino)-N-(6-(cyclopropylethynyl)pyridin-3-yl)- 7,8-dihydro-lH-[l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxamide;
and pharmaceutically acceptable salts thereof.
12. A compound selected from
2-((2-Chloro-6-fluorophenyl)amino)-N-(3-(trifluoromethyl)phenyl)-lH- imidazo [4,5 -f] quinoline-5 -carboxamide;
2-((2-Chloro-6-fluorophenyl)amino)-3-methyl-N-(3-(trifluoromethyl)phenyl)- 3H-imidazo[4,5-f]quinoxaline-5-carboxamide;
7-((2-Chloro-6-fluorophenyl)amino)-3,8-dimethyl-N-(3- (trifluoromethyl)phenyl)-3,8-dihydrobenzo[l,2-d:3,4-d']diimidazole-4-carboxamide;
7-((2-Chloro-6-fluorophenyl)amino)-2,3,8-trimethyl-N-(3- (trifluoromethyl)phenyl)-3,8-dihydrobenzo[l,2-d:3,4-d']diimidazole-4-carboxamide;
2-((2-Chloro-6-fluorophenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)phenyl)- l-methyl-7,8-dihydro-lH-[l,4]dioxino[2,3-d]imidazo[4,5-b]pyridine-5-carboxamide;
2-((2-Chloro-6-fluorophenyl)amino)-N-(4-fluoro-3 -(trifluoromethyl)phenyl)- 1 - methyl-7,8-dihydro-lH-[l,4]dioxino[2,3-d]imidazo[4,5-b]pyridine-5-carboxamide;
2-((2-Chloro-6-fluorophenyl)amino)-N-(4,4-dimethylcyclohexyl)-l-methyl- 7,8-dihydro-lH-[l,4]dioxino[2,3-d]imidazo[4,5-b]pyridine-5-carboxamide;
2-((2-Chloro-6-fluorophenyl)amino)-l-methyl-N-((lr,4r)-4- (trifluoromethyl)cyclohexyl)-7,8-dihydro- lH-[ 1 ,4]dioxino[2,3-d]imidazo[4,5- b]pyridine-5-carboxamide;
2-((2-Chloro-6-methylphenyl)amino)-N-(4-fluoro-3-(trifluoromethyl)phenyl)- l-methyl-7,8-dihydro-lH-[l,4]dioxino[2,3-d]imidazo[4,5-b]pyridine-5-carboxamide;
2-((2-Chloro-6-methylphenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)phenyl)- l-methyl-7,8-dihydro-lH-[l,4]dioxino[2,3-d]imidazo[4,5-b]pyridine-5-carboxamide; 2-((2-Chloro-6-methylphenyl)amino)- 1 -methyl-N-(3 -(trifluoromethyl)phenyl)- 7,8-dihydro-lH-[l,4]dioxino[2,3-d]imidazo[4,5-b]pyridine-5-carboxamide;
2-((2-Chloro-6-fiuorophenyl)amino)- 1 -methyl-N-(3 -(trifiuoromethyl)phenyl)- 7,8-dihydro-lH-[l,4]dioxino[2,3-d]imidazo[4,5-b]pyridine-5-carboxamide;
2-((2-Chloro-6-fluorophenyl)amino)-l-methyl-N-(4-(trifiuoromethyl)phenyl)- 7,8-dihydro-lH-[l,4]dioxino[2,3-d]imidazo[4,5-b]pyridine-5-carboxamide;
2-((2-Chloro-6-fluorophenyl)amino)-N-(2-fluoro-5-(trifiuoromethyl)phenyl)- l-methyl-7,8-dihydro-lH-[l,4]dioxino[2,3-d]imidazo[4,5-b]pyridine-5-carboxamide:
N-(2-Chloro-6-fiuorophenyl)-5-methyl-7,8-dihydro-lH-[l,4]dioxino[2,3- d]imidazo[4,5-b]pyridin-2-amine;
and pharmaceutically acceptable salts thereof.
13. A compound of the formula
Figure imgf000109_0001
or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 and a pharmaceutically acceptable excipient.
15. The pharmaceutical composition according to claim 14, wherein the pharmaceutically acceptable excipient is a carrier or diluent.
16. A method of treating a mPGES-1 mediated disease, disorder or syndrome in a subject comprising administering an effective amount of a compound according to any one of claims 1 to 13.
17. A method of treatment of disease, disorder, syndrome or condition selected from the group consisting of inflammation, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritable bowel syndrome, pain, inflammatory pain, chronic pain, acute pain, fever, migraine, headache, low back pain, fibromyalgia, myofascial disorders, viral infections, influenza, common cold, herpes zoster, hepatitis C, AIDS, bacterial infections, fungal infections, dysmenorrhea, burns, surgical or dental procedures, malignancies hyperprostaglandin E syndrome, classic Bartter syndrome, synovitis, 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, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes mellitus, cancer, neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis and multiple sclerosis, autoimmune diseases, allergic disorders, rhinitis, ulcers, mild to moderately active ulcerative colitis, familial adenomatous polyposis, coronary heart disease, and sarcoidosis comprising administering a compound according to any one of claims 1 to 13.
18. The method according to claim 17, wherein the disease, disorder, syndrome or condition is pain.
19. The method according to claim 17, wherein the disease, disorder, syndrome or condition is acute pain or chronic pain.
20. The method according to claim 17, wherein the disease, disorder, syndrome or condition is rheumatoid arthritic pain or osteoarthritic pain.
21. The method according to claim 17, wherein the disease, disorder, syndrome or condition is inflammation.
22. The method according to claim 17, wherein the disease, disorder, syndrome or condition is neurodegenerative disorders selected from Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis.
23. A method of treating, preventing or managing cancer comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1 to 13.
24. A process for preparing a compound of formula (III)
Figure imgf000110_0001
(III)
or a pharmaceutically acceptable salt thereof,
by reacting a compound of formula (Intermediate- 11 A) with a compound of formula
(5);
Figure imgf000111_0001
wherein,
R5 is hydrogen;
R6 is independently selected from hydrogen and methyl;
each occurrence of R is independently selected from halogen, nitro, cyano, hydroxyl, Ci_8alkyl, haloCi_8alkyl and C3_i2cycloalkyl;
Ra and Rb which may be the same or different, are independently selected from hydrogen, Ci_8alkyl, haloCi_8alkyl, C3-i2cycloalkyl, C3-8cycloalkylCi_8alkyl, C6-14aryl, C6-i4arylCi_8alkyl, 5-14 membered heteroaryl and 5-14 membered heteroarylCi_8alkyl;
Rz is independently selected from hydrogen, Ci_4alkyl and C3_6cycloalkyl;
'm' is an integer ranging from 0 to 5, both inclusive; and
LG is OH, CI, Br, 0-Ci_4alkyl, O-aryl or 0(C=0)-Ci_4alkyl.
25. A compound selected from
Methyl 2-((2-chloro-6-fluorophenyl)amino)-7,8-dihydro- 1H- [l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxylate;
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;
2-((2-Chloro-6-methylphenyl)amino)-l-methyl-7,8-dihydro-lH- [ 1 ,4] dioxino [2',3 ' : 3 ,4]benzo [ 1 ,2-d]imidazole-5 -carboxylic acid;
2-((2-Chloro-6-fluorophenyl)amino)- 1 -methyl-7,8-dihydro- 1H- [ 1 ,4] dioxino [2',3 ' : 3 ,4]benzo [ 1 ,2-d]imidazole-5 -carboxylic acid;
Methyl 2-((2-chloro-6-methylphenyl)amino)-7,8-dihydro- 1H- [l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxylate;
Methyl 2-((2-chloro-6-fluorophenyl)amino)- 1 -ethyl-7,8-dihydro- 1H- [l,4]dioxino[2',3':3,4]benzo[l,2-d]imidazole-5-carboxylate;
2-[(2-Chloro-6-methylphenyl)amino]-7,8-dihydro-lH-[l,4]dioxino[2,3- e]benzimidazole-5 -carboxylic acid; and
2-((2-Chloro-6-fluorophenyl)amino)-7,8-dihydro-lH- [ 1 ,4] dioxino [2',3 ' : 3 ,4]benzo [ 1 ,2-d]imidazole-5 -carboxylic acid.
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